Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome

Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome € tvall, MD,a Cezmi A. Akdis, MD,b Leonard B. Bacharier, MD,c Leif Bjermer, MD,d Thomas B. Casale, MD,e Jan Lo Adnan Custovic, MD,f Robert F. Lemanske, Jr, MD,g Andrew J. Wardlaw, MD,h Sally E. Wenzel, MD,i and Paul A. Greenberger, MDj G€ oteborg and Lund, Sweden, Davos, Switzerland, St Louis, Mo, Omaha, Neb, Manchester and Leicester, United Kingdom, Madison, Wis, Pittsburgh, Pa, and Chicago, Ill It is increasingly clear that asthma is a complex disease made up of number of disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment and can explain the failure to identify consistent genetic and environmental correlations to asthma. Here we describe a hypothesis whereby the asthma syndrome is divided into distinct disease entities with specific mechanisms, which we have called ‘‘asthma endotypes.’’ An ‘‘endotype’’ is proposed to be a subtype of a condition defined by a distinct pathophysiological mechanism. Criteria for defining asthma endotypes on the basis of their phenotypes and putative pathophysiology are suggested. Using these criteria, we identify several proposed asthma endotypes and propose how these new definitions can be used in clinical study design and drug development to target existing and novel therapies to patients most likely to benefit. This PRACTALL (PRACtical ALLergy) consensus report was produced by experts from the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. (J Allergy Clin Immunol 2011;127:355-60.)

From athe Krefting Research Center, University of Gothenburg, G€oteborg; bthe Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos; cthe Division of Allergy and Pulmonary Medicine, Washington University, St Louis; dthe Department of Respiratory Medicine and Allergology, Lund University Hospital; e the Creighton University School of Medicine, Omaha; fthe School of Translational Medicine, University of Manchester; gthe University of Wisconsin Hospital; hthe Institute for Lung Health, Department of Infection, Immunity and Inflammation, Glenfield Hospital, Leicester; ithe University of Pittsburgh Medical Center; and j the Division of Allergy/Immunology, Northwestern University Feinberg School of Medicine, Chicago. Disclosure of potential conflict of interest: J. L€otvall is a consultant for GlaxoSmithKline and Merck (MSD); receives speakers’ fees from GlaxoSmithKline, AstraZeneca, and Merck; receives research support from the Kreftin Foundation against asthma/allergy, the Swedish Medical Research Council, GlaxoSmithKline, AstraZeneca, and Novartis; and is president of the European Academy of Allergy and Clinical Immunology. C. A. Akdis receives research support from Novartis, Stallergenes, the Swiss National Science Foundation, the Global Allergy and Asthma European Network, and the Christine Kuhne Center for Allergy Research; has consultant arrangements with Actellion, Aventis, and Allergopharma; is a fellow and interest group member of the American Academy of Allergy, Asthma & Immunology; is vice-president of the European Academy of Allergy and Clinical Immunology; and is an ex–committee member WP leader for GA2LEN. L. B. Bacharier receives honoraria from AstraZeneca, Genentech, GlaxoSmithKline, Merck, Schering-Plough, and Aerocrine and is on advisory boards for Genentech, GlaxoSmithKline, Merck, Schering-Plough, and Aerocrine. T. B. Casale is executive vice-president of the American Academy of Allergy, Asthma & Immunology. A. Custovic receives research support from the Medical Research Council and the Moulton Charitable Trust. R. F. Lemanske Jr is a speaker for Merck, AstraZeneca, Doembacher Children’s Hospital, Washington University, Medicus Group, Park Nicolet Institute, ACAAI, LA Allergy Society, Michigan Allergy/Asthma Society,

Key words: Asthma, endotype, phenotype, cluster analysis, pathophysiology, epidemiology

