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• W2006174105 abstract "The term severe refractory asthma (SRA) in adults applies to patients who remain difficult to control despite extensive re-evaluation of diagnosis and management following an observational period of at least 6 months by a specialist. Factors that influence asthma control should be recognized and adequately addressed prior to confirming the diagnosis of SRA. This report presents statements according to the literature defining SRA in order address the important questions. Phenotyping SRA will improve our understanding of mechanisms, natural history, and prognosis. Female gender, obesity, and smoking are associated with SRA. Atopy is less frequent in SRA, but occupational sensitizers are common inducers of new-onset SRA. Viruses contribute to severe exacerbations and can persist in the airways for long periods. Inflammatory cells are in the airways of the majority of patients with SRA and persist despite steroid therapy. The TH2 immune process alone is inadequate to explain SRA. Reduced responsiveness to corticosteroids is common, and epithelial cell and smooth muscle abnormalities are found, contributing to airway narrowing. Large and small airway wall thickening is observed, but parenchymal abnormalities may influence airway limitation. Inhaled corticosteroids and bronchodilators are the mainstay of treatment, but patients with SRA remain uncontrolled, indicating a need for new therapies. The term severe refractory asthma (SRA) in adults applies to patients who remain difficult to control despite extensive re-evaluation of diagnosis and management following an observational period of at least 6 months by a specialist. Factors that influence asthma control should be recognized and adequately addressed prior to confirming the diagnosis of SRA. This report presents statements according to the literature defining SRA in order address the important questions. Phenotyping SRA will improve our understanding of mechanisms, natural history, and prognosis. Female gender, obesity, and smoking are associated with SRA. Atopy is less frequent in SRA, but occupational sensitizers are common inducers of new-onset SRA. Viruses contribute to severe exacerbations and can persist in the airways for long periods. Inflammatory cells are in the airways of the majority of patients with SRA and persist despite steroid therapy. The TH2 immune process alone is inadequate to explain SRA. Reduced responsiveness to corticosteroids is common, and epithelial cell and smooth muscle abnormalities are found, contributing to airway narrowing. Large and small airway wall thickening is observed, but parenchymal abnormalities may influence airway limitation. Inhaled corticosteroids and bronchodilators are the mainstay of treatment, but patients with SRA remain uncontrolled, indicating a need for new therapies. Severe asthma in adults continues to be a challenge for doctors and scientists involved in the field despite several international initiatives to better understand this complex condition. The current article reports a workshop held in Paris, France in February 2006, which was designed to give a comprehensive review of the current knowledge of this debilitating disease, but also to highlight the paucity of confirmed mechanisms and the poor understanding of management. By specifically addressing several unanswered questions, we hope this initiative will encourage more research and improve outcomes in severe asthma. The term severe refractory asthma applies to patients who remain difficult to control despite an extensive reevaluation of diagnosis, management, and an observational period of at least 6 months by an asthma specialist (Table I).Table IAssessment of patients with severe asthmaMedical history History of asthma Age of onset Family history of asthma Management of disease and response to treatment Exacerbations Frequency of severe asthma exacerbations Number of hospitalizations and intensive care unit admissions Environmental exposures Exposure to allergens, occupational agents, and chemicals/pollutants Smoking history Comorbidities and cofactors Rhinosinusitis or previous surgery for nasal polyps Use of aspirin, NSAIDs, β-blockers, angiotensin-converting enzyme inhibitors, and estrogens Gastroesophageal reflux disease Obstructive sleep apnea Influence of menstruation Adherence with medications History of psychiatric disease Psychosocial circumstancesPhysical examination (specific points of attention) Body mass index Evidence of comorbidities such as nasal polyps Evidence of alternative diagnoses such as cardiac failure Evidence of adverse effects of treatmentAssessment of severe asthma Diagnosis Spirometry (reversibility tests) Airway challenge Baseline investigations Health status and asthma control questionnaires Serum IgE and