Allergisk rinit (hösnuva) är ett globalt hälsoproblem som orsakar nedsatt funktionsförmåga och sjukdom i alla åldersgrupper. Prevalensen (andel sjuka) av allergisk rinit kan ligga så högt som 25-40 % i vissa länder och verkar vara i stigande.
Astma är spritt över hela världen, med ett uppskattat antal insjuknade på ca 300 miljoner. Prevalensen varierar från 1 % i de mest skonade områdena, till 18 % i de hårdast drabbade.
Det är klarlagt att det finns nära samband mellan allergisk rinit och astma. Bland annat finns det en uttalad samsjuklighet; mer än 75 % av astmatikerna har allergisk rinit. Astma är tätt kopplat till bronkiell hyperreaktivitet, dvs en benägenhet hos de stora luftvägarna att dra ihop sig vid retning. Även en stor andel patienter med diagnosen rinit uppvisar bronkiell hyperreaktivitet vid provokationstest med retande stimuli, trots att de inte har några astmasymptom. Bronkiell hyperreaktivitet är normalt ett kännetecken för astma, och det faktum att rinitpatienter kan ha luftvägsobstruktion utan symptom är anmärkningsvärt. Möjligen kan detta förklaras av en skillnad i utbredning och/eller grad av luftvägs-inflammation.
I denna avhandling var målet att studera utbredning, typ och grad av inflammation samt utbredning av luftvägsobstruktion i astmatiker jämfört med patienter med allergisk rinit med eller utan bronkiell hyperreaktivitet.
Vi fann att patienter med astma hade större förmåga att känna av den luftvägsobstruktion som inducerades under provokation med det luftvägsretande ämnet metakolin. Patienter med rinit och en bronkiell hyperreaktivitet av samma grad som astmatikerna fick mindre symptom från sina luftvägar. Genom att använda icke-invasiva metoder såsom sputuminduktion, mätning av kväveoxid i utandningsluften och impulsoscillometri i tillägg till provokationstest kunde vi identifiera tecken på ökad inflammatorisk aktivitet i de perifera luftvägarna i den astmatiska gruppen. Astmatikerna uppvisade också större resistansökning perifert i lungan under provokationstest, trots ungefär samma grad av central resistansökning som gruppen av rinitpatienter med bronkiell hyperreaktivitet. Överlag visade astmatikerna tecken på en mer aktiv och spridd inflammation i luftvägarna, jämfört med rinitpatienterna. Intressant nog så hade patienter med rinit och bronkiell hyperreaktivitet något högre nivåer av inflammationsmarkörer i sputum, jämfört med rinitpatienter utan bronkiell hyperreaktivitet. Sammantaget har jag i denna avhandling visat att astmatiker har ett engagemang av de perifera luftvägarna, något som inte finns i samma grad hos rinitpatienter. Detta kan möjligen delvis förklara skillnaden i förmåga att känna av luftvägsobstrukion. Övergången från rinit till astma är förmodligen gradvis, och utvecklandet av bronkiell hyperreaktivitet kan vara ett steg på vägen. Det perifera luftvägsengagemanget hos astmatiker medför implikationer för framtida behandlingstrategier, som bör innefatta hela luftvägsträdet.
ACKNOWLEDGEMENTS
I want to express my sincere thanks to everyone who made this thesis possible. I could not have made it without your support. I would especially like to acknowledge:
Leif Bjermer, my main supervisor, for your endless energy and confidence in me from the start. You have always taken your time to guide me, even though you have a very busy schedule. You epitomize the translational scientist; your broad knowledge of clinical and preclinical science has been truly inspiring.
Ellen Tufvesson, my secondary supervisor, for being the perfect match to Leif, providing me with down-to-earth advice on the day-to-day routines of science. You are probably the one who have taught me the most about the weird world of science.
All the patients, who volunteered to participate in the studies.
Jaro Ankerst, for sharing your unsurpassed clinical knowledge, and always backing me up when needed.
Anna Sikesjö, for your vital clinical assistance during the last years. Without you I would still be recruiting patients.
Gunilla Thorneman, for clinical assistance during the first years, and teaching me the basics of GCP.
The rest of “Enheten för lungforskning”, for laughs and generally good times, and for making sure I do not forget the basics of GCP!
Claes-Göran Löfdahl, for, among other things, advising me to enjoy my time in the spotlight!
