Background: Small airway dysfunction (SAD) is associated with impaired asthma control, but small airway physiology is not routinely assessed in clinical practice. Previously, we demonstrated impulse oscillometry (IOS)-defined small airway dysfunction (SAD) in dual responders (DRs) upon bronchoprovocation with various allergens. Aim: To compare lung physiology using spirometry and IOS following bronchoprovocation with methacholine (M) and inhaled house dust mite (HDM) extract in corticosteroid-naïve asthmatic subjects. Methods: Non-smoking, clinically stable HDM-allergic asthmatic subjects (18-55 years, FEV1 > 70% of pred.) underwent an M and inhaled HDM challenge on two separate days. Airway response was measured by IOS and spirometry, until a drop in FEV1 ≥ 20% (PC20) from post-diluent baseline (M), and up to 8 h post-allergen (HDM). Early (EAR) and late asthmatic response (LAR) to HDM were defined as ≥20% and ≥15% fall in FEV1 from post-diluent baseline during 0-3 h and 3-8 h post-challenge, respectively. IOS parameters (Rrs5, Rrs20, Rrs5-20, Xrs5, AX, Fres) were compared between mono-responders (MRs: EAR only) and dual responders (EAR + LAR). Correlations between maximal % change from baseline after the two airway challenges were calculated for both FEV1 and IOS parameters. Results: A total of 47 subjects were included (11 MRs; 36 DRs). FEV1 % predicted did not differ between MR and DR at baseline, but DR had lower median PC20M (0.84 (range 0.07-7.51) vs. MR (2.15 (0.53-11.29)); p = 0.036). During the LAR, DRs had higher IOS values than MRs. For IOS parameters (but not for FEV1), the maximal % change from baseline following M and HDM challenge were correlated. PC20M was inversely correlated with the % change in FEV1 and the % change in Xrs5 during the LAR (r= -0.443; p = 0.0018 and r= -0.389; p = 0.0075, respectively). Conclusions: During HDM-induced LAR, changes in small airway physiology can be non-invasively detected with IOS and are associated with increased airway hyperresponsiveness and changes in small airway physiology during methacholine challenge. DRs have a small airways phenotype, which reflects a more advanced airway disease.

Center for Primary Health Care Research Department of Clinical Sciences Malmö Lund University 21428 Malmö Sweden

Department of Clinical Pharmacy and Pharmacology University Medical Centre Groningen 9700 RB Groningen The Netherlands

Department of Epidemiology and Data Sciences Amsterdam University Medical Centre 1105 AZ Amsterdam The Netherlands

Department of Microbiology Immunology and Transplantation Catholic University of Leuven 3000 Leuven Belgium

Department of Pulmonary Medicine Amsterdam University Medical Centre 1007 MB Amsterdam The Netherlands

Department of Respiratory Medicine 1st Faculty of Medicine Thomayer Hospital Charles University 12108 Prague Czech Republic

Lung Function Centre O2CO2 2582 EZ The Hague The Netherlands

QPS NL 9713 AG Groningen The Netherlands

School of Medicine University of Dundee Dundee DD1 9SY UK

University Clinic Primary Care Skåne 29189 Kristianstad Region Skåne Sweden

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Usmani O.S., Barnes P.J. Assessing and treating small airways disease in asthma and chronic obstructive pulmonary disease. Ann. Med. 2012;44:146–156. doi: 10.3109/07853890.2011.585656. PubMed DOI

van der Wiel E., ten Hacken N.H., Postma D.S., van den Berge M. Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: A systematic review. J. Allergy Clin. Immunol. 2013;131:646–657. doi: 10.1016/j.jaci.2012.12.1567. PubMed DOI

Bergeron C., Hauber H.P., Gotfried M., Newman K., Dhanda R., Servi R.J., Ludwig M.S., Hamid Q. Evidence of remodeling in peripheral airways of patients with mild to moderate asthma: Effect of hydrofluoroalkane-flunisolide. J. Allergy Clin. Immunol. 2005;116:983–989. doi: 10.1016/j.jaci.2005.07.029. PubMed DOI