Asthma is recognized as a complex condition with differences in severity, natural history, comorbidities, and treatment response. It has been defined as ‘‘a common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and an underlying inflammation.’’1 However, when large cohorts of patients with asthma are studied, all the characteristics of this definition are not always found, or 1 or 2 may predominate. Furthermore, in some patients, a detectable inflammatory component may be lacking or limited, even though the other characteristic symptoms of asthma are present. Although evidence from twin and family studies suggests a strong genetic component, more than a decade of intensive research has failed to identify consistently reproducible associations between asthma and genetic variants, which is not surprising if asthma is truly a syndrome encompassing several disease entities/endotypes, and if cohorts of patients with asthma used for genetic studies include individuals with a series of different diseases.2

Medical College of Wisconsin, Fund for Medical Research and Education (Detroit), Children’s Hospital of Minnesota, Toronto Allergy Society, American Academy of Allergy, Asthma & Immunology, Beaumont Hospital (Detroit), University of Illinois, Canadian Society of Allergy and Clinical Immunology, New York Presbyterian, Med Media Educational Group, Onpointe Medical Communication, Medical University of South Carolina, Health Matters Communication, Bishop McCann, Donohue, Purohit, Miller, Inc, Center for Health Care Education, University of California–San Francisco, American Thoracic Society, University of Iowa, Indiana University, American Lung Association of Upper Midwest, Vanderbilt University, and Rochester Children’s Hospital; has consultant arrangements with AstraZeneca, Map Pharmaceuticals, Gray Consulting, Smith Research, Inc, Merck Childhood Asthma Network, Novartis, Quintiles/Innovax, RC Horowitz and Co, Inc, International Meetings and Science, Scienomics, Scientific Therapeutics, and Cognimed, Inc; is an author for Up-to-Date; and is a textbook editor for Elsevier. A. J. Wardlaw is on the advisory boards for GlaxoSmithKline and Cephalon and receives research support from GlaxoSmithKline, Pfizer, and AstraZeneca. S. E. Wenzel is a consultant for GlaxoSmithKline, Merck, and Amira and receives research support from GlaxoSmithKline, MedImmune, and Amgen. P. A. Greenberger is on the advisory board for Mylan (Dey); has provided legal consultation or expert witness testimony in cases related to drug allergy, immunology of IBD, and asthma; and is a past president of the American Academy of Allergy, Asthma & Immunology. The other author has declared that he has no conflict of interest. Received for publication May 21, 2010; revised November 8, 2010; accepted for publication November 12, 2010. Reprint requests: Jan L€otvall, MD, Krefting Research Centre, University of Gothenburg, PO Box 480, SE 405 30 G€oteborg, Sweden. E-mail: [email protected]. 0091-6749/$36.00 Ó 2011 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2010.11.037

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Abbreviations used ABPM: Allergic bronchopulmonary mycosis API: Asthma-predictive indices ASA: Aspirin-sensitive asthma NSAID: Nonsteroidal anti-inflammatory drug