Birgitta Wendel, for help with the administration.
Anders Malmström, for putting me in contact with Leif, and getting me started in the first place.
All the members of LURN, for interesting meetings and scientific discussions.
Former and present members of the LURN journal club, Annika, Kristina, Amelie, Pernilla, Monika, Lizbet, Lena, Kristoffer, Kristian, Michiko, Cecilia, Oskar, Anna-Karin, Lisa, Maria, Kristofer. Discussing science (and other things…) in a more casual atmosphere have been invaluable.
My Friends, for not asking me too many questions about my research! It has been nice to think about something else now and then.
My parents, Bo and Britten for trying your best to answer all those questions I had as a child. My sister, Elisabet, for giving me room to chatter back then. Now, the roles are reversed!
Cilla, for your endless patience, understanding and love, and Hillevi, for changing my life completely. I love you!
These studies were funded by Swedish Heart and Lung Foundation, Swedish Reasearch Council, Swedish Asthma and Allergy Association’s
Research Foundations, and National Institutes of Health Grant HL070645.
REFERENCES
[1]. Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic
rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108(5 SUPPL):S147-334.
[2]. Soni A. Allergic Rhinitis: Trends in use and expenditures,
2000 and 2005. MEPS Statistical Brief 2008;204.
[3]. Sly RM. Changing prevalence of allergic rhinitis and
asthma. Ann Allergy Asthma Immunol 1999;82(3):233-48 QUIZ 248-52.
[4]. Sears MR, Burrows B, Herbison GP, Holdaway MD,
Flannery EM. Atopy in childhood. II. Relationship to airway responsiveness, hay fever and asthma. Clin Exp Allergy 1993;23(11):949-56.
[5]. Nathan RA, Meltzer EO, Derebery J et al. The prevalence
of nasal symptoms attributed to allergies in the United States: findings from the burden of rhinitis in an America survey. Allergy Asthma Proc 2008;29(6):600-8.
[6]. Variations in the prevalence of respiratory symptoms,
self-reported asthma attacks, and use of asthma medication in the European Community Respiratory Health Survey (ECRHS). Eur Respir J 1996;9(4):687-95.
[7]. Strachan D, Sibbald B, Weiland S et al. Worldwide
variations in prevalence of symptoms of allergic rhinoconjunctivitis in children: the International Study of Asthma and Allergies in Childhood (ISAAC). Pediatr Allergy Immunol 1997;8(4):161-76.
[8]. Asher MI, Montefort S, Björkstén B et al. Worldwide time
trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 2006;368(9537):733-43.
[9]. Bråbäck L, Hjern A, Rasmussen F. Body mass index, asthma and allergic rhinoconjunctivitis in Swedish conscripts-a national cohort study over three decades. Respir Med 2005;99(8):1010-4.
[10]. International Consensus Report on the diagnosis and
management of rhinitis. International Rhinitis Management Working Group. Allergy 1994;49(19 SUPPL):1-34.
[11]. Barnes KC, Marsh DG. The genetics and complexity of
allergy and asthma. Immunol Today 1998;19(7):325-32.
[12]. Krämer U, Koch T, Ranft U, Ring J, Behrendt H.
Traffic-related air pollution is associated with atopy in children living in urban areas. Epidemiology 2000;11(1):64-70.
[13]. Katz KA, Pocock SJ, Strachan DP. Neonatal head
circumference, neonatal weight, and risk of hayfever, asthma and eczema in a large cohort of adolescents from Sheffield, England. Clin Exp
Allergy 2003;33(6):737-45.
[14]. Bråbäck L, Hedberg A. Perinatal risk factors for atopic
disease in conscripts. Clin Exp Allergy 1998;28(8):936-42.
[15]. Pattemore PK, Ellison-Loschmann L, Asher MI et al.
Asthma prevalence in European, Maori, and Pacific children in New Zealand: ISAAC study. Pediatr Pulmonol 2004;37(5):433-42.
[16]. Tedeschi A, Barcella M, Bo GA, Miadonna A. Onset of
allergy and asthma symptoms in extra-European immigrants to Milan, Italy: possible role of environmental factors. Clin Exp Allergy 2003;33(4):449-54.
[17]. Strachan DP. Hay fever, hygiene, and household size. BMJ
1989;299(6710):1259-60.
