Background and Epidemiology

Aspergillus is a genus of mold that is commonly found in soil and decaying organic material [1]. It is not the most prevalent fungi worldwide; however, it is one of the most ubiquitous with airborne conidia [1, 2]. The conidia are small enough in diameter to remain airborne both outdoors and indoors when released into the atmosphere. Analysis of air samples from various settings demonstrate that humans inhale hundreds of Aspergillus conidia daily [3–6]. The conidia reach the distal and terminal airways where they germinate and grow if a favorable environment is present. The pathogenicity of Aspergillus depends on the characteristics of the host. Allergic bronchopulmonary aspergillosis (ABPA) is a complex pulmonary disease resulting from an allergic immune response to Aspergillus, complicating the clinical course of patients with asthma or cystic fbrosis (CF). A similar syndrome called allergic bronchopulmonary mycosis (ABPM) can also occur with exposure to other mycoses.

In ABPA, germination of Aspergillus and growth of hyphae in the airways trigger an airway-centric T helper 2 (Th2) celland immunoglobulin E (IgE)-mediated hypersensitivity response, leading to bronchospasm and bronchiectasis. Patients with ABPA commonly present with wheezing, cough, and pulmonary infltrates with central bronchiectasis. These features are nonspecifc and overlap with other pulmonary diseases, which can lead to delays in diagnosis [7]. ABPA is often underdiagnosed, especially in areas with high rates of tuberculosis in which a misdiagnosis of ABPA as pulmonary tuberculosis may occur [8].

Patients with underlying airway diseases related to asthma and CF are most susceptible to ABPA. The prevalence of ABPA in patients with asthma widely varies depending on the region studied: Ireland 0.7% [9], New Zealand 3.5% [10], Saudi Arabia 2.7% [11], China 2.5% [12], Russia 4% [13], and North India 12.9–21.7% [14, 15]. A meta-analysis demonstrated a pooled prevalence of 12.9% of ABPA in patients with asthma in specialty referral clinics [16]. The global burden of ABPA is estimated to be 4.8 million patients of 193 million asthma patients according to a scoping review by Denning et al. [17].

The prevalence of ABPA appears to be higher in patients with CF than in those with asthma. As is the case with ABPA in asthma, the prevalence of ABPA in CF varies geographically. The Epidemiologic Registry of Cystic Fibrosis found a pooled ABPA prevalence of 7.8% in patients with CF in Europe [18]. The Epidemiologic Study of Cystic Fibrosis, a large multicenter observational registry from the United States and Canada, found a prevalence of 2% with a range of 0.9% in the southwestern region to 4% in the west [19]. Obtaining more defnite prevalence rates of ABPA is limited by the small number of studies and the inconsistency with

which diagnostic criteria are used. There is no clear gender predilection among all patients with ABPA; a male predominance was reported in one study of CF patients with ABPA, but this fnding was not replicated in another study [18, 20]. There are also rare cases of ABPA that have been reported in patients without asthma or cystic fbrosis including patients with chronic obstructive pulmonary disease (COPD) [21], sarcoidosis following in iximab therapy, [22] and previous tuberculosis [23, 24].

Pathophysiology

The pathophysiology of ABPA is complex, involving genetic alterations in innate and adaptive immunity in an allergic host and resulting in persistence of germinated Aspergillus in the airways. Although the pathogenesis of ABPA is incompletely understood, the continued presence of fungal hyphae, in turn, leads to T-lymphocyte activation and in ammatory cell recruitment with cytokine and immunoglobulin release. The resultant airway in ammation causes increased mucus production, bronchial hyperreactivity, and, over time, bronchiectasis and pulmonary fbrosis.

In people with an appropriate milieu of genetics and a predisposing condition, the presence of fungal hyphae in the airways leads to a robust hypersensitivity reaction. Aspergillus conidia lack immunogenicity due to the presence of a surface hydrophobin layer, which prevents recognition by the immune system [25]. Thick mucus in the airways as well as decreased mucociliary clearance in the case of patients with CF may disrupt the normal process of conidia removal, allowing the fungus to germinate into hyphae that are immunogenic [26]. Proliferation of Aspergillus leads to a high antigen burden. Aspergillus produces proteases that damage the airway epithelium, leading to desquamation and loss of the mechanical barrier [20, 27]. The proteases also induce the release of pro-in ammatory proteins such as interleukin (IL)-6, IL-8, and monocyte chemoattractant pro- tein-1 [27]. Serine protease activity in Aspergillus fumigatus has been shown to induce expression of the MUC5AC gene in bronchial epithelial cells, leading to mucin synthesis, which also contributes to decreased airway clearance [28]. Along with these events, the innate immune system responses lead to the release of further pro-in ammatory cytokines and chemokines with a signifcant in ammatory response [29].

Antigen-presenting cells such as dendritic cells process the fungal antigens for presentation and release a variety of specifc cytokines. Antigen presentation to naïve T lymphocytes in the bronchoalveolar lymphoid tissues primes and activates the T cells [30]. In ABPA, the T-cell response is polarized toward a Th2 phenotype [29]. The Th2 phenotype is not dependent on a specifc Aspergillus fumigatus antigen and