peripheral blood eosinophil count Allergy skin tests Assessment of airway inflammation Assessment of lung volumes Consider additional tests for comorbidities and alternative diagnoses Outcome measures Health status and asthma control questionnaires Assessment of airway inflammation Number and severity of exacerbations and use of health care Lung function Open table in a new tab Most patients with asthma have mild-to-moderate disease that can be well controlled with standard treatment, including the regular use of inhaled corticosteroids (ICSs) combined with short-acting inhaled β2-agonists (SABAs) or long-acting inhaled β2-agonists (LABAs). However, a subset of patients with asthma exist, in whom even high doses of these drugs fail to control the disease. Indeed, it is well recognized that some patients with asthma have more severe disease than others, and early descriptions identified a subset of patients with asthma whose disease was apparently unresponsive to corticosteroids. In the literature, these patients are labeled as having difficult-to-treat asthma, therapy-resistant asthma, steroid-dependent asthma, brittle asthma, and so on.1Bel E.H. Clinical phenotypes of asthma.Curr Opin Pulm Med. 2004; 10: 44-50Crossref PubMed Google Scholar In 1999, a European Respiratory Society Task Force adopted the term difficult asthma.2Chung K. 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.Eur Respir J. 1999; 13: 1198-1208PubMed Google Scholar In 2000, the American Thoracic Society (ATS) defined refractory asthma.3American Thoracic Society Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions.Am J Respir Crit Care Med. 2000; 162: 2341-2351Crossref PubMed Google Scholar The European Respiratory Society and ATS definitions differ from the recently updated Global Initiative for Asthma guideline for asthma management and prevention in that they include medication criteria.4National Institutes of Health NH, Lung, and Blood Institute Global strategy for asthma management and prevention.Global initiative for asthma. 1995; Google Scholar According to the ATS definition, patients who need oral corticosteroids (OCSs) or high-dose ICSs to remain under control as well as patients with ongoing asthma symptoms despite appropriate maintenance therapy should be regarded as having severe asthma. All of these definitions include an assessment of disease control, exacerbating factors/comorbidities, and response to treatment, which may influence control and treatment requirements. The diagnosis of severe asthma should be reserved for those who have refractory asthma after an extensive reevaluation and an appropriate observation period of at least 6 months. Spirometry, reversibility testing, and airway challenge tests (unless contraindicated) are mandatory in the reevaluation of the diagnosis of asthma. The diagnosis of severe asthma is predicated by a secure diagnosis of asthma. For this reason, the diagnosis of severe asthma must be confirmed by the presence of typical symptoms for asthma, together with objective evidence of variable airflow limitation and/or airway hyperresponsiveness.4National Institutes of Health NH, Lung, and Blood Institute Global strategy for asthma management and prevention.Global initiative for asthma. 1995; Google Scholar In addition, alternative diagnoses need to be considered and excluded. Demonstration of reversible airways obstruction by SABAs and/or corticosteroids is valuable, but bronchial provocation testing is more sensitive and specific5Hunter C.J. Brightling C.E. Woltmann G. Wardlaw A.J. Pavord I.D. A comparison of the validity of different diagnostic tests in adults with asthma.Chest. 2002; 121: 1051-1057Crossref PubMed Scopus (94) Google Scholar and should be performed when necessary to confirm the diagnosis of asthma. However, when airflow is very low, bronchial provocation may not be helpful and/or feasible from a safety and regulatory perspective. Factors that influence asthma control such as environmental exposures, comorbidities, adherence, and inhalation technique should be recognized and adequately addressed before confirming the diagnosis of severe asthma. Once the diagnosis of asthma is confirmed, numerous factors can contribute to refractory asthma. Managing these issues may in turn improve asthma control and therefore alter the classification of severity. It is important to recognize and, where possible, adequately manage environmental exposures, comorbidities, and adherence with therapy, including the inhalation technique, before confirming a diagnosis of severe asthma. The diagnosis and identification of additional factors influencing the severity of asthma should be approached systematically. Key features in the history, examination, and later investigations are highlighted in Table I. The success of tackling many of these issues is dependent