Recurrent Severe Preschool Wheeze: From Prespecified Diagnostic Labels to Underlying Endotypes

Polly F M Robinson, Sara Fontanella, Sachin Ananth, Aldara Martin Alonso, James Cook, Daphne Kaya-de Vries, Luisa Polo Silveira, Lisa Gregory, Clare Lloyd, Louise Fleming, Andrew Bush, Adnan Custovic, Sejal Saglani, Polly F M Robinson, Sara Fontanella, Sachin Ananth, Aldara Martin Alonso, James Cook, Daphne Kaya-de Vries, Luisa Polo Silveira, Lisa Gregory, Clare Lloyd, Louise Fleming, Andrew Bush, Adnan Custovic, Sejal Saglani

Abstract

Rationale: Preschool wheezing is heterogeneous, but the underlying mechanisms are poorly understood.Objectives: To investigate lower airway inflammation and infection in preschool children with different clinical diagnoses undergoing elective bronchoscopy and BAL.Methods: We recruited 136 children aged 1-5 years (105 with recurrent severe wheeze [RSW]; 31 with nonwheezing respiratory disease [NWRD]). Children with RSW were assigned as having episodic viral wheeze (EVW) or multiple-trigger wheeze (MTW). We compared lower airway inflammation and infection in different clinical diagnoses and undertook data-driven analyses to determine clusters of pathophysiological features, and we investigated their relationships with prespecified diagnostic labels.Measurements and Main Results: Blood eosinophil counts and percentages and allergic sensitization were significantly higher in children with RSW than in children with a NWRD. Blood neutrophil counts and percentages, BAL eosinophil and neutrophil percentages, and positive bacterial culture and virus detection rates were similar between groups. However, pathogen distribution differed significantly, with higher detection of rhinovirus in children with RSW and higher detection of Moraxella in sensitized children with RSW. Children with EVW and children with MTW did not differ in terms of blood or BAL-sample inflammation, or bacteria or virus detection. The Partition around Medoids algorithm revealed four clusters of pathophysiological features: 1) atopic (17.9%), 2) nonatopic with a low infection rate and high use of inhaled corticosteroids (31.3%), 3) nonatopic with a high infection rate (23.1%), and 4) nonatopic with a low infection rate and no use of inhaled corticosteroids (27.6%). Cluster allocation differed significantly between the RSW and NWRD groups (RSW was evenly distributed across clusters, and 60% of the NWRD group was assigned to cluster 4; P < 0.001). There was no difference in cluster membership between the EVW and MTW groups. Cluster 1 was dominated by Moraxella detection (P = 0.04), and cluster 3 was dominated by Haemophilus or Staphylococcus or Streptococcus detection (P = 0.02).Conclusions: We identified four clusters of severe preschool wheeze, which were distinguished by using sensitization, peripheral eosinophilia, lower airway neutrophilia, and bacteriology.

Keywords: cluster analysis; endotypes; infection; inflammation; pediatric wheeze.

