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Dobra R, Short C, Wong K, Saunders C, Abkir M, Irving S, Davies JC. Utility and interpretation of multiple breath washout in children with cystic fibrosis. Arch Dis Child Educ Pract Ed 2025:edpract-2024-328203. [PMID: 39805677 DOI: 10.1136/archdischild-2024-328203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/31/2024] [Indexed: 01/16/2025]
Abstract
Transformative changes in the health of children with cystic fibrosis (CF) mean that more sensitive outcome measures are needed to monitor paediatric CF lung disease. Multiple breath washout (MBW) and its primary readout lung clearance index are gaining increasing traction as an endpoint for clinical trials in the CF space and show promise as a clinical investigation. In this article, we use four clinically based questions to explore what MBW can and cannot (yet) do and highlight some of its strengths and weaknesses as an investigation. We end by discussing how we can increase the utility of MBW as an investigation in children with CF.
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Affiliation(s)
- Rebecca Dobra
- National Heart and Lung Institute, Imperial College London, London, UK
- Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK
| | - Christopher Short
- National Heart and Lung Institute, Imperial College London, London, UK
- Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK
| | - Kiyo Wong
- Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
| | - Clare Saunders
- National Heart and Lung Institute, Imperial College London, London, UK
- Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK
| | - Mary Abkir
- National Heart and Lung Institute, Imperial College London, London, UK
- Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK
| | - Samantha Irving
- Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK
| | - Jane C Davies
- National Heart and Lung Institute, Imperial College London, London, UK
- Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK
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Wojsyk-Banaszak I, Stachowiak Z, Więckowska B, Andrzejewska M, Tąpolska-Jóźwiak K, Szczepankiewicz A, Sobkowiak P, Bręborowicz A. How Does the Corrected Exhalyzer Software Change the Predictive Value of LCI in Pulmonary Exacerbations in Children with Cystic Fibrosis? Diagnostics (Basel) 2023; 13:2336. [PMID: 37510079 PMCID: PMC10377908 DOI: 10.3390/diagnostics13142336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 05/29/2023] [Accepted: 05/30/2023] [Indexed: 07/30/2023] Open
Abstract
Aim: Recently, the most commonly used for multiple breath washout device, the Exhalyzer D, has been shown to overestimate lung clearance index (LCI) results due to a software error. Our study aimed to compare the predictive values of LCI in the CF pulmonary exacerbations (PE) calculated with the updated (3.3.1) and the previous (3.2.1) version of the Spiroware software. Materials and Methods: The measurements were performed during 259 visits in CF pediatric patients. We used 39ΔPE pairs (PE preceded by stable visit) and 138ΔS pairs (stable visit preceded by stable visit) to compare the LCI changes during PE. The areas under the receiver operating curves (AUCROC) and odds ratios were calculated based on the differences between ΔPEs and ΔSs. The exacerbation risk was estimated using a logistic regression model with generalized estimating equations (GEE). Results: There were statistically significant differences in LCI 2.5% median values measured using the two versions of the software in the stable condition but not during PE. The AUCROC for changes between the two consecutive visits for LCI did not change significantly using the updated Spiroware software. Conclusions: Despite the lower median values, using the recalculated LCI values does not influence the diagnostic accuracy of this parameter in CF PE.
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Affiliation(s)
- Irena Wojsyk-Banaszak
- Department of Paediatric Pulmonology, Allergy and Clinical Immunology, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Zuzanna Stachowiak
- Molecular and Cell Biology Unit, Department of Paediatric Pulmonology, Allergy and Clinical Immunology, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Barbara Więckowska
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Marta Andrzejewska
- Department of Paediatric Pulmonology, Allergy and Clinical Immunology, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Katarzyna Tąpolska-Jóźwiak
- Department of Paediatric Pulmonology, Allergy and Clinical Immunology, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Aleksandra Szczepankiewicz
- Molecular and Cell Biology Unit, Department of Paediatric Pulmonology, Allergy and Clinical Immunology, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Paulina Sobkowiak
- Department of Paediatric Pulmonology, Allergy and Clinical Immunology, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Anna Bręborowicz
- Department of Paediatric Pulmonology, Allergy and Clinical Immunology, Poznan University of Medical Sciences, 60-572 Poznan, Poland
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Abstract
BACKGROUND Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review. OBJECTIVES To investigate efficacy and tolerability of nebulised hypertonic saline treatment in people with cystic fibrosis (CF) compared to placebo or other treatments that enhance mucociliary clearance. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also searched ongoing trials databases. Most recent search: 25 April 2022. SELECTION CRITERIA We included randomised and quasi-randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity). DATA COLLECTION AND ANALYSIS Two authors independently reviewed all identified trials and data, and assessed trial quality. We assessed the certainty of the evidence using GRADE. For cross-over trials we stipulated a one-week washout period. We planned to use results from a paired analysis in the review, but this was only possible in one trial. For other cross-over trials, we chose to treat the trials as if they were parallel. MAIN RESULTS We included 24 trials (1318 participants, aged one month to 56 years); we excluded 29 trials, two trials are ongoing and six are awaiting classification. We judged 15 of the 24 included trials to have a high risk of bias due to participants' ability to discern the taste of the solutions. Hypertonic saline 3% to 7% versus placebo (stable disease) We are uncertain whether the regular use of nebulised hypertonic saline in stable lung disease leads to an improvement in forced expiratory volume in one second (FEV1) % predicted at four weeks, (mean difference (MD) 3.30%, 95% confidence interval (CI) 0.71 to 5.89; 4 trials, 246 participants; very low-certainty evidence). In preschool children we found no difference in lung clearance index (LCI) at four weeks, but a small improvement after 48 weeks of treatment with hypertonic saline compared to isotonic saline (MD -0.60, 95% CI -1.00 to -0.19; 2 trials, 192 participants). We are also uncertain whether hypertonic saline made a difference to mucociliary clearance, pulmonary exacerbations or adverse events compared to placebo. Hypertonic saline versus control (acute exacerbation) Two trials compared hypertonic saline to control, but only one provided data. There may be little or no difference in lung function measured by FEV1 % predicted after hypertonic saline compared to isotonic saline (MD 5.10%, 95% CI -14.67 to 24.87; 1 trial, 130 participants). Neither trial reported any deaths or measures of sputum clearance. There were no serious adverse events. Hypertonic saline versus rhDNase Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two trials (61 participants) provided data for inclusion in the review. We are uncertain whether there was an effect of hypertonic saline on FEV1 % predicted after three weeks (MD 1.60%, 95% CI -7.96 to 11.16; 1 trial, 14 participants; very low-certainty evidence). At three months, rhDNase may lead to a greater increase in FEV1 % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease (MD 8.00%, 95% CI 2.00 to 14.00; low-certainty evidence). We are uncertain whether adverse events differed between the two treatments. No deaths were reported. Hypertonic saline versus amiloride One trial (12 participants) compared hypertonic saline to amiloride but did not report on most of our outcomes. The trial found that there was no difference between treatments in measures of sputum clearance (very low-certainty evidence). Hypertonic saline compared with sodium-2-mercaptoethane sulphonate (Mistabron®) One trial (29 participants) compared hypertonic saline to sodium-2-mercaptoethane sulphonate. The trial did not measure our primary outcomes. There was no difference between treatments in any measures of sputum clearance, courses of antibiotics or adverse events (very low-certainty evidence). Hypertonic saline versus mannitol One trial (12 participants) compared hypertonic saline to mannitol, but did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' (very low-certainty evidence). Hypertonic saline versus xylitol Two trials compared hypertonic saline to xylitol, but we are uncertain whether there is any difference in FEV1 % predicted or median time to exacerbation between groups (very low-certainty evidence). No other outcomes were reported in the review. Hypertonic saline 7% versus hypertonic saline 3% We are uncertain whether there was an improvement in FEV1 % predicted after treatment with 7% hypertonic saline compared with 3% (very low-certainty evidence). AUTHORS' CONCLUSIONS We are very uncertain if regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (three trials; very low-certainty evidence); there was no difference seen at 48 weeks (one trial; low-certainty evidence). Hypertonic saline improved LCI modestly in children under the age of six years. Evidence from one small cross-over trial in children indicates that rhDNase may lead to better lung function than hypertonic saline at three months; qualifying this, we highlight that while the study did demonstrate that the improvement in FEV1 was greater with daily rhDNase, there were no differences seen in any of the secondary outcomes. Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the certainty of the evidence ranged from very low to low at best, according to the GRADE criteria. The role of hypertonic saline in conjunction with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy now needs to be considered, and future research needs to focus on this aspect.
