Asthma phenotypes in adults and clinical implications

References

• Wenzel SE, Busse WW. Severe asthma: lessons from the Severe Asthma Research Program. J. Allergy Clin. Immunol.119(1), 14–21 (2007).
   PubMedGoogle Scholar
• National Asthma Education and Prevention Program. Expert panel report 3 (EPR3): guidelines for the diagnosis and management of asthma. J. Allergy Clin. Immunol.120(5 Suppl.), S94–S138 (2007).
   PubMed Web of Science ®Google Scholar
• Encarta World English Dictionary. Soukhanov Am (Ed.). St Martin Press, NY, USA (1999).
   Google Scholar
• D’silva L, Cook RJ, Allen CJ, Hargreave FE, Parameswaran K. Changing pattern of sputum cell counts during successive exacerbations of airway disease. Respir. Med.101(10), 2217–2220 (2007).
   PubMed Web of Science ®Google Scholar
• Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet368(9537), 804–813 (2006).
   PubMed Web of Science ®Google Scholar
• Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J. Allergy Clin. Immunol.113(1), 101–108 (2004).
   PubMed Web of Science ®Google Scholar
• Miller MK, Johnson C, Miller DP, Deniz Y, Bleecker ER, Wenzel SE; TENOR Study Group. Severity assessment in asthma: an evolving concept. J. Allergy Clin. Immunol.116(5), 990–995 (2005).
   PubMed Web of Science ®Google Scholar
• Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention (GINA). NIH, National Heart, Lung and Blood Institute, Bethesda, MD, USA, Report no. 02–3659 (2002).
   Google Scholar
• Bateman ED, Hurd SS, Barnes PJ et al. Global strategy for asthma management and prevention: GINA executive summary. Eur. Respir. J.31(1), 143–178 (2008).
   PubMed Web of Science ®Google Scholar
• Wenzel SE, Schwartz LB, Langmack EL et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am. J. Respir. Crit. Care Med.160(3), 1001–1008 (1999).
   PubMed Web of Science ®Google Scholar
• Wenzel SE, Fahy J, Irvin C, Peters S, Spector S, Szefler S. Proceedings of the ATS Workshop on Refractory Asthma. Am. J. Respir. Crit. Care Med.162(6), 2341–2351 (2000).
   PubMedGoogle Scholar
• Moore WC, Bleecker ER, Curran-Everett D et al.; for the National Heart, Lung, Blood Institute’s Severe Asthma Research Program. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. J. Allergy Clin. Immunol.119(2), 405–413 (2007).
   PubMed Web of Science ®Google Scholar
• The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma. Eur. Respir. J.22(3), 470–477 (2003).
   PubMed Web of Science ®Google Scholar
• Sorkness RL, Bleecker ER, Busse WW et al. National Heart, Lung, and Blood Institute Severe Asthma Research Program. Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation. J. Appl. Physiol.104(2), 394–403 (2008).
   PubMed Web of Science ®Google Scholar
• Fitzpatrick AM, Gaston BM, Erzurum SC, Teague WG. National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. Features of severe asthma in school-age children: Atopy and increased exhaled nitric oxide. J. Allergy Clin. Immunol.118(6), 1218–1225 (2006).
   PubMed Web of Science ®Google Scholar
• Chan MT, Leung DY, Szefler SJ, Spahn JD. Difficult-to-control asthma: clinical characteristics of steroid-insensitive asthma. J. Allergy Clin. Immunol.101(5), 594–601 (1998).
   PubMed Web of Science ®Google Scholar
• Thomson NC, Chaudhuri R. Identification and management of adults with asthma prone to exacerbations: can we do better? BMC Pulm. Med.8(27), 1–3 (2008).
   PubMedGoogle Scholar
• Dougherty RH, Fahy JV. Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype. Clin. Exp. Allergy39(2), 193–202 (2009).
   PubMed Web of Science ®Google Scholar
• ten Brinke A, Ouwerkerk ME, Zwinderman AH, Spinhoven P, Bel EH. Psychopathology in patients with severe asthma is associated with increased health care utilization. Am. J. Respir. Crit. Care Med.163(5), 1093–1096 (2001).
   PubMed Web of Science ®Google Scholar
• Busse W, Corren J, Lanier BQ et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J. Allergy Clin. Immunol.108(2), 184–190 (2001).
   PubMed Web of Science ®Google Scholar
• Solèr M, Matz J, Townley R et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur. Respir. J.18(2), 254–261 (2001).
   PubMed Web of Science ®Google Scholar
• Milgrom H, Berger W, Nayak A et al. Treatment of childhood asthma with anti- immunoglobulin E antibody (omalizumab). Pediatrics108, e36 (2001).
   PubMed Web of Science ®Google Scholar
• Haldar P, Brightling CE, Hargadon B et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med.360(10), 973–984 (2009).
   PubMed Web of Science ®Google Scholar
• Nair P, Pizzichini MM, Kjarsgaard M et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med.360(10), 985–993 (2009).
   PubMed Web of Science ®Google Scholar
• Covar RA, Spahn JD, Murphy JR, Szefler SJ; for the Childhood Asthma Management Program Research Group. Progression of asthma measured by lung function in the childhood asthma management program. Am. J. Respir. Crit. Care Med.170(3), 234–241 (2004).
   PubMed Web of Science ®Google Scholar
• Dolan CM, Fraher KE, Bleecker ER et al. Design and baseline characteristics of the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma. Ann. Allergy Asthma Immunol.92(1), 32–39 (2004).
   PubMed Web of Science ®Google Scholar
• Lee JH, Haselkorn T, Borish L, Rasouliyan L, Chipps BE, Wenzel SE. Risk factors associated with persistent airflow limitation in severe or difficult-to-treat asthma: insights from the TENOR study. Chest132(6), 1882–1889 (2007).
   PubMed Web of Science ®Google Scholar
• Bumbacea D, Campbell D, Nguyen L et al. Parameters associated with persistent airflow obstruction in chronic severe asthma. Eur. Respir. J.24(1), 122–128 (2004).
   PubMed Web of Science ®Google Scholar
• ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. Factors associated with persistent airflow limitation in severe asthma. Am. J. Respir. Crit. Care Med.164(5), 744–748 (2001).
   PubMed Web of Science ®Google Scholar
• Sandford AJ, Chagani T, Zhu S et al. Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. J. Allergy Clin. Immunol.106(1 Pt 1), 135–140 (2000).
