Inflammatory and Immune Profiles During a Severe Exacerbation in Preschool Asthmatic Children (<5 Years) (VIRASTHMA2)

Inflammatory and Immune Profiles at the Time of a Severe Exacerbation in Preschool Asthmatic Children (<5 Years), According to the Phenotype

Asthma/wheeze begins in the first years of life and is the most common chronic disease in preschool children (< 5 years).

Different phenotypes have been suggested: Episodic-Viral Wheeze (EVW), absence of symptoms between exacerbations, among which Severe Intermittent Wheeze (SIW); and Multiple-trigger wheeze (MTW). The determinants of these different clinical phenotypes and their evolution have been poorly studied.

The purpose of this study is to assess preschool wheezers at the time of a severe exacerbation: clinical features and biological determinants (virus/bacteria, molecules and cells involved in the inflammation) and at steady state (8 weeks later) and to follow them up until the age of 7. The investigators hypothesize that the nature of the inflammation at the time of the exacerbation is different between these clinical phenotypes and may be associated with different clinical and functional trajectories

Study Overview

• Status: Active, not recruiting
• Conditions: Asthma
• Intervention / Treatment: Other: Clinical, microbiological and inflammatory phenotype

Detailed Description

Asthma/wheeze begins in the first years of life and is the most common chronic disease in preschool children (< 5 years).

Different phenotypes have been suggested: Episodic-Viral Wheeze (EVW): wheezing during discrete time periods (exacerbations), absence of symptoms between exacerbations; among which Severe Intermittent Wheeze (SIW): EVW with ≥ 2 exacerbations over the last 6 months; and Multiple-trigger wheeze (MTW): wheezing during exacerbations but also symptoms (cough, exercise-induced symptoms,…) between episodes. The determinants of these different clinical phenotypes and their evolution have been poorly studied.

The purpose of this study is to assess preschool asthmatic children at the time of a severe exacerbation: clinical features and biological determinants (virus/bacteria, molecules and cells involved in the inflammation) and at steady state (8 weeks later) and to follow them up until the age of 7. The investigators hypothesize that the nature of the inflammation at the time of the exacerbation is different between these clinical phenotypes and may be associated with different clinical and functional trajectories.

The primary objective is to compare levels of IFNg, IL-5, IL-13, IL-33, TSLP in blood and induced sputum between the 2 main phenotypes: EVW and MTW.

Preschool asthmatic children hospitalized for a severe exacerbation (requiring a course of systemic steroids) are included in a pediatric ward of one of the hospitals involved in the study, in the Hauts-de-France Region, France.

Clinical phenotype: temporal pattern of wheeze (EVW, SIW, MTW), history and clinical data, allergy diagnosis work-up Microbiological phenotype: viral status (PCR in nasal swab sample), bacteriological status (culture of induced sputum) Inflammatory phenotype: profile of cytokines, phenotype of immune cells in the blood and the sputum, cytokine response to TLR ligands by peripheral blood mononuclear cells will be assessed at the time of inclusion and at steady state 8 weeks later.

Children will be follow-up until the age of 7 (clinical data, control of asthma, lung function).

• Study Type: Observational
• Enrollment (Estimated): 150

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 5 years (Child)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Preschool asthmatic children hospitalized for a severe exacerbation (requiring a course of systemic steroids), in a pediatric ward of one of the hospitals involved in the study, in the Hauts-de-France Region, France.

Description

Inclusion Criteria:

• Preschool children aged 1 to < 5 years
• Asthmatic / recurrent wheezers (≥ 3 discrete exacerbations since birth and/or symptoms between exacerbations, according to the definition from the French HAS and GINA guidelines)
• Hospitalized (less than 3 days ago) for a severe exacerbation (requiring a course of oral steroids)
• In a pediatric ward participating in the study (Hospital centers of Lille, Arras, Bethune, Douai, Lens, Roubaix, Tourcoing, Armentieres, Seclin)
• Parental consent

Exclusion Criteria:

• History of chronic disease (other than asthma)
• History of preterm birth (inf 36 weeks of amenorrhea)
• Lack of understanding from the parents