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Affiliation(s)
- Peter Wark
- Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, New Lambton, Australia
| | - Vanessa M McDonald
- Centre of Excellence in Severe Asthma and Priority Research Centre for Healthy Lungs, The University of Newcastle, Newcastle, Australia
| | - Sherie Smith
- Division of Child Health, Obstetrics & Gynaecology (COG), School of Medicine, University of Nottingham, Nottingham, UK
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Ullah SE, Zahoor MM, Gupta S, Boparai S, Muneeb M, Eltieb SA, Shankar A, Kidiavai HM, Vohra RR, Devi A, Bhura ZA, Aslam ZM, Shoaib M. Efficacy of hypertonic saline versus isotonic saline among children with cystic fibrosis: A systematic review and meta-analysis. CANADIAN JOURNAL OF RESPIRATORY THERAPY : CJRT = REVUE CANADIENNE DE LA THERAPIE RESPIRATOIRE : RCTR 2023; 59:1-7. [PMID: 36711047 PMCID: PMC9838740 DOI: 10.29390/cjrt-2022-046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Background Inhaled hypertonic saline (HS) reduces pulmonary exacerbations in patients with cystic fibrosis (CF) aged 6 or more years. However, the effectiveness of HS in improving clinical outcomes in younger children aged 6 or less years is not established. This study examines the efficacy of HS in younger CF patients. Methods Searches were conducted across three databases (Medline, Cochrane Central and EMBASE) from inception through July 2022. Randomized controlled trials assessing the impact of HS in younger CF patients were included. Trials involving only patients greater than 6 years or control group other than isotonic saline (IS) were excluded. Outcomes measured included lung clearance index (LCI), cystic fibrosis questionnaire (CFQ-R) score, spirometry measures, oxygen saturation, respiratory rate, height and weight. Outcomes were reported as mean differences (MDs) with 95% confidence intervals. Results Seven studies (n = 390 patients) were included in this review. HS significantly reduced the LCI (MD: -0.67; 95%CI, -1.05 to 0.29, P = 0.0006) compared to IS. In addition, HS was associated with significant improvements in height (MD: 2.23; 95%CI, -0.00 to 4.46, P = 0.05) and CFQ-R (MD: 4.30; 95%CI, 0.65-7.95, P = 0.02), but not in oxygen saturation (MD: -0.15; 95%CI, -0.54 to 0.25, P = 0.47), respiratory rate (MD: -0.21; 95%CI, -2.19 to 1.77, P = 0.83) or weight (MD: 0.70; 95%CI, -0.47 to 1.87, P = 0.24). Furthermore, HS did not significantly improve spirometry measures, including FEV1 (MD: -0.11; 95%CI, -0.21 to 0.43, P = 0.51) and forced vital capacity (MD: 0.27; 95%CI, -0.49 to 1.04, P = 0.48), but significantly improved FEF25-75 (MD: 0.12; 95% CI, 0.05-0.20; P = 0.002). Discussion Treatment with HS in younger children with CF improves lung clearance, symptoms and quality of life. FEF25-75 may prove a more sensitive measure for assessing intervention related improvements in pediatric CF trials. Conclusion The findings support HS as a therapeutic method in CF-affected children.
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Affiliation(s)
| | | | - Swatika Gupta
- Department of Medicine, Mahatma Gandhi Mission College and Hospital, Navi Mumbai, India
| | - Sukhman Boparai
- Department of Medicine, Acharya Shri Chander College of Medical Sciences and Hospital, Jammu, India
| | - Muhammad Muneeb
- Department of Medicine, Ziauddin University, Karachi, Pakistan
| | | | - Abhirami Shankar
- Department of Internal Medicine, West Anaheim Medical Center, Anaheim, CA
| | | | - Rimsha Rahim Vohra
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Anjuli Devi
- Department of Medicine, Ziauddin University, Karachi, Pakistan
| | - Zainab Asif Bhura
- Department of Internal Medicine, University Health Network, Toronto, ON
| | | | - Mudassir Shoaib
- Department of Medicine, Jinnah Medical and Dental College, Karachi, Pakistan
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Steinke E, Sommerburg O, Graeber SY, Joachim C, Labitzke C, Nissen G, Ricklefs I, Rudolf I, Kopp MV, Dittrich AM, Mall MA, Stahl M. TRACK-CF prospective cohort study: Understanding early cystic fibrosis lung disease. Front Med (Lausanne) 2023; 9:1034290. [PMID: 36687447 PMCID: PMC9853074 DOI: 10.3389/fmed.2022.1034290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/05/2022] [Indexed: 01/09/2023] Open
Abstract
Background Lung disease as major cause for morbidity in patients with cystic fibrosis (CF) starts early in life. Its large phenotypic heterogeneity is partially explained by the genotype but other contributing factors are not well delineated. The close relationship between mucus, inflammation and infection, drives morpho-functional alterations already early in pediatric CF disease, The TRACK-CF cohort has been established to gain insight to disease onset and progression, assessed by lung function testing and imaging to capture morpho-functional changes and to associate these with risk and protective factors, which contribute to the variation of the CF lung disease progression. Methods and design TRACK-CF is a prospective, longitudinal, observational cohort study following patients with CF from newborn screening or clinical diagnosis throughout childhood. The study protocol includes monthly telephone interviews, quarterly visits with microbiological sampling and multiple-breath washout and as well as a yearly chest magnetic resonance imaging. A parallel biobank has been set up to enable the translation from the deeply phenotyped cohort to the validation of relevant biomarkers. The main goal is to determine influencing factors by the combined analysis of clinical information and biomaterials. Primary endpoints are the lung clearance index by multiple breath washout and semi-quantitative magnetic resonance imaging scores. The frequency of pulmonary exacerbations, infection with pro-inflammatory pathogens and anthropometric data are defined as secondary endpoints. Discussion This extensive cohort includes children after diagnosis with comprehensive monitoring throughout childhood. The unique composition and the use of validated, sensitive methods with the attached biobank bears the potential to decisively advance the understanding of early CF lung disease. Ethics and trial registration The study protocol was approved by the Ethics Committees of the University of Heidelberg (approval S-211/2011) and each participating site and is registered at clinicaltrials.gov (NCT02270476).
