Aspergillus empyema

Pleural Aspergillosis

Overview

Pleural aspergillosis can be defined as direct Aspergillus infection of the pleura or pleural space and, despite being documented as early as 1842 (Rayer), the precise incidence remains unknown.  Aspergillus empyema is relatively uncommon amongst the spectrum of Aspergillus infection and is also uncommon when fungal empyema as a whole is examined; Candida spp. accounting for almost two thirds of cases (Ko et al 2000). 

The most common causative pathogen seen in pleural aspergillosis is Aspergillus fumigatus although both Aspergillus flavus (Albeda et al 1982) and Aspergillus terreus (Karthik and Sudarsnam 2009) have also been isolated.  Mixed species infections have also been reported within one empyema (Skorodin et al 1982).  Co-infection of the pleural space is not uncommon with up to 50% of reported cases of pleural aspergillosis being polymicrobial (Chung et al 1988); Staphylococcus aureus, beta haemolytic Streptococcus, Mycobacterium tuberculosis, Klebsiella spp. and Pseudomonas spp.  have all been isolated in conjunction with Aspergillus spp. (Hillerdal 1981, Chung et al 1988, Bonatti et al 2010).  It has also been reported that isolation of bacterial organisms including S. aureus, Acinetobacter and Klebsiella have preceded the pure isolation of Aspergillus spp. in some cases (Bonatti et al 2010). The subsequent isolation of Aspergillus spp. may represent inoculation following pleural instrumentation or could simply reflect an underlying degree of immune suppression/ debilitation in this patient group leading to an increased susceptibility to fungal infection.  In fact, a significant number of reported cases of pleural aspergillosis have had preceding pleural instrumentation (Irani et al 1971, Simelaro et al 1981, Kearon et al 1987) which may support direct inoculation of Aspergillus as a primary cause for disease development. 
More commonly pleural aspergillosis is associated with the presence of a bronchopleural fistula the formation of which is commonly associated with previous or pre-existing pulmonary tuberculosis (Krakowa 1970, Imura et al 1990, Karthick et al 2009), pleural drainage/pneumothorax (Krakowa 1970, Hillerdal 1981, Chung et al 1988, Massard G et al 1995, Purcell and Corris 1995, Karthick et al 2009) and thoracic surgery, particularly pneumonectomy (Manning et al 1959, Krakowa et al 1970, Parry  et al 1982, Utley 1993, Sundy et al 2007, Bonatti  et al 2010 Purohit et al 2012).  Lung transplantation is also considered when discussing pneumonectomy and two cases of pleural aspergillosis post transplantation have been described (Westney et al 1996, Lodge at al 2004).   
The presence of a direct communication between the airway and the pleural space allows seeding of the pleura by inhaled Aspergillus conidia or direct endobronchial spread of infection in patients with pre-existing disease, for example chronic pulmonary aspergillosis or aspergilloma, allowing normal parenchymal defence mechanisms to be bypassed or disrupted. Chung (1988) reported that bronchopleural fistulae aid the development of pleural aspergillosis by producing an aerobic environment in the presence of necrotic material which provides ideal growth conditions. It has been reported by some (Parry et al 1982, Sundy et al 2007) that the sutures associated with the bronchial stump involved in  bronchopleural fistula formation act as a nidus for Aspergillus infection, although this has been reported in <30 cases (Sundy et al 2007). Silk sutures appear to be most problematic in this regard with nylon and steel sutures rarely being reported as causal (Sundy et al 2007).  
“Surgical spillage” has also been reported as a cause of pleural aspergillosis with Aspergillus inoculation taking place at the time of thoracic surgery for parenchymal Aspergillus infection and/or aspergilloma resection (Wex et al 1993). A rarer, although similar, form of pleural inoculation has been described by Hussein et al (2013) with the rupture of an infected giant bullae presenting as an empyema with subsequent culture of Aspergillus spp. Peripheral lung cavities associated with underlying chronic pulmonary aspergillosis may also rupture causing pleural seeding and may or may not lead to the formation of a bronchopleural fistula. 
Tuberculosis is not alone in predisposing to the development of bronchopleural fistulae and in essence the only pre-requisite for bronchopleural fistula and pleural cavity formation is pre-existing parenchymal, usually cavitating, or pleural damage (Hillerdal 1981). Consequently both sarcoidosis (Colp and Cook 1975) and severe pneumonia with cavitation (Kearon et al 1987) have been associated with the development of bronchopleural fistulae and pleural aspergillosis. 
Pleural aspergillosis has also been described in the setting of disseminated invasive disease in the context of acute myeloid leukaemia (Miyake et al 2006), central nervous system and pulmonary aspergillosis following high dose oral corticosteroid therapy (Barquero-Artigao et al 2003), HIV (Bonatti et al 2010) and hepatitis B (Feng 2008). In contrast to the group of patients described above, where some patients were already known to be infected or colonised with Aspergillus, none of these patients were. It is therefore likely that a degree of immune suppression is important in the development of pleural aspergillosis in some individuals. This is supported by the work of Ko et al (2000) who, when looking at fungal empyemas as a whole, identified that 90% of patients had significant co-morbidity and 79% percent were immunocompromised due to malignancy. Co-morbidities considered significant were often associated with impaired T cell function, important in host defence against Aspergillus, and included diabetes, long term oral steroid use, cirrhosis, solid organ transplant, HIV and alcohol abuse.  In this group the method of inoculation of the pleural is not clear although it may be that pulmonary infection directly seeds the pleural either through haematogenous routes, direct fungal translocation or the subsequent development of a small bronchopleural fistula associated with pulmonary cavitation.
Given that the aetiology of pleural aspergillosis is not fully understood it is difficult to know whether pleural aspergillosis exists as a separate disease entity, or as a complication of more deep seated Aspergillus infection, in individual immuno-competent patients. The fact that Aspergillus precipitins have been identified as positive in some cases (Krakowa et al 1970, Hillerdal 1981 ) would suggest that, for a group of patients underlying chronic pulmonary aspergillosis may also co-exist, with pleural disease being a complication. This is supported by the fact that many of these patients, particularly the pre-operative group, would meet at least two of the diagnostic criteria (radiological cavitation and respiratory symptoms) prior to surgery and, without testing for Aspergillus spp., chronic pulmonary aspergillosis may be missed. Given that the global burden of chronic pulmonary aspergillosis is probably increasing and under reported this would not be surprising. In this group of patients pleural aspergillosis could be viewed as a complication of previously unrecognised disease and implies a need for long term antifungal treatment.  Although it can be difficult to define which individuals fall in to the category of pre-existing unrecognised chronic infection, this distinction has significant clinical relevance given the treatment regimens and potential for cure differ. 

