Chronic pulmonary aspergillosis

Chronic pulmonary aspergillosis includes two major clinical entities:

• aspergilloma which depicts a single pulmonary cavity, containing a fungal ball, which changes little over months or years of observation, and may spontaneously regress, and
• chronic cavitary pulmonary aspergillosis (CCPA) corresponding to the older surgical term complex aspergilloma, but not necessarily with an aspergilloma present.

The specific criteria for diagnosis are:

1) 1 large empty or 2 or more pulmonary cavities on chest imaging with or without a fungal ball (aspergilloma)

AND

2) Symptoms (usually weight loss, fatigue, cough, haemoptysis and breathlessness) for at least 3 months

AND

3) Serology, cultures or molecular detection implicating Aspergillus spp.

The distinction between an aspergilloma and chronic cavitary pulmonary aspergillosis may be somewhat semantic but does reflect the singularity of the aspergilloma as opposed to the multiple cavities typical of chronic cavitary pulmonary aspergillosis.

An additional late-stage entity ‘chronic fibrosing pulmonary aspergillosis’ (CFPA) is less clearly defined, but includes patients with respiratory failure caused by chronic pulmonary aspergillosis and complete opacification of one lung or both upper lobes (Denning, 2003) A degree of fibrosis accompanies all cases of CCPA, so CFPA refers to an advanced case with major loss of lung function.

An arbitrary duration of disease of at least 3 months distinguishes acute and subacute aspergillosis from chronic aspergillosis (Hope, 2005). Some patients with allergic (or eosinophilic) aspergillosis (such as ABPA) may develop CCPA, so the terms are not mutually exclusive.

Chronic pulmonary aspergillosis was the first manifestation of pulmonary aspergillosis to be described in man (with an aspergilloma) (Bennett, 1848). Numerous earlier evocative terms have been used previously for CCPA including ‘pulmonary aspergillosis with cavitation’, ‘symptomatic pulmonary aspergilloma’, ‘complex aspergilloma’, and ‘chronic granulomatous aspergillosis’. In the early 1980s, Gefter (1981) and Binder (1982) coined the terms ‘semi-invasive pulmonary aspergillosis’ and ‘chronic necrotizing pulmonary aspergillosis’, respectively. These last 3 entities are best regarded as subacute invasive aspergillosis (Hope, 2005). The term CCPA describes patients in whom there is formation and expansion of 1 or more pulmonary cavities over time. CCPA is preferred over complex aspergilloma because more than 50% such patients don’t have an aspergilloma visible radiologically and preferred over chronic necrotising pulmonary aspergillosis because pathological appearances are not known in the vast majority of cases, and ‘necrotising’ features are rarely seen, when tissue is obtained. The terminology is an arbitrary classification of a spectrum of disease entities whose precise definition and scope varies considerably.

Many patients with invasive aspergillosis now receive therapy for months or years, usually with continuing, usually radiological evidence of aspergillosis. Such patients can be termed to have chronic aspergillosis. No term has been proposed to cover this situation, although many have attempted to define ‘salvage’, without consensus yet. The term chronic on acute pulmonary aspergillosis should be considered.

Underlying pulmonary disease

Most patients with CPA have an underling pulmonary disease. The common underlying disease includes:

· Pulmonary tuberculosis

· Atypical mycobacterial pulmonary infection, especially M. malmoense infection (in the UK), M avium intracellulare, M. xenopi and M. kansasii.

· Stage III fibrocystic pulmonary sarcoidosis

· ABPA

· History of pneumothorax

· History of successfully treated lung cancer

Less common underlying diseases include asthma, prior severe pneumonia, histoplasmosis, pulmonary cysts, ankylosing spondylitis, bronchiectasis, rheumatoid pulmonary nodules, silicosis and emphysema (Procknow, 1960; Stiksa, 1976; Wollschlager & Khan, 1984; Butz, 1985; McConnochie, 1989; McGregor, 1989; Elliott, 1989, Caras, 1996; Hafeez, 2000; Kato, 2002 Denning, 2003; Parakh, 2005; Pamuk, 2005; Camuset, 2007)

Underlying immune defects

One or more subtle but important defects in systemic immunity may also be important in the pathogenesis; defects in mannose binding lectin, surfactant A2 and TLR 4 single nucleotide polymorphisms (SNPs) and alcohol abuse have all been reported in this regard (Crosdale, 2001; Vaid, 2007; Carvalho, 2008). A shift towards Th2 cytokine production profile was also seen, with SNPs showing reduced alpha TNF, low TGF beta, low IL-10 and high IL-15 and gamma IFN production (Sambatakou, 2006). Coeliac disease may be more common in these patients (personal observation).