Dolhnikoff M., da Silva L.F., de Araujo B.B., Gomes H.A., Fernezlian S., Mulder A., Lindeman J.H., Mauad T. The outer wall of small airways is a major site of remodeling in fatal asthma. J. Allergy Clin. Immunol. 2009;123:1090–1097.e1. doi: 10.1016/j.jaci.2009.02.032. PubMed DOI

Chan R., Duraikannu C., Thouseef M.J., Lipworth B. Impaired Respiratory System Resistance and Reactance Are Associated with Bronchial Wall Thickening in Persistent Asthma. J. Allergy Clin. Immunol. Pract. 2023;11:1459–1462.e3. doi: 10.1016/j.jaip.2022.12.040. PubMed DOI

Postma D.S., Brightling C., Fabbri L., van der Molen T., Nicolini G., Papi A., Rabe K.F., Siddiqui S., Singh D., Berge M.v.D., et al. Unmet needs for the assessment of small airways dysfunction in asthma: Introduction to the ATLANTIS study. Eur. Respir. J. 2015;45:1534–1538. doi: 10.1183/09031936.00214314. PubMed DOI

Ducharme F.M., Chan R. Oscillometry in the diagnosis, assessment, and monitoring of asthma in children and adults: Review article. Ann. Allergy Asthma Immunol. 2024. ahead of print . PubMed DOI

Cockcroft D.W. Direct challenge tests: Airway hyperresponsiveness in asthma: Its measurement and clinical significance. Chest. 2010;138((Suppl. S2)):18s–24s. doi: 10.1378/chest.10-0088. PubMed DOI

James A., Ryan G. Testing airway responsiveness using inhaled methacholine or histamine. Respirology. 1997;2:97–105. doi: 10.1111/j.1440-1843.1997.tb00061.x. PubMed DOI

Yoon J.W., Shin Y.H., Jee H.M., Chang S.J., Baek J.H., Choi S.H., Kim H.Y., Han M.Y. Useful marker of oscillatory lung function in methacholine challenge test-comparison of reactance and resistance with dose-response slope. Pediatr. Pulmonol. 2014;49:521–528. doi: 10.1002/ppul.22866. PubMed DOI

Schulze J., Smith H.-J., Fuchs J., Herrmann E., Dressler M., Rose M.A., Zielen S. Methacholine challenge in young children as evaluated by spirometry and impulse oscillometry. Respir. Med. 2012;106:627–634. doi: 10.1016/j.rmed.2012.01.007. PubMed DOI

Choi S.H., Sheen Y.H., Kim M.A., Baek J.H., Baek H.S., Lee S.J., Yoon J.W., Rha Y.H., Han M.Y. Clinical Implications of Oscillatory Lung Function during Methacholine Bronchoprovocation Testing of Preschool Children. BioMed Res. Int. 2017;2017:9460190. doi: 10.1155/2017/9460190. PubMed DOI PMC

Diamant Z., Gauvreau G.M., Cockcroft D.W., Boulet L.P., Sterk P.J., de Jongh F.H., Dahlén B., O’Byrne P.M. Inhaled allergen bronchoprovocation tests. J. Allergy Clin. Immunol. 2013;132:1045–1055.e6. doi: 10.1016/j.jaci.2013.08.023. PubMed DOI

Gauvreau G.M., Davis B.E., Scadding G., Boulet L.-P., Bjermer L., Chaker A., Cockcroft D.W., Dahlén B., Fokkens W., Hellings P., et al. Allergen provocation tests in respiratory research: Building on 50 years of experience. Eur. Respir. J. 2022;60:2102782. doi: 10.1183/13993003.02782-2021. PubMed DOI PMC

