Molecular endotypes and manifestations of chronic rhinosinusitis

项目总结：本项目研究的总体目标是检验炎症性 慢性鼻窦炎（CRS）的内型控制临床表现和共病气道疾病。CRS是 是美国成年人最常见的慢性疾病之一，影响约12.5%的美国人， 严重影响患者的生活质量和医疗费用。虽然CRS是最常见的治疗 对于抗生素、类固醇和过敏药物，它们的功效不是普遍的。由于反应不佳， 除了药物治疗外，美国每年进行超过400，000例外科手术。因此， 迫切需要对驱动CRS表型的致病机制有新的认识。CRS在临床上 鼻息肉可分为CRS伴鼻息肉（CRSwNP）和CRS不伴鼻息肉（CRSsNP）。两种形式都是 其特征在于强烈的炎性细胞浸润，这驱动了疾病的症状，但CRSwNP是 这两种疾病中更严重的一种，其特征是2型炎症，包括嗜酸性粒细胞增多症。相比 CRSsNP，CRSsNP中的炎症机制研究不足且知之甚少，尽管事实上 超过75%的CRS患者有这种表型。尽管来自欧洲的初步研究表明CRSsNP 以1型炎症为特征，我们发现只有一小部分CRSsNP患者表现出 1型炎症因此，我们假设CRSsNP中的炎症比CRSsNP中的炎症更异质。 CRSwNP，这会导致药物治疗的可变结果。在初步研究中，我们发现总体情况 CRSsNP伴1型、2型和3型炎症的频率分别为21%、50%和27%。这 支持了我们最初的假设，并表明靶向单一内型的药剂不会 对所有CRSsNP患者都有好处。该项目的一个中心假设是炎症内型控制 CRS和共病气道疾病的临床表型，并且它们预测CRS和共病气道疾病的可变结局。 药物治疗例如，我们已经获得的初步证据表明， 炎症选择性地与嗅觉丧失和共病哮喘相关。此外，我们发现， CRSwNP患者比CRSwNP男性患者的疾病更严重。因此，我们也假设， 影响CRS的内型、表型和共病。我们将与项目1合作 （西北大学的免疫病理学）和项目3（盖辛格和约翰霍普金斯的流行病学）来测试这些 在西北大学的三级护理患者中验证我们的假设，并在普通人群中验证我们的假设。 盖辛格目的1中的研究将鉴定CRSsNP的主要内型的炎症机制。 目的2中的研究将检验CRS的炎性内型控制临床表现的假设， 影响下呼吸道疾病的并发症。目标3中的研究将检验性别影响 CRS的内型和表型。我们相信，拟议的研究将有助于确定更准确的 有效预防CRS患者疾病并避免不必要治疗的药物策略。

PROJECT SUMMARY: The overall goal of the studies in this project is to test the hypothesis that inflammatory endotypes control clinical presentations and comorbid airway diseases in chronic rhinosinusitis (CRS). CRS is one of the most common chronic diseases in adults in the US, affecting approximately 12.5% of Americans, and has a severe impact on patients’ quality of life and healthcare costs. Although CRS is most commonly treated with antibiotics, steroids, and allergy medications, their efficacy is not universal. Due to poor responses to medical therapy, over 400,000 surgical procedures are performed annually in the US. There is therefore an urgent need for a new understanding of the pathogenic mechanisms that drive CRS phenotypes. CRS is clinically classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Both forms are characterized by intense inflammatory cell infiltration which drives symptoms of the disease, but CRSwNP is the more severe form of the two and is characterized by type 2 inflammation including eosinophilia. In contrast to CRSwNP, the mechanism of inflammation in CRSsNP is understudied and poorly understood, despite the fact that over 75% of CRS patients have this phenotype. Although initial studies from Europe suggested that CRSsNP is characterized by type 1 inflammation, we found that only a small subset of patients with CRSsNP did show type 1 inflammation. We therefore hypothesized that inflammation in CRSsNP is more heterogeneous than CRSwNP and this induces variable outcomes of medical treatment. In a preliminary study, we found the overall frequency of CRSsNP with type 1, 2 and 3 inflammation to be 21%, 50% and 27% of patients, respectively. This supports our initial hypothesis and suggests that a pharmaceutical agent targeting a single endotype will not benefit all patients with CRSsNP. A central hypothesis of this project is that inflammatory endotypes control clinical phenotypes of CRS and comorbid airway diseases, and they predict variable outcomes for pharmacological treatments. For example, we have obtained preliminary evidence showing that type 2 inflammation is selectively associated with smell loss and comorbid asthma. In addition, we found that females with CRSwNP have more severe disease than males with CRSwNP. We therefore also hypothesize that sex influences endotype, phenotype and comorbid diseases in CRS. We will collaborate with Project 1 (Immunopathology at Northwestern) and Project 3 (Epidemiology at Geisinger and Johns Hopkins) to test these hypotheses in tertiary care patients at Northwestern and to validate our hypothesis in the general population at Geisinger. Studies in Aim 1 will identify the mechanisms of inflammation for the major endotypes of CRSsNP. Studies in Aim 2 will test the hypothesis that inflammatory endotypes of CRS control clinical presentations and influence comorbidity of lower airway diseases. Studies in Aim 3 will test the hypothesis that sex influences endotype and phenotype of CRS. We believe that the proposed studies will help to identify more precise medicine strategy that effectively prevents disease in CRS patients and avoids unnecessary treatments.