human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 02270 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 02270 
    Output:
    