Diagnosing Asthma With Clinically Accessible, Non-invasive, and Efficient Tests: a Child-inclusive Translational Investigation

NCT ID: NCT07011394

Last Updated: 2025-06-08

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 123 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2024-04-09
• Study Completion Date: 2027-07-01

Brief Summary

Asthma is a common inflammatory respiratory disease affecting 11% of Canadians, but its diagnosis remains challenging, leading to delays in treatment or overtreatment. Spirometry with a reversibility test and bronchial provocation testing (BPT), considered the gold standard, are the reference diagnostic methods. However, access to BPT is limited as it is performed in hospital settings.

Type 2 inflammation biomarkers, the fractional exhaled nitric oxide (FeNO) and blood eosinophils (EOS), represent a potential alternative. In addition to their prognostic and theragnostic value, these markers predict a good response to inhaled corticosteroids in individuals aged ≥ 6 years with asthma. However, their use remains restricted to pulmonologists in specialized clinics and is not recommended as a diagnostic tool in Quebec.

Despite studies demonstrating their diagnostic value in specialized settings, these tests remain underexplored in primary care and insufficiently studied in children under 12 years.

The objective of ou study is to evaluate the relevance and performance of FeNO and blood eosinophils in the diagnosis of asthma in children referred in primary care with non-diagnostic spirometry.

Detailed Description

Background Asthma is a common inflammatory airway disease affecting 11% of Canadians. However, its diagnosis remains a significant challenge Spirometry is the first-line diagnostic test, aimed at detecting reversible bronchial obstruction. However, this test yields false-negative results in 40% of cases. The gold standard for diagnosis is the bronchial provocation test; in fact, 80% of patients with a positive provocation test had a normal spirometry result. However, this test requires a lengthy procedure and must be conducted in a hospital setting, making access difficult. Consequently, this leads to both over- and underdiagnosis.

Thus, it is necessary to explore other effective diagnostic methods. Fractional exhaled nitric oxide (FeNO) and blood eosinophil count (BEC) are biomarkers of type 2 inflammation in asthma. Elevated levels are associated with a worse prognosis but also predict a better response to inhaled corticosteroids. These biomarkers have demonstrated diagnostic utility in specialized contexts. However they remain rarely used and lack validation in primary care in Canada, especially in children under 12.

Hypothesis Measuring blood eosinophils and FeNO is a practical and precise diagnostic strategy for children with suspected asthma in primary care when spirometry results are inconclusive.

Objectives This prospective observational study aims to estimate and validate the diagnostic performance of type 2 inflammatory biomarkers, FeNO and/or BEC, in children aged 6 to <18 years referred by primary care providers for suspected asthma with inconclusive pre- and post-bronchodilator spirometry. Additionally, an exploratory analysis will assess inflammatory proteins (alarmins, type 2 cytokines, and chemokines) in serum and nasal epithelial fluid. These objectives will contribute to improving our knowledge of the mechanistic and operational value of type 2 inflammatory biomarkers in an under-studied population.

Methods In parallel with the DIVE study (NCT05992519; Nagano #2023-4791), the investigators propose extending the research to pediatric populations through this twin study (DIVE2), which involves 123 participants aged 6 to <18 years with non-diagnostic pre- and post-bronchodilator spirometry, referred from primary care for bronchial provocation testing. Before this test, participants will have their FeNO measured, undergo a blood test (for BEC, allergy testing, and inflammatory proteins), and nasosorption will be performed. The target sample size of 123 is powered at 90% to calculate the area under the curve (AUC) for three receiver operating characteristic (ROC) curves, with an AUC ≥ 0.7, which is significantly different from the null hypothesis (AUC = 0.5), using a conservatively corrected two-sided α error of < 0.016, assuming a positive/negative case ratio of 2.

These ROC curves will be developed based on the gold standard, bronchial provocation with methacholine (dose causing a 20% drop in FEV1 (DP20) <400 mcg. In line with our institutional procedures, the investigators will not apply the European DP20 threshold of ≤200 mcg but will analyze the impact of other thresholds.

Outcomes :

The primary analysis will assess the diagnostic performance of these biomarkers by calculating the ROC and AUC for FeNO, EOS, and their combination.

The exploratory outcomes are:

• Evaluation of the effectiveness of biomarkers as a diagnostic tool based on diagnostic delay and costs compared to methacholine challenges
• Analysis of biomarker levels in asthmatic patients at the time of diagnosis according to the ORACLE model, for stratification (https://www.oraclescore.com/fr)
• Univariate and multivariate modelling between eosinophils, FeNO, and inflammatory proteins in serum and nasal epithelial fluid (alarmins Thymic stromal lymphopoetin (TSLP) and IL-33; type-2 cytokines IL-4, -5, -13; chemokines eotaxin-3 and thymus activating regulatory cytokine (TARC), prostaglandine-D2 (PGD2), leukotriene-E4 (LTE4), interféron-gamma, tumour necrosis factor alpha (TNF-α))
• Evaluation of participants' and referring physicians' perception of biomarker measurement in relation to asthma diagnosis.
• Longitudinal follow-up of participants to assess medication, symptoms, quality of life, and exacerbations.
• The environmental impact of diagnostic delays due to unnecessary inhaler prescriptions and usage.

