Chronic rhinosinusitis (CRS) is a troublesome, chronic inflammatory disease that affects over 10% of the adult population, causing decreased quality of life, lost productivity, and lost time at work and leading to more than a million surgical interventions annually worldwide. The nose, paranasal sinuses, and associated lymphoid tissues play important roles in homeostasis and immunity, and CRS significantly impairs these normal functions. Pathogenic mechanisms of CRS have recently become the focus of intense investigations worldwide, and significant progress has been made. The two main forms of CRS that have been long recognized, with and without nasal polyps, are each now known to be heterogeneous, based on underlying mechanism, geographical location, and race. Loss of the immune barrier, including increased permeability of mucosal epithelium and reduced production of important antimicrobial substances and responses, is a common feature of many forms of CRS. One form of CRS with polyps found worldwide is driven by the cytokines IL-5 and IL-13 coming from Th2 cells, type 2 innate lymphoid cells, and probably mast cells. Type 2 cytokines activate inflammatory cells that are implicated in the pathogenic mechanism, including mast cells, basophils, and eosinophils. New classes of biological drugs that block the production or action of these cytokines are making important inroads toward new treatment paradigms in polypoid CRS.


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Literature Cited

  1. Meltzer EO, Hamilos DL, Hadley JA, Lanza DC, Marple BF. 1.  et al. 2004. Rhinosinusitis: establishing definitions for clinical research and patient care. J. Allergy Clin. Immunol. 114:6 Suppl155–212 [Google Scholar]
  2. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I. 2.  et al. 2012. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 50:11–12 [Google Scholar]
  3. Senior BA, Kennedy DW, Tanabodee J, Kroger H, Hassab M. 3.  et al. 1998. Long-term results of functional endoscopic sinus surgery. Laryngoscope 108:2151–57 [Google Scholar]
  4. Laidlaw TM, Boyce JA. 4.  2016. Aspirin-exacerbated respiratory disease—new prime suspects. N. Engl. J. Med. 374:5484–88 [Google Scholar]
  5. Bhattacharyya N, Orlandi RR, Grebner J, Martinson M. 5.  2011. Cost burden of chronic rhinosinusitis: a claims-based study. Otolaryngol. Head Neck Surg. 144:3440–45 [Google Scholar]
  6. Tan BK, Kern RC, Schleimer RP, Schwartz BS. 6.  2013. Chronic rhinosinusitis: the unrecognized epidemic. Am. J. Respir. Crit. Care Med. 188:111275–77 [Google Scholar]
  7. Stevens WW, Peters AT, Suh L, Norton JE, Kern RC. 7.  et al. 2015. A retrospective, cross-sectional study reveals that women with CRSwNP have more severe disease than men. Immun. Inflamm. Dis. 3:114–22 [Google Scholar]
  8. Sahin-Yilmaz A, Naclerio RM. 8.  2011. Anatomy and physiology of the upper airway. Proc. Am. Thorac. Soc. 8:131–39 [Google Scholar]
  9. Kato A, Hulse KE, Tan BK, Schleimer RP. 9.  2013. B-lymphocyte lineage cells and the respiratory system. J. Allergy Clin. Immunol. 131:4933–57 [Google Scholar]
  10. Avila PC, Schleimer RP. 10.  2008. Airway epithelium. Allergy and Allergic Diseases Vol. 1, ed. AB Kay, AP Kaplan, J Bousquet, PG Holt, pp. 366–97. Hoboken, NJ: Wiley-Blackwell. 2nd ed.
  11. Hopkins C, Browne JP, Slack R, Lund V, Brown P. 11.  2007. The Lund-Mackay staging system for chronic rhinosinusitis: How is it used and what does it predict?. Otolaryngol. Head Neck Surg. 137:4555–61 [Google Scholar]
  12. Tos M, Larsen PL, Larsen K, Caye-Thomasen P. 12.  2010. Pathogenesis and pathophysiology of nasal polyps. Nasal Polyposis TM Önerci, BJ Ferguson 53–63 Berlin: Springer-Verlag [Google Scholar]
  13. Akdis CA, Bachert C, Cingi C, Dykewicz MS, Hellings PW. 13.  et al. 2013. Endotypes and phenotypes of chronic rhinosinusitis: a PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J. Allergy Clin. Immunol. 131:61479–90 [Google Scholar]
  14. Tomassen P, Vandeplas G, Van Zele T, Cardell LO, Arebro J. 14.  et al. 2016. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J. Allergy Clin. Immunol. 137:51449–56 [Google Scholar]
  15. Kountakis SE, Arango P, Bradley D, Wade ZK, Borish L. 15.  2004. Molecular and cellular staging for the severity of chronic rhinosinusitis. Laryngoscope 114:111895–905 [Google Scholar]
  16. Van Bruaene N, Bachert C. 16.  2011. Tissue remodeling in chronic rhinosinusitis. Curr. Opin. Allergy Clin. Immunol. 11:18–11 [Google Scholar]
  17. Shi LL, Xiong P, Zhang L, Cao PP, Liao B. 17.  et al. 2013. Features of airway remodeling in different types of Chinese chronic rhinosinusitis are associated with inflammation patterns. Allergy 68:1101–9 [Google Scholar]
  18. Kim DK, Jin HR, Eun KM, Mutusamy S, Cho SH. 18.  et al. 2015. Non-eosinophilic nasal polyps shows increased epithelial proliferation and localized disease pattern in the early stage. PLOS ONE 10:10e0139945 [Google Scholar]
