occurs irrespective of which Aspergillus antigen is recognized [31]. Th2 cells release IL-4, IL-5, and IL-13, which causes an in ux of additional in ammatory cells such as neutrophils, eosinophils, and mast cells [27]. IL-4 is associated with B-cell isotype conversion to immunoglobulin E production. IL-4 and IL-13 increase expression of the vascular cell adhesion molecule-1 (VCAM-1) protein on endothelial cells, which increases recruitment of eosinophils and other immune cells and enhances IgE and IgA Fc receptor expression on eosinophils [29, 32]. Locally produced IgE activates mast cells. The degranulation of mast cells and eosinophils results in vasodilation and bronchoconstriction [29].

Host Characteristics

ABPA predominantly af icts patients with underlying airway diseases, such as asthma or CF. Although the prevalence rate of ABPA among patients with CF is higher than that among patients with asthma, more patients with ABPA have asthma as their comorbidity, given the much higher background prevalence of asthma in the general population.

Aspergillus is ubiquitous in the environment and frequently inhaled, yet only a small fraction of patients with asthma or CF develop ABPA [3–6, 17–19]. The reason for this remains unclear, but genetic attributes are believed to contribute to ABPA risk. A study of 164 patients with asthma and ABPA demonstrated a familial rate of 4.9% of ABPA in frst-degree relatives [33]. Gene association studies have demonstrated an association between ABPA and single-­ nucleotide polymorphisms in the following genes: IL4RA [34, 35], IL10 [36], IL13 [35], TLR3 [35], TLR9 [37], MBL2 [38], and SP-A2 [39]. Mutations in the cystic fbrosis transmembrane conductance regulator (CFTR) gene have also been associated with ABPA [40]. There is a higher-than-­ expected frequency of F508 mutations in patients with non-CF-related ABPA compared to that in the general population [41]. A study by Chauhan et al. found that allelic diversity in the major histocompatibility complex class II genes for human leukocyte antigen (HLA)-DR2 and HLA-DR5 contributes to the susceptibility to ABPA, whereas the HLA-DQ locus may confer resistance to the development of ABPA [42]. Taken together, these studies suggest a complex relationship between potentially multiple genetic factors in a host genetically susceptible to developing ABPA.

Beyond genetic risk factors, most patients also have concomitant atopy including allergic rhinitis and atopic dermatitis in addition to asthma or cystic fbrosis [32].

Asthma often presents in childhood, but ABPA associated with asthma is largely a disease of adulthood [33]. Although speculative, aging-related changes in airway function and immune responses, or airway damage accumulated over many years of disease, may contribute to the higher risk in

adulthood. Age of onset for ABPA associated with CF is more variable; childhood disease is observed but in one study was rare among patients younger than 6 years of age [18]. Historically, patients with CF had a reduced life expectancy, and reaching adulthood was uncommon. With dramatic improvements in clinical care, many patients with CF now reach adulthood with the average life expectancy ranging from 37 to 40 years of age [43]. Updated studies documenting the burden of ABPA among adults with CF are needed and will be illuminating with regard to the role of age in ABPA risk.

The regional rates of ABPA in asthma vary around the world [44]. Yet, when corrected for variations in the background rates of asthma, geography and other environmental factors have not been shown to vary the risk of ABPA. Aspergillus spores are ubiquitous in the environment around the globe and are virtually impossible to avoid. Even as environmental conditions differentially promote fungal growth and aerosolization of spores, the fnding that geography is not implicated as an asthma-independent risk factor for asthma-associated ABPA argues against a dose-dependent effect of exposure in most cases. More comprehensive global surveys, which compare ABPA rates among patients with asthma according to the geographic region, are necessary to confrm this. These fndings in asthma are in contrast to those in CF, in which regional differences in the prevalence of ABPA have been demonstrated, although not explained [19]. Modeling, which incorporates predicted climate changes, indicates that sensitization to fungal antigens may increase. Fungal spore production increases with increased environmental CO2 concentrations [45]. Therefore, it will be important to track the incidence of ABPA in coming years and continue surveillance for the role of environmental factors in the development of allergic fungal pulmonary diseases.

Clinical Manifestations

Symptoms

The symptoms of asthma and CF typically worsen with the development of ABPA. Accordingly, patients with ABPA can present with new or worsening cough, shortness of breath, wheezing, and increase in sputum production [46, 47]. Patients may also develop fevers, fatigue, and weight loss. Thick, viscous mucus production is common with expectoration of tan to brownish black mucus plugs noted in some but not all patients. Hemoptysis secondary to airway in ammation and bronchiectasis can occur. Patients may experience mild or minimal symptoms but may otherwise present with immunological and radiographic signs, which support a diagnosis of ABPA [48]. ABPA should be suspected in patients with diffcult-to-control or corticosteroid-­