*Article* **The Mediating Effect of Cytokines on the Association between Fungal Sensitization and Poor Clinical Outcome in Asthma**

**Ching-Hsiung Lin 1,2,3,4,\*, Yi-Rong Li 5, Chew-Teng Kor 6,7, Sheng-Hao Lin 1,4,5, Bin-Chuan Ji 1, Ming-Tai Lin <sup>1</sup> and Woei-Horng Chai <sup>1</sup>**


**Abstract:** Sensitization to fungal allergens is one of the proposed phenotypes in asthma. An association between fungal sensitization and worse clinical outcomes is apparent. Moreover, fungal sensitization in asthma that is associated with different type of immunological mechanism has been reported. How the role of cytokines mediates the association between fungal sensitization and poorer asthmatic outcomes remains unclear. We aimed to determine role of cytokines in the relationship between fungal sensitization and worse clinical outcomes in asthma. Method: We conducted a prospective study to recruit adult patients with asthma. Data including age, sex, height, weight, smoking history, medication, emergency visit and admission, pulmonary function testing result, and Asthma Control Test (ACT) scores were collected. We used the automated BioIC method to measure fungal allergen sIgE in sera. Serum levels of Interleukin (IL) -4, IL-13, IL-6, IL-9, IL-10, IL-17 A, IL-22, Interferon (IFN) -γ, Immunoglobulin E (IgE), Tumor necrosis factor-α (TNF-α), and Transforming growth factor-β (TGF-β) were measured using ELISA. Result: IL-6 and IL-17A had a significant positive correlation between sensitization and most fungi species compared to IgE. Sensitization to *Candida albicans* had strongly positive association both with IL-6 and IL-17A. However, only IL-17A had significant relationship with ED visit times. The mediation analysis result indicates that IL-17A had a significant positively mediating effect (ME) on the association between *Candida albicans* and ED visit times. Conclusion: IL-17A is a potential mediator to link *Candida albicans* sensitization and ED visits for asthma. We suggest that patients with fungal sensitization, such as *Candida albicans*, have poorer outcomes associated with Th17-mediated immune response rather than Th2.

**Keywords:** asthma; fungal sensitization; IL-17A; *Candida albicans*; mediation effect
