Aspergilloma

An aspergilloma is a rounded conglomerate of fungal hyphae, fibrin, mucus and cellular debris that arises in pre-existing pulmonary cavities that have become colonised with Aspergillus. The risk of developing an aspergilloma within a cavity of 2cm in diameter is 15-20%. The vast majority of fungal balls in the lungs are due to Aspergillus fumigatus with rare cases due to non-fumigatus Aspergillus species, Pseudallescheria boydii or Mucorales. If there is a solitary lesion, stable over several months, there is little symptomatology (e.g. only a cough) and no evidence of systemic inflammation, a simple aspergilloma is diagnosed. Conversely, complicated aspergillomas form part of chronic cavitary pulmonary aspergillosis, are associated with symptoms and require systemic antifungal therapy. This section focuses on simple aspergilloma.  

Aspergillomas are usually present in the upper lobes, reflecting the predilection for cavities to form there. The initial step in aspergilloma formation is colonisation of a cavity with Aspergillus. Mycelial growth arises from the cavity wall, subsequently spreading into the cavity lumen. Progressive layers of mycelia accumulate over months. Mycelial fronds eventually coalesce and create a ‘sponge’ which gradually becomes solid. At this stage, the fungus ball can be discernible with plain radiography; however, earlier changes can usually only be documented by CT scan (Roberts et al, 1987). If the fungus ball does not completely fill the cavity, it may be mobile and appear so on imaging. The presence of an air crescent between the aspergilloma and the cavity wall may not always be obvious, as there may be mycelial fronds in that space. The surrounding bronchioles may be compressed because of the mass effect and fibrosis, with resulting local bronchiectasis.

In countries with a current or prior high TB burden, a cavity resulting from previous tuberculosis is by far the most common cause of a simple aspergilloma (Smith & Denning, 2011). Other causes include atypical mycobacterial infection, lung cancer (both primary and metastatic) treated with radiofrequency ablation (Hiraki et al 2009, Daste et al 2014), pneumothorax with associated bulla formation, bronchiectasis, chronic obstructive pulmonary disease, fibrocavitary sarcoidosis, ankylosing spondylitis and previous Pneumocystis pneumonia in patients with HIV infection (Addrizzo-Harris et al, 1997). Aspergilloma arising in a pulmonary echinococcal cyst has been reported (Pandey et al, 2013). Endobronchial aspergillomas have also been reported.  

The most serious complication of a simple aspergilloma is haemoptysis which can be recurrent and life-threatening. Surgery is the mainstay of treatment for simple aspergilloma, and can be curative. Case series and case reports over several decades have described good outcomes with surgical resection. In a recent series (Farid et al, 2013), the usual presentations were haemoptysis and recurrent chest infections. Lobectomy was the most common procedure (67%), followed by wedge resection (25%), whereas one patient underwent segmentectomy and one had bullectomy and pleurectomy. In a large series of 96 patients from China, lobectomy was performed in the majority of patients (Chen et al, 2012). A thoracoscopic approach may be indicated for some patients, and may lead to reduced hospital stay; however it may need to be converted to a full thoracotomy because of intrapleural adhesions (Farid et al 2013). Video-assisted thoracic surgery has been used successfully (Chen et al, 2014).

Most series describe minimal or no post-operative mortality for simple aspergilloma, particularly with carefully selected patients (El-Oakley-R et al, 1997; Chen,et al, 1997). Post-operative complications are also less frequent for simple vs. for chronic cavitary pulmonary aspergillosis (complicated aspergilloma) (8.3% vs. 20% in Chen et al. 2012). Described complications include residual pleural space, prolonged air leak, excessive bleeding, wound dehiscence and respiratory insufficiency. The latter is much more common in patients with underlying lung disease who may not have enough respiratory reserve to tolerate a lobectomy. Recurrence of disease may occur, but is more common in the setting of pre-existing chronic cavitary pulmonary aspergillosis. Post-operatively, these patients need to be monitored for recurrence with serial Aspergillus IgG and yearly chest X-ray.

Antifungal therapy provides only limited benefit for the treatment of simple aspergilloma, although it is not completely clear that these patients did not have chronic cavitary pulmonary aspergillosis, with an aspergilloma. Systemic antifungal therapy with ketoconazole was ineffective. Among 14 patients who were treated with itraconazole for an average of 7 months (range 2-13 months), only 2 were considered to be cured (Dupont 1990). In another study, itraconazole 200mg daily was of marginal symptomatic benefit and little radiological benefit, and had no effect on levels of Aspergillus IgG in patients with aspergilloma (Campbell et al, 1991). Other series have shown variable results (De Beule et al, 1988, Lebeau et al, 1994). As itraconazole levels within the fungus ball are adequate (Tsubura, 1997), it is not clear why the response rate is suboptimal. There are no case series on the role of voriconazole in simple aspergilloma; however isolated case reports have shown benefit (Freymond et al 2005). Approximately 10% of aspergillomas resolve spontaneously making uncontrolled observations in small numbers of patients difficult to interpret (Hammerman et al 1973).

