Severe Asthma in Children
2014; Elsevier BV; Volume: 2; Issue: 5 Linguagem: Inglês
10.1016/j.jaip.2014.06.022
ISSN2213-2201
AutoresTheresa W. Guilbert, Leonard B. Bacharier, Anne M. Fitzpatrick,
Tópico(s)Inhalation and Respiratory Drug Delivery
ResumoSevere asthma in children is characterized by sustained symptoms despite treatment with high doses of inhaled corticosteroids or oral corticosteroids. Children with severe asthma may fall into 2 categories, difficult-to-treat asthma or severe therapy-resistant asthma. Difficult-to-treat asthma is defined as poor control due to an incorrect diagnosis or comorbidities, or poor adherence due to adverse psychological or environmental factors. In contrast, treatment resistant is defined as difficult asthma despite management of these factors. It is increasingly recognized that severe asthma is a highly heterogeneous disorder associated with a number of clinical and inflammatory phenotypes that have been described in children with severe asthma. Guideline-based drug therapy of severe childhood asthma is based primarily on extrapolated data from adult studies. The recommendation is that children with severe asthma be treated with higher-dose inhaled or oral corticosteroids combined with long-acting β-agonists and other add-on therapies, such as antileukotrienes and methylxanthines. It is important to identify and address the influences that make asthma difficult to control, including reviewing the diagnosis and removing causal or aggravating factors. Better definition of the phenotypes and better targeting of therapy based upon individual patient phenotypes is likely to improve asthma treatment in the future. Severe asthma in children is characterized by sustained symptoms despite treatment with high doses of inhaled corticosteroids or oral corticosteroids. Children with severe asthma may fall into 2 categories, difficult-to-treat asthma or severe therapy-resistant asthma. Difficult-to-treat asthma is defined as poor control due to an incorrect diagnosis or comorbidities, or poor adherence due to adverse psychological or environmental factors. In contrast, treatment resistant is defined as difficult asthma despite management of these factors. It is increasingly recognized that severe asthma is a highly heterogeneous disorder associated with a number of clinical and inflammatory phenotypes that have been described in children with severe asthma. Guideline-based drug therapy of severe childhood asthma is based primarily on extrapolated data from adult studies. The recommendation is that children with severe asthma be treated with higher-dose inhaled or oral corticosteroids combined with long-acting β-agonists and other add-on therapies, such as antileukotrienes and methylxanthines. It is important to identify and address the influences that make asthma difficult to control, including reviewing the diagnosis and removing causal or aggravating factors. Better definition of the phenotypes and better targeting of therapy based upon individual patient phenotypes is likely to improve asthma treatment in the future. INFORMATION FOR CATEGORY 1 CME CREDITCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The accompanying tests may only be submitted online at www.jaci-inpractice.org/. Fax or other copies will not be accepted.Date of Original Release: September 2014. Credit may be obtained for these courses until October 31, 2015.Copyright Statement: Copyright 2014-2016. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Theresa W. Guilbert, MD, MS, Leonard B. Bacharier, MD, and Anne M. Fitzpatrick, CPNP, PhDActivity Objectives1.To identify how severe asthma in children is defined and how it differs from adults2.To discuss how to evaluate a child with this disease and consider important comorbidities and other conditions that can have similar symptoms3.To consider evidence-based management of a child with severe asthmaRecognition of Commercial Support: This CME has not received external commercial support.Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: T. Guilbert is on the American Board of Pediatrics and the Pediatric Pulmonary Subboard; has received consultancy fees from Teva, GlaxoSmithKline, and Regeneron Pharmaceuticals; has received research support from the Centers for Disease Control, Department of Health and Human Services (DHHS FAB 20166; T72 MC00008-20-00), National Institutes of Health (NIH), University of Wisconsin Madison Medical and Education Research Committee, Teva, GlaxoSmithKline/Development Limited, CF Foundation Therapeutics, Roche/Genentech, and the NIH; receives royalties from UpToDate; and has received payment for development of educational presentations from Teva. L. B. Bacharier has received consultancy fees from Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Schering, Cephalon, and DBV Technologies; has received research support from the National Heart, Lung, and Blood Institute (NHLBI)/NIH AsthmaNet (NHLBI U10 HL098090; U10 HL109168; P01 HL070831); has received lecture fees from Aerocrine, AstraZeneca, Genentech/Novartis, GlaxoSmithKline, Merck, and Schering. A. M. Fitzpatrick has received research support from the NIH, NHLBI (R01 NR012021) and National Institute of Nursing Research (R01 NR013700); has received consultancy fees from MedImmune, Merck Scientific Advisory Board, GlaxoSmithKline Advisory Board, Genentech, and Boehringer Ingelheim. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The accompanying tests may only be submitted online at www.jaci-inpractice.org/. Fax or other copies will not be accepted. Date of Original Release: September 2014. Credit may be obtained for these courses until October 31, 2015. Copyright Statement: Copyright 2014-2016. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Theresa W. Guilbert, MD, MS, Leonard B. Bacharier, MD, and Anne M. Fitzpatrick, CPNP, PhD Activity Objectives1.To identify how severe asthma in children is defined and how it differs from adults2.To discuss how to evaluate a child with this disease and consider important comorbidities and other conditions that can have similar symptoms3.To consider evidence-based management of a child with severe asthma Recognition of Commercial Support: This CME has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: T. Guilbert is on the American Board of Pediatrics and the Pediatric Pulmonary Subboard; has received consultancy fees from Teva, GlaxoSmithKline, and Regeneron Pharmaceuticals; has received research support from the Centers for Disease Control, Department of Health and Human Services (DHHS FAB 20166; T72 MC00008-20-00), National Institutes of Health (NIH), University of Wisconsin Madison Medical and Education Research Committee, Teva, GlaxoSmithKline/Development Limited, CF Foundation Therapeutics, Roche/Genentech, and the NIH; receives royalties from UpToDate; and has received payment for development of educational presentations from Teva. L. B. Bacharier has received consultancy fees from Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Schering, Cephalon, and DBV Technologies; has received research support from the National Heart, Lung, and Blood Institute (NHLBI)/NIH AsthmaNet (NHLBI U10 HL098090; U10 HL109168; P01 HL070831); has received lecture fees from Aerocrine, AstraZeneca, Genentech/Novartis, GlaxoSmithKline, Merck, and Schering. A. M. Fitzpatrick has received research support from the NIH, NHLBI (R01 NR012021) and National Institute of Nursing Research (R01 NR013700); has received consultancy fees from MedImmune, Merck Scientific Advisory Board, GlaxoSmithKline Advisory Board, Genentech, and Boehringer Ingelheim. Asthma is the most common chronic lung disease of childhood, which affects >6.6 million children in the United States.1Centers for Disease Control and Prevention (CDC)Vital signs: asthma prevalence, disease characteristics, and self-management education: United States, 2001–2009.MMWR Morb Mortal Wkly Rep. 2011; 60: 547-552PubMed Google Scholar Most children with asthma achieve good symptom control when treated with low-to-medium doses (<500 mcg/d fluticasone equivalents) of inhaled corticosteroids (ICS). However, severe asthma in children is characterized by sustained symptoms despite treatment with high doses of ICS or oral corticosteroids2Bossley C.J. Saglani S. Kavanagh C. Payne D.N. Wilson N. Tsartsali L. et al.Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma.Eur Respir J. 2009; 34: 1052-1059Crossref PubMed Scopus (38) Google Scholar, 3Fitzpatrick A.M. Gaston B.M. Erzurum S.C. Teague W.G. Features of severe asthma in school-age children: atopy and increased exhaled nitric oxide.J Allergy Clin Immunol. 2006; 118: 1218-1225Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar and represents approximately 5% of childhood asthma cases.4Lang A. Carlsen K.H. Haaland G. Devulapalli C.S. Munthe-Kaas M. Mowinckel P. et al.Severe asthma in childhood: assessed in 10 year olds in a birth cohort study.Allergy. 2008; 63: 1054-1060Crossref PubMed Scopus (38) Google Scholar Although this form of asthma is the least common, it accounts for nearly 50% of all asthma-related expenditures.5Godard 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, 6Smith D.H. Malone D.C. Lawson K.A. Okamoto L.J. Battista C. Saunders W.B. A national estimate of the economic costs of asthma.Am J Respir Crit Care Med. 1997; 156: 787-793Crossref PubMed Google Scholar It has been suggested that children with severe asthma may fall into 2 categories, difficult-to-treat asthma or severe therapy-resistant asthma. Difficult-to-treat asthma is defined as poor control due to an incorrect diagnosis or comorbidities or poor adherence due to adverse psychological or environmental factors. In contrast, treatment resistant is defined as difficult asthma despite management of these factors.7Bush A. Hedlin G. Carlsen K.H. de Benedictis F. Lodrup-Carlsen K. Wilson N. Severe childhood asthma: a common international approach?.Lancet. 2008; 372: 1019-1021Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Analysis of data indicates that children with severe asthma begin to demonstrate symptoms early in life and that the majority have atopy and reversible airway obstruction.8Fitzpatrick A.M. Teague W.G. Severe asthma in children: insights from the National Heart, Lung, and Blood Institute's Severe Asthma Research Program.Pediatr Allergy Immunol Pulmonol. 2010; 23: 131-138Crossref PubMed Scopus (15) Google Scholar, 9Paton J.Y. Severe asthma in children. Symposium: Respiratory Medicine.Paediatr Child Health. 2007; 17: 180-187Abstract Full Text Full Text PDF Scopus (2) Google Scholar Although these data have helped define the scope of this disease in children, there are numerous questions left unanswered. This review will focus on severe asthma in school-age children (range, 5-17 years), from definition to management. Extrapolating adult severity classifications to children is difficult for a number of reasons. Adults with asthma are more likely to exhibit a persistent pattern, whereas children may have a pattern of rapidly evolving, frequent, and often severe exacerbations. Children have severe exacerbations triggered by viral infections and/or allergen exposure that can result in health care utilization but then often remain asymptomatic between these episodes.10Galant S.P. Morphew T. Amaro S. Liao O. Current asthma guidelines may not identify young children who have experienced significant morbidity.Pediatrics. 2006; 117: 1038-1045Crossref PubMed Scopus (19) Google Scholar, 11Gelfand E.W. Kraft M. The importance and features of the distal airways in children and adults.J Allergy Clin Immunol. 2009; 124: S84-S87Abstract Full Text Full Text PDF PubMed Google Scholar Phenotypes of severe asthma in children differ from those of adults and change more rapidly. It, therefore, is necessary to reassess phenotypes at regular intervals. Responses to medications12Drazen J.M. O'Byrne P.M. Risks of long-acting beta-agonists in achieving asthma control.N Engl J Med. 2009; 360: 1671-1672Crossref PubMed Scopus (59) Google Scholar and the more pronounced growth and bone maturation adverse effects of ICS13Bacharier L.B. Boner A. Carlsen K.H. Eigenmann P.A. Frischer T. Gotz M. et al.Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report.Allergy. 2008; 63: 5-34Crossref PubMed Scopus (312) Google Scholar also differ between childhood and adult asthma. Lung function measurements also show different patterns, are age-dependent, and may be within normal limits despite significant symptom burden and medication use.14Jenkins H.A. Cherniack R. Szefler S.J. Covar R. Gelfand E.W. Spahn J.D. A comparison of the clinical characteristics of children and adults with severe asthma.Chest. 