Progressive airflow limitation is a feature of children with severe asthma
2011; Elsevier BV; Volume: 127; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2010.10.036
ISSN1097-6825
AutoresAnne M. Fitzpatrick, W. Gerald Teague,
Tópico(s)Inhalation and Respiratory Drug Delivery
ResumoTo the Editor:Severe asthma in children is a heterogeneous disorder associated with extreme morbidity despite treatment with high doses of inhaled corticosteroids (ICSs). We previously reported the phenotypic features of children with mild-to-moderate and severe asthma (mean age, 10 years) enrolled in the National Heart, Lung, and Blood Institute's (NHLBI) Severe Asthma Research Program (SARP) at Emory University.1Fitzpatrick 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 (179) Google ScholarSimilar to adults with severe asthma,2Moore W.C. Bleecker E.R. Curran-Everett D. Erzurum S.C. Ameredes B.T. Bacharier L. et al.Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program.J Allergy Clin Immunol. 2007; 119: 405-413Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar children with severe asthma were characterized by baseline airflow limitation that was not completely reversed with bronchodilation.1Fitzpatrick 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 (179) Google Scholar However, the magnitude of airflow limitation was significantly less in children with severe asthma (FEV1, 81% of predicted value; FEV1/forced vital capacity [FVC] ratio, 0.74) compared with that seen in adults (FEV1, 62% of predicted value; FEV1/FVC ratio, 0.65).2Moore W.C. Bleecker E.R. Curran-Everett D. Erzurum S.C. Ameredes B.T. Bacharier L. et al.Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program.J Allergy Clin Immunol. 2007; 119: 405-413Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar These findings raise important questions about the stability of the severe asthma phenotype in children and the critical developmental time frame during which loss of lung function occurs. Although the answers to these questions are not entirely clear, longitudinal studies have shown that children with more severe, frequent symptoms have ongoing airflow limitation and more severe asthma throughout adulthood.3Wolfe R. Carlin J.B. Oswald H. Olinsky A. Phelan P.D. Robertson C.F. Association between allergy and asthma from childhood to middle adulthood in an Australian cohort study.Am J Respir Crit Care Med. 2000; 162: 2177-2181Crossref PubMed Scopus (53) Google Scholar, 4Rasmussen 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 (225) Google Scholar, 5Sears M.R. Greene J.M. Willan A.R. Wiecek E.M. Taylor D.R. Flannery E.M. et al.A longitudinal, population-based, cohort study of childhood asthma followed to adulthood.N Engl J Med. 2003; 349: 1414-1422Crossref PubMed Scopus (1027) Google Scholar Using longitudinal follow-up data from children previously characterized in the NHLBI’s SARP, we report that children with severe asthma have a premature loss of lung function during the adolescent years that is associated with an increased frequency of wheezing and asthma symptoms and greater allergic sensitization during childhood.Children with mild-to-moderate (n = 12, 67% male) and severe (n = 28, 57% male) asthma previously characterized in the NHLBI’s SARP at Emory University between 2004 and 2007 were re-evaluated between 2008 and 2010. At the follow-up visit, children repeated questionnaires and underwent severity classification assignment and spirometry, with maximal bronchodilator reversibility testing with up to 8 inhalations of albuterol sulfate (90 μg per inhalation), as previously described.1Fitzpatrick 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 (179) Google Scholar The differences between the initial and follow-up spirometric data were calculated and divided by the number of years between study visits. Multivariate logistic regression models were used to determine the association between characterization variables and changes in lung function.Mean ages at the initial evaluation and follow-up visit were 11 ± 3 and 14 ± 3 years, respectively, with a mean visit interval of 3 ± 2 years. There were no changes in subject severity classification between the initial characterization visit and the follow-up assessment.Demographic features were also similar to those of our previous report.1Fitzpatrick 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 (179) Google Scholar Children with severe asthma had a higher