Therapeutic strategies to reduce asthma exacerbations
2011; Elsevier BV; Volume: 128; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2011.03.035
ISSN1097-6825
Autores Tópico(s)Pediatric health and respiratory diseases
ResumoAsthma exacerbations can occur in patients with all degrees of asthma severity. They generally develop over 5 to 7 days and are most often initiated by an upper respiratory tract infection (usually with human rhinovirus) or by environmental allergen exposure in atopic subjects. Inhaled corticosteroids (ICSs) taken on a regular basis are very effective in reducing the risk of asthma exacerbations, and the combination of ICSs and long-acting inhaled β2-agonists further reduces this risk. In addition, use of the combination of the ICS budesonide and the long-acting inhaled β2-agonist formoterol, both as maintenance asthma treatment and also as rescue treatment (instead of a short-acting inhaled β2-agonist), has a significant further beneficial effect on asthma exacerbation risk. Other therapies that have been demonstrated to reduce severe asthma exacerbations are leukotriene receptor antagonists, which have been demonstrated to be effective most consistently in this regard in children, and anti-IgE mAbs, which are effective in subjects with difficult-to-treat allergic asthma. Approximately 50% of severe asthma exacerbations are eosinophilic in nature, whereas many of the remaining are neutrophilic. Several studies have demonstrated that making asthma treatment decisions based on minimizing airway eosinophil numbers (measured in induced sputum) can reduce the risks of severe exacerbations. In addition, treatment of patients with severe asthma with an anti–IL-5 mAb also reduces the number of severe asthma exacerbations, demonstrating a central role of eosinophils in many exacerbations. Asthma exacerbations can occur in patients with all degrees of asthma severity. They generally develop over 5 to 7 days and are most often initiated by an upper respiratory tract infection (usually with human rhinovirus) or by environmental allergen exposure in atopic subjects. Inhaled corticosteroids (ICSs) taken on a regular basis are very effective in reducing the risk of asthma exacerbations, and the combination of ICSs and long-acting inhaled β2-agonists further reduces this risk. In addition, use of the combination of the ICS budesonide and the long-acting inhaled β2-agonist formoterol, both as maintenance asthma treatment and also as rescue treatment (instead of a short-acting inhaled β2-agonist), has a significant further beneficial effect on asthma exacerbation risk. Other therapies that have been demonstrated to reduce severe asthma exacerbations are leukotriene receptor antagonists, which have been demonstrated to be effective most consistently in this regard in children, and anti-IgE mAbs, which are effective in subjects with difficult-to-treat allergic asthma. Approximately 50% of severe asthma exacerbations are eosinophilic in nature, whereas many of the remaining are neutrophilic. Several studies have demonstrated that making asthma treatment decisions based on minimizing airway eosinophil numbers (measured in induced sputum) can reduce the risks of severe exacerbations. In addition, treatment of patients with severe asthma with an anti–IL-5 mAb also reduces the number of severe asthma exacerbations, demonstrating a central role of eosinophils in many exacerbations. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: August 2011. Credit may be obtained for these courses until July 31, 2013.Copyright Statement: Copyright © 2011-2013. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Paul M. O'Byrne, MB, FRCP(C), FRSCActivity Objectives1.To recognize the adult and pediatric presentations of asthma exacerbations.2.To understand the causes and mechanisms of asthma exacerbations in these populations.3.To evaluate the classical therapeutic approaches, including corticosteroids, bronchodilators, and leukotriene blockers.4.To analyze the value of new therapies, including thermoplasty, anti–IL-5 and anti-IgE.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: P. M. O'Byrne is on the advisory boards for and has received speakers honoraria from AstraZeneca and GlaxoSmithKline; is on the advisory boards for Topigen, Wyeth, and Schering-Plough; and has received research support from AstraZeneca, GlaxoSmithKline, Merck, Wyeth, Schering-Plough, and Alexion.Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: August 2011. Credit may be obtained for these courses until July 31, 2013. Copyright Statement: Copyright © 2011-2013. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Paul M. O'Byrne, MB, FRCP(C), FRSC Activity Objectives1.To recognize the adult and pediatric presentations of asthma exacerbations.2.To understand the causes and mechanisms of asthma exacerbations in these populations.3.To evaluate the classical therapeutic approaches, including corticosteroids, bronchodilators, and leukotriene blockers.4.To analyze the value of new therapies, including thermoplasty, anti–IL-5 and anti-IgE. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: P. M. O'Byrne is on the advisory boards for and has received speakers honoraria from AstraZeneca and GlaxoSmithKline; is on the advisory boards for Topigen, Wyeth, and Schering-Plough; and has received research support from AstraZeneca, GlaxoSmithKline, Merck, Wyeth, Schering-Plough, and Alexion. Asthma exacerbations are common events in the lives of asthmatic patients. They pose the greatest risk for such patients, and they incur the greatest asthma-related treatment costs for the health care system and for society in general.1Barnett S.B. Nurmagambetov T.A. Costs of asthma in the United States: 2002-2007.J Allergy Clin Immunol. 2011; 127: 145-152Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar Asthma exacerbations range in severity from mild transient events lasting 1 to 2 days (previously called mild exacerbations) to severe life-threatening events. Mild exacerbations are now accepted to be part of poor current asthma control and have different therapeutic approaches to severe events.2O'Byrne P.M. Parameswaran K. Pharmacological management of mild or moderate persistent asthma.Lancet. 2006; 368: 794-803Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar A recently published American Thoracic Society/European Respiratory Society statement3Reddel H.K. Taylor D.R. Bateman E.D. Boulet L.P. Boushey H.A. Busse W.W. et al.An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.Am J Respir Crit Care Med. 2009; 180: 59-99Crossref PubMed Scopus (1564) Google Scholar defines severe asthma exacerbations as events that require urgent action on the part of the patient and physician to prevent a serious outcome, such as hospitalization or death from asthma, and moderate exacerbations as events that should result in a temporary change in treatment in an effort to prevent the exacerbation from coming severe. Mild exacerbations were not differentiated because these episodes are only just outside the normal range of variation for the individual patient and difficult to distinguish from transient loss of asthma control.3Reddel H.K. Taylor D.R. Bateman E.D. Boulet L.P. Boushey H.A. Busse W.W. et al.An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.Am J Respir Crit Care Med. 2009; 180: 59-99Crossref PubMed Scopus (1564) Google Scholar Severe asthma exacerbations can occur in patients with all degrees of asthma severity. Although their frequency can be increased in patients with difficult-to-control asthma, even patients considered to have mild, easy-to-treat asthma can experience severe asthma exacerbations,4Gauvreau G.M. Parameswaran K.N. Watson R.M. O'Byrne P.M. Inhaled leukotriene E(4), but not leukotriene D(4), increased airway inflammatory cells in subjects with atopic asthma.Am J Respir Crit Care Med. 2001; 164: 1495-1500Crossref PubMed Scopus (124) Google Scholar which are sometimes fatal.5Robertson C.F. Rubinfeld A.R. Bowes G. Deaths from asthma in Victoria: a 12-month survey.Med J Aust. 1990; 152: 511-517PubMed Google Scholar In a large clinical trial that enrolled patients with mild asthma who were followed for 1 year, the rate of severe exacerbations was almost 1 per patient per year.4Gauvreau G.M. Parameswaran K.N. Watson R.M. O'Byrne P.M. Inhaled leukotriene E(4), but not leukotriene D(4), increased airway inflammatory cells in subjects with atopic asthma.Am J Respir Crit Care Med. 2001; 164: 1495-1500Crossref PubMed Scopus (124) Google Scholar A common misperception of severe asthma exacerbations is that they are frequently sudden catastrophic events. In fact, almost all severe exacerbations develop over 5 to 7 days, with a gradual increase in asthma symptoms and deterioration in lung function before the exacerbation is recognized as an event requiring urgent intervention (Fig 1).6Tattersfield A.E. Postma D.S. Barnes P.J. Svensson K. Bauer C.A. O'Byrne P.M. et al.Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group.Am J Respir Crit Care Med. 1999; 160: 594-599Crossref PubMed Scopus (345) Google Scholar, 7Pauwels R.A. Lofdahl C.G. Postma D.S. Tattersfield A.E. O'Byrne P. Barnes P.J. et al.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: 1405-1411Crossref PubMed Scopus (1564) Google Scholar Once treatment for the severe exacerbation is initiated, most will resolve over 7 to 10 days (Fig 1).7Pauwels R.A. Lofdahl C.G. Postma D.S. Tattersfield A.E. O'Byrne P. Barnes P.J. et al.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: 1405-1411Crossref PubMed Scopus (1564) Google Scholar Severe asthma exacerbations are very often preceded by an upper respiratory tract infection (usually with human rhinovirus [HRV])8Johnston S.L. Pattemore P.K. Sanderson G. Smith S. Campbell M.J. Josephs L.K. et al.The relationship between upper respiratory infections and hospital admissions for asthma: a time-trend analysis.Am J Respir Crit Care Med. 1996; 154: 654-660Crossref PubMed Scopus (503) Google Scholar, 9Johnston S.L. Pattemore P.K. Sanderson G. Smith S. Lampe F. Josephs L. et al.Community study of role of viral infections in exacerbations of asthma in 9-11 year old children.BMJ. 1995; 310: 1225-1229Crossref PubMed Scopus (1720) Google Scholar or by environmental allergen exposure in atopic patients.10Boulet L.P. Cartier A. Thomson N.C. Roberts R.S. Dolovich J. Hargreave F.E. Asthma and increases in nonallergic bronchial responsiveness from seasonal pollen exposure.J Allergy Clin Immunol. 1983; 71: 399-406Abstract Full Text PDF PubMed Scopus (290) Google Scholar However, despite the fact that all children, including asthmatic patients, are infected with 1 or more strains of HRV each year, not all infections are associated with severe exacerbations. This has led to the speculation that HRV (or other respiratory tract viruses) acts as a cofactor in initiating acute severe events but that other conditions need to exist for this to happen and that respiratory tract viruses and environmental allergens interact to precipitate asthma exacerbations to an extent that neither alone can achieve. This is supported by epidemiologic evidence, which has indicated that the risks of being hospitalized with severe asthma exacerbations are increased by allergen sensitization alone (risk ratio, 2.3; 95% CI, 1.0-5.4) and further increased by the combination of sensitization, high exposure to 1 or more allergens, and viral detection (risk ratio, 8.4; 95% CI, 2.1-32.8).11Green R.M. Custovic A. Sanderson G. Hunter J. Johnston S.L. Woodcock A. Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study.BMJ. 2002; 324: 763Crossref PubMed Google Scholar Although severe asthma exacerbations are usually relatively transient events, with full symptomatic recovery by the patient, they can be associated with a decrease in lung function, which does not fully recover after the exacerbation has been treated and is resolved.12O'Byrne P.M. Pedersen S. Lamm C.J. Tan W.C. Busse W.W. Severe exacerbations and decline in lung function in asthma.Am J Respir Crit Care Med. 2009; 179: 19-24Crossref PubMed Scopus (354) Google Scholar The purpose of asthma treatment is to attempt to achieve total asthma control.13Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma—summary report 2007.J Allergy Clin Immunol. 2007; 120: S94-S138PubMed Google Scholar, 14Bateman E.D. Hurd S.S. Barnes P.J. Bousquet J. Drazen J.M. Fitzgerald M. et al.Global strategy for asthma management and prevention: GINA executive summary.Eur Respir J. 2008; 31: 143-178Crossref PubMed Scopus (2463) Google Scholar Asthma control consists of 2 domains: current control (impairment), which reflects the day-to-day symptoms an asthmatic patient experiences and the burden imposed by these symptoms, and future risk, which consists of asthma exacerbations, irreversible decrease in lung function, and side effects from asthma medications.13Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma—summary report 2007.J Allergy Clin Immunol. 