Molecular endotypes and manifestations of chronic rhinosinusitis

项目摘要：本项目研究的总体目标是检验炎症性疾病的假设 内型控制慢性鼻-鼻窦炎(CRS)的临床表现和并存的呼吸道疾病。CRS是 这是美国成年人中最常见的慢性病之一，影响了大约12.5%的美国人，以及 严重影响患者的生活质量和医疗成本。尽管CRS最常见的治疗方法是 对于抗生素、类固醇和过敏药物，它们的疗效并不是通用的。由于对以下问题反应不佳 在医学治疗方面，美国每年进行的外科手术超过40万例。因此，有一种 迫切需要对驱动CRS表型的致病机制有一个新的理解。慢性阻塞性肺疾病临床表现 分为CRS伴鼻息肉(CRSwNP)和CRS不伴鼻息肉(CRSsNP)。这两种形式都是 以强烈的炎性细胞渗透为特征，这会导致疾病的症状，但CRSwNP是 两者的更严重形式，以包括嗜酸性粒细胞增多症在内的II型炎症为特征。与之形成鲜明对比的是 CRSwNP，CRSsNP的炎症机制尚未得到充分的研究和了解，尽管事实是 超过75%的CRS患者具有这种表型。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患者确实表现出 1型炎症。因此，我们假设CRSsNP中的炎症比 CRSwNP，这会导致不同的医疗结果。在初步研究中，我们发现总体上 CRSsNP合并1型、2型和3型炎症的比例分别为21%、50%和27%。这 支持我们最初的假设，并表明针对单一内型的药剂不会 惠及所有CRSsNP患者。这个项目的一个中心假设是炎症性内型控制 CRS的临床表型和合并的呼吸道疾病，它们预测不同的预后 药物治疗。例如，我们已经获得了初步证据表明，类型2 炎症选择性地与嗅觉丧失和共病哮喘有关。此外，我们发现女性 CRSwNP患者的病情比男性CRSwNP患者更严重。因此，我们还假设性行为 影响CRS的内型、表型和并存疾病。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大学的流行病学)来测试这些 西北大学三级护理患者的假设，并在普通人群中验证我们的假设 盖辛格。目标1中的研究将确定CRSsNP主要内型的炎症机制。 AIM 2中的研究将检验CRS炎症内型控制临床表现和 影响下呼吸道疾病的共病。目标3中的研究将检验性别影响的假设 CRS的内生型和表型。我们相信，拟议的研究将有助于更准确地确定 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.