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Rationale: The lung clearance index (LCI) is responsive to acute respiratory events in preschool children with cystic fibrosis (CF), but its utility to identify and manage these events in school-ag...

Introduction: Increased equipment dead space relative to lung volume has been shown to impact multiple breath washout (MBW) outcomes (Benseler et al. Respirology, 2015). EcoMedics AG (Exhalyzer®D MBW device) recommends a weight-specific dead space reducer (DSR) to minimize burden in subjects with small lung volumes; subjects ≤35.0kg use DSR#2 (9.5mL dead space), subjects >35.0kg use DSR#3 (22mL dead space). We evaluated whether MBW outcomes are impacted in these subjects when using the recommended thresholds. Methods: Healthy children (HC) and children with cystic fibrosis (CF) performed MBW tests at three consecutive asymptomatic visits. At least two trials were obtained using both DSRs in random order at each visit. The difference in MBW outcomes between DSRs was compared using paired t-tests for each visit. Results: A total of 21 subjects (8 CF, 13 HC; 43% female) performed 56 paired measurements. The median (IQR) visits per subject was 3(2,3). Median (IQR) age at the initial visit was 9.1 years (8.4, 9.6) for HC and 10.3 years (9.5, 10.5) for CF subjects. Mean (SD) weight at first visit was 32.0 kg (2.1) and similar between groups. Lung clearance index was not systematically different between DSR#2 and #3 at first visit (Δ 0.14; 95% CI -0.05, 0.33; p=0.15). Measured functional residual capacity was lower using DSR#3 (Δ -0.09; 95% CI -0.14, -0.05; p Conclusion: Changing DSR at suggested weight threshold (35kg) does not systematically affect MBW outcomes. Funding: CFF and CF Canada

Background: Lung Clearance Index (LCI) is a sensitive measure of lung disease in children with cystic fibrosis (CF). The aim of this study was to determine whether there are modifiable factors that affect the course of lung disease during childhood. Methods: In this prospective two centre cohort study, we continued to follow a cohort (Stanojevic et al., AJRRCM 2017) of children with CF and age-matched healthy controls (HC) into school age (5-10 years). LCI was measured every 3 months for 24 months using Exhalyzer® D multiple breath nitrogen washout equipment. Detailed clinical data were extracted at each study visit, and for the years between the two follow-up periods. Mixed effects linear regression analyses were used. Results: In total 76% of the original preschool cohort (50/72 HC and 64/78 CF) were followed-up at school age. A total of 607 LCI measurements (HC) and 832 measurements (CF) were available for analysis. At the first school age visit, LCI was 2.15 units higher in the CF group compared to the controls (95%CI -2.68; 1.62); LCI was above 7.91 units (68.8%) in 40 children, of which 54% had abnormal LCI during the preschool period. A higher preschool LCI, faster rate of LCI deterioration during preschool years and a greater cumulative number of exacerbations were significant predictors of worse school age LCI. During the school age follow-up, LCI plateaued (slope = 0.07 (95% -0.1; 0.2) with age. Overall, a greater proportion of children received mucolytics and/or modulator treatments during the school age years compared with the preschool years. Conclusions: Early intervention before or during preschool are a critical time period to prevent future lung function impairment. Funded by NHLBI, CFF

Background: We previously demonstrated that the lung clearance index (LCI) worsens with acute respiratory events (ARE) in preschool children with cystic fibrosis (CF) (Rayment, Thorax 2018). We are now describing the functional consequences of ARE in school-age children. Methods: We extended this multisite prospective observational study into the school-age years. LCI and FEV1 were measured quarterly and during ARE over a 2-year period. We included pulmonary exacerbations (PEx), defined as ARE treated with antibiotics, and untreated increased cough events (UIC). A linear regression within a generalized estimating equation model, accounting for repeated events, was used to compare changes from a recent stable visit. Results: We enrolled 103 subjects with a mean (range) age of 9.8 (5-16.8) years. 360 stable visits, 83 PEx and 50 UIC were analyzed. Mean (range) LCI and FEV1 at enrolment were 9.5 units (5.9-17.2) and 93% predicted (39-125), respectively. LCI and FEV1 worsened with both PEx and UIC and did not recover at the next consecutive follow-up visit. At the first stable visit after follow-up, neither LCI or FEV1 recovered to baseline for the PEx group, and, for the UIC group, only FEV1 recovered. Conclusion: In school-age children with CF, lung function does not recover to baseline after PEx and, as detected by LCI, recovery is also incomplete after UIC.

Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma – viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2–3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma.

The lung clearance index (LCI) measured by the multiple breath washout (MBW) test is sensitive to early lung disease in children with cystic fibrosis. While LCI worsens during the preschool years in cystic fibrosis, there is limited evidence to clarify whether this continues during the early school age years, and whether the trajectory of disease progression as measured by LCI is modifiable.A cohort of children (healthy and cystic fibrosis) previously studied for 12 months as preschoolers were followed during school age (5–10 years). LCI was measured every 3 months for a period of 24 months using the Exhalyzer D MBW nitrogen washout device. Linear mixed effects regression was used to model changes in LCI over time.A total of 582 MBW measurements in 48 healthy subjects and 845 measurements in 64 cystic fibrosis subjects were available. The majority of children with cystic fibrosis had elevated LCI at the first preschool and first school age visits (57.8% (37 out of 64)), whereas all but six had normal forced expiratory volume in 1 s (FEV1) values at the first school age visit. During school age years, the course of disease was stable (−0.02 units·year−1 (95% CI −0.14–0.10). LCI measured during preschool years, as well as the rate of LCI change during this time period, were important determinants of LCI and FEV1, at school age.Preschool LCI was a major determinant of school age LCI; these findings further support that the preschool years are critical for early intervention strategies.