  19. Watelet JB, Bachert C, Claeys C, Van Cauwenberge P. 19.  2004. Matrix metalloproteinases MMP-7, MMP-9 and their tissue inhibitor TIMP-1: expression in chronic sinusitis versus nasal polyposis. Allergy 59:154–60 [Google Scholar]
  20. Nielsen LF, Moe D, Kirkeby S, Garbarsch C. 20.  1998. Sirius red and acid fuchsin staining mechanisms. Biotech Histochem 73:271–77 [Google Scholar]
  21. Eyibilen A, Cayli S, Aladag I, Koc S, Gurbuzler L. 21.  et al. 2011. Distribution of matrix metalloproteinases MMP-1, MMP-2, MMP-8 and tissue inhibitor of matrix metalloproteinases-2 in nasal polyposis and chronic rhinosinusitis. Histol. Histopathol. 26:5615–21 [Google Scholar]
  22. Kostamo K, Tervahartiala T, Sorsa T, Richardson M, Toskala E. 22.  2007. Metalloproteinase function in chronic rhinosinusitis with nasal polyposis. Laryngoscope 117:4638–43 [Google Scholar]
  23. Lechapt-Zalcman E, Coste A, d'Ortho MP, Frisdal E, Harf A. 23.  et al. 2001. Increased expression of matrix metalloproteinase-9 in nasal polyps. J. Pathol. 193:2233–41 [Google Scholar]
  24. Wang LF, Chien CY, Tai CF, Kuo WR, Hsi E. 24.  et al. 2010. Matrix metalloproteinase-9 gene polymorphisms in nasal polyposis. BMC Med. Genet 1185 [Google Scholar]
  25. Meng J, Zhou P, Liu Y, Liu F, Yi X. 25.  et al. 2013. The development of nasal polyp disease involves early nasal mucosal inflammation and remodelling. PLOS ONE 8:12e82373 [Google Scholar]
  26. Carroll WW, O'Connell BP, Schlosser RJ, Gudis DA, Karnezis TT. 26.  et al. 2016. Fibroblast levels are increased in chronic rhinosinusitis with nasal polyps and are associated with worse subjective disease severity. Int. Forum Allergy Rhinol. 6:2162–68 [Google Scholar]
  27. Yoshikawa M, Wada K, Yoshimura T, Asaka D, Okada N. 27.  et al. 2013. Increased CXCL10 expression in nasal fibroblasts from patients with refractory chronic rhinosinusitis and asthma. Allergol. Int. 62:4495–502 [Google Scholar]
  28. Takabayashi T, Kato A, Peters AT, Hulse KE, Suh LA. 28.  et al. 2013. Excessive fibrin deposition in nasal polyps caused by fibrinolytic impairment through reduction of tissue plasminogen activator expression. Am. J. Respir. Crit. Care Med. 187:149–57 [Google Scholar]
  29. Takabayashi T, Kato A, Peters AT, Hulse KE, Suh LA. 29.  et al. 2013. Increased expression of factor XIII-A in patients with chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 132:3584–592 [Google Scholar]
  30. Hulse KE, Stevens WW, Tan BK, Schleimer RP. 30.  2015. Pathogenesis of nasal polyposis. Clin. Exp. Allergy 45:2328–46 [Google Scholar]
  31. Lee H, Kim SR, Oh Y, Cho SH, Schleimer RP. 31.  et al. 2014. Targeting insulin-like growth factor-I and insulin-like growth factor-binding protein-3 signaling pathways. A novel therapeutic approach for asthma. Am. J. Respir. Cell Mol. Biol. 50:4667–77 [Google Scholar]
  32. Niessen CM. 32.  2007. Tight junctions/adherens junctions: basic structure and function. J. Investig. Dermatol. 127:112525–32 [Google Scholar]
  33. De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN. 33.  et al. 2011. Tight junction defects in patients with atopic dermatitis. J. Allergy Clin. Immunol. 127:3773–86 [Google Scholar]
  34. Barmeyer C, Schulzke JD, Fromm M. 34.  2015. Claudin-related intestinal diseases. Semin. Cell Dev. Biol. 42:30–38 [Google Scholar]
  35. Hackett TL. 35.  2012. Epithelial-mesenchymal transition in the pathophysiology of airway remodelling in asthma. Curr. Opin. Allergy Clin. Immunol. 12:153–59 [Google Scholar]
  36. Holgate ST. 36.  2011. The sentinel role of the airway epithelium in asthma pathogenesis. Immunol. Rev. 242:1205–19 [Google Scholar]
  37. Kalluri R, Weinberg RA. 37.  2009. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 119:61420–28 [Google Scholar]
  38. Pain M, Bermudez O, Lacoste P, Royer PJ, Botturi K. 38.  et al. 2014. Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype. Eur. Respir. Rev. 23:131118–30 [Google Scholar]
  39. Yang J, Weinberg RA. 39.  2008. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell. 14:6818–29 [Google Scholar]
  40. Taniguchi K, Wu LW, Grivennikov SI, de Jong PR, Lian I. 40.  et al. 2015. A gp130–Src–YAP module links inflammation to epithelial regeneration. Nature 519:754157–62 [Google Scholar]
  41. Lee SN, Lee DH, Sohn MH, Yoon JH. 41.  2013. Overexpressed proprotein convertase 1/3 induces an epithelial-mesenchymal transition in airway epithelium. Eur. Respir. J. 42:51379–90 [Google Scholar]
  42. Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG. 42.  et al. 2010. Roles of epithelial cell-derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma. PNAS 107:3214170–75 [Google Scholar]
  43. Bernstein JM, Gorfien J, Noble B, Yankaskas JR. 43.  1997. Nasal polyposis: immunohistochemistry and bioelectrical findings (a hypothesis for the development of nasal polyps). J. Allergy Clin. Immunol. 99:2165–75 [Google Scholar]