Feasibility The University Hospital Centre of Sherbrooke (CHUS), University Hospital Centre of Sainte Justine (CHUSJ), and Montreal Children's Hospital have a waiting list of over 1,300 methacholine challenge tests requested by primary care providers for pediatric patients.

Expected Results: the investigators expect to show type 2 biomarkers such as FeNO and BEC are a practical and effective alternative for diagnosing asthma in primary care particularly when access to standard tests is limited. The investigators expect to strengthen the mechanistic understanding of type 2 inflammatory asthma.

Impact: The investigators aim to provide scientific evidence that biomarkers such as FeNO and blood eosinophils can enhance and accelerate the diagnostic process for children aged 6 to <18 years. Due to their mechanistic, prognostic, and theranostic value, early detection of these biomarkers will allow for the timely initiation of appropriate treatment, ultimately improving asthma management, particularly in the pediatric population. This approach is expected to positively impact the reduction of overdiagnosis and underdiagnosis, benefiting prognosis, quality of life, and offering economic and ecological advantages.

Conditions

Diagnosis; Inflammation; Asthma in Children; Asthma

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Patients aged 6-18 with suspected asthma, referred by primary care for methacholine BPT

Patients will be recruited from a larger study, Propulsion Santé, which investigates the usefulness of FeNO and BEC in prioritizing patients whith suspected asthma for bronchial provocation testing in primary care. 1,500 participants will be invited to receive spirometry at 3 centers: CHUS, CHUSJ, and Montreal Children's Hospital. If spirometry is non-diagnostic, patients aged 6 to 18 years who are referred for methacholine challenge testing will be offered the opportunity to participate in the DIVE2 study.In addition to a medical assessment and standardized questionnaires (ACQ5, ACT, and EQ-5D), participants will undergo FeNO and BEC measurements, and additional blood tests (complete blood count with differential, C-reactive protein, total and specific serum immunoglobulin E, and biobank sample collection). a nasosorption and urine analysis will be performed as part of this protocol.

FeNO

Intervention Type: DIAGNOSTIC_TEST

FeNO will be measured before the bronchial provocation test using a FeNO VIOX device

Blood eosinophil count

Intervention Type: DIAGNOSTIC_TEST

a blood test will be performed om the day of bronchial provocation test

Interventions

FeNO

FeNO will be measured before the bronchial provocation test using a FeNO VIOX device

Intervention Type: DIAGNOSTIC_TEST

Blood eosinophil count

a blood test will be performed om the day of bronchial provocation test

Intervention Type: DIAGNOSTIC_TEST

Eligibility Criteria

Inclusion Criteria

• Individuals aged 6 to <18 years, presenting symptoms suggestive of asthma
• Patients referred for a methacholine bronchial provocation test by primary care (defined as non-pulmonologist, non-ENT specialist, non-allergist)
• Spirometry inconclusive

Exclusion Criteria

• Use of an inhaled or systemic corticosteroid in the previous 48 hours;
• Smoking in the previous 6 hours; history of viral and/or bacterial respiratory infection in the past 4 weeks;
• major cardiopulmonary disease, including: a) chronic obstructive pulmonary disease (COPD), defined by all of the following: i) aged ≥ 40 years , ii) permanent obstruction on spirometry (FEV1/FVC <0.7) and iii) a smoking history of >10 pack-years or known alpha-1-antitrypsin deficiency, b) lung conditions deemed significant by the investigator, including cystic fibrosis and bronchiectasis, and c) unstable heart disease.

• Minimum Eligible Age: 6 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Association Pulmonaire du Quebec

OTHER

Sponsor Role: collaborator

Fonds de la Recherche en Santé du Québec

OTHER_GOV

Sponsor Role: collaborator

Fondation JA DeSève

UNKNOWN

Sponsor Role: collaborator

Opération Enfant Soleil

UNKNOWN

Sponsor Role: collaborator

Université de Sherbrooke

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

CHU Sainte-Justine

Montreal, Quebec, Canada

Site Status: NOT_YET_RECRUITING

Montreal Children's Hospital

Montreal, Quebec, Canada

Site Status: NOT_YET_RECRUITING

CIUSSS de l'Estrie - CHUS

Sherbrooke, Quebec, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Simon Couilard, MD MSc

Role: CONTACT

s.couillard@usherbrooke.ca

+1-819-346-1110 ext. 15037

Facility Contacts

Garry Cormier, Inh

Role: primary

garry.cormier.hsj@ssss.gouv.qc.ca

+15143454931

Larry Lands, MD

Role: primary

larry.lands@mcgill.ca

+15144124400

Morgane Gronnier, MD

Role: primary

morgane.gronnier@usherbrooke.ca

+18193461110

Other Identifiers

2024-5346

Identifier Type: -

Identifier Source: org_study_id