Figures

Figure 1.
Figure 1.
Distribution of BAL-sample pathogens in recurrent severe wheeze (RSW) and nonwheezing respiratory disease (NWRD). Distribution of pathogens in BAL samples from children with RSW and positive results from (A) bacterial cultures (45 children) and (B) viral PCR analyses (44 children). Distribution of pathogens in BAL samples from children with NWRD and positive results from (C) bacterial cultures (14 children) and (D) viral PCR analyses (16 children). Multiple children had positive results for more than one pathogen in their BAL samples; hence, the total number of species is given under each graph. This differs from the total number of children with a positive infection rate. Not all participants had samples; results are only shown for samples successfully processed for infection results. RSV = respiratory syncytial virus.
Figure 2.
Figure 2.
BAL-sample neutrophilic inflammation and viral or bacterial detection in recurrent severe wheeze (RSW) and nonwheezing respiratory disease (NWRD). Percentage of BAL-sample neutrophils according to BAL-sample bacterial culture in (A) RSW (positive n = 36, negative n = 45) and (B) NWRD (positive n = 12, negative n = 16). Percentage of BAL-sample neutrophils according to BAL-sample viral PCR in (C) RSW (positive n = 31, negative n = 49) and (D) NWRD (positive n = 14, negative n = 13). Black circles represent children with positive BAL-sample infection results, and gray squares represent children with negative BAL-sample infection results. Not all participants had samples, as these were only taken if clinically indicated; results are only shown for samples successfully processed for both infection results and cellular inflammation. The n for each group is stated. Statistics represent (A and C) the results of D’Agostino and Pearson normality tests followed by Mann-Whitney tests for nonparametric data or (B and D) the results of Student’s t tests for parametric data. ***P < 0.001.
Figure 3.
Figure 3.
Relationship among allergic sensitization, use of inhaled corticosteroids (ICS), BAL-sample inflammation, and bacterial culture results in recurrent severe wheeze (RSW). (A) Bacterial culture results for RSW according to allergic sensitization. Black bars represent the proportion of patients with positive bacterial culture results (n = 16 with allergic sensitization, n = 28 with no allergic sensitization), and gray bars represent the proportion of patients with negative bacterial culture results (n = 13 with allergic sensitization, n = 40 with no allergic sensitization). (B and C) RSW BAL-sample inflammation according to BAL-sample bacterial culture results and allergic sensitization for (B) BAL-sample neutrophil percentages and (C) BAL-sample eosinophil percentages. Black circles represent children with RSW with positive bacterial culture results and allergic sensitization (n = 13), gray circles represent children with RSW with negative bacterial culture results and allergic sensitization (n = 8), black squares represent children with RSW with positive bacterial culture results and no allergic sensitization (n = 23), and gray squares represent children with RSW with negative bacterial culture results and no allergic sensitization (n = 24). (D) Bacterial culture results for RSW according to prescription of ICS. Black bars represent the proportion of patients with a positive bacterial culture result (n = 37 prescribed ICS, n = 8 not prescribed ICS), and gray bars represent the proportion of patients with a negative bacterial culture result (n = 39 prescribed ICS, n = 17 not prescribed ICS). (E and F) RSW BAL-sample inflammation according to BAL-sample bacterial culture results and prescription of ICS for (E) BAL-sample neutrophil percentages and (F) BAL-sample eosinophil percentages. Black circles represent children with RSW with positive bacterial culture results who were prescribed ICS (n = 32), gray circles represent children with RSW with negative bacterial culture results who prescribed ICS (n = 33), black squares represent children with RSW with positive bacterial culture results who were not prescribed ICS (n = 4), and gray squares represent children with RSW with negative bacterial culture results who were not prescribed ICS (n = 12). Not all participants had BAL samples, as these were only taken if clinically indicated; results are shown for samples successfully processed for cellular inflammation and/or bacterial infection in patients whose prescription of ICS or allergic sensitization status was known. Dashed red lines represent normal cutoff for BAL eosinophils. Statistics represent the results of chi-square tests for (A and D) categorical data or (B, C, E, and F) D’Agostino and Pearson normality tests followed by the Kruskal-Wallis tests for continuous nonparametric data, with Dunn’s correction for multiple comparisons being used *P < 0.05 and **P < 0.01.
Figure 4.
Figure 4.
Cluster characteristics and cluster distribution in preschool children with severe wheeze. (A–D) Within-cluster distribution of BAL-sample eosinophils (percentage), BAL-sample neutrophils (percentage), peripheral blood eosinophils (percentage), and peripheral blood neutrophils (percentage). Data were analyzed by using t tests. Boxplots represent the 25th and 75th percentiles and the median. (E–H) Within-cluster distribution of atopy, use of ICS, positive bacteriology results, and positive viral PCR results. Data were analyzed by using Fisher exact tests. Bar charts represent the relative frequency of each category. *P < 0.05 and ***P < 0.001. ICS = inhaled corticosteroids.

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