frequency of daily symptoms (46% vs 8%, P = .030) and hospitalization within the previous year (32% vs 0%, P = .037). This was despite higher daily doses of ICSs (744 ± 328 vs 365 ± 280 μg of fluticasone per day, P < .001) and a higher frequency of controller medication use (montelukast: 100% vs 75%, P = .029; long-acting β-agonists: 93% vs 17%, P < .001). Lung function percent predicted values also remained significantly lower in children with severe versus mild-to-moderate asthma at the follow-up assessment (FEV1, 78% ± 20% vs 102% ± 15%, P = .001; FVC, 96% ± 19% vs 105% ± 18%, P = .168; FEV1/FVC ratio, 82% ± 13% vs 97% ± 9%, P < .001).The average yearly change in FEV1 and FVC (in liters) and FEV1/FVC ratio (as a percentage) for each group is shown in Fig 1. Although FEV1 and FVC increased in both groups with age, the average yearly increase in FEV1 and FVC was significantly less in children with severe asthma. These findings were apparent before (Fig 1, A and C) and after (Fig 1, B and D) maximal bronchodilation and persisted after age-appropriate lung function reference equations (that account for variations in height during the adolescent growth spurt) were applied to the data.6Wang X. Dockery D.W. Wypij D. Fay M.E. Ferris Jr., B.G. Pulmonary function between 6 and 18 years of age.Pediatr Pulmonol. 1993; 15: 75-88Crossref PubMed Scopus (544) Google Scholar Similarly, the FEV1/FVC percent predicted values remained lower in children with severe asthma (Fig 1, E) and even worsened in a subset (Fig 1, F). Of further note, postbronchodilator FEV1 percent predicted values decreased in 46% of the children with severe asthma between the follow-up interval, and 29% of these children had postbronchodilator FEV1 decreases of more than 1% per year (Fig 2). Using multivariate models, race, sex, and health care use history (eg, prior hospitalizations, intubations, and emergency department visits) were not associated with significant decreases in FEV1 in the severe asthma group. However, daily asthma symptoms, including coughing or wheezing (odds ratio, 3.66; 95% CI, 1.29-10.34; P = .015), and the number of aeroallergen skin prick test responses (odds ratio, 1.29; 95% CI, 1.05-1.58; P = .011) at the initial evaluation were strong predictors of postbronchodilator FEV1 decreases of more than 1% per year.Fig 2Calculated yearly change in postbronchodilator FEV1 percent predicted values in children with mild-to-moderate and severe asthma. Lines represent the mean. ∗P < .05.View Large Image Figure ViewerDownload Hi-res image Download (PPT)These results support the hypothesis that progressive airflow limitation is a feature of severe asthma in children. Although progressive airflow limitation was previously observed in a subset of children with mild-to-moderate asthma enrolled in the Childhood Asthma Management Research Program, not all children in that subset had clinical evidence of more severe disease. Rather, the average postbronchodilator FEV1 in that subgroup was 108% at baseline and 96% at the completion of the study.7Covar R.A. Spahn J.D. Murphy J.R. Szefler S.J. Progression of asthma measured by lung function in the childhood asthma management program.Am J Respir Crit Care Med. 2004; 170: 234-241Crossref PubMed Google Scholar, 8Strunk 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 (113) Google Scholar However, further analysis revealed significantly lower lung function, greater allergic sensitization, and increased asthma morbidity in children with persistent versus remitting disease,9Covar 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: 359-366Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar which is similar to what we report here. Indeed, our sample of children with severe asthma was characterized by a high degree of morbidity and substantial airflow limitation that persisted throughout the follow-up interval, although the magnitude of airflow limitation in these children was significantly less than what is commonly seen in adults with severe asthma.2Moore W.C. Bleecker E.R. Curran-Everett D. Erzurum S.C. Ameredes B.T. Bacharier L. et al.Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program.J Allergy Clin Immunol. 