on providing sufficient education and support for the patient. Ongoing allergen exposure can induce an airway inflammatory process that may increase the severity of asthma, although in recent large-scale surveys, allergic responses have not been considered to be among the strongest contributing factors to asthma severity.6ENFUMOSA Study GroupThe ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma.Eur Respir J. 2003; 22: 470-477Crossref PubMed Scopus (359) Google Scholar The contribution of an exposure to a sensitizing agent at work should also be considered, and avoidance measures should be proposed when the relationship with the agent has been established.7Malo J.L. Asthma may be more severe if it is work-related.Am J Respir Crit Care Med. 2005; 172: 406-407Crossref PubMed Scopus (10) Google Scholar Smoking may contribute to the development and manifestations of severe asthma; smokers with asthma are more symptomatic and have more severe and frequent exacerbations and emergency care needs; have a reduced response to corticosteroid; and a more rapid decline in pulmonary function;8Thomson N.C. Chaudhuri R. Livingston E. Asthma and cigarette smoking.Eur Respir J. 2004; 24: 822-833Crossref PubMed Scopus (220) Google Scholar However, a recent large study did not find a relationship of smoking to severity or accelerated decline in FEV1.9de Marco R. Marcon A. Jarvis D. Accordini S. Almar E. Bugiani M. et al.Prognostic factors of asthma severity: a 9-year international prospective cohort study.J Allergy Clin Immunol. 2006; 117: 1249-1256Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Therefore, strategies to encourage smoking cessation are an important aspect of severe asthma management. Often comorbidities complicate severe asthma. For example, several factors have been associated with frequent exacerbations, including severe nasal and sinus disease, gastroesophageal reflux, recurrent respiratory infections, psychological dysfunction, and obstructive sleep apnea.10ten Brinke A. Sterk P.J. Masclee A.A. Spinhoven P. Schmidt J.T. Zwinderman A.H. et al.Risk factors of frequent exacerbations in difficult-to-treat asthma.Eur Respir J. 2005; 26: 812-818Crossref PubMed Scopus (153) Google Scholar Upper airway conditions such as allergic and nonallergic rhinosinusitis are frequently associated with severe asthma and have been considered to influence asthma outcomes, which seems to be particularly true when rhinosinusitis is associated with aspirin-exacerbated respiratory disease.11Mascia K. Haselkorn T. Deniz Y.M. Miller D.P. Bleecker E.R. Borish L. Aspirin sensitivity and severity of asthma: evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma.J Allergy Clin Immunol. 2005; 116: 970-975Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 12Wark P.A. Gibson P.G. Wilson A.J. Azoles for allergic bronchopulmonary aspergillosis associated with asthma.Cochrane Database Syst Rev. 2004; (CD001108)PubMed Google Scholar The association between severe asthma and gastroesophageal reflux disease is complex. As noted, gastroesophageal reflux has been implicated as a potential factor in uncontrolled asthma, but the frequent lack of improvement with treatment suggests that its contribution to asthma severity is variable.13Gibson P.G. Henry R.L. Coughlan J.L. Gastro-oesophageal reflux treatment for asthma in adults and children.Cochrane Database Syst Rev. 2003; (CD001496)Google Scholar Certainly significant hyperinflation and drugs such as steroids and theophylline can also contribute to the development of gastroesophageal reflux disease. Obesity is increasingly prevalent and has been associated with severe asthma in some studies.14Weiss S.T. Shore S. Obesity and asthma: directions for research.Am J Respir Crit Care Med. 2004; 169: 963-968Crossref PubMed Google Scholar One study showed that weight reduction is associated with better asthma control and a reduction in asthma severity.15Ford E.S. The epidemiology of obesity and asthma.J Allergy Clin Immunol. 2005; 115 (quiz 10): 897-909Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar The correlation between obesity and severe asthma seems to be more obvious in women, and hormonal influences may be involved.16Hancox R.J. Milne B.J. Poulton R. Taylor D.R. Greene J.M. McLachlan C.R. et al.Sex differences in the relation between body mass index and asthma and atopy in a birth cohort.Am J Respir Crit Care Med. 2005; 171: 440-445Crossref PubMed Scopus (146) Google Scholar, 17Saint-Pierre P. Bourdin A. Chanez P. Daures J.P. Godard P. Are overweight asthmatics more difficult to control?.Allergy. 2006; 61: 79-84PubMed Google Scholar Sleep apnea syndrome can be associated with asthma, although its influence on asthma severity remains to be fully established. Premenstrual worsening of asthma symptoms has been reported in up to 40% of female patients with asthma, but severe premenstrual exacerbations are rare and characterized by an impaired response to systemic corticosteroid and inhaled β2-agonists.18Tan K.S. Premenstrual asthma: epidemiology, pathogenesis and treatment.Drugs. 