Advertisement

Dilemmas, Confusion, and Misconceptions Related to Small Airways Directed Therapy

Published:February 04, 2017DOI:https://doi.org/10.1016/j.chest.2016.07.035
      During the past decade, there has been increasing evidence that the small airways (ie, airways < 2 mm in internal diameter) contribute substantially to the pathophysiologic and clinical expression of asthma and COPD. The increased interest in small airways is, at least in part, a result of innovation in small-particle aerosol formulations that better target the distal lung and also advanced physiologic methods of assessing small airway responses. Increasing the precision of drug deposition may improve targeting of specific diseases or receptor locations, decrease airway drug exposure and adverse effects, and thereby increase the efficiency and effectiveness of inhaled drug delivery. The availability of small-particle aerosols of corticosteroids, bronchodilators, or their combination enables a higher total lung deposition and better peripheral lung penetration and provides added clinical benefit, compared with large-particle aerosol treatment. However, a number of questions remain unanswered about the pragmatic approach relevant for clinicians to consider the role of small airways directed therapy in the day-to-day management of asthma and COPD. We thus have tried to clarify the dilemmas, confusion, and misconceptions related to small airways directed therapy. To this end, we have reviewed all studies on small-particle aerosol therapy systematically to address the dilemmas, confusion, and misconceptions related to small airways directed therapy.

      Key Words

      Abbreviations:

      BDP (beclomethasone dipropionate), CFC (chlorofluorocarbon), DPI (dry powder inhaler), GSD (geometric standard deviation), HFA (hydrofluoroalkane), ICS (inhaled corticosteroid), LABA (long-acting β2-adrenergic bronchodilator), MMAD (mass median aerodynamic diameter), pMDI (pressurized metered-dose inhaler), VHC (valved holding chamber)
      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

        • Darquenne C.
        • Fleming J.S.
        • Katz I.
        • et al.
        Bridging the gap between science and clinical efficacy: physiology, imaging and modelling of aerosol in the lung.
        J Aerosol Med Pulm Drug Deliv. 2016; 29: 1-19
        • Weibel E.R.
        Morphometry of the Human Lung.
        Springer-Verlag, Berlin, Germany1963: p4-9
        • Hogg J.C.
        • Chu F.
        • Utokaparch S.
        • et al.
        The nature of small-airway obstruction in chronic obstructive pulmonary disease.
        N Engl J Med. 2004; 350: 2645-2653
        • Hamid Q.
        • Song Y.
        • Kotsimbos T.C.
        • et al.
        Inflammation of small airways in asthma.
        J Allergy Clin Immunol. 1997; 100: 44-51
        • 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: 1016-1023
        • in’t Veen J.C.
        • Beekman A.J.
        • Bel E.H.
        • Sterk P.J.
        Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes.
        Am J Respir Crit Care Med. 2000; 161: 1902-1906
        • 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: 1513-1517
        • Wenzel S.E.
        Asthma: defining of the persistent adult phenotypes.
        Lancet. 2006; 368: 804-813
        • Kraft M.
        • Djukanovic R.
        • Wilson S.
        • Holgate S.T.
        • Martin R.J.
        Alveolar tissue inflammation in asthma.
        Am J Respir Crit Care Med. 1996; 154: 1505-1510
        • Kraft M.
        • Pak J.
        • Martin R.J.
        • Kaminsky D.
        • Irvin C.G.
        Distal lung dysfunction at night in nocturnal asthma.
        Am J Respir Crit Care Med. 2001; 163: 1551-1556
        • Kaminsky D.A.
        • Irvin C.G.
        • Gurka D.A.
        • et al.
        Peripheral airways responsiveness to cool, dry air in normal and asthmatic individuals.
        Am J Respir Crit Care Med. 1995; 152: 1784-1790
        • D’Amato G.
        • Liccardi G.
        • D’Amato M.
        • Cazzola M.
        Outdoor air pollution climatic changes and allergic bronchial asthma.
        Eur Respir J. 2002; 20: 763-776
        • Usmani O.S.
        Small airways dysfunction in asthma: evaluation and management to improve asthma control.