  44. Dejima K, Randell SH, Stutts MJ, Senior BA, Boucher RC. 44.  2006. Potential role of abnormal ion transport in the pathogenesis of chronic sinusitis. Arch. Otolaryngol. Head Neck Surg. 132:121352–62 [Google Scholar]
  45. Soyka MB, Wawrzyniak P, Eiwegger T, Holzmann D, Treis A. 45.  et al. 2012. Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-γ and IL-4. J. Allergy Clin. Immunol. 130:51087–96 [Google Scholar]
  46. Zhang N, Van Crombruggen K, Gevaert E, Bachert C. 46.  2016. Barrier function of the nasal mucosa in health and type-2 biased airway diseases. Allergy 71:3295–307 [Google Scholar]
  47. Jang YJ, Kim HG, Koo TW, Chung PS. 47.  2002. Localization of ZO-1 and E-cadherin in the nasal polyp epithelium. Eur. Arch. Otorhinolaryngol. 259:9465–69 [Google Scholar]
  48. Shahana S, Jaunmuktane Z, Asplund MS, Roomans GM. 48.  2006. Ultrastructural investigation of epithelial damage in asthmatic and non-asthmatic nasal polyps. Respir. Med. 100:112018–28 [Google Scholar]
  49. Rogers GA, Den Beste K, Parkos CA, Nusrat A, Delgaudio JM. 49.  et al. 2011. Epithelial tight junction alterations in nasal polyposis. Int. Forum Allergy Rhinol. 1:150–54 [Google Scholar]
  50. Hupin C, Gohy S, Bouzin C, Lecocq M, Polette M. 50.  et al. 2014. Features of mesenchymal transition in the airway epithelium from chronic rhinosinusitis. Allergy 69:111540–49 [Google Scholar]
  51. Johnson JR, Roos A, Berg T, Nord M, Fuxe J. 51.  2011. Chronic respiratory aeroallergen exposure in mice induces epithelial-mesenchymal transition in the large airways. PLOS ONE 6:1e16175 [Google Scholar]
  52. Steelant B, Farre R, Wawrzyniak P, Belmans J, Dekimpe E. 52.  et al. 2016. Impaired barrier function in patients with house dust mite–induced allergic rhinitis is accompanied by decreased occludin and zonula occludens-1 expression. J. Allergy Clin. Immunol. 137:41043–53 [Google Scholar]
  53. Wan H, Winton HL, Soeller C, Tovey ER, Gruenert DC. 53.  et al. 1999. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J. Clin. Investig. 104:1123–33 [Google Scholar]
  54. Richer SL, Truong-Tran AQ, Conley DB, Carter R, Vermylen D. 54.  et al. 2008. Epithelial genes in chronic rhinosinusitis with and without nasal polyps. Am. J. Rhinol. 22:3228–34 [Google Scholar]
  55. Tieu DD, Kern RC, Schleimer RP. 55.  2009. Alterations in epithelial barrier function and host defense responses in chronic rhinosinusitis. J. Allergy Clin. Immunol. 124:137–42 [Google Scholar]
  56. Heijink IH, Postma DS, Noordhoek JA, Broekema M, Kapus A. 56.  2010. House dust mite–promoted epithelial-to-mesenchymal transition in human bronchial epithelium. Am. J. Respir. Cell Mol. Biol. 42:169–79 [Google Scholar]
  57. Shin HW, Cho K, Kim DW, Han DH, Khalmuratova R. 57.  et al. 2012. Hypoxia-inducible factor 1 mediates nasal polypogenesis by inducing epithelial-to-mesenchymal transition. Am. J. Respir. Crit. Care. Med. 185:9944–54 [Google Scholar]
  58. Shaykhiev R, Crystal RG. 58.  2014. Early events in the pathogenesis of chronic obstructive pulmonary disease. Smoking-induced reprogramming of airway epithelial basal progenitor cells. Ann. Am. Thorac. Soc. 11:Suppl 5S252–8 [Google Scholar]
  59. Gevaert P, Van Bruaene N, Cattaert T, Van Steen K, Van Zele T. 59.  et al. 2011. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J. Allergy Clin. Immunol. 128:5989–95 [Google Scholar]
  60. Flood-Page P, Menzies-Gow A, Phipps S, Ying S, Wangoo A. 60.  et al. 2003. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J. Clin. Investig. 112:71029–36 [Google Scholar]
  61. Lee RCN. 61.  2016. Physiology of the nose and paranasal sinuses. Otolaryngology Head and Neck Surgery, ed. C deSouza et al New Delhi: Jaypee Publishers. In press. 2nd ed. [Google Scholar]
  62. Chen B, Shaari J, Claire SE, Palmer JN, Chiu AG. 62.  et al. 2006. Altered sinonasal ciliary dynamics in chronic rhinosinusitis. Am. J. Rhinol. 20:3325–29 [Google Scholar]
  63. Gudis D, Zhao KQ, Cohen NA. 63.  2012. Acquired cilia dysfunction in chronic rhinosinusitis. Am. J. Rhinol. Allergy 26:11–6 [Google Scholar]
  64. Li YY, Li CW, Chao SS, Yu FG, Yu XM. 64.  et al. 2014. Impairment of cilia architecture and ciliogenesis in hyperplastic nasal epithelium from nasal polyps. J. Allergy Clin. Immunol. 134:61282–92 [Google Scholar]
  65. Hamilos DL. 65.  2014. Host-microbial interactions in patients with chronic rhinosinusitis. J. Allergy Clin. Immunol. 133:3640–53 [Google Scholar]
  66. Stevens WW, Lee RJ, Schleimer RP, Cohen NA. 66.  2015. Chronic rhinosinusitis pathogenesis. J. Allergy Clin. Immunol. 136:61442–53 [Google Scholar]
  67. Van Crombruggen K, Jacob F, Zhang N, Bachert C. 67.  2013. Damage-associated molecular patterns and their receptors in upper airway pathologies. Cell Mol. Life Sci. 70:224307–21 [Google Scholar]
