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Novel Treatment-Refractory Preschool Wheeze Phenotypes Identified by Cluster Analysis of Lung Lavage Constituents
W Gerald Teague1, Monica G Lawrence2, Sanford Williams2
1Child Health Research Center, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Va; Division of Respiratory Medicine, Allergy, Immunology, and Sleep, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Va.
Insights
Preschool children with difficult-to-treat wheezing can be categorized into four distinct groups based on airway issues, reflux, viral infections, or inflammation. This research aids in developing targeted therapies for refractory wheeze in young children.
Area of Science:
- Pediatric Pulmonology
- Respiratory Medicine
- Clinical Immunology
Background:
- Preschool children with treatment-refractory wheeze frequently need emergency care.
- Current guidelines recommend inhaled corticosteroids, but alternative treatments may be more effective by addressing underlying issues.
Purpose of the Study:
- To identify distinct patient clusters in preschool children with treatment-refractory wheeze using unsupervised analysis of bronchoalveolar lavage (BAL) variables.
- To inform the development of targeted therapies for specific wheeze phenotypes.
Main Methods:
- 155 children aged 6 years or younger underwent bronchoscopy with BAL.
- Variables were analyzed using factor analysis and clustered with Ward's method, with membership confirmed by discriminant analysis.
- The model was validated on a separate sample, achieving 86% classification accuracy.
Main Results:
- Four clusters were identified: 1) early-onset wheeze with structural abnormalities (tracheomalacia) and low IgE; 2) later-onset wheeze with gastroesophageal reflux and increased lipid-laden macrophages; 3) mid-onset wheeze with human rhinovirus transcripts and neutrophilia; 4) older children with high IgE and eosinophilia.
Conclusions:
- Preschool children with refractory wheeze can be classified into four groups: airway malacia, gastroesophageal reflux, human rhinovirus bronchoalveolitis, and type-2 high inflammation.
- These findings support the utility of bronchoscopy for diagnosing refractory wheeze and developing novel therapies targeting specific causes like airway malacia, viral infections, and neutrophilia.
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.
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