2001; 61: 2079-2086Crossref PubMed Google Scholar Adherence is often suboptimal in asthma.19Lacasse Y. Archibald H. Ernst P. Boulet L.P. Patterns and determinants of compliance with inhaled steroids in adults with asthma.Can Respir J. 2005; 12: 211-217PubMed Google Scholar In children and adolescents, poor asthma control has been associated with insufficient corticosteroid treatment adherence. Adherence is a critical issue, but how to best assess and manage poor adherence remains a significant challenge. Additionally, poor adherence is not specific to severe asthma, with some studies suggesting adherence increases with increasing severity of disease.20Moser M. Cushman W. Handler J. Resistant or difficult-to-treat hypertension.J Clin Hypertens (Greenwich). 2006; 8: 434-440Crossref PubMed Scopus (9) Google Scholar Depression, anxiety, and behavioral problems may be detrimental to asthma control but also may be a consequence of it. No clear psychological profile is associated with severe asthma.21ten Brinke A. Ouwerkerk M.E. Bel E.H. Spinhoven P. Similar psychological characteristics in mild and severe asthma.J Psychosom Res. 2001; 50: 7-10Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Most associated factors suspected clinically can be confirmed as part of the routine investigation of severe asthma. However, the specific utility varies from patient to patient. The use of a range of objective outcome measures in the follow-up assessment of severe asthma is important. It is recommended that validated health status and asthma control questionnaires, lung function, assessment of airway inflammation, and history of exacerbations be recorded regularly during follow-up. Traditionally, spirometric measures have been the cardinal outcomes in severe asthma. Although these measures are of value, using these measures exclusively may miss other important aspects of the disease. Therefore, it is of paramount importance that multiple objective independent outcomes are assessed that capture a spectrum of the facets of severe asthma, including health status, disease control, exacerbations, airway inflammation, and lung function.22Schatz M. Mosen D. Apter A.J. Zeiger R.S. Vollmer W.M. Stibolt T.B. et al.Relationships among quality of life, severity, and control measures in asthma: an evaluation using factor analysis.J Allergy Clin Immunol. 2005; 115: 1049-1055Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Several composite objective health status/asthma control assessment questionnaires are now available that attempt to incorporate a range of these factors.23Juniper E.F. O'Byrne P.M. Guyatt G.H. Ferrie P.J. King D.R. Development and validation of a questionnaire to measure asthma control.Eur Respir J. 1999; 14: 902-907Crossref PubMed Scopus (836) Google Scholar Their use is encouraged. Asthma exacerbations are important outcomes in terms of their impact on the lives of patients and society. The most objective measures of exacerbations are need for OCS use, hospital admission, and episodes of life-threatening asthma. Noninvasive measures of airway inflammation include assessment of sputum cell counts and supernatants, exhaled nitric oxide (FENO), and breath condensates for pH and isoprostanes. In 2 large prospective studies, therapy directed at normalizing sputum eosinophil counts markedly reduced asthma exacerbations.24Green R.H. Brightling C.E. McKenna S. Hargadon B. Parker D. Bradding P. et al.Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.Lancet. 2002; 360: 1715-1721Abstract Full Text Full Text PDF PubMed Scopus (850) Google Scholar, 25Jayaram L. Pizzichini M.M. Cook R.J. Boulet L.P. Lemiere C. Pizzichini E. et al.Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations.Eur Respir J. 2006; 27: 483-494Crossref PubMed Scopus (273) Google Scholar Both of these studies included severe asthma patients, and the greatest benefit was observed in them.25Jayaram L. Pizzichini M.M. Cook R.J. Boulet L.P. Lemiere C. Pizzichini E. et al.Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations.Eur Respir J. 2006; 27: 483-494Crossref PubMed Scopus (273) Google Scholar Strategies that have incorporated measures of FeNO have not led to a reduction in asthma exacerbations in adults26Smith A.D. Cowan J.O. Brassett K.P. Herbison G.P. Taylor D.R. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma.N Engl J Med. 2005; 352: 2163-2173Crossref PubMed Scopus (619) Google Scholar or children,27Pijnenburg M.W. Bakker E.M. Hop W.C. De Jongste J.C. Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial.Am J Respir Crit Care Med. 2005; 172: 831-836Crossref PubMed Scopus (235) Google Scholar although these studies were performed in patients with milder disease. Thus, to date, sputum induction is the most robust measure of airway inflammation in asthma, but simpler assessment tools are needed. In addition to basic spirometric measures, assessment of small airway function, including dynamic hyperinflation, and inflammation may be valuable as there is increasing recognition that small airways are involved in severe asthma.28van Veen I.H. Sterk P.J. Schot R. Gauw S.A. Rabe K.F. Bel E.H. Alveolar nitric oxide versus measures of peripheral airway dysfunction in severe asthma.Eur Respir J. 2006; 27: 951-956PubMed Google Scholar Assessing asthma severity long term using objective lung function parameters also validates the diagnosis of severe asthma and enables an assessment of progression of disease over time. Severe asthma is a heterogeneous condition, which includes several different phenotypes. Phenotyping severe asthma will improve our understanding of underlying mechanisms, natural history, and prognosis; help to guide current and possibly future treatment; and provide clues for novel therapeutic interventions. Severe asthma is not one disease but a multifaceted condition that can be subdivided into different phenotypes. They can be classified using several features of the disease, including symptoms, health status, asthma control, airway obstruction (variable or partially fixed), bronchial hyperresponsiveness (BHR), atopy, inflammation, exacerbations, and response to treatment. This approach led to the recognition of several important clinical phenotypes: frequent exacerbators including near-fatal episodes, those with irreversible airway obstruction, and those with OCS dependency or resistance.1Bel E.H. Clinical phenotypes of asthma.Curr Opin Pulm Med. 2004; 10: 44-50Crossref PubMed Google Scholar Other features, such as date of onset of the symptoms, or triggers, such as aspirin sensitivity, may represent interesting additional phenotypes. Assessment of airway inflammation led to the identification of eosinophilic, neutrophilic, and paucigranulocytic asthma.29Green R.H. Brightling C.E. Woltmann G. Parker D. Wardlaw A.J. Pavord I.D. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids.Thorax. 2002; 57: 875-879Crossref PubMed Scopus (337) Google Scholar, 30Wenzel S. Severe asthma: epidemiology, pathophysiology and treatment.Mt Sinai J Med. 2003; 70: 185-190PubMed Google Scholar Phenotyping severe asthma can help to guide current therapy (sputum eosinophilia often predicts a favorable response to corticosteroid24Green R.H. Brightling C.E. McKenna S. Hargadon B. Parker D. Bradding P. et al.Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.Lancet. 2002; 360: 1715-1721Abstract Full Text Full Text PDF PubMed Scopus (850) Google Scholar, 25Jayaram L. Pizzichini M.M. Cook R.J. Boulet L.P. Lemiere C. Pizzichini E. et al.Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations.Eur Respir J. 2006; 27: 483-494Crossref PubMed Scopus (273) Google Scholar, 31ten Brinke A. Zwinderman A.H. Sterk P.J. Rabe K.F. Bel E.H. “Refractory” eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids.Am J Respir Crit Care Med. 2004; 170: 601-605Crossref PubMed Scopus (130) Google Scholar), to aid in understanding pathophysiology and natural history, as well as to better link genotype to disease. It is likely that categorizing patients into dichotomous groups will not reflect the true complexity of the disease. Alternatively, asthma phenotypes can be determined using complex statistical approaches such as cluster or factor analysis that use multiple parameters to describe multidimensional phenotypes.22Schatz M. Mosen D. Apter A.J. Zeiger R.S. Vollmer W.M. Stibolt T.B. et al.Relationships among quality of life, severity, and control measures in asthma: an evaluation using factor analysis.J Allergy Clin Immunol. 2005; 115: 1049-1055Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar The advent of new technologies to better image the lungs and measure multiple inflammatory markers and genetic polymorphisms enables us to use complex statistical models to better identify severe asthma phenotypes. The power to phenotype severe asthma will be further increased by establishing severe asthma networks, such as The European Network for Understanding Mechanisms of Severe Asthma (ENFUMOSA)6ENFUMOSA Study GroupThe ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma.Eur Respir J. 2003; 22: 470-477Crossref PubMed Scopus (359) Google Scholar and the National Heart, Lung, and Blood Institute network, which allow detailed characterization of hundreds of patients. 