Neutrophilic Steroid-Refractory Recurrent Wheeze and Eosinophilic Steroid-Refractory Asthma in Children.

BACKGROUND: Little is known about inflammatory pathways of severe recurrent wheeze in preschool children and severe asthma in children. OBJECTIVES: The aim of the Severe Asthma Molecular Phenotype cohort was to characterize phenotypes of severe recurrent wheeze and severe asthma during childhood in terms of triggers (allergic or not), involved cells (eosinophil or neutrophil), and corticoid responsiveness. METHODS: Children with moderate-to-severe asthma and preschool children with moderate-to-severe recurrent wheeze were enrolled prospectively. They underwent standardized clinical and blood workup, and bronchoalveolar lavage (BAL) evaluation. Cluster analysis was applied to 350 children with 34 variables. RESULTS: Three clusters were identified: cluster 1, Neutrophilic steroid-refractory recurrent wheeze phenotype, with 138 children uncontrolled despite high-dose inhaled corticosteroids (ICS) (92%, P < .001), with more history of pneumonia (31%, P < .001), more gastroesophageal reflux disease (37%, P < .001), and the highest blood neutrophil count (mean 4.524 cells/mm3, P = .05); cluster 2, Severe recurrent wheeze with sensitization to a single aeroallergen (12%, P = .002), with 104 children controlled with high-dose ICS (63%, P < .001); cluster 3, Eosinophilic steroid-refractory asthma phenotype, with 108 children uncontrolled despite high-dose ICS (76%, P < .001) with more allergic rhinitis, atopic dermatitis, and food allergies (82%, 40%, 31%, P < .001, respectively). They also had a higher blood eosinophil count and a higher percentage of BAL eosinophil (506/mm3, 2.6%, P < .001 respectively). CONCLUSIONS: Inflammation pathway of asthma and recurrent wheeze are related to eosinophil cells in older children and neutrophil cells in younger children. These results could improve personalized treatments.

Childhood allergic asthma is not a single phenotype.

OBJECTIVE: IgE-mediated allergic asthma phenotype appears to be heterogeneous. We set out to define distinct allergic phenotypes by unsupervised cluster analysis. STUDY DESIGN: A total of 18 variables were analyzed: sex and age, eczema and food allergy, asthma duration, asthma severity and control, severe exacerbations, total IgE level, allergic sensitization, fractional exhaled nitric oxide, and functional parameters. Clusters obtained were cross-tabulated with environmental parameters. RESULTS: Four clusters were identified in 125 children (average age 8.9 years): (1) 57 children constituted the "House dust mite Sensitization and Mild Asthma" cluster, 98% of these were monosensitized and had mild asthma (74%); (2) 12 children had "Pollen Sensitization with Severe Exacerbations," 92 % with severe exacerbations and pollen sensitization; (3) 20 children had "Multiple Allergies and Severe Asthma," with 95% having moderate to severe asthma, and a significantly decreased forced expiratory flow rate at 25%-75% of forced vital capacity, 100% had eczema and higher values of IgE (1123 kU/L) and fractional exhaled nitric oxide (67 ppb) (this cluster was associated with molds at home [P = .004]); and (4) 36 children had "Multiple Allergic Sensitizations and Mild Asthma," 97% of these with multiple sensitizations and 100% mild asthma. CONCLUSIONS: The identification of 2 novel severe allergic asthma phenotypes "Pollen Sensitization with Severe Exacerbations"and "Multiple Allergies and Severe Asthma" could lead to specific targeted treatment.

Wheeze phenotypes in young children have different courses during the preschool period.

