Allergic Bronchopulmonary Aspergillosis (ABPA) in the Era of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators

Abstract

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disease caused by Aspergillus fumigatus (Af), prevalent in persons with cystic fibrosis (CF) or asthma. In ABPA, Af proteases drive a T-helper cell-2 (Th2)-mediated allergic immune response leading to inflammation that contributes to permanent lung damage. Corticosteroids and antifungals are the mainstays of therapies for ABPA. However, their long-term use has negative sequelae. The treatment of patients with CF (pwCF) has been revolutionized by the efficacy of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Pharmacological improvement in CFTR function with highly effective elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes of pwCF. The mechanism behind the improvement in patient outcomes is a continued topic of investigation as our understanding of the role of CFTR function evolves. As ETI therapy gains traction in CF management, understanding its potential impact on ABPA, especially on the allergic immune response pathways and Af infection becomes increasingly crucial for optimizing patient outcomes. This literature review aims to examine the extent of these findings and expand our understanding of the already published research focusing on the intersection between ABPA therapeutic approaches in CF and the rapid impact of the evolving CFTR modulator landscape. While our literature search yielded limited reports specifically focusing on the role of CFTR modulator therapy on CF-ABPA, findings from epidemiologic and retrospective studies suggest the potential for CFTR modulator therapies to positively influence pulmonary outcomes by addressing the underlying pathophysiology of CF-ABPA, especially by decreasing inflammatory response and Af colonization. Thus, this review highlights the promising scope of CFTR modulator therapy in decreasing the overall prevalence and incidence of CF-ABPA.

Keywords: Aspergillus fumigatus; Aspergillus proteases; CFTR modulators; Th2 immune pathway; allergic bronchopulmonary aspergillosis; allergic inflammation; asthma; cystic fibrosis; elexacaftor–tezacaftor–ivacaftor (ETI).

Figure 1

Pathophysiology of ABPA. Detailed framework involving the molecular and cellular elements of the local innate response to Aspergillus in driving a T-helper cell-2 (Th2) adaptive immunity in the airway exposed to fungal protease allergens. Figure created with BioRender.com.

Figure 2

Computed tomography (CT) of chest. The CT chest of a pediatric patient with cystic fibrosis complicated by allergic bronchopulmonary aspergillosis showing: (A) bronchiectasis with the hallmark findings of dilated bronchi with bronchial wall thickening (blue arrows) and tree-in-bud pattern opacities (green arrow) indicating terminal airway mucus impaction and peribronchiolar inflammation; and (B) “finger in glove sign” (red arrow) characterized by tubular opacification resulting from mucus plugging of branching dilated bronchioles.

Figure 3

Schematic diagram of possible mode of actions for CFTR modulators on CF-ABPA. Possible positive impacts of CFTR modulators are represented by blue arrows and possible negative impacts are represented in purple blunt head arrows, which implicates the indirect but favorable effects (represented by blue dotted line) of CFTR modulators on CF-ABPA.