Bronchodilator response and lung function decline: Associations with exhaled nitric oxide with regard to sex and smoking status

doi:10.1016/j.waojou.2021.100544

. 2021 May 18;14(5):100544.

doi: 10.1016/j.waojou.2021.100544. eCollection 2021 May.

Bronchodilator response and lung function decline: Associations with exhaled nitric oxide with regard to sex and smoking status

Elisabet Nerpin^{1

2

3}, Diogenes Seraphim Ferreira^{4

5}, Joost Weyler⁶, Vivi Schlunnsen⁷, Rain Jogi⁸, Chantal Raherison Semjen⁹, Thorainn Gislasson^{10

11}, Pascal Demoly^{12

13}, Joachim Heinrich^{14

15

16}, Dennis Nowak^{17

18}, Angelo Corsico^{19

20}, Simone Accordini²¹, Alessandro Marcon²¹, Giulia Squillacioti²², Mario Olivieri²³, Rune Nielsen^{24

25}, Ane Johannessen^{26

27}, Francisco Gómez Real^{25

28}, Judith Garcia-Aymerich²⁹, Isabel Urrutia³⁰, Antonio Pereira-Vega³¹, Jose Antonio Gullón³², Anna-Carin Olin³³, Bertil Forsberg³⁴, Össur Ingi Emilsson¹, Isabelle Pin³⁵, Deborah Jarvis³⁶, Christer Janson¹, Andrei Malinovschi²

Affiliations

¹ Department of Medical Sciences, Respiratory Medicine, Allergy and Sleep, Uppsala University, Uppsala, Sweden.
² Department of Medical Sciences: Clinical Physiology, Uppsala University, Uppsala, Sweden.
³ Department of Medicine, Health and Social Studies, Dalarna University, Falun, Sweden.
⁴ Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Melbourne, Australia.
⁵ Alergia e Imunologia, Complexo Hospital de Clinicas, Universidade Federal do Paraná, Curitiba, Brazil.
⁶ Epidemiology and Social Medicine, University of Antwerp, Antwerp, Belgium.
⁷ Department of Environment Occupation & Health, Danish Ramazzini Centre, Aarhus University, Aarhus, Denmark.
⁸ Lung Clinic, Tartu University Hospital, Tartu, Estonia.
⁹ U1219, Bordeaux Population Health Research Center, Bordeaux, France.
¹⁰ Department of Sleep, Landspitali University Hospital, Reykjavik, Iceland.
¹¹ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹² Département de Pneumologie et Addictologie, Centre Hospitalier Universitaire de Montpellier, Hopital Arnaud de Villeneuve, Univ Montpellier, Montpellier, France.
¹³ Institut Pierre-Louis D'épidémiologie et de Santé Publique, Équipe EPAR, Sorbonne Université, INSERM, Paris, France.
¹⁴ Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital Munich, Ludwig Maximilians University Munich, Munich, Germany.
¹⁵ Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
¹⁶ Allergy and Lung Health Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁷ Hospital of the Ludwig-Maximilian University Munich, LMU Munich, Munich, Germany.
¹⁸ Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Munich, Germany.
¹⁹ Division of Respiratory Diseases, Medical Sciences and Infectious Diseases Department, IRCCS Policlinico San Matteo Foundation.
²⁰ Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.
²¹ Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
²² Department of Public Health and Pediatrics - University of Turin, Turin, Italy.
²³ Unit of Occupational Medicine, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
²⁴ Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway.
²⁵ Department of Clinical Science, University of Bergen, Bergen, Norway.
²⁶ Department of Global Public Health and Primary Care, Centre for International Health, University of Bergen, Bergen, Norway.
²⁷ Department of Occupational Medicine, Haukeland University Hospital, Bergen, Norway.
²⁸ Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
²⁹ ISGlobAL, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
³⁰ Pneumology Service of Galdakao Hospital in Bizkaia, Spain.
³¹ Pneumology and Allergy Service of the Juan Ramón Jiménez Hospital in Huelva, Spain.
³² Peumology. San Agustín Universitary Hospital, Avilés, Spain.
³³ Section of Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³⁴ Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
³⁵ CHU Grenoble Alpes, Inserm, Institut for Advanced Biosciences, Grenoble Alpes University, Grenoble, France.
³⁶ National Heart and Lung Institute, Imperial College London, London, UK.

