Airway surface mycosis in chronic TH2-associated airway disease

Abstract

Background Environmental fungi have been linked to T helper type 2 (Th2) cell-related airway inflammation and the Th2-associated chronic airway diseases asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and allergic fungal rhinosinusitis (AFRS), but whether these organisms participate directly or indirectly in disease pathology remains unknown. Objective To determine the frequency of fungus isolation and fungus-specific immunity in Th2-associated and non-associated airway disease patients. Methods Sinus lavage fluid and blood were collected from sinus surgery patients (n=118) including CRS patients with and without nasal polyps and AFRS and non-CRS/non-asthmatic control patients. Asthma status was deteremined from medical history. Sinus lavage fluids were cultured and directly examined for evidence of viable fungi. Peripheral blood mononuclear cells were restimulated with fungal antigens in an enzyme linked immunocell spot (ELISpot) assay to determine total memory fungus-specific IL-4-secreting cells. These data were compared to fungus-specific IgE levels measured from plasma by ELISA. Results Filamentous fungi were significantly more commonly cultured from Th2-associated airway disease subjects (asthma, CRSwNP, or AFRS: n=68) compared to non-Th2-associated control patients (n=31); 74% vs 16% respectively, p<0.001. Both fungus-specific IL-4 ELISpot (n=48) and specific IgE (n=70) data correlated with Th2-associated diseases (sensitivity 73% and specificity 100% vs. 50% and 77%, respectively). Conclusions The frequent isolation of fungi growing directly within the airways accompanied by specific immunity to these organisms only in patients with Th2-associated chronic airway diseases suggests that fungi participate directly in the pathogenesis of these conditions. Efforts to eradicate airway fungi from the airways should be considered in selected patients. Clinical Implications Airway fungi may contribute to the expression of sinusitis with nasal polyps and asthma, suggesting that efforts to eradicate fungi from the airways and environments of these patients should be considered.

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis

“…540,541 Some evidence suggests that IL-33 may play a role as well, but these studies have yet to demonstrate increased expression of this cytokine at the protein level in NP tissue. 374,[542][543][544] In regard to IL-25, evidence in CRS is scant. As mentioned earlier in this section EC chemokines also play a major role in the attraction and activation of innate effector cells including eosinophils, mast cells, neutrophils, macrophages, and likely ILCs.…”

“…372,373 The presence of fungi seen in the sinuses of CRS patients may be explained by delayed MCC, and may therefore be a downstream effect of inflammation rather than a cause. Although some studies have shown increased fungal loads in some CRS patients compared to controls, 374,375 others have revealed no difference in either prevalence rates of fungus or number of different fungi recovered. 361,376 Numerous studies, including multiple RCTs, have examined the role of antifungal treatment in CRS and none have shown a clinically meaningful improvement.…”

Role of Aspergillus fumigatus in Triggering Protease-Activated Receptor-2 in Airway Epithelial Cells and Skewing the Cells toward a T-helper 2 Bias

“…Porter et al recently reported that environmental fungi directly contribute to the pathogenesis of chronic Th2-related airway diseases (5). Recently, we have described the inhibition of IFN-β signaling through JAK-STAT1 by Aspergillus fumigatus (AF) in bronchial epithelium, resulting in reduced induction of CXCL10, also known as IFN-γ induced protein 10 (IP-10), a chemokine that attracts Th1 cells (6).…”

A Fungal Protease Allergen Provokes Airway Hyperresponsiveness in Asthma

“…Several factors may account for the presence of Alp 1 (and probably other protease allergens) in the bronchial submucosa in people with asthma but not in healthy people. Recent clinical studies have demonstrated higher rates of surface airway mycosis in subjects with asthma (74%) than in controls (16%), and fungal-induced T H 2 immunity is restricted to asthma 40 . Lungs of asthmatic subjects with Af sensitivity (positive skin prick test) may be more susceptible to germination of Af spores and have a higher burden of Af recoverable from sputum 41 .…”