[18]. Schaub B, Lauener R, von Mutius E. The many faces of the
hygiene hypothesis. J Allergy Clin Immunol 2006;117(5):969-77 QUIZ 978.
[19]. Dykewicz MS, Fineman S. Executive Summary of Joint Task Force Practice Parameters on Diagnosis and Management of Rhinitis. Ann Allergy Asthma Immunol 1998;81(5 PT 2):463-8.
[20]. Tschopp JM, Sistek D, Schindler C et al. Current allergic
asthma and rhinitis: diagnostic efficiency of three commonly used atopic markers (IgE, skin prick tests, and Phadiatop). Results from 8329 randomized adults from the SAPALDIA Study. Swiss Study on Air Pollution and Lung Diseases in Adults. Allergy 1998;53(6):608-13.
[21]. Global Initiative for Asthma. GINA Report, Global
Strategy for Asthma Management and Prevention. wwwginasthmacom 2006;.
[22]. Global Initiative for Asthma. Global Burden of Asthma.
wwwginasthmacom 2004;.
[23]. Pearce N, Aït-Khaled N, Beasley R et al. Worldwide trends
in the prevalence of asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax 2007;62(9):758-66.
[24]. Holloway JW, Beghé B, Holgate ST. The genetic basis of
atopic asthma. Clin Exp Allergy 1999;29(8):1023-32.
[25]. Ober C. Perspectives on the past decade of asthma genetics.
J Allergy Clin Immunol 2005;116(2):274-8.
[26]. Wiesch DG, Meyers DA, Bleecker ER. Genetics of asthma.
J Allergy Clin Immunol 1999;104(5):895-901.
[27]. Ober C, Hoffjan S. Asthma genetics 2006: the long and
winding road to gene discovery. Genes Immun 2006;7(2):95-100.
[28]. Ito K, Chung KF, Adcock IM. Update on glucocorticoid
action and resistance. J Allergy Clin Immunol 2006;117(3):522-43.
[29]. Wahn U, Lau S, Bergmann R et al. Indoor allergen
exposure is a risk factor for sensitization during the first three years of life. J Allergy Clin Immunol 1997;99(6 PT 1):763-9.
[30]. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med 2000;161(5):1501-7.
[31]. Chan-Yeung M, Malo JL. Aetiological agents in
occupational asthma. Eur Respir J 1994;7(2):346-71.
[32]. Strachan DP, Cook DG. Health effects of passive smoking.
6. Parental smoking and childhood asthma: longitudinal and case-control studies. Thorax 1998;53(3):204-12.
[33]. Devereux G, Seaton A. Diet as a risk factor for atopy and
asthma. J Allergy Clin Immunol 2005;115(6):1109-17 QUIZ 1118.
[34]. Künzli N, Bridevaux PO, Liu S et al. Traffic-Related Air
Pollution Correlates with Adult-Onset Asthma among Never-Smokers.
Thorax 2009;.
[35]. Braun-Fahrländer C. Environmental exposure to endotoxin
and other microbial products and the decreased risk of childhood atopy: evaluating developments since April 2002. Curr Opin Allergy Clin
Immunol 2003;3(5):325-9.
[36]. Leonardi-Bee J, Pritchard D, Britton J. Asthma and current
intestinal parasite infection: systematic review and meta-analysis. Am J
Respir Crit Care Med 2006;174(5):514-23.
[37]. Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ,
Martinez FD, Wright AL. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 2000;343(8):538-43.
[38]. Levy ML, Fletcher M, Price DB, Hausen T, Halbert RJ,
Yawn BP. International Primary Care Respiratory Group (IPCRG) Guidelines: diagnosis of respiratory diseases in primary care. Prim Care
[39]. Pellegrino R, Viegi G, Brusasco V et al. Interpretative strategies for lung function tests. Eur Respir J 2005;26(5):948-68.
[40]. Brand PL, Quanjer PH, Postma DS et al. Interpretation of
bronchodilator response in patients with obstructive airways disease. The Dutch Chronic Non-Specific Lung Disease (CNSLD) Study Group.
Thorax 1992;47(6):429-36.
[41]. Sterk PJ, Fabbri LM, Quanjer PH et al. Airway
responsiveness. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur
Respir J Suppl 1993;16:53-83.
[42]. Joos GF, O'Connor B, Anderson SD et al. Indirect airway
challenges. Eur Respir J 2003;21(6):1050-68.