   PubMed Web of Science ®Google Scholar
• Beghé B, Barton S, Rorke S et al. Polymorphisms in the interleukin-4 and interleukin-4 receptor α chain genes confer susceptibility to asthma and atopy in a Caucasian population. Clin. Exp. Allergy33(8), 1111–1117 (2003).
   PubMed Web of Science ®Google Scholar
• Pulleyn LJ, Newton R, Adcock IM, Barnes PJ. TGFβ1 allele association with asthma severity. Hum. Genet.109(6), 623–627 (2001).
   PubMed Web of Science ®Google Scholar
• Silverman ES, Palmer LJ, Subramaniam V et al. Transforming growth factor-β1 promoter polymorphism C-509T is associated with asthma. Am. J. Respir. Crit. Care Med.169(2), 214–219 (2004).
   PubMed Web of Science ®Google Scholar
• Ueda T, Niimi A, Matsumoto H et al. TGFB1 promoter polymorphism C-509T and pathophysiology of asthma. J. Allergy Clin. Immunol.121(3), 659–664 (2008).
   PubMed Web of Science ®Google Scholar
• Howard TD, Postma DS, Jongepier H et al. Association of a disintegrin and metalloprotease 33 (ADAM33) gene with asthma in ethnically diverse populations. J. Allergy Clin. Immunol.112(4), 717–722 (2003).
   PubMed Web of Science ®Google Scholar
• Lee JH, Park HS, Park SW et al. ADAM33 polymorphism: association with bronchial hyper-responsiveness in Korean asthmatics. Clin. Exp. Allergy34(6), 860–865 (2004).
   PubMed Web of Science ®Google Scholar
• Jongepier H, Boezen HM, Dijkstra A et al. Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma. Clin. Exp. Allergy34(5), 757–760 (2004).
   PubMed Web of Science ®Google Scholar
• van Diemen CC, Postma DS, Vonk JM, Bruinenberg M, Schouten JP, Boezen HM. A disintegrin and metalloprotease 33 polymorphisms and lung function decline in the general population. Am. J. Respir. Crit. Care Med.172(3), 329–333 (2005).
   PubMed Web of Science ®Google Scholar
• van Veen IH, ten Brinke A, van der Linden AC, Rabe KF, Bel EH. Deficient α-1-antitrypsin phenotypes and persistent airflow limitation in severe asthma. Respir. Med.100(9), 1534–1539 (2006).
   PubMed Web of Science ®Google Scholar
• Dijkstra A, Vonk JM, Jongepier H et al. Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex. Thorax61(2), 105–110 (2006).
   PubMed Web of Science ®Google Scholar
• Heaney LG, Robinson DS. Severe asthma treatment: need for characterising patients. Lancet365(9463), 974–976 (2005).
   PubMed Web of Science ®Google Scholar
• Adcock IM, Ito K. Steroid resistance in asthma: a major problem requiring novel solutions or a non-issue? Curr. Opin Pharmacol.4(3), 257–262 (2004).
   PubMed Web of Science ®Google Scholar
• Szefler SJ, Martin RJ, King TS et al.; Asthma Clinical Research Network of the National Heart Lung, and Blood Institute. Significant variability in response to inhaled corticosteroids for persistent asthma. J. Allergy Clin. Immunol.109(3), 410–418 (2002).
   PubMed Web of Science ®Google Scholar
• Martin RJ, Szefler SJ, King TS et al. National Heart, Lung, and Blood Institute’s Asthma Clinical Research Center. The Predicting Response to Inhaled Corticosteroid Efficacy (PRICE) trial. J. Allergy Clin. Immunol.119(1), 73–80 (2007).
   PubMed Web of Science ®Google Scholar
• Adcock IM, Lane SJ. Corticosteroid-insensitive asthma: molecular mechanisms. J. Endocrinol.178(3), 347–355 (2003).
   PubMed Web of Science ®Google Scholar
• Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid resistance. Chest134(2), 394–401 (2008).
   PubMed Web of Science ®Google Scholar
• Adcock IM, Ford PA, Bhavsar P, Ahmad T, Chung KF. Steroid resistance in asthma: mechanisms and treatment options. Curr. Allergy Asthma Rep.8(2), 171–178 (2008).
   PubMed Web of Science ®Google Scholar
• Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet373(9678), 1905–1917 (2009).
   PubMed Web of Science ®Google Scholar
• Bacci E, Cianchetti S, Bartoli M et al. Low sputum eosinophils predict the lack of response to beclomethasone in symptomatic asthmatic patients. Chest129(3), 565–572 (2006).
   PubMed Web of Science ®Google Scholar
• Tsoumakidou M, Papadopouli E, Tzanakis N, Siafakas NM. Airway inflammation and cellular stress in noneosinophilic atopic asthma. Chest129(5), 1194–1202 (2006).
   PubMedGoogle Scholar
• Pavord ID, Brightling CE, Woltmann G et al. Non-eosinophilic corticosteroid unresponsive asthma. Lancet353(9171), 2213–2214 (1999).
   PubMed Web of Science ®Google Scholar
• Green RH, Brightling CE, Woltmann G et al. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax57(10), 875–879 (2002).
   PubMed Web of Science ®Google Scholar
• Lane SJ, Adcock IM, Richards D, Hawrylowicz C, Barnes PJ, Lee TH. Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes. J. Clin. Invest.102(12), 2156–2164 (1998).
   PubMed Web of Science ®Google Scholar
• Kraft M, Hamid Q, Chrousos GP, Martin RJ, Leung DY. Decreased steroid responsiveness at night in nocturnal asthma. Is the macrophage responsible? Am. J. Respir. Crit. Care Med.163(5), 1219–1225 (2001).
   PubMed Web of Science ®Google Scholar
• Barnes PJ, Adcock IM, Ito K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur. Respir. J.25(3), 552–563 (2005).
   PubMed Web of Science ®Google Scholar
• Goleva E, Hauk PJ, Hall CF et al. Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages. J. Allergy Clin. Immunol.122(3), 550–559.e3 (2008).
   PubMed Web of Science ®Google Scholar
• McKinley L, Alcorn JF, Peterson A et al. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J. Immunol.181(6), 4089–4097 (2008).
   PubMed Web of Science ®Google Scholar
• Yang M, Kumar RK, Foster PS. Pathogenesis of steroid-resistant airway hyperresponsiveness: interaction between IFN-γ and TLR4/MyD88 pathways. J. Immunol.182(8), 5107–5115 (2009).
