Changing Paradigms in the Treatment of Severe Asthma: The Role of Biologic Therapies
2017; Elsevier BV; Volume: 5; Issue: 2 Linguagem: Inglês
10.1016/j.jaip.2016.11.029
ISSN2213-2201
AutoresRohit Katial, G. Bensch, William W. Busse, Bradley E. Chipps, Joshua L. Denson, Anthony N. Gerber, Joshua Jacobs, Monica Kraft, Richard J. Martin, Parameswaran Nair, Michael E. Wechsler,
Tópico(s)Eosinophilic Esophagitis
ResumoCytokine antagonists are monoclonal antibodies that offer new treatment options for refractory asthma but will also increase complexity because they are effective only for patients with certain asthma subtypes that remain to be more clearly defined. The clinical and inflammatory heterogeneity within refractory asthma makes it difficult to manage the disease and to determine which, if any, biologic therapy is suitable for a specific patient. The purpose of this article is to provide a data-driven discussion to clarify the use of biologic therapies in patients with refractory asthma. We first discuss the epidemiology and pathophysiology of refractory asthma. We then interpret current evidence for biomarkers of eosinophilic or type 2-high asthma so that clinicians can determine potential treatments for patients based on knowledge of their effectiveness in specific asthma phenotypes. We then assess clinical data on the efficacy, safety, and mechanisms of action of approved and pipeline biologic therapies. We conclude by discussing the potential of phenotyping or endotyping refractory asthma and how biologic therapies can play a role in treating patients with refractory asthma. Cytokine antagonists are monoclonal antibodies that offer new treatment options for refractory asthma but will also increase complexity because they are effective only for patients with certain asthma subtypes that remain to be more clearly defined. The clinical and inflammatory heterogeneity within refractory asthma makes it difficult to manage the disease and to determine which, if any, biologic therapy is suitable for a specific patient. The purpose of this article is to provide a data-driven discussion to clarify the use of biologic therapies in patients with refractory asthma. We first discuss the epidemiology and pathophysiology of refractory asthma. We then interpret current evidence for biomarkers of eosinophilic or type 2-high asthma so that clinicians can determine potential treatments for patients based on knowledge of their effectiveness in specific asthma phenotypes. We then assess clinical data on the efficacy, safety, and mechanisms of action of approved and pipeline biologic therapies. We conclude by discussing the potential of phenotyping or endotyping refractory asthma and how biologic therapies can play a role in treating patients with refractory asthma. Although a substantial proportion of suboptimal outcomes in asthma is related to poor adherence as well as both avoidable and unavoidable environmental exposures, increasing evidence suggests that there remain a group of patients with refractory asthma in whom standard therapies are ineffective.1Chung K.F. Wenzel S.E. Brozek J.L. Bush A. Castro M. Sterk P.J. et al.International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.Eur Respir J. 2014; 43: 343-373Crossref PubMed Scopus (425) Google Scholar Cytokine antagonists are monoclonal antibodies that offer new treatment options for refractory asthma but are effective only for patients with certain asthma subtypes. These specific asthma subtypes and the best measures to identify responders are still becoming recognized. Clinicians need to be able to distinguish between difficult-to-treat asthma, in which the patient is capable of asthma control with currently available treatments, and refractory asthma, in which the patient has poor asthma control despite taking high doses of inhaled corticosteroids (ICSs) with or without additional controller medications (including oral corticosteroids [OCSs]) or can maintain control only when taking OCSs. This article aims to clarify the use of biologic therapies by providing clinically relevant, evidence-based information to guide clinicians as new biologic therapies emerge for the treatment of refractory asthma. To facilitate these aims, a panel discussion was held in Denver, Colorado, and hosted by the Cohen Family Asthma Institute at National Jewish Health, bringing together 11 key opinion leaders from the United States and Canada to evaluate the role of emerging biologics and to discuss and debate the distinguishing characteristics of severe asthma, asthma phenotypes in treatment selection, the role of T helper cell type 2 (Th2) pathways in severe asthma, and the efficacy, safety, and mechanisms of action of emerging biologic therapies. In