A longstanding debate in the asthma field is whether asthma is a single disease with a variable presentation, or several diseases that have variable airflow obstruction as a common feature.3,4 In 2006, Wenzel5 proposed that the different phenotypes expressed by patients with asthma are partly dependent on different disease processes in each individual. Thus, the diagnostic label ‘‘asthma’’ likely encompasses many different disease variants with different etiologies and pathophysiologies; consequently, reproducible genetic and environmental links have remained elusive in studies of general cohorts of patients with asthma. Typically, a patient’s asthma is described in terms of the disease phenotypes. Thus, a phenotype describes ‘‘observable characteristics,’’ and in the context of asthma describes clinical, physiological, morphologic, and biochemical characteristics as well as the response to different treatments. Although phenotypes are usually clinically relevant, in terms of presentation, triggers, and treatment response, they do not necessarily relate to or give any insight into the underlying disease processes. In the current report, we have chosen to use the term ‘‘endotype,’’ previously introduced by Anderson,6 to define distinct subtypes of asthma. Here we define an endotype as ‘‘a subtype of a condition, which is defined by a distinct functional or pathophysiological mechanism.’’ Endotypes are thus a different form of classification from phenotypes and describe distinct disease entities with a defining etiology and/or a consistent pathophysiological mechanism (Fig 1). An example beyond asthma could be anemia, in which sickle cell disease encompasses a distinct endotype of anemia. Therefore, together with genetic and/or environmental influences, the endotype can explain the clinical presentation, epidemiology, and response to different treatments. It has been suggested previously that asthma is made up of several endotypes,6 and although currently the underlying mechanisms of many of the proposed endotypes are poorly understood, their definition will enable the identification of novel therapeutic targets and biomarkers that meet formal diagnostic and prognostic criteria. Furthermore, defining endotypes may help predict the response to treatment and thus facilitate improved management decisions with currently available treatments. Whereas phenotypic characteristics represent observations of clinical dimensions of asthma, an asthma endotype represents a mechanistically coherent disease entity. Table I presents the possible relationship between asthma phenotypes and proposed endotypes. Each endotype may encompass several phenotypes just as certain phenotypes may be present in more than 1 endotype. We suggest that asthma endotypes might begin to be identified as clusters of measurements from different dimensions of the disease (ie, clinical features, physiology, immunology, pathology, hereditary components, environmental influences, response to treatment, and so forth) that result from complex multivariate techniques, such as cluster analyses, or even from biased clinically based clustering. Identification of such ‘‘phenotypic clusters’’ would need to be followed up by detailed studies of the pathophysiological process to confirm that the phenotype cluster

FIG 1. Asthma is made up of different endotypes, each characterized by its pathophysiology.

does indeed represent an endotype.7-10 However, details of the pathophysiological mechanisms for many of the proposed endotypes require additional study.

PROPOSED RULES FOR DEFINING ASTHMA ENDOTYPES Until today, asthma endotypes have not been characterized, and although endotypes are defined by their pathophysiology, there are no generally accepted criteria that a condition should fulfill to be considered an endotype. To find out whether some asthma endotypes can already be identified, we selected 7 parameters— clinical characteristics, biomarkers, lung physiology, genetics, histopathology, epidemiology, and treatment response—to define each endotype. By group consensus, we proposed that each endotype should fulfill at least 5 of the 7 parameters. The chosen parameters were all considered relevant to disease pathogenesis; however, prospective studies will be necessary to evaluate this definition fully. Such studies could include the detailed evaluation of the proposed parameters in individuals present in already defined clusters of phenotypes, together with mechanistic studies. Several parameters were considered to be unsuitable for defining an endotype. Clearly, within an endotype, different patients can have differing disease severities and degrees of difficulty to treat. Severity can depend on several factors, including the activity of the intrinsic pathophysiologic process, the coincidence of exposure to external asthma exacerbants, or the complicating effects of a comorbidity. Treatment response can be influenced by the degree of allergic reactivity in an allergic asthma endotype, together with the degree of allergen exposure. Comorbidities were not included as a defining parameter for an endotype because these can influence the disease phenotype but not the endotype. For example, obesity has been identified in specific phenotype clusters within the asthma syndrome, but it is also recognized that pre-existing obesity is a risk factor for developing asthma in individuals with and without allergy.11 This does not exclude the possibility that a distinct endotype exists in asthma associated with obesity, although the observed clusters are likely to encompass several endotypes. Furthermore, it is known that rhinitis is a risk factor for developing asthma and is present in a majority of patients with asthma, but is present both in those with and without concomitant allergy, thus influencing the

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TABLE I. Proposed relationship between asthma phenotypes and endotypes: asthma phenotypes can be present in more than 1 endotype, and endotypes can contain more than 1 phenotype Phenotype: Phenotype:

Phenotype: Phenotype: Phenotype: Phenotype:

Eosinophilic asthma Endotypes: allergic asthma (adult),* aspirin-sensitive asthma, severe late-onset hypereosinophilic asthma,* ABPM* Exacerbation-prone asthma Endotypes: allergic asthma (adult),* aspirin-sensitive asthma,* late-onset hypereosinophilic asthma, API-positive preschool wheezer,* ABPM,* viral-exacerbated asthma, premenstrual asthma Phenotype: Obesity-related asthma Endotypes: airflow obstruction caused by obesity, severe steroid-dependent asthma, severe late-onset hypereosinophilic asthma* Exercise-induced asthma Endotypes: cross-country skiers’ asthma, other forms of elite-athlete asthma, allergic asthma, API-positive preschool wheezer* Adult-onset asthma Endotypes: aspirin-sensitive asthma,* infection-induced asthma, severe late-onset hypereosinophilic asthma* Fixed airflow limitation Endotypes: noneosinophilic (neutrophilic) asthma Poorly steroid-responsive asthma Endotypes: noneosinophilic (neutrophilic) asthma, steroid-insensitive eosinophilic asthma, airflow obstruction caused by obesity

*Proposed endotypes that appear in Table II.

progress of disease into asthma regardless of atopic status.12 Therefore, comorbidities can interact with different pathophysiological processes regardless of endotype but are unlikely to be useful as a part of the definition of a specific asthma endotype at this time. An additional factor that can shape the disease phenotype is patient behavior, such as adherence to treatment and/or smoking. Patient behavior can thus influence the severity of observable characteristics such as inflammation, symptomatology, and bronchial hyperresponsiveness and can affect the long-term disease outcome. High adherence to treatment may improve disease outcomes and may cluster in a mild phenotype. In contrast, other patient factors such as psychopathology or personality traits that are associated with risk behavior may be expressed in a more severe phenotype cluster independent of a specific pathophysiological mechanism.13 Although factors that influence severity and adherence to treatment must be considered in tailoring an effective therapeutic approach to the needs of the individual, these factors are difficult to associate with a particular disease endotype.

DESCRIPTION OF ENDOTYPES AND EVOLVING ENDOTYPES To differentiate endotypic categories, we chose 7 different parameters that were seen as clinically relevant, and we suggest that 5 of those should be met to describe a proposed asthma endotype. We applied these endotypic categories to several phenotypes that have been previously described in the literature, and we propose 6 endotypes that meet at least 5 of the 7 parameters (Table II). Obviously, the more parameters that could be populated and the more detail that could go into each parameter, the more likely it is that the proposed endotype is a real endotype of asthma. Much additional information will be needed to understand fully the disease processes in each of these proposed endotypes, but we argue that this tentative identification will accelerate our understanding of the pathophysiology, thereby resulting in better therapeutic outcomes in these patient subgroups. Aspirin-sensitive asthma (ASA) has been recognized as a subgroup of asthma for several decades. It has a distinct clinical presentation, appearing almost always in adulthood and often after ingestion of a non-steroidal anti-inflammatory (NSAID) medication. After NSAID ingestion, severe and prolonged airway

obstruction occurs, and this feature of ASA is typically accompanied by chronic/severe rhinosinusitis and nasal polyps (aspirinexacerbated respiratory disease), peripheral blood eosinophilia, and an elevation of urinary leukotrienes at baseline and after aspirin challenge. Pathophysiologically, ASA has been associated with increased cysteinyl leukotriene production and increased expression of leukotriene C4 synthase.14 Furthermore, single nucleotide polymorphisms have been identified in genes coding for proteins in the leukotriene synthesis pathway, which may lead to overexpression. Although they do not protect the patient from NSAID reactions, cysteinyl leukotriene receptor antagonists and leukotriene C4 synthesis inhibitors have a beneficial effect on ASA symptoms.15 Allergic bronchopulmonary mycosis (ABPM) is a well characterized hypersensitivity reaction to the colonization of the airways by molds, most frequently Aspergillus fumigatus. ABPM is reported in a small group of patients with asthma, particularly in more severe disease. This asthma endotype is characterized by a mixed pattern of neutrophilic and eosinophilic airway inflammation, elevated mold-specific IgE and IgG, episodic bronchial obstruction and mucoid impaction with the development of bronchiectasis, and fixed airflow obstruction.16 ABPM could be considered a complication of the allergic asthma endotype, or cystic fibrosis, whereas the later onset in life is generally not shared with the allergic asthma endotype. It is important to recognize the ABPM endotype clinically because it is associated with severe disease, recurrent exacerbations, and progressive lung damage but may respond to systemic glucocorticoids, antifungal agents, and the anti-IgE mAb omalizumab. Allergic asthma is a classic form of persistent asthma that typically has a childhood onset and is accompanied by allergic features, including sensitization to allergens and allergic rhinitis. Airway eosinophilia is a common feature, and this condition is thought to be driven by a TH2-dominant inflammatory process. Inhalation of a specific allergen triggers acute bronchoconstriction and subsequent inflammatory cell influx, often followed by a late asthmatic response. This endotype encompasses a wide range of disease severities and responses to treatment. The efficacy of omalizumab in severe allergic asthma, and the studies of IL-4/ IL-13 pathway modifiers in this endotype, point to a central role of IgE and TH2 cells/cytokines. Although patients may have multiple clinical presentations and substantial differences in severity,

