Pulmonary MRI of Ex-preterm Children With and Without BPD To Understand Risk of Emphysematous Changes
Condition: Bronchopulmonary Dysplasia
MeSH terms: Bronchopulmonary Dysplasia
Study type: Observational

Summary: 
      Health Issue: Bronchopulmonary dysplasia (BPD), a chronic lung disease, is the most common
      complication of being born premature. Damage to the still developing lung stops the normal
      formation of the alveoli. Young adults with a history of BPD have lower lung function, early
      heart disease, and increased risk of death, compared to those without BPD. Recently, it has
      been reported that they may also develop a type of lung disease typically seen in older
      adults with a longstanding history of smoking. The severity of lung disease is usually
      measured using pulmonary function tests (PFT), but these tests may be normal, even in the
      presence of important changes in the fine structure of the lung. Such structural changes may
      be early markers of future lung disease and can be detected using lung magnetic resonance
      imaging (MRI). Unlike other ways of imaging the lungs, MRI does not expose people to harmful
      X-rays. To date, no studies have been done to examine the fine structure of the lung of
      school-aged children who had a history of BPD, to determine whether there are signs of lung
      disease that might not otherwise be obvious. This is important because once armed with this
      information, preventive measures can be taken to avoid worsening of lung disease.

      Objective: 1) In 7-9 year-old children born extremely premature, lung MRI will be compared
      between those with and without BPD. The Investigators expect to observe more severe
      structural lung abnormalities in children with BPD, compared to those without BPD; 2) The
      Investigators will test to see if children with more severe MRI abnormalities also have worse
      lung function, and/or more symptoms of breathing problems. The Investigators expect to
      observe more PFT abnormalities in children with BPD than in those without and that these will
      match up with lung fine structure abnormalities identified on MRI.

      How will work be undertaken? Children 7-9 years old who were born extremely prematurely will
      be recruited to participate in this study. Participants will be identified from Neonatal
      Follow-up clinics they attended. The Investigators will enroll 20 children with BPD and 20
      without BPD. Participants will have lung MR images taken, during which they need to lie still
      for a few minutes. PFT will also be performed, during which they will blow into a machine.
      Parents will be asked to complete questionnaires about breathing problems, their living
      conditions (environment) and any doctor visits or hospital stays. Medical charts will be
      reviewed for information about their birth.

      Unique/Innovative Aspects: This will be the first study using MRI as an innovative way to
      visualize and measure fine structure of the lung in children born prematurely with and
      without BPD. These findings may be early markers of lung disease, which would identify
      children who have, or are at risk of developing lung disease later in life, for whom the
      Investigators may be able to offer treatments now and/or prevent worsening of lung disease.
    

Detailed description: 
      Knowledge to Date: Bronchopulmonary dysplasia (BPD), the most common pulmonary complication
      of prematurity, occurs in 41% of infants born before 28 weeks' gestation.

      Defined as a need for oxygen at 36 weeks' postmenstrual age,2 BPD results in longterm
      morbidity in children and adults, including reduced lung function, early cardiovascular
      disease and premature death The reported severity of such impairments varies, as studies have
      been conducted on small numbers of children with differing degrees of prematurity.
      Furthermore, it is unclear what markers are most sensitive to predict long-term respiratory
      compromise. While functional measures have been studied, micro-structural differences, that
      may be quantified using pulmonary magnetic resonance imaging (MRI), have not been evaluated
      in this population, and may provide earlier quantitative markers of future respiratory
      disease, including chronic obstructive pulmonary disease (COPD). Recent advances in the
      clinical care of preterm infants have permitted survival of ever more premature infants, in
      whom alveolar development is incomplete, representing a new, relatively unstudied and growing
      cohort with a new form of BPD.

      This BPD is associated with arrested alveolar growth and development, with reduction in
      alveolar surface area and pulmonary capillary blood volume. Yet, little is known about the
      trajectory of associated lung changes through childhood. Traditional measures of pulmonary
      function are lower in school aged children with history of BPD than in those preterm-born
      without BPD, but they may still be within normal reference ranges. There is, however,
      evidence that pulmonary function declines more steeply between age 8-18 years in those with
      BPD and that lower infant lung function predicts lower adult lung function.