this article, our objectives are to (1) discuss the epidemiology and distinguishing characteristics of refractory asthma, (2) interpret current data on the role of eosinophils in the pathophysiology of refractory asthma, (3) distinguish the treatment approaches that are effective in type 2-high (Th2-high) asthma endotypes, and (4) assess recent clinical data on the efficacy, safety, and mechanisms of action of biologic drugs in asthma. Although we recognize that non–type 2-high asthma remains a considerable challenge, our focus is on patients with type 2-mediated inflammation because to date that is the population that biologic therapies are targeting. Guidelines and publications have referred to poorly controlled asthma by a variety of terms: severe asthma, refractory asthma, severe refractory asthma, difficult/therapy-resistant asthma, difficult-to-treat asthma, and uncontrolled asthma.1Chung K.F. Wenzel S.E. Brozek J.L. Bush A. Castro M. Sterk P.J. et al.International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.Eur Respir J. 2014; 43: 343-373Crossref PubMed Scopus (425) Google Scholar, 2Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. Updated 2016. Available from: http://ginasthma.org/2016-gina-report-global-strategy-for-asthma-management-and-prevention/. Accessed October 24, 2016.Google Scholar, 3National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute (US), Bethesda, MD2007http://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/full-reportGoogle Scholar, 4Chung K.F. Godard P. Adelroth E. Ayres J. Barnes N. Barnes P. et al.Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European Respiratory Society.Eur Respir J. 1999; 13: 1198-1208PubMed Google Scholar, 5Proceedings of the ATS workshop on refractory asthma current understanding, recommendations, and unanswered questions. American Thoracic Society.Am J Respir Crit Care Med. 2000; 162: 2341-2351Crossref PubMed Google Scholar, 6The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma.Eur Respir J. 2003; 22: 470-477Crossref PubMed Scopus (439) Google Scholar, 7Dolan C.M. Fraher K.E. Bleecker E.R. Borish L. Chipps B. Hayden M.L. et al.Design and baseline characteristics of the epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma.Ann Allergy Asthma Immunol. 2004; 92: 32-39Abstract Full Text PDF PubMed Google Scholar, 8Chanez P. Wenzel S.E. Anderson G.P. Anto J.M. Bel E.H. Boulet L.P. et al.Severe asthma in adults: what are the important questions?.J Allergy Clin Immunol. 2007; 119: 1337-1348Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 9Taylor D.R. Bateman E.D. Boulet L.P. Boushey H.A. Busse W.W. Casale T.B. et al.A new perspective on concepts of asthma severity and control.Eur Respir J. 2008; 32: 545-554Crossref PubMed Scopus (238) Google Scholar, 10Bousquet J. Mantzouranis E. Cruz A.A. Ait-Khaled N. Baena-Cagnani C.E. Bleecker E.R. et al.Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma.J Allergy Clin Immunol. 2010; 126: 926-938Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar, 11Hedlin G. Bush A. Lodrup Carlsen K. Wennergren G. De Benedictis F.M. Melen E. et al.Problematic severe asthma in children, not one problem but many: a GA2LEN initiative.Eur Respir J. 2010; 36: 196-201Crossref PubMed Scopus (72) Google Scholar Definitions of these terms often overlap, but the terms do not necessarily refer to the same patient population or the same underlying reasons for poor asthma control. We define refractory asthma per the definition of Bel et al12Bel E.H. Sousa A. Fleming L. Bush A. Chung K.F. Versnel J. et al.Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI).Thorax. 2011; 66: 910-917Crossref PubMed Scopus (163) Google Scholar and the 2014 international European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines,1Chung K.F. Wenzel S.E. Brozek J.L. Bush A. Castro M. Sterk P.J. et al.International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.Eur Respir J. 2014; 43: 343-373Crossref PubMed Scopus (425) Google Scholar in which patients with refractory asthma are those for whom alternative diagnoses have been excluded, comorbidities have been treated, triggers have been removed, and compliance with treatment has been checked, but remain poorly controlled or with frequent, severe exacerbations despite the prescription of high-intensity treatment or who require systemic corticosteroids to maintain asthma control. This type of high-intensity treatment is referred to as Step 5 or Step 6 in the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3 (EPR-3) Guidelines for the Diagnosis and Management of Asthma3National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute (US), Bethesda, MD2007http://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/full-reportGoogle