Pathology and pathogenesis

Aspergilloma and sinus ball of the sinus

Both pulmonary aspergillomas and fungus balls of the sinus are rounded conglomerates of hyphae, mucus, and cellular debris. Pulmonary aspergillomas are often loosely attached to the wall of a pulmonary cavity, whereas in the sinus they appear are unattached. Pulmonary aspergillomas are typically mobile and they may vary in size over time as may the degree of adjacent pleural and cavity wall thickening. In the lung an aspergilloma is contained within a fibrotic and thickened wall and occupying a pre-existing pulmonary cavity. Histologically, pulmonary aspergillomas have a lamellar appearance on microscopic sections.

Chronic cavitary pulmonary aspergillosis

Why new cavities form in the lung remains unclear. Histologically they show chronic inflammation with localised fibrosis, usually without granulomas, necrosis or eosinophilic infiltrates. Presumably they expand when untreated because the cavity contains Aspergillus on its surface and either direct damage from Aspergillus secreted or products, on ongoing inflammation lead to progressive loss of lung tissue. Pleural thickening is common, but may not be present, and what drives this is unclear. In both CCPA and with aspergilloma, proliferation of small vessels from the bronchial or other systemic circulation form in the lung in the proximity of the cavity, which are responsible for coughing up blood, when they rupture. Why these vessels form is not clear being generally uncommon in pulmonary diseases, with the one exception of bronchiectasis.

The pathogenesis of chronic fibrosing pulmonary aspergillosis is not known (Denning, 2003). In those cases in which pulmonary tissue has been examined histologically, extensive fibrosis with a minor chronic inflammatory infiltrate are seen. In cases in which the fibrosis occurs immediately adjacent to cavities caused by Aspergillus, the stimulus is probably fungal-mediated with localised pulmonary repair and fibrosis processes operating. In instances where the fibrosis is more distant i.e. in an uninvolved ipsilateral lobe, the pathogenesis remains obscure.

Clinical and radiological features

Aspergilloma

There are no symptoms referable to the aspergilloma other than the occurrence of hemoptysis in 50-90% of patients. This is often infrequent and small in volume but on occasions may be massive. The appearance of a fungal ball in a pulmonary cavity is highly suggestive of an aspergilloma, as is localised pleural thickening overlying a cavity (Greene, 2007). Usually the fungal ball is mobile (CT scan images lying on the back and front show movement). , but The demonstration of precipitating antibodies to Aspergillus spp. is a useful diagnostic test to confirm a fungal aetiology, although repetitive Aspergillus cultures from sputum may also confirm the fungal aetiology. When there is uncertainty about the diagnosis, biopsy of the mass or cavity will yield hyphae, if an aspergilloma is present.

Chronic cavitary pulmonary aspergillosis

Most patients are middle aged, but may present as early as their 20s or as late as their 60thdecade. The commonest symptom complex consists of weight loss, chronic cough, hemoptysis, fatigue and shortness of breath (Denning, 2003, Camuset, 2007). While the clinical signs and symptoms of CCPA are non-specific, their presence and severity is an important point of distinction from simple aspergilloma. Although the diagnosis can often be inferred from a single chest radiograph, detailed review of prior radiological data may be required to confirm the typical features, as well as the very slow progression that is so characteristic of this CCPA. CT scans may be useful to further define the precise pattern, extent of disease and the presence or otherwise of any fungal ball. Radiological examination usually reveals one or more cavities, typically within the upper lobes which may or may not contain fungus balls. New cavity formation or expansion of one or more existing cavities over time is highly characteristic. Peri-cavitary infiltrates and adjacent pleural thickening are frequently observed and appear to be indicative of disease activity; these radiological abnormalities may remit with effective antifungal therapy leaving residual thin-walled empty cavities.

