RHiNO: Respiratory Health In Preterm Neonatal Outcomes

Preterm-births account for 10% of all world-wide births. Increasing numbers of prematurely born children are surviving into childhood and beyond but there is limited understanding of the long term outcomes of being born early. It is clear that those who are born extremely prematurely (32 weeks gestation or less) have decreases in their lung function in childhood and beyond. Perhaps this is not surprising as many of these babies receive mechanical ventilation and added oxygen therapy which both cause lung injury. However, we have recently shown that babies who are born only late prematurely at 33 - 34 weeks gestation also have marked lung function deficits even though they are usually not ventilated or receive oxygen after birth. We have received >7,000 responses to our questionnaire survey investigating respiratory symptoms and drug usage in preterm children born in Wales. The initial analyses show that children born prematurely have increased respiratory symptoms which increase with increasing immaturity when compared to children born on time. Prematurely-born children also have increased GP visits and increased hospital admissions during childhood but are often not receiving treatment which may be beneficial. Some are often labelled as asthmatics despite no evidence of traditional symptoms associated with asthma. Since 56,000 babies in the UK and 480,000 in the US each year are born prematurely, there is an urgent need to understand the reasons or mechanisms why premature babies have long term lung function abnormalities. The decreased lung function may be a consequence of being born early at an early stage of lung development, or there may be persistent lung inflammation, or they may have increased allergic reaction as in children with asthma, or they may have structural abnormalities of the airways. The list of potential causes is unending.

Our overall aims are to understand the underlying mechanisms that cause the airway obstruction in preterm-born children.

Our specific aims are:

1. to identify and accurately define the breathing disorder (including symptoms, lung function and growth) of 7 - 12 years old children who were born prematurely (<= 34 weeks gestation) and who had wheeze any time during their life ("wheeze-ever"); and to identify children with marked airway obstruction for detailed study of the mechanisms of why they may have airway obstruction. We shall also test if any airway obstruction responds to a single dose of inhaled drug typically used for asthma and related disorders.

2. to study the possible mechanisms of airway obstruction in children who had previous symptoms and have marked airway obstruction (defined as FEV1<=85%); this will include comprehensive lung function testing including exercise testing; role of allergy; airway inflammation, etc.

3. to determine if inhaled drug treatment (which is routinely used in asthma) can specifically affect the underlying mechanisms. The aim is to determine if drug therapy is effective in these children who had previous respiratory symptoms and if they affect any specific mechanism that cause the airway obstruction.

4. to use state-of-the-art MRI scanning technology to study the lung structure and function in prematurely-born children with marked airway obstruction especially those who do and do not respond to treatment comparing the results with children born prematurely or at term and who have normal lung function. The aim is to determine the structural consequences of being born prematurely using state-of-the-art MRI technology which is only available in 2-3 centres in the UK.

It is clear that this is a neglected but large population that needs further attention. By better understanding the mechanisms of why children born prematurely develop airway obstruction, we should be able to develop targeted drug therapies and avoid labelling them as suffering from asthma to ensure they receive the correct treatment.

Aim 1: Respiratory status of preterm-born children
The primary aim is to identify 7-12 year-old preterm-born children born at <=34 weeks gestation who have airway obstruction of FEV1<=85% for further detailed study. From our questionnaire study, 1,053 (55%) of the 1,926 children born at <=34 weeks gestation had "wheeze-ever". We shall randomly invite these children to identify 200 who have marked airway obstruction (%FEV1 <=85%). We shall also invite asymptomatic control children without airway obstruction (FEV1>85%) born preterm (n=50) or at term (n=50).

Aim 2: Assessment of mechanisms of airway obstruction:
a. Atopic status by skin prick testing
b. Exhaled breath condensate
c. Exhaled nitric oxide
d. Induced sputum
e. Pulmonary diffusion capacity
f. Whole body plethysmography
g. Lung spirometry
h. Maximal exercise by cycle ergometer
Mechanistic data will be compared between the preterm group with airway obstruction and preterm- and term-control groups.

Aim 3: Modification of the underlying mechanisms
After mechanistic study, children not on corticosteroids will be randomised to blinded treatment with inhaled active drugs or placebo. Children on corticosteroids will be "washed-out" and randomised to active drug treatment. b-g above will be repeated after the 12-week treatment period to assess the clinical and mechanistic responses to drug treatment in children born preterm with airway obstruction.

Aim 4: Study the pulmonary structure by hyperpolarised gas MRI in those with FEV1 <=85% (a) who do not respond to inhaled drug therapy compared to (b) responders; and (c) preterm and (d) term controls without airway obstruction. Children will undergo structure-functional imaging at 1.5T to assess structural changes in lung morphology and motion. Gd-DTPA contrast enhanced perfusion imaging will be used to assess perfusion heterogeneity and V/Q matching. The results will be compared between the groups to identify structural and functional differences.

Who will benefit from this research?
The work will benefit preterm-born children and their parents, care givers, policy makers and will provide potential for commercial companies to develop targeted inhaled drug therapies.

During our parent group discussions, all parents commented on the lack of information on longer-term outcomes of their preterm-born children. Whilst there are studies confirming limitation of lung function in extremely preterm group, few studies have investigated the far larger late preterm population. Furthermore, few good quality studies have investigated the role of inhaled drugs in this population of children. Thus the greatest beneficiaries of this study will be children who were born preterm and their parents as it will establish the reasons why they have long term lung deficits. It will permit more accurate assessment of these children and will suggest more targeted therapies than has occurred hitherto.

Secondly, paediatricians, GPs, and both adult and paediatric respiratory physicians will benefit enormously from this study. These children are often labelled as suffering from asthma but evidence suggests are often left untreated presumably due to lack of evidence of traditional asthma symptoms. We recently surveyed if respiratory physicians in the UK ask about early life events including being born preterm in their clinical practice. Most did not. Thus this study will delineate accurately the disease process that preterm children suffer from and will identify specific phenotypes which will directly change the clinical practice of many specialities throughout medicine. The project should provide a robust translational plan on how to investigate these children based on the mechanisms identified and on a robust evidence-based protocol on how to manage these children.

Thirdly, by outlining the mechanisms the study will identify potential therapeutic targets including the use and licensing of currently available drugs but also development of newer drugs targeting specific targets identified by this research, particularly for children who are unresponsive to existing drug therapy and have fixed airway disease. This will have direct impact on pharmaceutical companies as the work will provide opportunities for drug development for a substantial population.

Finally, the results will impact on policy makers as a new group of subjects that will need greater follow up will be identified. Although this may increase economic burden in childhood, it should potentially prevent the greater economic burden e.g. of development of long term respiratory disease such as COPD (chronic obstructive pulmonary disease). Whilst there may be economic considerations as these children may require prolonged drug treatment, the longer term benefits are likely to outweigh the shorter term investments but we shall collect sufficient data to start addressing this important aspect as part of the proposal.

How will they benefit from this research?

The study will identify the underlying mechanisms that result in airway obstruction in preterm-born children thus will provide data for specific investigations and specific targeted drug therapy and for development of newer interventions. The children will benefit as their increased reported symptoms will be alleviated and provide a better quality of life. Their physical performance at school and play should improve. For physicians the benefits of better understanding these new disease processes are enormous including improved health of their patients by better targeting drug therapy. For adult physicians, the data will provide a better understanding of long lasting effects of early life influences which may impact on their day-to-day practices later in life e.g. COPD. For policy makers there will be a better understanding of why these children need closer follow up than has occurred so far.