[43]. Macklem PT, Mead J. Resistance of central and peripheral
airways measured by a retrograde catheter. J Appl Physiol 1967;22(3):395-401.
[44]. Durham SR. Mechanisms of mucosal inflammation in the
nose and lungs. Clin Exp Allergy 1998;28 Suppl 2:11-6.
[45]. Venge P. Monitoring the allergic inflammation. Allergy
2004;59(1):26-32.
[46]. Barnes PJ. Immunology of asthma and chronic obstructive
pulmonary disease. Nat Rev Immunol 2008;8(3):183-92.
[47]. Masoli M, Fabian D, Holt S, Beasley R. The global burden
of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004;59(5):469-78.
[48]. Bousquet J, Vignola AM, Demoly P. Links between rhinitis
and asthma. Allergy 2003;58(8):691-706.
[49]. Walker S, Sheikh A. Self reported rhinitis is a significant
[50]. Alvarez MJ, Olaguibel JM, García BE, Rodríquez A, Tabar AI, Urbiola E. Airway inflammation in asthma and perennial allergic rhinitis. Relationship with nonspecific bronchial responsiveness and maximal airway narrowing. Allergy 2000;55(4):355-62.
[51]. Leynaert B, Bousquet J, Henry C, Liard R, Neukirch F. Is
bronchial hyperresponsiveness more frequent in women than in men? A population-based study. Am J Respir Crit Care Med 1997;156(5):1413-20.
[52]. Greisner WA, Settipane RJ, Settipane GA. Co-existence of
asthma and allergic rhinitis: a 23-year follow-up study of college students. Allergy Asthma Proc 1998;19(4):185-8.
[53]. Porsbjerg C, von Linstow ML, Ulrik CS,
Nepper-Christensen S, Backer V. Risk factors for onset of asthma: a 12-year prospective follow-up study. Chest 2006;129(2):309-16.
[54]. Passalacqua G, Ciprandi G, Canonica GW. The nose-lung
interaction in allergic rhinitis and asthma: united airways disease. Curr
Opin Allergy Clin Immunol 2001;1(1):7-13.
[55]. Krouse JH. The unified airway--conceptual framework.
Otolaryngol Clin North Am 2008;41(2):257-66 V.
[56]. Togias A. Rhinitis and asthma: evidence for respiratory
system integration. J Allergy Clin Immunol 2003;111(6):1171-83 QUIZ 1184.
[57]. Simons FE. Allergic rhinobronchitis: the asthma-allergic
rhinitis link. J Allergy Clin Immunol 1999;104(3 PT 1):534-40.
[58]. Braunstahl GJ, Kleinjan A, Overbeek SE, Prins JB,
Hoogsteden HC, Fokkens WJ. Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients. Am J Respir Crit Care
[59]. Bonay M, Neukirch C, Grandsaigne M et al. Changes in airway inflammation following nasal allergic challenge in patients with seasonal rhinitis. Allergy 2006;61(1):111-8.
[60]. Togias A. Systemic effects of local allergic disease. J
Allergy Clin Immunol 2004;113(1 SUPPL):S8-14.
[61]. Kay AB. Allergy and allergic diseases. First of two parts. N
Engl J Med 2001;344(1):30-7.
[62]. Kay AB. Allergy and allergic diseases. Second of two parts.
N Engl J Med 2001;344(2):109-13.
[63]. Broide DH. The pathophysiology of allergic
rhinoconjunctivitis. Allergy Asthma Proc 2007;28(4):398-403.
[64]. Barnes PJ, Chung KF, Page CP. Inflammatory mediators of
asthma: an update. Pharmacol Rev 1998;50(4):515-96.
[65]. John M, Hirst SJ, Jose PJ et al. Human airway smooth
muscle cells express and release RANTES in response to T helper 1 cytokines: regulation by T helper 2 cytokines and corticosteroids. J
Immunol 1997;158(4):1841-7.
[66]. Levine SJ. Bronchial epithelial cell-cytokine interactions in
airway inflammation. J Investig Med 1995;43(3):241-9.
[67]. Saunders MA, Mitchell JA, Seldon PM et al. Release of
granulocyte-macrophage colony stimulating factor by human cultured airway smooth muscle cells: suppression by dexamethasone. Br J
Pharmacol 1997;120(4):545-6.
[68]. Boix E, Torrent M, Sánchez D, Nogués MV. The
antipathogen activities of eosinophil cationic protein. Curr Pharm
Biotechnol 2008;9(3):141-52.