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Episodic viral wheezers (EVW); EVW: Wheezing during discrete time periods (exacerbations), absence of symptoms between exacerbations Among which SIW: EVW with ≥ 2 exacerbations over the last 6 months Clinical, microbiological and inflammatory phenotype	Other: Clinical, microbiological and inflammatory phenotype; Clinical phenotype: temporal pattern of wheeze (EVW, SIW, MTW), history and clinical data, allergy diagnosis work-up Microbiological phenotype: viral status (PCR in nasal swab sample), bacteriological status (culture of induced sputum) Inflammatory phenotype: profile of cytokines, phenotype of immune cells in the blood and the sputum, cytokine response to TLR ligands by peripheral blood mononuclear cells.
Multiple trigger wheezers (MTW); MTW : wheezing during exacerbations but also symptoms between episodes. Clinical, microbiological and inflammatory phenotype	Other: Clinical, microbiological and inflammatory phenotype; Clinical phenotype: temporal pattern of wheeze (EVW, SIW, MTW), history and clinical data, allergy diagnosis work-up Microbiological phenotype: viral status (PCR in nasal swab sample), bacteriological status (culture of induced sputum) Inflammatory phenotype: profile of cytokines, phenotype of immune cells in the blood and the sputum, cytokine response to TLR ligands by peripheral blood mononuclear cells.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory profile at exacerbation	concentration levels of IFNg, IL-5, IL-13, IL-33, TSLP in blood and induced sputum (all concentrations expressed in pg/ml, obtained with multiplex assays) between wheeze patterns: EVW (among which SIW) vs MTW	At the time of the inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory profile at steady state	concentration levels of IFNg, IL-5, IL-13, IL-33, TSLP in blood and induced sputum (all concentrations expressed in pg/ml, obtained with multiplex assays) between wheeze patterns: EVW (among which SIW) vs MTW	at baseline: consult at least 8 weeks after exacerbation
Change of inflammatory profile between exacerbation and steady state	concentration levels of IFNg, IL-5, IL-13, IL-33, TSLP in blood and induced sputum (all concentrations expressed in pg/ml, obtained with multiplex assays) between wheeze patterns: EVW (among which SIW) vs MTW	At the time of the inclusion and at baseline (consult at least 8 weeks after exacerbation)
Levels of cytokines in blood	Concentration levels of cytokines (IL-4, IL-17A, IL-22, TNF-alpha, IL-1beta, IL-6, IL-10) in blood (all concentrations expressed in pg/ml, obtained with multiplex assays) between wheeze patterns: EVW (among which SIW) vs MTW	At the time of the inclusion and at baseline (consult at least 8 weeks after exacerbation)
Levels of cytokines in induced sputum	Concentration levels of cytokines (IL-4, IL-17A, IL-22, TNF-alpha, IL-1beta, IL-6, IL-10) in induced sputum (all concentrations expressed in pg/ml, obtained with multiplex assays) between wheeze patterns: EVW (among which SIW) vs MTW	At the time of the inclusion and at baseline (consult at least 8 weeks after exacerbation)
Levels of interferons in blood	Concentrations levels of interferons (IFN-beta, IL-29) in blood (all concentrations expressed in pg/ml, obtained with multiplex assays) between wheeze patterns: EVW (among which SIW) vs MTW	At the time of the inclusion and at baseline (consult at least 8 weeks after exacerbation)
Levels of interferons in induced sputum	Concentration levels of interferons (IFN-beta, IL-29) in induced sputum (all concentrations expressed in pg/ml, obtained with multiplex assays) between wheeze patterns: EVW (among which SIW) vs MTW	At the time of the inclusion and at baseline (consult at least 8 weeks after exacerbation)
Levels of chemokines in blood	Concentration levels of chemokines (CXCL8, CXCL10, CCL5, CCL20) in blood (all concentrations expressed in pg/ml, obtained with multiplex assays) between wheeze patterns: EVW (among which SIW) vs MTW	At the time of the inclusion and at baseline (consult at least 8 weeks after exacerbation)
Levels of chemokines in induced sputum	Concentration levels of chemokines (CXCL8, CXCL10, CCL5, CCL20) in induced sputum (all concentrations expressed in pg/ml, obtained with multiplex assays) between wheeze patterns: EVW (among which SIW) vs MTW	At the time of the inclusion and at baseline (consult at least 8 weeks after exacerbation)
Expression patterns of mononuclear cells	Percentage of mononuclear cells in peripheral blood and sputum (sorted by flow cytometry): lymphocytes, dendritic cells, innate lymphoid cells	At the time of the inclusion and at baseline (consult at least 8 weeks after exacerbation)
Percentage of patients with tobacco exposure	Percentage of tobacco exposure (qualitative data)	At the time of the inclusion