Chronic fibrosing pulmonary aspergillosis

CFPA is generally an inferred diagnosis based on a current or prior diagnosis of chronic cavitary disease and/or aspergilloma, extensive upper or lower lobe fibrosis documented on radiology and by poor lung function (Denning, 2003). Lung function tests demonstrate extreme loss of vital capacity and reduced DLCO. Most patients are hypoxic at rest, and may require supplemental oxygen. Type I respiratory failure (normal or low CO2) is much more common than Type II (elevated CO2).

Microbiological diagnosis

Aspergillus IgG antibodies to A. fumigatus are present in almost all patients. Usually these are precipitating antibodies (so called Aspergillus precipitins). The titre of antibody does not reflect the severity of disease, as very late stage disease may have low titres, but changes in titre are useful for assessing response to treatment . Falling titres reflect a good response to treatment, although this takes months or years, whereas rising titres reflects emergence of resistance or relapse after therapy has been discontinued.

IgE anibodies to A. fumigatus are detectable in about 70% of patients, at low levels. These patients may have elevated total serum IgE, usally at modest levels (Denning, 2003). Sometimes A. fumigatus IgG antibodies are undetectable and instead A. fumigatus IgE antibodies are detectable. Rarely antibodies to A. flavus or A. niger are detectable and those to A. fumigatus are not. Aspergillus galactomannan antigen may be detectable before treatment.

Cultures of sputum may be positive for A. fumigatus (lung and often sinus) and isolates with abnormal morphology and/or conidiation and slow growth are relatively common. The yield of positive cultures varies from 11-40% (Camuset, 2007; Denning, 2003). Sometimes cultures from the pleural space are positive. Molecular detection of Aspergillus in sputum or bronchoalveolar lavage has not been described, but is highly likely.

Isolates should be susceptibility tested as azole resistance is common I this group. Many patients are exposed to low levels of itraconazole (because of low doses used, poor bioavailability in those on proton pump inhibitors or H2 blockers, other drug interactions and natural variation in absorption and metabolism), and this may predispose to the development of resistance. Approximately two thirds of isolates are also resistant to voriconazole or posaconazole or both. Azole resistant isolates are not cross resistant to amphotericin B or echinocandins.

Some aspergillomas, especially in diabetic patients, are caused by A. niger in which case oxalic acid crystals may be seen in sputum and the aspergilloma if resected (Severo, 1997).

Other important diagnostic features include the demonstration of elevated inflammatory markers such as ESR and CRP, and the exclusion of other infectious, neoplastic, and inflammatory entities which may mimic this syndrome (Denning, 2003). There appears to be a particularly strong link with atypical mycobacteria and these infections may be active simultaneously or sequentially. There is also the possibility of a pyogenic infection in a cavity which may require drainage and appropriate antibacterial therapy.

Antifungal and surgical treatment, and management of complications

Aspergilloma

Asymptomatic patients should be observed, quarterly or annually, for progression to chronic cavitary pulmonary aspergillosis (common) or spontaneous resolution (<10% of cases). Patients with single (or simple) aspergillomas generally do well with surgical resection (El-Oakley, 1997; Chen, 1997; Regnard, 2000; Kim, 2005; Shiraishi, 2006; Demir, 2006; Pratap, 2007). Patients with life-threatening or significant haemoptysis should undergo resection. All patients are best given pre- and post-operative antifungal agents (i.e. voriconazole) to prevent pleural aspergillosis, and bronchopleural fistulae. Prolonged sedation because of an interaction with benzodiazepines may occur with voriconazole. Young women with localized disease may prefer surgery to long term antifungal therapy as azole treatment is contraindicated in pregnancy. More recent surgical series have substantially lower mortality and morbidity rates, particularly if patients are selected carefully, i.e. <5% (Kim, 2005; Shiraishi, 2006; Demir, 2006; Pratap, 2007). Complications include Aspergillus empyema, persistent air leak, persistent pleural space, empyema, bronchopleural fistula, respiratory insufficiency and significant intercurrent infections, although all these are much more common in the case of chronic cavitary disease or complex aspergillomas. Post-thoracotomy pain is an occasional problem.