BACKGROUND: Rules for predicting the course of asthma in wheezy infants have low specificity. OBJECTIVE: To determine if the novel phenotypes-mild early viral wheeze (EVW), atopic multiple-trigger wheeze (MTW), and nonatopic uncontrolled wheeze (NAUW)-have different courses during the preschool period. METHODS: Part of the prospectively followed Trousseau Asthma Program cohort was phenotyped using cluster analysis with 12 parameters (sex, asthma severity and control with inhaled corticosteroid [ICS], parental asthma, allergic rhinitis, eczema, food allergy, EVW or MTW, and allergen exposure trigger). Wheezing trajectories were assessed by crossing the original phenotypes with the phenotypes obtained at 5 years. RESULTS: Four clusters were identified at 5 years of age: asymptomatic children (n = 47) with no wheezing (98%), children with mild EVW (n = 40, 87% with EVW, 50% with EVW controlled with low-dose ICS), those with atopic MTW (n = 30, 100% with MTW, only 17% with MTW controlled with low-dose ICS, more significant for pollen asthmatic trigger), and those with atopic severe UW (n = 33, 63% with UW uncontrolled despite high doses of ICS, more significant for allergic rhinitis and dust as asthmatic trigger). Those with mild EVW became asymptomatic or remained with mild EVW. Those with atopic MTW remained with atopic MTW and those with NAUW developed severe UW in most cases. CONCLUSION: These results show that remission is most frequently observed in mild EVW and that no remission is observed in atopic MTW.

Novel severe wheezy young children phenotypes: boys atopic multiple-trigger and girls nonatopic uncontrolled wheeze.

BACKGROUND: Recurrent wheezing during infancy is a heterogeneous disorder that has been associated with early-onset asthma. OBJECTIVE: To identify phenotypes of severe recurrent wheezing and therapeutic approaches. METHODS: We performed cluster analysis with 20 variables of 551 children with active asthma, younger than 36 months old, and enrolled in the Trousseau Asthma Program. RESULTS: We identified 3 independent clusters of children with wheezing. Cluster 1, mild episodic viral wheeze (n= 327), consisted of children with wheezing related only to colds (71%), mild disease (76%), and mainly normal chest x-ray results. Cluster 2, nonatopic uncontrolled wheeze (n = 157), was characterized by moderate to severe disease (91%), uncontrolled wheezing despite high doses of inhaled corticosteroids (55%), parents with asthma, and increased levels of ferritine. Cluster 3, atopic multiple-trigger wheeze (n = 67), included more children with multiple-trigger wheeze (68%) than did clusters 1 or 2; eczema (75%); a positive result from the Phadiatop Infant test (90%); increased levels of IgE, IgA, and IgG; and abnormal results from chest x-rays. In separate analysis, 1 parameter for boys (increased total level of IgE) and 2 parameters for girls (wheezing severity and increased total level of IgE) properly classified 90% of boys and 83% of girls in the appropriate cluster. Significant associations were found between overcrowding, molds and cockroaches at home, and atopic multiple-trigger wheeze and between day-care attendance and nonatopic uncontrolled wheeze in other parts. CONCLUSION: We identified different phenotypes of recurrent wheezing in young children by using cluster analysis with usual variables. These phenotypes require confirmation in longer, follow-up studies.

Two novel, severe asthma phenotypes identified during childhood using a clustering approach.

Unsupervised cluster analysis has already been used to identify severe phenotypes of childhood asthma, but without taking into account inflammatory markers. The aim of this study was to define independent homogeneous phenotypic clusters of severe asthma in a cohort of asthmatic children. Cluster analysis was applied to 19 variables from 315 children enrolled in the Trousseau Asthma Program in Paris, France. Three independent clusters of asthma were identified. Cluster 1, asthma with severe exacerbations and multiple allergies: 103 children had more sensitisations to inhaled allergens and food allergens, more blood eosinophils and basophils, more uncontrolled asthma despite high doses of inhaled corticosteroid and more hospitalisations for exacerbation. Cluster 2, severe asthma with bronchial obstruction: 72 children were significantly older, had the highest body mass index, a lower forced expiratory volume in 1 s, more pronounced blood neutrophils and significantly higher levels of all classes of immunoglobulin (Ig), except IgE. Cluster 3, mild asthma: 140 children did not show statistically significant features. These results could lead to improved management of severe asthma in children by optimising treatment strategies, i.e. anti-allergic drugs, such as anti-IgE for children with the allergic phenotype, and anti-neutrophil drugs, such as macrolides for those with the obstructive phenotype.