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Pleural aspergillosis

Overview and pathogenesis

Pleural aspergillosis was first described around 150 years ago (Rayer 1842) but remains a relatively rare entity when compared with other Aspergillus infections.  For the purposes of the following discussion, pleural aspergillosis is defined as direct involvement of the pleura or pleural space with Aspergillus and excludes cases of sterile pleural inflammatory response secondary to pulmonary disease.

Aspergillus fumigatus is almost exclusively the causative pathogen although there is a case of pleural aspergillosis due to A. flavus (Albelda et al. 1982). Pleural aspergillosis is most commonly observed in the setting of a bronchopulmonary fistula, the commonest cause of which is past or current pulmonary tuberculosis (Krakowka et al. 1970; 1983). Spontaneous (Krakowka et al. 1970) and therapeutic pneumothoraces (Krakowka et al. 1970; Hillerdal 1981) and lung resection surgery (Manning et al. 1959; Krakowka et al. 1970) represent other scenarios which may result in bronchopleural fistula formation and pleural aspergillosis. Presumably the presence of a fistula allows Aspergillus to bypass the usual host defence mechanisms which are usually highly efficient in preventing the establishment of invasive disease.  In this scenario the fistula is a conduit by which Aspergillus which has colonised the airway finds its way to the pleural space where it is able to establish infection.

Less commonly, pleural aspergillosis has been documented as a complication of open or closed pleural instrumentation (Chung et al. 1988) , following extension of established pulmonary aspergillosis into the pleural space, (Albelda et al. 1982) or after spillage of tissue containing Aspergillus at the time of thoracic surgery (Wex et al. 1993).

The presence of precipitating IgG antibodies to Aspergillus (Krakowka et al. 1970; Hillerdal 1981) in pleural aspergillosis has been attributed to an immunocompetent host displaying a vigorous immune response to deep infection. These antibodies are also seen in other Aspergillus associated diseases such as ABPA, aspergilloma and chronic pulmonary aspergillosis. Their presence in cases of pleural aspergillosis may well reflect the fact that the true primary diagnosis in many cited cases of pleural aspergillosis is in fact chronic pulmonary aspergillosis and the pleural disease represents a complication of this underlying condition. In such circumstances, the smouldering parenchymal infection that is typical of this syndrome seeds the pleura either directly or via a pre-existing fistula. This concept was conceived as early as 1981 by Hillerdal (Hillerdal 1981) prior to the description of this syndrome by Binder and Gefter in the early 1980s. While such a hypothesis remains largely untested, validity for such a scenario has been illustrated by a case of acute invasive pulmonary aspergillosis (IPA) with subsequent development of a bronchopleural fistula and Aspergillus empyema (Albelda et al. 1982)

The high proportion of cases who have preceding pleural instrumentation (Irani et al. 1971; Simelaro et al. 1981; Kearon et al. 1987) means that the distinction between simple inoculation and a complication of chronic pulmonary aspergillosis may be difficult. This may be of more than just academic importance since the natural history and therapeutic implications of each of these entities remains undefined, principally due to diagnostic inaccuracies and difficulties.

Diagnosis

The following table represents a summary of 23 cases of pleural aspergillosis. Culture alone predominates presumably because the chief diagnostic modality is a pleural aspirate. Precipitating IgG antibodies to Aspergillus may be a useful adjunct but the diagnosis rests with the demonstration by conventional means of Aspergillus in the pleural space.

Treatment

Medical and surgical techniques have both been employed to treat pleural aspergillosis and although untested it is likely a combination of the two provides optimal results. It is also clear that medical therapy should be long-term (months to years) and in some cases indefinite where bulky disease and/or host debility makes cure unobtainable. A combination of endpoints is required when deciding to cease therapy which may include symptoms, inflammatory markers and the demonstration of resolution or long term stability of radiological abnormalities. In a manner analogous to other chronic infections, surgical debridement may shorten the required duration of medical therapy to achieve cure through the removal of necrotic tissue which may harbour viable organisms.

Medical therapy

Medical therapy includes both systemic and topical antifungal regimens. Systemically administered amphotericin B has been the mainstay (historically at least) (Irani et al. 1971; Kearon et al. 1987) and while there is a paucity of literature concerning the role of azoles they undoubtedly have a valuable role especially in the provision of long-term consolidation therapy. The role of newer agents such as voriconazole and the echinocandins remains to be elucidated although there is no reason to doubt they will be efficacious as has been the case in other Aspergillus infections. It is our practice to prescribe induction therapy usually with amphotericin B, or a lipid preparation, for 2-4 weeks before changing to an azole as long-term consolidation therapy which is usually given to complete at least six months of therapy in total.

