Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary condition described in patients with asthma and cystic fibrosis (CF) caused by hypersensitivity to Aspergillus. It was first described in 1952 from the London Chest Hospital (Hinson et al, 1952). Although inhaled fungal conidia are normally removed from the airways of healthy people by
ABPA complicates about 1-4.1% of patients with asthma in secondary care (Benatar et al, 1980; Varshokar 2002; Donnelly et al, 1991; Eaton et al, 2000; Al-Mobeireek et al, 2001; Ma et al, 2011). It manifests as poorly controlled asthma, and exacerbations consist of fever, malaise, expectoration of mucus plugs and
Recognition of ABPA is important as it may, if uncontrolled, eventually lead to bronchiectasis and permanent lung damage. Therefore, the goal of treatment is to control asthma symptoms, reduce the frequency of exacerbations, and prevent
An acute exacerbation of ABPA is suspected on the basis of poorly controlled asthma, typical symptoms (mucous plugs, fever, malaise, and
Acute exacerbations are treated with systemic corticosteroid therapy. There are no established guidelines on the recommended regimen, and a dose of 0.5mg/kg or higher for a few weeks or months is usually used. A regimen recommended by Greenberger (2002) consists of prednisolone 0.5mg/kg/day for 1-2 weeks, then on alternate days for 6-8 weeks, then taper by 5-10 mg every 2 weeks until stopping. Higher steroid doses (prednisolone 0.75mg/kg) tapered more gradually over 6-12 months were associated with longer periods of remission but there are no direct comparisons between regimens (Agarwal et al, 2006). Shorter periods of high dose oral corticosteroids (ie 40mg prednisolone daily for 3 weeks tapered to zero over 2-4 weeks may also be effective. A
Patients who respond to steroids are classified as being in remission. Patients with frequent exacerbations or with recurrent symptoms when steroids are tapered are classified as steroid-dependent and may benefit from treatment with antifungal agents which may have a steroid-sparing effect.
The first report on antifungal treatment for ABPA was a case report of nystatin inhalations published in 1967 (Stark et al, 1967), followed by a report on inhaled natamycin (Henderson et al, 1968). In a small
Subsequently, the release of itraconazole yielded an alternative therapeutic avenue for ABPA. Itraconazole 200-400 mg/d showed benefit in several open studies. In one open study, all 3 patients experienced improvement in pulmonary function (Denning et al, 1991). In another series, as part of an international
In two placebo-controlled trials in asthmatic ABPA patients, there was a clear benefit of itraconazole (Stevens et al, 2000 and Wark et al, 2003). Stevens et al compared itraconazole 200mg twice daily to placebo for 16 weeks and then all patients received 16 weeks of 200mg daily.
For those with ABPA who are corticosteroid-dependent or severely disabled by the disease, a trial of itraconazole 400 mg/d is warranted. If there is no improvement over 16-32 weeks, measurement of serum concentrations may be useful as a guide to appropriate dosing or susceptibility testing of the infecting isolate of Aspergillus. For those who respond, at least 200mg daily should be continued until no further improvement is seen (usually 6-9 months). However, resistance has been noted to develop in ABPA patients, especially when itraconazole levels have been subtherapeutic (Howard et al, 2010). Therefore monitoring for evolving resistance is indicated in patients on itraconazole. Other azoles like voriconazole and posaconazole are also effective and can be used in cases of failure or intolerance of itraconazole (Chishimba et al, 2012; Mulliez 2010). Finally, a thorough search for drug interactions is essential for all azoles. For example, itraconazole has significant drug interactions with omeprazole, simvastatin
There is limited experience
Bronchiectasis is the most important complication of ABPA. It may be present initially when ABPA is diagnosed, or develop subsequently, especially when the disease exacerbations are not well controlled. The typical presentation is of central bronchiectasis, involving the inner
Finally, it may be helpful to
ABPA complicates up to 18% of patients with CF based on prevalence studies from various parts of the world (Geller 1999, Mastella 2000, Carneiro 2008, Sharma 2014). Aspergillus
The criteria used for ABPA diagnosis in asthma patients are not very satisfactory in CF because of the overlapping symptoms and findings caused by other processes as well as the deterioration caused by the underlying disease. In addition, precipitating antibodies to Aspergillus are common in adult CF patients and most of these do not have ABPA. Baxter et al proposed a classification system for the diagnosis of ABPA in CF patients (Baxter et al, 2013).
Systemic corticosteroids are recommended for exacerbations of ABPA in CF in the same doses used for ABPA in asthma as there are no data pertaining specifically to CF patients. Less evidence exists regarding the use of antifungals in CF compared to asthma and there are no
There has been more experience on the use of nebulized amphotericin B in CF patients with ABPA compared to asthmatics, but
The IgE monoclonal antibody omalizumab has been used in patients with ABPA and CF. In the first report of 3 children, it led to clinical improvement and discontinuation of steroids (Zirbes and Milla, 2008). Case reports or small case series were subsequently published (Kanu and Patel, 2008; Lebecque et al 2009; Elmallah et al, 2012; Wong et al, 2013; Zicari et al, 2014). In a series of 6 patients who received omalizumab because of steroid toxicity or treatment failure, all patients had an improvement in FEV1 (from an average of 57.5% to 62.3% after 3-4 months of omalizumab), and steroids could be tapered or discontinued.