**1. Introduction**

Asthma is a chronic inflammatory disease of the airways that significantly impairs quality of life [1]. It is also characterized by a variety of clinical presentations and outcomes, which can be classified into different phenotypes [2]. A previous study has suggested that sensitization to fungal allergens is one of the proposed phenotypes [3]. Cumulative studies demonstrate that fungal sensitization in patients with asthma has been associated with increased asthma severity as well as worse clinical outcomes, including worse asthma control, decreased lung function, increased hospital and intensive care unit (ICU) admissions, respiratory arrest, and asthma-related deaths [4–8]. Although an association between

**Citation:** Lin, C.-H.; Li, Y.-R.; Kor, C.-T.; Lin, S.-H.; Ji, B.-C.; Lin, M.-T.; Chai, W.-H. The Mediating Effect of Cytokines on the Association between Fungal Sensitization and Poor Clinical Outcome in Asthma. *Biomedicines* **2022**, *10*, 1452. https://doi.org/10.3390/ biomedicines10061452

Academic Editor: Stanislawa Bazan-Socha

Received: 2 June 2022 Accepted: 17 June 2022 Published: 19 June 2022

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fungal sensitization and worse clinical outcomes is apparent, whether such an association is causal remains unconfirmed.

Fungal sensitization is an immune-mediated response to a fungus without evidence of inflammation or tissue damage [9]. In previous studies, both innate and adaptive immunity related to fungal sensitization in asthma. A review study indicated that allergic sensitization to fungi is mediated by the innate immune response driven by the innate lymphoid cells group 2 and the adaptive immune response driven by TH2 cells [4]. However, immune responses to fungi are mediated by a network of innate and adaptive immune cells, including but not limited to ILC2s and Th2 cells. Fairs A et al. show elevated levels of neutrophils in *A. fumigatus*-IgE–sensitized patients in comparison to non-sensitized patients with asthma, suggesting a Th1- or Th17-mediated immune response [6]. Moreover, an animal model of fungal-sensitized asthma found that IL-1Ra deficiency enhanced Th1 and Th17 immunity, increased neutrophil recruitment, and exacerbated disease [10,11]. Furthermore, a murine acute allergic asthma model demonstrated that sensitization with *A. fumigatus cpe* also elicited a higher percentage of IL-17AF+ eosinophil cells compared with OVA sensitization [12]. These studies reflected that fungal sensitization in asthma are associated with different type of immunological mechanism, including neutrophil, eosinophil, Th1, Th2, and Th17.

Cytokines, or intracellular signaling proteins, target specific cells causing consequences such as cell-mediated immunity and allergic responses [13–15]. Therefore, cytokines were chosen in order to investigate known cytokines of interest in asthma and to also examine the complex groups of Th1, Th2, Tregs, and Th17 representative cytokines. A previous study suggested that Th1, Th2, and Th17 immune responses relate to fungal sensitization in asthma; however, the cytokine profile of asthmatic patients who are sensitized to fungi is rare. Recent study reported that interleukin-33 levels were higher in severe asthmatic patients with fungal sensitization than in those without fungal sensitization. However, the study only analyzed the association between multiple fungal sensitization and cytokine, the relationship between species-specific sensitization to fungi and cytokines was not revealed [16].

To understand the immunological mechanism between fungal sensitization and asthma is vital for devising therapeutic interventions to prevent worse outcomes. In this study, we aimed to determine role of cytokines in the relationship between fungal sensitization and worse clinical outcomes in asthma. Firstly, we analyzed the cytokine profile regarding Th1, Th2, and Th17 immune response associated with sensitization to specific fungi species. Secondly, we evaluate the role of cytokine in the association between fungal sensitization and measures of disease control and worsen outcomes in asthma.
