Search

Introduction: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane regulator (CFTR) gene, leading to progressive lung disease and systemic complications. Lung disease remains the primary cause of morbidity and mortality, making early detection of lung function decline crucial. The Lung Clearance Index (LCI), derived from the multiple breath washout (MBW) test, has emerged as a sensitive measure for identifying early airway disease., Areas Covered: This review examines the technical aspects and clinical relevance of LCI, its advantages over traditional lung function tests, and its application in CF clinical trials. A focused literature review highlights LCI's utility in evaluating treatment efficacy and its potential integration into routine CF care., Expert Opinion: LCI is more sensitive than spirometry for detecting early lung function decline and is predominantly used in pediatric settings. Its use is expanding in adult CF populations as advances in treatment allow adults to maintain stable lung function. In clinical trials, LCI is widely recognized as an outcome measure. While implemented into clinical care in many centers in Europe, this is not yet the case in North America. Faster testing protocols and point-of-care interpretation tools will support LCI's integration into routine CF monitoring.

Purpose: To compare phase-resolved functional lung (PREFUL) regional ventilation derived from a free breathing 3D UTE radial MRI acquisition to hyperpolarized 129 Xe-MRI (Xe-MRI), conventional 2D multi-slice PREFUL MRI, and pulmonary function tests in pediatric cystic fibrosis (CF) lung disease., Methods: Free-breathing 3D UTE and 2D multi-slice 1 H MRI as well as Xe-MRI were acquired in 12 stable pediatric CF patients. Using PREFUL, regional ventilation (RVent) maps were calculated from the free-breathing data. Ventilation defect percentage (VDP) was determined from 3D and 2D RVent maps (2D VDP RVent and 3D VDP RVent , respectively) and Xe-MRI ventilation (VDP Xe ). VDP was calculated for the whole lung and for eight regions based on left/right, anterior/posterior, and superior/inferior divisions of the lung. Global and regional VDP was compared between the three methods using Bland-Altman analysis, linear mixed model-based correlation, and one-way analysis of variance and multiple comparisons tests., Results: Global 3D VDP RVent , VDP Xe , and 2D VDP RVent were all strongly correlated (all R 2 > 0.62, p < 0.0001) and showed minimal, non-significant bias (all <2%, p > 0.05). Three dimensional and 2D VDP RVent significantly correlated to VDP Xe in most of the separate lung regions (R 2  = 0.18-0.74, p < 0.04), but showed lower inter-agreement. The superior/anterior lung regions showed the least agreement between all three methods (all p > 0.12)., Conclusion: Absolute VDP assessed by 3D UTE PREFUL MRI showed good global agreement with Xe-MRI and 2D multi-slice PREFUL MRI in pediatric CF lung disease. Therefore, 3D UTE PREFUL MRI offers a sensitive and potentially more accessible alternative to Xe-MRI for regional volumetric evaluation of ventilation., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Studying human fetal lungs can inform how developmental defects and disease states alter the function of the lungs. Here, we sequenced >150,000 single cells from 19 healthy human pseudoglandular fetal lung tissues ranging between gestational weeks 10-19. We capture dynamic developmental trajectories from progenitor cells that express abundant levels of the cystic fibrosis conductance transmembrane regulator (CFTR). These cells give rise to multiple specialized epithelial cell types. Combined with spatial transcriptomics, we show temporal regulation of key signalling pathways that may drive the temporal and spatial emergence of specialized epithelial cells including ciliated and pulmonary neuroendocrine cells. Finally, we show that human pluripotent stem cell-derived fetal lung models contain CFTR-expressing progenitor cells that capture similar lineage developmental trajectories as identified in the native tissue. Overall, this study provides a comprehensive single-cell atlas of the developing human lung, outlining the temporal and spatial complexities of cell lineage development and benchmarks fetal lung cultures from human pluripotent stem cell differentiations to similar developmental window., (© 2024. The Author(s).)

For those people with cystic fibrosis carrying rare CFTR mutations not responding to currently available therapies, there is an unmet need for relevant tissue models for therapy development. Here, we describe a new testing platform that employs patient-specific induced pluripotent stem cells (iPSCs) differentiated to lung progenitor cells that can be studied using a dynamic, high-throughput fluorescence-based assay of CFTR channel activity. Our proof-of-concept studies support the potential use of this platform, together with a Canadian bioresource that contains iPSC lines and matched nasal cultures from people with rare mutations, to advance patient-oriented therapy development. Interventions identified in the high-throughput, stem cell-based model and validated in primary nasal cultures from the same person have the potential to be advanced as therapies., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Compartment analysis (CA) based on nitrogen multiple-breath washout (N 2 MBW) has been shown to allow the assessment of specific volume and ventilation of faster- and slower-ventilating lung compartments of the lung in adults with cystic fibrosis (CF). The aim of this study was to extend previous findings into the pediatric age range., Methods: Cross-sectional multicenter observational study in children with CF and healthy controls (HC) was done with the assessment of N 2 MBW and spirometry. A two-lung compartment model-based analysis (CA) was used to estimate size and function of faster- and slower-ventilating lung compartments from N 2 MBW., Results: A total of 125 children with CF and 177 HC, median age 10.8 (range, 2.8-18.9) years, were included in the analysis. CA could be calculated in 66 (53%) children with CF compared with 48 (27%) HC (P < .0001). The proportion of the slower-ventilating lung compartment was significantly smaller in children with CF (53.5%; 95% confidence interval [CI]: 51.9%-55.7%) compared with HC (62.2%; 95% CI: 59.0%-65.0%) The regional specific ventilation of the slower compartment (rV T ,slow/rFRC,slow, %) was significantly lower in children with CF (4.9%; 95% CI: 4.5-5.9) compared with HC (9.7%, 95% CI: 9.2-10.9), and showed inverse correlation to lung clearance index (r 2  = -.65; P < .0001), S acin  × VT (r 2  = -.36; P = .003) and S cond  × VT (r 2  = -.51; P < .0001). There was no significant difference in pulmonary parameters between children with CF with and without feasible CA., Conclusion: CA is less feasible in children than in adults and correlated to other MBW parameters. The clinical value of CA is still unclear and is yet to be established., (© 2020 Wiley Periodicals, Inc.)

