Small airways dysfunction in asthma: Evaluation and management to improve asthma control

Allergy, Asthma and Immunology Research

Volumn 6, Issue 5, 2014, Pages 376-388

  Usmani, Omar S ^a  

^a IMPERIAL COLLEGE LONDON   (United Kingdom)

Author keywords

Aerosols; Asthma; Corticosteroids; Inhalation; Long acting beta agonists; Pharmacology; Physiology; Small airways

Indexed keywords

BETA ADRENERGIC RECEPTOR STIMULATING AGENT; CORTICOSTEROID;

AEROSOL; ASTHMA; BODY PLETHYSMOGRAPHY; COMORBIDITY; CORTICOSTEROID THERAPY; DISEASE CONTROL; DISEASE EXACERBATION; DRUG DELIVERY SYSTEM; DRUG EFFICACY; DRUG FORMULATION; FORCED EXPIRATORY VOLUME; HUMAN; INHALER; MONOTHERAPY; NITROGEN WASHOUT; NOCTURNAL ASTHMA; PHENOTYPE; REVIEW; SEVERE PERSISTENT ASTHMA; SMALL AIRWAY DISEASE; SPIROMETRY;

EID: 84906954413     PISSN: 20927355     EISSN: 20927363     Source Type: Journal    
DOI: 10.4168/aair.2014.6.5.376     Document Type: Review

References (115)

1. Usmani OS, Barnes PJ. Assessing and treating small airways disease in asthma and chronic obstructive pulmonary disease. Ann Med 2012;44:146-56.
2. Scichilone N, Contoli M, Paleari D, Pirina P, Rossi A, Sanguinetti CM, Santus P, Sofia M, Sverzellati N. Assessing and accessing the small airways; implications for asthma management. Pulm Pharmacol Ther 2013;26:172-9.
3. Contoli M, Bousquet J, Fabbri LM, Magnussen H, Rabe KF, Siafakas NM, Hamid Q, Kraft M. The small airways and distal lung compartment in asthma and COPD: a time for reappraisal. Allergy 2010; 65:141-51.
4. Burgel PR, de Blic J, Chanez P, Delacourt C, Devillier P, Didier A, Dubus JC, Frachon I, Garcia G, Humbert M, Laurent F, Louis R, Magnan A, Mahut B, Perez T, Roche N, Tillie-Leblond I, Tunon de Lara M, Dusser D. Update on the roles of distal airways in asthma.Eur Respir Rev 2009;18:80-95.
5. Demoly P, Annunziata K, Gubba E, Adamek L. Repeated cross-sectional survey of patient-reported asthma control in Europe in the past 5 years. Eur Respir Rev 2012;21:66-74.
6. Lai CK, De Guia TS, Kim YY, Kuo SH, Mukhopadhyay A, Soriano JB, Trung PL, Zhong NS, Zainudin N, Zainudin BM; Asthma Insights and Reality in Asia-Pacific Steering Committee. Asthma control in the Asia-Pacific region: the Asthma Insights and Reality in Asia-Pacific Study. J Allergy Clin Immunol 2003;111:263-8.
7. Lavorini F, Usmani OS. Correct inhalation technique is critical in achieving good asthma control. Prim Care Respir J 2013;22:385-6.
8. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group. Lancet 1994;344:219-24.
9. Usmani OS, Ito K, Maneechotesuwan K, Ito M, Johnson M, Barnes PJ, Adcock IM. Glucocorticoid receptor nuclear translocation in airway cells after inhaled combination therapy. Am J Respir Crit Care Med 2005;172:704-12.
10. Pauwels RA, Lo¨fdahl CG, Postma DS, Tattersfield AE, O'Byrne P, Barnes PJ, Ullman A. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997;337:1405-11.
11. O'Byrne PM, Naya IP, Kallen A, Postma DS, Barnes PJ. Increasing doses of inhaled corticosteroids compared to adding long-acting inhaled beta2-agonists in achieving asthma control. Chest 2008; 134:1192-9.
12. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, Pedersen SE; GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;170:836-44.
13. Breekveldt-Postma NS, Koerselman J, Erkens JA, van der Molen T, Lammers JW, Herings RM; CAMERA Study Group Members listed in the Appendix. Treatment with inhaled corticosteroids in asthma is too often discontinued. Pharmacoepidemiol Drug Saf 2008; 17:411-22.
14. Wenzel SE. Complex phenotypes in asthma: current definitions. Pulm Pharmacol Ther 2013;26:710-5.
15. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, Wardlaw AJ, Green RH. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008;178:218-24.
16. Wadsworth SJ, Sandford AJ. Personalised medicine and asthma diagnostics/management. Curr Allergy Asthma Rep 2013;13:118-29.
17. Usmani OS. Treating the small airways. Respiration 2012;84:441-53.
18. Macklem PT, Mead J. Resistance of central and peripheral airways measured by a retrograde catheter. J Appl Physiol 1967;22:395-401.
19. Green M. How big are the bronchioles? St Thomas Hosp Gaz 1967;63:136-9.
20. Weibel ER. Morphometry of the human lung. Berlin: Springer; 1963.
21. Hamid Q. Pathogenesis of small airways in asthma. Respiration 2012;84:4-11.
22. Hamid Q, Song Y, Kotsimbos TC, Minshall E, Bai TR, Hegele RG, Hogg JC. Inflammation of small airways in asthma. J Allergy Clin Immunol 1997;100:44-51.
23. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Pare´ PD. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645-53.
24. 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 (1985) 1992;72:1016-23.
25. Mead J. The lung's "quiet zone". N Engl J Med 1970;282:1318-9.
26. Verbanck S. Physiological measurement of the small airways. Respiration 2012;84:177-88.
27. Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med 1996; 154:1505-10.
28. Kraft M, Pak J, Martin RJ, Kaminsky D, Irvin CG. Distal lung dysfunction at night in nocturnal asthma. Am J Respir Crit Care Med 2001;163:1551-6.
29. Anderson SD. How does exercise cause asthma attacks? Curr Opin Allergy Clin Immunol 2006;6:37-42.
30. Kaminsky DA, Irvin CG, Gurka DA, Feldsien DC, Wagner EM, Liu MC, Wenzel SE. Peripheral airways responsiveness to cool, dry air in normal and asthmatic individuals. Am J Respir Crit Care Med 1995;152:1784-90.
31. Cosio M, Ghezzo H, Hogg JC, Corbin R, Loveland M, Dosman J, Macklem PT. The relations between structural changes in small airways and pulmonary-function tests. N Engl J Med 1978;298: 1277-81.
32. 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.
33. Verbanck S, Schuermans D, Noppen M, Van Muylem A, Paiva M, Vincken W. Evidence of acinar airway involvement in asthma. Am J Respir Crit Care Med 1999;159:1545-50.
34. Verbanck S, Thompson BR, Schuermans D, Kalsi H, Biddiscombe M, Stuart-Andrews C, Hanon S, Van Muylem A, Paiva M, Vincken W, Usmani O. Ventilation heterogeneity in the acinar and conductive zones of the normal ageing lung. Thorax 2012;67:789-95.
35. Thompson BR, Douglass JA, Ellis MJ, Kelly VJ, O'Hehir RE, King GG, Verbanck S. Peripheral lung function in patients with stable and unstable asthma. J Allergy Clin Immunol 2013;131:1322-8.
36. Global Initiative for Asthma (CA). Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2012 [Internet]. Vancouver: Global Initiative for Asthma; 2012 [cited 2014 Feb 21]. Available from: http://www.ginasthma.org/.
37. Paredi P, Kharitonov SA, Meah S, Barnes PJ, Usmani OS. A novel approach to partition central and peripheral airway nitric oxide. Chest 2014;145:113-9.