      This is particularly concerning since there is increasing recognition that preterm born
      adults have a significant burden of early lung disease. Emphysema has been reported in young
      adults with a history of prematurity less extreme than the prematurity seen today. X-ray
      computed tomography (CT) imaging detects pulmonary abnormalities in 98%, with emphysema in
      47% of this less premature cohort as young adults. Not all of those with CT abnormalities,
      however, have impaired pulmonary function tests (PFTs), thus highlighting the limitations of
      conventional PFTs to detect disease. In childhood, PFTs, while very powerful indicators of
      global lung health, may be relatively insensitive to detect early pulmonary structural
      changes and regional lung abnormalities. Pulmonary dysfunction may not cause symptoms at rest
      or correlate with PFTs in childhood, but may become apparent with exercise, infection, or
      aging. Structural changes in the lung parenchyma may already be present in childhood and may
      be earlier markers of current and future respiratory disease than conventional PFT. Such
      changes may be detected with pulmonary MRI of the lung, as has been shown in COPD and in
      pilot work in BPD MRI has significant advantages over CT, including lack of exposure to
      ionizing radiation and high resolution of fine tissue structure. Recent advances in pulmonary
      MRI, including ultra-short echo time pulse sequences, generate pulmonary images with enhanced
      parenchymal signal intensity which rival CT images for visualization of lung parenchyma and
      vasculature. MRI is emerging as a research tool and may ultimately replace CT for pediatric
      thoracic imaging tasks and serial evaluations.

      To the Investigators knowledge, conventional and ultra-short echo time 1H MRI studies of
      children with histories of prematurity and BPD have not been performed to quantify
      microstructural pulmonary abnormalities. The Investigators therefore propose a study to
      compare pulmonary micro-structural (MRI) and functional (PFT) abnormalities in premature
      children with and without history of BPD. The investigators hypothesize that pulmonary tissue
      destruction and/or emphysematous changes will be evident on MRI and will be worse in
      ex-premature infants with a history of BPD than in those without history of BPD. Further, the
      investigators hypothesize that MRI will be more sensitive to detect lung changes than PFT,
      but that MRI changes will correlate with PFT abnormalities. Ultimately, this information will
      form the basis of future longitudinal studies to evaluate progression of pulmonary disease
      and assess effects of new treatment strategies in this population.

      Research Questions Amongst 7-9 year old children with a history of prematurity (< 28 weeks'
      gestation), comparing those with and without a history of BPD

        1. Are there measureable differences in pulmonary micro-structure, quantified using MRI
           signal intensity (primary question)?

        2. What is the association between pulmonary micro-structural measurements quantified using
           pulmonary MRI and pulmonary function outcomes (secondary questions):

             1. airflow limitation, as measured by forced expiratory volume in one second (FEV1),
                FEV1/FVC, mid-expiratory flows (FEF25-75)

             2. lung volumes and gas trapping , as measured by total lung capacity (TLC), residual
                volume (RV) and RV/TLC ratio

             3. diffusion capacity of carbon monoxide (DLCO), a marker of pulmonary alveolar volume
                and pulmonary diffusing capacity

             4. respiratory symptoms, social and environmental exposure history and healthcare
                utilization, assessed by validated questionnaire (ATS-DLD-78-a) Methods Study
                Setting: This cross-sectional study will be carried out at three Canadian tertiary
                care pediatric centres (Children's Hospital of Eastern Ontario, Ottawa, Ontario,
                The Hospital for Sick Children, Toronto, Ontario and Centre Hospitalier
                Universitaire (CHU) Sainte-Justine, Montreal, Quebec). Ethics approval will be
                obtained at all participating sites. Analysis: Descriptive statistics will be used
                to describe the two groups. The primary analysis will be a comparison of signal
                intensity between children with a history of BPD and those without, adjusting for
                exposure to earlier (24-26 weeks) or later (27-28 weeks) gestational age, using a
                two-way analysis of variance. Secondary analyses will examine the association
                between MRI signal intensity and PFT, as well as signal intensity and respiratory
                symptoms from the ATS-DLD-78-c questionnaire, using Spearman correlations.
                Exploratory analyses will also examine the association between PFT and respiratory
                symptoms, as well as parental smoking exposure, the relationship of obstetrical and
                neonatal historical factors to signal intensity, PFT, and respiratory symptoms.

      Feasibility: Imaging Feasibility: The MRI pulse sequence that is the foundation for this
      study was previously developed and validated at 3T on a GE scanner by Dr. Parraga, who serves
      as Co-Principal Investigator of this proposed research.42 The MR acquisitions will be enabled
      using MR infrastructure at all 3 sites and 32 channel cardiac coils. Proof-of-concept for the
      presence of extensive emphysema is provided for a 25 year old with a history of prematurity
      and BPD, with significant MRI-evidence of widespread alveolar and acinar duct abnormalities
      that are consistent with emphysema Recruitment Feasibility: Each year, approximately 400
      infants born < 28 weeks' gestation attend neonatal clinic follow-up visits at 18 months of
      age, at the three participating centres. As there are already established databases of these
      children at each site, identification of those eligible for study participation will be
      easily achieved.