2007; 120: S94-S138PubMed Google Scholar Thus the prevention of asthma exacerbations is an important component of establishing ideal asthma control. The regular use of inhaled corticosteroids (ICSs) remains the most effective therapeutic strategy to reduce the risk of asthma exacerbations. This benefit was identified in studies conducted shortly after the introduction of ICSs15Juniper E.F. Kline P.A. Vanzieleghem M.A. Ramsdale E.H. O'Byrne P.M. Hargreave F.E. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics.Am Rev Respir Dis. 1990; 142: 832-836Crossref PubMed Scopus (529) Google Scholar, 16Juniper E.F. Kline P.A. Vanzieleghem M.A. Ramsdale E.H. O'Byrne P.M. Hargreave F.E. Long-term effects of budesonide on airway responsiveness and clinical asthma severity in inhaled steroid-dependent asthmatics.Eur Respir J. 1990; 3: 1122-1127PubMed Google Scholar, 17Dahl R. Lundback B. Malo J.L. Mazza J.A. Nieminen M.M. Saarelainen P. et al.A dose-ranging study of fluticasone propionate in adult patients with moderate asthma. International Study Group.Chest. 1993; 104: 1352-1358Crossref PubMed Scopus (162) Google Scholar; however, the first prospective evaluation of a dose-response benefit of ICSs in a study in which severe asthma exacerbations were the primary outcome variable was reported in 1997.7Pauwels R.A. Lofdahl C.G. Postma D.S. Tattersfield A.E. O'Byrne P. Barnes P.J. et al.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: 1405-1411Crossref PubMed Scopus (1564) Google Scholar This study evaluated asthmatic patients already taking moderate doses of ICSs but with poorly controlled asthma. During a run-in period, all patients were treated with high doses of ICSs (budesonide, 1600 μg/d) to try to achieve good control and were then randomized to low (budesonide, 200 μg/d) or moderate (budesonide, 800 μg/d) doses of ICSs. The risks of severe asthma exacerbations were reduced by almost 50% in the group receiving the higher dose of budesonide, from an annualized rate of 0.91 severe exacerbations per patient per year to 0.46 exacerbations per patient per year (Fig 2).7Pauwels R.A. Lofdahl C.G. Postma D.S. Tattersfield A.E. O'Byrne P. Barnes P.J. et al.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: 1405-1411Crossref PubMed Scopus (1564) Google Scholar An even larger magnitude of benefit was observed when a similar study was completed in patients with milder asthma who were not taking ICSs at the time of randomization, from 0.77 severe exacerbations per patient per year to 0.29 severe exacerbations per patient per year, a 74% reduction (Fig 3, group A).18O'Byrne P.M. Barnes P.J. Rodriguez-Roisin R. Runnerstrom E. Sandstrom T. Svensson K. et al.Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial.Am J Respir Crit Care Med. 2001; 164: 1392-1397Crossref PubMed Scopus (645) Google ScholarFig 3Number of severe asthma exacerbations (per patient per year) in the Optimal Management of Asthma study.18O'Byrne P.M. Barnes P.J. Rodriguez-Roisin R. Runnerstrom E. Sandstrom T. Svensson K. et al.Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial.Am J Respir Crit Care Med. 2001; 164: 1392-1397Crossref PubMed Scopus (645) Google Scholar The study consisted of 2 populations: group A, who were steroid naive at the time of study enrollment, and group B, who were already receiving low-dose ICS treatment at the time of study enrollment. In group A low-dose budesonide alone markedly reduced severe exacerbations, whereas in group B doubling the dose of budesonide alone did not reduce severe exacerbations, but adding the LABA formoterol did reduce severe exacerbation risk. BUD, Budesonide; F, formoterol.Redrawn from data in O'Byrne et al.18O'Byrne P.M. Barnes P.J. Rodriguez-Roisin R. Runnerstrom E. Sandstrom T. Svensson K. et al.Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial.Am J Respir Crit Care Med. 2001; 164: 1392-1397Crossref PubMed Scopus (645) Google ScholarView Large Image Figure ViewerDownload Hi-res image Download (PPT) A similar benefit of ICS treatment in reducing severe asthma exacerbations has been demonstrated in pediatric asthmatic patients,19Bisgaard H. Use of inhaled corticosteroids in pediatric asthma.Pediatr Pulmonol Suppl. 