Small airways function declines after allogeneic haematopoietic stem cell transplantation Agreement between multiple-breath nitrogen washout systems in children and adults. Effect of equipment dead space on multiple breath washout measures. The association between childhood asthma and adult chronic obstructive pulmonary disease European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia Aerobic Fitness in Children and Young Adults with Primary Ciliary Dyskinesia Lumacaftor/Ivacaftor in Patients Aged 6‐11 Years with Cystic Fibrosis and Homozygous for F508del‐CFTR Comparison of Lung Clearance Index and Magnetic Resonance Imaging for Assessment of Lung Disease in Children with Cystic Fibrosis The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis Multiple Breath Nitrogen Washout: A Feasible Alternative to Mass Spectrometry Study protocol, rationale and recruitment in a European multi-centre randomized controlled trial to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in primary ciliary dyskinesia Noninvasive assessment of airway alterations in smokers: the small airways revisited. Hypertonic saline improves the LCI in paediatric patients with CF with normal lung function Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial. Monitoring the lung periphery of transplanted lungs Lung structure–function correlation in patients with primary ciliary dyskinesia A randomized controlled trial to evaluate the lung clearance index as an outcome measure for early phase studies in patients with cystic fibrosis. Short-term effect of physiotherapy on variability of the lung clearance index in children with cystic fibrosis. Inert gas single-breath washout after heart-lung transplantation. Ventilatory response to nitrogen multiple-breath washout in infants. New time-saving predictor algorithm for multiple breath washout in adolescents Sensitivity of Lung Clearance Index and chest computed tomography in early CF lung disease. Lung clearance index as an outcome measure for clinical trials in young children with cystic fibrosis. A pilot study using inhaled hypertonic saline. Lung clearance index: normal values, repeatability, and reproducibility in healthy children and adolescents. Chest physiotherapy can affect the lung clearance index in cystic fibrosis patients
Bronchiolitis obliterans ( BO ) following  allogeneic haematopoietic stem cell transplantation ( HSCT ) affects peripheral airways . Detection of BO is presently delayed by the low sensitivity of spirometry . We examined the relationship between peripheral airway function and time since HSCT , and compared it with spirometry and clinical indices in 33 clinical ly stable allogeneic HSCT recipients . The following measurements were performed : lung function , exhaled nitric oxide , forced oscillatory respiratory system resistance and reactance , acinar ( Sacin ) and conductive airways ventilation heterogeneity and lung clearance index ( LCI ) measured by multiple breath nitrogen washout . 22 patients underwent repeat visits from which short-term changes were examined . Median time post HSCT was 12 months . Eight patients were clinical ly diagnosed as having BO . In multivariate analysis , time since HSCT was predicted by Sacin and forced expiratory volume in 1 s % predicted . 20 patients had abnormal Sacin with normal spirometry , whereas none had airflow obstruction with normal Sacin . Sacin and LCI were the only measures to change significantly between two visits , with both worsening . Change in Sacin was the only parameter to correlate with change in chronic graft-versus-host disease grade . In conclusion , peripheral airways ventilation heterogeneity worsens with time after HSCT . Sacin may be more sensitive than spirometry in detecting BO at an early stage , which needs confirmation in a prospect i ve study BACKGROUND Comparability of multiple breath washout ( MBW ) systems has been little explored . We assessed agreement in lung clearance index ( LCI ) from two similar , commercial nitrogen MBW setups in patients with Cystic Fibrosis ( CF ) and controls . METHODS The EasyOne Pro ( NDD ) and Exhalyzer D ( EM ) were r and omly applied in 85 adults ( 34 with CF ) and 97 children ( 47 with CF and normal forced expiratory volume in one second ) . We assessed differences between setups in LCI , lung volumes and breathing pattern and diagnostic performance for detecting abnormal lung function . RESULTS Compared to NDD , EM measured higher LCI , functional residual capacity and cumulative expired volume while respiratory rate was lower . Mean difference ( limits of agreement ) in LCI was 1.30 ( -2.34 to 4.94 ) . In CF , prevalence of abnormal LCI was greater in children and similar in adults using EM compared to NDD . CONCLUSIONS Agreement of MBW outcomes between setups is poor and explained by nitrogen measurement techniques and breathing pattern BACKGROUND AND OBJECTIVE Multiple breath inert gas washout ( MBW ) systems are design ed 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 st and ard 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 st and ard 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 r and om 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 result ed 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 result ed in better agreement . CONCLUSIONS Equipment Vd affects LCI measurements especially in young children where Vd is large relative to lung volumes Introduction There is epidemiological evidence to suggest that events in childhood influence lung growth and constitute a significant risk for adult COPD . The aim of the study is to evaluate for an association between