Introduction: The Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory score is a validated and widely used patient-reported outcome. This study aimed to establish changes in the score with acute respiratory events in preschool children with CF and to investigate its' relationship with physiological outcomes., Methods: The Parent CFQ-R, multiple breath washout test and spirometry were performed at six study visits over one year. The clinical status of participants, stable or symptomatic, was defined by the patient's physician. Linear regression and distribution-based statistical methods were used to examine the changes in the CFQ-R from the last stable visit and to investigate its relationship with physiological outcomes., Results: There were 272 stable and 115 symptomatic visits from 78 participants. The mean CFQ-R Respiratory score did not change between consecutive stable visits (-0.73, SD 20.4). The mean (SD) score deteriorated by 15.5 (20.7) points between stable and symptomatic visits and improved by 14.8 (20.1) points between symptomatic and stable follow-up visits. When a clinically important change is defined as 0.5SD change (10-points), the positive predictive value (PPV) was 45% and the negative predictive value (NPV) was 84%. For visits with a 10-point worsening in the CFQ-R Respiratory score and a 15% increase in LCI, the PPV was better (81%) than using either measure alone., Conclusion: The CFQ-R Respiratory score is responsive to acute respiratory events in preschool children with CF and its utility to monitor individual patients is improved when combined with LCI., Competing Interests: Conflict of Competing Interest None, (Copyright © 2020. Published by Elsevier B.V.)

Background: The multiple breath nitrogen washout (N 2 MBW) technique is increasingly used to assess the degree of ventilation inhomogeneity in school-aged children with lung disease. However, reference values for healthy children are currently not available. The aim of this study was to generate reference values for N 2 MBW outcomes in a cohort of healthy Caucasian school-aged children., Methods: N 2 MBW data from healthy Caucasian school-age children between 6 and 18 years old were collected from four experienced centres. Measurements were performed using an ultrasonic flowmeter (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) and were analysed with commercial software (Spiroware version 3.2.1, Eco Medics AG). Normative values and upper limits of normal (ULN) were generated for lung clearance index (LCI) at 2.5% (LCI 2.5% ) and at 5% (LCI 5% ) of the initial nitrogen concentration and for moment ratios (M 1 /M 0 and M 2 /M 0 ). A prediction equation was generated for functional residual capacity (FRC)., Results: Analysis used 485 trials from 180 healthy Caucasian children aged from 6 to 18 years old. While LCI increased with age, this increase was negligible (0.04 units·year -1 for LCI 2.5% ) and therefore fixed ULN were defined for this age group. These limits were 7.91 for LCI 2.5% , 5.73 for LCI 5% , 1.75 for M 1 /M 0 and 6.15 for M 2 /M 0 , respectively. Height and weight were found to be independent predictors of FRC., Conclusion: We report reference values for N 2 MBW outcomes measured on a commercially available ultrasonic flowmeter device (Exhalyzer D, Eco Medics AG) in healthy school-aged children to allow accurate interpretation of ventilation distribution outcomes and FRC in children with lung disease., Competing Interests: Conflict of interest: P. Anagnostopoulou has nothing to disclose. Conflict of interest: P. Latzin reports personal fees from Gilead, Novartis, Polyphor, Santhera, Schwabe, Vertex, Vifor and Zambon, as well as grants from Vertex, outside the submitted work. Conflict of interest: R. Jensen has nothing to disclose. Conflict of interest: M. Stahl reports personal fees from Vertex Pharmaceuticals, outside the submitted work. Conflict of interest: A. Harper has nothing to disclose. Conflict of interest: S. Yammine has nothing to disclose. Conflict of interest: J. Usemann has nothing to disclose. Conflict of interest: R.E. Foong has nothing to disclose. Conflict of interest: B. Spycher has nothing to disclose. Conflict of interest: G.L. Hall reports grants from the NHMRC and the Australia and USA CF Foundation, and non-financial support (loan of equipment) from ndd, during the conduct of the study. Conflict of interest: F. Singer reports personal fees from Vertex and Novartis, outside the submitted work. Conflict of interest: S. Stanojevic has nothing to disclose. Conflict of interest: M.A. Mall reports grants from the German Federal Ministry of Education and Research (82DZL004A1) and the Einstein Foundation Berlin (EP-2017-393), during the conduct of the study, and personal fees advisory board work, consultancy and lectures from Boehringer Ingelheim and Vertex Pharmaceuticals, outside the submitted work. Conflict of interest: F. Ratjen reports grants and personal fees for consultancy from Vertex, plus personal fees for consultancy from Novartis, Bayer, Roche and Genetech, outside the submitted work. Conflict of interest: K.A. Ramsey has nothing to disclose., (Copyright ©ERS 2020.)

Background: The ventilation defect percent (VDP), measured from hyperpolarized (HP) 129 Xe magnetic resonance imaging (MRI), is sensitive to functional changes in cystic fibrosis (CF) lung disease. The purpose of this study was to measure and compare VDP from HP 129 Xe MRI acquired at two institutions in stable pediatric CF subjects with preserved lung function., Methods: This retrospective analysis included 26 participants from two institutions (18 CF, 8 healthy, age range 10-17). Pulmonary function tests, N 2 multiple breath washout (to measure lung clearance index, LCI), and HP 129 Xe MRI were performed. VDP measurements were compared between two trained analysts using mean-anchored linear binning. Correlations were investigated for VDP compared to the forced expiratory volume in one second (FEV 1 ) and LCI., Results: VDP measurements agreed for the two analysts with an intraclass correlation coefficient of 0.99. In the combined dataset, VDP measured by Analyst 1 was 5.96 ± 1.82% and 15.96 ± 6.76% for the healthy and CF groups, respectively (p = .0004). Analyst 2 showed similar differences between healthy and CF (p = .0003). VDP measured by either analyst was shown to correlate with FEV 1 (R 2  = 0.33, p = .003; and R 2  = 0.26, p = .009 for Analysts 1 and 2, respectively) and LCI (R 2  = 0.76, p < .0001; and R 2  = 0.77, p < .0001 for Analysts 1 and 2, respectively)., Conclusion: HP 129 Xe MRI provides a robust measurement of ventilation heterogeneity in stable pediatric CF subjects at two sites. Since measurements performed at two sites yielded similar VDP values with near-identical values between different analysts, implementation of the technique in multi-center trials in CF appears feasible., (Copyright © 2019. Published by Elsevier B.V.)

