Breakthrough mold infections during long-term Nebulized Liposomal Amphotericin B prophylaxis in lung transplant recipients: a single-center cohort (NEBULA study)

Introduction: Aspergillus spp. and other mold infections are the most common fungal infections in lung transplant recipients (LTR). There is no established antifungal preventive strategy for LTR; however, lifelong nebulized liposomal amphotericin B (n-LAB) prophylaxis has been used in our center. This study evaluated breakthrough mold infections (b-MI) and the tolerability of n-LAB prophylaxis in a LTR cohort. Methods: This observational retrospective study included all consecutive adult LTR who received n-LAB prophylaxis between August 2013 and March 2023. Participants were followed up for at least one year post-transplant unless they died earlier. Only proven and probable mold infections during n-LAB exposure were included in the study. Results: Among 802 LTR (median age: 57.8 years; 41.9% female), 821 transplants were performed. The incidence of b-MI within the first year post-transplantation was 8.7%. Over a median follow-up of 2.56 years (IQR 1.01-5.25), 94 LTR (11.7%) developed b-MI, comprising 111 episodes of infection. Independent risk factors for b-MI included bronchial stenosis, bronchial stent placement, and single lung transplant. Prophylaxis with n-LAB was well tolerated, with discontinuation owing to adverse events occurring in only 18 participants (2.2%). Mold colonization and b-MI were both associated with an increased risk of death, aHR 5.38 (95% CI: 3.24-8.94) and 14.07 (95% CI: 8.50-23.28), respectively. No difference in mortality was observed between the amphotericin B-non-susceptible isolates. Conclusion: Lifelong n-LAB prophylaxis was associated with a low incidence of mold infection during prolonged follow-up and maintained excellent tolerability. The emergence of amphotericin B-non-susceptible molds was not associated with increased mortality.