Pathogenesis of Nasal Polyposis.docx

1、Pathogenesis of Nasal PolyposisPathogenesis of Nasal PolyposisKathryn E. Hulse, PhD1*, Whitney W. Stevens, MD, PhD1, Bruce K. Tan, MD2, Robert P. Schleimer, PhD1,21Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL USA; 2Departmen

2、t of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA*Corresponding author: Dr. Kathryn E. Hulse, Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine, 240 E. Huron St., McGaw Rm M-302, Chicago, IL, 60611, USA.Tel.: 312-503-2854Fax:

3、 312-503-0078Email: k-hulsenorthwestern.eduFunding: NIH R37 HL068546, R01 HL078860, R01 AI072570, P01 106683-01, K12HD055884, T32 AI083216-04, K23 DC012067 and the Ernest S. Bazley TrustAbstractChronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory condition that affects a large

4、 proportion of the population worldwide and is associated with high cost of management and significant morbidity. Yet, there is a lack of population-based epidemiologic studies using currentdefinitions of CRSwNP, and the mechanisms that drive pathogenesis in this disease remain unclear.In this revie

5、w, we summarize the current evidence for the plethora of factors that likely contribute to CRSwNP pathogenesis. Defects in the innate function of the airway epithelial barrier, including diminished expression of antimicrobial products and loss of barrier integrity, combined with colonization by fung

6、i and bacteria likely play a critical role in the development of chronic inflammation in CRSwNP. This chronic inflammation is characterized by elevated expression of many key inflammatory cytokines and chemokines, including IL-5, thymic stromal lymphopoietin, and CCL11, that help to initiate and per

7、petuate this chronic inflammatory response. Together, these factors likely combine to drive the influx of a variety of immune cells, including eosinophils, mast cells, type 2 innate lymphoid cells and lymphocytes, which participate in the chronic inflammatory response within the nasal polyps. Import

8、antly however, future studies are needed to demonstratethe necessity and sufficiency of these potential drivers of disease in CRSwNP. In addition to thedevelopment of new tools and models to aid mechanistic studies, the field of CRSwNP researchalso needs the type of robust epidemiologic data that ha

9、s served the asthma community so well. Given the high prevalence, costs, and morbidity, there is a great need for continued research into CRS that could facilitate the development of novel therapeutic strategies to improve treatment for patients that suffer from this disease.IntroductionThe purpose

10、of this review is to summarize the current state of knowledge regarding the pathogenesis of nasal polyposis. In this review, we focus on chronic rhinosinusitis with nasal polyps (CRSwNP), rather than other conditions associated with nasal polyp formation such as antrochoanal polyps, cystic fibrosis

11、or allergic fungal sinusitis, due to the significantly higher prevalence and associated costs of management of CRSwNP.Epidemiology of CRSwNPChronic rhinosinusitis (CRS) is characterized by the presence of four cardinal symptoms: nasal obstruction, drainage, smell loss and facial pain or pressure, wh

12、ich last for at least three months. In some patients with CRS, exuberant hyperplastic inflammatory growth of nasal polyps into the nasal airway is observed 1-3. There is a paucity of large population-based epidemiologic studies conducted using current definitions of CRS, and fewer studies yet that s

13、pecifically delineate the proportion of patients who have CRSwNP. Two recent population- based studies conducted in Europe and South Korea that used both symptom histories and endoscopic exams estimated the prevalence of CRS in the general population at 10.9% and 7.0% of adults, respectively, but th

14、ey did not define the proportion of CRS patients with nasal polyps 4, 5. Studies that have specifically examined CRSwNP suggest its population prevalence is around 2.7% of adults in a single municipality of Sweden 6, and its incidence has been estimated at 0.63 or 0.83 patients per thousand per year

15、 based on studies in a Danish county or in Central Pennsylvania, respectively 7, 8. Based on these studies, there is a predominance of men with CRSwNP, with a male to female ratio varying from 1.3-2.2, and a peak incidence between the ages of 45 and 65. While CRSwNP is the less common form of CRS, w

16、e have noted that the proportion of CRS patients with nasal polyps is substantially higher in surgical cohorts of tertiary care patients who had failed medical management (50%) when compared with incident cases where the proportion of CRS patients with nasal polyps may be as low as 7% 9, 10. Togethe