Scholar and Step 5 in the Global Initiative for Asthma (GINA) Global Strategy for Asthma Prevention and Management.2Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. Updated 2016. Available from: http://ginasthma.org/2016-gina-report-global-strategy-for-asthma-management-and-prevention/. Accessed October 24, 2016.Google Scholar However, for those in whom control is poor due to adherence issues and comorbidities, the term applied is "difficult-to-control" asthma. A recent study from the Netherlands reported that 17.4% of the asthma patient population had difficult-to-control asthma despite high-intensity treatment, but once poor medication adherence and incorrect inhaler technique were factored, 3.6% of the asthma patient population had severe refractory asthma.13Hekking P.P. Wener R.R. Amelink M. Zwinderman A.H. Bouvy M.L. Bel E.H. The prevalence of severe refractory asthma.J Allergy Clin Immunol. 2015; 135: 896-902Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar The 2000 ATS Workshop on Refractory Asthma estimated that less than 5% of patients with asthma have high medication requirements to maintain good asthma control or have persistent symptoms, exacerbations, or airflow obstruction despite high medication use.5Proceedings of the ATS workshop on refractory asthma current understanding, recommendations, and unanswered questions. American Thoracic Society.Am J Respir Crit Care Med. 2000; 162: 2341-2351Crossref PubMed Google Scholar This subset of patients has disproportionately high health care utilization.5Proceedings of the ATS workshop on refractory asthma current understanding, recommendations, and unanswered questions. American Thoracic Society.Am J Respir Crit Care Med. 2000; 162: 2341-2351Crossref PubMed Google Scholar Such patients account for much of the morbidity, mortality, medical resource use, and costs related to asthma care.14Taylor W.R. Newacheck P.W. Impact of childhood asthma on health.Pediatrics. 1992; 90: 657-662PubMed Google Scholar, 15Vollmer W.M. Markson L.E. O'Connor E. Frazier E.A. Berger M. Buist A.S. Association of asthma control with health care utilization: a prospective evaluation.Am J Respir Crit Care Med. 2002; 165: 195-199Crossref PubMed Google Scholar, 16Tough S.C. Hessel P.A. Ruff M. Green F.H. Mitchell I. Butt J.C. Features that distinguish those who die from asthma from community controls with asthma.J Asthma. 1998; 35: 657-665Crossref PubMed Google Scholar, 17Antonicelli L. Bucca C. Neri M. De Benedetto F. Sabbatani P. Bonifazi F. et al.Asthma severity and medical resource utilisation.Eur Respir J. 2004; 23: 723-729Crossref PubMed Scopus (176) Google Scholar Moreover, both adults and children with uncontrolled asthma have significant health care use as measured by rates of hospitalization in the previous year and the lifetime history of intubation.18Jarjour N.N. Erzurum S.C. Bleecker E.R. Calhoun W.J. Castro M. Comhair S.A. et al.Severe asthma: lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program.Am J Respir Crit Care Med. 2012; 185: 356-362Crossref PubMed Scopus (75) Google Scholar The cost, both direct and indirect, is particularly high in children with very poorly controlled asthma versus children with not-well-controlled or well-controlled asthma.19Szefler S.J. Zeiger R.S. Haselkorn T. Mink D.R. Kamath T.V. Fish J.E. et al.Economic burden of impairment in children with severe or difficult-to-treat asthma.Ann Allergy Asthma Immunol. 2011; 107: 110-119.e1Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar In the Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) observational study of children aged 6-12 years, mean annual total asthma costs in children with very poorly controlled asthma were more than twice as those in children with not-well-controlled asthma or well-controlled asthma.19Szefler S.J. Zeiger R.S. Haselkorn T. Mink D.R. Kamath T.V. Fish J.E. et al.Economic burden of impairment in children with severe or difficult-to-treat asthma.Ann Allergy Asthma Immunol. 2011; 107: 110-119.e1Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Clinically, there are differences among patients in terms of symptoms, airway function (eg, forced expiratory volume in 1 second [FEV1]), airway architecture, airway hyperresponsiveness, degree and type of inflammation, susceptibility to exacerbations, and response to corticosteroids. In addition, clinicians encounter many types of populations, including patients who respond well to standard treatment with ICSs and/or long-acting β-agonists (LABAs), patients with comorbidities, and patients who are exacerbation-prone but between exacerbations require very little medication. Physiologic abnormalities in asthma appear to be defined early in life. The Melbourne Asthma Study, a long-term cohort study that began in 1964, found that airflow limitation (FEV1) persisted throughout life, regardless of new therapies that became available over 50 years.20Phelan P.D. Robertson C.F. Olinsky A. The Melbourne Asthma Study: 1964-1999.J Allergy Clin Immunol. 