38. Michils A, Elkrim Y, Haccuria A, Van Muylem A. Adenosine 5'-monophosphate challenge elicits a more peripheral airway response than methacholine challenge. J Appl Physiol (1985) 2011; 110:1241-7.
39. Van Muylem A, Kerckx Y, Michils A. Axial distribution of nitric oxide airway production in asthma patients. Respir Physiol Neurobiol 2013;185:313-8.
40. 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.
41. Goldman MD, Saadeh C, Ross D. Clinical applications of forced oscillation to assess peripheral airway function. Respir Physiol Neurobiol 2005;148:179-94.
42. Paredi P, Goldman M, Alamen A, Ausin P, Usmani OS, Pride NB, Barnes PJ. Comparison of inspiratory and expiratory resistance and reactance in patients with asthma and chronic obstructive pulmonary disease. Thorax 2010;65:263-7.
43. Gonem S, Natarajan S, Desai D, Corkill S, Singapuri A, Bradding P, Gustafsson P, Costanza R, Kajekar R, Parmar H, Brightling CE, Siddiqui S. Clinical significance of small airway obstruction markers in patients with asthma. Clin Exp Allergy 2014;44:499-507.
44. 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.
45. 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.
46. Sorkness RL, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Chung KF, Curran-Everett D, Erzurum SC, Gaston BM, Israel E, Jarjour NN, Moore WC, Peters SP, Teague WG, Wenzel SE; 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.
47. Papi A, Paggiaro P, Nicolini G, Vignola AM, Fabbri LM; ICAT SE study group. Beclomethasone/formoterol vs fluticasone/salmeterol inhaled combination in moderate to severe asthma. Allergy 2007;62:1182-8.
48. Berry M, Hargadon B, Morgan A, Shelley M, Richter J, Shaw D, Green RH, Brightling C, Wardlaw AJ, Pavord ID. Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma. Eur Respir J 2005;25:986-91.
49. Zainudin BM, Biddiscombe M, Tolfree SE, Short M, Spiro SG. Comparison of bronchodilator responses and deposition patterns of salbutamol inhaled from a pressurised metered dose inhaler, as a dry powder, and as a nebulised solution. Thorax 1990;45:469-73.
50. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol 2003;56:588-99.
51. Usmani OS, Biddiscombe MF, Barnes PJ. Regional lung deposition and bronchodilator response as a function of beta2-agonist particle size. Am J Respir Crit Care Med 2005;172:1497-504.
52. 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.
53. Leach CL, Davidson PJ, Boudreau RJ. Improved airway targeting with the CFC-free HFA-beclomethasone metered-dose inhaler compared with CFC-beclomethasone. Eur Respir J 1998;12:1346-53.
54. Leach CL, Davidson PJ, Hasselquist BE, Boudreau RJ. 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;122:510-6.
55. Leach CL, Bethke TD, Boudreau RJ, Hasselquist BE, Drollmann A, Davidson P, Wurst W. 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;19:117-26.
56. Leach CL, Kuehl PJ, Chand R, Ketai L, Norenberg JP, McDonald JD. Characterization of respiratory deposition of fluticasone-salmeterol hydrofluoroalkane-134a and hydrofluoroalkane-134a beclomethasone in asthmatic patients. Ann Allergy Asthma Immunol 2012;108:195-200.
57. 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;100:375-84.
58. Nicolini G, Scichilone N, Bizzi A, Papi A, Fabbri LM. Beclomethasone/ formoterol fixed combination for the management of asthma: patient considerations. Ther Clin Risk Manag 2008;4:855-64.
59. Scichilone N, Spatafora M, Battaglia S, Arrigo R, Benfante A, Bellia V. Lung penetration and patient adherence considerations in the management of asthma: role of extra-fine formulations. J Asthma Allergy 2013;6:11-21.
60. De Backer W, Devolder A, Poli G, Acerbi D, Monno R, Herpich C, Sommerer K, Meyer T, Mariotti F. Lung deposition of BDP/formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients. J Aerosol Med Pulm Drug Deliv 2010;23:137-48.
