Respiratory Dysbiosis in Preschool Children with Asthma: Predictive of a Severe Form (DREAM)

The prevalence of asthma in preschool children is between 11 and12%. Inhaled corticosteroid therapy is the main therapy used, however this treatment seems insufficiently effective in some children.

Recent research in cystic fibrosis has made it possible to highlight pulmotypes corresponding to the different stages of pulmonary dysbiosis, and a predictive microbiological signature of an increased risk of early primocolonization to P. aeruginosa. These pulmotypes are the result of the so-called "enterotyping" analysis, a biostatistical method that makes it possible to stratify individuals according to the analysis of the microbiota. In the light of these data, it seems interesting to transcribe the concept of using a biomarker of the microbiota in the monitoring of a chronic lung disease such as asthma.

The hypothesis is that there is respiratory dysbiosis causing corticosteroid resistance to treatment in children under 3 years of age with severe asthma.

Study Overview

• Status: Recruiting
• Conditions: Dysbiosis; Asthma in Children
• Intervention / Treatment: Procedure: Stool test; Procedure: Blood test; Procedure: Induced sputum; Procedure: nasale virology

Detailed Description

The prevalence of asthma in preschool children is estimated to between 11 and 12%.

Inhaled corticosteroid therapy is the main therapy used, however this treatment seems insufficiently effective in some children.

Recent research in cystic fibrosis has made it possible to highlight pulmotypes corresponding to the different stages of pulmonary dysbiosis, and a predictive microbiological signature of an increased risk of early primocolonization to P. aeruginosa. These pulmotypes are the result of the so-called "enterotypeing" analysis, a biostatistical method that makes it possible to stratify individuals according to the analysis of the microbiota. In the light of these data, it seems interesting to transcribe the concept of using a biomarker of the microbiota in the monitoring of a chronic lung disease such as asthma.

The hypothesis is that there is respiratory dysbiosis causing corticosteroid resistance to treatment in children under 3 years of age with severe asthma.

The goal of this study is to research a difference between respiratory dysbiosis and severe asthma (i.e. resistant to doses of inhaled corticosteroids less than or equal to 200μg of fluticasone equivalent).

DREAM is a exploratory multicentric prospective case-control study.

The primary objective is to research a difference between respiratory dysbiosis and severe asthma (i.e. resistant to doses of inhaled corticosteroids less than or equal to 200μg of fluticasone equivalent) in children less than 36 months of age.

The secondary objectives are :

1. To compare the bacterial pulmotypes of children under 36 months of age with severe asthma with children with mild or moderate asthma.
2. To look for microbial biomarkers associated with corticosteroid resistance
3. To assess the association between digestive dysbiosis and severe asthma (i.e. resistant to inhaled corticosteroid doses less than or equal to 200μg fluticasone equivalent)
4. To look for an association between digestive dysbiosis and respiratory dysbiosis
5. To constitute a biocollection (sputum, stool, blood) of children with asthma for future analysis

30 patients are expected to be included in two arms : 15 uncontrolled asthmatic patients at moderate doses of inhaled corticosteroids and 15 asthmatic patients controlled at mild to moderate doses of inhaled corticosteroids.

Inclusion period : 12 months. Duration of patient's participation: 6 years Total study duration: 7 years

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Pierrick CROS; Phone Number: 02 98 22 36 59; Email: pierrick.cros@chu-brest.fr

Study Locations

• France
  • Finistère
    • Brest, Finistère, France, 29609
      • Recruiting
      • CHU de Brest
      • Contact: Pierrick CROS; Phone Number: 02 98 22 36 59; Email: pierrick.cros@chu-brest.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 3 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age greater than 1 year and less than 3 years
• Diagnosis of asthma by a pediatrician
• Parental consent
• Affiliation to the social security system

Exclusion Criteria:

• Chronic pathologies: congenital heart disease, immune deficiency, cystic fibrosis, bronchopulmonary dysplasia, encephalopathy, primary ciliary dyskinesia, laryngomalacia, digestive pathology requiring digestive surgery
• Premature < 34 SA
• Recent antibiotic therapy (< 7 days)
• Treatment with oral corticosteroid therapy within the previous 10 days.
• Patient whose parent(s) is (are) minor(s)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Case; Patients aged to 1 to 3 years with severe asthma (i.e. resistant to inhaled corticosteroid doses less than or equal to 200μg fluticasone equivalent). "Severe" asthma patients (cases) are defined by poor asthma control under doses of inhaled corticosteroids ≤200μg fluticasone equivalent.	Procedure: Stool test; At inclusion (day 0), stools will be collected with a kit for to remove to 5 mg for each patient.; Procedure: Blood test; Blood sample taken during inclusion (day 0) will be collected. There is between 19 and 26 mL for each patient.; Procedure: Induced sputum; At inclusion (day 0), bronchial aspiration after inhalation induction of 4 mL of 6% salt serum administered (after 200 μg of salbutamol via an inhalation chamber during a bronchial drainage session).; Procedure: nasale virology; At inclusion (Day 0), patients will be taken nasal swab for virology with swab adapted for nasal swab or with suction trap when blowing the child's nose (depending on center practice)and multiplex PCR.
Other: Control; Patients aged to 1 to 3 years with low or moderate asthma (controlled with mild to moderate doses of inhaled corticosteroids less than or equal to 200μg of fluticasone equivalent). "Mild to moderate" asthma patients (controls) are defined by disease control by first-line treatment in asthma, i.e. corticosteroids inhaled at mild to moderate doses of ≤200 micrograms/day of fluticasone equivalent.	Procedure: Stool test; At inclusion (day 0), stools will be collected with a kit for to remove to 5 mg for each patient.; Procedure: Blood test; Blood sample taken during inclusion (day 0) will be collected. There is between 19 and 26 mL for each patient.; Procedure: Induced sputum; At inclusion (day 0), bronchial aspiration after inhalation induction of 4 mL of 6% salt serum administered (after 200 μg of salbutamol via an inhalation chamber during a bronchial drainage session).; Procedure: nasale virology; At inclusion (Day 0), patients will be taken nasal swab for virology with swab adapted for nasal swab or with suction trap when blowing the child's nose (depending on center practice)and multiplex PCR.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of species in the microbial Community	The main evaluation is the comparison of respiratory biodiversity assessed using quantitative indices such as alpha diversity. Alpha diversity calculates the richness (number of species or OTU) by samples and how these OTUs are distributed (equitability). Richness will be measured with the Chao1 and equity with the Simpson index. The Shannon index is a composite measurethat allows us to have both information together, richness and equity in the same index.	Day 0
Index of microbial similarity of samples	The main evaluation is the comparison of respiratory biodiversity assessed using quantitative indices such beta diversity. Beta diversity analysis allows samples to be compared with each other. It calculates a matrix of distances between samples with the Bray Curtis/ Unifrac methods, weighted or not/ Jaccard by presence/absence. Next, the Principal Coordinate Analysis (PCoA ) will be used, multidimensional scaling to reduce this matrix to 2/3 dimensions. The samples from similar groups look alike with this analysis will be used.	Day 0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Enterotyping analysis	Characterization of bacterial pulmotypes by so-called "enterotyping" analysis in asthmatic children under 36 months of age. The enterotyping technique is a multifactorial technique that aims to group species / OTUs regularly found together. Enterotypes can characterize states of health or dysbiosis in the lung or intestines. OTU groups are used to classify individuals according to their lung / intestinal bacteria. The enterotypes / pulmotypes are considered already present in the literature and use PCA-type analyses to identify these groups of OTUs.	Day 0
Relative abundance	Relative abundance (expressed as a percentage) of each of the identified bacteriological taxa	Day 0
Indices of diversity	Types of indices of diversity of bacterial taxa identified in the digestive microbiota	Day 0

Collaborators and Investigators

• Sponsor: University Hospital, Brest

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2022
• Primary Completion (Estimated): February 4, 2028
• Study Completion (Estimated): February 4, 2028

Study Registration Dates

• First Submitted: November 16, 2021
• First Submitted That Met QC Criteria: December 30, 2021
• First Posted (Actual): January 14, 2022

Study Record Updates

• Last Update Posted (Actual): September 23, 2024
• Last Update Submitted That Met QC Criteria: September 19, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: asthma; respiratory microbiome; Paediatric Pulmonology
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Dysbiosis
• Other Study ID Numbers: 29BRC21.0252

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All collected data that underlie results in a publication
• IPD Sharing Time Frame: Data will be available after the publication of result and ending fifteen years following the last visit of the last patient
• IPD Sharing Access Criteria: Data access requests will be reviewed by the internal committee of Brest University Hospital. Requestors will be required to sign and complete a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No