Chronic Pulmonary Aspergillosis

This study evaluates and aims to optimize inhalation treatment with nebulized liposomal amphotericin B in patients with chronic pulmonary aspergillosis. The primary objective is to assess the pulmonary deposition and intrapulmonary distribution of liposomal amphotericin B after nebulization, using technetium-99m-labeled liposomal amphotericin B and SPECT/CT imaging. The study also aims to generate data to inform optimization of inhalation treatment design. Participants will receive two different doses of nebulized liposomal amphotericin B (12 mg and 24 mg) on separate study days. After each administration, participants will undergo SPECT/CT imaging to assess pulmonary deposition. Blood samples will be collected on both study days and after study treatment to evaluate safety and measure systemic amphotericin B concentrations. Participants will also perform spirometry using a handheld device and complete a treatment satisfaction questionnaire on both study days.

While ABPA and CPA represent two distinct manifestations of Aspergillus-related lung disease, there is an overlap of investigations that are currently used for the diagnosis of these entities. In a previous study, the authors have demonstrated that 22% of subjects with CPA fulfilled the obligatory criteria for ABPA. While the preferable therapy in patients with ABPA is systemic glucocorticoids, the primary therapy in CPA is oral triazoles. However, a different management protocol in the "overlap group" with low doses of glucocorticoids and triazoles, needs to be systematically explored. In this study the investigators intend to compare the clinical outcomes in subjects with ABPA-CPA overlap treated either with oral azoles or a combination of systemic glucocorticoids and oral azoles.

To develop and validate a novel disease-specific questionnaire for measuring HRQoL in patients with Chronic Pulmonary Aspergillosis (CPA-HAQ) for use in clinical research, including clinical trials.

This study compares the therapeutic (clinical and radiological) efficacy of a six-month treatment by itraconazole and nebulised Ambisome® (liposomal amphotericin B = LAmB) versus treatment by itraconazole alone, in non - or mildly - immunocompromised patients affected by Chronic Pulmonary Aspergillosis (single aspergilloma excluded). • Control arm: Itraconazole 200 mg x 2/day associated with inactive nebulised treatment twice a week during 24 weeks. • Experimental arm: Itraconazole 200 mg x 2/day associated with nebulised LAmB, at 25 mg twice a week during 24 weeks. Follow up duration for the patients will be 24 months (12 months minimum) after discontinuation of the treatment being studied.

The treatment of CPA is with oral itraconazole for 6-12 months. Oral itraconazole results in better clinical outcomes in CPA compared to supportive care. A recent study comparing 6 months with 12 months of oral itraconazole for longer duration treatment found longer duration reduced CPA relapse and improved clinical outcomes. However, longer duration of itraconazole could cause emergence of drug resistant Aspergillus fumigatus and therapy related adverse event. A recent study found nebulized amphotericin B non-inferior to oral itraconazole for treating CPA as primary therapy. However, the study was small and included patients with simple aspergilloma and used nebulized amphotericin B for 7 days.To be effective, an inhaled drug should be delivered in sufficient quantity to achieve therapeutic levels.The minimum inhibitory concentration of amphotericin B for A.fumigatus is 0.5 mg/L. In one study, nebulization of 30 mg of amphotericin B deoxycholate achieved a mean concentration of 0.68 mg/L in the bronchoalveolar lavage fluid. Notably, the serum levels of amphotericin B after nebulization are 20 times less than after systemic administration and is safer. Further, there is a dose-response relation with nebulized amphotericin B, the higher the dose used for nebulization, the higher are the levels achieved in the lung tissue. Nebulized amphotericin B has been used in lung transplant recipients to prevent invasive aspergillosis. Also, two recent studies have demonstrated that use of nebulized amphotericin B as maintenance therapy led to a reduction in ABPA relapse rates and prolonged time to exacerbation. We believe that inhaled amphotericin B as a maintenance therapy could reduce CPA relapse and prolong time to relapse. In this study, we plan to evaluate nebulized amphotericin B as a maintenance therapy in clinically stable CPA patients treated with 12 months of oral antifungal therapy