The Real-World Effectiveness of Antifungals in People with Cystic Fibrosis and <i>Aspergillus</i> -Positive Cultures

<b>Rationale:</b> The pathogenicity of <i>Aspergillus</i> in the cystic fibrosis (CF) airway is debated, leading to unclear clinical benefit of antifungal therapy for <i>Aspergillus</i> infection. <b>Objective:</b> To determine the real-world effectiveness of antifungal use in people with CF (PwCF) with <i>Aspergillus</i> species in the United States. <b>Methods:</b> We conducted a retrospective cohort study evaluating the association of antifungal use and respiratory outcomes in PwCF and <i>Aspergillus</i>-positive cultures using the Cystic Fibrosis Foundation Patient Registry. Marginal structural models using inverse-probability treatment weighted estimators were used to test whether antifungal exposure was associated with forced expiratory volume in 1 second percent predicted (FEV₁pp) and pulmonary exacerbation rate while controlling for fixed and time-varying confounders. We conducted sensitivity analyses on individuals with persistent <i>Aspergillus</i> and without concomitant allergic bronchopulmonary aspergillosis (ABPA). <b>Results:</b> A total of 14,754 individuals with <i>Aspergillus</i>-positive cultures between 2006 and 2019 were identified. Antifungals were prescribed to 3,575 (24.2%) unique PwCF during the study period. Antifungal use was not associated with FEV₁pp (adjusted estimate = -0.96 percentage points; 95% confidence interval [CI] = -2.21, 0.29). Antifungal use was associated with 29% increased rate of pulmonary exacerbations requiring intravenous (i.v.) antibiotics (adjusted incidence rate ratio = 1.29, 95% CI = 1.22, 1.37). In sensitivity analyses limited to individuals without ABPA, antifungals were associated with 1.88 lower FEV₁pp (95% CI = -3.35, -0.41) and an increased rate of pulmonary exacerbations (adjusted incidence rate ratio = 1.30; 95% CI = 1.21, 1.40), whereas in patients with persistent <i>Aspergillus</i> and persistent <i>Aspergillus</i> without concomitant ABPA, antifungals were not associated with FEV₁pp. <b>Conclusions:</b> Antifungal therapy in PwCF and <i>Aspergillus</i>-positive cultures was not associated with improvements in FEV₁pp, suggesting no observed benefit. Although antifungal therapy was associated with increased risk for pulmonary exacerbations, this could reflect confounding by severity of disease. Randomized clinical trials examining the clinical efficacy of antifungals in <i>Aspergillus</i> infections in CF are warranted.