2007; 119: 405-413Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar The fact that airflow limitation persisted and even worsened in many children with severe asthma despite high doses of ICSs and other asthma controller medications is intriguing and raises important questions about the corticosteroid sensitivity of this sample. Whether this loss of lung function represents a reduction in lung growth velocity or progression of airway remodeling is also unclear and warrants further study. To the Editor: Severe asthma in children is a heterogeneous disorder associated with extreme morbidity despite treatment with high doses of inhaled corticosteroids (ICSs). We previously reported the phenotypic features of children with mild-to-moderate and severe asthma (mean age, 10 years) enrolled in the National Heart, Lung, and Blood Institute's (NHLBI) Severe Asthma Research Program (SARP) at Emory University.1Fitzpatrick 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 (179) Google Scholar Similar to adults with severe asthma,2Moore W.C. Bleecker E.R. Curran-Everett D. Erzurum S.C. Ameredes B.T. Bacharier L. et al.Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program.J Allergy Clin Immunol. 2007; 119: 405-413Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar children with severe asthma were characterized by baseline airflow limitation that was not completely reversed with bronchodilation.1Fitzpatrick 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 (179) Google Scholar However, the magnitude of airflow limitation was significantly less in children with severe asthma (FEV1, 81% of predicted value; FEV1/forced vital capacity [FVC] ratio, 0.74) compared with that seen in adults (FEV1, 62% of predicted value; FEV1/FVC ratio, 0.65).2Moore W.C. Bleecker E.R. Curran-Everett D. Erzurum S.C. Ameredes B.T. Bacharier L. et al.Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program.J Allergy Clin Immunol. 2007; 119: 405-413Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar These findings raise important questions about the stability of the severe asthma phenotype in children and the critical developmental time frame during which loss of lung function occurs. Although the answers to these questions are not entirely clear, longitudinal studies have shown that children with more severe, frequent symptoms have ongoing airflow limitation and more severe asthma throughout adulthood.3Wolfe R. Carlin J.B. Oswald H. Olinsky A. Phelan P.D. Robertson C.F. Association between allergy and asthma from childhood to middle adulthood in an Australian cohort study.Am J Respir Crit Care Med. 2000; 162: 2177-2181Crossref PubMed Scopus (53) Google Scholar, 4Rasmussen 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 (225) Google Scholar, 5Sears M.R. Greene J.M. Willan A.R. Wiecek E.M. Taylor D.R. Flannery E.M. et al.A longitudinal, population-based, cohort study of childhood asthma followed to adulthood.N Engl J Med. 2003; 349: 1414-1422Crossref PubMed Scopus (1027) Google Scholar Using longitudinal follow-up data from children previously characterized in the NHLBI’s SARP, we report that children with severe asthma have a premature loss of lung function during the adolescent years that is associated with an increased frequency of wheezing and asthma symptoms and greater allergic sensitization during childhood. Children with mild-to-moderate (n = 12, 67% male) and severe (n = 28, 57% male) asthma previously characterized in the NHLBI’s SARP at Emory University between 2004 and 2007 were re-evaluated between 2008 and 2010. At the follow-up visit, children repeated questionnaires and underwent severity classification assignment and spirometry, with maximal bronchodilator reversibility testing with up to 8 inhalations of albuterol sulfate (90 μg per inhalation), as previously described.1Fitzpatrick 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 (179) Google Scholar The differences between the initial and follow-up spirometric data were calculated and divided by the number of years between study visits. Multivariate logistic regression models were used to determine the association between characterization variables and changes in lung function. Mean ages at the initial evaluation and follow-up visit were 11 ± 3 and 14 ± 3 years, respectively, with a mean visit interval of 3 ± 2 years. There were no changes in subject severity classification between the initial characterization visit and the follow-up assessment. Demographic features were also similar to those of our previous report.1Fitzpatrick 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 (179) Google Scholar Children with severe asthma had a higher frequency of daily symptoms (46% vs 8%, P = .030) and