childhood asthma and adult COPD . Methods This longitudinal , prospect i ve study of 6–7-year-old children with asthma has been regularly review ed every 7 years to the current analysis at 50 years of age . Participants completed respiratory question naires and lung function spirometry with postbronchodilator response . At the age of 50 , subjects were classified to the following subgroups : non-asthmatics , asthma remission , current asthma and COPD which was defined by FEV1 to FVC ratio postbronchodilator of less than 0.7 . Results Of the remaining survivors , 346 participated in the current study ( participation rate of 76 % ) of whom 197 completed both question naire and lung function testing . As compared with children without symptoms of wheeze to the age of 7 , ( non-asthmatics ) children with severe asthma had an adjusted 32 times higher risk for developing COPD ( 95 % CI 3.4 to 269 ) . In this cohort , 43 % of the COPD group had never smoked . There was no evidence of a difference in the rate of decline in FEV1 ( mL/year , 95th CI ) between the COPD group ( 17 , 10 to 23 ) and the other groups : non-asthmatics ( 16 , 12 to 21 ) , asthma remission ( 20 , 16 to 24 ) and current asthma ( 19 , 13 to 25 ) . Conclusions Children with severe asthma are at increased risk of developing COPD The diagnosis of primary ciliary dyskinesia is often confirmed with st and ard , albeit complex and expensive , tests . In many cases , however , the diagnosis remains difficult despite the array of sophisticated diagnostic tests . There is no “ gold st and ard ” reference test . Hence , a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence -based recommendations on diagnostic testing , especially in light of new developments in such tests , and the need for robust diagnoses of patients who might enter r and omised controlled trials of treatments . The guideline is based on pre-defined questions relevant for clinical care , a systematic review of the literature , and assessment of the evidence using the GRADE ( Grading of Recommendations , Assessment , Development and Evaluation ) approach . It focuses on clinical presentation , nasal nitric oxide , analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis , transmission electron microscopy , genotyping and immunofluorescence .  It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia ; and to provide advice when the diagnosis was not conclusive . Finally , this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia . International ERS guidelines recommend a combination of tests to diagnose  primary ciliary dyskinesia Background Although aerobic fitness is regarded as an overall prognostic measure of morbidity and mortality , its evaluation in the chronic progressive sinopulmonary disease primary ciliary dyskinesia ( PCD ) has been infrequently and inconsistently reported . Here we assessed peak oxygen uptake ( VO2peak ) in a large well-characterized cohort of PCD patients , and explored whether VO2peak was associated with parameters of pulmonary function , self-reported physical limitations , and physical activity level . Methods VO2peak , spirometry , diffusing capacity , whole-body plethysmography , and nitrogen multiple breath inert gas washout ( N2 MBW ) were assessed in a cross-sectional , single-occasion study of clinical ly stable children and young adults with PCD . We used a question naire including self-reported physical limitations in everyday life or in vigorous activities , and estimation of weekly hours of strenuous physical activity .  VO2peak in PCD patients was compared with that in matched , healthy control subjects and a national reference . Results Forty-four PCD patients aged 6–29 years exhibited reduced VO2peak compared to healthy controls ( P<0.001 ) and the national reference . VO2peak was abnormal ( z-score < –1.96 ) in 34 % of PCD patients . Spirometric values , RV/TLC , and indices of N2 MBW were significantly abnormal , but VO2peak only correlated with FEV1 and DLCO/VA . VO2peak correlated with complaints of moderate or significant limitations in vigorous activities ( P = 0.0001 ) , exhibited by 39 % of PCD patients . Conclusion One-third of PCD patients exhibited substantially lower aerobic fitness than healthy subjects . Aerobic fitness correlated with FEV1 , DLCO/VA and self-reported complaints of limitations in vigorous physical activity . These findings are most likely explained by PCD pulmonary disease and its impact on pulmonary function and physical ability . Considering fitness as an important outcome and including regular strenuous physical activity in PCD treatment would probably altogether increase pulmonary clearance , lung function , aerobic fitness , and quality of life , and prevent lifestyle-related diseases Rationale : Combination lumacaftor/ivacaftor has been shown to improve lung function and other endpoints in patients aged 12 years and older with cystic fibrosis and homozygous for F508del‐CFTR , but it has not been assessed in younger patients . Objectives : In this open‐label phase III trial , we evaluated the safety , tolerability , pharmacodynamics , and efficacy of lumacaftor/ivacaftor combination therapy in patients aged 6‐11 years with cystic fibrosis who were homozygous for F508del‐CFTR . Methods : Patients ( N = 58 ) received 200 mg lumacaftor/250 mg ivacaftor orally every 12 hours for 24 weeks in addition to their existing cystic fibrosis medications . Measurements and Main Results : Lumacaftor/ivacaftor was well tolerated ; the safety profile was generally similar to that observed in larger lumacaftor/ivacaftor trials with older patients . Four patients discontinued ( two because of drug‐related adverse events : elevated liver transaminases , n = 1 ; rash , n = 1 ) . No safety concerns were associated with spirometry . No significant changes in percent predicted FEV1 were observed ( change from baseline at Week 24 , + 2.5 percentage points ; 95 % confidence interval [ CI ] , −0.2 to 5.2 ; P = 0.0671 ) . At Week 24 , significant improvements from baseline were observed in sweat chloride ( −24.8 mmol/L ; 95 % CI , −29.1 to −20.5 ; P < 0.0001 ) , body mass index z score ( + 0.15 ; 95 % CI , 0.08 to 0.22 ; P < 0.0001 ) , Cystic Fibrosis Question naire‐Revised respiratory domain score ( + 5.4 ; 95 % CI , 1.4 to 9.4 ; P = 0.0085 ) , and lung clearance index based on lung volume turnover required to reach 2.5 % of starting N2 concentration ( −0.88 ; 95 % CI , −1.40 to −0.37 ; P = 0.0018 ) . Conclusions : Lumacaftor/ivacaftor was well tolerated in this young population ; no new safety concerns were identified . Improvements in lung clearance index , sweat chloride , nutritional status , and health‐related quality of life were observed after 24 weeks of treatment . Clinical trial registered with www . clinical trials.gov ( NCT01897233 ) Rationale : Early onset and progression of lung disease in children with cystic fibrosis ( CF ) indicates that sensitive noninvasive outcome measures are needed for diagnostic monitoring and early intervention clinical trials . The lung clearance index ( LCI ) and chest magnetic resonance imaging ( MRI )  were shown to detect early lung disease in CF ; however , the relationship between the two measures remains unknown . Objectives : To correlate the LCI with abnormalities detected by MRI and compare the sensitivity of the two techniques to detect responses to therapy for pulmonary exacerbations in children with CF . Methods : LCI determined by age‐adapted multiple breath washout techniques and MRI studies were performed in 97 clinical ly stable children with CF across the pediatric age range ( 0.2‐21.1 yr ) . Furthermore , LCI ( n = 26 ) or MRI ( n = 10 ) were performed at the time of pulmonary exacerbation and after antibiotic therapy . MRI was evaluated using a dedicated morphofunctional score . Measurements and Main Results : The LCI correlated with the global MRI score as well as MRI‐defined airway wall abnormalities , mucus plugging , and abnormal lung perfusion in infants and toddlers ( P < 0.05 to P < 0.001 ) and in older children ( P < 0.001 ) with CF . LCI and MRI were sensitive to detect response to antibiotic therapy for pulmonary exacerbations . Conclusions : Our results indicate that LCI and MRI may be useful complementary tools for noninvasive monitoring and as quantitative endpoints in early intervention trials in children with CF . In this context , MRI enables detection of disease heterogeneity , including regional mucus plugging associated with abnormal lung perfusion in early CF lung disease . Clinical trial registered with www . clinical trials.gov ( NCT 02270476 ) Outcome measures to assess therapeutic interventions in cystic fibrosis ( CF ) patients with mild lung disease are lacking . Our aim was to determine if the lung clearance index ( LCI ) can detect a treatment response to dornase alfa in paediatric CF patients with normal spirometry . CF patients between 6–18 yrs of age with FEV1 ≥80 % pred were eligible . In a crossover design , 17 patients received 4 weeks of dornase alfa and placebo in a r and omised sequence separated by a 4-week washout period . The primary end-point was the change in LCI  from dornase alfa versus placebo . A mixed model approach incorporating period-dependent baselines was used . The mean±sd age was 10.32±3.35 yrs . Dornase alfa improved LCI versus placebo ( 0.90±1.44 ; p = 0.022 ) . Forced expiratory flow at 25–75 % expired volume measured by % pred and z-scores also improved in subjects on dornase alfa ( 6.1%±10.34 % ; p = 0.03 and 0.28±0.46 z-score ; p = 0.03 ) . Dornase alfa  significantly improved LCI . Therefore the LCI may be a suitable tool to assess early intervention strategies in this patient population Background The lung clearance index ( LCI ) , measured by multiple breath washout ( MBW ) , reflects global ventilation inhomogeneity and is a sensitive marker of early cystic fibrosis ( CF ) lung disease . Current evidence is based on a customized mass spectrometry system that uses sulfur hexafluoride ( SF6 ) as a tracer gas , which is not widely available . Nitrogen ( N2 ) washout may be better suited for clinical use and multi-center trials . Objective To compare the results obtained from a N2 washout system to those generated by the SF6 based system in healthy children and children with CF . Methods Children with CF were recruited from outpatient clinics ; healthy children were recruited from the Research 4Kids online portal . Participants performed MBWSF6 ( Amis 2000 , Innovision , Denmark ) and MBWN2 ( ExhalyzerD , EcoMedics , Switzerl and ) in triplicate , in r and om order on the same day . Agreement between systems was assessed by Bl and -Altman plot . Results Sixty-two healthy and 61 children with CF completed measurements on both systems . In health there was good agreement between systems ( limits of agreement −0.7 to 1.9 ) ; on average N2 produced higher values of LCI ( mean difference 0.58 ( 95 % CI 0.42 to 0.74 ) ) . In CF the difference between systems was double that in health with a clear bias towards disproportionately higher LCIN2 compared to LCISF6 at higher mean values of LCI . Conclusion LCIN2 and LCISF6 have similar discriminative power and intra-session repeatability but are not interchangeable . MBWN2 