Pulmonary magnetic resonance imaging using hyperpolarised 129 Xe gas (XeMRI) can quantify ventilation inhomogeneity by measuring the percentage of unventilated lung volume (ventilation defect per cent (VDP)). While previous studies have demonstrated its sensitivity for detecting early cystic fibrosis (CF) lung disease, the utility of XeMRI to monitor response to therapy in CF is unknown. The aim of this study was to assess the ability of XeMRI to capture treatment response in paediatric CF patients undergoing inpatient antibiotic treatment for a pulmonary exacerbation.15 CF patients aged 8-18 years underwent XeMRI, spirometry, plethysmography and multiple-breath nitrogen washout at the beginning and end of inpatient treatment of a pulmonary exacerbation. VDP was calculated from XeMRI images obtained during a static breath hold using semi-automated k-means clustering and linear binning approaches.XeMRI was well tolerated. VDP, lung clearance index and the forced expiratory volume in 1 s all improved with treatment; however, response was not uniform in individual patients. Of all outcome measures, VDP showed the largest relative improvement (-42.1%, 95% CI -52.1--31.9%, p<0.0001).These data support further investigation of XeMRI as a tool to capture treatment response in CF lung disease., Competing Interests: Conflict of interest: J.H. Rayment has nothing to disclose. Conflict of interest: M.J. Couch reports partial salary support from Siemens Healthcare through the MITACS Elevate postdoctoral fellowship programme, during the conduct of the study. Conflict of interest: N. McDonald has nothing to disclose. Conflict of interest: N. Kanhere has nothing to disclose. Conflict of interest: D. Manson has nothing to disclose. Conflict of interest: G. Santyr has nothing to disclose. Conflict of interest: F. Ratjen has nothing to disclose., (Copyright ©ERS 2019.)

Background: The care of infants with recurrent wheezing relies largely on clinical assessment. The lung clearance index (LCI), a measure of ventilation inhomogeneity, is a sensitive marker of early airway disease in children with cystic fibrosis, but its utility has not been explored in infants with recurrent wheezing., Objective: To assess ventilation inhomogeneity using LCI among infants with a history of recurrent wheezing compared with healthy controls., Methods: This is a case-control study, including 37 infants with recurrent wheezing recruited from outpatient clinics, and 113 healthy infants from a longitudinal birth cohort, the Canadian Healthy Infant Longitudinal Development study. All infants, at a time of clinical stability, underwent functional assessment including multiple breath washout, forced expiratory flows and body plethysmography., Results: LCI z-score values among infants with recurrent wheeze were 0.84 units (95% CI 0.41 to 1.26) higher than healthy infants (mean (95% CI): 0.26 (-0.11 to 0.63) vs -0.58 (-0.79 to 0.36), p<0.001)). Nineteen percent of recurrently wheezing infants had LCI values that were above the upper limit of normal (>1.64 z-scores). Elevated exhaled nitric oxide, but not symptoms, was associated with abnormal LCI values in infants with recurrent wheeze (p=0.05)., Conclusions: Ventilation inhomogeneity is present in clinically stable infants with recurrent wheezing., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector. In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.

Background: The Infant Study of Inhaled Saline (ISIS) in CF was the first multicenter clinical trial to utilize infant pulmonary function tests (iPFTs) as an endpoint., Methods: Secondary analysis of ISIS data was conducted in order to assess feasibility of iPFT measures and their associations with respiratory symptoms. Standard deviations were calculated to aid in power calculations for future clinical trials., Results: Seventy-three participants enrolled, 70 returned for the final visit; 62 (89%) and 45 (64%) had acceptable paired functional residual capacity (FRC) and raised volume measurements, respectively. Mean baseline FEV0.5, FEF75 and FRC z-scores were 0.3 (SD: 1.2), -0.2 (SD: 2.0), and 1.8 (SD: 2.0)., Conclusions: iPFTs are not appropriate primary endpoints for multicenter clinical trials due to challenges of obtaining acceptable data and near-normal average raised volume measurements. Raised volume measures have potential to serve as secondary endpoints in future clinical CF trials., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Lung disease in patients with both primary ciliary dyskinesia (PCD) or cystic fibrosis (CF) is associated with impaired mucociliary clearance; however, clinical outcomes are typically worse in CF patients. We assessed whether CF and PCD patients differ in inflammatory response in the airways during pulmonary exacerbation.We first studied clinically stable PCD patients with a spectrum of bacterial pathogens to assess inflammatory response to different pathogens. Subsequently, PCD and CF patients with similar bacterial pathogens were studied at the time of a pulmonary exacerbation and after 21 days of antibiotics treatment. Qualitative and quantitative microbiology, cell counts, interleukin-8 concentrations, and neutrophil elastase activity were assessed in sputum samples obtained before and after treatment.In stable PCD patients, no significant differences were found in sputum inflammatory markers between individuals colonised with different bacterial pathogens. Pulmonary exacerbation severity assessed by a pulmonary exacerbation score and lung function decline from their previous baseline did not differ between CF and PCD patients. Bacterial density for Staphylococcus aureus and Haemophilus influenzae was higher in CF versus PCD (p<0.05), but absolute neutrophil counts were higher in PCD patients (p=0.02). While sputum elastase activity was similar in PCD and CF at the time of exacerbation, it decreased with antibiotic therapy in PCD (p<0.05) but not CF patients.PCD patients differ from those with CF in their responses to treatment of pulmonary exacerbations, with higher neutrophil elastase activity persisting in the CF airways at the end of treatment., (Copyright ©ERS 2016.)

Multiple breath inert gas washout (MBW) measurements in infants are performed supine and often obtained under sedation and thus are combined with other lung function tests such as raised volume rapid thoracoabdominal compression (RVRTC). In this study, we sought to determine the effects of RVRTC maneuvers on MBW measures. Compared with tests performed prior to RVRTC, MBW measured after RVRTC was associated with a small reduction in functional residual capacity and a more pronounced decrease in cumulative expired volume in both healthy children and children with obstructive lung disease (cystic fibrosis or recurrent wheeze) indicating a more efficient washout after the raised volume maneuvers. Lung Clearance Index (LCI) decreased significantly in infants with respiratory disease (change in LCI of -0.24 units post RVRTC; standard error (SE) ± 0.07 units; P = 0.0004), but not in healthy infants (change in LCI of -0.08 units; SE ± 0.11 units; P = 0.44). As the RVRTC maneuver affects MBW measurements in infants, the timing of testing procedures needs to be standardized in longitudinal studies., (© 2015 Wiley Periodicals, Inc.)