  68. Claeys S, de Belder T, Holtappels G, Gevaert P, Verhasselt B. 68.  et al. 2003. Human β-defensins and toll-like receptors in the upper airway. Allergy 58:8748–53 [Google Scholar]
  69. Sha Q, Truong-Tran AQ, Plitt JR, Beck LA, Schleimer RP. 69.  2004. Activation of airway epithelial cells by toll-like receptor agonists. Am. J. Respir. Cell Mol. Biol. 31:3358–64 [Google Scholar]
  70. Vandermeer J, Sha Q, Lane AP, Schleimer RP. 70.  2004. Innate immunity of the sinonasal cavity: expression of messenger RNA for complement cascade components and toll-like receptors. Arch. Otolaryngol. Head Neck Surg. 130:121374–80 [Google Scholar]
  71. Hirschberg A, Kiss M, Kadocsa E, Polyanka H, Szabo K. 71.  et al. 2015. Different activations of toll-like receptors and antimicrobial peptides in chronic rhinosinusitis with or without nasal polyposis. Eur. Arch. Otorhinolaryngol. 273:1779–88 [Google Scholar]
  72. Lane AP, Truong-Tran QA, Myers A, Bickel C, Schleimer RP. 72.  2006. Serum amyloid A, properdin, complement 3, and toll-like receptors are expressed locally in human sinonasal tissue. Am. J. Rhinol. 20:1117–23 [Google Scholar]
  73. Sun Y, Zhou B, Wang C, Huang Q, Zhang Q. 73.  et al. 2012. Biofilm formation and Toll-like receptor 2, Toll-like receptor 4, and NF-κB expression in sinus tissues of patients with chronic rhinosinusitis. Am. J. Rhinol. Allergy 26:2104–9 [Google Scholar]
  74. Ramanathan M Jr., Lee WK, Dubin MG, Lin S, Spannhake EW. 74.  et al. 2007. Sinonasal epithelial cell expression of Toll-like receptor 9 is decreased in chronic rhinosinusitis with polyps. Am. J. Rhinol. 21:1110–16 [Google Scholar]
  75. Zhang Q, Wang CS, Han DM, Sy C, Huang Q. 75.  et al. 2013. Differential expression of Toll-like receptor pathway genes in chronic rhinosinusitis with or without nasal polyps. Acta Otolaryngol 133:2165–73 [Google Scholar]
  76. Park CS, Cho JH, Park YJ. 76.  2011. Toll-like receptor 2 gene polymorphisms in a Korean population: association with chronic rhinosinusitis. Otolaryngol. Head Neck Surg. 144:196–100 [Google Scholar]
  77. Lee RJ, Xiong G, Kofonow JM, Chen B, Lysenko A. 77.  et al. 2012. T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection. J. Clin. Investig. 122:114145–59 [Google Scholar]
  78. Lee RJ, Cohen NA. 78.  2015. Role of the bitter taste receptor T2R38 in upper respiratory infection and chronic rhinosinusitis. Curr. Opin. Allergy Clin. Immunol. 15:114–20 [Google Scholar]
  79. Lee RJ, Kofonow JM, Rosen PL, Siebert AP, Chen B. 79.  et al. 2014. Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J. Clin. Investig. 124:31393–405 [Google Scholar]
  80. Adappa ND, Workman AD, Hadjiliadis D, Dorgan DJ, Frame D. 80.  et al. 2016. T2R38 genotype is correlated with sinonasal quality of life in homozygous ΔF508 cystic fibrosis patients. Int. Forum Allergy Rhinol. 6:4356–61 [Google Scholar]
  81. Adappa ND, Zhang Z, Palmer JN, Kennedy DW, Doghramji L. 81.  et al. 2014. The bitter taste receptor T2R38 is an independent risk factor for chronic rhinosinusitis requiring sinus surgery. Int. Forum Allergy Rhinol. 4:13–7 [Google Scholar]
  82. Mfuna-Endam L, Zhang Y, Desrosiers MY. 82.  2011. Genetics of rhinosinusitis. Curr. Allergy Asthma Rep. 11:3236–46 [Google Scholar]
  83. Wiener A, Shudler M, Levit A, Niv MY. 83.  2012. BitterDB: a database of bitter compounds. Nucleic Acids Res 40:Database issueD413–19 [Google Scholar]
  84. Zhang Z, Adappa ND, Lautenbach E, Chiu AG, Doghramji L. 84.  et al. 2014. The effect of diabetes mellitus on chronic rhinosinusitis and sinus surgery outcome. Int. Forum Allergy Rhinol. 4:4315–20 [Google Scholar]
  85. Bingle CD, Craven CJ. 85.  2002. PLUNC: a novel family of candidate host defence proteins expressed in the upper airways and nasopharynx. Hum. Mol. Genet. 11:8937–43 [Google Scholar]
  86. Min-man W, Hong S, Zhi-qiang X, Xue-ping F, Chang-qi L. 86.  et al. 2009. Differential proteomic analysis of nasal polyps, chronic sinusitis, and normal nasal mucosa tissues. Otolaryngol. Head Neck Surg. 141:3364–68 [Google Scholar]
  87. Ghafouri B, Kihlstrom E, Stahlbom B, Tagesson C, Lindahl M. 87.  2003. PLUNC (palate, lung and nasal epithelial clone) proteins in human nasal lavage fluid. Biochem. Soc. Trans. 31:Pt 4810–14 [Google Scholar]
  88. Seshadri S, Lin DC, Rosati M, Carter RG, Norton JE. 88.  et al. 2012. Reduced expression of antimicrobial PLUNC proteins in nasal polyp tissues of patients with chronic rhinosinusitis. Allergy 67:7920–28 [Google Scholar]
  89. Wei Y, Xia W, Ye X, Fan Y, Shi J. 89.  et al. 2014. The antimicrobial protein short palate, lung, and nasal epithelium clone 1 (SPLUNC1) is differentially modulated in eosinophilic and noneosinophilic chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 133:2420–28 [Google Scholar]
  90. Tsou YA, Peng MT, Wu YF, Lai CH, Lin CD. 90.  et al. 2014. Decreased PLUNC expression in nasal polyps is associated with multibacterial colonization in chronic rhinosinusitis patients. Eur. Arch. Otorhinolaryngol. 271:2299–304 [Google Scholar]