2002; 109: 189-194Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In addition, data from Rochester, Minnesota, showed that asthma began before age 4 in 80% of asthma cases.21Yunginger J.W. Reed C.E. O'Connell E.J. Melton III, L.J. O'Fallon W.M. Silverstein M.D. A community-based study of the epidemiology of asthma. Incidence rates, 1964-1983.Am Rev Respir Dis. 1992; 146: 888-894Crossref PubMed Google Scholar Recent cluster analyses within refractory asthma have highlighted heterogeneity of asthma in clinical presentation.22Haldar P. Pavord I.D. Shaw D.E. Berry M.A. Thomas M. Brightling C.E. et al.Cluster analysis and clinical asthma phenotypes.Am J Respir Crit Care Med. 2008; 178: 218-224Crossref PubMed Scopus (769) Google Scholar, 23Schatz M. Hsu J.W. Zeiger R.S. Chen W. Dorenbaum A. Chipps B.E. et al.Phenotypes determined by cluster analysis in severe or difficult-to-treat asthma.J Allergy Clin Immunol. 2014; 133: 1549-1556Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 24Newby C. Heaney L.G. Menzies-Gow A. Niven R.M. Mansur A. Bucknall C. et al.Statistical cluster analysis of the British Thoracic Society Severe refractory Asthma Registry: clinical outcomes and phenotype stability.PLoS One. 2014; 9: e102987Crossref PubMed Scopus (0) Google Scholar In a recent study of the British Thoracic Society Severe Refractory Asthma Registry, cluster analysis identified 5 clusters within refractory asthma: (1) atopic, early onset asthma with high exacerbation frequency and poor lung function but the greatest bronchodilator reversibility, (2) late onset disease in obese patients with frequent exacerbations and near-normal lung function, (3) nonatopic disease with normal lung function and infrequent exacerbations, (4) late onset with markedly elevated peripheral blood eosinophilia and frequent exacerbations, and (5) asthma with the lowest lung function but the least frequent exacerbations.24Newby C. Heaney L.G. Menzies-Gow A. Niven R.M. Mansur A. Bucknall C. et al.Statistical cluster analysis of the British Thoracic Society Severe refractory Asthma Registry: clinical outcomes and phenotype stability.PLoS One. 2014; 9: e102987Crossref PubMed Scopus (0) Google Scholar However, the endotypes, or underlying molecular bases for each of these phenotypic clusters, remain to be fully elucidated. Given that individuals with severe asthma can be phenotypically similar yet have heterogeneous responses to systemic corticosteroids, understanding underlying endotypes could help clinicians identify individuals who would most likely benefit from systemic corticosteroid step-up therapy in spite of their potential side effects.25Fitzpatrick A.M. Stephenson S.T. Brown M.R. Nguyen K. Douglas S. Brown L.A. Systemic corticosteroid responses in children with severe asthma: phenotypic and endotypic features.J Allergy Clin Immunol Pract. 2016; ([e-pub ahead of print])https://doi.org/10.1016/j.jaip.2016.08.001Abstract Full Text Full Text PDF Google Scholar Several studies have investigated clinical features that predict exacerbation risk or asthma symptoms. In the TENOR study, the largest cohort of patients with severe or difficult-to-treat asthma,26Chipps B.E. Zeiger R.S. Borish L. Wenzel S.E. Yegin A. Hayden M.L. et al.Key findings and clinical implications from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study.J Allergy Clin Immunol. 2012; 130: 332-342.e10Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar investigators found that the odds of a future asthma exacerbation increased more than 6-fold with a recent exacerbation.27Miller M.K. Lee J.H. Miller D.P. Wenzel S.E. TENOR Study Group. Recent asthma exacerbations: a key predictor of future exacerbations.Respir Med. 2007; 101: 481-489Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar This result suggests that recent exacerbation history should be part of clinical assessments of patients with severe or difficult-to-treat asthma.27Miller M.K. Lee J.H. Miller D.P. Wenzel S.E. TENOR Study Group. Recent asthma exacerbations: a key predictor of future exacerbations.Respir Med. 2007; 101: 481-489Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar A subsequent analysis of TENOR data showed that very poorly controlled asthma also predicted future exacerbations.28Haselkorn T. Fish J.E. Zeiger R.S. Szefler S.J. Miller D.P. Chipps B.E. et al.Consistently very poorly controlled asthma, as defined by the impairment domain of the Expert Panel Report 3 guidelines, increases risk for future severe asthma exacerbations in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study.J Allergy Clin Immunol. 