61. Huchon G, Magnussen H, Chuchalin A, Dymek L, Gonod FB, Bousquet J. Lung function and asthma control with beclomethasone and formoterol in a single inhaler. Respir Med 2009;103:41-9.
62. Reddel HK, Gibson PG, Peters MJ, Wark PA, Sand IB, Hoyos CM, Jenkins CR. Down-titration from high-dose combination therapy in asthma: removal of long-acting beta(2)-agonist. Respir Med 2010;104:1110-20.
63. Godard P, Greillier P, Pigearias B, Nachbaur G, Desfougeres JL, Attali V. Maintaining asthma control in persistent asthma: comparison of three strategies in a 6-month double-blind randomised study. Respir Med 2008;102:1124-31.
64. Bateman ED, Jacques L, Goldfrad C, Atienza T, Mihaescu T, Duggan M. Asthma control can be maintained when fluticasone propionate/ salmeterol in a single inhaler is stepped down. J Allergy Clin Immunol 2006;117:563-70.
65. Foresi A, Mastropasqua B, Chetta A, D'Ippolito R, Testi R, Olivieri D, Pelucchi A. Step-down compared to fixed-dose treatment with inhaled fluticasone propionate in asthma. Chest 2005;127:117-24.
66. Fardon T, Haggart K, Lee DK, Lipworth BJ. A proof of concept study to evaluate stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma. Respir Med 2007;101:1218-28.
67. Papi A, Nicolini G, Crimi N, Fabbri L, Olivieri D, Rossi A, Paggiaro P. Step-down from high dose fixed combination therapy in asthma patients: a randomized controlled trial. Respir Res 2012;13:54.
68. Hoshino M. Comparison of effectiveness in ciclesonide and fluticasone propionate on small airway function in mild asthma. Allergol Int 2010;59:59-66.
69. Usmani OS, Biddiscombe MF, Nightingale JA, Underwood SR, Barnes PJ. Effects of bronchodilator particle size in asthmatic patients using monodisperse aerosols. J Appl Physiol (1985) 2003;95: 2106-12.
70. Bateman E, Karpel J, Casale T, Wenzel S, Banerji D. Ciclesonide reduces the need for oral steroid use in adult patients with severe, persistent asthma. Chest 2006;129:1176-87.
71. Nelson HS, Bernstein IL, Fink J, Edwards TB, Spector SL, Storms WW, Tashkin DP. Oral glucocorticosteroid-sparing effect of budesonide administered by Turbuhaler: a double-blind, placebo-controlled study in adults with moderate-to-severe chronic asthma. Pulmicort Turbuhaler Study Group. Chest 1998;113:1264-71.
72. Nelson HS, Busse WW, deBoisblanc BP, Berger WE, Noonan MJ, Webb DR, Wolford JP, Mahajan PS, Hamedani AG, Shah T, Harding SM. Fluticasone propionate powder: oral corticosteroid-sparing effect and improved lung function and quality of life in patients with severe chronic asthma. J Allergy Clin Immunol 1999;103:267-75.
73. Zeidler MR, Kleerup EC, Goldin JG, Kim HJ, Truong DA, Simmons MD, Sayre JW, Liu W, Elashoff R, Tashkin DP. Montelukast improves regional air-trapping due to small airways obstruction in asthma. Eur Respir J 2006;27:307-15.
74. Goldin JG, Tashkin DP, Kleerup EC, Greaser LE, Haywood UM, Sayre JW, Simmons MD, Suttorp M, Colice GL, Vanden Burgt JA, Aberle DR. Comparative effects of hydrofluoroalkane and chlorofluorocarbon beclomethasone dipropionate inhalation on small airways: assessment with functional helical thin-section computed tomography. J Allergy Clin Immunol 1999;104:S258-67.
75. King GG. Tomographic imaging of small airways. Respiration 2012;84:265-74.
76. Fritscher LG, Rodrigues MT, Zamel N, Chapman KR. The effect of montelukast on exhaled nitric oxide of alveolar and bronchial origin in inhaled corticosteroid-treated asthma. Respir Med 2009; 103:296-300.