Percentage of patients with mould/moisture exposure	Percentage of visible mould/moisture exposure (qualitative data, based on declaration by the parents)	At the time of the inclusion
Percentage of patients with pet ownership	Percentage of pet ownership (qualitative data)	At the time of the inclusion
Percentage of patients living in urban area	Percentage of urban living (qualitative data)	At the time of the inclusion
number of asthma exacerbations in the previous year	number of asthma exacerbations in the previous year (quantitative data)	At the time of the inclusion
Percentage of patients with associated atopic diseases	Percentage of associated atopic disorders: atopic dermatitis, atopic rhinitis, food allergy (qualitative data)	At the time of the inclusion
Control of asthma	Control of asthma based on symptoms (breath, cough, breathlessness, impact on activity and social behavior) and previous exacerbations in the past year, and classified according to GINA criteria: well-controlled, partly controlled, uncontrolled (semi-quantitative)	At the time of the inclusion and at baseline (consult at least 8 weeks after exacerbation)
Features of the exacerbation: severity	Severity assessed during the first hour in the emergency department (before treatment), using PRAM severity score: mild asthma (0-3), moderate asthma (4-7), severe asthma (8-12) (quantitative data)	At the time of the inclusion
Features of the exacerbation: length	Length of stay and length of oxygen need (in days)	At the time of the inclusion
Atopy	Atopy: positivity of skin prick tests (≥ 3 mm diameter) and/or specific IgE (≥ 0,35 ku/l), mono or polysensitized status (qualitative data)	At the time of the inclusion and at the age of 7
Blood leukocyte count	Count of neutrophils and eosinophils (number/mm3)	At the time of the inclusion and at the age of 7
ImmunoCAP ISAC (Thermo Fisher Scientific)	Levels of component specific IgE antibodies will be expressed in ISAC standardized units (ISU). We will categorized the raw data into 4 sIgE semiquantitative discrete groups, according to the manufacturer's guidelines: no (<0.3 ISU), low (0.3-1 ISU), medium (1-15 ISU), and high (>15 ISU) sensitization	At the time of the inclusion and at the age of 7
Microbiological phenotype: viral status	Virus identification by PCR in nasal swab sample (qualitative data)	At the time of the inclusion and at baseline (consult at least 8 weeks after exacerbation)
Microbiological phenotype: bacteriological status	Positive identification of bacteria (positive if titer >= 10.4/ml) by culture of induced sputum (qualitative data)	At the time of the inclusion and at baseline (consult at least 8 weeks after exacerbation)
History at the age of 7	History of asthma exacerbations in the previous year, presence of other atopic diseases: atopic dermatitis, atopic rhinitis, food allergy (qualitative data)	At the age of 7
Control of asthma at the age of 7	Control of asthma based on symptoms (breath, cough, breathlessness, impact on activity and social behavior) and previous exacerbations in the past year, and classified according to GINA criteria: well-controlled, partly controlled, uncontrolled (semi-quantitative)	At the age of 7
Atopy at the age of 7	Atopy: positivity of skin prick tests (≥ 3 mm diameter) and/or specific IgE (≥ 0,35 ku/l), mono or polysensitized status (qualitative data)	At the age of 7
Lung function at the age of 7: forced expiratory volume in one second	Forced expiratory volume in one second (FEV1) after administration of short acting beta agonists, obtain with spirometry test (expressed in Z-score)	At the age of 7
Lung function at the age of 7 : forced vital capacity	Forced vital capacity (FVC) after administration of short acting beta agonists, obtain with spirometry test (expressed in Z-score)	At the age of 7

Collaborators and Investigators

• Sponsor: University Hospital, Lille
• Collaborators: Stallergenes Greer; Région Nord-Pas de Calais, France
• Investigators: Principal Investigator: Antoine Deschildre, MD, University Hospital, Lille

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2015
• Primary Completion (Actual): April 12, 2023
• Study Completion (Estimated): February 1, 2033

Study Registration Dates

• First Submitted: January 17, 2019
• First Submitted That Met QC Criteria: May 20, 2019
• First Posted (Actual): May 23, 2019

Study Record Updates

• Last Update Posted (Estimated): December 16, 2025
• Last Update Submitted That Met QC Criteria: December 8, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Asthma; preschool; phenotype; wheeze
• Additional Relevant MeSH Terms: Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Signs and Symptoms, Respiratory; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Asthma; Respiratory Sounds
• Other Study ID Numbers: 2014_20; 2014-A01687-40 (Other Identifier: ID-RCB number, ANSM)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No