Lesson 19, Volume 15—Diagnosis and Management of Aspergilloma

By Marc A. Judson, MD, FCCP

Objectives

1. Understand the criteria for the diagnosis of aspergilloma.
2. Identify conditions associated with the development of aspergilloma.
3. Identify indications for the treatment of aspergilloma.
4. Identify the surgical treatments for aspergilloma, including their indications and potential complications.
5. Identify nonsurgical treatments for aspergilloma, including their indications and potential complications.

Key words

aspergilloma; Aspergillus; hemoptysis; itraconazole; thoracic surgery; treatment

Abbreviations

ABPA = allergic bronchopulmonary aspergillosis; BAE = bronchial artery embolization; CNA = chronic necrotizing pulmonary aspergillosis

Pulmonary disease caused by Aspergillus spp presents with a wide spectrum of conditions (Fig 1). Invasive pulmonary aspergillosis is a devastating infection with a high mortality rate. The fungus itself is responsible for lung destruction. The progressive nature of the disease and its refractoriness to therapy are, in part, related to the organism’s rapid growth and its tendency to invade blood vessels.¹ This disease is almost exclusively seen in immunocompromised hosts such as patients with neutropenia,² bone marrow³ or organ transplant,⁴ or acquired immunodeficiency.⁵

Figure 1. Spectrum of Aspergillus pulmonary disease. Aspergillus lung disease ranges from invasive pulmonary aspergillosis, in which the fungus is pathogenic and destroys the lung, to allergic bronchopulmonary aspergillosis (ABPA), in which the lung destruction is the result of an allergic host response to the presence of Aspergillus spp, to aspergilloma, in which the fungus grows as a saprophyte in an area of devitalized lung tissue. Overlap syndromes exist between these three conditions, including chronic necrotizing aspergillosis, in which an aspergilloma may be locally invasive.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disease of the lungs almost always caused by Aspergillus fumigatus. Because ABPA is an allergic host response to the presence of Aspergillus spp in airways, corticosteroids remain the mainstay of treatment,¹ although a recent study suggested that itraconazole may be beneficial and steroid-sparing.⁶

Pulmonary aspergilloma is thought to be a benign saprophyitic colonization of the lung with Aspergillus. However, aspergillomas may cause hemoptysis that is potentially life-threatening. These balls of fungi tend to grow in areas of devitalized lung with a poor blood supply, such as in inactive cavitary lesions. As depicted in Figure 1, it is important to note that these three manifestations of Aspergillus lung disease overlap. In particular, there is a continuum between colonization seen with aspergilloma and tissue invasion with Aspergillus, as will be outlined. Concomitant aspergilloma and ABPA have also been reported.⁷

In this lesson, the clinical aspects of pulmonary aspergilloma will be discussed. Special attention will be paid to treatment issues that remain problematic and controversial.

Diagnosis

A pulmonary aspergilloma can be defined as a conglomeration, within a pulmonary cavity or ectatic bronchus, of intertwined Aspergillus hyphae matted together with fibrin, mucus, and cellular debris.⁸ Although a definitive diagnosis requires lung biopsy or resection, this is rarely done. The diagnosis is usually made clinically based on chest radiographic features coupled with serologic evidence of Aspergillus spp. On chest radiograph, a pulmonary aspergilloma appears as a solid rounded mass of water density, sometimes mobile, within a spherical or ovoid cavity. This ball-like mass is separated from the wall of the cavity by an airspace of variable size and shape.⁹ If peripheral, pleural thickening is characteristic and may predate the development of an aspergilloma.¹⁰ In certain cases, chest CT may be helpful in detecting the radiographic features of an aspergilloma that is not apparent on a chest radiograph.¹¹

The diagnosis of an aspergilloma is established when the above-mentioned radiographic features are found in a patient with serum precipitins that are positive for Aspergillus spp, a test with > 95% sensitivity for aspergilloma^10,12; however, some patients who receive corticosteroids may be seronegative. Although positive sputum cultures for Aspergillus are present in more than half of patients with aspergilloma, it is neither a sensitive nor a specific diagnostic marker.¹¹ Aspergillus antigen has been detected in BAL fluid of patients with aspergilloma,¹³ but the diagnostic value of this test is unknown. Rarely, an aspergilloma may be visualized bronchoscopically and successfully biopsied.¹⁴ Similarly, any form of lung biopsy of the rounded lesion that reveals Aspergillus spp on stains or cultures would be accepted as diagnostic of an aspergilloma, if the radiographic criteria were fulfilled.