2009; 124: 895-902.e1-4Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Children with consistently very poorly controlled asthma over a 2-year period had a 6.4-fold higher risk of hospitalization, emergency department (ED) visit, or OCS burst compared with children who improved from very poorly controlled asthma to not-well-controlled asthma or well-controlled asthma.28Haselkorn T. Fish J.E. Zeiger R.S. Szefler S.J. Miller D.P. Chipps B.E. et al.Consistently very poorly controlled asthma, as defined by the impairment domain of the Expert Panel Report 3 guidelines, increases risk for future severe asthma exacerbations in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study.J Allergy Clin Immunol. 2009; 124: 895-902.e1-4Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Adolescents and adults with consistently poorly controlled asthma over a 2-year period were also at higher risk of hospitalization, ED visit, or OCS burst compared with those patients who improved over the 2-year period.28Haselkorn T. Fish J.E. Zeiger R.S. Szefler S.J. Miller D.P. Chipps B.E. et al.Consistently very poorly controlled asthma, as defined by the impairment domain of the Expert Panel Report 3 guidelines, increases risk for future severe asthma exacerbations in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study.J Allergy Clin Immunol. 2009; 124: 895-902.e1-4Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar In a study of adolescents and adults with severe asthma, the greatest predictor of an exacerbation within 6 months was disease severity (GINA step 4 vs GINA step 3), with as-needed reliever use, postbronchodilator FEV1 (10% predicted normal value), asthma control as measured by the 5-item Asthma Control Questionnaire, and body mass index being smaller but significant predictors of exacerbations.29Bateman E.D. Buhl R. O'Byrne P.M. Humbert M. Reddel H.K. Sears M.R. et al.Development and validation of a novel risk score for asthma exacerbations: the risk score for exacerbations.J Allergy Clin Immunol. 2015; 135: 1457-1464.e4Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Furthermore, comorbidities play a role in difficult-to-control asthma. A recent study by the Severe Asthma Research Program found that blood eosinophils, bronchodilator responsiveness, body mass index, chronic sinusitis, and gastroesophageal reflux disease were associated with exacerbation-prone asthma.30Denlinger L.C. Phillips B.R. Ramratnam S. Ross K. Bhakta N.R. Cardet J.C. et al.Inflammatory and co-morbid features of patients with severe asthma and frequent exacerbations.Am J Respir Crit Care Med. 2017; 195: 302-313Crossref PubMed Scopus (0) Google Scholar A multicenter consortium in the European Union has initiated the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) project to identify phenotypes of severe asthma and new treatment targets in using a systems biology approach.31Shaw D.E. Sousa A.R. Fowler S.J. Fleming L.J. Roberts G. Corfield J. et al.Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort.Eur Respir J. 2015; 46: 1308-1321Crossref PubMed Scopus (42) Google Scholar, 32Fleming L. Murray C. Bansal A.T. Hashimoto S. Bisgaard H. Bush A. et al.The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts.Eur Respir J. 2015; 46: 1322-1333Crossref PubMed Scopus (0) Google Scholar Preliminary reports of baseline characteristics reveal that adult patients with severe asthma are characterized by poor symptom control, a higher exacerbation risk, increased comorbidity, and increased airway inflammation despite high levels of treatment.31Shaw D.E. Sousa A.R. Fowler S.J. Fleming L.J. Roberts G. Corfield J. et al.Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort.Eur Respir J. 2015; 46: 1308-1321Crossref PubMed Scopus (42) Google Scholar Pediatric patients with severe asthma or severe wheeze typically were atopic and, despite high-dose treatment, had more severe exacerbations and impaired quality of life associated with poor asthma control and airway obstruction.32Fleming L. Murray C. Bansal A.T. Hashimoto S. Bisgaard H. Bush A. et al.The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts.Eur Respir J. 2015; 46: 1322-1333Crossref PubMed Scopus (0) Google Scholar Thus, children with severe asthma or severe wheeze have a different phenotype than adults with severe asthma.32Fleming L. Murray C. Bansal A.T. Hashimoto S. Bisgaard H. Bush A. et al.The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts.Eur Respir J. 2015; 46: 1322-1333Crossref PubMed Scopus (0) Google Scholar Therefore, for patients with refractory asthma, it is important for clinicians