There are some data supporting the use of amphotericin B instillation through flexible plastic catheters (Giron, 1995). 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. Repeated instillations are labour intensive and not very effective for complex and/or bilateral aspergillomas. Alternative approaches include the incorporation of amphotericin B in gelatin or glycerin that solidifies at 37oC (Munk, 1993; Giron, 1995). In the UK this approach has become difficult to deliver because of regulations concerning aseptic drug preparation and unavailability of one key pharmaceutical component.

Chronic cavitary pulmonary aspergillosis

Itraconazole and voriconazole are the preferred oral agents for CCPA (Caras, 1996; Herbrecht, 2002; Denning, 2003; Jain, 2006; Sambatakou, 2006; Camuset, 2007; Walsh, 2008; Hagiwara, 2008) with posaconazole being substituted for failure, toxicity or emergence of resistance. Itraconazole capsules should be given at a dose of 200mg twice daily, with confirmation of adequate of blood concentrations to ensure adequate exposure. Itraconazole suspension is useful for those on treatment with proton pump inhibitors or H2 blockers to optimise bioavailability. Voriconazole is used in the same dose, although many patients require dosage adjustment up or down after plasma concentration measurement. About 40% of patients on either itraconazole or voriconazole require a dose or preparation adjustment. Low concentrations of antifungal probably predispose to itraconazole resistance (and azole cross-resistance). Generic preparations of itraconazole have variable bioavailability (Pasqualotto & Denning, 2007). High concentrations of itraconazole and voriconazole may be associated with adverse events (Boyd, 2003; Imhof, 2006; Pasquel, 2008) and drug costs can be saved by lowering the dose. Liver function tests and potassium levels should be monitored frequently in the first 3 months of therapy, and rarely become abnormal after 6 months of therapy.

Micafungin has also been used in a mixed population of patients with subacute invasive aspergillosis (chronic necrotising) and CPA, with reasonable success rates (Izumikawa, 2007; Ouchi, 2007).

CCPA probably requires life-long therapy; data are sparse, but relapse is common, as expected in patients with immune defects. Resistance to one or more azoles may occur during long term treatment and a positive culture, while on antifungal therapy, is an indication for susceptibility testing, or if not possible then a switch of therapy, if the patient is compliant and adequate plasma concentrations documented. Itraconazole resistance is considerably more common than voriconazole resistance.

Response to therapy can be assessed by assessing symptoms of chronic ill health, weight, fatigue and pulmonary symptoms, especially cough, sputum volume and breathlessness (Denning, 2003; Jain 2006; Camuset, 2007). Falling Aspergillus antibody (precipitins) titre is the most useful laboratory parameter to follow. Recurrence of haemoptysis may be a sign of antifungal failure, but lack of resolution may reflect either failure or persistence of a large vascular network, that would not be expected to resolve with control of the fungal infection.

Patients who fail oral therapy or who are very ill with extensive disease, may require a 3-4 week course of intravenous amphotericin B therapy. Maintenance of improved health on oral azoles is then achievable, even if therapeutic failure with azoles was first documented. Gamma interferon therapy may also be useful (anecdote only) (Denning, 2003). Glucocorticoids at modest doses should be used with caution in CCPA, especially early in the treatment course before antifungal response can be assessed, but may have a place in management for some patients who remain chronically ill, but have some evidence of control of Aspergillus. Anorexia and weight loss may respond to low doses of anabolic steroids such as megesterol.

Haemopytysis

In patients with moderate or severe haemoptysis embolisation may be appropriate if they are not fit to undergo surgery or have extensive disease. In most instances of haemoptysis, abnormal and novel vascular connections to the systemic circulation are implicated. Usually this is the bronchial circulation but it may be any of the other arteries supplying the chest, e.g. internal, subclavian or internal mammary arteries. Aspergillomas can also be associated with an extensive network of small vessels. Several abnormal connections may exist in a single patient.

