The Role of Volatile Organic Compounds (VOCs), Airway Mucins and the Microbiome in the Early Prediction of Bronchopulmonary Dysplasia (BPD) (INFANCY)

The Role of Volatile Organic Compounds (VOCs), Airway Mucins and Microbiome in the Development of Bronchopulmonary Dysplasia and the Feasibility of Exhaled Breath VOCs Analysis as an Early Detection Tool

Bronchopulmonary dysplasia (BPD), the most common respiratory complication of extremely preterm birth, significantly impacts healthcare with high morbidity and mortality rates.

Despite the well-established primordial role of inflammation and oxidative stress in the development of BPD, clinical practice does not incorporate the testing for biomarkers associated with the development of BPD. The diagnosis of BPD based on required respiratory support at 36 weeks PML, stresses the need for an early prediction tool which could identify patients with high levels of these biomarkers. This on its turn, could also improve treatment approaches in clinical practice which are currently mostly supportive or non-specific and do not target underlying pathophysiologic pathways.

Secondly, mucin expression aim to play a rol in other respiratory diseases, whereas in BPD only the potential role of MUC1 was explored.

Thirdly, the composition of the airway microbial composition of an infant is assumed to be influenced by different factors. From early on in pregnancy the airway microbiome of the infant is formed, offering a protective role against pathologies. On the other hand, the role of the airway microbiome in the development of BPD remains unclear and needs to be elucidated.

The threefold aim of this study is as follows:

I. The development of a non-invasive breath test that allows early detection of bronchopulmonary dysplasia, using the potential of VOCs in exhaled breath as biomarkers for inflammation and oxidative stress.

II. The exploration of the composition and diversity of the airway microbiome in infants with BPD, their association with exhaled VOCs and the exploration of the placental and vaginal microbiome.

III. The detection of potential alterations in airway mucin expression in BPD patients.

Through this comprehensive approach, we seek to gain a deeper understanding of how these mutual associations may contribute to the later development of BPD.

In total 140 preterm infants, including 70 BPD patients and 70 preterm controls, born below 30 weeks' gestation at the Antwerp University Hospital will be included.

Study Overview

• Status: Recruiting
• Conditions: Bronchopulmonary Dysplasia
• Intervention / Treatment: Diagnostic test: Breath test; Other: Throat swabs; Other: Endotracheal aspirates; Other: Placental samples; Other: Vaginal swab

Detailed Description

After birth, a swab and samples will be collected from the placenta, next to a maternal vaginal swab for microbiome analysis. Breath samples, two oropharyngeal swabs and endotracheal aspirates - in case intubated - will be collected from the infant on different days in the first 28 days of life.

At 36 weeks PMA, BPD is diagnosed if the infant still requires respiratory support. An oxygen reduction test will also be performed to determine if the infant can maintain saturations within a predetermined target range (90-96% in our hospital) during a stepwise reduction of oxygen, while closely monitoring the neonate. At 36 weeks PMA, infants diagnosed with BPD - as well as controls - will undergo a one-time capillary (or venous) blood gas test, which will be mostly done as part of routine care. The blood gas test will be combined with a continuous transcutaneous capnography (tcPCO2) for 24 hours to assess the degree of severity of lung damage, i.e. grade of alveolar hypoventilation by means of hypercapnia.

All enrolled participants, regardless of BPD diagnosis, will have two clinical follow-up study visits after discharge to home, at 6 and at 12 months corrected age. Another oropharyngeal swab will be collected at these visits for microbiome analysis. To assess lung function in all BPD patients, a multiple breath washout test during natural sleep after the administration of melatonin, will be performed at 6 and 12 months corrected age. At 6 and 12 months corrected age, a chest CT will be performed in severe BPD-cases to assess lung structure. Results of follow-up investigations, clinical data, as well as respiratory questionnaires will be used to correlate to findings of the analysis of all samples taken in the NICU. With this approach, it is not only possible to explore if possible biomarkers found in the early weeks of life could predict BPD at 36 weeks PML, but also respiratory/pulmonary outcome at 6 and 12 months corrected age.

• Study Type: Observational
• Enrollment (Estimated): 140

Contacts and Locations

• Study Contact: Name: Inès Ghys, MD; Phone Number: +3232655230; Email: ines.ghys@uantwerpen.be
• Study Contact Backup: Name: Kristien Vanhaverbeke, MD, PhD

Study Locations

• Belgium
  • Antwerp
    • Edegem, Antwerp, Belgium, 2650
      • Recruiting
      • University Hospital Antwerp
      • Contact: Inès Ghys; Email: ines.ghys@uantwerpen.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Newborn infants born preterm < 30 weeks gestational age at the Antwerp University Hospital and admitted to the neonatal intensive care unit.