Diagnosis

The main diagnostic modality for pleural aspergillosis is demonstration of Aspergillus within the pleural space. This can be achieved either by visualising characteristic hyphae and/or direct culture of the fungus from pleural fluid or pleural biopsy with supportive cytology/histological examination. Pleural fluid is turbid, with a high protein, low glucose and usually a neutrophil predominant cell count. Galactomannan (Aspergillus antigen) may be detectable in pleural fluid, sometimes in high concentration.  There may be a role for serological testing such as Aspergillus precipitins /Aspergillus specific IgG although there are cases reported where these have been negative (Miyake et al 2006). Galactomannan is unlikely to be detectable in blood, unless pleural aspergillosis is a component of invasive aspergillosis. Beta D glucan may be elevated (Miyake et al 2006). A similar pattern, where galactomannan and circulating aspergillus DNA have not been identified in known infection, has been described in a subphrenic abscess where, as in the pleural cavity, infection is largely encapsulated preventing dissemination of fungal markers (Verweij et al 2000).  Chest radiograph, pleural ultrasound and CT imaging all have a place in the diagnostic work up of pleural effusion although no specific radiological diagnostic criteria are described in relation to pleural aspergillosis . Complex loculated effusions have been described in this setting (Lodge at al 2004) and when looking at a series of fungal empyema, encompassing multiple fungal pathogens including Aspergillus, loculation was reported in 41% (Ko et al 2000).  Tikkakoski et al (1995) described the radiological ultrasound appearances of a small series of Aspergillus related intrapulmonary abscesses or pleural effusions. However pleural collections were described as oval and hypoechoic which is sadly nonspecific. Other reported radiological appearances include none specific pleural thickening and intra-pleural aspergilloma (Baquero-Artigao et al 2003).  

Treatment

There are no clearly defined management pathways for pleural aspergillosis although it is likely that a combination of medical and surgical interventions provide the best outcome.  Bonatti et al (2010) most recently advocated a combined approach of surgical/medical drainage, followed by prolonged antifungal therapy (systemic and intrapleural) with subsequent surgical closure of the residual bronchopleural fistula or chest wall defect may be the most effective treatment strategy. The duration of medical therapy is unclear, but may encompass months to years, and is guided by individual response and burden of disease.  In some individuals lifelong therapy may be considered if burden of disease or co-morbidity precludes appropriate surgical management. A satisfactory endpoint for cessation of treatment is best achieved through an MDT approach considering inflammatory and serological markers of infection, patient condition and radiological appearances. 

