Evolution and assessment of lung function

Recent evidence suggests that lung function is diminished in infants with cystic fibrosis (CF) soon after a clinical diagnosis is made, and fails to improve despite care in a specialist centre. Respiratory function in infancy is worse in the presence of pulmonary inflammation and/or infection; however these findings are technique dependant. Those techniques sensitive to changes in the peripheral lung, such as the assessment of ventilation distribution using the multiple breath washout (MBW) or the low-frequency forced oscillation technique (LFOT), appear to be more sensitive than traditional infant techniques such as the raised volume technique (RVT).

There are two major limitations to our existing knowledge on the development of respiratory function during infancy in CF. Firstly, the majority of studies conducted to date are cross-sectional in nature and therefore are not able to provide any insight into the progressive influence of the onset of pulmonary infection, increasing inflammation or the development of structural damage within the lung and whether or not lung function techniques are sensitive to changes in these clinically relevant markers of disease severity over time. Secondly, there are few studies in which infants with CF diagnosed by newborn screening (NBS) have been studied at the time of diagnosis, limiting our knowledge on the level of respiratory function impairment inherent to CF lung disease, before the onset of symptoms or clinically detected lower respiratory illness.

Longitudinal studies conducted at the time of diagnosis by NBS using lung function techniques sensitive to changes in the peripheral lung are critical as preventing deterioration in lung function is a major aim of therapy. Early identification of diminished lung function would therefore suggest the need for earlier targeting of interventions and monitoring of outcomes.

Research questions / aims / hypotheses
We hypothesise that infants with CF will demonstrate abnormal peripheral lung function associated with increased pulmonary inflammation prior to the onset of pulmonary infection and irreversible structural damage. The general aims of the program are: to evaluate the evolution of lung function in infants with CF from diagnosis by NBS through to the early school age years; to assess the associations between lung function and its evolution during infancy and clinical outcomes of disease severity relevant to CF lung disease.

These aims will be achieved through the use of our established lung function techniques and the development of new methodologies suitable for widespread application. In particular we will use the assessment of parenchymal mechanics using the LFOT (a highly specialised technique unsuitable for widespread use) to identify those markers of ventilation inhomogeneity most indicative of peripheral lung function and therefore most likely to be sensitive to clinically relevant outcomes in CF lung disease.

Anticipated outcomes
We aim to determine whether lung function can be used as a surrogate marker of pulmonary infection, inflammation and structural changes in infants with CF and to determine how useful lung function will be as outcome measures in trials of novels treatments that are currently being developed for the early treatment of CF. Additional long term aims are to examine which combination of infant lung function outcomes best predicts clinical outcome in the pre-school (3-5 years) and early school years (5-6 years).