2003; 124: 1318-1324Crossref PubMed Scopus (77) Google Scholar, 15Bacharier L.B. Strunk R.C. Mauger D. White D. Lemanske Jr., R.F. Sorkness C.A. Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function.Am J Respir Crit Care Med. 2004; 170: 426-432Crossref PubMed Scopus (188) Google Scholar, 16Spahn J.D. Cherniack R. Paull K. Gelfand E.W. Is forced expiratory volume in one second the best measure of severity in childhood asthma?.Am J Respir Crit Care Med. 2004; 169: 784-786Crossref PubMed Google Scholar The distal airways are more affected, and increased distal lung resistance, in the absence of significant large airway involvement, likely explains the often unimpaired FEV1 values.17Hogg J.C. Macklem P.T. Thurlbeck W.M. Site and nature of airway obstruction in chronic obstructive lung disease.N Engl J Med. 1968; 278: 1355-1360Crossref PubMed Google Scholar Furthermore, other measures of lung function, such as FEV1 per forced vital capacity, forced expiratory flow at 25% to 75% of forced vital capacity predicted, or the degree of airway responsiveness to bronchodilators may relate better to asthma severity.15Bacharier L.B. Strunk R.C. Mauger D. White D. Lemanske Jr., R.F. Sorkness C.A. Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function.Am J Respir Crit Care Med. 2004; 170: 426-432Crossref PubMed Scopus (188) Google Scholar Children, particularly boys, demonstrate more hyperinflation with increased residual volume and total lung capacity.18Spahn J.D. Covar R.A. Jain N. Gleason M. Shimamoto R. Szefler S.J. et al.Effect of montelukast on peripheral airflow obstruction in children with asthma.Ann Allergy Asthma Immunol. 2006; 96: 541-549Abstract Full Text PDF PubMed Google Scholar Girls with severe asthma also exhibit some air-trapping and airflow limitation during bronchodilator abstinence but to a lesser magnitude than seen with boys, and this finding is generally reversible with bronchodilation.19Sorkness R.L. Teague W.G. Penugonda M. Fitzpatrick A.M. Sex dependence of airflow limitation and air trapping in children with severe asthma.J Allergy Clin Immunol. 2011; 127: 1073-1074Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Results of epidemiology studies indicate that children with atopic asthma have a slow decline in lung function over time.14Jenkins H.A. Cherniack R. Szefler S.J. Covar R. Gelfand E.W. Spahn J.D. A comparison of the clinical characteristics of children and adults with severe asthma.Chest. 2003; 124: 1318-1324Crossref PubMed Scopus (77) Google Scholar, 20Martinez F.D. Wright A.L. Taussig L.M. Holberg C.J. Halonen M. Morgan W.J. Asthma and wheezing in the first six years of life. The Group Health Medical Associates.N Engl J Med. 1995; 332: 133-138Crossref PubMed Scopus (2328) Google Scholar, 21Strunk R.C. Weiss S.T. Yates K.P. Tonascia J. Zeiger R.S. Szefler S.J. Mild to moderate asthma affects lung growth in children and adolescents.J Allergy Clin Immunol. 2006; 118: 1040-1047Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar This decline in lung function may be accelerated in children with severe asthma. Children with severe asthma typically are more atopic, with higher serum IgE levels and demonstrate reversible airway obstruction compared with their adult counterparts. Children with severe asthma are differentiated by higher exhaled nitric oxide (FENO), higher IgE and eosinophil levels, and differential patterns of sensitization to aeroallergens, especially molds.3Fitzpatrick A.M. Gaston B.M. Erzurum S.C. Teague W.G. Features of severe asthma in school-age children: atopy and increased exhaled nitric oxide.J Allergy Clin Immunol. 2006; 118: 1218-1225Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar Severe asthma may be due to underlying severity of the disease from persistent airway inflammation and relative corticosteroid insensitivity,22Bhavsar P. Hew M. Khorasani N. Torrego A. Barnes P.J. Adcock I. et al.Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma.Thorax. 2008; 63: 784-790Crossref PubMed Scopus (103) Google Scholar, 23Hew M. Bhavsar P. Torrego A. Meah S. Khorasani N. 