O’Byrne P.M., Dolovich J., Hargreave F.E. Late asthmatic responses. Am. Rev. Respir. Dis. 1987;136:740–751. doi: 10.1164/ajrccm/136.3.740. PubMed DOI

Zhu Y., Esnault S., Ge Y., Jarjour N.N., Brasier A.R. Airway fibrin formation cascade in allergic asthma exacerbation: Implications for inflammation and remodeling. Clin. Proteom. 2022;19:15. doi: 10.1186/s12014-022-09351-3. PubMed DOI PMC

Metzger W.J., Nugent K., Richerson H.B. Site of airflow obstruction during early and late phase asthmatic responses to allergen bronchoprovocation. Chest. 1985;88:369–375. doi: 10.1378/chest.88.3.369. PubMed DOI

Stenberg H., Diamant Z., Ankerst J., Bjermer L., Tufvesson E. Small airway involvement in the late allergic response in asthma. Clin. Exp. Allergy. 2017;47:1555–1565. doi: 10.1111/cea.13036. PubMed DOI

Boulet L.P., Cote A., Abd-Elaziz K., Gauvreau G., Diamant Z. Allergen bronchoprovocation test: An important research tool supporting precision medicine. Curr. Opin. Pulm. Med. 2021;27:15–22. doi: 10.1097/MCP.0000000000000742. PubMed DOI

Contoli M., Santus P., Papi A. Small airway disease in asthma: Pathophysiological and diagnostic considerations. Curr. Opin. Pulm. Med. 2015;21:68–73. doi: 10.1097/MCP.0000000000000122. PubMed DOI

Donohue P.A., Kaminsky D.A. The role of oscillometry in asthma. Curr. Opin. Pulm. Med. 2024;30:268–275. doi: 10.1097/MCP.0000000000001057. PubMed DOI

Kleinhendler E., Rosman M., Fireman E., Freund O., Gershman I., Pumin I., Perluk T., Tiran B., Unterman A., Bar-Shai A. Impulse Oscillometry as an Alternative Lung Function Test for Hospitalized Adults. Respir. Care. 2024;69:415–421. doi: 10.4187/respcare.10963. PubMed DOI PMC

Global Initiative for Asthma Global Strategy for Asthma Management and Prevention. 2018. [(accessed on 12 January 2024)]. Available online: www.ginasthma.org.

Miller M.R., Hankinson J.A.T.S., Brusasco V., Burgos F., Casaburi R., Coates A., Crapo R., Enright P., Van Der Grinten C.P.M., Gustafsson P. Standardisation of spirometry. Eur. Respir. J. 2005;26:319–338. doi: 10.1183/09031936.05.00034805. PubMed DOI

Oostveen E., MacLeod D., Lorino H., Farré R., Hantos Z., Desager K., Marchal F., ERS Task Force on Respiratory Impedance Measurements The forced oscillation technique in clinical practice: Methodology, recommendations and future developments. Eur. Respir. J. 2003;22:1026–1041. doi: 10.1183/09031936.03.00089403. PubMed DOI

Chan R., Lipworth B. Identifying poorer asthma control using oscillometry ratios. J. Allergy Clin. Immunol. Pract. 2024;12:506–508.e1. doi: 10.1016/j.jaip.2023.10.048. PubMed DOI

Coates A.L., Wanger J., Cockcroft D.W., Culver B.H., Force T.B.T.T., Carlsen K.-H., Diamant Z., Gauvreau G., Hall G.L., Hallstrand T.S., et al. ERS technical standard on bronchial challenge testing: General considerations and performance of methacholine challenge tests. Eur. Respir. J. 2017;49:1601526. doi: 10.1183/13993003.01526-2016. PubMed DOI

Sterk P.J., Fabbri L.M., Quanjer P.H., Cockcroft D.W., O’Byrne P.M., Anderson S.D., Juniper E.F., Malo J.L. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Eur. Respir. J. 1993;6((Suppl. S16)):53–83. doi: 10.1183/09041950.053s1693. PubMed DOI