offers a valid new tool to investigate early obstructive lung disease in CF , but requires independent normative values Background Clinical management of primary ciliary dyskinesia ( PCD ) respiratory disease is currently based on improving mucociliary clearance and controlling respiratory infections , through the administration of antibiotics . Treatment practice s in PCD are largely extrapolated from more common chronic respiratory disorders , particularly cystic fibrosis , but no r and omized controlled trials ( RCT ) have ever evaluated efficacy and safety of any pharmacotherapeutics used in the treatment of PCD . Maintenance therapy , with the macrolide antibiotic azithromycin , is currently widely used in chronic respiratory diseases including PCD . In addition to its antibacterial properties , azithromycin is considered to have beneficial anti-inflammatory and anti-quorum-sensing properties . The aim of this study is to determine the efficacy of azithromycin maintenance therapy for 6 months on respiratory exacerbations in PCD . The secondary objectives are to evaluate the efficacy of azithromycin on lung function , ventilation inhomogeneity , hearing impairment , and symptoms ( respiratory , sinus , ears and hearing ) measured on a PCD-specific health-related quality of life instrument , and to assess the safety of azithromycin  maintenance therapy in PCD . Methods The BESTCILIA trial is a European multi-centre , double-blind , r and omized , placebo-controlled , parallel group study . The intervention is tablets of azithromycin 250/500 mg according to body weight or placebo administered three times a week for 6 months . Subjects with a confirmed diagnosis of PCD , age 7–50 years , are eligible for inclusion . Chronic pulmonary infections with Gram-negative bacteria or any recent occurrence of non-tuberculous mycobacteria are exclusion criteria . The planned number of subjects to be included is 125 . The trial has been approved by the Research Ethics Committees of the participating institutions . Discussion We present a study protocol of an ongoing RCT , evaluating for the first time , the efficacy and safety of a pharmacotherapeutic treatment for patients with PCD . The RCT evaluates azithromycin maintenance therapy , a drug already commonly prescribed in other chronic respiratory disorders . Furthermore , the trial will utilize the Lung clearance index and new , PCD-specific quality of life instruments as outcome measures for PCD . Recruitment is hampered by frequent occurrence of Pseudomonas aeruginosa infection , exacerbations at enrolment , and the patients ’ perception of disease severity and necessity of additional management and treatment during trial participation . Trial registration EudraCT 2013 - 004664 - 58 ( date of registration : 2014 - 04 - 08 ) It has been shown that structural changes in small airways of smokers with average smoking histories greater than 35 pack-years could be reflected in the single-breath washout test . The more sophisticated multiple breath washout test ( MBW ) has the potential to anatomically locate the affected small airways in acinar and conductive lung zones through increased phase III slope indices S(acin ) and S(cond ) , respectively . Pulmonary function , S(acin ) , and S(cond ) were obtained in 63 normal never-smokers and in 169 smokers classified according to smoking history ( < 10 pack-years ; 10 - 20 pack-years ; 20 - 30 pack-years ; > 30 pack-years ) . Compared with never-smokers , significant changes in S(acin ) ( p = 0.02 ) , S(cond ) ( p < 0.001 ) , and diffusing capacity ( DL(CO ) ; p < 0.001 ) were detected from greater than 10 pack-years onwards . Spirometric abnormality was significant only from greater than 20 pack-years onwards . In smokers with greater than 30 pack-years and DL(CO ) less than 60 % predicted , the presence of emphysema result ed in disproportionally larger S(acin ) than S(cond ) increases . We conclude that S(cond ) and S(acin ) can noninvasively detect airway changes from as early as 10 pack-years onwards , locating the earliest manifestations of smoking-induced small airways alterations around the acinar entrance . In these early stages , the associated DL(CO ) decrease may be a reflection of ventilation heterogeneity rather than true parenchymal destruction . In more advanced stages of smoking-induced lung disease , differential patterns of S(acin ) and S(cond ) are characteristic of the presence of parenchymal destruction in addition to peripheral airways alterations Background and aims Sensitive outcome measures to assess the efficacy of therapeutic interventions in patients with cystic fibrosis ( CF ) with mild lung disease are currently lacking . Our objective was to study the ability of the lung clearance index ( LCI ) , a measure of ventilation inhomogeneity , to detect a treatment response to hypertonic saline inhalation in paediatric patients with CF with normal spirometry . Methods In a crossover trial , 20 patients with CF received 4 weeks of hypertonic saline ( HS ) and isotonic saline ( IS ) in a r and omised sequence separated by a 4 week washout period . The primary end point was the change in the LCI due to HS versus IS . Results Baseline characteristics including the LCI were not significantly different between both study periods . Four weeks of twice-daily HS inhalation significantly improved the LCI compared with IS ( 1.16 , 95 % CI 0.26 to 2.05 ; p=0.016 ) , whereas other outcome measures such as spirometry and quality of life failed to reach statistical significance . R and omisation order had no significant impact on the treatment effect . Conclusions The LCI , but not spirometry was able to detect a treatment effect from HS inhalation in patients with CF with mild disease and may be a suitable tool to assess early intervention strategies in this patient population . Clinical trial number NCT00635141 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 underst and factors explaining the heterogeneous response . A systematic literature search was performed to identify prospect i ve 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 . Lung clearance index response to therapy for pulmonary exacerbations is heterogeneous in cystic fibrosis patients BACKGROUND Ivacaftor has shown a clinical benefit in patients with cystic fibrosis who have the G551D-CFTR mutation and reduced lung function .  