Critique of trials in allergic bronchopulmonary aspergillosis and fungal allergy

Treatment of allergic bronchopulmonary aspergillosis (ABPA) emerged from uncontrolled published series of patients on prolonged oral glucocorticosteroids. Oral steroids remain the mainstay of treatment, but dose regime and duration have never been standardized. Oral steroids are problematic due to frequency of relapse, lack of steroid action on airway fungal burden and toxicities. Prospective randomized double-blind placebo-controlled trials of inhaled corticosteroids (n = 1) or oral itraconazole (n = 2) in patients with asthma and ABPA have shown efficacy for the latter drug only. Itraconazole is an effective steroid-sparing agent with anti-inflammatory aspects. Use of inhaled budesonide with itraconazole can lead to adrenal suppression due to inhibition of hepatic cytochrome P450. Despite combined use of oral steroids and itraconazole in ABPA, relapses and steroid dependence or toxicity have led to examination of alternative agents in uncontrolled case reports and series. Reports of nebulized amphotericin B in several patients with cystic fibrosis (CF) and ABPA suggest a potential benefit. Voriconazole has also been used with some success but also some toxicity. Both itraconazole and voriconazole have also been used in some CF-ABPA patients as monotherapy with mixed results. A recent report described treatment of refractory CF-ABPA with monthly high-dose intravenous (IV) methylprednisolone, also with mixed results. No controlled trials of voriconazole, inhaled amphotericin, or IV pulse steroids have been published. Future studies should focus on controlled trials of antifungal and immunomodulatory agents since conventional steroid therapy remains problematic.