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from our study was that CF had high CD19 and plasma cells. This is consistent with the literature, which states that CF patients have elevated levels of IgG, IgM, and IgA, especially during an infection. 29 So it is very likely that immunoglobulin also contributes to combating the bacterial sinus infection commonly encountered in CF patients. The treatment for CRS in CF patients will likely involve multimodal treatments. One treatment would be to loosen the tenacious mucus with inhaled dornase alfa 30 or hypertonic sinus irrigation. Topical nasal ste- roid spray can be used to decrease the local inflammation of the sinuses. Also, because LTB4 is increased in CF patients, especially with an active pseu- domonas infection, zileuton could be used to block the production of LTB4 and minimize PMN recruitment that causes local epithelial destruction. By minimizing PMN recruitment and release of elastase, immunoglobulin can be spared to prevent bacterial infection along mucosal surfaces. 31 It is theoretical that zileuton has the possibil- ity of improving the upper respiratory tract as well as the lower respiratory tract. However, the liver needs to be carefully monitored for liver toxicity when using of zileuton. As a last resort and after medical treatment has failed, if sinus surgery is needed, making large an- trostomies and opening up all the sinuses should be considered. By creating large opening into the sinuses, this will allow for topical medication to get into the sinuses and to prevent future sinus surgery. 32 Limitations There are some limitations of the proposed subclas- sification of CRS. First, this classification of CRS may not address all the different forms of CRS, such as CRS due to vasculitis or sarcoidosis. Another limitation is that although the presence or absence of allergy and asthma was documented, the severity was not. For allergy, total serum IgE could be used as a measure to determine the severity of the allergy. However, this was difficult to do in this study because some of the patients received a radioallergosorbent test, whereas others received skin prick testing. One other limitation is that the innate immunity was not investigated in the CRS study group. It is likely that innate immunity may play a role for some of the CRS subclasses, especially for non- asthmatic sinusitis. Finally, the number of patients in each CRS subclasses was not large. With a higher num- ber of specimens in each CRS subclass, statistical significance may be found that was not demonstrated in this study. However, this study nonetheless is an impres- sive undertaking. This is the first study to comprehensively compile the phenotype characteristics among CRS patients and also include the difference of biomarker with intracellular staining of cytokines among CRS patients. CONCLUSION Nasal mucosal swelling and polyps are the end product of sinus inflammation. By characterizing the phenotype and pathway of nasal polyp inflammation for

various types of CRS, well-characterized and distinct groups of CRS have been defined. By defining the differ- ent discrete category for CRS, a targeted treatment plan for each CRS subclass has been discussed in the article. Also, by defining specific CRS entities, hopefully these CRS subclassifications can be use in future bench and clinical research studies. Acknowledgement First of all, I would like to thank God who made all things possible. I appreciate Larry Borish, MD and Thomas Platts-Mill, MD for helping me better understand allergy. I am grateful to Marc Silverberg, MD for his ex- pertise in the histologic examination and Elena Galkina, PhD in the flow cytometry. I extend my graditude to Christopher Benson, Rachel Moebus, and Matthew Butcher for their insightful perspective and assistance. Finally for her inspiration and constant support, I owe my thesis to my wonderful wife Caroline Han, MD. BIBLIOGRAPHY 1. Chester AC, Antisdel JL, Sindwani R. Symptom specific outcomes of endo- scopic sinus surgery: a systemic review. Otolaryngol Head Neck Surg 2009;140:633–639. 2. Ebbens, FA, Georgala C, Luiten S, et al. The effect of topical amphotericin B on inflammatory markers in patients with chronic rhinosinusitis: a multicenter randomized controlled study. Laryngoscope 2009;119:401– 408. 3. Wallwork B, Coman W, MacKay-Sim A, et al. A double-blind randomized placebo controlled trial of macrolide in the treatment of chronic rhinosi- nusitis. Laryngoscope 2006;116:189–193. 4. Haruna, S, Shimada C, Ozawa M, et al. A study of poor responders for long term low dose macrolide for chronic sinusitis. Rhinology 2009;47:66–71. 5. Demarcantonio MA, Han JK. Systemic therapies in managing sinonasal inflammation. Otolaryngol Clin North Am 2010;43:551–563. 6. Krouse JH, Brown RW, Fineman SJ, et al. Asthma and the unified airway. Otolaryngol Head Neck Surg 2007;136(5 suppl):S75–S106. 7. Caughey RJ, Jameson MJ, Gross CW, et al. Anatomic risk factors for sinus disease: fact or fiction? Am J Rhinol 2005;19:334–339. 8. Payne SC, Han JK, Huyett P, et al. Microarray analysis of distinct gene transcription profiles in noneosinophilic chronic sinusitis with nasal pol- yps. Am J Rhinol 2008;22:568–581. 9. Early SB, Hise K, Han JK, et al. Hypoxia stimulates inflammatory and fibrotic responses from nasal polyp derived fibroblasts. Laryngoscope 2007;117:511–515. 10. Hekiert AM, Kofonow JM, Doghramji, et al. Biofilms correlate with Th1 inflammation in the sinonasal tissue of patients with chronic rhinosinu- sitis. Otolaryng Head Neck Surg 2009;141:448–453. 11. Braunstahl GJ, Overbeek SE, Kleinjan A, et al. Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. J Allergy Clin Immunol 107:469–476. 12. Oh CK, Geba GP, Molfino N. Investigational therapeutics targeting the IL4/IL13/STAT 6 pathway for treatment of asthma. Eur Respir Rev 2000;19:46–54. 13. Bachert C, Zhang N, Holtappels G, et al. Presence of IL5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma. J Allergy Clin Immunol 2010;126:962–968. 14. Steinke JW, Payne SC, Tessier ME, et al. Pilot study of budesonide inhal- ant suspension irrigations for chronic eosinophilic sinusitis. J Allergy Clin Immunol 2009;124:1352–1354. 15. Tanaka A, Obashi Y, Kakinoki Y, et al. Immunotherapy suppresses both Th1 and Th2 responses by allergen stimulation, but suppression of the Th2 response is more important mechanism related to the clinical effi- cacy of immunotherapy for perennial allergic rhinitis. Scand J Immunol 1998;48:201–211. 16. Nelson HS. Advances in upper airway diseases and allergen immunother- apy. J Allergy Clin Immunol 2007;119:872–880. 17. Kim BS, Park SM, Uhm TG, et al. Effect of single nucleotide polymorphisms within IL4 promoter on aspirin intolerance in asth- matics and IL4 promoter activity. Pharmacogenet Genomics 2010;20:748–758. 18. Higashi N, Taniguchi M, Mita H, et al. Clinical features of asthmatic patients with increase urinary LTE4 excretion; Involvement of chronic hyperplastic rhinosinusitis with nasal polyposis. J Allergy Clin Immunol 2004;113:277–283.

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