Topical therapy with amphotericin B (Irani et al. 1971; Colp et al. 1975; Simelaro et al. 1981; Parry et al. 1982) and nystatin (Krakowka et al. 1970; Colp et al. 1975; Chung et al. 1988) have also been used. Examples of doses and regimens used of amphotericin B include 25 mg in 35 mls 5% dextrose instilled daily (Colp et al. 1975) , 5mg daily (Irani et al. 1971) , 0.25-0.75 mg/kg/day administered three times per day (Simelaro et al. 1981) and for nystatin 30ml of 2500U/ml daily (Colp et al. 1975), 25ml of 100,000U/ml daily (Chung et al. 1988), 500,000U in 4 ml daily or second daily (Manning et al. 1959). The current role for topical therapy is unclear but is a valuable alternative when surgery and other conventional medical options are precluded.

Surgical therapy

Surgery for pleuropulmonary aspergillosis is associated with significant morbidity and mortality because the procedures are technically demanding in a patient group for whom limited respiratory reserve, significant co-morbidities and poor nutritional status is the norm. This should not discount, however, careful consideration of its use in each individual case. In broad terms surgical treatment of empyema involves bringing the lung to the chest wall (decortication) or the chest wall to the lung (thoracoplasty) (Wex et al. 1993). Pleural aspergillosis offers special challenges to this paradigm in that the lung is often scarred and fistulous and the pleura is heavily involved in an inflammatory mass (Wex et al. 1993). This has lead to a variety of procedures designed to safely drain the empyema, resect infected contiguous tissue, obliterate any residual cavity and protect remaining structures such as the bronchial stump.  Several surgical approaches have been described which include thoracotomy with decortication (Herring et al. 1976) with limited wedge resection of underlying lung (Wex et al. 1993), pneumonectomy with thoracoplasty to obliterate the pleural space and provide tissue coverage for the bronchial stump (Utley 1993), thorocotomy, pleurectomy and placement of a muscle flap for limited disease (Wex et al. 1993) or thoracomyoplasty for more extensive disease (Wex et al. 1993), thorocostomy 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 involves the creation of a flap which acts as a one way valve. This enables drainage of the contents of the empyema while allowing maintenance of negative intra-thoracic pressure.  As the empyema drains the lung expands and seals the inner opening of the flap drainage (Eloesser 1969). Post-surgical complications include persistent air-leak from bronchopleural fistulae (Wex et al. 1993), haemorrhage from the bronchial stump (Utley 1993), necrosis of the muscle flap (Wex et al. 1993) and multi-organ failure secondary to persistent pleural space infection (Utley 1993) .

Despite difficulties, surgery should be considered for all patients with pleural aspergillosis since it may be the only modality by which a cure can be achieved and at the very least, as stated earlier, it may shorten the total duration of medical therapy.  It is certainly indicated in those who have uncontrolled pleural infection despite optimal antifungal therapy (Utley 1993). Surgery for pulmonary aspergillosis should be conducted under optimal systemic antifungal therapy which should be continued through the peri-operative period and until the clinical course of the patient is defined.

Summary

1. The recognised diagnostic entities include

(a) Pleural aspergillosis complicating bronchopleural fistula without evidence of chronic pulmonary aspergillosis (ie occurring after spontaneous pneumothorax, lung resection surgery)

(b) Pleural aspergillosis complicating pulmonary aspergillosis either with or without a bronchopleural fistula.

(c) Iatrogenic pleural aspergillosis

    (i) following open or closed pleural instrumentation

    (ii) following spillage of tissue containing Aspergillus at the time of thoracic surgery.

2. The optimal therapy for pleural aspergillosis is unknown but a combination of medical and surgical approaches probably yields the best results.  Unfortunately surgery is not straightforward and the risks may outweigh benefits but it should at least be considered for each patient and especially in those with uncontrolled pleural infection despite optimal medical therapy.  Induction therapy most frequently consists of amphotericin B but azoles are increasingly likely to assume such a role.  The safety, tolerability and efficacy of azoles makes them ideal agents for the long-term consolidation therapy that is required in pleural aspergillosis.  Topical therapy may be beneficial in a limited number of cases.

Prepared by:
Dr William Hope
School of Medicine
University of Manchester and Wythenshawe Hospital
Manchester, UK

April 2003

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