77. Gelb AF, Taylor CF, Simmons M, Shinar C. Role of add-on zileuton on total exhaled, large airway, and small airway/alveolar nitric oxide in moderate-severe persistent adult asthmatics on fluticasone 250 microg/Salmeterol 50 microg. Pulm Pharmacol Ther 2009;22: 516-21.
78. Nieto A, Pamies R, Oliver F, Medina A, Caballero L, Mazon A. Montelukast improves pulmonary function measured by impulse oscillometry in children with asthma (Mio study). Respir Med 2006;100:1180-5.
79. Berger P, Scotto-Gomez E, Molimard M, Marthan R, Le Gros V, Tunon-de-Lara JM. Omalizumab decreases nonspecific airway hyperresponsiveness in vitro. Allergy 2007;62:154-61.
80. Hanania NA, Wenzel S, Rose´n K, Hsieh HJ, Mosesova S, Choy DF, Lal P, Arron JR, Harris JM, Busse W. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 2013;187:804-11.
81. Matsuno O, Komori C, Hang Y, Matsumoto T, Minamoto S. Effectiveness of omalizumab in a patient with severe asthma, low serum IgE level, and lack of sensitized allergens induced by oral steroid therapy: the usefulness of impulse oscillation for assessment of omalizumab therapy. J Asthma 2012;49:839-42.
82. Price D, Thomas M. Breaking new ground: challenging existing asthma guidelines. BMC Pulm Med 2006;6 Suppl 1:S6.
83. Roche N, Reddel HK, Agusti A, Bateman ED, Krishnan JA, Martin RJ, Papi A, Postma D, Thomas M, Brusselle G, Israel E, Rand C, Chisholm A, Price D; Respiratory Effectiveness Group. Integrating real-life studies in the global therapeutic research framework. Lancet Respir Med 2013;1:e29-30.
84. Price D, Martin RJ, Barnes N, Dorinsky P, Israel E, Roche N, Chisholm A, Hillyer EV, Kemp L, Lee AJ, von Ziegenweidt J, Colice G. Prescribing practices and asthma control with hydrofluoroalkane-beclomethasone and fluticasone: a real-world observational study. J Allergy Clin Immunol 2010;126:511-8.e1-10.
85. Barnes N, Price D, Colice G, Chisholm A, Dorinsky P, Hillyer EV, Burden A, Lee AJ, Martin RJ, Roche N, von Ziegenweidt J, Israel E. Asthma control with extrafine-particle hydrofluoroalkane-beclometasone vs. large-particle chlorofluorocarbon-beclometasone: a real-world observational study. Clin Exp Allergy 2011;41:1521-32.
86. Colice G, Martin RJ, Israel E, Roche N, Barnes N, Burden A, Polos P, Dorinsky P, Hillyer EV, Lee AJ, Chisholm A, von Ziegenweidt J, Barion F, Price D. Asthma outcomes and costs of therapy with extrafine beclomethasone and fluticasone. J Allergy Clin Immunol 2013;132:45-54.
87. Allegra L, Cremonesi G, Girbino G, Ingrassia E, Marsico S, Nicolini G, Terzano C; PRISMA (PRospectIve Study on asthMA control) Study Group. Real-life prospective study on asthma control in Italy: cross-sectional phase results. Respir Med 2012;106:205-14.
88. Terzano C, Cremonesi G, Girbino G, Ingrassia E, Marsico S, Nicolini G, Allegra L; PRISMA (PRospectIve Study on asthMA control) Study Group. 1-year prospective real life monitoring of asthma control and quality of life in Italy. Respir Res 2012;13:112.
89. Mu¨ller V, Ga´lffy G, Eszes N, Losonczy G, Bizzi A, Nicolini G, Chrystyn H, Tama´si L. Asthma control in patients receiving inhaled corticosteroid and long-acting beta2-agonist fixed combinations. A real-life study comparing dry powder inhalers and a pressurized metered dose inhaler extrafine formulation. BMC Pulm Med 2011;11:40.
