Biomarkers and Respiratory Omics as New CHildren Opportunities - Study of Clinical Outcomes and Predictivity Evaluation

Official title

Biomarkers and Respiratory Omics as New CHildren Opportunities - Study of Clinical Outcomes and Predictivity Evaluation - a Multi-cohort, Multi-center Study

Overview

The goal of this observational study is to improve the identification of biomarkers that predict disease progression and to assess the effectiveness of current therapies in children with asthma and protracted bacterial bronchitis. The main aim of the study is to evaluate the microbiome composition and diversity, cellular composition, and metabolomic profile. In addition, to assess their correlation on subsequent treatment and disease course in children with asthma, protracted bacterial bronchitis, and in those receiving inhaled glucocorticosteroids without a diagnosis of asthma. Participants will undergo fiberoptic bronchoscopy. During bronchoscopy, the performing physician will collect Bronchoalveolar lavage fluid samples for metagenomic and metabolomic analysis, as well as mucosal biopsies for histopathological evaluation.

Detailed description

This prospective cohort study will enroll 160 participants and allocate them into study arms according to their medical history. The planned arms include: children with asthma, children with protracted bacterial bronchitis, children without asthma who are exposed to inhaled glucocorticosteroids, children with chronic cough, and a control group.

Participants will be recruited from the Pediatric Pulmonology Departments of the Medical Universities in Warsaw and Lodz. At baseline, investigators will administer a standardized medical questionnaire approved by both medical centers. All participants will undergo a single fiberoptic bronchoscopy during hospitalization according to clinical indications and with informed consent. During bronchoscopy, bronchoalveolar lavage (BAL) fluid samples will be collected for metagenomic, metabolomic, culture, biochemical, and cytological analyses. Additional mucosal biopsies will be obtained with separate consent if applicable.

Follow-up visits will include blood sample collection, sputum sampling (for cooperative children), spirometry, impulse oscillometry, and Fractional Exhaled Nitric Oxide measurements, without repeat bronchoscopy. The bronchoscopy procedure will not be repeated.

The study involves analysis of biological samples obtained during clinically indicated bronchoscopy, followed by a 5-year observation period. The findings will aid in distinguishing asthma phenotypes, identifying risk factors for asthma and protracted bacterial bronchitis, and improving the understanding of factors contributing to poor treatment response in these conditions.

Interventions

• Procedure fiberoptic bronchoscopy
  During procedure performing physician will evaluate respiratory tract anatomy. Samples of bronchoalveolar lavage fluid will be collected for culture, cellular composition analysis, amphiregulin level, cytokine profiling, metagenomic sequencing, metabolomic assessment, additionally mucosal biopsy will be performed using forceps and brush techniques for histopathological evaluation
• Procedure blood sample collection
  5 mL sample of blood will be collected in each individual at baseline and during follow-up visits for complete blood count and Immunoglobulin E levels
• Diagnostic test Respiratory functional tests
  At baseline and during each follow-up visit children will perform spirometry, Impulse Oscillometry and Fractional Exhaled Nitric Oxide
• Diagnostic test Sputum culture
  At baseline and during first follow-up visit sputum will be collected from each individual for culture

Primary outcome measures

• Evaluation on microbiome composition and diversity, cellular composition, and metabolomic profile between study groups [Time frame: Index hospitalization, immediately after the procedure]
• Correlation of metagenomic and metabolomic findings on subsequent treatment and disease course between groups [Time frame: 2 years]

Secondary outcome measures (12)

• Comparison of the previous medical history and demographic characteristics across the study groups [Time frame: At baseline]
• Assessment of the degree of asthma control among children diagnosed with asthma according to Global Initiative for Asthma [Time frame: 5 years]
• Evaluation how the place of residence influences the incidence and clinical course of the studied diseases [Time frame: 5 years]
• Assessment of exposure to PM10 dust at the place of residence during the year preceding study inclusion in children from each group [Time frame: At baseline]
• Comparison of the normalized difference vegetation index (NDVI) and chlorophyll index (CI) green levels between study groups at baseline [Time frame: At baseline]
• Comparison of the sputum culture at baseline and at the control visit [Time frame: 2 years]
• Comparison of the baseline sputum culture findings with BALF culture and metagenomic results [Time frame: 2 years]
• Evaluation of the initial Immunoglobulin E (IgE) concentrations and their dynamics of change between groups [Time frame: 5 years]
• Comparison of the eosinophil concentrations according to disease type and course [Time frame: 5 years]
• Assessment of the correlation between ICS used without an asthma diagnosis and airway dysbiosis [Time frame: 2 years]
• Evaluation of asthma treatment response, exacerbation rates, and need for bronchodilators according to airway metabolome profiles [Time frame: 5 years]
• Comparison of the asthma subtypes and evaluate possibilities for developing personalized treatment in selected pediatric groups [Time frame: 2 years]