   PubMedGoogle Scholar
• Wenzel S. Severe/fatal asthma. Chest123(3 Suppl.), 405S–410S (2003).
   Google Scholar
• Weidinger S, O’Sullivan M, Illig T et al. Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J. Allergy Clin. Immunol.121(5), 1203–1209.e1 (2008).
   PubMed Web of Science ®Google Scholar
• Marenholz I, Kerscher T, Bauerfeind A et al. An interaction between filaggrin mutations and early food sensitization improves the prediction of childhood asthma. J. Allergy Clin. Immunol.123(4), 911–916 (2009).
   PubMedGoogle Scholar
• Moffatt MF, Kabesch M, Liang L et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature448(7152), 470–473 (2007).
   PubMed Web of Science ®Google Scholar
• Bouzigon E, Corda E, Aschard H et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N. Engl. J. Med.359(19), 1985–1994 (2008).
   PubMed Web of Science ®Google Scholar
• Morita H, Nagai R, Bouzigon E, Siroux V, Demenais F. Smoking exposure, 17q21 variants, and early-onset asthma. N. Engl. J. Med.360(12), 1255–1256 (2009).
   PubMedGoogle Scholar
• Tang EA, Matsui E, Wiesch DG, Samet JM. Epidemiology of asthma and allergic diseases. In: Middleton’s Allergy: Principles and Practice (7th Edition). Adkinson NF Jr, Yunginger J, Busse W (Eds). Mosby, MO, USA, 1715–1756 (2008).
   Google Scholar
• Celedon JC, Wright RJ, Litonjua AA et al. Day care attendance in early life, maternal history of asthma, and asthma at the age of 6 years. Am. J. Respir. Crit. Care Med.167(9), 1239–1243 (2003).
   PubMed Web of Science ®Google Scholar
• Illi S, von Mutius E, Lau S et al.; Multicenter Allergy Study Group. The pattern of atopic sensitization is associated with the development of asthma in childhood. J. Allergy Clin. Immunol.108(5), 709–714 (2001).
   PubMed Web of Science ®Google Scholar
• Celedón JC, Litonjua AA, Ryan L, Platts-Mills T, Weiss ST, Gold DR. Exposure to cat allergen, maternal history of asthma, and wheezing in first 5 years of life. Lancet360(9335), 781–782 (2002).
   PubMed Web of Science ®Google Scholar
• Lau S, Illi S, Platts-Mills TA et al.; Multicentre Allergy Study Group. Longitudinal study on the relationship between cat allergen and endotoxin exposure, sensitization, cat-specific IgG and development of asthma in childhood – report of the German Multicentre Allergy Study (MAS 90). Allergy60(6), 766–773 (2005).
   PubMed Web of Science ®Google Scholar
• Rosenstreich DL, Eggleston P, Kattan M et al. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N. Engl. J. Med.336(19), 1356–1363 (1997).
   PubMed Web of Science ®Google Scholar
• Perzanowski MS, Miller RL, Thorne PS et al. Endotoxin in inner-city homes: associations with wheeze and eczema in early childhood. J. Allergy Clin. Immunol.117(5), 1082–1089 (2006).
   PubMed Web of Science ®Google Scholar
• Donohue KM, Al-alem U, Perzanowski MS et al. Anti-cockroach and anti-mouse IgE are associated with early wheeze and atopy in an inner-city birth cohort. J. Allergy Clin. Immunol.122(5), 914–920 (2008).
   PubMed Web of Science ®Google Scholar
• Martinez FD, Holt PG. Role of microbial burden in aetiology of allergy and asthma. Lancet354(Suppl. 2), SII12–SII15 (1999).
   PubMedGoogle Scholar
• Hesselmar B, Aberg N, Aberg B, Eriksson B, Björkstén B. Does early exposure to cat or dog protect against later allergy development? Clin. Exp. Allergy29(5), 611–617 (1999).
   PubMed Web of Science ®Google Scholar
• Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ, Martinez FD, Wright AL. Siblings, day-care attendance, and risk of asthma and wheezing during childhood. N. Engl. J. Med.343(8), 538–543 (2000).
   PubMed Web of Science ®Google Scholar
• Gereda JE, Leung DY, Liu AH. Levels of environmental endotoxin and prevalence of atopic disease. JAMA284(13), 1652–1653 (2000).
   PubMedGoogle Scholar
• Remes ST, Castro-Rodriguez JA, Holberg CJ, Martinez FD, Wright AL. Dog exposure in infancy decreases the subsequent risk of frequent wheeze but not of atopy. J. Allergy Clin. Immunol.108(4), 509–515 (2001).
   PubMed Web of Science ®Google Scholar
• Riedler J, Braun-Fahrländer C, Eder W et al.; ALEX Study Team. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet358(9288), 1129–1133 (2001).
   PubMed Web of Science ®Google Scholar
• Nafstad P, Magnus P, Gaarder PI, Jaakkola JJ. Exposure to pets and atopy-related diseases in the first 4 years of life. Allergy56(4), 307–312 (2001).
   PubMed Web of Science ®Google Scholar
• Braun-Fahrländer C, Riedler J, Herz U et al.; Allergy and Endotoxin Study Team. Environmental exposure to endotoxin and its relation to asthma in school-age children. N. Engl. J. Med.347(12), 869–877 (2002).
   PubMed Web of Science ®Google Scholar
• Ege MJ, Frei R, Bieli C et al.; PARSIFAL Study team. Not all farming environments protect against the development of asthma and wheeze in children. J. Allergy Clin. Immunol.119(5), 1140–1147 (2007).
   PubMed Web of Science ®Google Scholar
• Wills-Karp M, Luyimbazi J, Xu X et al. Interleukin-13: central mediator of allergic asthma. Science282(5397), 2258–2261 (1998).
   PubMed Web of Science ®Google Scholar
• Grünig G, Warnock M, Wakil AE et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science282(5397), 2261–2263 (1998).
   PubMed Web of Science ®Google Scholar
• Wills-Karp M. Murine models of asthma in understanding immune dysregulation in human asthma. Immunopharmacology48(3), 263–268 (2000).
   PubMedGoogle Scholar
• Wills-Karp M. Interleukin-13 in asthma pathogenesis. Immunol. Rev.202, 175–190 (2004).
   PubMed Web of Science ®Google Scholar
• Kay AB. The role of T lymphocytes in asthma. Chem. Immunol. Allergy91, 59–75 (2006).