Pulmonary exacerbations treated with intravenous antibiotics have significant, well-characterized negative consequences on clinical outcomes in cystic fibrosis (CF). The impact of milder exacerbations in children with CF, commonly treated with oral antibiotics, are less well defined. Pulmonary exacerbations have multiple triggers, but viral infections are particularly common in children. Children with CF and healthy control subjects have similar frequencies of viral respiratory infections, but there is evidence of greater virus-related morbidity in patients with CF, likely due to a combination of increased viral load, more pronounced inflammatory response, and more pronounced impairment in mucociliary clearance. In recent clinical trials in children, definitions have been used that are more symptom based rather than intervention based. These studies have demonstrated differences in the spectrum of symptoms between children and older patients but have also shown that, despite low threshold definitions, a considerable number of patients receive treatment for events not fulfilling the pulmonary exacerbation criteria. Additional research is needed to determine the impact of these milder exacerbations on lung function recovery and time to subsequent exacerbation as well as long-term outcomes such as mortality.

Pulmonary exacerbations are important clinical events for cystic fibrosis (CF) patients. Studies assessing the ability of the lung clearance index (LCI) to detect treatment response for pulmonary exacerbations have yielded heterogeneous results. Here, we conduct a retrospective analysis of pooled LCI data to assess treatment with intravenous antibiotics for pulmonary exacerbations and to understand factors explaining the heterogeneous response.A systematic literature search was performed to identify prospective observational studies. Factors predicting the relative change in LCI and spirometry were evaluated while adjusting for within-study clustering.Six previously reported studies and one unpublished study, which included 176 pulmonary exacerbations in both paediatric and adult patients, were included. Overall, LCI significantly decreased by 0.40 units (95% CI -0.60- -0.19, p=0.004) or 2.5% following treatment. The relative change in LCI was significantly correlated with the relative change in forced expiratory volume in 1 s (FEV1), but results were discordant in 42.5% of subjects (80 out of 188). Higher (worse) baseline LCI was associated with a greater improvement in LCI (slope: -0.9%, 95% CI -1.0- -0.4%).LCI response to therapy for pulmonary exacerbations is heterogeneous in CF patients; the overall effect size is small and results are often discordant with FEV1., (Copyright ©ERS 2015.)

Background and Objective: Multiple breath inert gas washout (MBW) systems are designed to minimize equipment dead space volume (Vd). Animal and infant studies have demonstrated the impact of increased Vd on MBW measurements. In this study, we investigate the effect of Vd of a nitrogen (N2 ) MBW system on MBW measurements in preschool children., Methods: N2 MBW measurements were performed in healthy adults under standard conditions; Vd was added to match the relationship between Vd and lung volumes observed in preschool children. Subsequently, subjects were measured on a sulfur hexafluoride (SF6 ) MBW system under standard conditions and with Vd added to match that of the N2 MBW system. Healthy preschool children and children with cystic fibrosis were tested on both the N2 MBW and SF6 MBW in random order on the same day. A correction equation was derived based on the adult experiments and tested on the preschool data., Results: Increasing the Vd of the N2 MBW system resulted in a higher lung clearance index (LCI). A strong non-linear relationship between N2 LCI and the Vd/tidal volume was observed. When the Vd was equivalent between systems, LCI measured by the SF6 MBW system was similar to that measured by the N2 MBW. LCI was higher on the N2 MBW than the SF6 MBW in preschool children. Correcting for the equipment Vd of the N2 MBW resulted in better agreement., Conclusions: Equipment Vd affects LCI measurements especially in young children where Vd is large relative to lung volumes., (© 2015 Asian Pacific Society of Respirology.)

The activity of arginase is increased in airway secretions of patients with cystic fibrosis (CF). Downstream products of arginase activity may contribute to CF lung disease. We hypothesized that pulmonary arginase expression and activity would be increased in mouse models of CF and disproportionally increased in CF mice with Pseudomonas aeruginosa pneumonia. Expression of arginase isoforms in lung tissue was quantified with reverse transcriptase-PCR in naive cystic fibrosis transmembrane conductance regulator (Cftr)-deficient mice and β-epithelial sodium channel-overexpressing [β-ENaC-transgenic (Tg)] mice. An isolated lung stable isotope perfusion model was used to measure arginase activity in Cftr-deficient mice before and after intratracheal instillation of Pseudomonas aeruginosa. The expression of arginase-2 in lung was increased in adult Cftr-deficient animals and in newborn β-ENaC-Tg. Arginase-1 lung expression was normal in Cftr-deficient and in newborn β-ENaC-Tg mice, but was increased in β-ENaC-Tg mice at age 1, 3, and 6 wk. Arginase activity was significantly higher in lung (5.0 ± 0.7 vs. 3.2 ± 0.3 nmol·(-1)·h(-1), P = 0.016) and airways (204.6 ± 49.8 vs. 79.3 ± 17.2 nmol·(-1)·h(-1), P = 0.045) of naive Cftr-deficient mice compared with sex-matched wild-type littermate controls. Infection with Pseudomonas aeruginosa resulted in a far greater increase in lung arginase activity in Cftr-deficient mice (10-fold) than in wild-type controls (6-fold) (P = 0.01). This is the first ex vivo characterization of arginase expression and activity in CF mouse lung and airways. Our data show that pulmonary arginase expression and activity is increased in CF mice, especially with Pseudomonas aeruginosa infections., (Copyright © 2014 the American Physiological Society.)