Eligibility criteria

Inclusion criteria

• Age at the beginning of the study 0-17 years old
• Clinical indication and qualification by the attending physician for fiberoptic bronchoscopy under general anesthesia:

• Obstruction of the airways:
• Suspicion of foreign body aspiration
• Persistent stridor
• Abnormal result of functional tests of respiratory system - flattening of inspiratory or expiratory curve, presence of restriction (tested vital capacity <5 percentile) or irreversible obstruction (persistence of Tiffneau index <5 percentile despite administration of bronchodilators)
• Radiological findings located in the course of the larynx, trachea or bronchi
• Persistent atelectasis on subsequent radiological examinations
• Persistent cough >4 weeks
• Hemoptysis
• Suspected laryngomalacia or tracheobronchomalacia
• Suspected tracheoesophageal fistula
• Persistent dyspnea unresponsive to anti-asthmatic treatment used for min. 2 months, with no other identifiable causes
• Radiologically detected mediastinal abnormalities
• Suspected presence of a vascular ring
• Presence of excessive secretions that are impossible for the patient to expectorate
• Fine needle biopsy of cystic lesions
• Obtained consent from patient/legal guardian for participation in the study

Exclusion criteria

• Active acute respiratory infection up to 4 weeks before the procedure
• Taking antibiotics or systemic glucocorticosteroids up to 4 weeks before the procedure
• Patients with very severe comorbidities (congenital immunodeficiencies, genetic disorders, neurological or neuromuscular diseases, cancer, severe congenital heart defects, heart failure, liver failure, inflammatory bowel disease, celiac disease)
• Patients with blood clotting disorders
• Children with diagnosed respiratory diseases other than asthma and protracted bacterial bronchitis - including interstitial diseases, tuberculosis, inflammation of small and medium-sized blood vessels
• Patients for whom >48 hours have passed between suspicion of foreign body aspiration and interventional bronchoscopy
• Children with foreign body aspiration having a foreign body located in the trachea

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Poland · 1 center

• Żwirki i Wigury 63A — Warsaw

Publications

• Martin J, Townshend J, Brodlie M. Diagnosis and management of asthma in children. BMJ Paediatr Open. 2022 Apr;6(1):e001277. doi: 10.1136/bmjpo-2021-001277. PMID 35648804
• Thomas R, Marchant JM, Goyal V, Masters IB, Yerkovich ST, Chang AB. Clinical utility of elective paediatric flexible bronchoscopy and impact on the quality of life: protocol for a single-centre, single-blind, randomised controlled trial. BMJ Open Respir Res. 2024 Feb 26;11(1):e001704. doi: 10.1136/bmjresp-2023-001704. PMID 38413121
• Licata MA, Mencarini P, Mastrobattista A, Carli SM, Cerva C, Mosti S, Libertone R, Zolezzi A, Vittozzi P, Nisii C, Mazzarelli A, Cannas A, Navarra A, Ianniello S, Trisolini R, Goletti D, Palmieri F, Gualano G. Clinical Utility of Induced Sputum and Bronchoalveolar Lavage Cultures in Diagnosing Nontuberculous Mycobacterial Pulmonary Disease. Pathogens. 2024 Dec 3;13(12):1064. doi: 10.3390/pathogens PMID 39770324
• Chang AB, Upham JW, Masters IB, Redding GR, Gibson PG, Marchant JM, Grimwood K. Protracted bacterial bronchitis: The last decade and the road ahead. Pediatr Pulmonol. 2016 Mar;51(3):225-42. doi: 10.1002/ppul.23351. Epub 2015 Dec 4. PMID 26636654
• Gallucci M, Pedretti M, Giannetti A, di Palmo E, Bertelli L, Pession A, Ricci G. When the Cough Does Not Improve: A Review on Protracted Bacterial Bronchitis in Children. Front Pediatr. 2020 Aug 7;8:433. doi: 10.3389/fped.2020.00433. eCollection 2020. PMID 32850546
• Weiss AJ, Liang L, Martin K. Overview of Hospital Stays Among Children and Adolescents, 2019. 2022 Nov 29. In: Healthcare Cost and Utilization Project (HCUP) Statistical Briefs [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2006 Feb-. Statistical Brief #299. Available from http://www.ncbi.nlm.nih.gov/books/NBK588376/ PMID 36622925
• Levy ML, Fleming L, Warner JO, Bush A. Paediatric asthma care in the UK: fragmented and fatally fallible. Br J Gen Pract. 2019 Aug;69(685):405-406. doi: 10.3399/bjgp19X704933. No abstract available. PMID 31345822
• Januska MN, Goldman DL, Webley W, Teague WG, Cohen RT, Bunyavanich S, Vicencio AG. Bronchoscopy in severe childhood asthma: Irresponsible or irreplaceable? Pediatr Pulmonol. 2020 Mar;55(3):795-802. doi: 10.1002/ppul.24569. Epub 2019 Nov 15. PMID 31730298

Identifiers

NCT: NCT07232550 · KB/100/2025

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