   PubMedGoogle Scholar
• Perkins C, Wills-Karp M, Finkelman FD. IL-4 induces IL-13-independent allergic airway inflammation. J. Allergy Clin. Immunol.118(2), 410–419 (2006).
   PubMed Web of Science ®Google Scholar
• Gundel R, Lindell D, Harris P, Fournel M, Jesmok G, Gerritsen ME. IL-4 induced leukocyte trafficking in cynomolgus monkeys: correlation with expression of adhesion molecules and chemokine generation. Clin. Exp. Allergy26(6), 719–729 (1996).
   PubMedGoogle Scholar
• Blease K, Jakubzick C, Westwick J, Lukacs N, Kunkel SL, Hogaboam CM. Therapeutic effect of IL-13 immunoneutralization during chronic experimental fungal asthma. J. Immunol.166(8), 5219–5224 (2001).
   PubMed Web of Science ®Google Scholar
• Tomkinson A, Duez C, Cieslewicz G et al. A murine IL-4 receptor antagonist that inhibits IL-4- and IL-13-induced responses prevents antigen-induced airway eosinophilia and airway hyperresponsiveness. J. Immunol.166(9), 5792–5800 (2001).
   PubMedGoogle Scholar
• Hessel EM, Chu M, Lizcano JO et al. Immunostimulatory oligonucleotides block allergic airway inflammation by inhibiting Th2 cell activation and IgE-mediated cytokine induction. J. Exp. Med.202(11), 1563–1573 (2005).
   PubMed Web of Science ®Google Scholar
• Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two Phase 2a studies. Lancet370(9596), 1422–1431 (2007).
   PubMed Web of Science ®Google Scholar
• Hytönen AM, Löwhagen O, Arvidsson M et al. Haplotypes of the interleukin-4 receptor α chain gene associate with susceptibility to and severity of atopic asthma. Clin. Exp. Allergy34(10), 1570–1575 (2004).
   PubMed Web of Science ®Google Scholar
• Isidoro-García M, Dávila I, Laffond E, Moreno E, Lorente F, González-Sarmiento R. Interleukin-4 (IL4) and interleukin-4 receptor (IL4RA) polymorphisms in asthma: a case control study. Clin. Mol. Allergy3(15), 1–7 (2005).
   PubMedGoogle Scholar
• Ober C, Hoffjan S. Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun.7(2), 95–100 (2006).
   PubMed Web of Science ®Google Scholar
• Wenzel SE, Balzar S, Ampleford E et al. IL4R α mutations are associated with asthma exacerbations and mast cell/IgE expression. Am. J. Respir. Crit. Care Med.175(6), 570–576 (2007).
   PubMed Web of Science ®Google Scholar
• Daley D, Lemire M, Akhabir L et al. Analyses of associations with asthma in four asthma population samples from Canada and Australia. Hum. Genet.125(4), 445–459 (2009).
   PubMedGoogle Scholar
• Weiss ST, Raby BA, Rogers A. Asthma genetics and genomics 2009. Curr. Opin. Genet. Dev.19(3), 279–282 (2009).
   PubMed Web of Science ®Google Scholar
• Woodruff PG, Modrek B, Choy DF et al. Th2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med.180(5), 388–395 (2009).
   PubMed Web of Science ®Google Scholar
• Black S, Teixeira AS, Loh AX et al. Contribution of functional variation in the IL13 gene to allergy, hay fever and asthma in the NSHD longitudinal 1946 birth cohort. Allergy64(8), 1172–1178 (2009).
   PubMed Web of Science ®Google Scholar
• Marenholz I, Nickel R, Rüschendorf F et al. Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J. Allergy Clin. Immunol.118(4), 866–871 (2006).
   PubMed Web of Science ®Google Scholar
• Henderson J, Northstone K, Lee SP et al. The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study. J. Allergy Clin. Immunol.121(4), 872–877.e9 (2008).
   PubMedGoogle Scholar
• van den Oord RA, Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. Br. Med. J. DOI: 10.1136/bmj.b1203(2009) (Epub ahead of print).
   PubMedGoogle Scholar
• Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst. Rev.4, CD001186 (2003).
   PubMedGoogle Scholar
• Cevit O, Kendirli SG, Yilmaz M, Altintas DU, Karakoc GB. Specific allergen immunotherapy: effect on immunologic markers and clinical parameters in asthmatic children. J. Investig. Allergol. Clin. Immunol.17(5), 286–291 (2007).
   PubMed Web of Science ®Google Scholar
• Buhl R, Solèr M, Matz J et al. Omalizumab provides long-term control in patients with moderate-to-severe allergic asthma. Eur. Respir. J.20(1), 73–78 (2002).
   PubMed Web of Science ®Google Scholar
• Bosquet J, Cabrera P, Berkman N et al. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma. Allergy60(3), 302–308 (2005).
   PubMedGoogle Scholar
• Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J. Allergy Clin. Immunol.111(5), 913–921 (2003).
   PubMed Web of Science ®Google Scholar
• Stevenson DD, Szczeklik A. Clinical and pathologic perspectives on aspirin sensitivity and asthma. J. Allergy Clin. Immunol.118(4), 773–786 (2006).
   PubMed Web of Science ®Google Scholar
• Szczeklik A. Aspirin-induced asthma as a viral disease. Clin. Allergy18(1), 15–20 (1988).
   PubMedGoogle Scholar
• Szczeklik A, Sanak M. The broken balance in aspirin hypersensitivity. Eur. J. Pharmacol.533(1–3), 145–155 (2006).
   PubMed Web of Science ®Google Scholar
• Sousa AR, Lams BE, Pfister R, Christie PE, Schmitz M, Lee TH. Expression of interleukin-5 and granulocyte–macrophage colony-stimulating factor in aspirin-sensitive and non-aspirin-sensitive asthmatic airways. Am. J. Respir. Crit. Care Med.156(5), 1384–1389 (1997).
   PubMedGoogle Scholar
• Sousa AR, Parikh A, Scadding G, Corrigan CJ, Lee TH. Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N. Engl. J. Med.347(19), 1493–1499 (2002).
   PubMed Web of Science ®Google Scholar
• Corrigan C, Mallett K, Ying S et al. Expression of the cysteinyl leukotriene receptors cysLT(1) and cysLT(2) in aspirin-sensitive and aspirin-tolerant chronic rhinosinusitis. J. Allergy Clin. Immunol.115(2), 316–322 (2005).
