Phenotype of Severe Asthma: Pediatric Perspectives

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1 Severe Asthma Symposium Phenotype of Severe Asthma: Pediatric Perspectives Department of Pediatrics, College of Medicine, Korea University, Seoul, Korea Young Yoo Asthma is a chronic, persistent disorder characterized by airway inflammation and often reversible airflow obstruction. Asthma in children is a heterogeneous disorder with many phenotypes. Most of patients have mild-to-moderate disease that can be controlled with inhaled corticosteroids and inhaled short-acting β-adrenergic agonists. However, estimated about 5% to 10% of patients with asthma have severe disease that is recalcitrant to typical treatment modalities, including administration of systemic corticosteroids. Children with severe asthma are differentiated by ongoing symptoms and airway inflammation despite treatment with high dose of inhaled corticosteroids (ICSs) and other controller medications. Although the prevalence of severe asthma is low, these children have extreme morbidity and disproportionate amount of health care burden. Interest in the underlying biological mechanisms of severe asthma and specialized diagnostic and management strategies for the disorder have increased substantially in recent years. This review will therefore discuss recent findings related to severe asthma in children that shed new light on the burden and peculiarities of the disorder. Assessment of asthma severity According to the Global Initiative for Asthma (GINA) and the National Asthma Education and Prevention Program (NAEPP) Guidelines for the Diagnosis and Management of Asthma, asthma can be divided into four levels of asthma severity; mild intermittent, mild persistent, moderate persistent, and, severe persistent. In children older than five years, three major features are recommended in determining level of severity; frequency of asthma symptoms during the day, frequency of nighttime asthma symptoms, and measures of pulmonary function. So, severe asthma is defined primarily by lung function abnormalities, persistent symptoms, and exacerbations despite appropriate therapy. There is increasing evidence, however, that this approach does not reflect the heterogeneous characteristics of the disorder. This suggests that more specific approaches are needed to differentiate asthma heterogeneity in children to assess better the risk and S 183

2 impairment associated with the disorder as well as to guide clinical asthma therapies. Heterogeneity of severe asthma 1. Severe asthma research program Although 5% to 10% of patients with asthma have severe disease that is unresponsive to typical therapeutics, they are disproportionately affected by their disease, in terms of both impaired lifestyle and health care costs. Given the importance of severe asthma to the costs of the health care system and the lack of well-defined insights into disease mechanisms, the National Heart, Lung, and Blood Institute (NHLBI) sponsored a workshop titled Severe Asthma Research Program (SARP). The goals of SARP were (1) define the characteristics of severe asthma, (2) identify the mechanistic factors associated with severe asthma, (3) discuss the potential approaches for study and treatment, and (4) present recommendations for future research needs and direction. 2. Cluster analysis Cluster analysis is an unsupervised analytical approach that is useful in the refinement of pediatric asthma diagnosis and severity assessment. The NHLBI s SARP investigators identified four unique cluster phenotypes of childhood asthma defined by different degrees of lung function, asthma duration, and asthma controller medication use. The magnitude of atopy, airflow limitation, hyperinflation, exhaled nitric oxide (eno) concentrations, and the age of asthma symptom onset are also major determinants of asthma phenotype in this cluster analysis. 1) Cluster 1: Late-onset symptomatic asthma with normal lung function This cluster is younger and differentiated by an older age of symptom onset and shorter asthma duration. The magnitude of allergic sensitization is relatively lesser compared to other clusters, with lower eno concentrations. Despite having airway hyperresponsiveness (AHR) to methacholine, these children have relatively normal lung function with minimal hyperinflation. Children in cluster 1 are treated with relatively fewer controller medications including a significant lower daily dose of ICS. 2) Cluster 2: Early-onset atopic asthma with normal lung function Children are similar in age to cluster 1 but have an earlier age of asthma onset, a longer duration of asthma symptoms, and increased markers of atopy. Although children in this group are treated more frequently with controller medications as well as higher daily doses of ICS, lung function, including spirometric and lung volume variables, and best post-bronchodilator responses are similar to those observed in cluster 1. 3) Cluster 3: Early-onset atopic asthma with mild airflow limitation This cluster included subjects with an earlier onset asthma symptoms and the longest asthma duration. Children in cluster 3 also have elevated eno concentrations compared with clusters 1 and 2 and significant S 184