Exercise is beneficial for patients with cystic fibrosis (CF) but long-term effects of physical activity on lung function evolution are unknown. We evaluated the longitudinal relationship between changes in habitual physical activity (HPA) and rate of decline in lung function in patients with CF. We tracked HPA using the Habitual Activity Estimation Scale, forced expiratory volume in 1 s (FEV₁) and Stage I exercise tests in 212 patients with CF over a 9-year period. Adjusting for sex, baseline age and FEV₁, mucoid Pseudomonas aeruginosa and CF-related diabetes, mean ± sd FEV₁ % predicted decreased by 1.63 ± 0.08% per year (p<0.0001) while mean ± sd HPA increased by 0.28 ± 0.03 h·day(-1) per year (p<0.0001) over the study period. A greater increase in HPA was associated with a slower rate of decline in FEV₁ (r=0.19, p<0.0069). Dividing subjects into "high" and "low" activity (above or below the mean rate of change of activity, respectively), a steeper rate of FEV₁ decline was observed for low (-1.90% per year) compared to high (-1.39% per year) (p=0.002). Increases in HPA are feasible despite progression of lung disease and are associated with a slower rate of decline in FEV₁, highlighting the benefit of regular physical activity, and its positive impact on lung function in patients with CF.

Cystic fibrosis airways are deficient for L-arginine, a substrate for nitric oxide synthases (NOSs) and arginases. The rationale for this study was to quantify NOS and arginase activity in the mouse lung. Anesthetized unventilated mice received a primed constant stable isotope intravenous infusion containing labeled L-arginine, ornithine, and citrulline. The isotopic enrichment of each of the infused isotopomers and its product amino acids were measured in plasma and organ homogenates using liquid chromatography-tandem mass spectrometry. The effect of infection was studied three days after direct tracheal instillation of Pseudomonas-coated agar beads. In the infusion model, lung infection resulted in a significant (28-fold) increase in NOS activity in lung but not in trachea, kidney, liver, or plasma. Absolute rates of arginase activity in solid tissues could not be calculated in this model. In an isolated lung perfusion model used for comparison increased NOS activity in infected lungs was confirmed (28.5-fold) and lung arginase activity was increased 9.7-fold. The activity of L-arginine metabolizing enzymes can be measured using stable isotope conversion in the mouse. Accumulation of L-ornithine in the whole mouse model hindered the exact quantification of arginase activity in the lung, a problem that was overcome utilizing an isolated lung perfusion model.

Rationale: Denufosol stimulates chloride secretion independent of the chloride channel which is dysfunctional in cystic fibrosis (CF) and therefore has the potential to benefit CF patients regardless of genotype., Objectives: To assess the efficacy of denufosol in CF patients with mild lung function impairment age 5 years and older., Methods: This multicenter, randomized, parallel group double-blind placebo-controlled trial was conducted at 102 CF care centers in Australia, Canada and the United States (NCT00625612) The active group (n=233) received 60 mg denufosol via inhalation three times daily The primary efficacy endpoint was change in FEV(1) in liters from Day 0 to week 48., Measurements and Main Results: 685 patients were screened for the study and 466 patients (233 in each group) were randomized to study treatment. The adjusted mean change in FEV(1)was 40 mL for denufosol and 32 mL for placebo with a resulting treatment effect of 8 mL (95% CI -0.040, 0.056). The average rate of change in FEV(1) percent of predicted over 0 to 48 weeks was -3.04% for placebo vs. -2.30 for denufosol (a difference of 24% relative to placebo) among all patients. The incidence of pulmonary exacerbation was 26% vs. 21% for the placebo and denufosol groups with no differences in the time to first event. The study treatments were well tolerated and there was no evidence of systemic effects in any safety parameter assessed., Conclusions: In patients with CF treatment with denufosol for 48 weeks did not improve pulmonary function or reduce the incidence of pulmonary exacerbations., (Copyright © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Purpose: To determine if fluorine 18 fluorodeoxyglucose (FDG) positron emission tomographic (PET)/computed tomographic (CT) imaging can depict a treatment effect from intravenous antibiotics for pulmonary exacerbation in cystic fibrosis (CF)., Materials and Methods: The study was approved by the institutional review board of the Hospital for Sick Children and by Health Canada. Consent was obtained from all subjects. Patients with CF who were between 6 and 18 years of age and were admitted for a pulmonary exacerbation were eligible for the study. FDG PET/CT examinations (with low-dose CT) were performed on days 1 and 14 of admission (±72 hours). PET activity was quantified by using standardized uptake values (SUVs) through assessment of background activity (mean SUV [SUV(mean)]) and superimposed focal uptake (maximum SUV [SUV(max)]) for each lung zone. CT studies were scored by using the CF-CT model. SUVs from pre- and posttherapy studies were compared by using paired t tests. Unpaired t tests were used to compare data in patients with CF and data in 10 control subjects., Results: Twenty patients with CF were enrolled. Antibiotic therapy resulted in a significant decrease in SUV(max) (mean difference, 2.3 ± 2.1 [standard deviation], P < .0001). Pretherapy SUV(max) and SUV(mean) and posttherapy SUV(max) were significantly different from those in control subjects. The change in SUV(max) and percentage predicted forced expiratory volume in 1 second was negatively correlated. (R = -0.72, P = .004). Overall CF-CT scores significantly correlated with SUV(max) (R = 0.40, P = .01)., Conclusion: FDG PET/CT is a useful tool for detecting inflammatory changes resulting from treatment for pulmonary exacerbations in pediatric patients with CF. Inflammatory changes detected by using FDG PET/CT correlated with lung function, sputum neutrophil counts, and CF-CT scores. Analyzing focal lung inflammation (with SUV(max)) may be a feasible way to measure airway inflammation in patients with CF., (© RSNA, 2012)

It is unknown what proportion of long-term lung function decline in cystic fibrosis (CF) is explained by pulmonary exacerbations. The aim of this study was to determine how exacerbations requiring hospitalisation contribute to the course of CF lung disease. This was a retrospective cohort study. The primary outcome was the rate of decline of forced expiratory volume in 1 s (FEV(1)) % predicted. Out of 851 subjects, 415 (48.8%) subjects had ≥ 1 exacerbation. After adjustment for confounders, the annual rate of FEV(1) decline in those without an exacerbation was 1.2% per yr (95% CI 1.0-1.5), compared with 2.5% per yr (95% CI 2.1-2.8) in those with an exacerbation. The proportion of overall FEV(1) decline associated with ≥ 1 exacerbation was 52% (95% CI 35.0-68.9). For a given number of exacerbations, the annual rate of FEV(1) decline was greatest in subjects with ≤ 6 months between exacerbations. Half of FEV(1) decline seen in CF patients was associated with pulmonary exacerbations. Time between exacerbations, specifically ≤ 6 months between exacerbations, plays an important contribution to overall lung function decline. These findings support using time to next exacerbation as a clinical end-point for CF trials.