17、r, these studies suggest that compared to CRSsNP, CRSwNP may persist for a longer duration, be relatively recalcitrant to medical management, more frequently lead to surgical management and/or require more surgeries to address. While total CRS management costs are estimated to be over $8 billion ann

18、ually in the United States 11, there are no studies, to our knowledge, that have provided estimates of direct costs associated with CRSwNP management. In addition to direct costs of management, studies have shown that CRS patients seen in a tertiary care setting suffer a significantly impairedqualit

19、y of life comparable to congestive heart failure and chronic obstructive pulmonary disease 12. Although our unpublished data suggests that patients with CRSwNP may have marginally less impairment of quality of life than those without polyps, other studies have shown that CRSwNP patients are more bot

20、hered by rhinorrhea and smell/taste disturbances and less bothered by facial pain 13. Certainly, it is well established that patients with CRSwNP do have more frequent impairment from co-morbid conditions such as asthma and atopic multi- sensitization than the general population 8, 10. While epidemi

21、ologic study of CRSwNP is in its infancy, sorely needed studies in primary care populations will hopefully yield important information regarding the environmental or occupational factors that drive disease formation and persistence.Aspirin-Exacerbated Respiratory Disease (AERD)It is important to emp

22、hasize that there is a specific subset of patients with CRSwNP with severe disease that suffers from aspirin-exacerbated respiratory disease (AERD), otherwise known as Samters triad. These patients have asthma, CRSwNP, and develop exacerbated airway responses following ingestion of medications that

23、inhibit the cyclooxygenase (COX) 1 enzyme. Although AERD patients often present with the most severe manifestations of both asthma and nasal polyposis, this disease is less common than either CRSwNP or asthma and is currently understudied. The prevalence of AERD has been estimated to be as much as 0

24、.6- 2.5% in the general population, with higher prevalence among asthmatic and CRSwNP patients 14-16. However, the published work on AERD has been hampered by differing definitions of AERD used by different groups of investigators. For example, while some require documented airway reactions to COX-1

25、 inhibitors along with asthma and CRSwNP for AERD diagnosis, others do not specify the type of reaction to COX-1 inhibitors in their patients, and some studies do not require patients to have CRSwNP for their definition of AERD. Thus, the population prevalence estimates above may not truly reflect t

26、he population of patients who have the triad ofasthma, CRSwNP and airway responses to COX-1 inhibitors. Thus, it is unclear whether AERD represents the severe end of the CRSwNP disease spectrum, or if it is a distinct clinical entity. Although, it is clear that, AERD patients uniquely respond to asp

27、irin desensitization therapy 17, and have higher baseline levels of urinary leukotriene E4 18, suggesting that distinct molecular mechanisms, such as dysregulation of arachidonic acid metabolism, drive this unique disease 19-21. The pathogenesis of AERD is not discussed further in this review.Allerg

28、ic Fungal Rhinosinusitis (AFRS)Patients with allergic fungal rhinosinusitis (AFRS) represent another distinct subset of CRSwNP. These patients are often atopic and have highly elevated serum IgE levels 22, and they can be distinguished from other CRSwNP patients by the presence of eosinophilic mucin

29、 without fungal invasion of the mucosa, mucus with positive fungal staining, and often, bony erosion 23. Interestingly, the estimated prevalence of AFRS varies widely across different geographic regions of the United States, such that AFRS has been estimated to account for20% of all patients undergo

30、ing endoscopic sinus procedures in southern areas of the country, such as Memphis, but only 0-4% of these same patients in northern regions of the country 24. Like AERD, it is not clear whether AFRS is driven by distinct pathogenic mechanisms from CRSwNP, or is simply part of the CRSwNP disease spec

31、trum 23, and we will not discuss the pathogenesis of AFRS further in this review.Eastern Versus Western Presentations of CRSwNPCRSwNP in Western populations is often characterized by type 2 inflammation, with elevated levels of type 2 cytokines, such as IL-5 and IL-13, along with eosinophilia. Howev

32、er, there is accumulating evidence from Asian countries, especially in China, Korea and Japan, that CRSwNP in their populations may be characterized by a mixed type 1 or type 3 inflammation, with a more neutrophilic inflammation than observed in NP in patients from the US or Europe25. The mechanisms that drive these different phenotypes are unclear at this time. Interestingly, recent work from our group found that tissue from NP from second generation Asian patients born in and living in the US were considerably less eosinophilic than NP tissue from Caucasian, Afric