90. Popov TA, Petrova D, Kralimarkova TZ, Ivanov Y, Popova T, Peneva M, Odzhakova T, Ilieva Y, Yakovliev P, Lazarova T, Georgiev O, Hodzhev V, Hodzheva E, Staevska MT, Dimitrov VD. Real life clinical study design supporting the effectiveness of extra-fine inhaled beclomethasone/formoterol at the level of small airways of asthmatics. Pulm Pharmacol Ther 2013;26:624-9.
91. Brusselle G, Peche´ R, Van den Brande P, Verhulst A, Hollanders W, Bruhwyler J. Real-life effectiveness of extrafine beclometasone dipropionate/ formoterol in adults with persistent asthma according to smoking status. Respir Med 2012;106:811-9.
92. Price D, Small I, Haughney J, Ryan D, Gruffydd-Jones K, Lavorini F, Harris T, Burden A, Brockman J, King C, Papi A. Clinical and cost effectiveness of switching asthma patients from fluticasone-salmeterol to extra-fine particle beclometasone-formoterol: a retrospective matched observational study of real-world patients. Prim Care Respir J 2013;22:439-48.
93. Compalati E, Ridolo E, Passalacqua G, Braido F, Villa E, Canonica GW. The link between allergic rhinitis and asthma: the united airways disease. Expert Rev Clin Immunol 2010;6:413-23.
94. Corren J, Manning BE, Thompson SF, Hennessy S, Strom BL. Rhinitis therapy and the prevention of hospital care for asthma: a case-control study. J Allergy Clin Immunol 2004;113:415-9.
95. Hargreave FE. Induced sputum for the investigation of airway inflammation: evidence for its clinical application. Can Respir J 1999;6:169-74.
96. Papi A, Paggiaro PL, Nicolini G, Vignola AM, Fabbri LM; Inhaled Combination Asthma Treatment versus SYmbicort (ICAT SY) Study Group. Beclomethasone/formoterol versus budesonide/formoterol combination therapy in asthma. Eur Respir J 2007; 29:682-9.
97. Barnes N, van Noord JA, Brindicci C, Lindemann L, Varoli G, Perpiña M, Guastalla D, Casula D, Patel S, Chanez P; FACTO (Foster® As Complete Treatment Option) Study Group. Stepping-across controlled asthmatic patients to extrafine beclometasone/formoterol combination. Pulm Pharmacol Ther 2013;26:555-61.
98. Scichilone N, Battaglia S, Sorino C, Paglino G, Martino L, Paterno` A, Santagata R, Spatafora M, Nicolini G, Bellia V. Effects of extra-fine inhaled beclomethasone/formoterol on both large and small airways in asthma. Allergy 2010;65:897-902.
99. Corda L, Gardenghi GG, Modina D, Montemurro LT, Novali M, Tantucci C. Effects on small airway obstruction of long-term treatments with beclomethasone/formoterol hydrofluoroalkane (metered-dose inhaler) versus fluticasone/salmeterol (dry-powder inhaler) in asthma: a preliminary study. Allergy Asthma Proc 2011; 32:29-34.
100. Dahl R, Engelsta¨tter R, Trebas-Pietras E, Kuna P. A 24-week comparison of low-dose ciclesonide and fluticasone propionate in mild to moderate asthma. Respir Med 2010;104:1121-30.
101. Pedersen S, Engelsta¨tter R, Weber HJ, Hirsch S, Barkai L, Emeryk A, Weber H, Vermeulen J. Efficacy and safety of ciclesonide once daily and fluticasone propionate twice daily in children with asthma. Pulm Pharmacol Ther 2009;22:214-20.
102. Bateman ED, Linnhof AE, Homik L, Freudensprung U, Smau L, Engelsta¨tter R. Comparison of twice-daily inhaled ciclesonide and fluticasone propionate in patients with moderate-to-severe persistent asthma. Pulm Pharmacol Ther 2008;21:264-75.
