Phenotypes of Recurrent Wheezing in Preschool Children: Identification by Latent Class Analysis and Utility in Prediction of Future Exacerbation

Abstract

Background: Recurrent preschool wheezing is a heterogeneous disorder with significant morbidity, yet little is known about phenotypic determinants and their impact on clinical outcomes.

Objective: Latent class analysis (LCA) was used to identify latent classes of recurrent preschool wheeze and their association with future exacerbations and inhaled corticosteroid (ICS) treatment response.

Methods: Data from 5 clinical trials of 1708 children aged 12 to 71 months with recurrent wheezing were merged. LCA was performed on 10 demographic, exposure, and sensitization variables to determine the optimal number of latent classes. The primary outcome was the annualized rate of wheezing exacerbations requiring systemic corticosteroids during the study intervention period; the secondary outcome was the time to first exacerbation. Exploratory analyses examined the effect of daily ICS treatment on exacerbation outcomes.

Results: Four latent classes of recurrent wheezing were identified; these were not distinguished by current symptoms or historical exacerbations but differed with regard to allergen sensitization and/or exposures. Annualized exacerbation rates (mean ± SEM/year) were 0.65 ± 0.06 for class 1 ("minimal sensitization"), 0.93 ± 0.10 for class 2 ("sensitization with indoor pet exposure"), 0.60 ± 0.07 for class 3 ("sensitization with tobacco smoke exposure"), and 0.81 ± 0.10 for class 4 ("multiple sensitization and eczema") (P < .001). In a research setting of high adherence, daily ICS treatment improved exacerbation rates in classes 2 and 4 but not the other groups.

Conclusions: Sensitization and exposure assessments are useful in the prediction of future exacerbation and may identify children most likely to respond favorably to daily ICS treatment.

Keywords: Asthma exacerbation; Asthma in children; Inhaled corticosteroid; Latent class analysis; Phenotype; Preschool child; Sensitization; Type 2 inflammation; Wheeze.

Figure 1.

(A) Distribution of studies, (B) episode-free days and (C) albuterol inhalations during the study run-in periods (mean ± SEM), and (D) prior year healthcare utilization for wheezing or asthma symptoms in all participants (N=1708) and each latent class (1 = minimal sensitization [N=494], 2 = sensitization with indoor pets [N=409], 3 = sensitization with tobacco smoke exposure [N=452], 4 = multiple sensitization with eczema [N=353]).

Figure 2.

(A) Annualized rate (mean ± SEM) and (B) probability of exacerbation in placebo-treated children with minimal sensitization (latent class 1, N=151), sensitization with indoor pets (latent class 2, N=104), sensitization with tobacco smoke exposure (latent class 3, N=132), and multiple sensitization with eczema (latent class 4, N=102) in the PEAK, AIMS, and APRIL studies. Numbers correspond to latent class groups.

Figure 3.

(A) Annualized rate (mean ± SEM) and (B) probability of exacerbation in the PEAK study placebo (solid bar) and daily inhaled corticosteroid (ICS, hatched bar) treatment arms. Numbers correspond to latent class groups (1 = minimal sensitization, 2 = sensitization with indoor pets, 3 = sensitization with tobacco smoke exposure, 4 = multiple sensitization with eczema).

Figure E1.

Class (i.e., phenotype) membership probability for all participants for the 4-class model. Results demonstrate that for each of the 4 latent classes, the probability of assignment to that latent class was >0.80 on average for each participant.

Figure E2.

Class (i.e., phenotype) membership probability for participants included in outcome analysis, utilizing the 4-class model. Results demonstrate that for each of the 4 latent classes, the probability of assignment to that latent class was >0.80 on average for each participant.

Figure E3.

(A) Distribution of studies, (B) episode-free days and (C) albuterol inhalations during the study run-in periods (mean ± SEM), and (D) healthcare utilization during the previous year in participants selected for outcome assessment (All, N = 489) and in the identified latent classes (1 = minimal sensitization, 2 = sensitization with indoor pets, 3 = sensitization with tobacco smoke exposure, 4 = multiple sensitization with eczema).