  91. Thaikoottathil JV, Martin RJ, Di PY, Minor M, Case S. 91.  et al. 2012. SPLUNC1 deficiency enhances airway eosinophilic inflammation in mice. Am. J. Respir. Cell Mol. Biol. 47:2253–60 [Google Scholar]
  92. Barnes KC, Grant A, Gao P, Baltadjieva D, Berg T. 92.  et al. 2006. Polymorphisms in the novel gene acyloxyacyl hydroxylase (AOAH) are associated with asthma and associated phenotypes. J. Allergy Clin. Immunol. 118:170–77 [Google Scholar]
  93. Zhang Y, Endam LM, Filali-Mouhim A, Zhao L, Desrosiers M. 93.  et al. 2012. Polymorphisms in RYBP and AOAH genes are associated with chronic rhinosinusitis in a Chinese population: a replication study. PLOS ONE 7:6e39247 [Google Scholar]
  94. Bryborn M, Adner M, Cardell LO. 94.  2005. Psoriasin, one of several new proteins identified in nasal lavage fluid from allergic and non-allergic individuals using 2-dimensional gel electrophoresis and mass spectrometry. Respir. Res. 6:118 [Google Scholar]
  95. Tieu DD, Peters AT, Carter RG, Suh L, Conley DB. 95.  et al. 2010. Evidence for diminished levels of epithelial psoriasin and calprotectin in chronic rhinosinusitis. J. Allergy Clin. Immunol. 125:3667–75 [Google Scholar]
  96. Kvarnhammar AM, Rydberg C, Jarnkrants M, Eriksson M, Uddman R. 96.  et al. 2012. Diminished levels of nasal S100A7 (psoriasin) in seasonal allergic rhinitis: an effect mediated by Th2 cytokines. Respir. Res. 13:2 [Google Scholar]
  97. Van Crombruggen K, Vogl T, Perez-Novo C, Holtappels G, Bachert C. 97.  2016. Differential release and deposition of S100A8/A9 proteins in inflamed upper airway tissue. Eur. Respir. J. 47:1264–74 [Google Scholar]
  98. Cho SH, Hong SJ, Han B, Lee SH, Suh L. 98.  et al. 2012. Age-related differences in the pathogenesis of chronic rhinosinusitis. J. Allergy Clin. Immunol. 129:3858–60 [Google Scholar]
  99. Dong D, Yulin Z, Yan X, Hongyan Z, Shitao Z. 99.  et al. 2014. Enhanced expressions of lysozyme, SLPI and glycoprotein 340 in biofilm-associated chronic rhinosinusitis. Eur. Arch. Otorhinolaryngol. 271:61563–71 [Google Scholar]
  100. Ishida M, Matsunaga T, Uda H. 100.  1984. An immunohistological study of nasal and paranasal mucosa of patients with relapsing chronic sinusitis. Rhinology 22:2115–18 [Google Scholar]
  101. Jeney EV, Raphael GD, Meredith SD, Kaliner MA. 101.  1990. Abnormal nasal glandular secretion in recurrent sinusitis. J. Allergy Clin. Immunol. 86:110–18 [Google Scholar]
  102. Psaltis AJ, Wormald PJ, Ha KR, Tan LW. 102.  2008. Reduced levels of lactoferrin in biofilm-associated chronic rhinosinusitis. Laryngoscope 118:5895–901 [Google Scholar]
  103. Tewfik MA, Latterich M, DiFalco MR, Samaha M. 103.  2007. Proteomics of nasal mucus in chronic rhinosinusitis. Am. J. Rhinol. 21:6680–85 [Google Scholar]
  104. Gaunsbaek MQ, Lange B, Kjeldsen AD, Svane-Knudsen V, Skjoedt K. 104.  et al. 2012. Complement defects in patients with chronic rhinosinusitis. PLOS ONE 7:11e47383 [Google Scholar]
  105. Hamilos DL. 105.  2015. Drivers of chronic rhinosinusitis: inflammation versus infection. J. Allergy Clin. Immunol. 136:61454–59 [Google Scholar]
  106. Liu T, Li TL, Zhao F, Xie C, Liu AM. 106.  et al. 2011. Role of thymic stromal lymphopoietin in the pathogenesis of nasal polyposis. Am. J. Med. Sci 341140–47 [Google Scholar]
  107. Miljkovic D, Bassiouni A, Cooksley C, Ou J, Hauben E. 107.  et al. 2014. Association between group 2 innate lymphoid cells enrichment, nasal polyps and allergy in chronic rhinosinusitis. Allergy 69:91154–61 [Google Scholar]
  108. Nagarkar DR, Poposki JA, Tan BK, Comeau MR, Peters AT. 108.  et al. 2013. Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis. J. Allergy Clin. Immunol. 132:3593–600 [Google Scholar]
  109. Lund S, Walford HH, Doherty TA. 109.  2013. Type 2 innate lymphoid cells in allergic disease. Curr. Immunol. Rev. 9:4214–21 [Google Scholar]
  110. McKenzie AN, Spits H, Eberl G. 110.  2014. Innate lymphoid cells in inflammation and immunity. Immunity 41:3366–74 [Google Scholar]
  111. Stevens WW, Ocampo CJ, Berdnikovs S, Sakashita M, Mahdavinia M. 111.  et al. 2015. Cytokines in chronic rhinosinusitis. Role in eosinophilia and aspirin-exacerbated respiratory disease. Am. J. Respir. Crit. Care. Med. 192:6682–94 [Google Scholar]
  112. Ho J, Bailey M, Zaunders J, Mrad N, Sacks R. 112.  et al. 2015. Group 2 innate lymphoid cells (ILC2s) are increased in chronic rhinosinusitis with nasal polyps or eosinophilia. Clin. Exp. Allergy 45:2394–403 [Google Scholar]
  113. Mjosberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM. 113.  et al. 2011. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat. Immunol. 12:111055–62 [Google Scholar]
  114. Shaw JL, Fakhri S, Citardi MJ, Porter PC, Corry DB. 114.  et al. 2013. IL-33-responsive innate lymphoid cells are an important source of IL-13 in chronic rhinosinusitis with nasal polyps. Am. J. Respir. Crit. Care. Med. 188:4432–39 [Google Scholar]