   PubMedGoogle Scholar
• Stankovic KM, Goldsztein H, Reh DD, Platt MP, Metson R. Gene expression profiling of nasal polyps associated with chronic sinusitis and aspirin-sensitive asthma. Laryngoscope118(5), 881–889 (2008).
   PubMed Web of Science ®Google Scholar
• Kim SH, Hur GY, Choi JH, Park HS. Pharmacogenetics of aspirin-intolerant asthma. Pharmacogenomics9(1), 85–91 (2008).
   PubMed Web of Science ®Google Scholar
• Sanak M, Simon HU, Szczeklik A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet350(9091), 1599–1600 (1997).
   PubMed Web of Science ®Google Scholar
• Cowburn AS, Sladek K, Soja J et al. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J. Clin. Invest.101(4), 834–846 (1998).
   PubMed Web of Science ®Google Scholar
• Sanak M, Pierzchalska M, Bazan-Socha S, Szczeklik A. Enhanced expression of the leukotriene C(4) synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma. Am. J. Respir. Cell. Mol. Biol.23(3), 290–296 (2000).
   PubMed Web of Science ®Google Scholar
• Sanak M, Szczeklik A. Leukotriene C4 synthase polymorphism and aspirin-induced asthma. J. Allergy Clin. Immunol.107(3), 561–562 (2001).
   PubMedGoogle Scholar
• Kawagishi Y, Mita H, Taniguchi M et al. Leukotriene C4 synthase promoter polymorphism in Japanese patients with aspirin-induced asthma. J. Allergy Clin. Immunol.109(6), 936–942 (2002).
   PubMed Web of Science ®Google Scholar
• Kim SH, Oh JM, Kim YS et al. Cysteinyl leukotriene receptor 1 promoter polymorphism is associated with aspirin-intolerant asthma in males. Clin. Exp. Allergy36(4), 433–439 (2006).
   PubMed Web of Science ®Google Scholar
• Kim SH, Yang EM, Park HJ, Ye YM, Lee HY, Park HS. Differential contribution of the CysLTR1 gene in patients with aspirin hypersensitivity. J. Clin. Immunol.27(6), 613–619 (2007).
   PubMedGoogle Scholar
• Kim SH, Ye YM, Hur GY et al. CysLTR1 promoter polymorphism and requirement for leukotriene receptor antagonist in aspirin-intolerant asthma patients. Pharmacogenomics8(9), 1143–1150 (2007).
   PubMed Web of Science ®Google Scholar
• Dahlén B, Nizankowska E, Szczeklik A et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am. J. Respir. Crit. Care Med.157(4 Pt 1), 1187–1194 (1998).
   PubMed Web of Science ®Google Scholar
• Dahlén SE, Malmström K, Nizankowska E et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am. J. Respir. Crit. Care Med.165(1), 9–14 (2002).
   PubMed Web of Science ®Google Scholar
• American Thoracic Society. Guidelines for assessing and managing asthma risk at work, school and recreation. Am. J. Respir. Crit. Care Med.169(7), 873–881 (2004).
   PubMed Web of Science ®Google Scholar
• Mapp CE, Boschetto P, Maestrelli P, Fabbri LM. Occupational asthma. Am. J. Respir. Crit. Care Med.172(3), 280–305 (2005).
   PubMed Web of Science ®Google Scholar
• Mapp CE, Miotto D, Boschetto P. Occupational asthma. Med. Lav.97(2), 404–409 (2006).
   PubMedGoogle Scholar
• Bush RK. Current perspectives in occupational asthma. J. Allergy Clin. Immunol.123(3), 567–568 (2009).
   PubMedGoogle Scholar
• Maestrelli P, Boschetto P, Fabbri LM, Mapp CE. Mechanisms of occupational asthma. J. Allergy Clin. Immunol.123(3), 531–542 (2009).
   PubMed Web of Science ®Google Scholar
• Malo JL, Chan-Yeung M. Agents causing occupational asthma. J. Allergy Clin. Immunol.123(3), 545–550 (2009).
   PubMed Web of Science ®Google Scholar
• Vandenplas O, Malo JL. Definitions and types of work-related asthma: a nosological approach. Eur. Respir. J.21(4), 706–712 (2003).
   PubMed Web of Science ®Google Scholar
• Dykewicz MS. Occupational asthma: current concepts in pathogenesis, diagnosis, and management. J. Allergy Clin. Immunol.123(3), 519–528 (2009).
   PubMed Web of Science ®Google Scholar
• Saetta M, Di Stefano A, Maestrelli P et al. Airway mucosal inflammation in occupational asthma induced by toluene diisocyanate. Am. Rev. Respir. Dis.145(1), 160–168 (1992).
   PubMed Web of Science ®Google Scholar
• Frew AJ, Chan H, Lam S, Chan-Yeung M. Bronchial inflammation in occupational asthma due to western red cedar. Am. J. Respir. Crit. Care Med.151(2 Pt 1), 340–344 (1995).
   PubMed Web of Science ®Google Scholar
• Lemière C, Malo JL, Boutet M. Reactive airways dysfunction syndrome due to chlorine: sequential bronchial biopsies and functional assessment. Eur. Respir. J.10(1), 241–244 (1997).
   PubMed Web of Science ®Google Scholar
• Piirilä P, Wikman H, Luukkonen R et al. Glutathione S-transferase genotypes and allergic responses to diisocyanate exposure. Pharmacogenetics11(5), 437–445 (2001).
   PubMedGoogle Scholar
• Mapp CE, Beghé B, Balboni A et al. Association between HLA genes and susceptibility to toluene diisocyanate-induced asthma. Clin. Exp. Allergy30(5), 651–656 (2000).
   PubMed Web of Science ®Google Scholar
• Young RP, Barker RD, Pile KD, Cookson WO, Taylor AJ. The association of HLA-DR3 with specific IgE to inhaled acid anhydrides. Am. J. Respir. Crit. Care Med.151(1), 219–221 (1995).
   PubMedGoogle Scholar
• Horne C, Quintana PJ, Keown PA, Dimich-Ward H, Chan-Yeung M. Distribution of DRB1 and DQB1 HLA class II alleles in occupational asthma due to western red cedar. Eur. Respir. J.15(5), 911–914 (2001).
   Google Scholar
• Smith AM, Bernstein DI. Management of work-related asthma. J. Allergy Clin. Immunol.123(3), 551–557 (2009).
   PubMed Web of Science ®Google Scholar
• Maestrelli P. Natural history of adult-onset asthma: insights from model of occupational asthma. Am. J. Respir. Crit. Care Med.169(3), 331–332 (2004).