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Affiliation(s)
- Eva Steinke
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité–Universitätsmedizin Berlin, Berlin, Germany,German Center for Lung Research (DZL), Associated Partner Site, Berlin, Germany,Berlin Institute of Health (BIH) at Charité, Berlin, Germany,*Correspondence: Eva Steinke ✉
| | - Olaf Sommerburg
- Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Translational Pulmonology, University of Heidelberg, Heidelberg, Germany,Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany
| | - Simon Y. Graeber
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité–Universitätsmedizin Berlin, Berlin, Germany,German Center for Lung Research (DZL), Associated Partner Site, Berlin, Germany,Berlin Institute of Health (BIH) at Charité, Berlin, Germany
| | - Cornelia Joachim
- Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Translational Pulmonology, University of Heidelberg, Heidelberg, Germany,Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany
| | - Christiane Labitzke
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Gyde Nissen
- Division of Pediatric Pneumology and Allergology, University of Lübeck, Lübeck, Germany,Airway Research Center North (ARCN), German Center for Lung Research (DZL), Lübeck, Germany
| | - Isabell Ricklefs
- Division of Pediatric Pneumology and Allergology, University of Lübeck, Lübeck, Germany,Airway Research Center North (ARCN), German Center for Lung Research (DZL), Lübeck, Germany
| | - Isa Rudolf
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany,Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - Matthias V. Kopp
- Division of Pediatric Pneumology and Allergology, University of Lübeck, Lübeck, Germany,Airway Research Center North (ARCN), German Center for Lung Research (DZL), Lübeck, Germany,Division of Respiratory Medicine, Department of Pediatrics, University Children's Hospital, Inselspital, University of Bern, Bern, Switzerland
| | - Anna-Maria Dittrich
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany,Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - Marcus A. Mall
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité–Universitätsmedizin Berlin, Berlin, Germany,German Center for Lung Research (DZL), Associated Partner Site, Berlin, Germany,Berlin Institute of Health (BIH) at Charité, Berlin, Germany
| | - Mirjam Stahl
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité–Universitätsmedizin Berlin, Berlin, Germany,German Center for Lung Research (DZL), Associated Partner Site, Berlin, Germany,Berlin Institute of Health (BIH) at Charité, Berlin, Germany
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Avdimiretz N, Radtke T, Benden C. Monitoring practices of chronic lung allograft dysfunction in pediatric lung transplantation. Pediatr Pulmonol 2023; 58:213-221. [PMID: 36200536 DOI: 10.1002/ppul.26187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/10/2022] [Accepted: 10/04/2022] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Chronic lung allograft dysfunction (CLAD) continues to negatively impact the survival of pediatric lung transplant (LTx) recipients. Current consensus guidelines are adult-focused. We sought to examine CLAD detection and monitoring practices at pediatric LTx programs. METHODS We conducted a survey among the International Pediatric Lung Transplant Collaborative. Questions consisted of practitioner's experience, LTx program demographics, and querying tests used for CLAD surveillance and detection. Investigations queried included: chest x-ray (CXR), chest computed tomography (CT), lung magnetic resonance imaging (MRI), ventilation/perfusion scanning, conventional pulmonary function testing (PFT), multiple breath washout (MBW), infant/preschool PFT, bronchoalveolar lavage, transbronchial biopsies (TBBx), or other tissue sampling techniques. Preferences for certain modalities over others were questioned based on a five-point Likert scale. RESULTS Twenty-four of 25 programs responded. Chest CT and CXR are used generally for both CLAD surveillance and detection. No programs use lung MRI clinically, it may have some utility in the future. While all centers use conventional PFT, MBW, and infant/preschool PFT are used in one-fifth and one-third of centers, respectively. While the majority of programs use TBBx, only 41.7% would obtain a diagnosis based on tissue histopathology over noninvasive techniques if CLAD is suspected. Utilization of biomarkers is still limited. CONCLUSIONS Our results indicate continued use of conventional PFT along with chest CT and less so CXR for CLAD detection and monitoring in the large majority of centers. Infant/preschool PFT and novel methods such as MBW are used in a few centers only. Respondents agreed there is a timely need for pediatric consensus guidelines on CLAD detection and monitoring.
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Affiliation(s)
- Nicholas Avdimiretz
- Division of Pediatric Respiratory Medicine, Stollery Children Hospital, University of Alberta, Edmonton, Canada
| | - Thomas Radtke
- Division of Occupational and Environmental Medicine, Epidemiology, Biostatistics, and Prevention Institute, University of Zurich & University Hospital Zurich, Zurich, Switzerland
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Sommerburg O, Wielpütz MO. [Update on cystic fibrosis : From neonatal screening to causal treatment]. RADIOLOGIE (HEIDELBERG, GERMANY) 2022; 62:981-994. [PMID: 36278998 DOI: 10.1007/s00117-022-01076-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/07/2022] [Indexed: 06/16/2023]
Abstract
Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approximately 90% of the morbidity and mortality are caused by pulmonary involvement. The mean life expectancy of patients with CF in 2020 was more than 52 years in Germany. The introduction of neonatal screening for CF and the development of a causally acting CFTR modulator treatment have clearly improved the prognosis of these patients. As an introduction, this article describes important aspects of CF in this context in order to go into details of the CF neonatal screening which was introduced in Germany in 2016.
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Affiliation(s)
- Olaf Sommerburg
- Sektion für Pädiatrische Pneumologie, Allergologie und Mukoviszdose-Zentrum, Zentrum für Kinder- und Jugendmedizin, Klinik III, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Deutschland.
- Translational Lung Research Center Heidelberg (TLRC), Deutsches Zentrum für Lungenforschung (DZL), Im Neuenheimer Feld 156, 69120, Heidelberg, Deutschland.
| | - Mark Oliver Wielpütz
- Translational Lung Research Center Heidelberg (TLRC), Deutsches Zentrum für Lungenforschung (DZL), Im Neuenheimer Feld 156, 69120, Heidelberg, Deutschland
- Klinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 420, 69120, Heidelberg, Deutschland
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Bowerman C, Ratjen F, Stanojevic S. Estimating the minimum sample size for interventional and observational studies using the lung clearance index as an endpoint✰. J Cyst Fibros 2022; 22:356-362. [PMID: 36402729 DOI: 10.1016/j.jcf.2022.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 10/16/2022] [Accepted: 11/10/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND With the increasing availability of highly effective modulators for people living with cystic fibrosis (CF), there is a need to re-design research studies to reflect the changing epidemiology of the CF population. The lung clearance index (LCI), a sensitive physiological measure of lung function, may be ideally suited as an endpoint in the era of CF modulator therapies. In this study we describe study design considerations for implementing LCI into interventional and observational research. METHODS Simulations were used to estimate the required sample size to detect a range of treatment effects for interventional studies (including cross-over trials) and to track lung disease progression in observational studies. RESULTS Using published treatment effects to inform the design of prospective studies can lead to inefficient study designs. Large improvements in LCI for a few individuals can skew results and can influence interpretations of treatment effects. Adjusting for baseline LCI can help to improve the efficiency of a study. Compared to the forced expiratory volume in 1 second (FEV1), analysis using LCI as an endpoint requires as little as one third of the total sample size. CONCLUSIONS Planning of prospective studies that include LCI as an endpoint need to consider baseline LCI and disease severity of the study population; whereas interpretation of results needs to consider whether a few individuals skew the overall treatment effect.
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Tiddens HAWM, Chen Y, Andrinopoulou ER, Davis SD, Rosenfeld M, Ratjen F, Kronmal RA, Hinckley Stukovsky KD, Dasiewicz A, Stick SM. The effect of inhaled hypertonic saline on lung structure in children aged 3-6 years with cystic fibrosis (SHIP-CT): a multicentre, randomised, double-blind, controlled trial. THE LANCET. RESPIRATORY MEDICINE 2022; 10:669-678. [PMID: 35286860 DOI: 10.1016/s2213-2600(21)00546-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 11/19/2021] [Accepted: 11/22/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND In the Saline Hypertonic in Preschoolers (SHIP) study, inhaled 7% hypertonic saline improved the lung clearance index in children aged 3-6 years with cystic fibrosis, but it remained unclear whether improvement is also seen in structural lung disease. We aimed to assess the effect of inhaled hypertonic saline on chest CT imaging in children aged 3-6 years with cystic fibrosis. METHODS Children with cystic fibrosis were enrolled in this multicentre, randomised, double-blind, controlled study at 23 cystic fibrosis centres in Spain, Denmark, the Netherlands, Italy, France, Belgium, the USA, Canada, and Australia. Eligible participants were children aged 3-6 years who were able to cooperate with chest CT imaging and comply with daily nebuliser treatment. Participants were randomly assigned 1:1 to receive inhaled 2 puffs of 100 μg salbutamol followed by 4mL of either 7% hypertonic saline or 0·9% isotonic saline twice per day for 48 weeks. Randomisation was stratified by age in North America and Australia, and by age and country in Europe. Chest CTs were obtained at baseline and 48 weeks and scored using the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis (PRAGMA-CF) method. The primary outcome was the difference between groups in the percentage of total lung volume occupied by abnormal airways (PRAGMA-CF %Disease) measured by chest CT at 48 weeks. Analysis was by intention-to-treat. This study is registered with Clinicaltrials.gov, NCT02950883. FINDINGS Between May 24, 2016, and Dec 18, 2019, 134 children were assessed for inclusion. 18 patients were excluded (nine had incomplete or unsuccessful chest CT at enrolment visit, two could not comply with CT training, two had acute respiratory infection, two withdrew consent, two for reasons unknown, and one was already on hypertonic saline). 116 participants were enrolled and randomly assigned to hypertonic saline (n=56) or isotonic saline (n=60). 12 patients dropped out of the study (seven in the hypertonic saline group and five in the isotonic saline group). Mean PRAGMA-CF %Disease at 48 weeks was 0·88% (95% CI 0·60-1·16) in the hypertonic saline group and 1·55% (1·25-1·84) in the isotonic saline group (mean difference 0·67%, 95% CI 0·26-1·08; p=0·0092) based on a linear regression model adjusted for baseline %Disease values and baseline age. Most adverse events in both groups were rated as mild, and the most common adverse event in both groups was cough. INTERPRETATION Inhaled hypertonic saline for 48 weeks had a positive effect on structural lung changes in children aged 3-6 years with cystic fibrosis relative to isotonic saline. This is the first demonstration of an intervention that alters structural lung disease in children aged 3-6 years with cystic fibrosis. FUNDING Cystic Fibrosis Foundation.
