Assessment of SAD, based on SAdf by the different lung function parameters
Parameters
Asthma (n = 198)
ACO (n = 152)
COPD (n = 338)
All (n = 688)
SAD [n (%)]
a
81 (40.9)
113 (74.3)
305 (90.2)
499 (72.5)
No SAD [n (%)]
7 (3.5)
1 (0.7)
0 (0)
8 (1.2)
One SAdf-parameter [no SAD; n (%)]
b
70 (35.4)
8 (5.3)
2 (0.6)
80 (11.6)
Two SAdf-parameters [no SAD; n (%)]
c
40 (20.2)
30 (19.7)
31 (9.2)
101 (14.7)
Declarations
Acknowledgments
The authors are grateful to the staff of all study centers, especially to the study nurses for their excellent and enduring work in data collection, and the authors thank Prof. Sabina Gallati from Human Genetics of Hirslanden Precise, Zürich, for the critical reviews of the manuscript.
Author contributions
RK: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. HM: Writing—review & editing. Both authors read and approved the submitted version.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Ethical approval
The study was planned according to the Federal Law of Human Research, conceptualized according to the Swiss Ethics Committees on research involving humans, and was conducted in accordance with the tenets of the Declaration of Helsinki. The study is part of the framework of the project entitled “Functional diversification of the Asthma-ACO-COPD multi-center study” (ID 2017-00259), approved by the Governmental Ethics Committees of the State of Bern, St. Gallen, Solothurn, and Zürich (project KEK-BE PB_2017-00104).
Consent to participate
All 4 Ethics Committees exempted the informed consent to participate since the data were retrospectively evaluated and anonymous.
Consent to publication
Not applicable.
Availability of data and materials
Master-files have been stored and secured in the Clinical Trial Unit (CTU), Hirslanden, Corporate Office, CH-8152 Glattpark, Switzerland, and are available upon request from the corresponding author (richard.kraemer@hirslanden.ch) or the office manager, Mr. Daniel Tschopp, Head Clinical Trial Unit, Hirslanden (ClinicalTrialUnit.Hirslanden@hirslanden.ch).
Weibel ER. Morphometry of the human lung. Berlin, Heidelberg: Springer-Verlag Berlin Heidelberg GmbH; 1963.
Macklem PT, Mead J. Resistance of central and peripheral airways measured by a retrograde catheter.J Appl Physiol. 1967;22:395–401. [DOI] [PubMed]
Contoli M, Kraft M, Hamid Q, Bousquet J, Rabe KF, Fabbri LM, et al. Do small airway abnormalities characterize asthma phenotypes? In search of proof.Clin Exp Allergy. 2012;42:1150–60. [DOI] [PubMed]
van der Wiel E, ten Hacken NH, Postma DS, van den Berge M. Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: a systematic review.J Allergy Clin Immunol. 2013;131:646–57. [DOI] [PubMed]
Usmani OS, Singh D, Spinola M, Bizzi A, Barnes PJ. The prevalence of small airways disease in adult asthma: a systematic literature review.Respir Med. 2016;116:19–27. [DOI] [PubMed]
Abdo M, Trinkmann F, Kirsten AM, Pedersen F, Herzmann C, von Mutius E, et al.; Study Group. Small airway dysfunction links asthma severity with physical activity and symptom control.J Allergy Clin Immunol Pract. 2021;9:3359–68.E1. [DOI] [PubMed]
Usmani OS, Barnes PJ. Assessing and treating small airways disease in asthma and chronic obstructive pulmonary disease.Ann Med. 2012;44:146–56. [DOI] [PubMed]
Scichilone N, Battaglia S, Taormina S, Modica V, Pozzecco E, Bellia V. Alveolar nitric oxide and asthma control in mild untreated asthma.J Allergy Clin Immunol. 2013;131:1513–7.Erratum in: J Allergy Clin Immunol. 2013;132:1015. [DOI] [PubMed]
Takeda T, Oga T, Niimi A, Matsumoto H, Ito I, Yamaguchi M, et al. Relationship between small airway function and health status, dyspnea and disease control in asthma.Respiration. 2010;80:120–6. [DOI] [PubMed]
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;161:1902–6. [DOI] [PubMed]
Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: What are its features and how important is it?Thorax. 2009;64:728–35. [DOI] [PubMed]
