To the Editors:
Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disorder that results from a hypersensitivity reaction to Aspergillus spp. It has been estimated to occur in 1–3% of people with chronic asthma and 2–15% of those with cystic fibrosis [1]. The natural history of ABPA is characterised by exacerbations that can threaten the patient’s survival and prognosis [1]. Repetition of such exacerbations is responsible for the development of bronchiectasis, permanent obstructive ventilation defect or fibrotic lung lesions. Prognosis mainly depends on the very early treatment of exacerbations before bronchiectasis sets in. In 2008, the guidelines of the Infectious Diseases Society of America advised combination therapy in ABPA [2]: systemic glucocorticoids to limit the inflammatory component and antifungals to limit mycelium proliferation. However, even though glucocorticoid therapy and antifungals are the treatment of choice for acute-stage ABPA and exacerbations, there are no data to guide the duration of this treatment. Therefore, the current objectives for the management of ABPA are a decrease in the frequency and duration of exacerbations, and a limited solicitation of glucocorticoids. Consequently, the maintenance treatment in the management of ABPA remains a current and progressive problem for pneumologists.
We describe a case of ABPA that was difficult to control using the standard treatment regimen, but which improved dramatically and durably following administration of nebulised liposomal amphotericin B (LAmB).
In May 2010, a 67-yr-old female presented with fever and productive cough, with sputum plugs and a history of epilepsy treated with phenobarbital. In the preceding 3 months, she had presented recurrent chest infections resistant to amoxicillin and ciprofloxacin; glucocorticoids (1 mg·kg−1·day−1 prednisolone for 2 weeks) had been started without any clear improvement.
At that time, ABPA was suspected. A thoracic computed tomography (CT) scan showed right upper lobe consolidation with a bronchocele and the patient’s absolute eosinophil count was 1,170 cells·μL−1. Further investigations showed increased total immunoglobulin (Ig)E (1,154 IU·mL−1) and specific anti-Aspergillus fumigatus IgE levels (12.9 kU·L−1), and the presence of specific anti-A. fumigatus precipitins in the serum (four lines). Corticosteroids were maintained for 2 weeks (1 mg·kg−1·day−1), after which the dose was reduced (5-mg decrease every 2 weeks) and itraconazole was added (200 mg b.i.d.).
After 4 weeks of treatment, the patient’s clinical status deteriorated and new consolidations appeared on the CT scan (fig. 1a and b); due to phenobarbital interaction, plasma itraconazole concentration was very low, so itraconazole treatment was withdrawn. The patient was therefore treated with the following regimen: prednisolone (0.5 mg·kg−1·day−1 for 2 weeks, then reduced by 5 mg every 2 weeks until discontinuation), associated with nebulisations of LAmB (25 mg twice weekly) until steroids were stopped, followed by a maintenance dose of LAmB (25 mg once weekly) to prevent subsequent ABPA exacerbations. As shown on figure 1c and d, the patient improved dramatically and durably, with a significant decrease in eosinophil count, precipitins and total and specific IgE levels over time (values after 6 months of LAmB were 370 cells·μL−1, two lines, 133 IU·mL−1 and 3.05 kU·L−1, respectively, and 6 months after discontinuation of LAmB were 310 cells·μL−1, two lines, 236 IU·mL−1 and 3.28 kU·L−1, respectively). After 2 months of this regimen, prednisolone was stopped and nebulised LAmB continued (25 mg once weekly) for 6 months as maintenance therapy. In our case, clinical and radiological improvement accompanied that of biological values, without any side-effects.
Systemic glucocorticoids are the treatment of choice for acute ABPA and exacerbations of ABPA. The Cystic Fibrosis Foundation Consensus Conference on ABPA did not propose a specific treatment plan [1]. Two small, uncontrolled clinical trials evaluated glucocorticoids in ABPA with different glucocorticoid regimens that varied in doses and durations (from 2 to 6 months) [2]. Short-term glucocorticoids reduced the number of exacerbations and improved lung function, but caused long-term side-effects (diabetes, dyslipidaemia and osteopenia) and exposed patients to the risk of severe infection (ABPA progression to invasive pulmonary aspergillosis).
