311 - Airway endotypes define severity and treatment responses in pediatric acute asthma exacerbations in the emergency department

Publication Number: 2300.311

Nidhya Navanandan, University of Colorado School of Medicine, Aurora, CO, United States; Nathan Jackson, National Jewish Health, Denver, CO, United States; Jamie Everman, National Jewish Health, Morrison, CO, United States; Katrina Diener, National Jewish Health, Denver, CO, United States; Elizabeth Secor, National Jewish Health, Denver, CO, United States; Katharine L. Hamlington, University of Colorado Anschutz, Aurora, CO, United States; Melisa Tanverdi, University of Colorado School of Medicine, Aurora, CO, United States; Iriam J. Islas, University of Colorado School of Medicine, Denver, CO, United States; Christopher Linn, University of Colorado School of Medicine, Aurora, CO, United States; Cesar I. Romero Carreon, Children's Hospital Colorado, Aurora, CO, United States; Rebecca Helmuth, University of Colorado School of Medicine, Parker, CO, United States; Todd A. Florin, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States; Camille M. Moore, National Jewish Health, Denver, CO, United States; Rakesh D. Mistry, Yale School of Medicine, New Haven, CT, United States; Stanley J. Szefler, University of Colorado School of Medicine, Aurora, CO, United States; Andrew H. Liu, Children's Hospital Colorado, Aurora, CO, United States; Max A.. Seibold, National Jewish Health, Denver, CO, United States

Background: Asthma exacerbations are a leading cause of pediatric emergency department (ED) visits and hospitalizations. ED management of exacerbations remains uniform despite substantial heterogeneity in severity and treatment responses. Defining airway pathobiology underlying asthma exacerbations could enable personalized ED asthma care.

Objective: To identify airway molecular endotypes during asthma exacerbations in the ED and determine their associations with exacerbation severity and treatment response.

Design/Methods: We enrolled children 4-18 years presenting to a pediatric ED with asthma exacerbations from 6/22-5/24. Nasal swabs collected prior to standard ED asthma treatment, including systemic corticosteroids and inhaled bronchodilators, were used to perform whole-transcriptome RNA seq and viral metagenomic analysis. Using network analysis, participants were profiled as low-, medium-, or highly-expressing type 1 (T1) [interferon and anti-viral responses], type 2 (T2) [epithelial response to T2 cytokines], and type 17 (T17) [neutrophil and macrophage activation] airway endotypes. Outcomes assessed: 1) acute severity, measured by clinician impression (mild vs moderate/severe), and 2) response to standard ED treatment, defined as discharge home and receipt of no additional intensive therapies (i.e., continuous albuterol, IV magnesium, IV terbutaline, and IM epinephrine). Generalized linear models were used to assess association between airway endotypes and outcomes.

Results: Of 108 children, 59% had moderate/severe exacerbations and 56% demonstrated treatment response (Table 1). Network analysis revealed a cluster of antiviral immune response driven networks that included T1 (interferon) and T17 (IL-17, macrophage/neutrophil) inflammatory networks. In contrast, an orthogonal set of epithelial activation networks was identified that included an epithelial T2 cytokine response network (Figure 1). Classification of illnesses into low, moderate, and high T1 expressing groups, found T1 inflammation level was strongly related to higher viral load, lower severity, and treatment success. In contrast, similar classification of illnesses by T2 inflammation found these levels were related to severe illness and treatment failure (Figure 2).

Conclusion(s): Pediatric asthma exacerbations can be clustered by airway pathobiology into mild, T1-viral immune-driven or severe, T2 epithelial activation endotypes. These findings establish the prognostic utility of nasal airway endotypes for asthma exacerbations and highlight epithelial T2 inflammation as a target for therapeutic intervention to improve ED asthma outcomes for children.

Table 1. Baseline characteristics and clinical course of study cohort.


Figure 1. A-B) The frequency of study participants with airway T1-high and T2-high asthma endotypes.
A) A heat map of 104 network genes as expressed among the study cohort, hierarchically clustered into T1-low (T1-L), T1-medium (T1-M), and T1-high (T1H) groups. B) Similar to A but based on 19 T2 network genes.

Figure 2. A-B) T1 and T2 asthma endotype association with exacerbation severity and treatment response.
A) Bar plot depicting percentage of patients with moderate/severe exacerbations by T1 and T2 status. B) Bar plot depicting percentage of patients with treatment response by T1 and T2 status.