It is important to confirm that the radiographic findings are the result of an Aspergillus sp, as there are alternate causes of this radiographic pattern. The radiographic differential diagnosis includes cavitating neoplasm, blood clot in a pulmonary cavity following hemorrhage, disintegrating hydatid cyst, and pulmonary abscess with necrosis¹¹ (Table 1). In addition, a number of fungi other than Aspergillus have been reported to cause mycetoma, including Petriellidium, Sporotrichum, Torulopsis, Candida, and Streptomyces.^8,10,15-17 This broad differential diagnosis reinforces the need to obtain positive precipitins to Aspergillus spp to appropriately diagnose an aspergilloma. A fumigatus is almost always the species present in aspergilloma, although rarely the positive precipitin reaction is directed against another Aspergillus sp such as Aspergillus niger, Aspergillus flavus, or Aspergillus nidulans.¹⁸ The differentiation of Aspergillus species may be important since azole therapy may have a role in the treatment of aspergilloma (vide infra).

Pathogenesis

It is thought that a pulmonary aspergilloma does not initiate the destructive pulmonary process that is seen in invasive aspergillosis and ABPA. Most cases of aspergilloma are thought to arise from colonization and proliferation of the fungus in a preexisting pulmonary cavity ("secondary aspergilloma").¹¹

The fungi tend to grow in areas of devitalized lung with a poor blood supply. Underlying pulmonary conditions in which aspergilloma may develop include tuberculous cavities,⁹ fibrocystic sarcoidosis,¹⁹ cavitary neoplasm,²⁰ pulmonary fibrosis,²¹ lung abscess,²² bronchial cyst,²² asbestosis,²³ histoplasmosis,²⁴ blastomycosis,²⁵ ankylosing spondylitis,²⁶ bronchiectasis,²⁷ pneumonia,²² cyanotic heart disease,²⁸ and pulmonary infarction²⁹ (Table 2).

As mentioned, an aspergilloma can be seen with other Aspergillus lung diseases, such as invasive aspergillosis¹² and ABPA.⁷ Recently, HIV-infected individuals have been found to be at risk for the development of aspergilloma.³⁰ In such patients, aspergillomas have developed not only in old tuberculous cavities, but also in cystic spaces resulting from previous Pneumocystis carinii infection.³⁰

Although hemoptysis is a frequent and potentially life-threatening complication of aspergilloma, the pathogenesis of hemoptysis remains unclear. Current theories of the cause of hemoptysis from aspergilloma include damage of the hypervascular cavity wall by friction of the mobile fungus ball,³¹ toxins and enzymes released from the fungus,³² a type III inflammatory injury,³³ and development of localized fungal invasion.³⁴ In addition, the hemoptysis may be the result of associated tracheitis or bronchitis and not directly related to the aspergilloma itself.³⁵

Clinical Presentation

Most patients with pulmonary aspergilloma are asymptomatic.¹¹ When present, symptoms are varied and are often difficult to ascribe to the aspergilloma in the presence of underlying pulmonary disease.¹¹ The most common presenting symptom is hemoptysis, reported in 50 to 80% of patients.¹¹ Hemoptysis is usually intermittent and scanty but may be life-threatening.⁹ In some series^9,12 cough is more common than hemoptysis, but this may relate to the underlying pulmonary disease rather than the aspergilloma.⁹ Dyspnea, malaise, and weight loss are additional symptoms found with aspergilloma that may be attributable to the underlying pulmonary disease.⁹ Wheezing has been reported⁹ but is probably a manifestation of concomitant ABPA.¹¹

Fever is an unusual finding in aspergilloma,⁹ and other sources of fever should be searched for diligently. Fever may suggest a concurrent bacterial infection,¹¹ an allergic process with a type III response,¹¹ or possibly the development of an overlap syndrome,³¹ such as chronic necrotizing aspergillosis (vide infra).

Physical examination is generally nonspecific, although localizing signs such as decreased air movement, bronchial breath sounds, and adventititial sounds are almost always heard.¹⁸ Obviously, the chest radiographic findings and the presence of Aspergillus precipitins are essential for the diagnosis of aspergilloma. However, standard laboratory studies are of little diagnostic use. Total white blood cell counts are usually normal, and eosinophilia is rare.^9,11 Positive cultures for Aspergillus spp are found in slightly more than half of the patients, but this finding is neither specific nor sensitive.¹¹ However, sputum cultures may still be useful to suggest which fungus is responsible for the fungus ball, which may affect the choice of therapy.

