BronchoPulmonary Dysplasia: an inflammatory disorder in children? The BPD PINK study

Bronchopulmonary dysplasia (BPD) is the most common complication of extremely
preterm birth affecting 250-300 children in the Netherlands US every year. BPD
is characterized by an arrest in lung and pulmonary vascular development and
has lifelong consequences. Children with BPD have more respiratory symptoms and
related hospital admissions compared to term or preterm born controls without
BPD. A recent study showed that adults born before 28 weeks of gestation had an
Odds ratio of 7.4 for the development of Chronic Obstructive Pulmonary Disease
(COPD) and this OR was even higher in adults with BPD.
In addition to symptoms, the forced expiratory volume in 1 second (FEV1) in
children with BPD is reduced with a 16% lower mean compared to healthy
controls. More notable, this lung function deficit further deteriorates during
childhood with as much as 0.1 Zscore FEV1 per year.
Unfortunately, the underlying pathophysiology of increased, progressive
pulmonary morbidity is unclear.

Ongoing oxidative stress and/or neutrophilic inflammation have been suggested
as mechanisms responsible for the decline in lung function in patients with
BPD, although only few studies assessed inflammation in older children with
BPD, and the potential relationship with pulmonary morbidity. One study in 52
school children with BPD showed higher levels of 8isoprostane, a biomarker of
oxidative stress, in exhaled breath condensate (EBC). Another study in 36
preterm born school children found higher neutrophil and lymphocytes counts,
and higher interleukin (IL)8/protein values in sputum suggesting ongoing
neutrophilic inflammation. In contrast, a third study did not show significant
differences in markers of eosinophilic or neutrophilic inflammation, nor for
oxidative stress between preterm born school children with or without BPD and
controls. In a bronchoscopy study in young adults with BPD a T cell pattern as
in COPD was found in bronchoalveloar lavage fluid. BPD subjects had a higher
proportion of CD8+ T-cells, a lower proportion of CD4+ T-cells and a higher
proportion of activated T-cells in patients, possibly leading to tissue
remodelling and deterioration of lung function.

In summary, patients with BPD are at risk of long-term deterioration of
pulmonary function. However, the pathophysiology of BPD after the neonatal
period is unclear although inflammation and oxidative stress most likely play a
role.

The aim of this project is to unravel whether BPD after the neonatal period is
a chronic inflammatory disease, and if markers of inflammation and/or oxidative
stress are related to pulmonary morbidity in patients with BPD. Based on these
findings, targeted, individualized specific care can be developed to improve
pulmonary health in patients with BPD.

Primary Objective: to study if preterm born patients with BPD have signs of
increased oxidative stress and/or inflammation as compared to matched healthy
subjects.

Secondary Objective(s):
To study if:
- Markers of oxidative stress/ inflammation correlate with symptoms, lung
function and CT scores in children with BPD.

This is an exploratory prospective pilot study with 1 study visit.
Patients will be recruited from the long-term BPD follow up clinic in Erasmus
MC and Amsterdam UMC. During this follow up, all BPD patients perform routinely
lung function tests (spirometry before and after a bronchodilator) at the age
of 5 and 8 years. In Erasmus MC all children with BPD undergo chest CT scanning
at the age of 8-10 years, in Amsterdam UMC CT scanning is performed in
individual children on clinical indication.
We aim to include 36 patients with BPD and 36 healthy age-matched controls.
In all children we will sample exhaled breath (gas-chromatography-mass
spectrometry analysis in Amsterdam UMC) at the study visit.
Children with BPD perform spirometry before and after a bronchodilator. Healthy
children will only perform spriometry without bronchodilator reversibility
testing. Additionally, all children will perform analysis of nitric oxide in
exhaled air (FeNO), as marker of eosinophilic inflammation, as study test.

The risks associated with participation are considered negligible and the
burden minimal: study procedures will be performed during a routine clinic
visit. Exhaled breath collection is non-invasive and the procedure to obtain
exhaled breath takes few minutes.
Spirometry is routine care for the BPD patients but extra for the healthy
controls. In general, children experience spirometry as *fun* as we use
computer games to stimulate and motivate them. In many studies spirometry has
been performed in healthy controls (e.g. Generation R) without any problems.
This study cannot be performed in adults or other groups as we want to get
insight in the pathophysiology of BPD in school children. It is important to
identify potential therapeutic targets in childhood when lung growth and
development take place, in order to improve respiratory health in children,
which will also improve respiratory health during the life course.