1997; 15: 27-33Crossref PubMed Scopus (42) Google Scholar and ICSs have been shown to be superior to the antileukotriene agent montelukast in this regard in children.20Covar R.A. Szefler S.J. Zeiger R.S. Sorkness C.A. Moss M. Mauger D.T. et al.Factors associated with asthma exacerbations during a long-term clinical trial of controller medications in children.J Allergy Clin Immunol. 2008; 122: 741-747Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar The corticosteroid budesonide has also been evaluated as a nebulized solution in very young children (age, 2-3 years) and again was demonstrated to be effective in reducing exacerbations,21Guilbert T.W. Morgan W.J. Zeiger R.S. Mauger D.T. Boehmer S.J. Szefler S.J. et al.Long-term inhaled corticosteroids in preschool children at high risk for asthma.N Engl J Med. 2006; 354: 1985-1997Crossref PubMed Scopus (908) Google Scholar but this benefit was lost once the nebulized budesonide was discontinued. This lack of continuing benefit after discontinuation of ICSs has also been demonstrated in older children.22Strunk R.C. Sternberg A.L. Szefler S.J. Zeiger R.S. Bender B. Tonascia J. Long-term budesonide or nedocromil treatment, once discontinued, does not alter the course of mild to moderate asthma in children and adolescents.J Pediatr. 2009; 154: 682-687Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar ICSs appear to achieve much of their clinical benefit from reducing the number and state of activation of airway eosinophils.23Gibson P.G. Saltos N. Borgas T. Airway mast cells and eosinophils correlate with clinical severity and airway hyperresponsiveness in corticosteroid-treated asthma.J Allergy Clin Immunol. 2000; 105: 752-759Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 24Brightling C.E. Green R.H. Pavord I.D. Biomarkers predicting response to corticosteroid therapy in asthma.Treat Respir Med. 2005; 4: 309-316Crossref PubMed Scopus (54) Google Scholar Approximately 50% of severe asthma exacerbations are associated with an increase in airway eosinophil numbers,25Turner M.O. Hussack P. Sears M.R. Dolovich J. Hargreave F.E. Exacerbations of asthma without sputum eosinophilia.Thorax. 1995; 50: 1057-1061Crossref PubMed Scopus (132) Google Scholar whereas in others there is prominent airway neutrophilia.25Turner M.O. Hussack P. Sears M.R. Dolovich J. Hargreave F.E. Exacerbations of asthma without sputum eosinophilia.Thorax. 1995; 50: 1057-1061Crossref PubMed Scopus (132) Google Scholar, 26Fahy J.V. Kim K.W. Liu J. 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Glucocorticoid treatment inhibits apoptosis in human neutrophils. Separation of survival and activation outcomes.J Immunol. 1995; 154: 4719-4725PubMed Google Scholar might largely explain why ICS treatment does not appear to eliminate the risk of all severe asthma exacerbations; although this has never been formally demonstrated, eosinophilic asthma exacerbations can, however, still occasionally occur in patients with difficult-to-treat asthma who are using ICSs.30Haldar P. Brightling C.E. Hargadon B. Gupta S. Monteiro W. Sousa A. et al.Mepolizumab and exacerbations of refractory eosinophilic asthma.N Engl J Med. 2009; 360: 973-984Crossref PubMed Scopus (1614) Google Scholar, 31Nair P. Pizzichini M.M. Kjarsgaard M. Inman M.D. Efthimiadis A. 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Concerns about the use of LABAs as monotherapy for asthma and the evidence of a deleterious effect that exists for some patients38Castle W. Fuller R. Hall J. Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment.BMJ. 1993; 306: 1034-1037Crossref PubMed Scopus (434) Google Scholar in the early 1990s resulted in the development of a clinical trial being designed, which examined whether combinations of ICSs and LABAs change the risks of severe asthma exacerbations when compared with ICS treatment alone.7Pauwels R.A. Lofdahl C.G. Postma D.S. Tattersfield A.E. O'Byrne P. Barnes P.J. et al.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: 1405-1411Crossref PubMed Scopus (1564) Google Scholar As described above, the patient population was asthmatic patients with poorly controlled asthma and a history of prior severe exacerbations. The study demonstrated that the combination of the ICS budesonide and the LABA formoterol significantly reduced the risks of both mild and severe asthma exace
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