Medical

Medical therapy for Aspergillus empyema consists of a combination of systemic antifungal therapy with the addition of topical antifungals applied directly to the pleural space.  Although the diffusion of antifungal therapy to the pleura is likely to be variable, Stern, Girard, and Calindro (2004) demonstrated systemic voriconazole treatment resulted in the presence of the drug within the pleural fluid. Further work has demonstrated that both systemic voriconazole and micafungin are delivered to the pleura in levels greater than the required MIC for A. fumigatus (Matusuda et al 2010).
Initially systemic therapy took the form of nystatin (Manning 1959) and subsequently i.v. amphotericin has been widely used (Irani et al 1971, Kearon et al 1987, Purcell and Corris 1995, Baquero-Artigao et al 2003, Lodge et al 2004, Karthik 2009).  However the introduction of triazoles and echinocandins has resulted in itraconazole (Purcell and Corris 1995, Lodge et al 2004), voriconazole (Stern et al 2004, Sundy et al 2007, Bonatti et al 2010, Matsuda 2010, Purohit et al 2012, Hussein et al 2013), posaconazole (Lodge et al 2004, Purohit 2010), caspofungin (Sundy et al 2007, Bonatt et al 2010, Purohit et al 2012) and micafungin (Matsuda 2010) being used as systemic treatment in place of the more toxic amphotericin B. The majority of reported cases of treatment with azole therapy use voriconazole as first line, with the use of posaconazole only in patients failing to respond. The echinocandins have largely been used as salvage therapy for failure to respond to systemic azole therapy although there are isolated reports of voriconazole and micafungin being used in combination as first line therapy (Matsuda et al 2010).  
The use of topical therapy has been widely described in pleural aspergillosis with the use of both nystatin (Krakowa et al 1970, Colp et al 1975, Chung et al 1988) and amphotericin B (Irani et al 1971, Colp et al 1975, Simelaro et al 1981, Parry et al 1982, Skorodin et al 1982, Baquero-Aritgao 2003, Bonatti et al 2010, Purohit 2012); intrapleural administration of amphotericin appearing to avoid the sometimes severe side effects seen with intravenous administration. No standardised regimen exists for the administration of topical intra-pleural agents with the volume irrigated determined by patient tolerability, higher volumes often being coughed out.  Recently described regimens include 5mg of amphotericin B in 20ml of 5% dextrose infused daily with a gradual dose increase to 50mg of amphotericin (Baquero-Artigao et al 2003) and 25ml of 100,000U/ML of nystatin infused daily (Chung et al 1988).   The role of topical antifungal therapy has not yet been fully evaluated but it may be at its’ most valuable in those patients where surgery is not possible. There effects may also extend beyond the antibiotic with a possible sclerosant role also being described (Baquero-Artigao et al 2003).  The use of pleural irrigation without topical antifungal agents (saline-iodine solution) has also been described, in combination with systemic voriconazole therapy, with complete clinical and radiological resolution (Stern et al 2004) 
Purcell and Corris (1995) described the use of nebulised amphotericin B in the successful treatment of an Aspergillus empyema however nebulised antifungals have not been widely used. It is unlikely that, even in the presence of a substantial bronchopleural fistula, inhaled therapy could deliver the drug doses required to reach an adequate MIC particularly when other treatment modalities are available.
Combined intrapleural fibrinolytic therapy (tPA/DNase) is now being used in some centres for the treatment of loculated parapneumonic effusion/empyema however there use has not been studied in the setting of fungal empyema. 
The duration of treatment for pleural aspergillosisis is not clearly defined and therapy is prolonged, often up to six months in total, with a period of oral azole consolidation therapy following initial treatment. If pleural aspergillosis is a feature of chronic pulmonary aspergillosis, then long term therapy is indicated for both the pleural and pulmonary components of the disease.