Severe haemotpysis can be managed with blood transfusion and administration of recombinant activated factor VII (rFVIIa) (Samarzija, 2008), although not licensed for this indication. Tranexamic acid is also useful. Temporary relief of haemoptysis may be gained with tranexamic acid, although it is not licensed for this indication. It is widely used throughout the UK for haemoptysis. Tranexamic acid increases infarction potential, and a low rate of ischaemic strokes etc is reported after its use, and it may not be well tolerated. A typical dose is 500mg three times daily.

Embolisation is used to permanently occlude the vessels that bleed. 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 and the patient has to lie still and flat for 2-4 hours during the procedure which can be difficult. Depending on the radiologist and the anatomy, approximately 50-90% of embolisation procedures are successful (Jardin, 1988; Corr, 2006). However a relapse rate of 50% is typical if antifungal therapy is not optimised, which can be minimized with long term antifungal therapy. Complications of local pain, stroke or chest wall or spinal cord infarction may occur uncommonly after embolisation, as well as reactions to the radiological dye.

Surgery

Surgery is problematic for chronic cavitary pulmonary aspergillosis, usually resulting in serious complications and embolisation is preferred for problematic haemoptysis.

Surgical removal of aspergillomas is difficult because of the very vascular, adherent pleura and because the remaining chest cavity may become infected with Aspergillus (Daly, 1986). Surgical removal of pleural aspergillomas and thoracoplasty is also prone to many complications and should be avoided if possible (Massard, 1983). In addition, many patients have underlying respiratory insufficiency and removal of a lobe of the lung would leave them unacceptably breathless. However several recent series describe better results with 2-5% mortality and ~25% complication rate overall (Kim, 2005; Shiraishi, 2006; Demir, 2006; Pratap, 2007). This may be preferable to long term antifungal therapy for some patients. Complications of surgery include empyema, space infection, bronchopleural fistula, post-throracotomy pain and breathlessness. Drainage of an Aspergillus empyema may require partial or full decortication an/or creation of a deep pleurocutaneous fistula (e.g. an Eloesser flap) (Eloesser, 1969).

Gamma interferon

Numerous in vitro and preclinical data indicate that a Th2-derived immune response perpetuates invasive aspergillosis whereas a Th1 response contributes of resolution of disease. Gamma interferon (IFN) is a key component of the TH1 cytokine group, and might be expected to contribute to resolution of infection. Several patients with CPA who apparently benefited are described (Denning, 2003; Kelleher, 2006; Bandera, 2008), as well as some patients with chronic granulomatous disease and subacute invasive aspergillosis. The optimal dose is not established, but might be in the 50-100 µg per dose, given three times weekly subcutaneously. The side-effect profile is considerable, and doses are best administered at night. 10 -50 weeks of treatment have been given.

Supportive care

Some patients end up not being able to take any antifungal therapy because of adverse events, antifungal resistance or choice. Maintenance of weight, avoidance or treatment of depression, and oxygen for very breathless patients are helpful, Some patients have derived benefit from milk thistle (personal observation), though an unknown mechanism.

Prognosis

Historically, patients with chronic pulmonary aspergillosis have much morbidity and usually die early. However, in those patients with major haemoptysis and simple aspergillomas, surgery offers an 84% five year survival compared with a 41% survival with conservative therapy (Jewkes, 1983). Follow up of a London collection of 85 patients over 5 years in the 1970’s and 1980’s showed 41 deaths (48%), with diverse causes of death (Jewkes, 1983). An older review of patients managed in another institution with either TB or sarcoidosis as the underlying cause of CPA showed much higher and earlier mortality in the sarcoidosis patients (Tomlinson, 1987), possibly attributable to corticosteroid therapy given to those with sarcoidosis (Figure 3). This was in the era before oral antifungal therapy was available. Much improved surgical and medical results are now reported, with long periods of remission on azole therapy, or after surgical resection.

David W. Denning FRCP FRCPath FIDSA FMedSci
Professor of Medicine and Medical Mycology
Director, National Aspergillosis Centre
Education and Research Centre
University Hospital of South Manchester (Wythenshawe Hospital)
Southmoor Road
Manchester M23 9LT UK

January 2009