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Sejal Saglani: Pediatric severe asthma – Differences from adult disease in diagnosis and phenotypes

Summary of a presentation given on June 19 at EAACI 2017

Most children with severe asthma have eosinophilic airway inflammation. The question is, whether the eosinophils should be targeted therapeutically. It could be shown in adults and children that lower airways eosinophil measurements in the bronchoalveolar lavage (BAL) correlate positively with the noninvasive assessment of eosinophils in the sputum. Importantly, in adults, when sputum eosinophils were targeted to address treatment, patients with sputum eosinophils had fewer exacerbations compared to those who were treated according to clinical guidelines. However, targeting sputum eosinophils in children had no great benefit (Fleming 2012). This negative outcome could be due to the fact that the eosinophilic phenotype in children is highly variable over time in the same patient.  Interestingly, when taking a closer look, the phenotype variability over time in adults is not that different from children. A study by Al Samri and colleagues revealed that sputum eosinophilic phenotype instability in adults with severe asthma was similar to that of the instability found in children (Al Samri 2010). The reason why targeting eosinophils was effective in adults might stem from the fact that the study included patients with a more moderate disease.

The search for stable clusters

For targeted treatment, it would be desirable to do a longitudinal profiling, an idea that has already taken shape in studies with adult patients. In the ADEPT-study (ADEPT = Airways Disease Endotyping for Personalized Therapeutics), Silkoff and colleagues demonstrated that asthma patients’ phenotypes are highly unstable, especially when looking at type 2 markers. Also, in children, no longitudinal relationship between fractional exhaled nitric oxide (FeNO) and sputum eosinophils could be found (Fleming 2013). Thus, sputum eosinophils alone cannot be used to target treatment. A better way would be to use cluster analyses to identify phenotypes that are stable over time. Zaihra and colleagues (Zaihra 2016) identified four clusters in adult patients: predominantly severe asthma with late onset disease (A), female patients with severe asthma and high BMI (B), severe asthma with early onset, atopic (C), moderate asthma with good lung function (D). Yet, over one year, only half of the patients remained in the same cluster. Patients with variability in sputum eosinophil count were especially unlikely to stay in their cluster. There exists one interesting sub-group of patients with severe asthma, those who are persistently eosinophilic in their sputum. The persistent sputum eosinophilic phenotype in adult severe asthma is associated with increased exacerbation risk (Walsh 2016), and these patients benefit from the treatment with mepolizumab (Pavord 2012). According to Sejal Saglani, if children with a persistently eosinophilic sub-phenotype could be identified, they might also profit from mepolizumab.

Data from the ADEPT cohort and the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome Consortium) cohort revealed longitudinal stable clusters (Loza 2016). Cluster 1 consists of patients with mild asthma not treated with steroids, well-controlled with preserved lung function and a low-inflammatory phenotype. Cluster 2 is partially controlled, with mild airflow obstruction but severe airway hyperresponsiveness and a Th2 phenotype (brittle phenotype). Cluster 3 is partially controlled with mild airflow obstruction, but reduced vital capacity, less bronchodilator reversibility, and a non-Th2 phenotype with neutrophilic inflammation (COPD-like). Cluster 4 is poorly controlled, with marked airflow obstruction, marked bronchodilator reversibility, and a mixed inflammatory phenotype.

Neutrophils – are they good or bad?

One phenotype that has been identified in adults as being longitudinally stable is a non-type 2 neutrophilic phenotype. Is this the same in children? Probably not, since even in a subgroup of pediatric patients with persistent neutrophilia, no relationship between neutrophils and exacerbations could be found. In a study involving adult patients with severe asthma, azithromycin did not reduce severe exacerbations and lower respiratory tract infections compared to the placebo group (Brusselle 2013). However, when patients were split into those who were eosinophilic and non-eosinophilic, azithromycin did seem to reduce severe exacerbations in the non-eosinophilic subgroup. Could neutrophils serve as a therapeutic target in pediatric severe asthma? It is not clear whether the neutrophils are good or bad. Maybe they are there because they are fighting infection. In a study with pediatric patients with severe therapy-resistant asthma, no increase in BAL neutrophils could be found compared to a control group (Andersson 2017).