PMID: 34093956
PMCID: PMC8142084
DOI: 10.1016/j.waojou.2021.100544

Bronchodilator response and lung function decline: Associations with exhaled nitric oxide with regard to sex and smoking status

Elisabet Nerpin et al. World Allergy Organ J. 2021.

. 2021 May 18;14(5):100544.

doi: 10.1016/j.waojou.2021.100544. eCollection 2021 May.

Authors

Affiliations

¹ Department of Medical Sciences, Respiratory Medicine, Allergy and Sleep, Uppsala University, Uppsala, Sweden.
² Department of Medical Sciences: Clinical Physiology, Uppsala University, Uppsala, Sweden.
³ Department of Medicine, Health and Social Studies, Dalarna University, Falun, Sweden.
⁴ Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Melbourne, Australia.
⁵ Alergia e Imunologia, Complexo Hospital de Clinicas, Universidade Federal do Paraná, Curitiba, Brazil.
⁶ Epidemiology and Social Medicine, University of Antwerp, Antwerp, Belgium.
⁷ Department of Environment Occupation & Health, Danish Ramazzini Centre, Aarhus University, Aarhus, Denmark.
⁸ Lung Clinic, Tartu University Hospital, Tartu, Estonia.
⁹ U1219, Bordeaux Population Health Research Center, Bordeaux, France.
¹⁰ Department of Sleep, Landspitali University Hospital, Reykjavik, Iceland.
¹¹ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹² Département de Pneumologie et Addictologie, Centre Hospitalier Universitaire de Montpellier, Hopital Arnaud de Villeneuve, Univ Montpellier, Montpellier, France.
¹³ Institut Pierre-Louis D'épidémiologie et de Santé Publique, Équipe EPAR, Sorbonne Université, INSERM, Paris, France.
¹⁴ Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital Munich, Ludwig Maximilians University Munich, Munich, Germany.
¹⁵ Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
¹⁶ Allergy and Lung Health Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁷ Hospital of the Ludwig-Maximilian University Munich, LMU Munich, Munich, Germany.
¹⁸ Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Munich, Germany.
¹⁹ Division of Respiratory Diseases, Medical Sciences and Infectious Diseases Department, IRCCS Policlinico San Matteo Foundation.
²⁰ Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.
²¹ Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
²² Department of Public Health and Pediatrics - University of Turin, Turin, Italy.
²³ Unit of Occupational Medicine, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
²⁴ Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway.
²⁵ Department of Clinical Science, University of Bergen, Bergen, Norway.
²⁶ Department of Global Public Health and Primary Care, Centre for International Health, University of Bergen, Bergen, Norway.
²⁷ Department of Occupational Medicine, Haukeland University Hospital, Bergen, Norway.
²⁸ Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
²⁹ ISGlobAL, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
³⁰ Pneumology Service of Galdakao Hospital in Bizkaia, Spain.
³¹ Pneumology and Allergy Service of the Juan Ramón Jiménez Hospital in Huelva, Spain.
³² Peumology. San Agustín Universitary Hospital, Avilés, Spain.
³³ Section of Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³⁴ Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
³⁵ CHU Grenoble Alpes, Inserm, Institut for Advanced Biosciences, Grenoble Alpes University, Grenoble, France.
³⁶ National Heart and Lung Institute, Imperial College London, London, UK.

PMID: 34093956
PMCID: PMC8142084
DOI: 10.1016/j.waojou.2021.100544

Abstract

Background: Fractional exhaled nitric oxide (FeNO) is a marker of type-2 inflammation used both to support diagnosis of asthma and follow up asthma patients. The associations of FeNO with lung function decline and bronchodilator (BD) response have been studied only scarcely in large populations.

Objectives: To study the association between FeNO and a) retrospective lung function decline over 20 years, and b) lung function response to BD among asthmatic subjects compared with non-asthmatic subjects and with regards to current smoking and sex.

Methods: Longitudinal analyses of previous lung function decline and FeNO level at follow-up and cross-sectional analyses of BD response and FeNO levels in 4257 participants (651 asthmatics) from the European Community Respiratory Health Survey.

Results: Among asthmatic subjects, higher percentage declines of FEV₁ and FEV₁/FVC were associated with higher FeNO levels (p = 0.001 for both) at follow-up. These correlations were found mainly among non-smoking individuals (p = 0.001) and females (p = 0.001) in stratified analyses.Percentage increase in FEV₁ after BD was positively associated with FeNO levels in non-asthmatic subjects. Further, after stratified for sex and smoking separately, a positive association was seen between FEV₁ and FeNO levels in non-smokers and women, regardless of asthma status.