The poor responses observed with antifungal therapy alone may be explained by the genetic variability exhibited by Aspergillus strains within fungal balls. In a study that used microsatellite typing to determine genetic type of Aspergillus cultured from removed aspergillomas, multiple strains were isolated from each patient, often with differing azole sensitivity profiles. Genetic analysis showed that these strains were closely related but different, suggesting evolution through progressive sequential mutations (Howard et al, 2013). Importantly, resistance patterns were not detected with diagnostic testing for any of the patients before surgery. Indeed, aspergillomas have been considered a risk factor for azole resistance. Finally, biofilm formation plays an important role in pathogenicity and in the outcome of antifungal therapy. In aspergilloma, as opposed to invasive aspergillosis, a typical biofilm is produced, where fungal hyphae are surrounded by a thick extracellular matrix containing polysaccharides like galactomannan and α-1.3-glucan (Loussert et al, 2010).

Although not studied, pre- and post-operative antifungal therapy is routinely employed in simple aspergilloma. The rationale is to prevent spread of fungal organisms into the pleural cavity during the procedure, which may result in an Aspergillus empyema. The optimal agent is voriconazole because of its intrinsic activity and the availability of both oral and IV formulations. If possible, voriconazole should be given for one to two weeks before surgery. If the aspergilloma was fully resected without any spillage of the contents of the cavity into the pleura, then a maximum of four-week post-operative voriconazole course is reasonable. If there is spillage, then a minimum of 12 weeks of therapy is recommended. In addition, pleural washout with amphotericin B or taurolidine 2% may be used, although the efficacy is unproven. Taurolidine was found to be active in vitro against all Aspergillus isolates from patients who underwent surgery for aspergillomas, and used for pleural decontamination during surgery. Its usefulness is difficult to assess, as all patients received adjuvant antifungal therapy (Farid et al, 2013). Retrospective studies of adjuvant antifungal peri-operative therapy found no long-term survival benefit (Sagan et al 2010).

Instillation of nystatin and amphotericin B has been tried with some benefit in some cases (especially with amphotericin B). Early data consisted of single instillations through a metal needle. Recently flexible plastic catheters have been used. Repeated instillations are usually necessary (in one study daily for 15 days (Lee, 1993)). Communication between the cavity and the airways is usual so the instilled agent usually leaks into the airways. Amphotericin B has been incorporated in gelatin or glycerin that solidifies at 37^oC (Giron, et al, 1993; Munk et al, 1993). Intracavitary instillation of amphotericin B, N-acetylcysteine and aminocaproic acid was described in 6 patients (Shapiro et al. 1988). A recent retrospective study assessed the outcomes in 20 patients after percutaneous intracavitary instillation of amphotericin B (Kravitz et al 2013). Most patients did not have persistent haemoptysis at follow up 1 month after the procedure, although 30% eventually had recurrence of serious haemoptysis. Pneumothorax occurred in 26%, but without serious sequelae.

Embolisation of the bleeding artery may be undertaken for patients who present with large volume haemoptysis. Bronchial artery embolization may precede surgery be more definitive for those who are not fit for surgery. In most instances of haemoptysis, abnormal and novel vascular connections to the systemic circulation are implicated. This is usually the bronchial circulation but it may be any of the other arteries supplying the chest, e.g. internal or external mammary arteries etc. Aspergillomas also lead to an extensive network of small vessels. Several abnormal connections may exist in a single patient. The objective of embolisation is to permanently occlude these vessels. Patients with a communication between an intercostal and the anterior spinal artery can only be embolised safely if the catheter is introduced well past the anterior spinal artery. These patients require a skilled interventional radiologist for these difficult procedures. The patient has to be able to lie still for a prolonged period of time during the procedure which can be a major limiting factor. Each case has to be assessed on its merits. Depending on the radiologist, approximately 50-70% of embolisation procedures are successful (Remy & Jardin, 1990, Corr, 2006, Swanson et al, 2002, Serasli et al, 2008). However a relapse rate of 50% is typical, and may be worse than for other benign causes of haemoptysis (Chen J et al, 2014, Woo et al, 2013).

In summary, simple aspergillomas can be followed clinically if asymptomatic, but they are usually managed surgically with lobectomy if they are associated with significant haemoptysis or if there is doubt about the diagnosis. Modalities for patients not fit for surgery may be embolization and instillation of amphotericin B. Long-term antifungal treatment has not proven beneficial; however, pre- and post-operative antifungal treatment are routinely used to prevent recurrence. 

Christos Kosmidis & David W. Denning FRCP FRCPath FIDSA FMedSci
National Aspergillosis Centre
Education and Research Centre
University Hospital of South Manchester (Wythenshawe Hospital)
Southmoor Road
Manchester M23 9LT UK

Images of aspergilloma

Intracavity instillation of amphotericin B