   PubMedGoogle Scholar
• Schatz M, Dombrowski MP, Wise R et al. Asthma morbidity during pregnancy can be predicted by severity classification. J. Allergy Clin. Immunol.112(2), 283–288 (2003).
   PubMed Web of Science ®Google Scholar
• Sunday L, Tran MM, Krause DN, Duckles SP. Estrogen and progestagens differentially modulate vascular proinflammatory factors. Am. J. Physiol. Endocrinol. Metab.291(2), E261–E267 (2006).
   PubMed Web of Science ®Google Scholar
• Murphy VE, Gibson PG. Premenstrual asthma: prevalence, cycle-to-cycle variability and relationship to oral contraceptive use and menstrual symptoms. J. Asthma45(8), 696–704 (2008).
   PubMed Web of Science ®Google Scholar
• Skobeloff EM, Spivey WH, Silverman R, Eskin BA, Harchelroad F, Alessi TV. The effect of the menstrual cycle on asthma presentations in the emergency department. Arch. Intern. Med.156(16), 1837–1840 (1996).
   PubMed Web of Science ®Google Scholar
• Brenner BE, Holmes TM, Mazal B, Camargo CA Jr. Relation between phase of the menstrual cycle and asthma presentations in the emergency department. Thorax60(10), 806–809 (2005).
   PubMed Web of Science ®Google Scholar
• Martinez-Moragón E, Plaza V, Serrano J et al. Near-fatal asthma related to menstruation. J. Allergy Clin. Immunol.113(2), 242–244 (2004).
   PubMedGoogle Scholar
• Real FG, Svanes C, Omenaas ER et al. Menstrual irregularity and asthma and lung function. J. Allergy Clin. Immunol.120(3), 557–564 (2007).
   PubMed Web of Science ®Google Scholar
• Farha S, Asosingh K, Laskowski D et al. Effects of the menstrual cycle on lung function variables in women with asthma. Am. J. Respir. Crit. Care Med.180(4), 304–310 (2009).
   PubMed Web of Science ®Google Scholar
• Ensom MH, Chong G, Zhou D, Beaudin B, Shalansky S, Bai TR. Estradiol in premenstrual asthma: a double-blind, randomized, placebo-controlled, crossover study. Pharmacotherapy23(5), 561–571 (2003).
   PubMed Web of Science ®Google Scholar
• Schoene RB, Giboney K, Schimmel C et al. Spirometry and airway reactivity in elite track and field athletes. Clin. J. Sport Med.7(4), 257–261 (1997).
   PubMedGoogle Scholar
• Wilber RL, Rundell KW, Szmedra L, Jenkinson DM, Im J, Drake SD. Incidence of exercise-induced bronchospasm in Olympic winter sport athletes. Med. Sci. Sports Exerc.32(4), 732–737 (2000).
   PubMed Web of Science ®Google Scholar
• Karjalainen EM, Laitinen A, Sue-Chu M, Altraja A, Bjermer L, Laitinen LA. Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine. Am. J. Respir. Crit. Care Med.161(6), 2086–2091 (2000).
   PubMed Web of Science ®Google Scholar
• Hallstrand TS, Moody MW, Aitken ML, Henderson WR Jr. Airway immunopathology of asthma with exercise-induced bronchoconstriction. J. Allergy Clin. Immunol.116(3), 586–593 (2005).
   PubMed Web of Science ®Google Scholar
• Hallstrand TS, Moody MW, Wurfel MM, Schwartz LB, Henderson WR Jr, Aitken ML. Inflammatory basis of exercise-induced bronchoconstriction. Am. J. Respir. Crit. Care Med.172(6), 679–686 (2005).
   PubMed Web of Science ®Google Scholar
• Gwynn RC. Risk factors for asthma in US adults: results from the 2000 Behavioral Risk Factor Surveillance System. J. Asthma41(1), 91–98 (2004).
   PubMed Web of Science ®Google Scholar
• Eisner MD, Yelin EH, Trupin L, Blanc PD. Asthma and smoking status in a population-based study of California adults. Public Health Rep.116(2), 148–157 (2001).
   PubMed Web of Science ®Google Scholar
• Piipari R, Jaakkola JJ, Jaakkola N, Jaakkola MS. Smoking and asthma in adults. Eur. Respir. J.24(5), 734–739 (2004).
   PubMed Web of Science ®Google Scholar
• Troisi RJ, Speizer FE, Rosner B, Trichopoulos D, Willett WC. Cigarette smoking and incidence of chronic bronchitis and asthma in women. Chest108(6), 1557–1561 (1995).
   PubMed Web of Science ®Google Scholar
• Nadel JA, Comroe JH Jr. Acute effects of inhalation of cigarette smoke on airway conductance. J. Appl. Physiol.16, 713–716 (1961).
   PubMed Web of Science ®Google Scholar
• Lange P, Parner J, Vestbo J et al. A 15-year follow-up study of ventilation function in adults with asthma. N. Engl. J. Med.339(17), 1194–1200 (1998).
   PubMed Web of Science ®Google Scholar
• Apostol GG, Jacobs DR Jr, Tsai AW et al. Early life factors contribute to the decrease in lung function between ages 18 and 40: the Coronary Artery Risk Development in Young Adults study. Am. J. Respir. Crit. Care Med.166(2), 166–172 (2002).
   PubMed Web of Science ®Google Scholar
• Chalmers GW, MacLeod KJ, Thomson L, Little SA, McSharry C, Thomson NC. Smoking and airway inflammation in patients with mild asthma. Chest120(6), 1917–1922 (2001).
   PubMed Web of Science ®Google Scholar
• Chalmers GW, Macleod KJ, Little SA, Thomson LJ, McSharry CP, Thomson NC. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax57(3), 226–230 (2002).
   PubMed Web of Science ®Google Scholar
• Sunyer J, Springer G, Jamieson B et al. Effects of asthma on cell components in peripheral blood among smokers and non-smokers. Clin. Exp. Allergy33(11), 1500–1505 (2003).
   PubMedGoogle Scholar
• Verleden GM, Dupont LJ, Verpeut AC, Demedts MG. The effect of cigarette smoking on exhaled nitric oxide in mild steroid-naive asthmatics. Chest116(1), 59–64 (1999).