      At CHU Sainte-Justine, approximately 80 children aged 5-7 years are seen annually and from a
      previous study recruiting at 5 years, participation rate was 60%, further supporting
      feasibility for this study. Anticipated Results and Conclusions The Investigators anticipate
      that there will be significantly more severe pulmonary micro-structural abnormalities, as
      evidenced by lower pulmonary mean signal intensity, in 7-9 year olds born at less than 28
      weeks' gestation, with a history of BPD, as compared to children born at less than 28 weeks'
      gestation without BPD. The investigators expect that mean MRI-derived signal intensity will
      correlate significantly with PFT measurements, as well as with the presence of chronic
      respiratory symptoms and increased healthcare utilization. This is the first study using
      innovative MRI techniques in relation to functional testing that will help characterize
      regional pulmonary tissue destruction and/or emphysematous changes present in children with a
      history of extreme prematurity, with and without BPD. In particular, MRI measurements may be
      more sensitive markers of early lung disease than PFT or respiratory symptoms. Since these
      children may only manifest signs of respiratory impairment in the presence of stressors,
      knowledge of these MRI changes may prompt earlier or more aggressive respiratory support and
      treatment to prevent respiratory compromise. Ultimately, there may be opportunity in future
      to intervene with additional treatments that may halt progression to adult lung disease. This
      is particularly important, given the increasing body of evidence for early COPD-like disease
      in this group. This work may identify a BPD-COPD overlap syndrome, with unique
      pathophysiology and potentially differential response to treatments from traditional COPD.

      Potential Challenges: Children will be recruited for this study from neonatal follow-up
      clinic databases that capture all of those graduating from the neonatal nursery and surviving
      to 18 months. It is possible that some families may have since relocated or have been lost to
      follow-up and/or that those willing to participate in a research study at age 7-9 years will
      differ from those not willing/able to participate. Further, by studying children able to
      perform PFT and to cooperate for MRI, the investigators will exclude those with significant
      neurodevelopmental delay, who may also have more severe lung disease. As these are the main
      study outcomes, however, this will be necessary. Inclusion of children with a history of BPD
      ensures that those at the more severe end of the spectrum of early pulmonary complications,
      who are expected to have more severe lung disease, are studied. Exercise testing is another
      methodology to assess pulmonary and cardiovascular function. It is beyond the feasibility and
      budget ($200 per test) for this study and also requires coordination tasks that may be
      challenging for some participants. Nonetheless, it is an important consideration for future
      work. There are few precedents for pulmonary MRI in children, particularly in those with
      prematurity and BPD. Traditionally, MRI has been considered suboptimal in comparison to CT
      for lung parenchyma imaging, due to the low tissue density and loss of signal from magnetic
      field inhomogeneity at the air lung interfaces. Novel ultra-short echo time (UTE) pulse
      sequences, however, permit greater signal from the pulmonary parenchyma, which makes MRI a
      viable strategy to assess emphysematous changes in this population, without exposure to
      ionizing radiation. In the neonatal intensive care unit, MRI has shown signal decreases
      suggestive of alveolar simplification (emphysema) in those with severe BPD. It is possible
      that children with a history of extreme prematurity without BPD will also have some degree of
      pulmonary parenchymal change on MRI, although it is still expected that abnormalities will be
      more severe in those with a history of BPD. This study is, however, powered to detect smaller
      differences in signal intensity between groups than observed in adult COPD studies. The
      investigators are not using a healthy term control group because the purpose of this research
      is to assess radiological and functional biomarkers that will help clinicians and researchers
      identify among preterm born children those at greater risk of long-lasting pulmonary problems
      who would benefit the most from treatment.

      Relevance: The ever growing population of extremely preterm born individuals, representing
      approximately 27,000 Canadians less than 18 years old, of whom approximately 40% have BPD, is
      at risk of development of early COPD-like emphysematous changes. Thus, neonatal conditions
      may be at the origin of a substantial and disproportionately high burden of adult lung
      disease, associated with significant morbidity and mortality. Prematurity and BPD, in
      addition to smoking, is one of the strongest predictors of obstructive airways disease in
      later life. In order to promote lung health and reduce the global burden of chronic lung
      disease, it is necessary to understand the trajectory of lung growth, development and decline
      across the lifespan in this at-risk population. Use of novel imaging strategies, more
      sensitive than PFT or respiratory symptoms to quantify early changes in the lung, provides
      new knowledge about the natural history of BPD in this population. Furthermore, MRI changes
      can quantify improvement associated with therapeutic interventions and can be safely serially
      evaluated across the lifespan. This is particularly important and exciting, given new
      therapies on the horizon to treat BPD, including stem cell treatments.
    

Observational model: Other
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        Children born pre-term at less than 28 weeks' gestation, currently aged 7-9 years, with and
        without BPD will be included. BPD will be defined as need for oxygen at 36 weeks'
        postmenstrual age,2 which includes those with moderate-severe disease.47 Children 7-9 years
        of age were selected in order to include the youngest age at which pulmonary function,
        including lung volumes and single breath pulmonary diffusing capacity for carbon monoxide,
        can routinely be reliably measured using methods that require subject cooperation.
      
Keywords: Prematurity; Bronchopulmonary dysplasia; MRI; PFT; Emphysema