        Allergy Asthma Immunol Res. 2014; 6: 376-388
        • Usmani O.S.
        Small-airway disease in asthma: pharmacological considerations.
        Curr Opin Pulm Med. 2015; 21: 55-67
        • Usmani O.S.
        Treating the small airways.
        Respiration. 2012; 84: 441-453
        • Chapman K.R.
        • Fogarty C.M.
        • Peckitt C.
        • et al.
        Delivery characteristics and patients’ handling of two single-dose dry-powder inhalers used in COPD.
        Int J Obstruct Pulmon Dis. 2011; 6: 353-363
        • Colthorpe P.
        • Voshaar T.
        • Kieckbusch T.
        • Cuoghi E.
        • Jauernig J.
        Delivery characteristics of a low-resistance dry-powder inhaler used to deliver the long-acting muscarinic antagonist glycopyrronium.
        J Drug Assess. 2013; 2: 11-16
      1. Lock DJ, Watkins A, Munro A. DPI performance modelling using an inhalation simulator and oropharyngeal model: a more patient-relevant approach for device development. Paper presented at: Drug Delivery to the Lungs DDL25 Conference; December 10, 2014; Edinburgh, UK.

        • Lavorini F.
        • Fontana G.A.
        • Usmani O.S.
        New inhaler devices; the good, the bad and the ugly.
        Respiration. 2014; 88: 3-15
        • Labiris N.R.
        • Dolovich M.B.
        Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications.
        Br J Clin Pharmacol. 2003; 56: 588-599
        • Corradi M.
        • Chrystyn H.
        • Cosio B.G.
        • et al.
        NEXThaler, an innovative dry powder inhaler delivering an extrafine fixed combination of beclometasone and formoterol to treat large and small airways in asthma.
        Exp Opin Drug Deliv. 2014; 11: 1497-1506
        • Dalby R.N.
        • Eicher J.
        • Zierenberg B.
        Development of Respimat Soft Mist inhaler and its clinical utility in respiratory disorders.
        Med Devices (Auckl). 2011; 4: 145-155
        • Hoshino M.
        Comparison of effectiveness in ciclesonide and fluticasone propionate on small airway function in mild asthma.
        Allergol Int. 2010; 59: 59-66
        • Huchon G.
        • Magnussen H.
        • Chuchalin A.
        • et al.
        Lung function and asthma control with beclomethasone and formoterol in a single inhaler.
        Respir Med. 2009; 103: 41-49
        • Papi A.
        • Paggiaro P.
        • Nicolini G.
        • et al.
        • and the ICAT SE study group
        Beclomethasone/formoterol vs fluticasone/salmeterol inhaled combination in moderate to severe asthma.
        Allergy. 2007; 62: 1182-1188
        • Postma D.S.
        • Roche N.
        • Colice G.
        • et al.
        Comparing the effectiveness of small-particle versus large-particle inhaled corticosteroid in COPD.
        Int J Chron Obstruct Pulmon Dis. 2014; 9: 1163-1186
        • de Boer A.H.
        • Gjaltema D.
        • Hagedoorn P.
        • Frijlink H.W.
        Can ‘extrafine’ dry powder aerosols improve lung deposition?.
        Eur J Pharm Biopharm. 2015; 96: 143-151
        • Chrystyn H.
        • Price D.
        Not all asthma inhalers are the same: factors to consider when prescribing an inhaler.
        Prim Care Respir J. 2009; 18: 243-249
        • Mitchell J.
        • Newman S.
        • Chan H.K.
        In vitro and in vivo aspects of cascade impactor tests and inhaler performance: a review.
        AAPS PharmSciTech. 2007; 8: E110
        • Laube B.
        • Janssens H.M.
        • de Jongh F.H.
        • et al.
        What the pulmonary specialist should know about the new inhalation therapies.
        Eur Respir J. 2011; 37: 1308-1331
        • Leach C.L.
        • Davidson P.J.
        • Hasselquist B.E.
        • Boudreau R.J.
        Lung deposition of hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone: a cross-over study in healthy volunteers.
        Chest. 2002; 122: 510-516
        • Agertoft L.
        • Laulund L.W.
        • Harrison L.I.