hospitalization within the previous year (32% vs 0%, P = .037). This was despite higher daily doses of ICSs (744 ± 328 vs 365 ± 280 μg of fluticasone per day, P < .001) and a higher frequency of controller medication use (montelukast: 100% vs 75%, P = .029; long-acting β-agonists: 93% vs 17%, P < .001). Lung function percent predicted values also remained significantly lower in children with severe versus mild-to-moderate asthma at the follow-up assessment (FEV1, 78% ± 20% vs 102% ± 15%, P = .001; FVC, 96% ± 19% vs 105% ± 18%, P = .168; FEV1/FVC ratio, 82% ± 13% vs 97% ± 9%, P < .001). The average yearly change in FEV1 and FVC (in liters) and FEV1/FVC ratio (as a percentage) for each group is shown in Fig 1. Although FEV1 and FVC increased in both groups with age, the average yearly increase in FEV1 and FVC was significantly less in children with severe asthma. These findings were apparent before (Fig 1, A and C) and after (Fig 1, B and D) maximal bronchodilation and persisted after age-appropriate lung function reference equations (that account for variations in height during the adolescent growth spurt) were applied to the data.6Wang X. Dockery D.W. Wypij D. Fay M.E. Ferris Jr., B.G. Pulmonary function between 6 and 18 years of age.Pediatr Pulmonol. 1993; 15: 75-88Crossref PubMed Scopus (544) Google Scholar Similarly, the FEV1/FVC percent predicted values remained lower in children with severe asthma (Fig 1, E) and even worsened in a subset (Fig 1, F). Of further note, postbronchodilator FEV1 percent predicted values decreased in 46% of the children with severe asthma between the follow-up interval, and 29% of these children had postbronchodilator FEV1 decreases of more than 1% per year (Fig 2). Using multivariate models, race, sex, and health care use history (eg, prior hospitalizations, intubations, and emergency department visits) were not associated with significant decreases in FEV1 in the severe asthma group. However, daily asthma symptoms, including coughing or wheezing (odds ratio, 3.66; 95% CI, 1.29-10.34; P = .015), and the number of aeroallergen skin prick test responses (odds ratio, 1.29; 95% CI, 1.05-1.58; P = .011) at the initial evaluation were strong predictors of postbronchodilator FEV1 decreases of more than 1% per year. These results support the hypothesis that progressive airflow limitation is a feature of severe asthma in children. Although progressive airflow limitation was previously observed in a subset of children with mild-to-moderate asthma enrolled in the Childhood Asthma Management Research Program, not all children in that subset had clinical evidence of more severe disease. Rather, the average postbronchodilator FEV1 in that subgroup was 108% at baseline and 96% at the completion of the study.7Covar R.A. Spahn J.D. Murphy J.R. Szefler S.J. Progression of asthma measured by lung function in the childhood asthma management program.Am J Respir Crit Care Med. 2004; 170: 234-241Crossref PubMed Google Scholar, 8Strunk 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 (113) Google Scholar However, further analysis revealed significantly lower lung function, greater allergic sensitization, and increased asthma morbidity in children with persistent versus remitting disease,9Covar 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: 359-366Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar which is similar to what we report here. Indeed, our sample of children with severe asthma was characterized by a high degree of morbidity and substantial airflow limitation that persisted throughout the follow-up interval, although the magnitude of airflow limitation in these children was significantly less than what is commonly seen in adults with severe asthma.2Moore W.C. Bleecker E.R. Curran-Everett D. Erzurum S.C. Ameredes B.T. Bacharier L. et al.Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program.J Allergy Clin Immunol. 2007; 119: 405-413Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar The fact that airflow limitation persisted and even worsened in many children with severe asthma despite high doses of ICSs and other asthma controller medications is intriguing and raises important questions about the corticosteroid sensitivity of this sample. Whether this loss of lung function represents a reduction in lung growth velocity or progression of airway remodeling is also unclear and warrants further study.
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