Advertisement

Interrelationships Among Small Airways Dysfunction, Neutrophilic Inflammation, and Exacerbation Frequency in COPD

Published:November 24, 2020DOI:https://doi.org/10.1016/j.chest.2020.11.018

      Background

      Small airways disease (SAD) is a key component of COPD and is a main contributing factor to lung function decline.

      Research Question

      Is SAD a key feature of frequent COPD exacerbators and is this related to airway inflammation?

      Study Design and Methods

      Thirty-nine COPD patients defined as either frequent exacerbator (FE) group (≥ 2 exacerbations/y; n = 17) and infrequent exacerbator (IFE) group (≤ 1 exacerbation/y; n = 22) underwent the forced oscillation technique (resistance at 5 Hz minus 19 Hz [R5-R19], area of reactance [AX]), multiple breath nitrogen washout (conducting airways ventilation heterogeneity, acinar ventilation heterogeneity [Sacin]), plethysmography (ratio of residual volume to total lung capacity), single-breath transfer factor of the lung for carbon monoxide, spirometry (FEV1, FEV1/FVC), and paired inspiratory-expiratory CT scans to ascertain SAD. A subpopulation underwent bronchoscopy to enable enumeration of BAL cell proportions.

      Results

      Sacin was significantly higher in the COPD FE group compared with the IFE group (P = .027). In the FE group, markers of SAD were associated strongly with BAL neutrophil proportions, R5-R19 (P = .001, r = 0.795), AX (P = .049, ρ = 0.560), residual volume to total lung capacity ratio (P = .004, r = 0.730), and the mean lung density of the paired CT scans (P = .018, r = 0.639).

      Interpretation

      Increased Sacin may be a consequence of previous exacerbations or may highlight a group of patients prone to exacerbations. Measures of SAD were associated strongly with neutrophilic inflammation in the small airways of FE patients, supporting the hypothesis that frequent exacerbations are associated with SAD related to increased cellular inflammation.

      Key Words

      Abbreviations:

      AX (area of reactance), FE (frequent exacerbator), FOT (forced oscillation technique), HRCT (high-resolution CT), ICS (inhaled corticosteroids), IFE (infrequent exacerbator), MBNW (multiple breath nitrogen washout), MLD E/I (ratio of the mean lung density of expiration to inspiration), R5-R19 (resistance at 5 Hz minus 19 Hz), Sacin (acinar ventilation heterogeneity), SAD (small airways disease), Scond (conducting airways ventilation heterogeneity)
      To read this article in full you will need to make a payment
      Subscribe to CHEST
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Vogelmeier C.F.
        • Criner G.J.
        • Martinez F.J.
        • et al.
        Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary.
        Eur Respir J. 2017; 49 (1700214)
        • Ostridge K.
        • Gove K.
        • Paas K.H.W.
        • et al.
        Using novel computed tomography analysis to describe the contribution and distribution of emphysema and small airways disease in chronic obstructive pulmonary disease.
        Ann Am Thorac Soc. 2019; 16: 990-997
        • Hogg J.C.
        • McDonough J.E.
        • Gosselink J.V.
        • et al.
        What drives the peripheral lung-remodeling process in chronic obstructive pulmonary disease?.
        Proc Am Thorac Soc. 2009; 6: 668-672
        • Cosio M.
        • Ghezzo H.
        • Hogg J.C.
        • et al.
        The relations between structural changes in small airways and pulmonary-function tests.
        N Engl J Med. 1978; 298: 1277-1281
        • Black P.N.
        • Ching P.S.T.
        • Beaumont B.
        • et al.
        Changes in elastic fibres in the small airways and alveoli in COPD.
        Eur Respir J. 2008; 31: 998-1004
        • Yanai M.
        • Sekizawa K.
        • Ohrui T.
        • et al.
        Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure.
        J Appl Physiol. 1992; 72: 1016-1023
        • Vestbo J.
        • Hurd S.S.
        • Rodriguez-Roisin R.
        The 2011 revision of the global strategy for the diagnosis, management and prevention of COPD (GOLD)—why and what?.
        Clin Respir J. 2012; 6: 208-214
        • Wedzicha J.A.
        • Brill S.E.
        • Allinson J.P.
        • et al.
        Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease.
        BMC Med. 2013; 11: 181
        • Han M.K.
        • Kazerooni E.A.
        • Lynch D.A.
        • et al.
        Chronic obstructive pulmonary disease exacerbations in the COPDGene Study: associated radiologic phenotypes.
        Radiology. 2011; 261: 274-282
        • Williams N.P.
        • Coombs N.A.
        • Johnson M.J.
        • et al.
        Seasonality, risk factors and burden of community-acquired pneumonia in COPD patients: a population database study using linked health care records.
        Int J Chron Obstruct Pulmon Dis. 2017; 12: 313-322
        • Wedzicha J.A.
        • Wilkinson T.
        Impact of chronic obstructive pulmonary disease exacerbations on patients and payers.
        Proc Am Thorac Soc. 2006; 3: 218-221
        • Quint J.K.
        • Wedzicha J.A.
        The neutrophil in chronic obstructive pulmonary disease.
        J Allergy Clin Immunol. 2007; 119: 1065-1071
        • Mayhew D.
        • Devos N.
        • Lambert C.
        • et al.
        Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations.
        Thorax. 2018; 73: 422-430
        • Ruppel G.L.
        What is the clinical value of lung volumes?.
        Respir Care. 2012; 57: 26-38
        • Bommart S.
        • Marin G.
        • Bourdin A.
        • et al.
        Relationship between CT air trapping criteria and lung function in small airway impairment quantification.
        BMC Pulm Med. 2014; 14: 29
        • Ostridge K.
        • Wilkinson T.M.A.
        Present and future utility of computed tomography scanning in the assessment and management of COPD.
        Eur Respir J. 2016; 48: 216-228
        • Bell A.S.
        • Lawrence P.J.
        • Singh D.
        • et al.
        Feasibility and challenges of using multiple breath washout in COPD.
        Int J Chron Obstruct Pulmon Dis. 2018; 13: 2113-2119
        • Gove K.
        • Wilkinson T.
        • Jack S.
        • et al.
        Systematic review of evidence for relationships between physiological and CT indices of small airways and clinical outcomes in COPD.
        Respir Med. 2018; 139: 117-125
        • Goldman M.D.
        • Saadeh C.
        • Ross D.
        Clinical applications of forced oscillation to assess peripheral airway function.
        Respir Physiol Neurobiol. 2005; 148: 179-194
        • Grimby G.
        • Takishima T.
        • Graham W.
        • et al.
        Frequency dependence of flow resistance in patients with obstructive lung disease.
        J Clin Invest. 1968; 47: 1455-1465
        • Bates J.H.T.
        The role of airway shunt elastance on the compartmentalization of respiratory system impedance.
        J Eng Sci Med Diagn Ther. 2019; 2 (011001-1-011001-8)
        • Cauberghs M.
        • Van de Woestijne K.P.
        Effect of upper airway shunt and series properties on respiratory impedance measurements.
        J Appl Physiol (1985). 1989; 66: 2274-2279
        • Lutchen K.R.
        • Gillis H.
        Relationship between heterogeneous changes in airway morphometry and lung resistance and elastance.