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Spinhoven P. Bel E.H. Psychopathology in patients with severe asthma is associated with increased health care utilization.Am J Respir Crit Care Med. 2001; 163: 1093-1096Crossref PubMed Google Scholar Adolescents are at an increased risk of a higher prevalence of severe asthma and death from asthma due to reduced adherence to treatment and increased risk-taking behaviors (smoking, illicit drug use). Poor adherence also is associated with complex treatment regimens, familial strain, inadequate supervision of the child, and possible secondary gains linked to poorly controlled asthma.27Chung 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 (21) Google Scholar Poor asthma control may be due to the child's clinician failing to use evidence-based asthma treatment guidelines or failure to adequately assess a child's symptom burden.28Baker K.M. Brand D.A. Hen Jr., J. Classifying asthma: disagreement among specialists.Chest. 2003; 124: 2156-2163Crossref PubMed Scopus (47) Google Scholar Finally, children can have comorbid conditions, such as sinusitis and vocal cord dysfunction, that may exacerbate or mimic asthma but will not respond to asthma treatment.9Paton J.Y. Severe asthma in children. Symposium: Respiratory Medicine.Paediatr Child Health. 2007; 17: 180-187Abstract Full Text Full Text PDF Scopus (2) Google Scholar Epidemiologic studies have described risk factors for severe asthma and airway hyperresponsiveness. Many children with severe asthma present when school age (range, 6-11 years); however, they report the onset of asthma symptoms earlier in childhood (first 3 years of life) than children with mild-to-moderate asthma (5 years mean).3Fitzpatrick A.M. Gaston B.M. Erzurum S.C. Teague W.G. Features of severe asthma in school-age children: atopy and increased exhaled nitric oxide.J Allergy Clin Immunol. 2006; 118: 1218-1225Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 29Stern D.A. Morgan W.J. Halonen M. Wright A.L. Martinez F.D. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study.Lancet. 2008; 372: 1058-1064Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar Another risk factor for asthma and severe airway hyperresponsiveness may be lower lung function present shortly after birth. Infants with the lowest pulmonary function (fraction of expiratory time to peak tidal expiratory flow) had a higher risk of current asthma and severe airway hyperresponsiveness at 10 years of age30Haland G. Carlsen K.C. Sandvik L. Devulapalli C.S. Munthe-Kaas M.C. Pettersen M. et al.Reduced lung function at birth and the risk of asthma at 10 years of age.N Engl J Med. 2006; 355: 1682-1689Crossref PubMed Scopus (144) Google Scholar and increased airway obstruction on lung function testing at 22 years of age31Stern D.A. Morgan W.J. Wright A.L. Guerra S. Martinez F.D. Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study.Lancet. 2007; 370: 758-764Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar compared with infants with higher lung function. Children with severe asthma also had increased airway obstruction and air trapping.2Bossley C.J. Saglani S. Kavanagh C. Payne D.N. Wilson N. 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Comparison of asthma exacerbations in pediatric and adult patients with severe or difficult-to-treat asthma.J Allergy Clin Immunol. 2009; 124: 1106-1108Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Moreover, children with airway hyperresponsiveness at 9 years of age were 3 times more likely to develop functional abnormalities (low postbronchodilator FEV1/vital capacity ratio) in adolescence and early adulthood, which may reflect underlying structural airway remodeling.35Rasmussen F. Taylor D.R. Flannery E.M. Cowan J.O. Greene J.M. Herbison G.P. et al.Risk factors for airway remodeling in asthma manifested by a low postbronchodilator FEV1/vital capacity ratio: a longitudinal population study from childhood to adulthood.Am J Respir Crit Care Med. 2002; 165: 1480-1488Crossref PubMed Scopus (169) Google Scholar In one longitudinal cohort study, subsets of children with asthma demonstrated decline in lung function over time.36The Childhood Asthma Management Program Research GroupLong-term effects of budesonide or nedocromil in