Surgical

Surgery associated with pleural aspergillosis is often a significant undertaking due to the burden of disease and the associated patient population, who are often debilitated by illness, may have had recent or previous thoracic surgery with the associated technical difficulties this brings and who often have significant systemic and respiratory co-morbidity. Although there are many procedures associated with the treatment of pleural aspergillosis the one key principal is that any persistent bronchopleural fistula must be closed as persistent leak leads to continuous pleural seeding which negates any attempt at cure. 
Surgical treatment of empyema of any form usually takes the form of either decortication or thoracoplasty which can be challenging in this population as the pleural tissue itself is often very heavily involved, often as an independent inflammatory mass, and the lung may be scarred from previous surgery or disease (Wex et al 1993). The key aims therefore are: 
1) drainage of the pleural cavity, 
2) resection of necrotic and infected tissue, 
3) obliteration of any residual cavity present and 
4) closure of bronchopleural fistula(e) whilst protecting adjacent structures.  
Multiple surgical techniques have been employed to achieve this including removal of infected chest wall implants used to reconstruct either the chest wall, diaphragm or pericardial surfaces post-pneumonectomy  (Sundy et al 2007), thoracic window techniques to allow drainage with subsequent spongostan and amphotericin-B talc poudrage (Purohit et al 2012), surgical debridement of only the bronchial stump following lobectomy/pneumonectomy (Bonatti et al 2010), pleuro-pneumonectomy and nystatin irrigation  (Chung 1988), thoracotomy and decortication of the affected side (Herring et al 1976, Kearon 1987) and thoracoplasty (Imura et al 1990).  
More complicated procedures include pneumonectomy with thoracoplasty to obliterate the pleural space and provide tissue coverage for the bronchial stump (Utley 1993), thoracotomy, pleurectomy and placement of a muscle flap for limited disease (Wex et al. 1993), thoracomyoplasty being employed for more extensive disease (Wex et al. 1993), thoracostomy with daily insertion of guaze impregnated with amphotericin B followed by either a muscle (Shirakusa et al. 1989) or an omental flap (Shirakusa et al. 1990; Wex et al. 1993) and the Eloesser procedure (Eloesser 1969). The Eloesser procedure is less disfiguring than a free muscle flap or extensive thoracoplasty, although still allows the creation a deep pleurocutaneous fistula, allowing drainage of the pleural cavity whilst maintaining negative pressure through the creation of a one way valve. The inner opening of the flap should be sealed as the lung expands with increased drainage of pleural fluid.
More recently video-assisted thoracoscopy has been reported as being successful in the treatment of an Aspergillus empyema following failure of medical therapy with complete resolution and no recurrence at five months (Feng et al 2008).
Despite the wealth of techniques available, complications following surgery of any kind can be severe and include necrosis of the muscle flap, haemorrhage from the bronchial stump, persistent air leak and multi-organ failure due persistent infection (Wex et al 1993, Utley 1993). Surgical candidates should therefore be chosen carefully and adjunctive medical therapy used where appropriate. This includes systemic antifungal therapy pre and, at least, peri-operatively. Patients who are very wasted may need feeding through a percutaneous endoscopic gastrostomy (PEG) or enteral feeding, pre-operatively, to minimise post-operative complications. 
Surgery may shorten the duration of medical therapy in pleural aspergillosis however it may not be the only chance an individual has of cure with reports of recovery with antifungal agents and intercostal drainage alone.  There will however always be a place for thoracic surgery in uncontrolled infection and, as treatment modalities and patient outcomes become clearer, it may well form part of a three pronged treatment regimen – surgery, drainage and azole therapy.  

Surgical and medical techniques can be combined at the time of surgery to reduce the likelihood of postoperative Aspergillus empyema in patients deemed to be high risk (Farid, 2013). In the presence of extensive cavitation fourteen days of peri-operative voriconazole is given, or micafungin if there is known or suspected azole resistance, and continued peri and immediately post operatively. Should spillage of Aspergillus spp. occur intra-operatively both taurolidine 2% and amphotericin B deoxycholate pleural lavage, in combination with iv micafungin (150mg), have been used to try to achieve sterilisation of the pleural space (Farid et al 2013). In the event of spillage post-operative antifungal therapy should be continued for at least eight weeks and should disease be incompletely excised treatment may be continued indefinitely. 

Summary

The aetiology of pleural aspergillosis is complex with the large majority of cases being associated with the presence of a bronchopleural fistula although iatrogenic disease, associations with chronic pulmonary and invasive aspergillosis and immunosuppression are also reported. Pleural aspergillosis remains a rare disease that conveys significant morbidity with optimal therapeutic regimens not yet fully defined. It is likely a combination of intercostal drainage, surgery and prolonged systemic antifungal therapy, with first line azole therapy, will provide disease control and, in some cases, cure. 

Gemma Hayes
University Hospital of South Manchester and University of Manchester
gemma.hayes@manchester.ac.uk

March 2014