Context: Inhaled hypertonic saline is recommended as therapy for patients 6 years or older with cystic fibrosis (CF), but its efficacy has never been evaluated in patients younger than 6 years with CF., Objective: To determine if hypertonic saline reduces the rate of protocol-defined pulmonary exacerbations in patients younger than 6 years with CF., Design, Setting, and Participants: The Infant Study of Inhaled Saline in Cystic Fibrosis (ISIS), a multicenter, randomized, double-blind, placebo-controlled trial conducted from April 2009 to October 2011 at 30 CF care centers in the United States and Canada. Participants were aged 4 to 60 months and had an established diagnosis of CF. A total of 344 patients were assessed for eligibility; 321 participants were randomized; 29 (9%) withdrew prematurely., Intervention: The active treatment group (n = 158) received 7% hypertonic saline and the control group (n = 163) received 0.9% isotonic saline, nebulized twice daily for 48 weeks. Both groups received albuterol or levalbuterol prior to each study drug dose., Main Outcome Measures: Rate during the 48-week treatment period of protocol-defined pulmonary exacerbations treated with oral, inhaled, or intravenous antibiotics., Results: The mean pulmonary exacerbation rate (events per person-year) was 2.3 (95% CI, 2.0-2.5) in the active treatment group and 2.3 (95% CI, 2.1-2.6) in the control group; the adjusted rate ratio was 0.98 (95% CI, 0.84-1.15). Among participants with pulmonary exacerbations, the mean number of total antibiotic treatment days for a pulmonary exacerbation was 60 (95% CI, 49-70) in the active treatment group and 52 (95% CI, 43-61) in the control group. There was no significant difference in secondary end points including height, weight, respiratory rate, oxygen saturation, cough, or respiratory symptom scores. Infant pulmonary function testing performed as an exploratory outcome in a subgroup (n = 73, with acceptable measurements at 2 visits in 45 participants) did not demonstrate significant differences between groups except for the mean change in forced expiratory volume in 0.5 seconds, which was 38 mL (95% CI, 1-76) greater in the active treatment group. Adherence determined by returned study drug ampoules was at least 75% in each group. Adverse event profiles were also similar, with the most common adverse event of moderate or severe severity in each group being cough (39% of active treatment group, 38% of control group)., Conclusion: Among infants and children younger than 6 years with cystic fibrosis, the use of inhaled hypertonic saline compared with isotonic saline did not reduce the rate of pulmonary exacerbations over the course of 48 weeks of treatment., Trial Registration: clinicaltrials.gov Identifier: NCT00709280.

Background: Management of asymptomatic congenital pulmonary airway malformations remains controversial when addressing the optimal timing of surgical resection. Neonatal resection is advocated by some based on the theory that earlier lobectomy results in greater compensatory lung growth. We examined whether age at lobectomy is correlated with better pulmonary outcomes as reflected by pulmonary function and exercise testing., Methods: Patients who had lobectomy for congenital pulmonary airway malformation between 1985 and 2002 were identified and underwent detailed clinical history, physical examination, pulmonary function testing (total lung capacity, forced vital capacity, forced expiratory volume in 1 second), and exercise testing (power, maximal oxygen uptake [Vo(2)max])., Results: Of 87 patients identified, 47 met the inclusion criteria, and 28 were tested prospectively. Age at the time of lobectomy ranged from 3 days to 56 months. There was no correlation between age at lobectomy and pulmonary function (total lung capacity, P = .408; forced vital capacity, P = .319; forced expiratory volume in 1 second, P = .174) or maximal work capacity (power, P = .280). There was a trend toward lower Vo(2)max in patients who had undergone lobectomy at an older age (Vo(2)max, P = .055)., Conclusion: Most children undergoing lobectomy have normal long-term pulmonary function. We found no correlation between age at lobectomy and future pulmonary function. Cardiopulmonary exercise testing should be considered in evaluating functional outcome in these patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The clinical course of cystic fibrosis (CF) lung disease varies between patients bearing identical CFTR mutations. This suggests that additional genetic modifiers may contribute to the pulmonary phenotype. The highly conserved ancestral haplotype 8.1 (8.1AH), carried by up to one quarter of Caucasians, comprises linked gene polymorphisms on chromosome 6 that play a key role in the inflammatory response: LTA +252A/G; TNF -308G/A, HSP70-2 +1267A/G and RAGE -429T/C. As inflammation is a key component inducing CF lung damage, we investigated whether the 8.1AH represents a lung function modifier in CF., Methods: We analyzed the lung function of 404 European CF patients from France (n=230), Germany (n=95) and UK (n=79). FEV(1) differences between 8.1AH carriers and non-carriers were calculated in each country and pooled using a random effects model., Results: The frequency of 8.1AH carriers was similar between French (22%), German (29%) and UK (27%) patients. We found that 8.1AH carriers had significantly lower FEV(1), adjusted for age classes and countries (P<0.04, mean FEV(1) difference -6.4% CI95% [-12.4%, -0.5%]). No difference was observed with respect to BMI Z-scores and chronic colonization with P. aeruginosa., Conclusions: These findings support the concept that 8.1AH is an important genetic modifier of lung disease in CF. To conclude, multiple linked genes outside the CF locus might explain some of the variability in lung phenotype., (Copyright © 2011 European Cystic Fibrosis Society. All rights reserved.)