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Affiliation(s)
- Harm A W M Tiddens
- Department of Paediatrics, Division of Respiratory Medicine and Allergology, Sophia Children's Hospital, Erasmus MC, Rotterdam, Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands.
| | - Yuxin Chen
- Department of Paediatrics, Division of Respiratory Medicine and Allergology, Sophia Children's Hospital, Erasmus MC, Rotterdam, Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands
| | | | - Stephanie D Davis
- Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Felix Ratjen
- Division of Respiratory Medicine, Translational Medicine, Research Institute, Hospital for Sick Children, Toronto, ON, Canada
| | - Richard A Kronmal
- Collaborative Health Studies Coordinating Center, University of Washington, Seattle, WA USA
| | | | - Alison Dasiewicz
- Centre for Global Child Health, Hospital for Sick Children, Toronto, ON, Canada
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10
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Koucký V, Komárek A, Pohunek P. Repeatability of lung clearance index in infants with cystic fibrosis and recurrent wheeze. Pediatr Pulmonol 2022; 57:1608-1617. [PMID: 35419996 DOI: 10.1002/ppul.25921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 04/06/2022] [Accepted: 04/10/2022] [Indexed: 11/12/2022]
Abstract
OBJECTIVES To describe the short- and medium-term repeatability of lung clearance index at 2.5% (LCI2.5 ) in infants and calculate the number of patients needed to enroll in a study (N) using LCI2.5 as a primary outcome. METHODS An 8-month follow-up observational study was employed for assessing short-term [coefficient of repeatability (CR) and intraclass correlation (ICC)] and medium-term repeatability (Bland-Altman method) of LCI2.5 in infants with cystic fibrosis (CF) or recurrent wheeze (RW) measured by the nitrogen multiple-breath washout test (N2 -MBW). Using these variability data, the N to reach 90% test power at the level of statistical significance (0.05) was calculated. RESULTS Forty infants with CF and 21 with RW were enrolled. Initial N2 -MBW testing was successful in 33 and 17 patients, respectively. Follow-up data were available for 23 and 11 infants, respectively. Short-term repeatability of LCI2.5 was high (CR = 1.10 and 1.04 in CF and RW patients, respectively; ICC = 0.88 and 0.83 in CF and RW patients, respectively). The between-subject standard deviation was <13% of the actual LCI2.5 value. In clinically stable patients, LCI2.5 did not significantly change during the 8-month follow-up. Mean LCI2.5 change was -0.08 (1% of baseline) in CF and -0.05 (0.6%) in RW, with 95% limits of agreement being (-1.70; 1.53) in CF and (-1.51; 1.40) in RW patients. N = 23 infants if both intragroup differences of LCI2.5 and minimal difference to be detected would be 2.0. CONCLUSION N2 -MBW may be a reproducible tool with reasonable test power to detect differences in infant studies.
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Affiliation(s)
- Václav Koucký
- Department of Pediatrics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Arnošt Komárek
- Department of Probability and Mathematical Statistics, Faculty of Mathematics and Physics, Charles University, Prague, Czech Republic
| | - Petr Pohunek
- Department of Pediatrics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
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11
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Caudri D, Turkovic L, de Klerk NH, Rosenow T, Murray CP, Steyerberg EW, Ranganathan SC, Sly P, Stick SM, Breuer O. A screening tool to identify risk for bronchiectasis progression in children with cystic fibrosis. Pediatr Pulmonol 2022; 57:122-131. [PMID: 34596357 PMCID: PMC9292934 DOI: 10.1002/ppul.25712] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/26/2021] [Accepted: 09/23/2021] [Indexed: 12/03/2022]
Abstract
BACKGROUND The marked heterogeneity in cystic fibrosis (CF) disease complicates the selection of those most likely to benefit from existing or emergent treatments. OBJECTIVE We aimed to predict the progression of bronchiectasis in preschool children with CF. METHODS Using data collected up to 3 years of age, in the Australian Respiratory Early Surveillance Team for CF cohort study, clinical information, chest computed tomography (CT) scores, and biomarkers from bronchoalveolar lavage were assessed in a multivariable linear regression model as predictors for CT bronchiectasis at age 5-6. RESULTS Follow-up at 5-6 years was available in 171 children. Bronchiectasis prevalence at 5-6 was 134/171 (78%) and median bronchiectasis score was 3 (range 0-12). The internally validated multivariate model retained eight independent predictors accounting for 37% (adjusted R2 ) of the variance in bronchiectasis score. The strongest predictors of future bronchiectasis were: pancreatic insufficiency, repeated intravenous treatment courses, recurrent lower respiratory infections in the first 3 years of life, and lower airway inflammation. Dichotomizing the resulting prediction score at a bronchiectasis score of above the median resulted in a diagnostic odds ratio of 13 (95% confidence interval [CI], 6.3-27) with positive and negative predictive values of 80% (95% CI, 72%-86%) and 77% (95% CI, 69%-83%), respectively. CONCLUSION Early assessment of bronchiectasis risk in children with CF is feasible with reasonable precision at a group level, which can assist in high-risk patient selection for interventional trials. The unexplained variability in disease progression at individual patient levels remains high, limiting the use of this model as a clinical prediction tool.
