4.5 Article

Novel Treatment-Refractory Preschool Wheeze Phenotypes Identified by Cluster Analysis of Lung Lavage Constituents

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ELSEVIER
DOI: 10.1016/j.jaip.2021.03.059

Keywords

Asthma; Phenotypes; Rhinovirus; Asthma; cluster analysis; Child; preschool; Wheeze; Wheezing syndromes

Funding

  1. National Institutes of Health/National Heart, Lung, and Blood Institute's Severe Asthma Research Program [U10HL109250-07]
  2. National Institute of Allergy and Infectious Diseases [U01A123337, R21 A151496]

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Preschool children with treatment-refractory wheeze were classified into four clusters based on lung lavage variables, including airway malacia, gastroesophageal reflux, indolent human rhinovirus bronchoalveolitis, and type-2 high inflammation. The results provide insights into diagnosing the causes of treatment-refractory wheeze and developing novel therapies targeting airway malacia, human rhinovirus infection, and BAL neutrophilia in preschool children.
BACKGROUND: Preschool children with treatment-refractory wheeze often require unscheduled acute care. Current guidelines advise treatment of persistent wheeze with inhaled corticosteroids. Alternative treatments targeting structural abnormalities and specific inflammatory patterns could be more effective. OBJECTIVE: To apply unsupervised analysis of lung lavage (bronchoalveolar lavage [BAL]) variables to identify clusters of preschool children with treatment-refractory wheeze. METHODS: A total of 155 children 6 years or younger underwent bronchoscopy with BAL for evaluation of airway structure, inflammatory markers, and pathogens. Variables were screened with factor analysis and sorted into clusters by Ward's method, and membership was confirmed by discriminant analysis. Superscript/Subscript Available ABSTRACT BACKGROUND: Preschool children with treatment-refractory wheeze often require unscheduled acute care. Current guidelines advise treatment of persistent wheeze with inhaled corticosteroids. Alternative treatments targeting structural abnormalities and specific inflammatory patterns could be more effective. OBJECTIVE: To apply unsupervised analysis of lung lavage (bronchoalveolar lavage [BAL]) variables to identify clusters of preschool children with treatment-refractory wheeze. METHODS: A total of 155 children 6 years or younger underwent bronchoscopy with BAL for evaluation of airway structure, inflammatory markers, and pathogens. Variables were screened with factor analysis and sorted into clusters by Ward's method, and membership was confirmed by discriminant analysis. RESULTS: The model was repeatable in a 48-case validation sample and accurately classified 86% of cases. Cluster 1 (n = 60) had early-onset wheeze, 85% with structural abnormalities, mostly tracheamalacia, with low total IgE and agranulocytic BAL. Cluster 2 (n = 42) had later-onset wheeze, the highest prevalence of gastroesophageal reflux, little atopy, and two-third had increased BAL lipid-laden macrophages. Cluster 3 (n = 46) had mid-onset wheeze, low total IgE, and two-third had BAL viral transcripts, predominately human rhinovirus, with BAL neutrophilia. Cluster 4 (n = 7) was older, with high total IgE, blood eosinophilia, and mixed BAL eosinophils and neutrophils. CONCLUSIONS: Preschool children with recurrent wheeze refractory to inhaled corticosteroid treatment include 4 clusters: airway malacia, gastroesophageal reflux, indolent human rhinovirus bronchoalveolitis, and type-2high inflammation. The results support the risk and cost of invasive bronchoscopy to diagnose causes of treatment-refractory wheeze and develop novel therapies targeting airway malacia, human rhinovirus infection, and BAL neutrophilia in preschool children. (c) 2021 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2021;9:2792-801)

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