Lung clearance index ( LCI ) using multiple-breath washout might be an alternative to and more sensitive method than forced expiratory volume in 1 s ( FEV1 ) to assess treatment response in the growing number of children and young adults with cystic fibrosis who have normal spirometry . The aim of the study was to assess the treatment effects of ivacaftor on LCI in patients with cystic fibrosis , a G551D-CFTR mutation , and an FEV1 > 90 % predicted . METHODS This phase 2 , multicentre , placebo-controlled , double-blind 2 × 2 crossover study of ivacaftor treatment was conducted in patients with cystic fibrosis , at least one G551D-CFTR allele , and an FEV1 > 90 % predicted . Patients also had to have an LCI higher than 7·4 at screening , age of 6 years or older , and a weight higher than or equal to 15 kg . Eligible patients were r and omly allocated to receive one of two treatment sequences ( placebo first followed by ivacaftor 150 mg twice daily [ sequence 1 ] or ivacaftor 150 mg twice daily first followed by placebo [ sequence 2 ] ) of 28 days ' treatment in each period , with a 28-day washout between the two treatment periods . R and omisation ( ratio 1:1 ) was done with block sizes of 4 , and all site personnel including the investigator , the study monitor , and the Vertex study team were masked to treatment assignment . The primary outcome measure was change from baseline in LCI . The study is registered at Clinical Trials.gov , NCT01262352 . FINDINGS Between February and November , 2011 , 21 patients were enrolled , of which 11 were assigned to the sequence 1 group , and 10 to the sequence 2 group . 20 of these patients received treatment and 17 completed the trial ( eight in sequence 1 group and 9 in sequence 2 group ) . Treatment with ivacaftor  led to significant improvements compared with placebo in LCI ( difference between groups in the average of mean changes from baseline at days 15 and 29 was -2·16 [ 95 % CI -2·88 to -1·44 ] ; p<0·0001 ) . Adverse events experienced by study participants were similar between treatment groups ; at least one adverse event was reported by 15 ( 79 % ) of 19 patients who received placebo and 13 ( 72 % ) of 18 patients who received ivacaftor . No deaths occurred during study period . INTERPRETATION In patients with cystic fibrosis aged 6 years or older who have at least one G551D-CFTR allele , ivacaftor led to improvements in LCI . LCI might be a more sensitive alternative to FEV1 in detecting response to intervention in these patients with mild lung disease . FUNDING Vertex Pharmaceuticals Incorporated Lung transplantation is now accepted as a viable therapeutic option for patients with end-stage lung diseases , but long-term survival is threatened by bronchiolitis obliterans ( BO ) , which is regarded as a manifestation of chronic allograft rejection . We have used studies of ventilation distribution for the early detection of this complication . In a prospect i ve study of 57 bilateral-lung transplant recipients , we showed that the slope of phase III of the helium single-breath washout , which targets inhomogeneities of ventilation distribution in the terminal and respiratory bronchioles , was particularly sensitive to the development of BO . In a preliminary study using nitrogen multiple-breath washouts , we showed that S(acin ) and S(cond ) , which reflect structural changes in the acinar and conductive lung zones , were both markedly increased in patients with BO . Taken together , these studies demonstrate that monitoring the function of the allograft by measuring the distribution of ventilation in the lung periphery may be a clinical ly valuable tool Background Primary ciliary dyskinesia ( PCD ) is a rare disease , characterised by chronic airway infection . In cystic fibrosis , FEV1 is insensitive to detect patients with structural damage , and Lung Clearance Index ( LCI ) was proposed as a better marker of early lung damage . In PCD , the relationship between functional and structural abnormalities has been less studied . We aim ed to re-examine this in a cohort of children and adults with mild to moderate PCD . Methods Thirty-eight patients with PCD ( 5.2–25.0 years ) and 70 healthy controls ( 4.4–25.8 years ) were recruited to compare  LCI  , measured by N2 multiple breath washout and FEV1 in a prospect i ve observational trial . In a subset of 30 patients who underwent chest imaging , structural abnormalities were evaluated with cystic fibrosis computed tomography ( CFCT ) scores . Results LCI was abnormal in 28 of 38 patients and a moderate correlation was observed between LCI and FEV1 ( r=−0.519 , p=0.001 ) . Moreover , LCI correlated well with CFCT total score ( r=0.800 , p<0.001 ) and also with subscores for airway wall thickening ( r=0.809 , p<0.001 ) , mucus plugging ( r=0.720 , p<0.001 ) and bronchiectasis ( r=0.494 , p<0.001 ) . Concordance was seen between