Heterogeneity of severe asthma in childhood: Confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program

Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 02/2011; 127(2):382-389.e1-13. DOI: 10.1016/j.jaci.2010.11.015
Source: PubMed


Asthma in children is a heterogeneous disorder with many phenotypes. Although unsupervised cluster analysis is a useful tool for identifying phenotypes, it has not been applied to school-age children with persistent asthma across a wide range of severities.
This study determined how children with severe asthma are distributed across a cluster analysis and how well these clusters conform to current definitions of asthma severity.
Cluster analysis was applied to 12 continuous and composite variables from 161 children at 5 centers enrolled in the Severe Asthma Research Program.
Four clusters of asthma were identified. Children in cluster 1 (n = 48) had relatively normal lung function and less atopy. Children in cluster 2 (n = 52) had slightly lower lung function, more atopy, and increased symptoms and medication use. Cluster 3 (n = 32) had greater comorbidity, increased bronchial responsiveness, and lower lung function. Cluster 4 (n = 29) had the lowest lung function and the greatest symptoms and medication use. Predictors of cluster assignment were asthma duration, the number of asthma controller medications, and baseline lung function. Children with severe asthma were present in all clusters, and no cluster corresponded to definitions of asthma severity provided in asthma treatment guidelines.
Severe asthma in children is highly heterogeneous. Unique phenotypic clusters previously identified in adults can also be identified in children, but with important differences. Larger validation and longitudinal studies are needed to determine the baseline and predictive validity of these phenotypic clusters in the larger clinical setting.

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Available from: Xingnan Li, Oct 05, 2015
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    • "Wheezing during infancy is common, but is not necessarily caused by asthma. Epidemiological studies have described different phenotypes of asthma [3], [8], [14], [15], many of which are transient conditions with low risk of asthma and allergy later in life. However, 30–50% of the children involved have been reported to develop persistent asthma, especially if they are sensitized [2], [3], [16]. "
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    ABSTRACT: BackgroundChildren with atopic eczema in infancy often develop allergic rhinoconjunctivitis and asthma, but the term “atopic march” has been questioned as the relations between atopic disorders seem more complicated than one condition progressing into another.ObjectiveIn this prospective multicenter study we followed children with eczema from infancy to the age of 10 years focusing on sensitization to allergens, severity of eczema and development of allergic airway symptoms at 4.5 and 10 years of age.MethodsOn inclusion, 123 children were examined. Hanifin-Rajka criteria and SCORAD index were used to describe the eczema. Episodes of wheezing were registered, skin prick tests and IgE tests were conducted and questionnaires were filled out. Procedures were repeated at 4.5 and 10 years of age with additional examinations for ARC and asthma.Results94 out of 123 completed the entire study. High SCORAD points on inclusion were correlated with the risk of developing ARC, (B = 9.86, P = 0.01) and asthma, (B = 10.17, P = 0.01). For infants with eczema and wheezing at the first visit, the OR for developing asthma was 4.05(P = 0.01). ARC at 4.5 years of age resulted in an OR of 11.28(P = 0.00) for asthma development at 10 years.ConclusionThis study indicates that infant eczema with high SCORAD points is associated with an increased risk of asthma at 10 years of age. Children with eczema and wheezing episodes during infancy are more likely to develop asthma than are infants with eczema alone. Eczema in infancy combined with early onset of ARC seems to indicate a more severe allergic disease, which often leads to asthma development. The progression from eczema in infancy to ARC at an early age and asthma later in childhood shown in this study supports the relevance of the term “atopic march”, at least in more severe allergic disease.
    PLoS ONE 06/2014; 9(6):e99609. DOI:10.1371/journal.pone.0099609 · 3.23 Impact Factor
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    • "This finding suggests that RSV infection predisposes individuals to recurrent wheezing through an atopy-independent mechanism. Several asthmatic or wheezing phenotypes exist in children (Fitzpatrick et al., 2011). Therefore, respiratory virus-induced wheezing illnesses can encompass multiple sub-phenotypes that relate to asthma in different ways. "
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    ABSTRACT: Asthma inception is associated with respiratory viral infection, especially infection with respiratory syncytial virus (RSV) and/or human rhinovirus (HRV), in the vast majority of cases. However, the reason why RSV and HRV induce the majority of bronchiolitis cases during early childhood and why only a small percentage of children with RSV- and HRV-induced bronchiolitis later develop asthma remains unclear. A genetic association study has revealed the important interaction between viral illness and genetic variants in patients with asthma. Severe RSV- and HRV-induced bronchiolitis may be associated with a deficiency in the innate immune response to RSV and HRV. RSV and HRV infections in infants with deficient innate immune response and the dysfunction of regulatory T cells are considered to be a risk factor for the development of asthma. Sensitization to aeroallergens, beginning in the first year of life, consistently predisposes children to HRV-induced wheezing illnesses, but the converse is not true. Some evidence of virus specificity exists, in that allergic sensitization specifically increased the risk of wheezing in individuals infected with HRV, but not RSV. Administration of Palivizumab, a humanized monoclonal antibody that targets the A antigenic site of the Fusion-protein of RSV, decreases the risk of hospitalization in high-risk infants and the risk of recurrent of wheezing. However, palivizumab did not have any effect on subsequent recurrent wheezing in children with a family history of atopy. These findings suggest that infection with RSV and infection with HRV might predispose individuals to recurrent wheezing through an atopy-independent and an atopy-dependent mechanism, respectively. Respiratory virus-induced wheezing illnesses may encompass multiple sub-phenotypes that relate to asthma in different ways.
    Frontiers in Microbiology 08/2013; 4:252. DOI:10.3389/fmicb.2013.00252 · 3.99 Impact Factor
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    • "Severe asthma in children is a heterogeneous disorder with many phenotypes. An SARP cohort defined the phenotypes of 161 children with severe asthma (ATS criteria) on the basis of their clinical features and inflammatory biomarker levels (cluster analysis)8). Four clusters of severe childhood asthma were identified: (1) late-onset symptomatic asthma with normal pulmonary function test (PFT) results and less atopy, (2) early-onset atopic asthma with normal PFT results, (3) early-onset atopic asthma with greater comorbidity and mild airflow limitations, and (4) early-onset atopic asthma with advanced airflow limitations and the greatest symptoms and medication use9). "
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    ABSTRACT: Severe childhood asthma is a complicated and heterogeneous disorder with distinct phenotypes. Children with severe asthma have more persistent symptoms despite receiving treatment, more atopy, greater airway obstruction, and more air trapping than those with mild-to-moderate asthma. They also have higher morbidity and substantial airflow limitations that persist throughout adulthood. Identification of the phenotype clusters and endotypes of severe asthma can allow further modulation of the natural history of severe asthma and may provide the pathophysiologic rationale for appropriate management strategies.
    Korean Journal of Pediatrics 05/2013; 56(5):191-5. DOI:10.3345/kjp.2013.56.5.191
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