Zeki AA, Schivo M, Chan A, Albertson TE, Louie S. The asthma-COPD overlap syndrome: a common clinical problem in the elderly.J Allergy (Cairo). 2011;2011:861926. [DOI] [PubMed] [PMC]
Kauppi P, Kupiainen H, Lindqvist A, Tammilehto L, Kilpelainen M, Kinnula VL, et al. Overlap syndrome of asthma and COPD predicts low quality of life.J Asthma. 2011;48:279–85. [DOI] [PubMed]
Diaz-Guzman E, Khosravi M, Mannino DM. Asthma, chronic obstructive pulmonary disease, and mortality in the U.S. population.COPD. 2011;8:400–7. [DOI]
Louie S, Zeki AA, Schivo M, Chan AL, Yoneda KY, Avdalovic M, et al. The asthma-chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations.Expert Rev Clin Pharmacol. 2013;6:197–219. [DOI] [PubMed] [PMC]
de Marco R, Pesce G, Marcon A, Accordini S, Antonicelli L, Bugiani M, et al. The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.PLoS One. 2013;8:e62985. [DOI] [PubMed] [PMC]
Milanese M, Di Marco F, Corsico AG, Rolla G, Sposato B, Chieco-Bianchi F, et al.; ELSA Study Group. Asthma control in elderly asthmatics. An Italian observational study.Respir Med. 2014;108:1091–9. [DOI] [PubMed]
Global strategy for prevention, diagnosis and management of COPD: 2023 report [Internet].Global Initiative for Chronic Obstructive Lung Disease; c2024 [cited 2023 Feb 17]. Available from: https://goldcopd.org/2023-gold-report-2/
Agusti A, Vestbo J. Current controversies and future perspectives in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2011;184:507–13. [DOI] [PubMed]
Faner R, Agustí Á. Multilevel, dynamic chronic obstructive pulmonary disease heterogeneity. A challenge for personalized medicine.Ann Am Thorac Soc. 2016;13:S466–70. [DOI] [PubMed]
Han MK, Quibrera PM, Carretta EE, Barr RG, Bleecker ER, Bowler RP, et al.; SPIROMICS investigators. Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort.Lancet Respir Med. 2017;5:619–26. [DOI] [PubMed] [PMC]
Agusti A, MacNee W. The COPD control panel: towards personalised medicine in COPD.Thorax. 2013;68:687–90. [DOI] [PubMed]
Hogg JC, Macklem PT, Thurlbeck WM. The resistance of small airways in normal and diseased human lungs.Aspen Emphysema Conf. 1967;10:433–41. [PubMed]
Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease.N Engl J Med. 1968;278:1355–60. [DOI] [PubMed]
Bates JH, Suki B. Assessment of peripheral lung mechanics.Respir Physiol Neurobiol. 2008;163:54–63. [DOI] [PubMed] [PMC]
Bhatt SP, Soler X, Wang X, Murray S, Anzueto AR, Beaty TH, et al.; COPDGene Investigators. Association between functional small airway disease and FEV1 decline in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2016;194:178–84. [DOI] [PubMed] [PMC]
Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agusti A, Bakke P, et al.; ECLIPSE Investigators. Changes in forced expiratory volume in 1 second over time in COPD.N Engl J Med. 2011;365:1184–92. [DOI] [PubMed]
Herpel LB, Kanner RE, Lee SM, Fessler HE, Sciurba FC, Connett JE, et al.; National Emphysema Treatment Trial Research Group. Variability of spirometry in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2006;173:1106–13. [DOI] [PubMed] [PMC]
Pennock BE, Rogers RM, McCaffree DR. Changes in measured spirometric indices: What is significant?Chest. 1981;80:97–9. [DOI] [PubMed]
Alobaidi NY, Almeshari MA, Stockley JA, Stockley RA, Sapey E. The prevalence of bronchodilator responsiveness of the small airway (using mid-maximal expiratory flow) in COPD - a retrospective study.BMC Pulm Med. 2022;22:493. [DOI] [PubMed] [PMC]
McDonough JE, Yuan R, Suzuki M, Seyednejad N, Elliott WM, Sanchez PG, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease.N Engl J Med. 2011;365:1567–75. [DOI] [PubMed] [PMC]
Hogg JC, McDonough JE, Suzuki M. Small airway obstruction in COPD: new insights based on micro-CT imaging and MRI imaging.Chest. 2013;143:1436–43. [DOI] [PubMed] [PMC]
Mirsadraee M, Boskabady MH, Attaran D. Diagnosis of chronic obstructive pulmonary disease earlier than current Global Initiative for Obstructive Lung Disease guidelines using a feasible spirometry parameter (maximal-mid expiratory flow/forced vital capacity).Chron Respir Dis. 2013;10:191–6. [DOI] [PubMed]
