We are at the cusp of a paradigm shift in conceptualizing treatment of CRSwNP, especially eosinophilic disease, as not a surgical one but perhaps in some patients better managed with medications alone or in combination with an immunomodulatory therapy. Tomatidine Omalizumab, mepolizumab, reslizumab, and benralizumab are FDA approved (2003, 2015, 2016, and 2017 respectively) for the treatment of severe subsets of asthma (allergic or concomitant eosinophilia) and dupilumab as a treatment for moderate-to-severe atopic dermatitis (2017). antibody therapies have shown encouraging results and phase 3 trials are underway. IL-4/IL-13 inhibition has shown the most promise to date. Further larger, well-designed trials are needed to improve understanding of these molecules and to offer endotype-driven therapies in the management of Rabbit Polyclonal to OR52E4 CRS. None of these therapeutics have shown long-term immunomodulation when discontinued and therefore further investigation into the pathomechanism of disease continues to be needed. no polyps) to disease endotype is still in its infancy. The endotype explains the pathomechanism which allows for differentiation of disease subtypes at a functional and pathologic level based on molecular and cellular characteristics.4 Understanding the differences in, for example, T-helper cell populations, cytokine composition, and downstream effectors can help to delineate these endotypes and hopefully lead to more effective, precise therapy. The recent application of biologic therapies that modulate immune effectors in eosinophilic CRS show promising results and are currently changing the way CRS therapy is usually conceptualized. Currently CRS is usually divided into two subtypes, with nasal polyposis (CRSwNP) and without nasal polyposis (CRSsP). CRSwNP has a 20%C60% association with comorbid asthma and has a poorer prognosis with recurrence rates of 38C60% at 12 months.5, 6, 7, 8 In Western Caucasian patients, there is a Th2 inflammatory response with production of IL-4, IL-5, and IL-13 with corresponding predominance of eosinophilia, mast cells, and basophils while in Asian CRSwNP, neutrophilic predominance has been observed with Th1, Th17, or Th22 inflammatory responses.9 IL-4 and IL-13 Tomatidine play a role in IgE isotype switching and upregulate sIgE receptors on eosinophils, mast cells, monocytes and basophils. IL-4 is also responsible for inflammatory cell chemotaxis with upregulation of vascular cell adhesion molecule-1 (VCAM-1). IL-5 plays a role in maturation, differentiation and activation of eosinophils and IL-5 and IL-13 are also involved in the innate immune epithelial responses. The Th-2 inflammatory response in CRSwNP is usually further amplified by the epithelial cell-activated type 2 innate lymphoid cells (ILC2s). These cells are early responders within the sinonasal mucosal and are activated by local epithelial factors (thymic stromal lymphopoietin (TSLP), IL-33 and IL-25).10, 11, 12 Other subtypes of CRS include allergic fungal rhinosinusitis (AFRS) and aspirin exacerbated respiratory disease (AERD). AFRS is usually characterized by an IgE-mediated hypersensitivity to fungus and presents with variable severity, from unilateral disease to pan-sinus involvement with fungal debris, polyps and eosinophilic mucin.13 It appears that serum-specific IgE levels have been shown to correlate with disease severity.14 The pathogenesis of AFRS is incompletely understood, but a local epithelial response triggered by fungus, Tomatidine and possibly August 20, 2018). Cytokines and Fc fusion proteins may also serve as targets in the future for the treatment of CRS either by recombinant therapies, competitive inhibition, or direct receptor stimulation. RNA molecules also show promise using small double-stranded RNA, antisense oligonucleotides, kinase inhibitors, and antichemokine strategies. These strategies have not yet made their way into the treatment of CRS but it is possible that targeting these inflammatory pathways maybe effective. Conversation Advanced immunomodulatory therapies are just on the horizon for the treatment of CRSwNP. We are at Tomatidine the cusp of a paradigm shift in conceptualizing treatment of CRSwNP, especially eosinophilic disease, as not a surgical one but perhaps in some patients better.