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TABLE II. Examples of endotypes that fulfill at least 5 of 7 prespecified disease characteristics Endotype of the asthma syndrome

Disease characteristics Clinical characteristics

Biomarkers

Lung physiology BHR, FEV1, reversibility

Proposed endotype

History, physical examination, comorbidities

Eosinophilia, FeNO, SPT, IgE

Aspirinsensitive asthma

Polyposis, often more severe asthma

Often eosinophilic, Response to aspirin increased urinary challenge LTs

ABPM

Blood eosinophilia, Less Severe, mucus reversible/fixed markedly production, airflow elevated IgE and adult/long obstruction specific IgE disease duration Specific Positive SPT, Allergen associated allergic elevated IgE/ symptoms/allergic bronchospasm elevated FeNO rhinitis

Allergic asthma (adults)

API-positive preschool wheezer

>3 episodes per year, 1 major or 2 minor characteristics

SNPs and pathways

Histopathology Tissue/lung characteristics

Often LT-related eosinophilic gene polymorphisms

HLA and rare CF variants

TH2 pathway SNPs

Unknown Potential increased risk of loss of lung function

No evidence Bronchodilator– resistant, episodic fall in lung function, steroid–sensitive FeNO normal, Mild to moderate Unknown Methacholine normal blood severity, and or exercise eosinophil count, symptoms mostly positive, usually increased LTE4 related to exercise, negative to URTI commonly mannitol or in urine reported AMP challenge

Severe Severe exacerbations, late-onset late-onset hypereosinophilic disease Asthma in crosscountry skiers

Often >4% eosinophils in blood (minor), aeroallergenspecific IgE Peripheral blood eosinophilia

Genetics

Bronchiectasis/ eosinophils and PMNs, bronchocentric granulomatosis Eosinophils, SBM thickening

Epidemiology

Treatment response

Proposed mechanism

Prevalence, risk factors, and natural history

Response or lack of response to a specific treatment

Specific biological pathway or process

Adult onset, severe disease poor prognosis, prevalence 2% to 5% Long duration/ adult onset/poor prognosis

Responds to anti-LT, especially 5-LO inhibitors

Likely eicosanoidsrelated

Glucocorticoids, antifungals, possibly omalizumab

Colonization of airways

Childhood onset, history of eczema

Responds to glucocorticoids and omalizumab, possible IL-4/13 pathway inhibition Responds well to daily inhaled glucocorticoids

TH2–dominant

TH2–dominant

Unknown

Mother or father with asthma

High blood eosinophil count and eosinophils in tissue SBM thickening with low-grade noneosinophilic inflammation, increased neutrophils in sputum related to training intensity or duration, BALT in airway mucosa

Nonatopic, Approximately 20% Glucocorticoidotherwise sensitive, of severe asthma unknown often oral steroid– populations dependent, responds to anti–IL-5 Cold, dry air 15% to 25% of elite Responds poorly to induces inhaled skiers, highest chronic glucocorticoid prevalence among stress to treatment, improves those training in the airways, when training a cold, dry subclinical intensity diminishes environment viral infections?