        J Appl Physiol (1985). 1997; 83: 1192-1201
        • Foy B.H.
        • Soares M.
        • Bordas R.
        • et al.
        Lung computational models and the role of the small airways in asthma.
        Am J Respir Crit Care Med. 2019; 200: 982-991
        • Verbanck S.
        • Schuermans D.
        • Vanmuylem A.
        • et al.
        Conductive and acinar lung-zone contributions to ventilation inhomogeneity in COPD.
        Am J Respir Crit Care Med. 1998; 157: 1573-1577
        • Verbanck S.
        Physiological measurement of the small airways.
        Respiration. 2012; 84: 177-188
        • Verbanck S.
        • Thompson B.R.
        • Schuermans D.
        • et al.
        Ventilation heterogeneity in the acinar and conductive zones of the normal ageing lung.
        Thorax. 2012; 67: 789-795
        • Jarenback L.
        • Ankerst J.
        • Bjermer L.
        • et al.
        Acinar ventilation heterogeneity in COPD relates to diffusion capacity, resistance and reactance.
        Respir Med. 2016; 110: 28-33
        • Van Muylem A.
        • De Vuyst P.
        • Yernault J.C.
        • et al.
        Inert gas single-breath washout and structural alteration of respiratory bronchioles.
        Am Rev Respir Dis. 1992; 146: 1167-1172
        • Verbanck S.
        • King G.G.
        • Paiva M.
        • et al.
        The functional correlate of the loss of terminal bronchioles in chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2018; 197: 1633-1635
        • McNulty W.
        • Usmani O.S.
        Techniques of assessing small airways dysfunction.
        Eur Clin Respir J. 2014; 1
        • O’Donnell R.A.
        • Peebles C.
        • Ward J.A.
        • et al.
        Relationship between peripheral airway dysfunction, airway obstruction, and neutrophilic inflammation in COPD.
        Thorax. 2004; 59: 837-842
        • Baraldo S.
        • Turato G.
        • Badin C.
        • et al.
        Neutrophilic infiltration within the airway smooth muscle in patients with COPD.
        Thorax. 2004; 59: 308-312
        • Zimmermann S.C.
        • Tonga K.O.
        • Thamrin C.
        Dismantling airway disease with the use of new pulmonary function indices.
        Eur Respir Rev. 2019; 28: 180122
        • Watson A.
        • Spalluto C.M.
        • McCrae C.
        • et al.
        Dynamics of IFN-β responses during respiratory viral infection. Insights for therapeutic strategies.
        Am J Respir Crit Care Med. 2020; 201: 83-94
        • Miller M.R.
        • Hankinson J.
        • Brusasco V.
        • et al.
        Standardisation of spirometry.
        Eur Respir J. 2005; 26: 319-338
        • MacIntyre N.
        • Crapo R.O.
        • Viegi G.
        • et al.
        Standardisation of the single-breath determination of carbon monoxide uptake in the lung.
        Eur Respir J. 2005; 26: 720-735
        • Ostridge K.
        • Williams N.
        • Kim V.
        • et al.
        Relationship between pulmonary matrix metalloproteinases and quantitative CT markers of small airways disease and emphysema in COPD.
        Thorax. 2016; 71: 126-132
        • Lutchen K.R.
        • Habib R.H.
        • Dorkin H.L.
        • et al.
        Respiratory impedance and multibreath N2 washout in healthy, asthmatic, and cystic fibrosis subjects.
        J Appl Physiol. 1990; 68: 2139-2149
        • Verbanck S.
        • Schuermans D.
        • Meysman M.
        • et al.
        Noninvasive assessment of airway alterations in smokers: the small airways revisited.
        Am J Respir Crit Care Med. 2004; 170: 414-419
        • Verbanck S.
        • Schuermans D.
        • Vincken W.
        Small airways ventilation heterogeneity and hyperinflation in COPD: response to tiotropium bromide.
        Int J Chron Obstruct Pulmon Dis. 2007; 2: 625-634
        • Wright J.L.
        • Lawson L.M.
        • Pare P.D.
        • et al.
        The detection of small airways disease.
        Am Rev Respir Dis. 1984; 129: 989-994
        • Vermeulen F.
        • Proesmans M.
        • Boon M.
        • et al.
        Lung clearance index predicts pulmonary exacerbations in young patients with cystic fibrosis.
        Thorax. 2014; 69: 39-45
        • O’Neill K.
        • Bradley J.M.
        • Johnston E.
        • et al.
        Reduced bacterial colony count of anaerobic bacteria is associated with a worsening in lung clearance index and inflammation in cystic fibrosis.
        PLoS One. 2015; 10e0126980
        • Postma D.S.
        • Brightling C.
        • Baldi S.
        • et al.
        Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study.
        Lancet Respir Med. 2019; 7: 402-416
        • Jetmalani K.
        • Thamrin C.
        • Farah C.S.
        • et al.
        Peripheral airway dysfunction and relationship with symptoms in smokers with preserved spirometry.
        Respirology. 2018; 23: 512-518
        • Lapperre T.S.
        • Willems L.N.
        • Timens W.
        • et al.
        Small airways dysfunction and neutrophilic inflammation in bronchial biopsies and BAL in COPD.
        Chest. 2007; 131: 53-59
        • Ostridge K.
        • Williams N.
        • Kim V.
        • et al.
        Distinct emphysema subtypes defined by quantitative CT analysis are associated with specific pulmonary matrix metalloproteinases.
        Respir Res. 2016; 17: 92