Natural History

Pulmonary aspergillomas are not static lesions: They undergo a repetitive process of growth and death of fungal elements. Therefore, aspergillomas may increase, decrease, or remain stable in size.⁹ Spontaneous lysis occurs in < 10% of cases and is often associated with bacterial superinfection of the cavity.⁹

Pulmonary aspergillomas may develop into invasive lesions. Chronic necrotizing pulmonary aspergillosis (CNA) is an overlap syndrome (Fig 1) that has been described with radiographically persistent or progressive cavitary lesions, often with mycetomas.³⁴ Confirmation of the diagnosis is established by the demonstration of locally invasive Aspergillus spp on lung biopsy.³⁴ Severely immunocompromised patients are excluded in making this diagnosis,³⁴ although many patients with CNA are receiving corticosteroids.³⁴ The diagnosis also requires that the Aspergillus infection is confined to the lung, ie, there is no evidence of disseminated disease. Fever is more common in CNA than with aspergilloma.^9,34 A clinical diagnosis of CNA may be established without a lung biopsy if (1) an Aspergillus sp is grown from a sputum, bronchoscopic, or lung biopsy; (2) radiographs show progressive pulmonary lesions, usually with mycetomas; (3) the patient has a good clinical response to antifungal therapy; and (4) there is no evidence of disseminated aspergillosis at the time of diagnosis.³¹

Patients with aspergilloma may also develop disseminated aspergillosis that may prove fatal.¹² Fatal hemoptysis may also occur.¹² Death in pulmonary aspergilloma patients may also be the result of underlying comorbid conditions, as these patients often have diseases that place them at a relatively high mortality risk.⁹

Several risk factors have been identified that suggest a poor prognosis for patients with aspergilloma (Table 3). These include the severity of the underlying pulmonary disease, increasing size or number of aspergillomas on chest radiograph,⁹ immunosuppression (including corticosteroids),¹² increasing Aspergillus-specific IgG titers,³⁶ underlying sarcoidosis,³⁷ and HIV infection.³⁰

Therapy

There is no consensus in the treatment of aspergilloma.¹ No double-blind, placebo-controlled, or randomized trials have been undertaken. Data concerning treatment have been derived from uncontrolled trials, case series, and case reports. The first major decision in the management of aspergilloma is whether therapy is required. Because life-threatening hemoptysis occurs in a minority of patients, it is inappropriate to subject all patients with aspergilloma to therapy, especially as therapy is often associated with significant morbidity and mortality.

Definitive treatment of aspergilloma is surgical resection.³⁸ However, surgery is associated with a high morbidity and mortality.^39-47 The technique ranks among the most complex in thoracic surgery.⁴⁸ Years of chronic infection and inflammation produce thickened fibrotic tissue, induration of the hilar structures, and complete obliteration of the pleural space and fissures.⁴⁸ Serious postoperative complications include hemorrhage, bronchopleural fistula, a residual pleural space, and empyema.^44,48 An important factor that contributes to the high surgical risk is that aspergillomas tend to develop in clinically ill individuals with poor pulmonary function.⁴¹ Indeed, in many patients, surgery is contraindicated because of severe pulmonary impairment. It has been suggested that surgical resection of aspergilloma be restricted to patients with severe hemoptysis and adequate pulmonary function,⁴¹ and considered for patients with a poor prognosis, such as those with underlying sarcoidosis, immunocompromised patients, and those with Aspergillus-specific IgG titers.¹ The unpredictable course of the illness in the absence of surgical intervention confounds decisions about surgical intervention.

However, recent reports suggest a lower rate of postoperative complications after resection of aspergilloma^49-51 that may relate to more careful patient selection and improved operative techniques. It has been recommended that the surgeon be especially attentive to reducing both air leaks and postoperative hemorrhage; the use of a supplementary thoracoplasty to obliterate the potential space has been suggested.⁴⁸ Extrapleural resection may improve outcome, as traditional transpleural, transfissural, and direct hilar exposures are not easily applicable.⁴⁶ Fibrous tissue obliteration of serosal surfaces, fissures, and pulmonary artery branches makes the standard operative approach dangerous and incident-prone. The pleuropulmonary inflammatory disease process rarely extends outside the parietal pleura, so that a natural surgical plane exists between parietal pleura and endothoracic fascia for an extrapulmonary resection to be performed.⁴⁶

The most challenging patients are those with life-threatening hemoptysis who are unfit for lung resection because of severe pulmonary dysfunction. In this instance, a cavernostomy may be attempted, although the results from this procedure are poor and mortality is high.^48,51 This procedure is usually performed under local anesthesia via an incision over the cavity, guided by CT scans. The cavity is identified and incised, and the fungus ball is removed. A rib resection is usually performed and a drain is placed. Often a latissimus dorsi muscle flap is mobilized to fill the residual space.⁵¹