3 Young Yoo:Phenotype of Severe Asthma: Pediatric Perspectives comorbidities, including a higher prevalence of gastroesophageal reflux and chronic sinusitis requiring antibiotic treatment. Children in this cluster are also more likely to be treated with oral corticosteroids. Although children in cluster 3 have an enhanced bronchodilator response, airflow limitation is not completely reversed after 6 to 8 inhalations of albuterol. Children in this cluster also have a lower total lung capacity (TLC), increased airway resistance, and greater AHR to methacholine. More than one half of this group reports asthma symptoms with daily activities such as walking and climbing stairs. 4) Cluster 4: Early-onset atopic asthma with advanced airflow limitation Children in this cluster are classified as having severe asthma according to ATS criteria. Cluster 4 is similar to cluster 3 with regard to asthma onset and asthma duration, although there are fewer comorbidities. This cluster is further differentiated by the highest eno values. Almost all children in this cluster see a physician for an acute exacerbation within the previous year, and half of them hospitalizes and approximately 30% requiring intensive care. Children in cluster 4 are therefore treated with the highest daily doses of ICS, and most are receiving at least 3 asthma controller medications. This cluster is also differentiated by the lowest lung function, including baseline airflow limitation and hyperinflation that are not completely reversed with bronchodilator administration. Similar to cluster 3, children in this cluster also have increased airway resistance and greater AHR to methacholine. Lower TLC is also observed in this cluster. Daily symptoms requiring short-acting bronchodilator treatment are also common in this group, and nearly one half reports asthma symptoms with activities of daily living. Phenotypes of Severe Asthma 1. Clinical characteristics Severe asthma in childhood is characterized by poor symptom control and elevated eno despite high-dose ICS treatment, greater airway obstruction, increased markers of allergic sensitization, increased AHR to methacholine, and lung hyperinflation. Unlike severe asthma in adults, severe asthma in children is characterized by a relatively narrow spectrum of derangements that includes marked atopy and increased eno levels. 2. Physiological characteristics The degree of lung function impairment is significantly lesser than adults. The magnitude of FEV 1 bronchodilator administration is significantly greater in children and suggests that fixed airflow limitation is not a distinguishing feature of severe asthma in children. In the Melbourne birth cohort study, children with severe asthma at 10 years of age had the lowest FEV 1 and FEV 1 /FVC ratios throughout the first 42 years of life. Thus the magnitude of airflow limitation in childhood asthma may represent an important marker of progressive asthma that worsens and results in more severe disease in adults over time. This observation may be related to impaired lung growth, which could result in accelerated lung function decline in the adult years. S 185

4 3. Pathophysiology Asthma is defined and diagnosed by a combination of clinical symptoms and physiologic abnormalities without reliance on pathologic/biologic markers. These definitions leave room for multiple pathologic processes to produce similar clinical endpoints. Several lines of evidence suggest that severe asthma is not a single disease or, at a minimum, that it is the same disease but with widely varying host responses. The IL-4/IL-13 signaling pathway accounts for the symptoms experienced by a subset of severe asthmatics with allergen-associated symptoms and high serum immunoglobulin E (IgE) levels. The IL-5/IL-33 signaling pathway is likely to play a key role in the disease pathogenesis corticosteroid resistant asthma. The IL-17 signaling pathway is thought to contribute to neutrophilic asthma. 4. Radiological characteristics High-resolution CT (HRCT) scanning plays a role in the diagnostic workup of patients with severe asthma. HRCT scan studies in asthmatic subjects reveal abnormal findings, such as bronchial wall thickening, bronchial wall dilatation, bronchiectasis, mosaic lung attenuation, mucus plugging, prominent centrilobular opacities, emphysema, and atelectasis. The detection of bronchial wall changes, in particular bronchiectasis, is important in patients with severe asthma as this may impact the management strategy. FEV 1 /FVC ratio is the strongest predictors of bronchiectasis and bronchial wall thickening. 5. Molecular characteristics By using the high-dimensional data reduction techniques on bronchoalveolar lavage (BAL) and airway macrophages (AM) inflammatory markers in children with severe asthma, the molecular phenotype of severe asthma is revealed. Whereas cytokine and chemokine concentrations in the BAL and AM cell lysate does not differ between children with moderate and severe asthma, the linear combination of these biomarkers results in clear separation of the two asthmatic groups. In the BAL fluid, growth-related oncogene (CXCL1), RANTES (CCL5), IL-12, IFN-γ, and IL-10 characterize severe asthma in children. Severe asthma in children is not simply a Th2-mediated disease with relative loss of Th1-mediated cytokine production, so it is characterized by a distinct airway molecular phenotype that does not have a clear Th1 or Th2 pattern. Furthermore, given that both neutrophils and eosinophils are elevated in children with severe asthma, the patterns of cellular inflammation are also complex and likely do not involve one cell type independent of others. Severe asthma in children is associated with unique patterns of airway inflammation that persist despite corticosteroid treatment. 6. Histopathologic characteristics A survey of bronchoscopic studies of patients with asthma of varying severity demonstrates wide ranges in cellular inflammation and structural changes. Airway remodeling is a distinctive pathologic feature of asthma, S 186