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Affiliation(s)
- Daan Caudri
- Telethon Kids Institute, The University of Western Australia, Perth, Australia.,Department of Respiratory Medicine, Princess Margaret Hospital, Perth, Australia.,Department of Pediatrics/Respiratory Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Lidija Turkovic
- Telethon Kids Institute, The University of Western Australia, Perth, Australia
| | - Nicholas H de Klerk
- Telethon Kids Institute, The University of Western Australia, Perth, Australia
| | - Tim Rosenow
- Telethon Kids Institute, The University of Western Australia, Perth, Australia
| | - Conor P Murray
- Department of Diagnostic Imaging, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
| | - Ewout W Steyerberg
- Department of Public Health, Erasmus MC, Rotterdam, The Netherlands.,Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
| | - Sarath C Ranganathan
- Murdoch Children's Research Institute, Parkville, Australia.,Department of Respiratory Medicine, Royal Children's Hospital, Parkville, Australia.,Department of Paediatrics, University of Melbourne, Parkville, Australia
| | - Peter Sly
- Child Health Research Centre, The University of Queensland, Brisbane, Australia
| | - Stephen M Stick
- Telethon Kids Institute, The University of Western Australia, Perth, Australia.,Department of Respiratory Medicine, Princess Margaret Hospital, Perth, Australia
| | - Oded Breuer
- Telethon Kids Institute, The University of Western Australia, Perth, Australia.,Department of Respiratory Medicine, Princess Margaret Hospital, Perth, Australia.,Pediatric Pulmonology and CF Unit, Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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12
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Cohen-Cymberknoh M, Ben Meir E, Gartner S, Reiter J, Spangenberg A, Garriga L, Eisenstadt I, Israeli T, Tsabari R, Shoseyov D, Gileles-Hillel A, Breuer O, Simanovsky N, Kerem E. How abnormal is the normal? Clinical characteristics of CF patients with normal FEV 1. Pediatr Pulmonol 2021; 56:2007-2013. [PMID: 33704929 DOI: 10.1002/ppul.25371] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 02/23/2021] [Accepted: 02/24/2021] [Indexed: 11/07/2022]
Abstract
BACKGROUND Normal values (>80%) of Forced Expiratory Volume in one second (FEV1 ) in patients with cystic fibrosis (CF) may lead to the interpretation that there is no lung disease. This study is a comprehensive analysis of lung involvement in CF patients having normal FEV1 . METHODS Patients were recruited from two CF centers: Hadassah Medical Center, Jerusalem and Vall d' Hebron Hospital, Barcelona. Lung disease was assessed by lung clearance index (LCI), chest CT-Brody score, respiratory cultures, number of pulmonary exacerbations (PEx), and days of antibiotic treatment in the year before the assessment. RESULTS Of the 247 patients, 89 (36%) had FEV1 ≥80% and were included in the study (mean age, 17.6; range, 4.25-49 years). Chronic Pseudomonas aeruginosa infection was found in 21%, and 31% had at least one major PEx in the year before the study. Abnormally elevated LCI was found in 86% of patients, ranging between 7.52 and 18.97, and total Brody score (TBS) was abnormal in 92% (range, 5.0-96.5). Patients with chronic P. aeruginosa had significantly higher LCI (p = .01) and TBS (p = .02) which were associated with more major PEx (p < .01 and p = .01, respectively) and more days of intravenous (IV) antibiotic treatment in the preceding year (p = .03 and p = .001, respectively). CONCLUSIONS Most CF patients with normal FEV1 have already physiological and structural lung abnormalities which were associated with more PEx and IV antibiotic treatment. Further studies are needed to determine if better adherence to the currently used therapies and the new cystic fibrosis transmembrane modulators will prevent the progression of lung disease.
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Affiliation(s)
- Malena Cohen-Cymberknoh
- Pediatric Pulmonology Unit and Cystic Fibrosis Center, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Elad Ben Meir
- Pediatric Pulmonology Unit and Cystic Fibrosis Center, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Silvia Gartner
- Pediatric Pulmonology Unit and Cystic Fibrosis Center, Hospital Universitari Vall d' Hebron, Barcelona, Spain
| | - Joel Reiter
- Pediatric Pulmonology Unit and Cystic Fibrosis Center, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Angeles Spangenberg
- Pediatric Pulmonology Unit and Cystic Fibrosis Center, Hospital Universitari Vall d' Hebron, Barcelona, Spain
| | - Laura Garriga
- Pediatric Pulmonology Unit and Cystic Fibrosis Center, Hospital Universitari Vall d' Hebron, Barcelona, Spain
| | - Iris Eisenstadt
- Department of Physiotherapy and Cystic Fibrosis Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Tomer Israeli
- Department of Physiotherapy and Cystic Fibrosis Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Reuven Tsabari
- Pediatric Pulmonology Unit and Cystic Fibrosis Center, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - David Shoseyov
- Pediatric Pulmonology Unit and Cystic Fibrosis Center, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Alex Gileles-Hillel
- Pediatric Pulmonology Unit and Cystic Fibrosis Center, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Oded Breuer
- Pediatric Pulmonology Unit and Cystic Fibrosis Center, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Natalia Simanovsky
- Department of Radiology, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Eitan Kerem
- Pediatric Pulmonology Unit and Cystic Fibrosis Center, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
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13
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Sandvik R, Gustafsson PM, Lindblad A, Robinson PD, Nielsen K. Improved agreement between N 2 and SF 6 multiple-breath washout in healthy infants and toddlers with improved EXHALYZER D sensor performance. J Appl Physiol (1985) 2021; 131:107-118. [PMID: 34043468 DOI: 10.1152/japplphysiol.00129.2021] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Recent studies indicate limited utility of nitrogen multiple-breath washout (N2MBW) in infancy and advocate for using sulfur hexafluoride (SF6) MBW in this age-group. Modern N2MBW systems, such as EXHALYZER D (ECO MEDICS AG, Duernten, Switzerland), use O2 and CO2 sensors to calculate N2 concentrations (in principle, N2% = 100 - CO2% - O2%). High O2 and CO2 concentrations have now been shown to significantly suppress signal output from the other sensor, raising apparent N2 concentrations. We examined whether improved EXHALYZER D N2 signal, accomplished after thorough examination of this CO2 and O2 interaction on gas sensors and its correction, leads to better agreement between N2MBW and SF6MBW in healthy infants and toddlers. Within the same session, 52 healthy children aged 1-36 mo [mean = 1.30 (SD = 0.72) yr] completed SF6MBW and N2MBW recordings (EXHALYZER D, SPIROWARE version 3.2.1) during supine quiet sleep. SF6 and N2 SPIROWARE files were reanalyzed offline with in-house software using identical algorithms as in SPIROWARE with or without application of the new correction factors for N2MBW provided by ECO MEDICS AG. Applying the improved N2 signal significantly reduced mean [95% confidence interval (CI)] differences between N2MBW and SF6MBW recorded functional residual capacity (FRC) and lung clearance index (LCI): for FRC, from 26.1 (21.0, 31.2) mL, P < 0.0001, to 1.18 (-2.3, 4.5) mL, P = 0.5, and for LCI, from 1.86 (1.68, 2.02), P < 0.001, to 0.44 (0.33, 0.55), P < 0.001. Correction of N2 signal for CO2 and O2 interactions on gas sensors resulted in markedly closer agreement between N2MBW and SF6MBW outcomes in healthy infants and toddlers.NEW & NOTEWORTHY Modern nitrogen multiple-breath washout (N2MBW) systems such as EXHALYZER D use O2 and CO2 sensors to calculate N2 concentrations. New corrections for interactions between high O2 and CO2 concentrations on the gas sensors now provide accurate N2 signals. The correct N2 signal led to much improved agreement between N2MBW and sulfur hexafluoride (SF6) MBW functional residual capacity (FRC) and lung clearance index (LCI) in 52 sleeping healthy infants and toddlers, suggesting a role for N2MBW in this age-group.
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Affiliation(s)
- Rikke Sandvik
- Danish Paediatric Pulmonary Service, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Per M Gustafsson
- Department of Paediatrics, Central Hospital, Skövde, Sweden.,Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anders Lindblad
- Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Gothenburg CF Centre, Queen Silvia Children's Hospital, Gothenburg, Sweden
| | - Paul D Robinson
- Department of Respiratory Medicine, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.,The Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Kim Nielsen
- Danish Paediatric Pulmonary Service, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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14
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Quantification of Phenotypic Variability of Lung Disease in Children with Cystic Fibrosis. Genes (Basel) 2021; 12:genes12060803. [PMID: 34070354 PMCID: PMC8229033 DOI: 10.3390/genes12060803] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/15/2021] [Accepted: 05/19/2021] [Indexed: 12/28/2022] Open
Abstract
Cystic fibrosis (CF) lung disease has the greatest impact on the morbidity and mortality of patients suffering from this autosomal-recessive multiorgan disorder. Although CF is a monogenic disorder, considerable phenotypic variability of lung disease is observed in patients with CF, even in those carrying the same mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or CFTR mutations with comparable functional consequences. In most patients with CF, lung disease progresses from childhood to adulthood, but is already present in infants soon after birth. In addition to the CFTR genotype, the variability of early CF lung disease can be influenced by several factors, including modifier genes, age at diagnosis (following newborn screening vs. clinical symptoms) and environmental factors. The early onset of CF lung disease requires sensitive, noninvasive measures to detect and monitor changes in lung structure and function. In this context, we review recent progress with using multiple-breath washout (MBW) and lung magnetic resonance imaging (MRI) to detect and quantify CF lung disease from infancy to adulthood. Further, we discuss emerging data on the impact of variability of lung disease severity in the first years of life on long-term outcomes and the potential use of this information to improve personalized medicine for patients with CF.