Description

Inclusion Criteria:

• Born at a gestational age < 30 weeks

Exclusion Criteria:

• Major congenital defect or disorder
• Patients with an unstable general condition as deemed by the attending neonatologist

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Preterm infants; all included infants will undergo a breath test and two throat swabs, in case the infant is intubated also endotracheal aspirates will be collected	Diagnostic test: Breath test; Early detection of volatile organic compounds (VOCs) in breath from preterm infants, collected at several timepoints within the first 4 weeks of life to predict BPD before diagnosis is made at 36 weeks PMA.; Other Names: Exhaled breath analysis; Volatomics; Exhaled Volatile Organic Compounds; Exhaled VOCs; Other: Throat swabs; A throat swab will be taken on several timepoints within the first 4 weeks of life to detect airway mucin expression. A second throat swab will be taken as proxy for the airway microbiome.; Other: Endotracheal aspirates; Collection of aspirates, as part of routine care, to detect mucin expression and the lung microbiome.; Other Names: Aspirates
Mothers of preterm infants; placental biopsies, a placental swab and a vaginal swab will be taken after birth	Other: Placental samples; After birth, placental biopsies will be collected for headspace VOCs analysis. A placental swab and a biopsy will be taken for microbiome analysis.; Other Names: Placental headspace VOCs analysis; Placental swabs; Other: Vaginal swab; A vaginal swab will be taken before birth for microbiome analysis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Airway mucin profiles	Genetic expression of airway mucins in BPD and preterm controls on oropharyngeal samples via qRT-PCR	first 4 weeks of life
Placental headspace VOCs	Abbundance of VOCs in the headspace of placental samples to distinguish BPD from preterm controls	at delivery
Placental microbiome	Metagenomic shotgun sequencing after extraction of bacterial DNA from samples and subamniotic swabs after birth	at delivery
Vaginal microbiome	Metagenomic shotgun sequencing after extraction of bacterial DNA from vaginal swabs after birth	right before delivery
Exhaled breath Volatile Organic Compounds (VOCs)	Abbundance of VOCs in breath samples to distinguish BPD from preterm controls by means of GC-MS: direct samples in the respiratory circuit as well as indirect samples from air in the incubator	first 4 weeks of life
Airway microbial profiles	16S RNA sequencing or metagenomic shotgun sequencing after extraction of bacterial DNA from oropharyngeal swabs and aspirates in BPD and preterm controls	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hypercapnia	BPD patients will undergo a blood gas test to assess the degree of lung damage severity	3 months
Follow-up structural lung imaging	Chest CT scan in severe BPD cases	12 months
Pulmonary function	To determine lung function - as an objective outcome parameter - a multiple breath washout (MBW) test will be performed, all infants with BPD, at the corrected age of 6 and 12 months.	12 months
Chronic lung disease outcome 6 months corrected age	Validated respiratory questionnaire will be completed by the parents at 6 months corrected age. The questionnaire at 6 months is based on the Liverpool Respiratory Symptom Questionnaire (LRSQ), a validated tool for evaluating the prevalence of common paediatric respiratory symptoms amongst preschool children. It consists of eight domains, each containing between three and five items. The first six domains assess respiratory symptoms and the remaining two assess the impact of symptoms on the child and family.	6 months
Chronic lung disease outcome 12 months corrected age	At 12 months the validated questionnaire 'A parent-completed respiratory questionnaire for 1-year-old children' will be used.	12 months

Collaborators and Investigators

• Sponsor: University Hospital, Antwerp
• Investigators: Principal Investigator: Antonius Mulder, MD, PhD,prof, University Hospital Antwerp, Belgium; Study Director: Stijn L Verhulst, MD, PhD,prof, University Hospital Antwerp, Belgium

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: March 13, 2024
• First Submitted That Met QC Criteria: March 28, 2024
• First Posted (Actual): April 2, 2024

Study Record Updates

• Last Update Posted (Actual): May 9, 2025
• Last Update Submitted That Met QC Criteria: May 5, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Volatile Organic Compounds; Preterm birth; Respiratory morbidity; Exhaled breath analysis; Vaginal microbiome; Inflammation Lungs; Airway microbiome; Airway mucins; Placental microbiome; Early prediction of BPD; multiple breath washout test
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Ventilator-Induced Lung Injury; Bronchopulmonary Dysplasia
• Other Study ID Numbers: 6007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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