Juniper E.F., Frith P.A., Dunnett C., Cockcroft D.W., Hargreave F.E. Reproducibility and comparison of responses to inhaled histamine and methacholine. Thorax. 1978;33:705–710. doi: 10.1136/thx.33.6.705. PubMed DOI PMC

Davis B.E., Cockcroft D.W. Calculation of provocative concentration causing a 20% fall in FEV1: Comparison of lowest vs highest post-challenge FEV1. Chest. 2000;117:881–883. doi: 10.1378/chest.117.3.881. PubMed DOI

Galant S.P., Komarow H.D., Shin H.-W., Siddiqui S., Lipworth B.J. The case for impulse oscillometry in the management of asthma in children and adults. Ann. Allergy Asthma Immunol. 2017;118:664–671. doi: 10.1016/j.anai.2017.04.009. PubMed DOI PMC

Ravensberg A.J., Van Rensen E.L.J., Grootendorst D.C., De Kluijver J., Diamant Z., Ricciardolo F.L.M., Sterk P.J. Validated safety predictions of airway responses to house dust mite in asthma. Clin. Exp. Allergy. 2007;37:100–107. doi: 10.1111/j.1365-2222.2006.02617.x. PubMed DOI

Cockcroft D., Murdock K., Kirby J., Hargreave F. Prediction of airway responsiveness to allergen from skin sensitivity to allergen and airway responsiveness to histamine. Am. Rev. Respir. Dis. 1987;135:264–267. PubMed

Meijer G.G., Postma D.S., Mulder P.G., van Aalderen W.M. Long-term circadian effects of salmeterol in asthmatic children treated with inhaled corticosteroids. Pt 1Am. J. Respir. Crit. Care Med. 1995;152:1887–1892. doi: 10.1164/ajrccm.152.6.8520751. PubMed DOI

Barkas G.I., Daniil Z., Kotsiou O.S. The Role of Small Airway Disease in Pulmonary Fibrotic Diseases. J. Pers. Med. 2023;13:1600. doi: 10.3390/jpm13111600. PubMed DOI PMC

Tota M., Łacwik J., Laska J., Sędek Ł., Gomulka K. The Role of Eosinophil-Derived Neurotoxin and Vascular Endothelial Growth Factor in the Pathogenesis of Eosinophilic Asthma. Cells. 2023;12:1326. doi: 10.3390/cells12091326. PubMed DOI PMC

Naji N., Keung E., Kane J., Watson R.M., Killian K.J., Gauvreau G.M. Comparison of changes in lung function measured by plethymography and IOS after bronchoprovocation. Respir. Med. 2013;107:503–510. doi: 10.1016/j.rmed.2012.12.022. PubMed DOI

O’Byrne P.M., Inman M.D. Airway hyperresponsiveness. Chest. 2003;123((Suppl. S3)):411S–416S. doi: 10.1378/chest.123.3_suppl.411S. PubMed DOI

Gauvreau G.M., Watson R.M., O’Byrne P.M. Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation. Am. J. Respir. Crit. Care Med. 1999;160:640–647. doi: 10.1164/ajrccm.160.2.9809130. PubMed DOI

Busse W.W. The relationship of airway hyperresponsiveness and airway inflammation: Airway hyperresponsiveness in asthma: Its measurement and clinical significance. Chest. 2010;138((Suppl. S2)):4S–10S. doi: 10.1378/chest.10-0100. PubMed DOI PMC

Kuo C.R., Jabbal S., Lipworth B. Is small airways dysfunction related to asthma control and type 2 inflammation? Ann. Allergy Asthma Immunol. 2018;121:631–632. doi: 10.1016/j.anai.2018.08.009. PubMed DOI