   PubMed Web of Science ®Google Scholar
• Kerstjens HA, Overbeek SE, Schouten JP, Brand PL, Postma DS. Airways hyperresponsiveness, bronchodilator response, allergy and smoking predict improvement in FEV1 during long-term inhaled corticosteroid treatment. Dutch CNSLD Study Group. Eur. Respir. J.6(6), 868–876 (1993).
   PubMed Web of Science ®Google Scholar
• Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am. J. Respir. Crit. Care Med.168(11), 1308–1311 (2003).
   PubMed Web of Science ®Google Scholar
• Lazarus SC, Chinchilli VM, Rollings NJ et al.; National Heart Lung and Blood Institute’s Asthma Clinical Research Network. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am. J. Respir. Crit. Care Med.175(8), 783–790 (2007).
   PubMed Web of Science ®Google Scholar
• Simpson JL, Scott RJ, Boyle MJ, Gibson PG. Differential proteolytic enzyme activity in eosinophilic and neutrophilic asthma. Am. J. Respir. Crit. Care Med.172(5), 559–565 (2005).
   PubMed Web of Science ®Google Scholar
• Brightling CE. Clinical applications of induced sputum. Chest129(5), 1344–1348 (2006).
   PubMed Web of Science ®Google Scholar
• Payne DN, Adcock IM, Wilson NM, Oates T, Scallan M, Bush A. Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in children with difficult asthma, after treatment with oral prednisolone. Am. J. Respir. Crit. Care Med.164(8 Pt 1), 1376–1381 (2001).
   PubMed Web of Science ®Google Scholar
• Green RH, Brightling CE, McKenna S et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet360(9347), 1715–1721 (2002).
   PubMed Web of Science ®Google Scholar
• Gibson PG, Simpson JL, Hankin R, Powell H, Henry RL. Relationship between induced sputum eosinophils and the clinical pattern of childhood asthma. Thorax58(2), 116–121 (2003).
   PubMed Web of Science ®Google Scholar
• Haldar P, Pavord ID, Shaw DE et al. Cluster analysis and clinical asthma phenotypes. Am. J. Respir. Crit. Care Med.178(3), 218–224 (2008).
   PubMed Web of Science ®Google Scholar
• Pizzichini MM, Pizzichini E, Clelland L et al. Prednisone-dependent asthma: inflammatory indices in induced sputum. Eur. Respir. J.13(1), 15–21 (1999).
   PubMed Web of Science ®Google Scholar
• Jatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am. J. Respir. Crit. Care Med.161(1), 64–72 (2000).
   PubMed Web of Science ®Google Scholar
• Gibson PG, Simpson JL, Saltos N. Heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest119(5), 1329–1336 (2001).
   PubMed Web of Science ®Google Scholar
• Djukanović R, Wilson JW, Britten KM et al. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am. Rev. Respir. Dis.145(3), 669–674 (1992).
   PubMed Web of Science ®Google Scholar
• Maestrelli P, Saetta M, Di Stefano A et al. Comparison of leukocyte counts in sputum, bronchial biopsies, and bronchoalveolar lavage. Am. J. Respir. Crit. Care Med.152(6 Pt 1), 1926–1931 (1995).
   PubMed Web of Science ®Google Scholar
• Grootendorst DC, Sont JK, Willems LN et al. Comparison of inflammatory cell counts in asthma: induced sputum vs bronchoalveolar lavage and bronchial biopsies. Clin. Exp. Allergy27(7), 769–779 (1997).
   PubMed Web of Science ®Google Scholar
• Chu HW, Balzar S, Seedorf GJ et al. Transforming growth factor-β2 induces bronchial epithelial mucin expression in asthma. Am. J. Pathol.165(4), 1097–1106 (2004).
   PubMed Web of Science ®Google Scholar
• Balzar S, Chu HW, Silkoff P et al. Increased TGF-β2 in severe asthma with eosinophilia. J. Allergy Clin. Immunol.115(1), 110–117 (2005).
   PubMed Web of Science ®Google Scholar
• Shin HD, Kim LH, Park BL et al. Association of eotaxin gene family with asthma and serum total IgE. Hum. Mol. Genet.12(11), 1279–1285 (2003).
   PubMedGoogle Scholar
• Chae SC, Lee YC, Park YR et al. Analysis of the polymorphisms in eotaxin gene family and their association with asthma, IgE, and eosinophil. Biochem. Biophys. Res. Commun.320(1), 131–137 (2004).
   PubMedGoogle Scholar
• Raby BA, Van Steen K, Lazarus R, Celedón JC, Silverman EK, Weiss ST. Eotaxin polymorphisms and serum total IgE levels in children with asthma. J. Allergy Clin. Immunol.117(2), 298–305 (2006).
   PubMed Web of Science ®Google Scholar
• Batra J, Rajpoot R, Ahluwalia J et al. A hexanucleotide repeat upstream of eotaxin gene promoter is associated with asthma, serum total IgE and plasma eotaxin levels. J. Med. Genet.44(6), 397–403 (2007).
   PubMedGoogle Scholar
• Gudbjartsson DF, Bjornsdottir US, Halapi E et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat. Genet.41(3), 342–347 (2009).
   PubMed Web of Science ®Google Scholar
• Jayaram L, Pizzichini MM, Cook RJ et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur. Respir. J.27(3), 483–494 (2006).
   PubMed Web of Science ®Google Scholar
• Petsky HL, Kynaston JA, Turner C et al. Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev.2, CD005603 (2007).
   Google Scholar
• ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. ‘Refractory’ eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am. J. Respir. Crit. Care Med.170(6), 601–605 (2004).
   PubMed Web of Science ®Google Scholar
• Zacharasiewicz A, Wilson N, Lex C et al. Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children. Am. J. Respir. Crit. Care Med.171(10), 1077–1082 (2005).
   PubMed Web of Science ®Google Scholar
• Leckie MJ, ten Brinke A, Khan J et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet356(9248), 2144–2148 (2000).
   PubMed Web of Science ®Google Scholar
• Flood-Page P, Swenson C, Faiferman I et al.; International Mepolizumab Study Group. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am. J. Respir. Crit. Care Med.176(11), 1062–1071 (2007).
   PubMed Web of Science ®Google Scholar
• Haldar P, Pavord ID. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J. Allergy Clin. Immunol.119(5), 1043–1052 (2007).
   PubMed Web of Science ®Google Scholar
• Drews AC, Pizzichini MM, Pizzichini E et al. Neutrophilic airway inflammation is a main feature of induced sputum in nonatopic asthmatic children. Allergy64(11), 1597–1601 (2009).