        • Pedersen S.
        Influence of particle size on lung deposition and pharmacokinetics of beclomethasone dipropionate in children.
        Pediatr Pulmonol. 2003; 35: 192-199
        • Leach C.L.
        • Davidson P.J.
        • Boudreau R.J.
        Improved airway targeting with the CFC-free HFA beclomethasone metered-dose inhaler compared with CFC-beclomethasone.
        Eur Respir J. 1998; 12: 1346-1353
        • Zanen P.
        • Laube B.L.
        Targeting the lungs with therapeutic aerosols.
        in: Bisgaard H. O’Callaghan C. Smaldone G. Drug Delivery to the Lungs. Marcel Dekker, New York, NY2001: 211-261
        • Usmani O.S.
        • Biddiscombe M.F.
        • Nightingale J.A.
        • Underwood S.R.
        • Barnes P.J.
        Effects of bronchodilator particle size in asthmatic patients using monodisperse aerosols.
        J Appl Physiol (1985). 2003; 95: 2106-2112
        • Usmani O.S.
        • Biddiscombe M.F.
        • Barnes P.J.
        Regional lung deposition and bronchodilator response as a function of beta2-agonist particle size.
        Am J Respir Crit Care Med. 2005; 172: 1497-1504
        • Zanen P.
        • Go L.T.
        • Lammers J.W.
        Optimal particle size for beta 2 agonist and anticholinergic aerosols in patients with severe airflow obstruction.
        Thorax. 1996; 51: 977-980
        • Borrill Z.L.
        • Houghton C.M.
        • Tal-Singer R.
        • et al.
        The use of plethysmography and oscillometry to compare long-acting bronchodilators in patients with COPD.
        Br J Clin Pharmacol. 2008; 65: 244-252
        • Al-Bazzaz F.J.
        Single-breath nitrogen washout: effects of alterations of lung volumes and elastic recoil.
        Chest. 1979; 76: 83-88
        • Bourdin A.
        • Paganin F.
        • Préfaut C.
        • Kieseler D.
        • Godard P.
        • Chanez P.
        Nitrogen washout slope in poorly controlled asthma.
        Allergy. 2006; 61: 85-89
        • Leach C.L.
        Effect of formulation parameters on hydrofluoroalkane-beclomethasone dipropionate drug deposition in humans.
        J Allergy Clin Immunol. 1999; 104: S250-S252
        • Leach C.L.
        • Bethke T.D.
        • Boudreau R.J.
        • et al.
        Two-dimensional and three-dimensional imaging show ciclesonide has high lung deposition and peripheral distribution: a nonrandomized study in healthy volunteers.
        J Aerosol Med. 2006; 19: 117-126
        • Newman S.
        • Salmon A.
        • Nave R.
        • Drollmann A.
        High lung deposition of 99mTc-labeled ciclesonide administered via HFA-MDI to patients with asthma.
        Respir Med. 2006; 100: 375-384
        • de Vries T.W.
        • Rottier B.L.
        • Gjaltema D.
        • Hagedoorn P.
        • Frijlink H.W.
        • de Boer A.H.
        Comparative in vitro evaluation of four corticosteroid metered dose inhalers: consistency of delivered dose and particle size distribution.
        Respir Med. 2009; 103: 1167-1173
        • Zierenberg B.
        Optimizing the in vitro performance of Respimat.
        J Aerosol Med. 1999; 12: S19-S24
        • Pitcairn G.
        • Reader S.
        • Pavia D.
        • Newman S.
        Deposition of corticosteroid aerosol in the human lung by Respimat Soft Mist inhaler compared to deposition by metered dose inhaler or by Turbuhaler dry powder inhaler.
        J Aerosol Med. 2005; 18: 264-272
        • Nicolini G.
        • Scichilone N.
        • Bizzi A.
        • et al.
        Beclomethasone/formoterol fixed combination for the management of asthma: patient considerations.
        Ther Clin Risk Manag. 2008; 4: 855-864
        • Leach C.L.
        • Kuehl P.J.
        • Chand R.
        • Ketai L.
        • Norenberg J.P.
        • McDonald J.D.