Agusti A, Bel E, Thomas M, Vogelmeier C, Brusselle G, Holgate S, et al. Treatable traits: toward precision medicine of chronic airway diseases.Eur Respir J. 2016;47:410–9. [DOI] [PubMed]
Agustí A, Bafadhel M, Beasley R, Bel EH, Faner R, Gibson PG, et al. Precision medicine in airway diseases: moving to clinical practice.Eur Respir J. 2017;50:1701655. [DOI] [PubMed]
Franssen FM, Alter P, Bar N, Benedikter BJ, Iurato S, Maier D, et al. Personalized medicine for patients with COPD: Where are we?Int J Chron Obstruct Pulmon Dis. 2019;14:1465–84. [DOI] [PubMed] [PMC]
Brightling C, Greening N. Airway inflammation in COPD: progress to precision medicine.Eur Respir J. 2019;54:1900651. [DOI] [PubMed]
McDonald VM, Fingleton J, Agusti A, Hiles SA, Clark VL, Holland AE, et al. Treatable traits: a new paradigm for 21st century management of chronic airway diseases: Treatable Traits Down Under International Workshop report.Eur Respir J. 2019;53:1802058. [DOI] [PubMed]
Leung JM, Obeidat M, Sadatsafavi M, Sin DD. Introduction to precision medicine in COPD.Eur Respir J. 2019;53:1802460. [DOI] [PubMed]
Brandsma CA, Van den Berge M, Hackett TL, Brusselle G, Timens W. Recent advances in chronic obstructive pulmonary disease pathogenesis: from disease mechanisms to precision medicine.J Pathol. 2020;250:624–35. [DOI] [PubMed] [PMC]
Cardoso J, Ferreira AJ, Guimarães M, Oliveira AS, Simão P, Sucena M. Treatable traits in COPD – a proposed approach.Int J Chron Obstruct Pulmon Dis. 2021;16:3167–82. [DOI] [PubMed] [PMC]
Lopez-Campos JL, Centanni S. Current approaches for phenotyping as a target for precision medicine in COPD management.COPD. 2018;15:108–17. [DOI] [PubMed]
Lopes-Pacheco M. CFTR modulators: the changing face of cystic fibrosis in the era of precision medicine.Front Pharmacol. 2019;10:1662. [DOI] [PubMed] [PMC]
Chan R, Lipworth BJ. Impact of biologic therapy on the small airways asthma phenotype.Lung. 2022;200:691–6. [DOI] [PubMed] [PMC]
Qin R, An J, Xie J, Huang R, Xie Y, He L, et al. 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;9:3649–59.E6. [DOI] [PubMed]
Perez T, Chanez P, Dusser D, Devillier P. Small airway impairment in moderate to severe asthmatics without significant proximal airway obstruction.Respir Med. 2013;107:1667–74. [DOI] [PubMed]
Kraemer R, Smith HJ, Gardin F, Barandun J, Minder S, Kern L, et al. Bronchodilator response in patients with COPD, asthma-COPD-overlap (ACO) and asthma, evaluated by plethysmographic and spirometric z-score target parameters.Int J Chron Obstruct Pulmon Dis. 2021;16:2487–500. [DOI] [PubMed] [PMC]
Kraemer R, Gardin F, Smith HJ, Baty F, Barandun J, Piecyk A, et al. Functional predictors discriminating asthma–COPD overlap (ACO) from chronic obstructive pulmonary disease (COPD).Int J Chron Obstruct Pulmon Dis. 2022;17:2723–43. [DOI] [PubMed] [PMC]
Mahut B, Caumont-Prim A, Plantier L, Gillet-Juvin K, Callens E, Sanchez O, et al. Relationships between respiratory and airway resistances and activity-related dyspnea in patients with chronic obstructive pulmonary disease.Int J Chron Obstruct Pulmon Dis. 2012;7:165–71. [DOI] [PubMed] [PMC]
Matthys H, Orth U. Comparative measurements of airway resistance.Respiration. 1975;32:121–34. [DOI] [PubMed]
Cotes JE, Chinn DJ, Quanjer PH, Roca J, Yernault JC. Standardization of the measurement of transfer factor (diffusing capacity).Eur Respir J. 1993;6:41–52. [PubMed]
American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies.Am Rev Respir Dis. 1991;144:1202–18. [DOI] [PubMed]
Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests.Eur Respir J. 2005;26:948–68. [DOI] [PubMed]
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al.; ATS/ERS Task Force. Standardisation of spirometry.Eur Respir J. 2005;26:319–38. [DOI] [PubMed]
Goldman M, Smith HJ, Ulmer WT. Whole-body plethysmography.Eur Respir Mon. 2005;31:15–43.