The researchers identified a subgroup of children with severe asthma who had intraepithelial neutrophils. The more intraepithelial neutrophils there were, the better the lung function – a result that was contrary to the expectations of the researchers. Therefore, targeting neutrophils in children might not be the right approach. This also makes sense in the context of the fact that children who grow up on traditional farms, such as Amish children, are less prone to asthma. Stein and colleagues found a significantly higher concentration of neutrophils in Amish children compared to children from Hutterite communities, where industrial farming is prevalent (Stein 2016). The same research team showed that mice that had been given inhaled house dust from Amish homes had reduced airway hyperresponsiveness, while Hutterite house dust reduced the lung function. Moreover, the mice given the Amish house dust had increased neutrophils and decreased eosinophils. In a similar study by Sejal Saglani and her team, mice were given inhaled house dust and Acinetobacter lwoffii, a bacterium found in farm yards in German communities with low asthma prevalence (unpublished data, in collaboration with Erika von Mutius). These mice were completely protected from airway hyperresponsiveness. Furthermore, the A. lwoffii-mice had reduced inflammation, less eosinophils and significantly more neutrophils. The role of neutrophils in pediatric severe asthma is still uncertain, but they might be protective.

Summary:

Eosinophilic asthma is a heterogenous disease. There is a significant variability in inflammation, airway remodeling and clinical phenotype between patients. It is necessary to look at each element in relationship to the individual child in order to develop an individualized targeted treatment plan. There are fewer differences between adult and child phenotypes than previously thought. If a sub-group of pediatric patients with persistent eosinophilia can be found, a treatment with mepolizumab or reslizumab could prove beneficial. The role neutrophils play in pediatric severe asthma is uncertain, but neutrophils might be protective. A prerequisite for designing a targeted treatment plan for children with severe asthma is a longitudinal phenotyping which reveals phenotypes that are stable over time. 

Sejal Saglani is Professor in Pediatric Respiratory Medicine at the Imperial College London, UK.

References:

Al Samri MT, Benedetti A, Prefontaine D et al. Variability of sputum inflammatory cells in asthmatic patients receiving corticosteroid therapy: a prospective study using multiple samples. J Allergy Clin Immunol 2010; 125:1161–3, e4

Andersson CK, Adams A, Nagakumar P et al. Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function. Journal of Allergy and Clinical Immunology 2017; 139: 1819–1829.e11

Brusselle GG, Vanderstichele C, Jordens P et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013; 68: 322–9

Fleming L, Tsartsali L, Wilson N et al. Longitudinal Relationship between Sputum Eosinophils and Exhaled Nitric Oxide in Children with Asthma." American Journal of Respiratory and Critical Care Medicine 2013; 188: 400–402

Fleming L, Wilson N, Regamey N et al. Use of sputum eosinophil counts to guide management in children with severe asthma. Thorax 2012; 67:193–8

Loza MJ, Adcock I, Auffray C et al. Longitudinally Stable, Clinically Defined Clusters of Patients with Asthma Independently Identified in the ADEPT and U-BIOPRED Asthma Studies. Ann Am Thorac Soc. 2016: 13 Suppl 1: S102–3

Pavord ID, Korn S, Howarth P et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380: 651–9

Silkoff PE, Strambu I, Laviolette M et al. Asthma characteristics and biomarkers from the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) longitudinal profiling study. Respiratory Research 2015; 16:142

Stein MM, Hrusch CL, Gozdz JG et al. Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children. N Engl J Med 2016; 375: 411–421

Walsh CJ , T Zaihra T, Benedetti A et al. Exacerbation Risk in Severe Asthma Is Stratified by Inflammatory Phenotype Using Longitudinal Measures of Sputum Eosinophils. Clin Exp Allergy 2016; 46: 1291–1302

Zaihra T, Walsh CJ, Ahmed S et al. Phenotyping of difficult asthma using longitudinal physiological and biomarker measurements reveals significant differences in stability between clusters. BMC Pulmonary Medicine 2016; 16:74

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