Emerging Endotypes of Chronic Rhinosinusitis and Its Application to Precision Medicine

Abstract

Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory disease with various underlying pathophysiologic mechanisms which translate to endotypes, in contrast to clinical phenotypes or histological subtypes. Defining endotypes can help clinicians predict disease prognosis, select subjects suitable for a specific therapy, and assess risks for comorbid conditions, including asthma. Therefore, with recent advancement of biologicals in CRS clinical trials, endotyping can be a breakthrough in treating recalcitrant CRS. CRS is caused by dysregulated immunologic responses to external stimuli, which induce various inflammatory mediators from inflammatory cells, including innate lymphoid cells (ILCs) and T lymphocytes as well as epithelial cells. Thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33, which are mainly secreted by epithelial cells in response to external stimuli, act on type 2 ILCs and T helper 2 (Th2) cells, inducing IL-4, IL-5, and IL-13. Local immunoglobulin E (IgE) production is also a signature event in nasal polyps (NP). These inflammatory mediators are novel potential therapeutic targets for recalcitrant CRS. This article reviews recent publications regarding endotypes and endotype-based therapeutic strategies in CRS and NP.

Sentinels at the wall: epithelial‐derived cytokines serve as triggers of upper airway type 2 inflammation

“…36,37 Studies have implicated epithelial-derived cytokines, TSLP, IL-25, and IL-33, in a type-2 predominant eosinophilic endotype in asthma as well as CRS with nasal polyps. 38 …”

Airway epithelial barrier dysfunction in the pathogenesis and prognosis of respiratory tract diseases in childhood and adulthood

“…IL-4 and IL-3, cytokines associated with Th2-mediated immune response, and the epithelium-derived cytokines IL-25, IL-33, and Thymic stromal lymphopoietin (TSLP) have crucial roles in the pathogenesis of atopic asthma, allergic rhinitis (AR), and chronic rhinosinusitis (CRS). 10,11,17,40,41,42,43 Another important role of the epithelium lies in its relation to the underlying mesenchyme, and cytokine and growth factors are excreted as a result of the connection between these 2 structures; this superstructure is called the epithelial-mesenchymal trophic unit (EMTU). 44 Epithelial mesenchymal transition (EMT) is a process in which epithelial cells lose their epithelial character and gain mesenchymal properties.…”

Novel innate and adaptive lymphocytes: The new players in the pathogenesis of inflammatory upper airway diseases

“…CRS and AR are frequently associated with lower airway diseases, including asthma and chronic obstructive pulmonary disease (COPD) . Current treatment protocols for CRS include non‐specific management with antibiotics, corticosteroids and surgery, which leave us with substantial residual morbidity . Also, a considerable number of AR patients are unsatisfied with pharmaceutical medicines and even immunotherapy .…”

“…Particularly, AR and eosinophilic CRSwNP display a Th2‐dominated response . In recent years, biologic agents targeting Th2 pathway and IgE, including humanized anti‐IgE, anti‐IL‐5, and anti‐IL‐4 and IL‐13 receptor antibody, have shown promising effects for the treatment of AR and CRSwNP . These biologics relieve the symptoms and spare symptomatic drug use in AR patients, and shrink the polyps and reduce the need for surgery in patients with CRSwNP .…”

“…3 Current treatment protocols for CRS include non-specific management with antibiotics, corticosteroids and surgery, which leave us with substantial residual morbidity. 1,4 Also, a considerable number of AR patients are unsatisfied with pharmaceutical medicines and even immunotherapy. 2 Hence, there appears to be a compelling need for new approaches to treat CRS and AR.…”