        Characterization of respiratory deposition of fluticasone-salmeterol hydrofluoroalkane-134a and hydrofluoroalkane-134a beclomethasone in asthmatic patients.
        Ann Allergy Asthma Immunol. 2012; 108: 195-200
        • Chrystyn H.
        Methods to identify drug deposition in the lungs following inhalation.
        Br J Clin Pharmacol. 2001; 51: 289-299
        • Lipworth B.J.
        Pharmacokinetics of inhaled drugs.
        Br J Clin Pharmacol. 1996; 42: 697-705
        • Bateman E.D.
        • Linnhof A.E.
        • Homik L.
        • et al.
        Comparison of twice-daily inhaled ciclesonide and fluticasone propionate in patients with moderate-to-severe persistent asthma.
        Pulm Pharmacol Ther. 2008; 21: 264-275
        • Derom E.
        • Van De Velde V.
        • Marissens S.
        • et al.
        Effects of inhaled ciclesonide and fluticasone propionate on cortisol secretion and airway responsiveness to adenosine 5’monophosphate in asthmatic patients.
        Pulm Pharmacol Ther. 2005; 18: 328-336
        • Derom E.
        • Louis R.
        • Tiesler C.
        • Engelstätter R.
        • Kaufman J.M.
        • Joos G.F.
        Effects of ciclesonide and fluticasone on cortisol secretion in patients with persistent asthma.
        Eur Respir J. 2009; 33: 1277-1286
        • Gerrity T.R.
        • Lee P.S.
        • Hass F.J.
        • Marinelli A.
        • Werner P.
        • Lourenço R.V.
        Calculated deposition of inhaled particles in the airway generations of normal subjects.
        J Appl Physiol. 1979; 47: 867-873
        • Heyder J.
        Assessment of airway geometry with inert aerosols.
        J Aerosol Sci. 1989; 2: 89-97
        • Warren S.
        • Taylor G.
        • Smith J.
        • Buck H.
        • Parry-Billings M.
        Gamma scintigraphic evaluation of a novel budesonide dry powder inhaler using a validated radiolabeling technique.
        J Aerosol Med. 2002; 15: 15-25
        • 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
        • Scichilone N.
        • Contoli M.
        • Paleari D.
        • et al.
        Assessing and accessing the small airways: implications for asthma management.
        Pulm Pharmacol Ther. 2013; 26: 172-179
        • Kelly H.W.
        Ultrafine-particle inhalers, the Holy Grail of inhaled corticosteroid therapy, or not!.
        J Allergy Clin Immunol Pract. 2015; 3: 732-733
        • National Asthma Education and Prevention Program
        Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma—Full Report No.: 07-4051.
        National Heart, Lung, and Blood Institute, Bethesda, MD2007
        • Roche N.
        • Reddel H.K.
        • Agusti A.
        • Bateman E.D.
        • et al.
        • and the Respiratory Effectiveness Group
        Integrating real-life studies in the global therapeutic research framework.
        Lancet Respir Med. 2013; 1: e29-e30
        • Herland K.
        • Akselsen J.P.
        • Skjønsberg O.H.
        • Bjermer L.
        How representative are clinical study patients with asthma or COPD for a larger ‘real life’ population of patients with obstructive lung disease?.
        Respir Med. 2005; 99: 11-19
        • van Aalderen W.M.
        • Grigg J.
        • Guilbert T.W.
        • et al.
        Small-particle inhaled corticosteroid as first-line or step-up controller therapy in childhood asthma.
        J Allergy Clin Immunol Pract. 2015; 3 (721.e16-731.e16)
        • VandenBurgt J.A.
        • Busse W.W.
        • Martin R.J.
        • Szefler S.J.
        • Donnell D.
        Efficacy and safety overview of a new inhaled corticosteroid, QVAR (hydrofluoroalkane-beclomethasone extrafine inhalation aerosol), in asthma.
        J Allergy Clin Immunol. 2000; 106: 1209-1226
        • Thompson P.J.
        • Davies R.J.
        • Young W.F.
        • et al.
        Safety of hydrofluoalkane-134a beclomethasone dipropionate extrafine aerosol.
        Respir Med. 1998; 92: 33-39
        • Singh D.