Conclusions: We found a relationship between elevated FeNO and larger FEV₁ decline over 20 years among subjects with asthma who were non-smokers or women. The association between elevated FeNO levels and larger BD response was found in both non-asthmatic and asthmatic subjects, mainly in women and non-smoking subjects.

Keywords: Bronchodilatation; Epidemiology; FeNO; Lung function.

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Conflict of interest statement

DF reports grants from Asthma Foundation of Victoria, grants from Allen and Hanbury’s, grants from National Health & Medical Research Council, during the conduct of the study. VS reports grants from The Wood Dust Foundation (Project No. 444508795), during the conduct of the study. RJ reports grants from Estonian Research Council Personal Research Grant no 562, during the conduct of the study; personal fees from Consultancy, grants from Grants/grants pending, personal fees from Payment for lectures, personal fees from Travel/accommodations/meeting expenses, outside the submitted work. PD reports grants from ALK, Stallergenes Greer, grants from AstraZeneca, ThermoFisherScientific, Ménarini, grants from Bausch & Lomb, personal fees from Sanofi, Regeneron, outside the submitted work. RN reports grants and personal fees from AstraZeneca, grants from Novartis, grants from Boehringer Ingelheim, grants and personal fees from GlaxoSmithKline, outside the submitted work. IP reports other from NOVARTIS, other from ASTRA ZENECA, personal fees from AGIRadom, outside the submitted work. All other authors declare no conflicts of interests. The following grants contributed to funding ECRHS I. Australia: Asthma Foundation of Victoria, Allen and Hanbury’s. Belgium: Belgian Science Policy Office, National Fund for Scientific Research. Denmark: The Danish Lung Association. Estonia: Estonian Science Foundation, grant no 1088. France: Ministère de la Santé, Glaxo France, Institut Pneumologique d'Aquitaine, Contrat de Plan Etat-Région Languedoc-Rousillon, CNMATS, CNMRT (90MR/10, 91AF/6), Ministre delegué de la santé, RNSP, France; GSF. Germany: Bundesminister für Forschung und Technologie. Greece: The Greek Secretary General of Research and Technology, Fisons, Astra and Boehringer-Ingelheim. India: Bombay Hospital Trust. Italy: Ministero dell'Università e della Ricerca Scientifica e Tecnologica, CNR, Regione Veneto grant RSF n. 381/05.93. New Zealand: Asthma Foundation of New Zealand, Lotteries Grant Board, Health Research Council of New Zealand. Norway: Norwegian Research Council project no. 101422/310. Portugal: Glaxo Farmacêutica Lda, Sandoz Portugesa. Spain: Fondo de Investigación Sanitaria (#91/0016-060-05/E, 92/0319 and #93/0393), Hospital General de Albacete, Hospital General Juan Ramón Jiménez, Dirección Regional de Salud Pública (Consejería de Sanidad del Principado de Asturias), CIRIT (1997 SGR 00079), and Servicio Andaluz de Salud. Sweden: The Swedish Medical Research Council, the Swedish Heart Lung Foundation, and the Swedish Association against Asthma and Allergy. Switzerland: Swiss National Science Foundation grant 4026-28099. UK: National Asthma Campaign, British Lung Foundation, Department of Health, South Thames Regional Health Authority. USA: United States Department of Health, Education and Welfare Public Health Service (grant #2 S07 RR05521-28). The coordination of this work was supported by the European Commission. The following grants contributed to funding ECRHS III. Australia: National Health & Medical Research Council. Belgium: Antwerp South, Antwerp City – Research Foundation Flanders (FWO), grant code G.0.410.08.N.10 (both sites). Estonia: Tartu – SF0180060s09 from the Estonian Ministry of Education. France: (All) Ministère de la Santé, Programme Hospitalier de Recherche Clinique (PHRC) national 2010. Bordeaux: INSERM U897 Université Bordeaux Segalen. Grenoble: Comite Scientifique AGIRadom 2011. Paris: Agence Nationale de la Santé, Région Ile de France, domaine d’intérêt majeur (DIM). Germany: Erfurt: German Research Foundation HE 3294/10-1. Hamburg: German Research Foundation MA 711/6-1, NO 262/7-1. Iceland: Reykjavik, The Landspítali University Hospital Research Fund, University of Iceland Research Fund, ResMed Foundation, California, USA, Orkuveita Reykjavíkur (Geothermal plant), Vegagerðin (The Icelandic Road Administration (ICERA). Italy: All Italian centres were funded by the Italian Ministry of Health, Chiesi Farmaceutici SpA. Verona received additional funding from the Cariverona foundation, Education Ministry (MIUR). Norway: Norwegian Research Council grant no 214123, Western Norway Regional Health Authorities grant no 911631, Bergen Medical Research Foundation. Spain: Fondo de Investigación Sanitaria (PS09/02457, PS09/00716 09/01511) PS09/02185 PS09/03190), Servicio Andaluz de Salud, Sociedad Española de Neumología y Cirurgía Torácica (SEPAR 1001/2010), Fondo de Investigación Sanitaria (PS09/02457). Barcelona: Fondo de Investigación Sanitaria (FIS PS09/00716). Galdakao:Fondo de Investigación Sanitaria (FIS 09/01511). Huelva: Fondo de Investigación Sanitaria (FIS PS09/02185) and Servicio Andaluz de Salud. Oviedo: Fondo de Investigación Sanitaria(FIS PS09/03190). Sweden: All centres were funded by the Swedish Heart and Lung Foundation, the Swedish Asthma and Allergy Association, the Swedish Association against Lung and Heart Disease, and the Swedish Research Council for Health, Working Life and Welfare (FORTE). Göteborg also received further funding from the Swedish Council for Working Life and Social Research. Umeå also received funding from a Västerbotten County Council ALF grant. Switzerland: The Swiss National Science Foundation (grants no 33CSCO-134276/1, 33CSCO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099), The Federal office for Forest, Environment and Landscape, The Federal Office of Public Health, The Federal Office of Roads and Transport, the canton’s government of Aargan, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Zürich, the Swiss Lung League, the canton’s Lung League of Basel Stadt/ Basel, Landschaft, Geneva, Ticino, Valais, and Zurich, SUVA, Freiwillige Akademische Gesellschaft, UBS Wealth Foundation, Talecris Biotherapeutics GmbH, Abbott Diagnostics, European Commission 018996 (GABRIEL), Wellcome Trust WT 084703MA, UK: Medical Research Council (Grant Number 92091). Support was also provided by the National Institute for Health Research through the Primary Care Research Network.