  115. Zaiss DM, Gause WC, Osborne LC, Artis D. 115.  2015. Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity 42:2216–26 [Google Scholar]
  116. Pothoven KL, Norton JE, Hulse KE, Suh LA, Carter RG. 116.  et al. 2015. Oncostatin M promotes mucosal epithelial barrier dysfunction, and its expression is increased in patients with eosinophilic mucosal disease. J. Allergy Clin. Immunol. 136:3737–46 [Google Scholar]
  117. Homma T, Kato A, Masafumi S, Norton J, Suh L. 117.  et al. 2015. Involvement of EGFR ligands and MMP-1 in pathogenesis of CRS. Am. J. Respir. Crit. Care Med. 191:A1377 (Abstr.) [Google Scholar]
  118. Gevaert P, Holtappels G, Johansson SG, Cuvelier C, Cauwenberge P. 118.  et al. 2005. Organization of secondary lymphoid tissue and local IgE formation to Staphylococcus aureus enterotoxins in nasal polyp tissue. Allergy 60:171–79 [Google Scholar]
  119. Hulse KE, Norton JE, Suh L, Zhong Q, Mahdavinia M. 119.  et al. 2013. Chronic rhinosinusitis with nasal polyps is characterized by B-cell inflammation and EBV-induced protein 2 expression. J. Allergy Clin. Immunol. 131:41075–83 [Google Scholar]
  120. Mechtcheriakova D, Sobanov Y, Holtappels G, Bajna E, Svoboda M. 120.  et al. 2011. Activation-induced cytidine deaminase (AID)-associated multigene signature to assess impact of AID in etiology of diseases with inflammatory component. PLOS ONE 6:10e25611 [Google Scholar]
  121. Bachert C, Zhang N, Holtappels G, De Lobel L, van Cauwenberge P. 121.  et al. 2010. Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma. J. Allergy Clin. Immunol. 126:5962–68 [Google Scholar]
  122. Tan BK, Li QZ, Suh L, Kato A, Conley DB. 122.  et al. 2011. Evidence for intranasal antinuclear autoantibodies in patients with chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 128:61198–206 [Google Scholar]
  123. Jeffe JS, Seshadri S, Hamill KJ, Huang JH, Carter R. 123.  et al. 2013. A role for anti-BP180 autoantibodies in chronic rhinosinusitis. Laryngoscope 123:92104–11 [Google Scholar]
  124. Van Roey GA, Vanison C, Huang H, Kern R, Chandra R. 124.  et al. 2015. Complement activation in nasal tissue of patients with chronic rhinosinusitis. J. Allergy Clin. Immunol. 135:2AB237 [Google Scholar]
  125. Kato A, Peters A, Suh L, Carter R, Harris KE. 125.  et al. 2008. Evidence of a role for B cell-activating factor of the TNF family in the pathogenesis of chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 121:61385–92 [Google Scholar]
  126. Bachert C, Mannent L, Naclerio RM, Mullol J, Ferguson BJ. 126.  et al. 2016. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA 315:5469–79 [Google Scholar]
  127. Bochner BS, Schleimer RP. 127.  2001. Mast cells, basophils, and eosinophils: distinct but overlapping pathways for recruitment. Immunol. Rev. 179:5–15 [Google Scholar]
  128. Poposki JA, Uzzaman A, Nagarkar DR, Chustz RT, Peters AT. 128.  et al. 2011. Increased expression of the chemokine CCL23 in eosinophilic chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 128:173–81 [Google Scholar]
  129. Cao PP, Li HB, Wang BF, Wang SB, You XJ. 129.  et al. 2009. Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J. Allergy Clin. Immunol. 124:3478–84 [Google Scholar]
  130. Saitoh T, Kusunoki T, Yao T, Kawano K, Kojima Y. 130.  et al. 2010. Role of interleukin-17A in the eosinophil accumulation and mucosal remodeling in chronic rhinosinusitis with nasal polyps associated with asthma. Int. Arch. Allergy Immunol. 151:18–16 [Google Scholar]
  131. Shen Y, Pan CK, Tang XY, Yang YC, Ke X. 131.  et al. 2011. Significance of interleukin-17A in patients with nasal polyposis. Asian Pac. J. Allergy Immunol. 29:2169–75 [Google Scholar]
  132. Cao PP, Zhang YN, Liao B, Ma J, Wang BF. 132.  et al. 2014. Increased local IgE production induced by common aeroallergens and phenotypic alteration of mast cells in Chinese eosinophilic, but not non-eosinophilic, chronic rhinosinusitis with nasal polyps. Clin. Exp. Allergy 44:5690–700 [Google Scholar]
  133. Ho J, Bailey M, Zaunders J, Mrad N, Sacks R. 133.  et al. 2015. Cellular comparison of sinus mucosa versus polyp tissue from a single sinus cavity in chronic rhinosinusitis. Int. Forum Allergy Rhinol. 5:114–27 [Google Scholar]
  134. Jin J, Chang DY, Kim SH, Rha KS, Mo JH. 134.  et al. 2014. Role of hypoxia-inducible factor-1α expression in regulatory T cells on nasal polypogenesis. Laryngoscope 124:5E151–59 [Google Scholar]
  135. Van Bruaene N, Perez-Novo CA, Basinski TM, Van Zele T, Holtappels G. 135.  et al. 2008. T-cell regulation in chronic paranasal sinus disease. J. Allergy Clin. Immunol. 121:61435–41 [Google Scholar]
  136. Bachert C, Wagenmann M, Hauser U, Rudack C. 136.  1997. IL-5 synthesis is upregulated in human nasal polyp tissue. J. Allergy Clin. Immunol. 99:6837–42 [Google Scholar]