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15
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Perrem L, Stanojevic S, Shaw M, Jensen R, McDonald N, Isaac SM, Davis M, Clem C, Guido J, Jara S, France L, Solomon M, Grasemann H, Waters V, Sweezey N, Sanders DB, Davis SD, Ratjen F. Lung Clearance Index to Track Acute Respiratory Events in School-Age Children with Cystic Fibrosis. Am J Respir Crit Care Med 2021; 203:977-986. [PMID: 33030967 DOI: 10.1164/rccm.202006-2433oc] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Rationale: The lung clearance index (LCI) is responsive to acute respiratory events in preschool children with cystic fibrosis (CF), but its utility to identify and manage these events in school-age children with CF is not well defined.Objectives: To describe changes in LCI with acute respiratory events in school-age children with CF.Methods: In a multisite prospective observational study, the LCI and FEV1 were measured quarterly and during acute respiratory events. Linear regression was used to compare relative changes in LCI and FEV1% predicted at acute respiratory events. Logistic regression was used to compare the odds of a significant worsening in LCI and FEV1% predicted at acute respiratory events. Generalized estimating equation models were used to account for repeated events in the same subject.Measurements and Main Results: A total of 98 children with CF were followed for 2 years. There were 265 acute respiratory events. Relative to a stable baseline measure, LCI (+8.9%; 95% confidence interval, 6.5 to 11.3) and FEV1% predicted (-6.6%; 95% confidence interval, -8.3 to -5.0) worsened with acute respiratory events. A greater proportion of events had a worsening in LCI compared with a decline in FEV1% predicted (41.7% vs. 30.0%; P = 0.012); 53.9% of events were associated with worsening in LCI or FEV1. Neither LCI nor FEV1 recovered to baseline values at the next follow-up visit.Conclusions: In school-age children with CF, the LCI is a sensitive measure to assess lung function worsening with acute respiratory events and incomplete recovery at follow-up. In combination, the LCI and FEV1 capture a higher proportion of events with functional impairment.
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Affiliation(s)
- Lucy Perrem
- Division of Respiratory Medicine and.,Department of Paediatrics and.,Translational Medicine Program, SickKids Research Institute, Toronto, Ontario, Canada.,Royal College of Surgeons in Ireland, Dublin, Ireland.,National Children's Research Centre, Children's Health Ireland, Dublin, Ireland
| | - Sanja Stanojevic
- Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.,Translational Medicine Program, SickKids Research Institute, Toronto, Ontario, Canada
| | - Michelle Shaw
- Translational Medicine Program, SickKids Research Institute, Toronto, Ontario, Canada
| | - Renee Jensen
- Division of Respiratory Medicine and.,Translational Medicine Program, SickKids Research Institute, Toronto, Ontario, Canada
| | - Nancy McDonald
- Division of Respiratory Medicine and.,Translational Medicine Program, SickKids Research Institute, Toronto, Ontario, Canada
| | - Sarah M Isaac
- Translational Medicine Program, SickKids Research Institute, Toronto, Ontario, Canada
| | - Miriam Davis
- Division of Pediatric Pulmonology, Riley Hospital for Children, Indianapolis, Indiana; and
| | - Charles Clem
- Division of Pediatric Pulmonology, Riley Hospital for Children, Indianapolis, Indiana; and
| | - Julia Guido
- Translational Medicine Program, SickKids Research Institute, Toronto, Ontario, Canada
| | - Sylvia Jara
- Division of Pediatric Pulmonology, Riley Hospital for Children, Indianapolis, Indiana; and
| | - Lisa France
- Division of Pediatric Pulmonology, Riley Hospital for Children, Indianapolis, Indiana; and
| | - Melinda Solomon
- Division of Respiratory Medicine and.,Department of Paediatrics and.,Translational Medicine Program, SickKids Research Institute, Toronto, Ontario, Canada
| | - Hartmut Grasemann
- Division of Respiratory Medicine and.,Department of Paediatrics and.,Translational Medicine Program, SickKids Research Institute, Toronto, Ontario, Canada
| | - Valerie Waters
- Division of Infectious Diseases, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Paediatrics and.,Translational Medicine Program, SickKids Research Institute, Toronto, Ontario, Canada
| | - Neil Sweezey
- Division of Respiratory Medicine and.,Department of Paediatrics and.,Translational Medicine Program, SickKids Research Institute, Toronto, Ontario, Canada
| | - Don B Sanders
- Division of Pediatric Pulmonology, Riley Hospital for Children, Indianapolis, Indiana; and
| | - Stephanie D Davis
- Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina
| | - Felix Ratjen
- Division of Respiratory Medicine and.,Department of Paediatrics and.,Translational Medicine Program, SickKids Research Institute, Toronto, Ontario, Canada
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16
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Bayfield KJ, Douglas TA, Rosenow T, Davies JC, Elborn SJ, Mall M, Paproki A, Ratjen F, Sly PD, Smyth AR, Stick S, Wainwright CE, Robinson PD. Time to get serious about the detection and monitoring of early lung disease in cystic fibrosis. Thorax 2021; 76:1255-1265. [PMID: 33927017 DOI: 10.1136/thoraxjnl-2020-216085] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 02/24/2021] [Accepted: 03/10/2021] [Indexed: 12/26/2022]
Abstract
Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV1) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV1 decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life. Spirometry-based classifications of 'normal' (FEV1≥90% predicted) and 'mild lung disease' (FEV1 70%-89% predicted) are inappropriate, given the failure of spirometry to detect significant structural or functional abnormalities shown by more sensitive imaging and lung function techniques. The state and readiness of two imaging (CT and MRI) and two functional (multiple breath washout and oscillometry) tools for the detection and monitoring of early lung disease in children and adults with CF are discussed in this article.Prospective research programmes and technological advances in these techniques mean that well-designed interventional trials in early lung disease, particularly in young children and infants, are possible. Age appropriate, randomised controlled trials are critical to determine the safety, efficacy and best use of new therapies in young children. Regulatory bodies continue to approve medications in young children based on safety data alone and extrapolation of efficacy results from older age groups. Harnessing the complementary information from structural and functional tools, with measures of inflammation and infection, will significantly advance our understanding of early CF lung disease pathophysiology and responses to therapy. Defining clinical utility for these novel techniques will require effective collaboration across multiple disciplines to address important remaining research questions. Future impact on existing management burden for patients with CF and their family must be considered, assessed and minimised.To address the possible role of these techniques in early lung disease, a meeting of international leaders and experts in the field was convened in August 2019 at the Australiasian Cystic Fibrosis Conference. The meeting entitiled 'Shaping imaging and functional testing for early disease detection of lung disease in Cystic Fibrosis', was attended by representatives across the range of disciplines involved in modern CF care. This document summarises the proceedings, key priorities and important research questions highlighted.
