First reported in detail in 1952 from the London Chest Hospital (Hinson et al, 1952) allergic bronchopulmonary aspergillosis (ABPA) is classified into five stages. These are acute remission, exacerbation, corticosteroid-dependent, asthma and fibrotic (Patterson et al, 1982). ABPA complicates asthma and cystic fibrosis (CF). Clearly the staging system has less meaning in cystic fibrosis because of progressive deterioration in respiratory status over many years. Precipitating antibodies to Aspergillus are common in adult cystics and in most cases ABPA is not present. Criteria for defining ABPA in CF are unclear.
Patients in remission require no therapy. Acute exacerbations are best treated with systemic corticosteroid therapy, usually a daily dose of 40-60 mg prednisolone for 7-10 days. Response to therapy can be gauged both clinically and serologically; serum IgE levels should fall and radiological infiltrates should clear. There is no useful data available on whether corticosteroids and/or antifungal agents slow the progression of the ABPA to pulmonary fibrosis which generally occurs between 5 and 11 years after the diagnosis. Long term corticosteroids may be necessary in those who deteriorate after steroid withdrawal (Greenberger, 1994).
In patients with frequent exacerbations, inhaled corticosteroids are useful in reducing the frequency of attacks. Probably this also lowers the risk of fibrosis in later years which is frequent otherwise. Many of these patients, however, require continuous systemic corticosteroid therapy to sustain remission.
For steroid-dependant patients a number of different antifungal strategies have been tried. Oral ketoconazole is ineffective (Shale et al, 1987; Fournier, 1987). In the first controlled trial of antifungal therapy in this condition, inhaled natamycin twice daily was also ineffective (Currie, 1990). There have been occasional anecdotal reports of the more commonly used polyene (amphotericin B) showing some benefit given by inhalation. The release of the new azole itraconazole yielded an alternative therapeutic avenue for ABPA. Itraconazole 200-400 mg/d has shown benefit in four open studies. In one open study of six patients who were corticosteroid dependent (3 with CF and 3 with asthma) five of the six patients responded (Denning et al, 1991). One patient with a low serum itraconazole concentration did not. In another series, as part of an international open-labelled compassionate use program several patients responded but the stage of disease and measurement of response was not well characterised (de Beule et al, 1988). Two other open studies have been published. One study of 16 patients with ABPA and cystic fibrosis demonstrated fewer exacerbations and a reduction in oral corticosteroid dose (Pacheco et al, 1993). Another compared a 2 year period before introduction of itraconazole with that on 200mg daily of itraconazole in 14 patients with ABPA and asthma (Salez et al, 1999). Compared with the reference period, blood eosinophilia, total IgE and Aspergillus precipitating antibody decreased, although Aspergillusspecific IgE did not. Respiratory function as measured by FEV1, and FEF25-75 improved on itraconazole. Corticosteroid dose (prednisolone) was reduced from a mean of 22 to 6.5mg daily.
Recently a controlled trial of oral itraconazole versus placebo was completed and there was a clear benefit of itraconazole over placebo. (Stevens et al, 2000). In this study in asthmatic patients with ABPA, itraconazole 200mg twice daily was compared to placebo for 16 weeks and then all patients received 16 weeks of 200mg daily. Response was defined as 3 components - at least a 50% reduction in steroid dose and at least a 25% reduction in total IgE and either an increase by at least 25% increase in exercise tolerance or pulmonary function tests or an absence of pulmonary infiltrates. The study was conducted in the USA in 57 patients, typically about 50 years old of whom 25 had bronchietasis as determined on chest X-rays. In the first phase of the study, 13 of 28 (46%) of patients receiving itraconazole responded compared with 5 or 27(19%) receiving placebo (p=0.04). Patients older than 50 were more likely to respond (p=0.045), as were those without bronchietasis as determined on chest X-rays. No relapses occurred on the lower dose in the second phase of the study in those who responded, and an additional 12 (36%) patients responded, 8 of whom had received placebo previously. Only a few isolates of Aspergillus were collected. Those that were resistant (MIC 6.25g/ml) or tolerant (MIC <6.25g/ml and MFC6.25g/ml) to itraconazole were associated with a lack of response to 200mg daily of itraconazole.
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).
Occasionally ABPA is not caused by Aspergillus but by other fungi such as Candida orTrichophyton. In these circumstances, if antifungal therapy is appropriate this should be guided by known activity of the agent against the fungus in question.