BALT, Bronchus-associated lymphoid tissue; BHR, bronchial hyperresponsiveness; CF, cystic fibrosis; FeNO, fractional exhaled nitric oxide; LT, leukotriene; LTE4, leukotriene E4; 5-LO, 5-lipoxygenase; SBM, subepithelial basement membrane; SNP, single nucleotide polymorphism; SPT, skin prick test; URTI, upper respiratory tract infection.

cluster analysis of asthma phenotypes supports the existence of allergic asthma as a distinct asthma endotype.4 Children with asthma-predictive indices (API) have a clearly increased risk of developing asthma and may or may not encompass the classic ‘‘allergic asthma endotype.’’ This subpopulation of children has been defined by having repeated wheezing episodes (>3 episodes in the first 3 years of life) and at least 1 of 3 major criteria (personal atopic dermatitis, parental asthma, or sensitization to an aeroallergen) or 2 of 3 minor criteria (peripheral eosinophils > _4%, wheezing unrelated to the common cold, or sensitization to a food allergen). Children satisfying these criteria at 3 years of age have approximately a 65% likelihood of having active asthma symptoms at 6 years of age.17,18 Studies of individuals with late-onset asthma in adulthood have identified a distinctive subgroup of patients with a pattern of severe exacerbations prevented by systemic but not inhaled steroid and hypereosinophilia in blood (>1000/mm3) and sputum (>10%) who meet the criteria for an asthma endotype.4,19 They account for about 20% of patients who meet the definition of refractory asthma and are seldom found in cohorts of patients with

asthma drawn from primary care populations. Other characteristic features are a lower prevalence of atopy than the ‘‘allergic asthma’’ endotype. The levels of bronchodilator responsiveness and nonspecific airway hyperresponsiveness may be lower than in the allergic asthma endotype. Preliminary studies with anti–IL-5 therapy suggest that this treatment approach may also be clinically useful in this endotype.20 Cross-country skiers’ asthma is clinically defined as attacks of asthma symptoms and/or wheeze closely related to strenuous skiing-related exercise, with concomitant hyperresponsiveness of the airways. Exposure to cold, dry air is believed to be a major risk factor for this endotype, probably established during strenuous exercise while having a mild respiratory tract infection. An extremely cold, dry climate has been shown to favor the development of this type of asthma compared with warmer, more humid conditions.21 In contrast with other forms of exercise-induced asthma,22 this endotype is seldom associated with allergic sensitization, but is characterized by airway inflammation dominated by increased numbers of lymphocytes, macrophages, and neutrophils, but seldom eosinophils.

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Furthermore, bronchoscopic studies can identify lymphoid aggregates in the form of bronchus-associated lymphoid tissue in the mucosa, as well as evidence of airway remodeling with thickening of the reticuloepithelial membrane.23 Cross-country skiers’ asthma is not responsive to treatment with inhaled glucocorticoids alone but often improves with a reduction in training intensity.