Objective: Our aim was to assess the effect of treatment of early infection of P. aeruginosa on pulmonary function in pediatric CF patients., Methods: This was a retrospective cohort study of P. aeruginosa negative CF patients followed at Sick Kids from 1990 to 2007. Early P. aeruginosa infection was defined as the first respiratory culture for P. aeruginosa; patients were included if 5 years of follow-up pulmonary function data were available. Patients were divided into three groups (group 1: never infected, group 2: infected with subsequent clearance, and group 3: chronic infection or still receiving antipseudomonal antibiotics). Hierarchical linear models were used to estimate the effect of P. aeruginosa infection on spirometry. FEV(1) % predicted was the primary outcome., Results: 116 patients were included. Forty-six (40%) patients remained P. aeruginosa negative throughout the observation period, 29 (25%) patients transiently infected with P. aeruginosa, and 41 (35%) patients were either currently infected or still receiving treatment. Baseline lung function was the same for all groups. Annual decline in FEV(1) % predicted during the study period was not different (-0.6%/year for patients that were never infected and -1.3%/year among patients previously infected)., Conclusions: Lung function was not different between patients with early P. aeruginosa infection and those that never had P. aeruginosa infection. However given the slow rate of FEV(1) decline in the study population, a longer observation period and/or more sensitive outcomes measures may be required to exclude long-term detrimental effects of transient P. aeruginosa infection on lung function in CF patients., (Copyright © 2011 Wiley-Liss, Inc.)

Rationale: Nitric oxide formation is deficient in airways of patients with cystic fibrosis (CF). Since nitric oxide has bronchodilatory effects, nitric oxide deficiency may contribute to airway obstruction in CF., Objectives: We reasoned that inhalation of l-arginine, the precursor of enzymatic nitric oxide formation, could improve airway nitric oxide formation and pulmonary function in patients with CF., Measurements: Exhaled nitric oxide, pulmonary function, and peripheral oxygen saturation were measured before and after a single inhalation of nebulized l-arginine solution in patients with CF and in healthy subjects. A saline solution of similar osmolarity (1.7%) was used as control., Results: Nebulized l-arginine not only significantly increased exhaled nitric oxide concentrations but also resulted in a sustained improvement of FEV(1) in patients with CF. Oxygen saturation also increased significantly after the inhalation of l-arginine. Nebulized saline resulted in a small but significant increase in exhaled nitric oxide but a decrease in FEV(1) in patients with CF. In control subjects inhalation of l-arginine increased exhaled nitric oxide concentrations, but FEV(1) decreased. No effect of saline on exhaled nitric oxide, pulmonary function, or oxygen saturation was observed in healthy subjects., Conclusions: These data suggest that a single inhalation of l-arginine acutely and transiently improves pulmonary function in CF through the formation of nitric oxide. Augmentation of airway nitric oxide formation by inhalation of l-arginine is a promising therapeutic approach in patients with CF.

Background: In a cross-sectional analysis of cystic fibrosis (CF) patients with mild lung disease, reduced surfactant activity was correlated to increased neutrophilic airway inflammation, but not to lung function. So far, longitudinal measurements of surfactant function in CF patients are lacking and it remains unclear how these alterations relate to the progression of airway inflammation as well as decline in pulmonary function over time., Methods: As part of the BEAT trial, a longitudinal study to assess the course of airway inflammation in CF, we studied lung function, surfactant function and endobronchial inflammation using bronchoalveolar lavage fluid from 20 CF patients with normal pulmonary function (median FEV1 94% of predicted) at three times over a three year period., Results: There was a progressive loss of surfactant function, assessed as minimal surface tension. The decline in surfactant function was negatively correlated to an increase in neutrophilic inflammation and a decrease in lung function, assessed by FEV1, MEF(75/25%VC), and MEF(25%VC). The concentrations of the surfactant specific proteins A, C and D did not change, whereas SP-B increased during this time period., Conclusion: Our findings suggest a link between loss of surfactant function driven by progressive airway inflammation and loss of small airway function in CF patients with limited lung disease.

Reduced glutathione (GSH), a major antioxidant and modulator of cell proliferation, is decreased in the bronchoalveolar lavage fluid (BALF) of cystic fibrosis (CF) patients. We previously have shown that GSH inhalation in CF patients significantly increased GSH levels in BALF and improved lung function (M. Griese et al., 2004, Am. J. Respir. Crit. Care Med.169, 822-828). GSH depletion in vitro enhances susceptibility to oxidative stress, increases inflammatory cytokine release, and impairs T cell responses. We therefore hypothesized that an increase in GSH in BALF reduces oxidative stress, decreases inflammation, and modulates T cell responses in lungs of CF patients. BALF from 17 CF patients (median FEV1 67% (43-105%) of predicted) was assessed before and after GSH inhalation for total protein, markers of oxidative stress (8-isoprostane, myeloperoxidase, and ascorbic and uric acid), pattern of protein oxidation, prostaglandin E2 (PGE2), and proinflammatory cytokines. BALF cells were differentiated using cytospin slides, and lymphocytes were further analyzed by flow cytometry. Inhalation of GSH decreased BALF levels of PGE2 and increased CD4+ and CD8+ lymphocytes in BALF significantly but had no effect on markers of oxidative stress. BALF lymphocytes correlated positively with lung function, whereas levels of PGE2 showed an inverse correlation. The patients with the greatest improvement in lung function after GSH treatment also had the largest decline in PGE2 levels. We conclude that GSH inhalation in CF patients increases lymphocytes and suppresses PGE2 in the bronchoalveolar space. Thus, GSH primarily affected the pulmonary immune response rather than the oxidative status in CF patients. The effect of GSH inhalation on PGE2 levels and lymphocytes in CF warrants further investigation.

In children with malignancies and immunosuppression, significant morbidity and mortality result from respiratory complications. The aim of the present study was to investigate whether or not this is associated with altered surfactant components or functions. Bronchoalveolar lavage fluid from 24 children with malignancies, immunosuppression, pulmonary infiltrates and fever unresponsive to empirical antibiotic treatment were compared to that from 24 healthy children. Levels of surfactant protein (SP) A and D and their binding capacity for Pseudomonas aeruginosa, as well as levels of SP-B and SP-C, were assessed by enzyme-linked immunosorbent assay. The large and small surfactant aggregate forms were separated and the biophysical activity of large surfactant aggregates was determined using a pulsating bubble surfactometer. Compared to healthy controls, SP-A levels were increased four-fold, the increase being most pronounced in those children with pathogens recovered from their bronchoalveolar lavage fluid. In children with malignancies, levels of SP-C were increased two-fold and of small surfactant aggregates five-fold. No differences were observed in levels of SP-B or SP-D, binding capacity of SP-A or SP-D or the surface activity of large surfactant aggregates. The increased levels of surfactant protein A, particularly in children with recovered microorganisms, and unchanged binding capacity of surfactant protein A are consistent with upregulated local host defence mechanisms. Increased surfactant protein A and C may also be responsible for the conserved biophysical activity of surfactant in children with malignancies, immunosuppression, pulmonary infiltrates and fever.