103. Knox A, Langan J, Martinot JB, Gruss C, Ha¨fner D. Comparison of a step-down dose of once-daily ciclesonide with a continued dose of twice-daily fluticasone propionate in maintaining control of asthma. Curr Med Res Opin 2007;23:2387-94.
104. Magnussen H, Hofman J, Staneta P, Lawo JP, Hellwig M, Engelsta¨tter R. Similar efficacy of ciclesonide once daily versus fluticasone propionate twice daily in patients with persistent asthma. J Asthma 2007;44:555-63.
105. von Berg A, Engelsta¨tter R, Minic P, Sre´ckovic M, Garcia Garcia ML, Latos T, Vermeulen JH, Leichtl S, Hellbardt S, Bethke TD. Comparison of the efficacy and safety of ciclesonide 160 microg once daily vs. budesonide 400 microg once daily in children with asthma. Pediatr Allergy Immunol 2007;18:391-400.
106. Adachi M, Ishihara K, Inoue H, Kudo K, Takahashi K, Morita Y, Masuda K, Sakai T, Kato R, Miyamoto T. Efficacy and safety of inhaled ciclesonide compared with chlorofluorocarbon beclomethasone dipropionate in adults with moderate to severe persistent asthma. Respirology 2007;12:573-80.
107. Boulet LP, Bateman ED, Voves R, Mu¨ller T, Wolf S, Engelsta¨tter R. A randomized study comparing ciclesonide and fluticasone propionate in patients with moderate persistent asthma. Respir Med 2007;101:1677-86.
108. Ukena D, Biberger C, Steinijans V, von Behren V, Malek R, Weber HH, Beck E, Linnhoff A. Ciclesonide is more effective than budesonide in the treatment of persistent asthma. Pulm Pharmacol Ther 2007;20:562-70.
109. Pedersen S, Garcia Garcia ML, Manjra A, Theron I, Engelsta¨tter R. A comparative study of inhaled ciclesonide 160 μg/day and fluticasone propionate 176 μg/day in children with asthma. Pediatr Pulmonol 2006;41:954-61.
110. Hansel TT, Benezet O, Kafe´ H, Ponitz HH, Cheung D, Engelsta¨tter R, Barnes PJ. A multinational, 12-week, randomized study comparing the efficacy and tolerability of ciclesonide and budesonide in patients with asthma. Clin Ther 2006;28:906-20.
111. Buhl R, Vinkler I, Magyar P, Gyo¨ri Z, Rybacki C, Middle MV, Escher A, Engelsta¨tter R. Comparable efficacy of ciclesonide once daily versus fluticasone propionate twice daily in asthma. Pulm Pharmacol Ther 2006;19:404-12.
112. Zietkowski Z, Bodzenta-Lukaszyk A, Tomasiak MM, Szymanski W, Skiepko R. Effect of ciclesonide and fluticasone on exhaled nitric oxide in patients with mild allergic asthma. Respir Med 2006;100: 1651-6.
113. Boulet LP, Drollmann A, Magyar P, Timar M, Knight A, Engelsta¨tter R, Fabbri L. Comparative efficacy of once-daily ciclesonide and budesonide in the treatment of persistent asthma. Respir Med 2006;100:785-94.
114. Niphadkar P, Jagannath K, Joshi JM, Awad N, Boss H, Hellbardt S, Gadgil DA. Comparison of the efficacy of ciclesonide 160 μg QD and budesonide 200 μg BID in adults with persistent asthma: a phase III, randomized, double-dummy, open-label study. Clin Ther 2005;27:1752-63.
115. Lee DK, Fardon TC, Bates CE, Haggart K, McFarlane LC, Lipworth BJ. Airway and systemic effects of hydrofluoroalkane formulations of high-dose ciclesonide and fluticasone in moderate persistent asthma. Chest 2005;127:851-60.