1.What is the actual prevalence of severe asthma and its various phenotypes?2.Will phenotypic markers for severe asthma, for example, biomarkers of airway inflammation or tests for small airway function, allow better distinction of subgroups?3.How well does treatment of comorbidities lessen asthma severity?4.How can complex statistical models be used to create simpler clinical algorithms to improve our ability to phenotype severe asthma? Severe asthma is associated with an increased risk of hospitalization and death. Severe asthma in children but not in adults is associated with increased IgE. Female gender, obesity, and smoking are associated with more severe asthma and a poor response to therapy. Few studies have attempted to quantify the prevalence of severe asthma, in large part because of variation between clinical and epidemiological definitions.30Wenzel S. Severe asthma: epidemiology, pathophysiology and treatment.Mt Sinai J Med. 2003; 70: 185-190PubMed Google Scholar However, it is estimated that 5% to 10% of the population with asthma has symptomatic disease despite maximum recommended treatment with combinations of anti-inflammatory and bronchodilator drugs. This group accounts for up to 50% of the total health costs through hospital admissions, use of emergency services, and unscheduled physician visits.32Godard P. Chanez P. Siraudin L. Nicoloyannis N. Duru G. Costs of asthma are correlated with severity: a 1-yr prospective study.Eur Respir J. 2002; 19: 61-67Crossref PubMed Google Scholar Although severe asthma is a major risk factor for hospital admissions and death, studies are needed to determine how much of this is from inadequate treatment versus refractoriness to therapy. Tobacco smoking in particular contributes to greater symptoms, increased fixed airflow limitation (in most but not all studies,9de Marco R. Marcon A. Jarvis D. Accordini S. Almar E. Bugiani M. et al.Prognostic factors of asthma severity: a 9-year international prospective cohort study.J Allergy Clin Immunol. 2006; 117: 1249-1256Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar with an accelerated decline over time), and resistance to corticosteroid.33Adcock I.M. Ito K. Barnes P.J. Glucocorticoids: effects on gene transcription.Proc Am Thorac Soc. 2004; 1: 247-254Crossref PubMed Google Scholar Other risk factors in adults include female gender with links to the menarche, menstrual cycle, pregnancy hormone genetics, and obesity.6ENFUMOSA Study GroupThe ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma.Eur Respir J. 2003; 22: 470-477Crossref PubMed Scopus (359) Google Scholar Available evidence, all based on studies before the widespread adoption of inhaled steroid therapy, suggests that severity is often determined early in life and that severity grade is not usually a progression from mild-to-severe disease over time. In children, a strong association exists among total serum IgE, atopy, and severe asthma. Childhood atopy is a risk for severe asthma in adults, but the relationship weakens possibly because of the greater proportion of patients with late-onset nonallergy asthma in this group and the increasing complexity of the disease.34Miranda C. Busacker A. Balzar S. Trudeau J. Wenzel S.E. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation.J Allergy Clin Immunol. 2004; 113: 101-108Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar Emerging evidence suggests genetic factors play a role in asthma severity. Partial phenotypes (BHR, IgE, decline in lung function) have proven useful in genetic studies of severe asthma. Genes by environment interactions are likely to be of critical importance in the development of severe asthma (extract tobacco smoke, LPS). Overwhelming evidence exists for the importance of genetic factors in a disease where heritability is reported to be as high as 70%. However, relatively little attention has been paid to identifying genetic factors that influence disease severity or outcomes. ADAM33 is one gene for which association with asthma relates to both the severity of BHR and the decline in lung function.35Jongepier H. Boezen H.M. Dijkstra A. Howard T.D. Vonk J.M. Koppelman G.H. et al.Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma.Clin Exp Allergy. 2004; 34: 757-760Crossref PubMed Scopus (126) Google Scholar, 36Lee J.Y. Park S.W. Chang H.K. Kim H.Y. Rhim T. Lee J.H. et al.A disintegrin and metalloproteinase 33 protein in patients with asthma: relevance to airflow limitation.Am J Respir Crit Care Med. 2006; 173: 729-735Crossref PubMed Scopus (62) Google Scholar In addition, polymorphisms in TGF-ß1, IL-4, and IL-4Rα have all been independently replicated and associated with lower FEV1 and, for IL-4 and IL-4Rα, with severe exacerbations.37Pulleyn L.J. Newton R. Adcock I.M. Barnes P.J. TGFbeta1 allele association with asthma severity.Hum Genet. 2001;" @default.
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• W2006174105 title "Severe asthma in adults: What are the important questions?" @default.
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