  137. Bolard F, Gosset P, Lamblin C, Bergoin C, Tonnel AB. 137.  et al. 2001. Cell and cytokine profiles in nasal secretions from patients with nasal polyposis: effects of topical steroids and surgical treatment. Allergy 56:4333–38 [Google Scholar]
  138. Kim YM, Munoz A, Hwang PH, Nadeau KC. 138.  2010. Migration of regulatory T cells toward airway epithelial cells is impaired in chronic rhinosinusitis with nasal polyposis. Clin. Immunol. 137:1111–21 [Google Scholar]
  139. Riechelmann H, Deutschle T, Rozsasi A, Keck T, Polzehl D. 139.  et al. 2005. Nasal biomarker profiles in acute and chronic rhinosinusitis. Clin. Exp. Allergy 35:91186–91 [Google Scholar]
  140. Lan F, Zhang N, Zhang J, Krysko O, Zhang Q. 140.  et al. 2013. Forkhead box protein 3 in human nasal polyp regulatory T cells is regulated by the protein suppressor of cytokine signaling 3. J. Allergy Clin. Immunol. 132:61314–21 [Google Scholar]
  141. Liu T, Song CH, Liu AM, Xie C, Zhao F. 141.  et al. 2011. Forkhead box P3+ T cells express interleukin-17 in nasal mucosa of patients with both allergic rhinitis and polyposis. Clin. Exp. Immunol. 163:159–64 [Google Scholar]
  142. Oakley GM, Curtin K, Orb Q, Schaefer C, Orlandi RR. 142.  et al. 2015. Familial risk of chronic rhinosinusitis with and without nasal polyposis: genetics or environment. Int. Forum Allergy Rhinol. 5:4276–82 [Google Scholar]
  143. Padia R, Curtin K, Peterson K, Orlandi RR, Alt J. 143.  2016. Eosinophilic esophagitis strongly linked to chronic rhinosinusitis. Laryngoscope 126:61279–83 [Google Scholar]
  144. Hsu J, Avila PC, Kern RC, Hayes MG, Schleimer RP. 144.  et al. 2013. Genetics of chronic rhinosinusitis: state of the field and directions forward. J. Allergy Clin. Immunol. 131:4977–93 [Google Scholar]
  145. Pinto JM, Hayes MG, Schneider D, Naclerio RM, Ober C. 145.  2008. A genomewide screen for chronic rhinosinusitis genes identifies a locus on chromosome 7q. Laryngoscope 118:112067–72 [Google Scholar]
  146. Wang X, Moylan B, Leopold DA, Kim J, Rubenstein RC. 146.  et al. 2000. Mutation in the gene responsible for cystic fibrosis and predisposition to chronic rhinosinusitis in the general population. JAMA 284:141814–19 [Google Scholar]
  147. Bosse Y, Bacot F, Montpetit A, Rung J, Qu HQ. 147.  et al. 2009. Identification of susceptibility genes for complex diseases using pooling-based genome-wide association scans. Hum. Genet. 125:3305–18 [Google Scholar]
  148. Mygind N, Dahl R, Bachert C. 148.  2000. Nasal polyposis, eosinophil dominated inflammation, and allergy. Thorax 55:Suppl. 2S79–83 [Google Scholar]
  149. Schleimer R, Kato A, Kern RC. 149.  2012. Eosinophils and chronic rhinosinusitis. Eosinophils in Health and Disease JJ Lee, H Rosenberg 508–519 London: Elsevier [Google Scholar]
  150. Tokunaga T, Sakashita M, Haruna T, Asaka D, Takeno S. 150.  et al. 2015. Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study. Allergy 70:8995–1003 [Google Scholar]
  151. George L, Brightling CE. 151.  2016. Eosinophilic airway inflammation: role in asthma and chronic obstructive pulmonary disease. Ther. Adv. Chronic Dis. 7:134–51 [Google Scholar]
  152. Lee JJ, Jacobsen EA, McGarry MP, Schleimer RP, Lee NA. 152.  2010. Eosinophils in health and disease: the LIAR hypothesis. Clin. Exp. Allergy 40:4563–75 [Google Scholar]
  153. Postma DS, Rabe KF. 153.  2015. The asthma-COPD overlap syndrome. N. Engl. J. Med. 373:131241–49 [Google Scholar]
  154. Lavin J, Meen E, Lam K, Kato A, Huang H. 154.  et al. 2013. The impact and nature of inflammation in the olfactory cleft on olfaction in patients with chronic rhinosinusitis. J. Allergy Clin. Immunol. 131:2AB59 [Google Scholar]
  155. Yoshimura K, Kawata R, Haruna S, Moriyama H, Hirakawa K. 155.  et al. 2011. Clinical epidemiological study of 553 patients with chronic rhinosinusitis in Japan. Allergol. Int. 60:4491–96 [Google Scholar]
  156. Wang ET, Zheng Y, Liu PF, Guo LJ. 156.  2014. Eosinophilic chronic rhinosinusitis in East Asians. World J. Clin. Cases 2:12873–82 [Google Scholar]
  157. Kim SJ, Lee KH, Kim SW, Cho JS, Park YK. 157.  et al. 2013. Changes in histological features of nasal polyps in a Korean population over a 17-year period. Otolaryngol. Head Neck Surg. 149:3431–37 [Google Scholar]
  158. Hu Y, Cao PP, Liang GT, Cui YH, Liu Z. 158.  2012. Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults. Laryngoscope 122:3498–503 [Google Scholar]
  159. Katotomichelakis M, Tantilipikorn P, Holtappels G, De Ruyck N, Feng L. 159.  et al. 2013. Inflammatory patterns in upper airway disease in the same geographical area may change over time. Am. J. Rhinol. Allergy 27:5354–60 [Google Scholar]
  160. Matsusaka M, Kabata H, Fukunaga K, Suzuki Y, Masaki K. 160.  et al. 2015. Phenotype of asthma related with high serum periostin levels. Allergol. Int. 64:2175–80 [Google Scholar]