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Affiliation(s)
- Katie J Bayfield
- Department of Respiratory Medicine, Children's Hospital at Westmead, Westmead, New South Wales, Australia
| | - Tonia A Douglas
- Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, South Brisbane, Queensland, Australia.,Child Health Research Centre, The University of Queensland, Brisbane, Queensland, Australia
| | - Tim Rosenow
- Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia.,Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.,Centre for Microscopy, Characterisation and Analysis, The University of Western Australia, Perth, Western Australia, Australia
| | - Jane C Davies
- National Heart and Lung Institute, Imperial College London, London, UK.,Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Stuart J Elborn
- Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
| | - Marcus Mall
- Department of Pediatric Pulmonology, Immunology, and Critical Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health, Berlin, Germany.,Department of Translational Pulmonology, German Center for Lung Research, Berlin, Germany
| | - Anthony Paproki
- The Australian e-Health Research Centre, CSIRO, Brisbane, Queensland, Australia
| | - Felix Ratjen
- Translational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.,University of Toronto, Toronto, Ontario, Canada
| | - Peter D Sly
- Children's Health and Environment Program, Child Health Research Centre, The University of Queenland, Herston, Queensland, Australia
| | - Alan R Smyth
- Division of Child Health, Obstetrics & Gynaecology. School of Medicine, University of Nottingham, Nottingham, Nottinghamshire, UK
| | - Stephen Stick
- Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia.,Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.,Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
| | - Claire E Wainwright
- Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, South Brisbane, Queensland, Australia.,Child Health Research Centre, The University of Queensland, Brisbane, Queensland, Australia
| | - Paul D Robinson
- Department of Respiratory Medicine, Children's Hospital at Westmead, Westmead, New South Wales, Australia .,Airway Physiology and Imaging Group, Woolcock Institute of Medical Research, Glebe, New South Wales, Australia.,The Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, New South Wales, Australia
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17
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Hatziagorou E, Kampouras A, Avramidou V, Toulia I, Chrysochoou EA, Galogavrou M, Kirvassilis F, Tsanakas J. Toward the Establishment of New Clinical Endpoints for Cystic Fibrosis: The Role of Lung Clearance Index and Cardiopulmonary Exercise Testing. Front Pediatr 2021; 9:635719. [PMID: 33718306 PMCID: PMC7946844 DOI: 10.3389/fped.2021.635719] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/03/2021] [Indexed: 01/25/2023] Open
Abstract
As Cystic Fibrosis (CF) treatment advances, research evidence has highlighted the value and applicability of Lung Clearance Index and Cardiopulmonary Exercise Testing as endpoints for clinical trials. In the context of these new endpoints for CF trials, we have explored the use of these two test outcomes for routine CF care. In this review we have presented the use of these methods in assessing disease severity, disease progression, and the efficacy of new interventions with considerations for future research.
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Affiliation(s)
- Elpis Hatziagorou
- Pediatric Pulmonology and Cystic Fibrosis Unit, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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18
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Muston HN, Perrem L, Davis MD, Ratjen F, Ren CL. The remaining barriers to normalcy in CF: Advances in assessment of CF lung disease. Pediatr Pulmonol 2021; 56 Suppl 1:S90-S96. [PMID: 32589821 DOI: 10.1002/ppul.24929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/20/2020] [Accepted: 06/23/2020] [Indexed: 11/12/2022]
Abstract
Despite early diagnosis of cystic fibrosis (CF) through newborn screening, a substantial proportion of infants and young children with CF still demonstrate physiologic and structural evidence of lung disease progression, such as obstructive airway disease and bronchiectasis. The growing availability of highly effective CF transmembrane conductance regulatory modulator therapy to the vast majority of people with CF has led to the potential to alter the natural history of CF lung disease, but to assess the full impact of these therapies on CF lung disease and to help guide treatment, sensitive measures of early and mild disease are needed. Chest imaging using computed tomography or magnetic resonance imaging is one approach, but technologic barriers and/or concern about exposure to ionizing radiation may limit its use. However, advances in physiologic measurement techniques and exhaled breath analysis offer another option for assessment of CF lung disease.
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Affiliation(s)
- Heather N Muston
- Division of Pediatric Pulmonology, Allergy, and Sleep Medicine, Indiana University School of Medicine, Indianapolis, Indiana.,Riley Hospital for Children, Indianapolis, Indiana
| | - Lucy Perrem
- Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada.,Translational Medicine Program, SickKids Research Institute, Toronto, Canada
| | - Michael D Davis
- Division of Pediatric Pulmonology, Allergy, and Sleep Medicine, Indiana University School of Medicine, Indianapolis, Indiana.,Riley Hospital for Children, Indianapolis, Indiana
| | - Felix Ratjen
- Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada.,Translational Medicine Program, SickKids Research Institute, Toronto, Canada
| | - Clement L Ren
- Division of Pediatric Pulmonology, Allergy, and Sleep Medicine, Indiana University School of Medicine, Indianapolis, Indiana.,Riley Hospital for Children, Indianapolis, Indiana
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19
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Willmering MM, Roach DJ, Kramer EL, Walkup LL, Cleveland ZI, Woods JC. Sensitive structural and functional measurements and 1-year pulmonary outcomes in pediatric cystic fibrosis. J Cyst Fibros 2020; 20:533-539. [PMID: 33288474 DOI: 10.1016/j.jcf.2020.11.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/17/2020] [Accepted: 11/25/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Two functional measurements (multiple breath washout [MBW] and hyperpolarized 129Xe ventilation magnetic resonance imaging [129Xe MRI]) have been shown to be more sensitive to cystic fibrosis (CF) lung obstruction than traditional spirometry. However, functional techniques may be sensitive to different underlying structural abnormalities. The purpose of this study was to determine relationships between these functional markers, their pathophysiology, and 1-year clinical outcomes. METHODS Spirometry, MBW, 129Xe MRI, and ultrashort echo-time (UTE) MRI were obtained in a same-day assessment of 27 pediatric CF patients (ages 11.5±5.0) who had not begun CFTR modulator therapies. UTE MRI was scored for structural abnormalities and functional metrics obtained via spirometry, MBW and 129Xe MRI. 1-year outcomes (ΔFEV1 and pulmonary exacerbations), during which ≈50% initiated modulator therapy, were obtained from the electronic medical record. RESULTS MBW, 129Xe MRI, and UTE MRI detected clinically significant disease in more subjects (>78%) compared to spirometry (<30%). UTE MRI suggests increased odds of bronchial changes when mucus plugging is present in the same lobe. MBW and 129Xe MRI correlated best with mucus plugging, while spirometry correlated best with consolidations. Bronchial abnormalities were associated with future pulmonary exacerbations. CONCLUSIONS MBW, 129Xe MRI, and UTE MRI are more sensitive for detection of pediatric CF lung disease when compared to spirometry. MBW and 129Xe MRI correlated with structural abnormalities which occur in early CF disease, suggesting MBW and 129Xe MRI are valuable tools in mild CF lung disease that can guide clinical decision making.
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Affiliation(s)
- Matthew M Willmering
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States
| | - David J Roach
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States
| | - Elizabeth L Kramer
- Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Department of Pediatrics, University of Cincinnati Medical Center, Cincinnati, OH 45229, United States
| | - Laura L Walkup
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Department of Pediatrics, University of Cincinnati Medical Center, Cincinnati, OH 45229, United States; Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH 45229, United States
| | - Zackary I Cleveland
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Department of Pediatrics, University of Cincinnati Medical Center, Cincinnati, OH 45229, United States; Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH 45229, United States
| | - Jason C Woods
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Department of Pediatrics, University of Cincinnati Medical Center, Cincinnati, OH 45229, United States; Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Department of Physics, University of Cincinnati, Cincinnati, OH 45229, United States.
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20
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Donaldson SH, Danielle Samulski T, LaFave C, Zeman K, Wu J, Trimble A, Ceppe A, Bennett WD, Davis SD. A four week trial of hypertonic saline in children with mild cystic fibrosis lung disease: Effect on mucociliary clearance and clinical outcomes. J Cyst Fibros 2020; 19:942-948. [PMID: 32669217 PMCID: PMC7736104 DOI: 10.1016/j.jcf.2020.07.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 01/05/2023]
Abstract
BACKGROUND Hypertonic saline (HS) is commonly prescribed for children with cystic fibrosis (CF) despite the absence of strong data indicating clinical efficacy in a population with mild lung disease. We hypothesized that HS treatment would result in a sustained improvement in mucociliary clearance (MCC) in children with CF who had minimal lung disease, thus providing evidence for a biologically relevant effect that also may be associated with clinical improvements. METHODS We performed a randomized, placebo controlled, double blind study of 6% versus 0.12% sodium chloride, delivered three-times daily with an eFlow nebulizer for 4 weeks. MCC was measured using gamma scintigraphy at baseline, 2-hours after the first study treatment, and ~12-hours after the final dose (at day 28). Spirometry, respiratory symptoms (CFQ-R), and safety were also assessed. RESULTS Study treatments were generally well tolerated and safe. HS (6% sodium chloride) resulted in a significant, sustained improvement from baseline in whole lung clearance after 4 weeks of therapy (p = 0.014), despite absence of a prolonged single-dose effect after the initial dose. This sustained change (12 hrs after prior dose) was significantly greater when compared to placebo (0.12% sodium chloride) treatment (p = 0.016). Improvements in spirometry with HS did not reach statistical significance but correlated with MCC changes. CONCLUSIONS The observed sustained improvement in MCC with HS suggests that this treatment may yield health benefits, even in relatively mildly affected children with CF. Highlighting this physiologic finding is important due to the lack of meaningful, validated endpoints in this population.