IDENTIFYING THE MECHANISM OF ASTHMA ENDOTYPES The core pathophysiological mechanisms causing the asthma endotypes are likely to be fundamentally different. Therefore, understanding disease processes from the concept that asthma is a syndrome consisting of several endotypes is likely to be challenging. We suggest that multiple approaches will be required to identify endotype-specific mechanisms of disease, including careful immunophenotyping, studies of functionality of structural cells in the airways, proteomics, and genomics. However, any such study should be performed in very well characterized patients with very similar phenotypic characteristics, which would suggest that they might represent the same endotype. Such studies may not only describe detailed mechanisms of an endotype but also discover biomarkers that could enable more precise diagnosis of the asthma endotype in individual patients. When exploring mechanisms of asthma in different proposed endotypes, research may identify mechanisms that are either endotype-specific or common to all asthma. It is therefore crucial that several different well characterized groups of patients with asthma are included in such research to determine whether the explored biological process is unique for the studied endotype or present among different endotypes. This also emphasizes the necessity to have closely matched control subjects for comparison. The approaches used could select patients either in a hypothesis-driven way or in an unbiased way from a large cohort by determining clusters of different phenotypes. IMPLICATIONS FOR CLINICAL TRIAL DESIGN AND FUTURE DRUG DEVELOPMENT The outcomes of many clinical trials in asthma have been biased by adopting inclusion and exclusion criteria that require subjects to conform to the generic description of the disease—for example, a high degree of bronchodilator reversibility. Trials performed in this way do not necessarily establish whether a studied medication works equally well among all patients with the asthma syndrome, or whether patients with different asthma endotypes respond differently to the tested treatment. For instance, it has been shown that inhaled glucocorticoid treatment results in a better short-term response in patients with eosinophilic airway inflammation than in those without.24 This finding argues that patients with different characteristics/endotypes may respond differently even to currently available treatment, and possibly even more so in future treatments targeting specific mechanisms. One example of a treatment that is focused on a specific mechanism is omalizumab, which primarily reduces free concentrations of IgE and binding of IgE to mast cells and basophils. This treatment resulted in fewer exacerbations in patients with moderate to severe asthma and allergic sensitization when they were exposed to allergens.25 These patients may represent a specific asthma endotype that is responsive to this medication. With more generic treatments, such as

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inhaled glucocorticoids with or without concomitant treatment with a long-acting b2-agonist, it is possible that patients who demonstrate clinical benefit evolve from several endotypes, because the treatments are functional antagonists rather than targeting specific disease mechanisms. We suggest that one of the major unmet needs in asthma lies with delivering mechanism-specific treatments that are highly effective in specific endotypes of asthma. To realize this goal, inclusion criteria for clinical studies would have to be more endotype-specific than they are now, and might also require measurement of different endpoints than are traditionally used. In this report, we propose that one of the major obstacles to understanding the causes of asthma and improving treatment is the failure to understand the underlying disease mechanisms in individuals with different types of disease. It has become increasingly clear that asthma is a complex syndrome, likely made up of a number of disease endotypes, each with a distinct pathophysiology. Population-based studies aimed at identifying genetic and environmental links to asthma must therefore focus on more homogeneous groups rather than groups of patients with asthma with clearly different disease features, because they then are likely to include patients with different pathophysiologies. To improve our understanding of asthma, it will be necessary to classify patients according to the underlying disease mechanism rather than relatively crude clinical characteristics such as bronchodilator reversibility or bronchial hyperresponsiveness. We have therefore proposed criteria for defining endotypes of asthma, and on the basis of these criteria, we propose several asthma endotypes. However, the robustness of these endotype definitions remains to be tested in prospective clinical studies. We propose that the classification of patients with asthma by endotype will facilitate future research to establish genetic associations, identify biomarkers for disease endotypes, and test novel therapeutic targets and endotype-specific treatments. Therefore, the use of endotypes in clinical research could identify patient groups that will benefit most from new and existing treatments, substantially improving future asthma care. The workshop in which this concept and article were developed was financed by the European Academy of Allergy and Clinical Immunology. We acknowledge the helpful editorial support of Ron Hogg, Omniscience SA, who was financed by a grant from the European Academy of Allergy and Clinical Immunology. We also acknowledge Serena O’Neil, University of Gothenburg, for reviewing the article and Sladjana Scepan for organizing the workshop. REFERENCES 1. National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services. Expert panel report 3: guidelines for the diagnosis and management of asthma. Section 2, p. 1. 2007. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed April 13, 2010. 2. Ober C, Hoffjan S. Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun 2006;7:95-100. 3. Gibson PG, Simpson JL, Saltos N. Heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest 2001;119:1329-36. 4. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008;178: 218-24. 5. Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet 2006;368: 804-13. 6. Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 2008;372:1107-19.

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