to focus on the constellation of data including symptoms, lung function, exacerbation risk, and patient demographics rather than a single marker of disease. Moreover, a recent analysis of U-BIOPRED bronchial biopsies and bronchial epithelial brushings found that severe asthma exists despite suppressed endobronchial tissue inflammation with the proximal airways, suggesting that severe asthma is affected by additional mechanisms in the central airways or altered peripheral airway changes.33Wilson S.J. Ward J.A. Sousa A.R. Corfield J. Bansal A.T. De Meulder B. et al.Severe asthma exists despite suppressed tissue inflammation: findings of the U-BIOPRED study.Eur Respir J. 2016; 48: 1307-1319Crossref PubMed Scopus (32) Google Scholar Although refractory asthma is closely linked with absolute or relative resistance to steroid-based therapies, this simple correlation fails to capture the range of factors that contribute to steroid-refractory disease, including the epithelium, airway smooth muscle, immune cells, immunoglobulin E (IgE) and cytokines, environmental exposures such as viral infections and cigarette smoking, medications, and patient features such as genetics and comorbid disease. Furthermore, the complexity of the immune response in refractory asthma renders it challenging to untangle the interplay of the epithelium and airway smooth muscle with different types of immune cells and how these factors together determine phenotypic manifestations of severe asthma such as excessive mucus production and airway remodeling (Figure 1).34Pelaia G. Vatrella A. Busceti M.T. Gallelli L. Calabrese C. Terracciano R. et al.Cellular mechanisms underlying eosinophilic and neutrophilic airway inflammation in asthma.Mediators Inflamm. 2015; 2015: 879783Crossref PubMed Scopus (0) Google Scholar The obstacles associated with pinpointing immune modulators at the cellular level are further highlighted by emerging data on group 2 innate lymphoid (ILC2) cells, a relatively rare innate immune cell subtype that has only recently been implicated in generating substantial quantities of type 2 cytokines, such as IL-5, IL-4, and IL-13, in asthma. Thus, the nomenclature was changed from Th2, which implied production of these cytokines solely from T cells, to type 2. Studies are increasingly characterizing immunological phenotypes of refractory asthma, guiding the way to targeted therapies. In a 1999 study, Wenzel et al35Wenzel S.E. Schwartz L.B. Langmack E.L. Halliday J.L. Trudeau J.B. Gibbs R.L. et al.Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics.Am J Respir Crit Care Med. 1999; 160: 1001-1008Crossref PubMed Google Scholar demonstrated that severe, corticosteroid-dependent asthma can be divided into 2 inflammatory subtypes: a type 2-high phenotype characterized by high levels of eosinophils and a type 2-low phenotype characterized by low levels of eosinophils. Each phenotype was associated with distinct physiologic and clinical characteristics.35Wenzel S.E. Schwartz L.B. Langmack E.L. Halliday J.L. Trudeau J.B. Gibbs R.L. et al.Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics.Am J Respir Crit Care Med. 1999; 160: 1001-1008Crossref PubMed Google Scholar Analysis of sputum samples from the patients in the Belgian Severe Asthma Registry showed that approximately half (55%) of severe asthma cases were eosinophilic, with the remainder having other inflammatory phenotypes including neutrophilic (21%), paucigranulocytic (18%), and mixed granulocytic (6%).36Schleich F. Brusselle G. Louis R. Vandenplas O. Michils A. Pilette C. et al.Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR).Respir Med. 2014; 108: 1723-1732Abstract Full Text Full Text PDF PubMed Google Scholar These investigators also presented criteria defining type 2-high and type 2-low phenotypes, with the type 2-high phenotype being defined as a sputum eosinophil count of ≥3% or the presence of both exhaled nitric oxide (eNO) ≥27 ppb and blood eosinophil count ≥188/μL. By this definition, 57% of patients in the Belgian Severe Asthma Registry had eosinophilic (type 2-high) asthma and 43% had noneosinophilic (type 2-low) asthma.36Schleich F. Brusselle G. Louis R. Vandenplas O. Michils A. Pilette C. et al.Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR).Respir Med. 2014; 108: 1723-1732Abstract Full Text Full Text PDF PubMed Google Scholar It is important to note that within eosinophilic refractory asthma, the presence of eosinophils does not necessarily mean that they are the dominant effector cell type in an individual patient or that the patient's asthma is completely driven by allergic inflammation. Accordingly, giving a patient with eosinophilic asthma an anti-eo
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