Zuiker R.G., Tribouley C., Diamant Z., Boot J.D., Cohen A.F., Van Dyck K., De Lepeleire I., Rivas V.M., Malkov V.A., Burggraaf J., et al. Sputum RNA signature in allergic asthmatics following allergen bronchoprovocation test. Eur. Clin. Respir. J. 2016;3:31324. doi: 10.3402/ecrj.v3.31324. PubMed DOI PMC

Fahy J.V., Fleming H.E., Wong H.H., Liu J.T., Su J.Q., Reimann J., Fick R.B., Jr., Boushey H.A. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am. J. Respir. Crit. Care Med. 1997;155:1828–1834. doi: 10.1164/ajrccm.155.6.9196082. PubMed DOI

Busse W.W., Melén E., Menzies-Gow A.N. Holy Grail: The journey towards disease modification in asthma. Eur. Respir. Rev. 2022;31:210183. doi: 10.1183/16000617.0183-2021. PubMed DOI PMC

Van Rensen E.L., Evertse C.E., Van Schadewijk W.A., Van Wijngaarden S., Ayre G., Mauad T., Hiemstra P.S., Sterk P.J., Rabe K.F. Eosinophils in bronchial mucosa of asthmatics after allergen challenge: Effect of anti-IgE treatment. Allergy. 2009;64:72–80. doi: 10.1111/j.1398-9995.2008.01881.x. PubMed DOI

Chan R., Kuo C.R., Lipworth B. Real-life small airway outcomes in severe asthma patients receiving biologic therapies. J. Allergy Clin. Immunol. Pract. 2021;9:2907–2909. doi: 10.1016/j.jaip.2021.01.029. PubMed DOI

Qin R., An J., Xie J., Huang R., Xie Y., He L., Xv H., Qian G., Li J. FEF25–75% Is a More Sensitive Measure Reflecting Airway Dysfunction in Patients with Asthma: A Comparison Study Using FEF25–75% and FEV1. J. Allergy Clin. Immunol. Pract. 2021;9:3649–3659.e6. doi: 10.1016/j.jaip.2021.06.027. PubMed DOI

Quanjer P.H., Weiner D.J., Pretto J.J., Brazzale D.J., Boros P.W. Measurement of FEF25–75% and FEF75% does not contribute to clinical decision making. Eur. Respir. J. 2014;43:1051–1058. doi: 10.1183/09031936.00128113. PubMed DOI

Gauvreau G.M., O’Byrne P.M., Boulet L.P., Wang Y., Cockcroft D., Bigler J., FitzGerald J.M., Boedigheimer M., Davis B.E., Dias C., et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N. Engl. J. Med. 2014;370:2102–2110. doi: 10.1056/NEJMoa1402895. PubMed DOI

Diver S., Khalfaoui L., Emson C., Wenzel S.E., Menzies-Gow A., Wechsler M.E., Johnston J., Molfino N., Parnes J.R., Megally A., et al. Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): A double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir. Med. 2021;9:1299–1312. doi: 10.1016/S2213-2600(21)00226-5. PubMed DOI

Chan R., Lipworth B.J. Impact of Biologic Therapy on the Small Airways Asthma Phenotype. Lung. 2022;200:691–696. doi: 10.1007/s00408-022-00579-2. PubMed DOI PMC

Diamant Z., van Maaren M., Muraro A., Jesenak M., Striz I. Allergen immunotherapy for allergic asthma: The future seems bright. Respir. Med. 2023;210:107125. doi: 10.1016/j.rmed.2023.107125. PubMed DOI

Van Bever H.P., Stevens W.J. Evolution of the late asthmatic reaction during immunotherapy and after stopping immunotherapy. J. Allergy Clin. Immunol. 1990;86:141–146. doi: 10.1016/S0091-6749(05)80058-2. PubMed DOI