Systemic antifungal treatments have been recommended in association with glucocorticoids: the objective being the attenuation or even the eradication of the intrabronchial Aspergillus burden, in order to decrease or stop glucocorticoid therapy. Itraconazole is the antifungal agent of choice for this indication, according to the results of two randomised controlled trials showing the superiority of the antifungal arm [2]. Itraconazole doses varied from 200 to 400 mg·day−1 and follow-up did not extend beyond the 16-week treatment period. Furthermore, itraconazole use also raises several issues, such as drug interactions and hepatic toxicity [3]. In our case, the absence of relapse 12 months after steroid discontinuation could indicate that the addition of nebulised LAmB to oral glucocorticoids would be more effective for controlling ABPA exacerbations than steroids alone, as shown with itraconazole. Indeed, the addition of itraconazole to oral glucocorticoids decreases the number of ABPA exacerbations compared with glucocorticoids alone (mean±sem 0.93±0.4 versus 2.4±0.2 exacerbations per patient and per year, respectively) [4].
The first stage in the pathogenesis of ABPA includes the inhalation of Aspergillus spp. spores, the colonisation of the airways by germinated Aspergillus and its proliferation in airway mucus. The administration of an antifungal treatment by inhalation could provide a new, simple therapeutic approach consistent with the pathophysiology of ABPA. Nebulised LAmB has been proposed to prevent invasive fungal infections in heart and/or lung transplant patients, and to cure patients refractory to conventional treatment [5]. A randomised, placebo-controlled trial performed in neutropenic patients demonstrated a dramatic reduction of invasive aspergillosis with 12.5 mg LAmB administered twice weekly (14% and 4% in the placebo and LAmB groups, respectively) [6]. In a cohort study of 27 lung transplant patients, a single weekly administration of nebulised LAmB (25 mg) yielded levels of amphotericin B in patient bronchoalveolar lavage that were high enough to inhibit growth of Aspergillus spp. (>2 μg·mL−1), which persisted for 2 weeks [7]. Furthermore, nebulised LAmB tolerance has been reported as being quite satisfactory, particularly since the use of lipid formulations, which contain phospholipids and cholesterol that have properties similar to those of the natural surfactant [8]. Nebulised LAmB also decreases the risk of drug interactions observed with azoles. It allows higher lung tissue concentrations (compared with systemic administration) and only limited passage into blood plasma, as demonstrated by almost undetectable serum concentrations after administration of nebulised LAmB [7]. Finally, data regarding the efficacy of nebulised amphotericin B in ABPA are based on a few case reports; these suggest biological and clinical efficacy along with the possibility of reducing oral prednisolone doses, although they did not consider liposomal formulations [8, 9].
Yet another problem is the emergence of azole resistance and the use of a fungicide, such as nebulised AmBisome® (Astellas Pharma US Inc., Deerfield, IL, USA), could be of interest in limiting the risks of emerging azole-resistant strains and subsequent failure to respond to therapy [10].
In conclusion, this particular case demonstrates the efficacy of nebulised LAmB in controlling prednisolone-dependent ABPA. No relapse occurred 12 months after discontinuation of glucocorticoid therapy when nebulised LAmB had been continued as maintenance therapy for 6 months. In our opinion, in an attempt to reduce recourse to systemic glucocorticoid therapy and because the emergence of azole-resistance of Aspergillus is becoming a major concern, nebulised LAmB may have a place in the treatment of acute exacerbations of ABPA and, possibly, in the prevention of ABPA exacerbations. However, the efficacy and the safety of this treatment should be further investigated in a phase II prospective trial.
Footnotes
Statement of Interest
Statements of interest for C. Godet and J. Cadranel can be found at www.erj.ersjournals.com/site/misc/statements.xhtml
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