[69]. Koh GC, Shek LP, Goh DY, Van Bever H, Koh DS.
Eosinophil cationic protein: is it useful in asthma? A systematic review.
[70]. Poole JA, Rosenwasser LJ. The role of immunoglobulin E and immune inflammation: implications in allergic rhinitis. Curr Allergy
Asthma Rep 2005;5(3):252-8.
[71]. Smurthwaite L, Durham SR. Local IgE synthesis in allergic
rhinitis and asthma. Curr Allergy Asthma Rep 2002;2(3):231-8.
[72]. Peters-Golden M, Gleason MM, Togias A. Cysteinyl
leukotrienes: multi-functional mediators in allergic rhinitis. Clin Exp
Allergy 2006;36(6):689-703.
[73]. Wenzel SE. The role of leukotrienes in asthma.
Prostaglandins Leukot Essent Fatty Acids 2003;69(2-3):145-55.
[74]. Redington AE, Howarth PH. Airway wall remodelling in
asthma. Thorax 1997;52(4):310-2.
[75]. Holgate ST. Airway inflammation and remodeling in
asthma: current concepts. Mol Biotechnol 2002;22(2):179-89.
[76]. Brown PJ, Greville HW, Finucane KE. Asthma and
irreversible airflow obstruction. Thorax 1984;39(2):131-6.
[77]. Paré PD, Roberts CR, Bai TR, Wiggs BJ. The functional
consequences of airway remodeling in asthma. Monaldi Arch Chest Dis 1997;52(6):589-96.
[78]. Bjermer L, Lundgren R, Hällgren R. Hyaluronan and type
III procollagen peptide concentrations in bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis. Thorax 1989;44(2):126-31.
[79]. Nilsson K, Henriksson R, Hellström S, Tengblad A,
Bjermer L. Hyaluronan reflects the pre-fibrotic inflammation in irradiated rat lung: concomitant analysis of parenchymal tissues and bronchoalveolar lavage. Int J Radiat Biol 1990;58(3):519-30.
[80]. Salib RJ, Howarth PH. Remodelling of the upper airways in
allergic rhinitis: is it a feature of the disease? Clin Exp Allergy 2003;33(12):1629-33.
[81]. Bousquet J, Jacot W, Vignola AM, Bachert C, Van Cauwenberge P, Jacquot W. Allergic rhinitis: a disease remodeling the upper airways? J Allergy Clin Immunol 2004;113(1):43-9.
[82]. Bjermer L. History and future perspectives of treating
asthma as a systemic and small airways disease. Respir Med 2001;95(9):703-19.
[83]. Hamid Q, Song Y, Kotsimbos TC et al. Inflammation of
small airways in asthma. J Allergy Clin Immunol 1997;100(1):44-51.
[84]. Wagner EM, Liu MC, Weinmann GG, Permutt S, Bleecker
ER. Peripheral lung resistance in normal and asthmatic subjects. Am Rev
Respir Dis 1990;141(3):584-8.
[85]. Carroll N, Cooke C, James A. The distribution of
eosinophils and lymphocytes in the large and small airways of asthmatics. Eur Respir J 1997;10(2):292-300.
[86]. Merkus PJ, van Pelt W, van Houwelingen JC et al. Inhaled
corticosteroids and growth of airway function in asthmatic children. Eur
Respir J 2004;23(6):861-8.
[87]. Kraft M, Martin RJ, Wilson S, Djukanovic R, Holgate ST.
Lymphocyte and eosinophil influx into alveolar tissue in nocturnal asthma. Am J Respir Crit Care Med 1999;159(1):228-34.
[88]. Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ.
Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med 1996;154(5):1505-10.
[89]. Yanai M, Sekizawa K, Ohrui T, Sasaki H, Takishima T.
Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure. J Appl Physiol 1992;72(3):1016-23.
[90]. Carroll N, Elliot J, Morton A, James A. The structure of
large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 1993;147(2):405-10.
[91]. in 't Veen JC, Beekman AJ, Bel EH, Sterk PJ. Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med 2000;161(6):1902-6.
[92]. Goldin JG, McNitt-Gray MF, Sorenson SM et al. Airway
hyperreactivity: assessment with helical thin-section CT. Radiology 1998;208(2):321-9.