Intracavitary instillation of an antifungal agent should be considered as alternative treatment in patients with severe pulmonary dysfunction who are poor operative risks. Percutaneous instillation of amphotericin B, with placement usually guided by CT scans, has been shown to be effective for aspergilloma in several reports.^52-58 This technique has been successful in cases of massive hemoptysis,⁵⁶ with resolution of hemoptysis within 5 days.⁵⁵ The response to percutaneous injection of amphotericin B is sustainable for several months with absence of recurrent symptoms, improvement or resolution of radiographic abnormalities, and reduction or elimination of serum Aspergillus antibody titers.^52-54,56 Other antifungal agents including sodium and potassium bromide have been percutaneously injected into aspergilloma cavities with good clinical results.⁵⁹ Endobronchial instillation of ketoconazole via fiberoptic bronchoscopy has also been successful.⁶⁰ A major limitation of topical therapy is that it is labor-intensive and would be problematic with multiple aspergilloma. Topical therapy is ideal for patients with a solitary aspergilloma who have severe hemoptysis and severe pulmonary dysfunction or contraindications to surgical resection.

Bronchial artery embolization (BAE) has been used in the management of hemoptysis in patients with aspergilloma.⁶¹ Unfortunately, BAE is usually unsuccessful or is only temporarily effective. Collateral vascular channels from the pulmonary and systemic circulation eventually supply enough bloodflow to the involved area that hemoptysis recurs and often cannot be successfully re-embolized.^62,63 BAE should be considered a temporizing procedure for a patient with life-threatening hemoptysis until definitive therapy for the aspergilloma can be arranged.

A case report of successful treatment of pulmonary aspergilloma by radiation therapy has been published.⁶⁴ Because radiation would result in death of more lung tissue, theoretically such therapy might predispose to growth of an aspergilloma. Indeed, 8 weeks after therapy the patient had three additional bouts of hemoptysis, although additional radiation therapy resulted in resolution of hemoptysis for the 8-month follow-up period. Intermittent inhalation therapy with miconazole has also been reported to be effective for one patient with an aspergilloma.⁶⁵

IV amphotericin B in the treatment of pulmonary aspergilloma has been shown to offer no advantage over routine pulmonary toilet.⁶⁶ This is most likely because of inadequate penetration of amphotericin B in Aspergillus cavities.⁵⁸

Itraconazole is an orally active triazole antifungal agent with less toxicity and greater in vitro activity against A fumigatus than amphotericin B.⁶⁷ In addition, the high tissue penetration of itraconazole makes it a potentially useful agent for the treatment of pulmonary aspergilloma. Data supporting the use of itraconazole in treating aspergilloma are based on open-label studies with different doses and duration of therapy with varied clinical endpoints.⁶⁸ Nonetheless, the results have shown a general trend toward radiographic and symptomatic improvement in one half to two thirds of patients, with occasional patients having a complete response.^69-73 Serum itraconazole levels were not measured in most of these studies, but effective doses were usually 200 to 400 mg/d with a duration of treatment of 6 to 18 months.^69-73 A recent study of itraconazole (100 to 200 mg/d) for pulmonary aspergilloma demonstrated significant itraconazole levels within the aspergilloma cavities,⁷³ confirming that adequate itraconazole levels at the site of action can be achieved using standard dosing. The major limitation of itraconazole is that it works slowly and would be risky to use in cases of life-threatening hemoptysis.

The success of itraconazole emphasizes the need to identify the fungus responsible for the mycetoma, as different fungi may require different chemotherapy. Although sputum cultures do not have a diagnostic role for aspergilloma, positive cultures might direct therapeutic decisions.

Figure 2 outlines the author’s proposed algorithm for the treatment of pulmonary aspergilloma. The treatment of pulmonary aspergilloma depends, in large part, upon four factors: symptoms (hemoptysis); pulmonary function; prognostic risk of aspergilloma based on underlying disease (Table 3); and isolated vs multiple aspergillomas. It should be recognized that the prognosis of pulmonary aspergilloma is poor if all four of the above factors are unfavorable, ie, massive hemoptysis, poor pulmonary function, poor prognostic risk factors for the aspergilloma based on underlying disease (Table 3), and multiple aspergillomas.

Figure 2. Proposed algorithm for treatment of aspergilloma. *See Table 3 for more information on risk factors. PFT = pulmonary function test.

Summary

Pulmonary aspergillomas are part of the continuum of Aspergillus lung disease. Aspergillomas are thought to arise from fungal colonization and proliferation in preexisting pulmonary cavities. The diagnosis requires fulfillment of radiographic criteria as well as evidence of Aspergillus spp, usually via positive precipitins for Aspergillus. Most patients with aspergilloma remain asymptomatic, but hemoptysis may occur that can be life-threatening. Definitive treatment of aspergilloma is surgical resection. However, surgery is difficult and has a high morbidity and mortality. Alternatives to surgery include percutaneous injection of antifungal drugs under CT guidance and oral itraconazole. Although newer antifungal agents have not been studied, drugs with good lung penetration and activity against Aspergillus spp would have a potential role in the treatment of aspergilloma.

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