Allergic Bronchopulmonary Aspergillosis–A Luminal Hypereosinophilic Disease With Extracellular Trap Cell Death

Abstract

Allergic bronchopulmonary aspergillosis (ABPA) is characterized by an early allergic response and late-phase lung injury in response to repeated exposure to Aspergillus antigens, as a consequence of persistent fungal colonization of the airways. Here, we summarize the clinical and pathological features of ABPA, focusing on thick mucus plugging, a key observation in ABPA. Recent findings have indicated that luminal eosinophils undergo cytolytic extracellular trap cell death (ETosis) and release filamentous chromatin fibers (extracellular traps, ETs) by direct interaction with Aspergillus fumigatus. Production of ETs is considered to be an innate immune response against non-phagocytable pathogens using a “trap and kill” mechanism, although eosinophil ETs do not promote A. fumigatus damage or killing. Compared with neutrophils, eosinophil ETs are composed of stable and condensed chromatin fibers and thus might contribute to the higher viscosity of eosinophilic mucus. The major fate of massively accumulated eosinophils in the airways is ETosis, which potentially induces the release of toxic granule proteins and damage-associated molecular patterns, epithelial damage, and further decreases mucus clearance. This new perspective on ABPA as a luminal hypereosinophilic disease with ETosis/ETs could provide a better understanding of airway mucus plugging and contribute to future therapeutic strategies for this challenging disease.

Clinical relevance of Aspergillus fumigatus sensitization in cystic fibrosis

“…Both IL‐5 and IL‐13 are produced by TH‐2 cells and are key activators of eosinophils and IgE production. In this context, repeated A fumigatus exposure in sensitized patients may lead to massive accumulation of eosinophils and activated TH‐2 cells in the bronchial lumen that results in bronchial impaction, a hallmark of severe asthma and ABPA . Considerable evidence indicates that IgE sensitization to A fumigatus and/or colonialization of the respiratory tract by A fumigatus in asthmatic patients is associated with reduced lung function and severe disease .…”

“…In this context, repeated A fumigatus exposure in sensitized patients may lead to massive accumulation of eosinophils and activated TH-2 cells in the bronchial lumen that results in bronchial impaction, a hallmark of severe asthma and ABPA. 41,42 Considerable evidence indicates that IgE sensitization to A fumigatus and/or colonialization of the respiratory tract by A fumigatus in asthmatic patients is associated with reduced lung function and severe disease. 2,43,44 The important role of sIgE in response to A fumigatus is further highlighted by several clinical studies that show omalizumab as an interesting therapeutic strategy in ABPA, since it is associated with fewer side-effects compared to long-term corticosteroids.…”

Sialodochitis fibrinosa: Salivary duct obstruction by eosinophil extracellular traps?

“…Another recent study demonstrated that EETosis‐mediated CLCs directly promote inflammasome activation, Th2 lymphocyte priming, IgE synthesis and possible mucus plug formation in patients with asthma and patients with chronic rhinosinusitis (Persson et al., 2019). Thus, the pathological consequence of sialodochitis fibrinosa appears analogous to these “luminal hypereosinophilic diseases” (Ueki, Hebisawa, Kitani, Asano, & Neves, 2018).…”

Allergic Bronchopulmonary Aspergillosis

“…The pathogenesis of ABPA is attributed to mucoid impaction of the bronchi with fungal hyphae, eosinophilic pneumonia or bronchitis, and bronchocentric granulomatosis with tissue eosinophilia [13]. In the airways, septated hyphae with acute dichotomous branching is seen in the lumen without invasion of the mucosa.…”