The cystic fibrosis membrane conductance regulator can be activated through beta2-adrenoceptor (beta2AR) stimulation. We tested the hypothesis that coding sequence polymorphisms in the beta2AR gene contribute to the disease state in patients with cystic fibrosis. The Arg16Gly, Gln27Glu, and Thr164Ile beta2AR polymorphisms were studied by specific polymerase chain reaction and restriction fragment length polymorphism analysis in 126 cystic fibrosis patients. Forced expiratory volume in 1 s was significantly (P < 0.05) reduced in cystic fibrosis patients carrying the Gly16 allele in either homozygous or heterozygous form (Gly16Gly + Arg16Gly) compared to patients homozygous for the Arg16 allele (60.3 +/- 3.5% versus 75.7 +/- 4.9% predicted). Similarly, forced vital capacity and flows at lower lung volumes were significantly (P < 0.05 and P < 0.01) lower in cystic fibrosis patients carrying the Gly16 allele. In addition, the Gly16 allele was associated with a greater 5 year decline in pulmonary function (P < 0.01). Bronchodilator responses to albuterol were not significantly different between the groups. The Thr164Ile variant was found in four patients; these patients had markedly reduced pulmonary function. Isoproterenol-stimulated cyclic AMP formation was significantly blunted in cystic fibrosis patients carrying either the Gly16 allele or Thr164Ile genotype compared to cystic fibrosis patients homozygous for the respective Arg16 alleles. These data provide the first evidence suggesting that polymorphisms of the beta2AR gene contribute to clinical severity and disease progression in cystic fibrosis.

The expression of muscle membrane-associated neuronal nitric oxide synthase (NOS1) is significantly impaired in Duchenne muscular dystrophy. Mean (+/- SEM) exhaled NO in 13 male patients with Duchenne muscular dystrophy was significantly lower than in 11 healthy age-matched male control subjects (7.5 +/- 1.4 vs 16.6 +/- 3.2 parts per billion, P <.02) or 17 adult male control subjects (18.5 +/- 1.8 parts per billion, P <.001). These findings provide indirect evidence that NOS1 contributes significantly to fractional exhaled nitric oxide in healthy children.

Airway nitric oxide (NO) and its metabolites are involved in a number of physiological and pathophysiological processes. For instance, NO relaxes airway smooth muscle, improves airway ciliary motility, has antimicrobial effects, and increases expression of the CFTR (cystic fibrosis transmembrane regulator) protein in airway epithelial cells. Of interest, concentrations of NO and of bioactive S-nitrosothiols (SNOs) are decreased in the airways of patients with cystic fibrosis (CF). When compared to patients with relatively normal pulmonary NO formation, CF patients with low NO-concentrations have a significantly reduced pulmonary function and a higher frequency of bacterial colonisation of the airways with pathogens such as P. aeruginosa. As a consequence of these observations clinical trails have now been initiated to study possible effects of an augmented bronchial NO-concentration in CF-patients.

This review summarizes current knowledge about the role of nitric oxide (NO) in cystic fibrosis (CF) lung disease. NO is endogenously produced by a group of enzymes, the NO synthases (NOSs). There are three isoforms of NOS, each encoded by different genes: neuronal (nNOS), immune or inducible (iNOS), and endothelial (eNOS) nitric oxide synthase.(1) They all form NO and L-citrulline by enzymatic oxidation of L-arginine. This reaction requires a number of cosubstrates, including molecular oxygen and tetrahydrobiopterin. It is now known whether all three isoenzymes are constitutively expressed in cells of the respiratory tract and that their gene expression is inducible.(2,3) NO production by iNOS, the "high-output" NOS, is stimulated by bacterial lipopolysaccharide (LPS) as well as proinflammatory cytokines such as interleukin (IL)-1gamma, IL-2, interferon (IFN)-gamma, and tumor necrosis factor (TNF). In contrast to nNOS and eNOS, activation of iNOS does not require an increase in intracellular Ca(2+) concentration., (Copyright 1999 Wiley-Liss, Inc.)

Newborn infants, in contrast to adults, dynamically maintain end-expiratory lung volume (EEV) above relaxation volume. The purpose of this study was to determine at what age children develop a breathing strategy that is relaxed, i.e., determined by the mechanical characteristics of the lung and chest wall. Forty studies were performed in 27 healthy infants and children aged 1 mo to 8 yr during natural sleep. Volume changes were recorded with the use of respiratory inductance plethysmography (RIP). The volume signal was differentiated to yield flow. Flow-volume representations were generated for a random sample of the recorded breaths to determine the predominant breathing strategy utilized, i.e., relaxed, interrupted, or indeterminate. The respiratory pattern was predominantly interrupted below 6 mo of age and predominantly relaxed over 1 yr of age. Mixed patterns were observed in children 6-12 mo of age. The number of breaths that could not be classified (indeterminate) decreased with age. Respiratory frequency measured from the sample of breaths decreased with age and was accompanied by an increase in expiratory time. We conclude that a relaxed EEV develops at the end of the first year of life and may be related to changes in the mechanical properties of the chest wall associated with growth as well as changes in respiratory timing.

We used respiratory inductance plethysmography to record tidal respiration in 27 healthy unsedated infants and children 1 mo to 8 yr of age during sleep. Rib cage and abdominal outputs were present at approximately equal gains and summed to obtain an estimate of volume. Flow-volume curves were generated from the uncalibrated volume signal and its flow derivative. Expiratory time constants (tau) were obtained by visually drawing a line through the linear portion of the expiratory flow-volume relationship. tau increased significantly during the first 10 mo of life. After 10 mo, the estimated rate of increase of tau for older children was less than 5% of the estimated initial rate and not significantly different from zero. Prolongation of tau was paralleled by an increase in expiratory time (Te), and no changes in Te/tau were observed in the first 2 yr of life. These changes in tau likely reflect the increase in lung compliance induced by rapid alveolar growth during infancy. After the first year, expiratory time constants appear to remain relatively constant and may be consistent with balanced changes in compliance and resistance beyond infancy.