LCI and CFCT in 25 of 30 ( 83 % ) patients , but between FEV1 and CFCT in only 16 of 30 ( 53 % ) patients . LCI was more sensitive ( 90.9 % , 95 % CI 70.8 to 98.6 ) to detect patients with structural abnormalities than FEV1 ( 36.4 % , 95 % CI 17.2 to 59.3 ) . Conclusions We demonstrated that measuring LCI in patients with PCD is of clinical relevance ; it was more frequently abnormal than FEV1 , correlated well with CFCT and was more sensitive than FEV1 to detect patients with structural abnormalities BACKGROUND Outcome measures that can evaluate treatment efficacy are important to enhance development of new therapeutic agents for Cystic Fibrosis ( CF ) . We investigated whether the lung clearance index ( LCI ) measured by multiple breath washout ( MBW ) can detect a treatment effect of hypertonic saline ( HS ) inhalation after single dosing within a 24 h period . METHODS In this r and omized controlled cross-over trial , CF patients received inhalation of HS and isotonic saline ( IS ) . MBW and spirometry were performed at 5 time points over 24 h. LCI was measured using both a nitrogen washout technique ( LCIN2 ) and sulfur hexafluoride as a tracer gas ( LCISF6 ) . The primary endpoint was the change in the LCIN2 between baseline and 24 h. Secondary endpoints included change in LCISF6 and spirometry outcomes . RESULTS Twenty-one patients were r and omized . Sixteen completed all study visits and all time point measurements . Eighteen patients contributed to the intention to treat analysis . Significant changes were not detected for either LCI or the spirometry outcomes . However , the primary outcome parameter ( change in LCI between the baseline visits and 24 h after inhalation ) demonstrated a trend towards improved LCI , in the HS treatment arm compared with the IS treatment arm , -0.60 LCIN2 ( SE 0.32 ) , p = 0.08 ) ; similar trends were not observed for spirometric measures . The overall effect size of HS was smaller than in previous studies of longer duration . CONCLUSIONS These data suggest that LCI may potentially be used as an outcome measure in early phase trials with therapeutic agents that have a larger treatment effects than a single inhalation of HS Multiple breath washout ( MBW ) for measuring the lung clearance index ( LCI ) has been proposed as a non-invasive tool for detecting early cystic fibrosis ( CF ) lung disease . The LCI is highly repeatable and reproducible in healthy subjects . In patients with CF , within-test variability is low . However , application of physiotherapy ( PT ) immediately preceding MBW may affect LCI variability in CF patients and thus interpretation of repeat measurements and treatment effects . Therefore , the aim of the present study was to prospect ively assess the short-term effect of PT on LCI in CF patients in order to address the question whether or not st and ardized timing of PT and MBW has to be considered when introducing MBW into clinical CF management . Twenty-seven out of 32 patients ( 5.7 - 15.9 years ) with CF successfully performed two technically acceptable MBW tests with the EasyOne Pro , MBW Module ( ndd , Switzerl and ) at intervals of 1(1/2 ) hr . Sixteen out of 27 received 30 min PT in between , whereas 11/27 did not . Repeatability expressed as intraindividual coefficient of variation ( CV ) was 6.1 % pre-PT and 6.5 % post-PT . Mean difference ( 95 % CI ) of LCI between the two tests was -0.20 ( -0.51 ; 0.11 ) . Reproducibility ( SD ) was 4.6 % ( 3.1 ) . Repeatability was 4.2 % and 7.1 % without intervention . Mean difference ( 95 % CI ) of LCI between 1st and 2nd test was 0.07 ( -0.22 ; 0.35 ) . Reproducibility ( SD ) was 2.6 % (2.1).In conclusion , PT does not have a consistent effect on the LCI . Repeatability was slightly poorer than published for healthy subjects possibly reflecting variable mucus plugging , and , thus , variable trapped air in patients with CF . Reproducibility was good and independent on intervention . From our data , we conclude that timing of PT in relation to MBW can be ignored when design ing study protocol s or when interpreting longitudinal data and treatment effects We prospect ively studied the distribution of ventilation in 22 heart-lung transplant ( HLT ) recipients . At entry into study , the patients had undergone surgery an average of 6.7 mo earlier , and were followed for a mean period of 16 mo .  Vital-capacity ( VC )  single-breath washouts as well as single-breath washouts using a 1-L inspiration from FRC were performed on a total of 395 occasions . The inhaled gas mixture consisted of 5 % He , 5 % SF6 , and 90 % O2 , and the expired N2 , He , and SF6 concentrations were analyzed . Six patients showed normal st and ard pulmonary-function tests and indexes of ventilation distribution throughout the study . Five patients gradually developed an irreversible airflow obstruction , presumably due to obliterative bronchiolitis ( OB ) . They showed increases in the slopes of the N2 , SF6 , and He alveolar plateaus ( SN2 , SSF6 , S(He ) ) , but because S(He ) increased more than SSF6 , the slope difference ( SSF6-S(He ) ) invariably decreased and became negative in four of five patients . Thirteen patients developed 16 episodes of reversible airflow obstruction as a result of acute infection or rejection of the lung allograft . The alterations in ventilation distribution were qualitatively similar to those seen in patients with OB . We conclude that : ( 1 ) ventilation distribution in the lung periphery is normal in HLT recipients with adequate allograft function ; ( 2 ) the airflow obstruction elicited by OB and acute episodes of lung infection or rejection is accompanied by increases in SN2 , SSF6 , and S(He ) and decreases in SSF6-(He ) ) . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND Nitrogen multiple-breath washout ( N2 MBW ) using 100 % oxygen ( O2 ) has regained interest to assess efficiency of tracer gas clearance in , for example , children with Cystic Fibrosis ( CF ) . However , the influence of hyperoxia on the infants ' respiratory control is unclear . We assessed safety and impact on breathing pattern from hyperoxia , and if exposure to 40 % O2 first induces tolerance to subsequent 100 % O2 for N2 MBW . METHODS We prospect ively enrolled 39 infants aged 3 - 57 weeks : 15 infants with CF ( 8 se date d for testing ) and 24 healthy controls . Infants were consecutively allocated to the protocol s comprising of 100 % O2 or 40/100 % O2 administered for 30 breaths . Lung function was measured using an ultrasonic flowmeter setup . Primary outcome was tidal volume ( VT ) . RESULTS None of the infants experienced apnea , desaturation , or bradycardia . Both protocol s initially induced hypoventilation . VT temporarily declined in 33/39 infants across 10 - 25 breaths . Hypoventilation occurred independent of age , disease , and sedation . In the new 40/100 % O2 protocol , VT returned to baseline during 40 % O2 and remained stable during 100 % O2 exposure . End-tidal carbon dioxide monitored online did not change . CONCLUSION The classical N2 MBW protocol with 100 % O2 may change breathing patterns of the infants . The new protocol with 40 % O2 induces hyperoxia-tolerance and does not lead to changes in breathing patterns during later N2 washout using 100 % O2 . Both protocol s are safe , the new protocol seems an attractive option for N2 MBW in infants Background : Multiple breath washout ( MBW ) is an informative but time-consuming test . This study evaluates the uncertainty of a time-saving predictor algorithm in adolescents . Methods : Adolescents were recruited from the Copenhagen Prospect i ve Study on Asthma in Childhood ( COPSAC2000 ) birth cohort .  MBW trials were performed at 13 y of age with Innocor model Inn00400 using sulfur hexafluoride ( SF6 ) as tracer gas . Measurements were analyzed using a mixed model focusing on two prediction points doubling ( t5 % ) and quadrupling ( t10 % ) the st and ard end point ( t2.5 % ) . Results : One hundred and seventy-two MBW trials conducted in 78 adolescents with and without asthma from COPSAC2000 were included . At t10 % , the washout time ( WoT ) was reduced by 41 % , and an uncertainty of 0.159 lung clearance index ( LCI ) units was introduced ( ±2 SD ) , ±1.27 ) . At t5 % , the WoT was reduced by 25 % , with an uncertainty of 0.083 LCI units ( ±0.558 ) . The optimal prediction point , which led to most saved time and least uncertainty was t5 % . Conclusion : The predictor algorithm is capable of shortening the MBW test time but introduces an increasing uncertainty with earlier prediction points . This first-of-a-kind prediction algorithm holds promise in shortening the MBW test in children but should be used with caution in subjects with normal LCI values It is widely accepted that CF lung disease starts before clinical symptoms become apparent or spirometry deteriorates . Computed chest tomography ( CT ) is the reference method for identifying structural changes in CF ; however , radiation exposure limits its use as a monitoring tool . It has been suggested that the Lung Clearance Index ( LCI ) measured by Multiple Breath Washout ( MBW ) for assessing ventilation inhomogeneity is a more sensitive surrogate marker than spirometry allowing non-invasive monitoring of CF lung disease . The aim of this study was to prospect ively investigate the diagnostic accuracy of the LCI in comparison to CT in CF patients with early lung disease and normal FEV(1 ) ( > 80 % pred . ) .  MBW and ultra-low-dose CT were performed in 34 patients ( 6 - 26 years ) .  LCI was abnormal in 76.5 % subjects . LCI and  CT  correlated significantly in 82.3 % . LCI was related to presence and extent of structural lung changes observed on CT with a sensitivity of 88 % . Diagnostic accuracy of the LCI for detecting CF lung disease in patients with normal FEV(1 ) was good when compared to CT . Results indicate that structural changes are unlikely if a normal LCI is measured . We speculate that serial measurements of the LCI for assessing ventilation inhomogeneity may help to identify early structural lung disease and help to reduce the individual cumulative radiation dose . The LCI may be a suitable surrogate marker for monitoring progression of CF lung disease and effect of treatment in both , clinical care and research setting RATIONALE Lung clearance index ( LCI ) , measured by multiple breath washout ( MBW ) , is a noninvasive measure of ventilation inhomogeneity that holds promise as an objective physiologic endpoint for clinical trials in infants and preschool children with cystic fibrosis ( CF ) . OBJECTIVES To study the feasibility of using LCI to assess treatment effect outcomes in CF trials of infants and preschoolers . METHODS The Infant Study of Inhaled Saline trial was a multicenter , r and omized , controlled trial of hypertonic ( 7 % ) versus isotonic ( 0.9 % ) saline inhaled twice daily for 48 weeks in children with CF under 6 years of age .  