children with asthma.N Engl J Med. 2000; 343: 1054-1063Crossref PubMed Scopus (979) Google Scholar In school-age and adolescent children, those with severe asthma were more likely to have increased allergic sensitization (serum IgE), more aeroallergen skin prick test responses early in life, a higher prevalence of atopic dermatitis, greater bronchial hyperresponsiveness, airway obstruction, and higher FENO, and to report being of African American or more than 1 race than children with milder disease.3Fitzpatrick A.M. Gaston B.M. Erzurum S.C. Teague W.G. Features of severe asthma in school-age children: atopy and increased exhaled nitric oxide.J Allergy Clin Immunol. 2006; 118: 1218-1225Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 6Smith D.H. Malone D.C. Lawson K.A. Okamoto L.J. Battista C. Saunders W.B. A national estimate of the economic costs of asthma.Am J Respir Crit Care Med. 1997; 156: 787-793Crossref PubMed Google Scholar, 20Martinez F.D. Wright A.L. Taussig L.M. Holberg C.J. Halonen M. Morgan W.J. Asthma and wheezing in the first six years of life. The Group Health Medical Associates.N Engl J Med. 1995; 332: 133-138Crossref PubMed Scopus (2328) Google Scholar, 29Stern D.A. Morgan W.J. Halonen M. Wright A.L. Martinez F.D. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study.Lancet. 2008; 372: 1058-1064Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 35Rasmussen F. Taylor D.R. Flannery E.M. Cowan J.O. Greene J.M. Herbison G.P. et al.Risk factors for airway remodeling in asthma manifested by a low postbronchodilator FEV1/vital capacity ratio: a longitudinal population study from childhood to adulthood.Am J Respir Crit Care Med. 2002; 165: 1480-1488Crossref PubMed Scopus (169) Google Scholar, 37Covar R.A. Strunk R. Zeiger R.S. Wilson L.A. Liu A.H. Weiss S. et al.Predictors of remitting, periodic, and persistent childhood asthma.J Allergy Clin Immunol. 2010; 125: 359-366.e3Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 38Spycher B.D. Silverman M. Brooke A.M. Minder C.E. Kuehni C.E. Distinguishing phenotypes of childhood wheeze and cough using latent class analysis.Eur Respir J. 2008; 31: 974-981Crossref PubMed Scopus (73) Google Scholar Although several definitions of "severe asthma" have been proposed, no single definition has gained universal acceptance due to the complex nature of the disease and the lack of validated criterion standards for diagnosis. To further complicate matters, "asthma" itself is a highly heterogeneous condition that remains poorly understood in children. In a recent review of large cohorts of school-age children with asthma, 122 publications yielded 60 different operational definitions of asthma, which greatly impacted prevalence and clinical outcome assessments.39Van Wonderen K.E. Van Der Mark L.B. Mohrs J. Bindels P.J. Van Aalderen W.M. Ter Riet G. Different definitions in childhood asthma: how dependable is the dependent variable?.Eur Respir J. 2010; 36: 48-56Crossref PubMed Scopus (21) Google Scholar Nonetheless, the traditional views of asthma as proposed by both the National Asthma Education and Prevention Program40National Asthma Education and Prevention ProgramExpert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma: Clinical Practice Guidelines. NIH/National Heart, Lung, and Blood Institute, Bethesda, Md2007Google Scholar and past versions of the Global Initiative on Asthma41Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA) 2006. Available from: http://www.ginasthma.org. Accessed June 25, 2014.Google Scholar assume that (1) asthma is a single disease entity with a spectrum of inflammation, (2) there is concordance between inflammation and symptoms, and (3) the nature of inflammation is responsive to corticosteroid treatment. According to these guidelines, severe asthma corresponds to the "top" of the disease spectrum and, therefore, is thought to be associated with a high degree of airway inflammation and resulting symptoms. Thus, the proposed definitions of severe asthma are based on symptom burden, short-acting β-agonist use, the limitation of activities, frequency and severity of exacerbations, and lung function (Table I). Howe
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