Stolz D, Barandun J, Borer H, Bridevaux PO, Brun P, Brutsche M, et al. Diagnosis, prevention and treatment of stable COPD and acute exacerbations of COPD: the Swiss recommendations 2018.Respiration. 2018;96:382–98. [DOI] [PubMed]
Stocks J, Quanjer PH. Reference values for residual volume, functional residual capacity and total lung capacity. ATS Workshop on lung volume measurements. Official statement of the European Respiratory Society.Eur Respir J. 1995;8:492–506. [DOI] [PubMed]
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population.Am J Respir Crit Care Med. 1999;159:179–87. [DOI] [PubMed]
Kraemer R, Smith HJ, Sigrist T, Giger G, Keller R, Frey M. Diagnostic accuracy of methacholine challenge tests assessing airway hyperreactivity in asthmatic patients - a multifunctional approach.Respir Res. 2016;17:154. [DOI] [PubMed] [PMC]
Sorkness RL, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Chung KF, 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 (1985). 2008;104:394–403. [DOI] [PubMed]
Mahut B, Bokov P, Delclaux C. Abnormalities of plethysmographic lung volumes in asthmatic children.Respir Med. 2010;104:966–71. [DOI] [PubMed]
Lipworth B, Manoharan A, Anderson W. Unlocking the quiet zone: the small airway asthma phenotype.Lancet Respir Med. 2014;2:497–506. [DOI] [PubMed]
Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS; GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2001;163:1256–76. [DOI] [PubMed]
Swanney MP, Ruppel G, Enright PL, Pedersen OF, Crapo RO, Miller MR, et al. Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction.Thorax. 2008;63:1046–51. [DOI] [PubMed]
Quanjer PH, Enright PL, Miller MR, Stocks J, Ruppel G, Swanney MP, et al. The need to change the method for defining mild airway obstruction.Eur Respir J. 2011;37:720–2. [DOI] [PubMed]
Scholes S, Moody A, Mindell JS. Estimating population prevalence of potential airflow obstruction using different spirometric criteria: a pooled cross-sectional analysis of persons aged 40–95 years in England and Wales.BMJ Open. 2014;4:e005685. [DOI] [PubMed] [PMC]
Cosio M, Ghezzo H, Hogg JC, Corbin R, Loveland M, Dosman J, et al. The relations between structural changes in small airways and pulmonary-function tests.N Engl J Med. 1978;298:1277–81. [DOI] [PubMed]
Riley CM, Wenzel SE, Castro M, Erzurum SC, Chung KF, Fitzpatrick AM, et al. Clinical implications of having reduced mid forced expiratory flow rates (FEF25-75), independently of FEV1, in adult patients with asthma.PLoS One. 2015;10:e0145476. [DOI] [PubMed] [PMC]
Cottini M, Licini A, Lombardi C, Berti A. Prevalence and features of IOS-defined small airway disease across asthma severities.Respir Med. 2021;176:106243. [DOI] [PubMed]
Burgel PR. The role of small airways in obstructive airway diseases.Eur Respir Rev. 2011;20:23–33.Erratum in: Eur Respir Rev. 2011;20:123. Erratum in: Eur Respir Rev. 2011;20:124. [DOI] [PubMed] [PMC]
Postma DS, Brightling C, Baldi S, Van den Berge M, Fabbri LM, Gagnatelli A, et al.; ATLANTIS study group. Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study.Lancet Respir Med. 2019;7:402–16.Erratum in: Lancet Respir Med. 2019;7:e28. [DOI] [PubMed]
Cottini M, Lombardi C, Passalacqua G, Bagnasco D, Berti A, Comberiati P, et al. Small airways: the “silent zone” of 2021 GINA report?Front Med (Lausanne). 2022;9:884679. [DOI] [PubMed] [PMC]
Anderson WJ, Zajda E, Lipworth BJ. Are we overlooking persistent small airways dysfunction in community-managed asthma?Ann Allergy Asthma Immunol. 2012;109:185–9.E2. [DOI] [PubMed]
Santus P, Radovanovic D, Pecchiari M, Ferrando M, Tursi F, Patella V, et al. The relevance of targeting treatment to small airways in asthma and COPD.Respir Care. 2020;65:1392–412. [DOI] [PubMed]
Lipworth B. Targeting the small airways asthma phenotype: If we can reach it, should we treat it?Ann Allergy Asthma Immunol. 2013;110:233–9. [DOI] [PubMed]