5 Young Yoo:Phenotype of Severe Asthma: Pediatric Perspectives and is thought to be the result of an aberrant reparative process associated with ongoing allergic inflammation. The histopathologic changes that occur within the airways of asthmatics include epithelial desquamation and regeneration, goblet cell hyperplasia, submucosal gland hypertrophy, subepithelial fibrosis or thickening of the basement membrane, inflammatory cell infiltration, hyperplasia and hypertrophy of the bronchial smooth muscle, and vascular changes. These demonstrate that extensive airway remodeling can be present in children with severe asthma, despite aggressive anti-inflammatory therapy. Phenotype Differences between Pediatric and Adult Asthma In a cross-sectional analysis of severe asthma, the clinical differences in children and adults are considerable. Children are more likely to be male, to be more sensitive to the suppressive effects of glucocorticoids, and to have less impaired lung function. Similar to adults with severe asthma, children with severe asthma are characterized by baseline airflow limitation that is not completely reversed with bronchodilation. However, the magnitude of airflow limitation is significantly less in children with severe asthma compared with that seen in adults. 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. Longitudinal studies have shown that children with more severe, frequent symptoms have ongoing airflow limitation and more severe asthma throughout adulthood. According to the longitudinal follow-up data from NHLBI s SARP, the 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. Interestingly, whereas prepubertal girls with severe asthma have no residual air trapping after maximal bronchodilation, boys with severe asthma have incomplete reversal of air trapping with persistent elevations in the ratio of residual volume to total lung capacity (RV/TLC). These finding suggests that the adult physiological patterns of severe asthma are already present in school-age boys but may not yet be fully developed in girls. The years surrounding puberty may represent a critical window when the phenotype of severe asthma in children intensifies and worsens. The SARP suggests that over time severe asthma becomes more diverse; that is, cadre of children with the common phenotype do progress, but are joined by new onset severe asthmatics in which obesity and fixed airflow obstruction are visible characteristics. Whether these new phenotypes evolve from the common one as manifestations of the recurrent hits hypothesis due environmental exposures versus new onset disease or both will require long-term longitudinal cohort studies. Asthma endotypes The challenge now is to link pathophysiology to these clinical phenotypes, and perhaps to use pathobiology S 187

6 to identify clinical phenotypes not yet recognized. None of the phenotype approaches introduced above have globally identified a specific pathobiology, biomarker, genetic element, stability over time or critically, a robust response to therapy targeted to the biology associated with that phenotype. Endotype is a term applied to a subtype of a condition which is defined by a distinct functional or pathophysiological mechanism. It is clear that asthma is a complex disease made up of number of disease variants with different underlying pathophysiologies. Asthma syndrome is divided into distinct disease entities with specific mechanisms, which was called asthma endotypes. To define asthma endotypes, seven parameters were selected; clinical characteristics, biomarkers, lung physiology, genetics, histopathology, epidemiology, and treatment response. Although considerable advances have been made in the understanding of severe asthma in children over the past decade, the next decade will inevitably be focused on personalized medicine for the disorder. However, the biologic linking phenotypic characteristics to clinical responses remain unknown. More attention on the endotype of asthma is clearly needed. Conclusion Indeed, there is an important distinction between the severity of exacerbations and overall asthma control. Asthma severity and control are related but not interchangeable concepts. Whereas asthma severity refers to the required level of therapy during active treatment of asthma symptoms (ie, the magnitude of disease severity), asthma control refers to the extent to which asthma symptoms are alleviated by treatment. Whereas the GINA and NAEPP criteria for severe asthma are based primarily on symptoms and lung function, pediatric asthma clusters by NHLBI s SARP are determined as much by the magnitude of atopy, exhaled nitric oxide concentrations, the age of asthma symptom onset, and duration of asthma as by airflow limitation and hyperinflation. Cluster analysis identifies distinct phenotypes of asthma in children that do not correspond to definitions of asthma severity proposed by current guidelines. In conclusion, childhood asthma, particularly severe asthma, is a highly heterogeneous disorder. Importantly, no identified cluster corresponded entirely to definitions of severe asthma proposed by various guidelines including ATS. A consensus-based definition of severe asthma may also require further validation in children. References 1. Bacharier LB. Classifying asthma severity in children. Am J Respir Crit Care med 2004;170: Fitzpatrick AM. Features of severe asthma in school-age children: Atopy and increased exhaled nitric oxide. J Allergy Clin Immunol 2006;118: Proceedings of the ATS workshop on refractory asthma: Current understanding, recommendations, and unanswered questions. Am J Respir Crit Care med 2000;162: Busse WW. Pathophysiology of severe asthma. J Allergy Clin Immunol 2000;106: S 188

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