Figures

**Fig. 1**
Flowchart showing the selection process and numbers of subjects available for analyses. Definitions of asthma and bronchodilator (BD) are specified in the methods section. ECRHS, European Community Respiratory Health Survey. FeNO, fractional exhaled nitric oxide

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[1] Nijkamp F.P., Folkerts G. Nitric oxide and bronchial hyperresponsiveness. Arch Int Pharmacodyn Ther. 1995;329(1):81–96. - PubMed

[2] Nijkamp F.P., Folkerts G. Nitric oxide and bronchial hyperresponsiveness. Arch Int Pharmacodyn Ther. 1995;329(1):81–96. - PubMed

[3] Guo F.H., Uetani K., Haque S.J. Interferon gamma and interleukin 4 stimulate prolonged expression of inducible nitric oxide synthase in human airway epithelium through synthesis of soluble mediators. J Clin Invest. 1997;100(4):829–838. - PMC - PubMed

[4] Guo F.H., Uetani K., Haque S.J. Interferon gamma and interleukin 4 stimulate prolonged expression of inducible nitric oxide synthase in human airway epithelium through synthesis of soluble mediators. J Clin Invest. 1997;100(4):829–838. - PMC - PubMed

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[7] Price D.B., Buhl R., Chan A. Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial. Lancet Respir Med. 2018;6(1):29–39. - PubMed

[8] Price D.B., Buhl R., Chan A. Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial. Lancet Respir Med. 2018;6(1):29–39. - PubMed

[9] Kuo C.R., Spears M., Haughney J. Scottish consensus statement on the role of FeNO in adult asthma. Respir Med. 2019;155:54–57. - PubMed

[10] Kuo C.R., Spears M., Haughney J. Scottish consensus statement on the role of FeNO in adult asthma. Respir Med. 2019;155:54–57. - PubMed

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Bronchodilator response and lung function decline: Associations with exhaled nitric oxide with regard to sex and smoking status

Affiliations

Bronchodilator response and lung function decline: Associations with exhaled nitric oxide with regard to sex and smoking status

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Affiliations

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