        • Piccinno A.
        • Borrill Z.
        • et al.
        Tolerability of high cumulative doses of the HFA modulite beclomethasone dipropionate/formoterol combination inhaler in asthmatic patients.
        Pulm Pharmacol Ther. 2008; 21: 551-557
        • Busse W.W.
        • Brazinsky S.
        • Jacobson K.
        • et al.
        Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant.
        J Allergy Clin Immunol. 1999; 104: 1215-1222
        • Davies R.J.
        • Stampone P.
        • O’Connor B.J.
        Hydrofluroalkane-134a beclomethasone dipropionate extrafine aerosol provides equivalent asthma control to chlorofluorocarbon beclomethasone dipropionate at approximately half the total daily dose.
        Respir Med. 1998; 92: 23-31
        • van Schayck C.P.
        • Donnell D.
        The efficacy and safety of QVAR (hydrofluoroalkane-beclomethasone dipropionate extrafine aerosol) in asthma (part I): an update of clinical experience in adults.
        Int J Clin Pract. 2004; 58: 678-688
        • Papi A.
        • Paggiaro P.L.
        • Nicolini G.
        • et al.
        Beclomethasone/formoterol vs. budesonide/formoterol combination therapy in asthma.
        Eur Respir J. 2007; 29: 682-689
        • Bousquet J.
        • Poli G.
        • Acerbi D.
        • Monno R.
        • Ramael S.
        • Nollevaux F.
        Systemic exposure and implications for lung deposition with an extra-fine hydrofluoroalkane beclomethasone dipropionate/formoterol fixed combination.
        Clin Pharmacokinet. 2009; 48: 347-358
        • Ohbayashi H.
        • Adachi M.
        Hydrofluoroalkane-beclomethasone dipropionate effectively improves airway eosinophilic inflammation including the distal airways of patients with mild to moderate persistent asthma as compared with fluticasone propionate in a randomized open double-cross study.
        Allergol Int. 2008; 57: 1-9
        • Lavorini F.
        • Fontana G.A.
        Targeting drugs to the airways: the role of spacer devices.
        Expert Opin Drug Deliv. 2009; 6: 91-102
        • Nikander K.
        • Nicholls C.
        • Denyer J.
        • Pritchard J.
        The evolution of spacers and valved holding chambers.
        J Aerosol Med Pulm Drug Deliv. 2014; 27: S-4-S-23
        • Roller C.M.
        • Zhang G.
        • Troedson R.G.
        • Leach C.L.
        • Le Souëf P.N.
        • Devadason S.G.
        Spacer inhalation technique and deposition of extrafine aerosol in asthmatic children.
        Eur Respir J. 2007; 29: 299-306
        • Berger W.E.
        • Tashkin D.P.
        Flunisolide hydrofluoroalkane with integrated spacer for treating asthma: an updated review.
        Allergy Asthma Proc. 2015; 36: 105-115
        • Singh D.
        • Collarini S.
        • Poli G.
        • Acerbi D.
        • Amadasi A.
        • Rusca A.
        Effect of AeroChamber Plus™ on the lung and systemic bioavailability of beclomethasone dipropionate/formoterol pMDI.
        Br J Clin Pharmacol. 2011; 72: 932-939
        • Kuna P.
        • Govoni M.
        • Lucci G.
        • Scuri M.
        • Acerbi D.
        • Stelmach I.
        Pharmacokinetics and pharmacodynamics of an extrafine fixed pMDI combination of beclomethasone dipropionate/formoterol fumarate in adolescent asthma.
        Br J Clin Pharmacol. 2015; 80: 569-580
        • Perez T.
        Is it really time to look at distal airways to improve asthma phenotyping and treatment.
        Eur Respir J. 2011; 38: 1252-1254
        • Lipworth B.
        Targeting the small airways asthma phenotype: if we can reach it, should we treat it?.
        Ann Allergy Asthma Immunol. 2013; 110: 233-239
        • Kelly H.W.
        Alveolar nitric oxide concentration, small airways inflammation, and targeted asthma therapy: are we there yet?.
        J Allergy Clin Immunol. 2010; 126: 736-737