Cystic Fibrosis, (CF) is associated with chronic respiratory disease, which is responsible for the shortened life span in most patients. There is increasing evidence that CF lung disease begins shortly after birth and progresses even in the absence of clinical signs and symptoms. Traditional measures of lung function, such as spirometry, are difficult to measure in young children and are not able to detect abnormalities in this age group. Therefore, more sensitive and easier measures of lung function are needed for clinical studies in CF patients younger than 6 years. Multiple breath washout testing (MBW) measures the efficiency with which gas mixes in the lungs, and has been shown to detect abnormalities in lung function before traditional measures of lung function. In addition the test requires minimal cooperation as it is performed during normal breathing and is therefore ideally suited for younger children. There is currently no validated multiple breath washout system available for centers in North America. Recently, a commercial system has been developed, but the data in younger children (aged 3-6 years), a critical window for disease progression, is currently lacking. However, there is minimal data to define what constitutes a significant change in LCI over time. The overall aim of this proposal is to develop the lung clearance index into a tool for interventional studies and for clinical care in CF patients younger than 6 years of age. This will be accomplished through three specific aims:
Aim 1 : Validation of the LCI measured by nitrogen washout against the gold standard in preschool children.
Aim 2 : Define repeatability of LCI measurements at time intervals relevant for clinical trials.
Aim 3 : Determine the utility of LC as a monitoring tool in a clinical setting. The validation study in Aim 1 is essential to verify agreement with the gold standard, and to refine the protocol for this age group. Following validation, we will utilize the nitrogen washout system to characterize the reproducibility of LCI n health and CF, in order to define the limits of normal measurement variation that are both statistically valid, and clinically relevant. This will be done in a one-year longitudinal study tht mimics the design of interventional trials. This information will be directly applicable to the design and interpretation of clinical studies for children with CF in this age group. Finally, we wll test the clinical utility of the LCI to monitor pulmonary exacerbations in preschool children, and to assess whether the LCI can be used to track changes in clinical disease severity over time. These studies will form the basis for subsequent interventional trials in preschool children with CF and for future studies on the utility of LCI in CF infants. Furthermore, the information gained in this study will be a critical step for subsequent studies in other airway diseases such as asthma and primary ciliary dyskinesia.

Public Health Relevance

The multiple breath washout test, specifically the lung clearance index is a promising marker for early lung disease in children with CF. This proposal aims to develop the nitrogen multiple breath washout as a test for use in interventional trials in young children. This will help identify children who will benefit from intervention, and monitor the efficacy of interventions in young children with CF.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-F (S1))
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Banks-Schlegel, Susan P
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Hospital for Sick Chldrn (Toronto)
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M5 1-X8
Oude Engberink, Esther; Ratjen, Felix; Davis, Stephanie D et al. (2017) Inter-test reproducibility of the lung clearance index measured by multiple breath washout. Eur Respir J 50:
Stanojevic, Sanja; Davis, Stephanie D; Retsch-Bogart, George et al. (2017) Progression of Lung Disease in Preschool Patients with Cystic Fibrosis. Am J Respir Crit Care Med 195:1216-1225
Stanojevic, Sanja; Ratjen, Felix (2016) Physiologic endpoints for clinical studies for cystic fibrosis. J Cyst Fibros 15:416-23
Jensen, Renee; Stanojevic, Sanja; Klingel, Michelle et al. (2016) A Systematic Approach to Multiple Breath Nitrogen Washout Test Quality. PLoS One 11:e0157523
Benseler, Anouk; Stanojevic, Sanja; Jensen, Renee et al. (2015) Effect of equipment dead space on multiple breath washout measures. Respirology 20:459-66
Konstan, Michael W; Ratjen, Felix (2012) Effect of dornase alfa on inflammation and lung function: potential role in the early treatment of cystic fibrosis. J Cyst Fibros 11:78-83