Arvidsson M.B., Löwhagen O., Rak S. Allergen specific immunotherapy attenuates early and late phase reactions in lower airways of birch pollen asthmatic patients: A double blind placebo-controlled study. Allergy. 2004;59:74–80. doi: 10.1046/j.1398-9995.2003.00334.x. PubMed DOI

Castro M., Corren J., Pavord I.D., Maspero J., Wenzel S., Rabe K.F., Busse W.W., Ford L., Sher L., Fitzgerald J.M., et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N. Engl. J. Med. 2018;378:2486–2496. doi: 10.1056/NEJMoa1804092. PubMed DOI

Chan R., Stewart K., Kuo C.R., Lipworth B. Evaluation of dupilumab and benralizumab on peripheral airway resistance and reactance. Allergy. 2024;79:2862–2864. doi: 10.1111/all.16214. PubMed DOI

Mead J. The lung’s “quiet zone”. N. Engl. J. Med. 1970;282:1318–1319. doi: 10.1056/NEJM197006042822311. PubMed DOI

Chan R., Misirovs R., Lipworth B. Repeatability of impulse oscillometry in patients with severe asthma. Eur. Respir. J. 2022;59:2101679. doi: 10.1183/13993003.01679-2021. PubMed DOI

Chan R., Gochicoa-Rangel L., Cottini M., Comberiati P., Gaillard E.A., Ducharme F.M., Galant S.P. Ascertainment of small airway dysfunction using oscillometry to better define asthma control and future risk: Are we ready to implement it in clinical practice? Chest. 2024. ahead of print . PubMed DOI

Manson M.L., Säfholm J., James A., Johnsson A.-K., Bergman P., Al-Ameri M., Orre A.-C., Kärrman-Mårdh C., Dahlén S.-E., Adner M. IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways. J. Allergy Clin. Immunol. 2020;145:808–817.e2. doi: 10.1016/j.jaci.2019.10.037. PubMed DOI

Kidney J.C., Boulet L.-P., Hargreave F.E., Deschesnes F., Swystun V.A., O’Byrne P.M., Choudry N., Morrisa M.M., Jennings B., Andersson N., et al. Evaluation of single-dose inhaled corticosteroid activity with an allergen challenge model. J. Allergy Clin. Immunol. 1997;100:65–70. doi: 10.1016/S0091-6749(97)70196-9. PubMed DOI

Foy B.H., Soares M., Bordas R., Richardson M., Bell A., Singapuri A., Hargadon B., Brightling C., Burrowes K., Kay D., et al. Lung Computational Models and the Role of the Small Airways in Asthma. Am. J. Respir. Crit. Care Med. 2019;200:982–991. doi: 10.1164/rccm.201812-2322OC. PubMed DOI PMC

Kaminsky D.A., Simpson S.J., Berger K.I., Calverley P., de Melo P.L., Dandurand R., Dellacà R.L., Farah C.S., Farré R., Hall G.L., et al. Clinical significance and applications of oscillometry. Eur. Respir. Rev. 2022;31:210208. doi: 10.1183/16000617.0208-2021. PubMed DOI PMC

Cottini M., Lombardi C., Comberiati P., Berti A., Menzella F., Dandurand R.J., Diamant Z., Chan R. Oscillometry-defined small airways dysfunction as a treatable trait in asthma. Ann. Allergy Asthma Immunol. 2024. ahead of print . PubMed DOI

Menzies-Gow A., Colice G., Griffiths J.M., Almqvist G., Ponnarambil S., Kaur P., Ruberto G., Bowen K., Hellqvist Å., Mo M., et al. NAVIGATOR: A phase 3 multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma. Respir. Res. 2020;21:266. doi: 10.1186/s12931-020-01526-6. PubMed DOI PMC

Gibson P.G., Yang I.A., Upham J.W., Reynolds P.N., Hodge S., James A.L., Jenkins C., Peters M.J., Marks G.B., Baraket M., et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): A randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:659–668. doi: 10.1016/S0140-6736(17)31281-3. PubMed DOI