   PubMedGoogle Scholar
• Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ. Neutrophilic inflammation in severe persistent asthma. Am. J. Respir. Crit. Care Med.160(5 Pt 1), 1532–1539 (1999).
   PubMed Web of Science ®Google Scholar
• Lovett CJ, Whitehead BF, Gibson PG. Eosinophilic airway inflammation and the prognosis of childhood asthma. Clin. Exp. Allergy37(11), 1594–1601 (2007).
   PubMed Web of Science ®Google Scholar
• Cundall M, Sun Y, Miranda C, Trudeau JB, Barnes S, Wenzel SE. Neutrophil-derived matrix metalloproteinase-9 is increased in severe asthma and poorly inhibited by glucocorticoids. J. Allergy Clin. Immunol.112(6), 1064–1071 (2003).
   PubMed Web of Science ®Google Scholar
• Wenzel SE, Balzar S, Cundall M, Chu HW. Subepithelial basement membrane immunoreactivity for matrix metalloproteinase 9: association with asthma severity, neutrophilic inflammation, and wound repair. J. Allergy Clin. Immunol.111(6), 1345–1352 (2003).
   PubMed Web of Science ®Google Scholar
• Sur S, Crotty TB, Kephart GM et al. Sudden-onset fatal asthma. A distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa? Am. Rev. Respir. Dis.148(3), 713–719 (1993).
   PubMed Web of Science ®Google Scholar
• James AL, Elliot JG, Abramson MJ, Walters EH. Time to death, airway wall inflammation and remodeling in fatal asthma. Eur. Respir. J.26(3), 429–434 (2005).
   PubMedGoogle Scholar
• Shiang C, Mauad T, Senhorini A et al. Pulmonary periarterial inflammation in fatal asthma. Clin. Exp. Allergy39(10), 1499–1507 (2009).
   PubMedGoogle Scholar
• Thomson NC, Chaudhuri R, Livingston E. Asthma and cigarette smoking. Eur. Respir. J.24(5), 822–833 (2004).
   PubMed Web of Science ®Google Scholar
• Zhang JJ, McCreanor JE, Cullinan P et al. Health effects of real-world exposure to diesel exhaust in persons with asthma. Res. Rep. Health Eff. Inst.138, 5–109 (2009).
   Google Scholar
• Wark PA, Johnston SL, Moric I, Simpson JL, Hensley MJ, Gibson PG. Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma. Eur. Respir. J.19(1), 68–75 (2002).
   PubMed Web of Science ®Google Scholar
• Turner MO, Hussack P, Sears MR, Dolovich J, Hargreave FE. Exacerbations of asthma without sputum eosinophilia. Thorax50(10), 1057–1061 (1995).
   PubMed Web of Science ®Google Scholar
• Fahy JV, Kim KW, Liu J, Boushey HA. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J. Allergy Clin. Immunol.95(4), 843–852 (1995).
   PubMed Web of Science ®Google Scholar
• Ordoñez CL, Shaughnessy TE, Matthay MA, Fahy JV. Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: clinical and biologic significance. Am. J. Respir. Crit. Care Med.161(4 Pt 1), 1185–1190 (2000).
   PubMed Web of Science ®Google Scholar
• Fabbri LM, Boschetto P, Zocca E et al. Bronchoalveolar neutrophilia during late asthmatic reactions induced by toluene diisocyanate. Am. Rev. Respir. Dis.136(1), 36–42 (1987).
   PubMed Web of Science ®Google Scholar
• Nguyen LT, Lim S, Oates T, Chung KF. Increase in airway neutrophils after oral but not inhaled corticosteroid therapy in mild asthma. Respir. Med.99(2), 200–207 (2005).
   PubMed Web of Science ®Google Scholar
• Wenzel SE, Szefler SJ, Leung DY, Sloan SI, Rex MD, Martin RJ. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am. J. Respir. Crit. Care Med.156(3 Pt 1), 737–743 (1997).
   PubMed Web of Science ®Google Scholar
• Kikuchi S, Kikuchi I, Takaku Y et al. Neutrophilic inflammation and CXC chemokines in patients with refractory asthma. Int. Arch. Allergy Immunol.149(Suppl. 1), 87–93 (2009).
   PubMedGoogle Scholar
• Fahy JV. Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies. Proc. Am. Thorac. Soc.6(3), 256–259 (2009).
   PubMedGoogle Scholar
• Simpson JL, Grissell TV, Douwes J, Scott RJ, Boyle MJ, Gibson PG. Innate immune activation in neutrophilic asthma and bronchiectasis. Thorax62(3), 211–218 (2007).
   PubMed Web of Science ®Google Scholar
• Hauk PJ, Krawiec M, Murphy J et al. Neutrophilic airway inflammation and association with bacterial lipopolysaccharide in children with asthma and wheezing. Pediatr. Pulmonol.43(9), 916–923 (2008).
   PubMed Web of Science ®Google Scholar
• Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am. J. Respir. Crit. Care Med.177(2), 148–155 (2008).
   PubMed Web of Science ®Google Scholar
• Benayoun L, Druilhe A, Dombret MC, Aubier M, Pretolani M. Airway structural alterations selectively associated with severe asthma. Am. J. Respir. Crit. Care Med.167(10), 1360–1368 (2003).
   PubMed Web of Science ®Google Scholar
• Bradding P, Walls AF, Holgate ST. The role of the mast cell in the pathophysiology of asthma. J. Allergy Clin. Immunol.117(6), 1277–1284 (2006).
   PubMed Web of Science ®Google Scholar
• Slats AM, Janssen K, van Schadewijk A et al. Bronchial inflammation and airway responses to deep inspiration in asthma and chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med.176(2), 121–128 (2007).
   PubMedGoogle Scholar
• Rosi E, Ronchi MC, Grazzini M, Duranti R, Scano G. Sputum analysis, bronchial hyperresponsiveness, and airway function in asthma: results of a factor analysis. J. Allergy Clin. Immunol.103(2 Pt 1), 232–237 (1999).
   PubMed Web of Science ®Google Scholar
• Moore WC, Meyers DA, Li H, D’Agostino R, Peters SP, Bleecker ER. Identification of asthma phenotypes using cluster analysis in the severe asthma research program. Presented at: 2009 American Thoracic Society International Conference. San Diego, CA, USA, 15–20 May 2009. Am. J. Respir. Crit. Care Med. (2009) (Epub ahead of print).
   Google Scholar