[93]. Zeidler MR, Goldin JG, Kleerup EC et al. Small airways
response to naturalistic cat allergen exposure in subjects with asthma. J
Allergy Clin Immunol 2006;118(5):1075-81.
[94]. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release
accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327(6122):524-6.
[95]. Lundberg JO, Farkas-Szallasi T, Weitzberg E et al. High
nitric oxide production in human paranasal sinuses. Nat Med 1995;1(4):370-3.
[96]. Lundberg JO, Weitzberg E, Lundberg JM, Alving K. Nitric
oxide in exhaled air. Eur Respir J 1996;9(12):2671-80.
[97]. Alving K, Weitzberg E, Lundberg JM. Increased amount of
nitric oxide in exhaled air of asthmatics. Eur Respir J 1993;6(9):1368-70.
[98]. Kharitonov SA, Rajakulasingam K, O'Connor B, Durham
SR, Barnes PJ. Nasal nitric oxide is increased in patients with asthma and allergic rhinitis and may be modulated by nasal glucocorticoids. J Allergy
Clin Immunol 1997;99(1 PT 1):58-64.
[99]. Taylor DR. Nitric oxide as a clinical guide for asthma
management. J Allergy Clin Immunol 2006;117(2):259-62.
[100]. Jatakanon A, Lim S, Kharitonov SA, Chung KF, Barnes PJ.
Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax 1998;53(2):91-5.
[101]. George SC, Hogman M, Permutt S, Silkoff PE. Modeling pulmonary nitric oxide exchange. J Appl Physiol 2004;96(3):831-9.
[102]. Arnal JF, Didier A, Rami J et al. Nasal nitric oxide is
increased in allergic rhinitis. Clin Exp Allergy 1997;27(4):358-62.
[103]. Wilson AM, Dempsey OJ, Sims EJ, Lipworth BJ.
Subjective and objective markers of treatment response in patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol 2000;85(2):111-4.
[104]. Pizzichini E, Pizzichini MM, Efthimiadis A et al. Indices of
airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit Care Med 1996;154(2 PT 1):308-17.
[105]. Belda J, Leigh R, Parameswaran K, O'Byrne PM, Sears
MR, Hargreave FE. Induced sputum cell counts in healthy adults. Am J
Respir Crit Care Med 2000;161(2 PT 1):475-8.
[106]. Jayaram L, Pizzichini MM, Cook RJ et al. Determining
asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J 2006;27(3):483-94.
[107]. Green RH, Brightling CE, McKenna S et al. Asthma
exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002;360(9347):1715-21.
[108]. 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 2000;161(6):2086-91.
[109]. Helenius IJ, Rytilä P, Metso T, Haahtela T, Venge P,
Tikkanen HO. Respiratory symptoms, bronchial responsiveness, and cellular characteristics of induced sputum in elite swimmers. Allergy 1998;53(4):346-52.
[110]. Bonsignore MR, Morici G, Riccobono L et al. Airway inflammation in nonasthmatic amateur runners. Am J Physiol Lung Cell
Mol Physiol 2001;281(3):L668-76.
[111]. Vignola AM, Rennar SI, Hargreave FE et al. Standardised
methodology of sputum induction and processing. Future directions. Eur
Respir J Suppl 2002;37:51s-5S.
[112]. Miller MR, Hankinson J, Brusasco V et al. Standardisation
of spirometry. Eur Respir J 2005;26(2):319-38.
[113]. Killian KJ, Watson R, Otis J, St Amand TA, O'Byrne PM.
Symptom perception during acute bronchoconstriction. Am J Respir Crit
Care Med 2000;162(2 PT 1):490-6.
[114]. Dubois AB, Brody AW, Lewis DH, Burgess BF.
Oscillation mechanics of lungs and chest in man. J Appl Physiol 1956;8(6):587-94.
[115]. Oostveen E, MacLeod D, Lorino H et al. The forced
oscillation technique in clinical practice: methodology, recommendations and future developments. Eur Respir J 2003;22(6):1026-41.
[116]. Lötvall J, Inman M, O'Byrne P. Measurement of airway
hyperresponsiveness: new considerations. Thorax 1998;53(5):419-24.
[117]. Black JL. Asthma--more muscle cells or more muscular
cells? Am J Respir Crit Care Med 2004;169(9):980-1.
[118]. Hogg JC, Pare PD, Moreno R. The effect of submucosal