LCI measurements were performed in a single-center pilot sub study at baseline and 48 weeks using a respiratory mass spectrometer and sulfur hexafluoride as the tracer gas . LCI measurements were st and ardized using published normative data ( zLCI ) to account for height-related changes in LCI during early childhood . A generalized estimating equation model with an interaction between treatment group and test occasion was used to estimate a treatment effect . MEASUREMENTS AND MAIN RESULTS A total of 27 participants were r and omized ; 25 participants , aged ( median [ range ] ) 2.6 ( 0.34 - 4.95 ) years , had acceptable baseline and follow-up LCI measures . On average , LCI decreased in the hypertonic saline group ( n = 12 ) by 1.19 z-scores units ( 95 % confidence interval [ CI ] = -2.46 to 0.06 ) , and remained stable in the isotonic saline group ( n = 13 ) at 0.81 ( 95 % CI = -0.40 to 2.02 ) . A significant treatment effect was observed for zLCI ( 2.01 ; 95 % CI = 0.26 to 3.76 ; P = 0.025 ) . CONCLUSIONS MBW testing is feasible in an interventional study in infants and preschool children with CF . These pilot findings support the development of MBW and LCI as an objective outcome measure in interventional trials in young children with CF , and provide estimates for sample size calculations for future studies There is increasing interest in using the Multiple Breath Washout technique and the lung clearance index ( LCI ) for detecting early pulmonary changes , for example , in cystic fibrosis lung disease . However , there are still limited data regarding equipment specific reference ranges , repeatability and reproducibility . The aim of this prospect i ve study was to assess within-test repeatability , short term reproducibility and long term reproducibility , and to establish normal values for the LCI in healthy children and adolescents using the sidestream ultrasonic flow sensor ( EasyOne Pro , MBW Module , ndd Medical Technologies , Switzerl and ) . Fourty-four volunteers ( 5.3 - 20.3 years ) were recruited for the 1st test . Twenty-two out of 44 were measured on a 2nd test occasion after an interval of 1 hr ( 2nd test ) . Thirty-four out of 44 agreed to come back for a follow up test 6 - 15 months later ( 3rd test ) . Mean LCI ( SD ) was 6.2 ( 0.4 ) , 6.3 ( 0.4 ) , and 6.0 ( 0.4 ) at the 1st , 2nd , and 3rd test . The upper limit of normal was 7.0 for all subjects . Within-test repeatability was 5.1 % . Short-term reproducibility ( 1st test vs. 2nd test ) was 4.2 % with a mean difference of -0.13 ( 95 % CI -0.350 ; 0.087 ) . Long-term reproducibility ( 1st test vs. 3rd test ) was 5.1 % , with a mean difference of 0.017 ( 95 % CI -0.016 ; 0.348 ) . With this low variability of the LCI for both , within and between tests , our study demonstrates reliability and robustness of equipment , protocol and analysis and the reliability of the MBW technique in general . The present data will help to interpret the effect of therapeutic interventions and interpretation of longitudinal data in patients with pulmonary diseases OBJECTIVES The lung clearance index ( LCI ) is determined by multiple-breath washout lung function ( MBW ) . It is increasingly used as an endpoint in clinical trials . Chest physiotherapy ( CP ) is part of routine cystic fibrosis ( CF ) care . Whether the LCI is useful in detecting short-term treatment effects of CP has not been sufficiently investigated . We assessed the short-term influence of CP with highly st and ardized high-frequency chest wall oscillation ( HFCWO ) on the LCI in CF patients . METHODS In this r and omized controlled study , the LCI was obtained in 20 CF patients ( 7 - 34 years ) hospitalized for infective pulmonary exacerbation prior to and immediately after a single treatment of HFCWO . Twenty-one control group CF patients ( 7 - 51 years ) received no treatment .  We calculated the coefficient of repeatability ( CR ) to estimate the clinical relevance of possible treatment effects . RESULTS HFCWO improved ( ie , decreased ) the LCI by a median of 0.9 ( range -0.45 ; 3.47 ; P = 0.002 ) ; the LCI decreased in 15 of 20 intervention group patients . In five patients the decrease in LCI exceeded the CR ( 2.15 ) , indicating a clinical ly relevant treatment effect ; in five patients the LCI increased but did not exceed the CR . The LCI did not change significantly in the control group patients . CONCLUSIONS HFCWO can have a short-term decreasing effect on the LCI , but the treatment response is heterogeneous . In future trials using LCI as an endpoint , the timing of CP in relation to MBW should be considered a possible bias
Multiple breath inert gas washout ( MBW ) is a lung function technique to measure ventilation inhomogeneity .
The technique was developed more than 60 years ago , but not much used for many decades .
Technical improvements , easy protocol s and higher sensitivity compared with st and ard lung function tests in some disease groups have led to a recent renaissance of MBW .
The lung clearance index ( LCI ) is a common measure derived from MBW tests , and offers information on lung pathology complementary to that from conventional lung function tests such as spirometry .
The LCI measures the overall degree of pulmonary ventilation inhomogeneity .
There are other MBW-derived parameters , which describe more regional airway ventilation and enable specific information on conductive or acinar ventilation inhomogeneity .
These benefits and the additional physiological information on ventilation inhomogeneity early in the course of lung diseases have led to increasing research activities and clinical application of MBW , especially in paediatric lung diseases such as cystic fibrosis ( CF ) .
We first explain the physiological and technical background to this technique with a short explanation of several method ological aspects that are important for underst and ing the principle behind the technique and enable high quality measurements .