  161. Mahdavinia M, Suh LA, Carter RG, Stevens WW, Norton JE. 161.  et al. 2015. Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second-generation Asians suggest genetic regulation of eosinophilia. J. Allergy Clin. Immunol. 135:2576–79 [Google Scholar]
  162. Alexander ES, Martin LJ, Collins MH, Kottyan LC, Sucharew H. 162.  et al. 2014. Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis. J. Allergy Clin. Immunol. 134:51084–92 [Google Scholar]
  163. Rothenberg ME. 163.  2009. Biology and treatment of eosinophilic esophagitis. Gastroenterology 137:41238–49 [Google Scholar]
  164. Leong AB, Ramsey CD, Celedon JC. 164.  2012. The challenge of asthma in minority populations. Clin. Rev. Allergy Immunol. 43:1–2156–83 [Google Scholar]
  165. Pino-Yanes M, Thakur N, Gignoux CR, Galanter JM, Roth LA. 165.  et al. 2015. Genetic ancestry influences asthma susceptibility and lung function among Latinos. J. Allergy Clin. Immunol. 135:1228–35 [Google Scholar]
  166. Soler ZM, Mace JC, Litvack JR, Smith TL. 166.  2012. Chronic rhinosinusitis, race, and ethnicity. Am. J. Rhinol. Allergy 26:2110–16 [Google Scholar]
  167. Mahdavinia M, Benhammuda M, Codispoti CD, Tobin MC, Losavio PS. 167.  et al. 2016. African American patients with chronic rhinosinusitis have a distinct phenotype of polyposis associated with increased asthma hospitalization. J. Allergy Clin. Immunol. Pract. 4:4658–64 [Google Scholar]
  168. Pinto JM, Schneider J, Perez R, DeTineo M, Baroody FM. 168.  et al. 2008. Serum 25-hydroxyvitamin D levels are lower in urban African American subjects with chronic rhinosinusitis. J. Allergy Clin. Immunol. 122:2415–17 [Google Scholar]
  169. Bush CM, Jang DW, Champagne JP, Kountakis SE. 169.  2013. Epidemiologic factors and surgical outcomes in patients with nasal polyposis and asthma. ORL J. Otorhinolaryngol. Relat. Spec. 75:6320–24 [Google Scholar]
  170. Ponikau JU, Sherris DA, Kephart GM, Adolphson C, Kita H. 170.  2006. The role of ubiquitous airborne fungi in chronic rhinosinusitis. Clin. Rev. Allergy Immunol. 30:3187–94 [Google Scholar]
  171. Fokkens WJ, van Drunen C, Georgalas C, Ebbens F. 171.  2012. Role of fungi in pathogenesis of chronic rhinosinusitis: the hypothesis rejected. Curr. Opin. Otolaryngol. Head Neck Surg. 20:119–23 [Google Scholar]
  172. Bachert C, Gevaert P, van Cauwenberge P. 172.  2002. Staphylococcus aureus enterotoxins: A key in airway disease?. Allergy 57:6480–87 [Google Scholar]
  173. Ramadan HH, Sanclement JA, Thomas JG. 173.  2005. Chronic rhinosinusitis and biofilms. Otolaryngol. Head Neck Surg. 132:3414–17 [Google Scholar]
  174. Sanderson AR, Leid JG, Hunsaker D. 174.  2006. Bacterial biofilms on the sinus mucosa of human subjects with chronic rhinosinusitis. Laryngoscope 116:71121–26 [Google Scholar]
  175. Rank MA, Wollan P, Kita H, Yawn BP. 175.  2010. Acute exacerbations of chronic rhinosinusitis occur in a distinct seasonal pattern. J. Allergy Clin. Immunol. 126:1168–69 [Google Scholar]
  176. Chalermwatanachai T, Velasquez LC, Bachert C. 176.  2015. The microbiome of the upper airways: focus on chronic rhinosinusitis. World Allergy Organ. J. 8:13 [Google Scholar]
  177. Mahdavinia M, Keshavarzian A, Tobin MC, Landay AL, Schleimer RP. 177.  2016. A comprehensive review of the nasal microbiome in chronic rhinosinusitis (CRS). Clin. Exp. Allergy 46:121–41 [Google Scholar]
  178. Bachert C, Holtappels G. 178.  2015. Pathophysiology of chronic rhinosinusitis, pharmaceutical therapy options. GMS Curr. Top. Otorhinolaryngol. Head Neck Surg. 14:Doc09 [Google Scholar]
  179. Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N. 179.  et al. 2013. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J. Allergy Clin. Immunol. 131:1110–16 [Google Scholar]
  180. Kiwamoto T, Kawasaki N, Paulson JC, Bochner BS. 180.  2012. Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions. Pharmacol. Ther. 135:3327–36 [Google Scholar]
  181. Krug N, Hohlfeld JM, Kirsten AM, Kornmann O, Beeh KM. 181.  et al. 2015. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N. Engl. J. Med. 372:211987–95 [Google Scholar]
  182. Ly TW, Bacon KB. 182.  2005. Small-molecule CRTH2 antagonists for the treatment of allergic inflammation: an overview. Expert Opin. Investig. Drugs 14:7769–73 [Google Scholar]
  183. Markham A. 183.  2016. Reslizumab: first global approval. Drugs 76:8907–11 Erratum 2016. Drugs 76:111159 [Google Scholar]
  184. Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P. 184.  et al. 2014. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir. Med. 2:11879–90 [Google Scholar]
  185. Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV. 185.  et al. 2011. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365:121088–98 [Google Scholar]
  186. Schwartz DM, Bonelli M, Gadina M, O'Shea JJ. 186.  2016. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat. Rev. Rheumatol. 12:125–36 [Google Scholar]

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