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Affiliation(s)
- Scott H Donaldson
- University of North Carolina School of Medicine at Chapel Hill, NC, Pulmonary and Critical Care Medicine, Chapel Hill, USA.
| | - T Danielle Samulski
- University of North Carolina School of Medicine at Chapel Hill, NC, Pulmonary and Critical Care Medicine, Chapel Hill, USA
| | - Caroline LaFave
- University of North Carolina School of Medicine at Chapel Hill, NC, Pulmonary and Critical Care Medicine, Chapel Hill, USA; Department of Pediatrics, Chapel Hill, USA
| | - Kirby Zeman
- Center for Environmental Medicine, Asthma and Lung Biology, Chapel Hill, USA
| | - Jihong Wu
- Center for Environmental Medicine, Asthma and Lung Biology, Chapel Hill, USA
| | - Aaron Trimble
- University of North Carolina School of Medicine at Chapel Hill, NC, Pulmonary and Critical Care Medicine, Chapel Hill, USA
| | - Agathe Ceppe
- University of North Carolina School of Medicine at Chapel Hill, NC, Pulmonary and Critical Care Medicine, Chapel Hill, USA
| | - William D Bennett
- University of North Carolina School of Medicine at Chapel Hill, NC, Pulmonary and Critical Care Medicine, Chapel Hill, USA; Center for Environmental Medicine, Asthma and Lung Biology, Chapel Hill, USA
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21
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Perrem L, Ratjen F. Designing Clinical Trials for Anti-Inflammatory Therapies in Cystic Fibrosis. Front Pharmacol 2020; 11:576293. [PMID: 33013419 PMCID: PMC7516261 DOI: 10.3389/fphar.2020.576293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 08/24/2020] [Indexed: 01/15/2023] Open
Abstract
The inflammatory response in the CF airway begins early in the disease process and becomes persistent through life in most patients. Inflammation, which is predominantly neutrophilic, worsens airway obstruction and plays a critical role in the development of structural lung damage. While cystic fibrosis transmembrane regulator modulators will likely have a dramatic impact on the trajectory of CF lung disease over the coming years, addressing other important aspects of lung disease such as inflammation will nevertheless remain a priority. Considering the central role of neutrophils and their products in the inflammatory response, potential therapies should ultimately affect neutrophils and their products. The ideal anti-inflammatory therapy would exert a dual effect on the pro-inflammatory and pro-resolution arms of the inflammatory cascade, both of which contribute to dysregulated inflammation in CF. This review outlines the key factors to be considered in the design of clinical trials evaluating anti-inflammatory therapies in CF. Important lessons have been learned from previous clinical trials in this area and choosing the right efficacy endpoints is key to the success of any anti-inflammatory drug development program. Identifying and validating non-invasive biomarkers, novel imaging techniques and sensitive lung function tests capable of monitoring disease activity and therapeutic response are important areas of research and will be useful for the design of future anti-inflammatory drug trials.
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Affiliation(s)
- Lucy Perrem
- Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Paediatrics, University of Toronto, Toronto, ON, Canada.,Translational Medicine Program, SickKids Research Institute, Toronto, ON, Canada
| | - Felix Ratjen
- Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Paediatrics, University of Toronto, Toronto, ON, Canada.,Translational Medicine Program, SickKids Research Institute, Toronto, ON, Canada
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22
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Weiner GA, Forno E, Weiner DJ. The effects of high-frequency chest compression on end-tidal CO 2. Pediatr Pulmonol 2020; 55:646-648. [PMID: 31765524 DOI: 10.1002/ppul.24588] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 11/11/2019] [Indexed: 12/12/2022]
Abstract
INTRODUCTION High-frequency chest compression (HFCC) is used for airway clearance, but may have other effects. We sought to determine if HFCC provides augmented ventilation. METHODS During treatment, capnometry was measured with the HFCC vest set to 6-20 Hz. End-tidal CO2 (etCO2 ) was compared using generalized estimating equations. RESULTS Twenty-four measurements were obtained from 15 subjects with mean age 15.2 ± 2.5 years and forced expiratory volume in one second (FEV1 ) % predicted 70 ± 23. EtCO2 decreased with HFCC at 6 Hz when compared with baseline (P < .001), with small changes with increasing oscillation frequency. Change in etCO2 was not predicted by FEV1 , body mass index, age, or sex. CONCLUSIONS While HFCC has been shown to be a suitable method of airway clearance, investigators have failed to demonstrate differences between techniques. Assessment of these methodologies will become important as new airway clearance devices are proposed. Other outcome measures (besides FEV1 ) may be needed to assess effects of airway clearance, and we propose that physiologic measures might be one such measure which deserves further exploration.
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Affiliation(s)
- Gabriel A Weiner
- Division of Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Erick Forno
- Division of Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Daniel J Weiner
- Division of Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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23
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Elkins M, Dentice R, Cochrane Cystic Fibrosis and Genetic Disorders Group. Timing of hypertonic saline inhalation for cystic fibrosis. Cochrane Database Syst Rev 2020; 2:CD008816. [PMID: 32107770 PMCID: PMC7046936 DOI: 10.1002/14651858.cd008816.pub4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Inhalation of hypertonic saline improves sputum rheology, accelerates mucociliary clearance and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane Review. OBJECTIVES To determine whether the timing of hypertonic saline inhalation (in relation to airway clearance techniques or in relation to time of day) has an impact on its clinical efficacy in people with cystic fibrosis. SEARCH METHODS We identified relevant randomised and quasi-randomised controlled trials from the Cochrane Cystic Fibrosis Trials Register, the Physiotherapy Evidence Database (PEDro), and international cystic fibrosis conference proceedings. Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register: 28 February 2019. SELECTION CRITERIA Any trial of hypertonic saline in people with cystic fibrosis where timing of inhalation was the randomised element in the study protocol with either: inhalation up to six hours before airway clearance techniques compared to inhalation during airway clearance techniques compared to inhalation up to six hours after airway clearance techniques; or morning compared to evening inhalation with any definition provided by the author. DATA COLLECTION AND ANALYSIS Both authors independently assessed the trials identified by the search for potential inclusion in the review. The certainty of the evidence was assessed using GRADE. MAIN RESULTS The searches identified 104 trial reports which represented 51 trials, of which three cross-over trials (providing data on 77 participants) met our inclusion criteria. We present three comparisons: inhalation before versus during airway clearance techniques; inhalation before versus after airway clearance techniques; and inhalation during versus after airway clearance techniques. One trial (50 participants), given its three-arm design, was eligible for all three comparisons. No trials compared morning versus evening inhalation of hypertonic saline. The evidence from the three trials was judged to be of low quality downgraded for limitations (high risk of bias due to blinding) and indirectness (all participants are adults, and therefore not applicable to children). Intervention periods ranged from one treatment to three treatments in one day. There were no clinically important differences between the timing regimens of inhaling hypertonic saline before, during or after airway clearance techniques in the mean amount of improvement in lung function or symptom scores (77 participants), with the between-group comparisons being non-significant (low-certainty evidence). While there may be little or no difference in the rating of satisfaction when hypertonic saline was inhaled before versus during the airway clearance techniques (64 participants) (with the 95% confidence interval including the possibility of both a higher and lower rating of satisfaction), satisfaction may be lower on a 100-mm scale when inhaled after the airway clearance techniques compared to before: mean difference (MD) 20.38 mm (95% confidence interval (CI) 12.10 to 28.66) and when compared to during the techniques, MD 14.80 mm (95% CI 5.70 to 23.90). Perceived effectiveness showed similar results: little or no difference for inhalation before versus during airway clearance techniques (64 participants); may be lower when inhaled after the airway clearance techniques compared to before, MD 10.62 (95% CI 2.54 to 18.70); and also when compared to during the techniques, MD 15.60 (95% CI 7.55 to 23.65). There were no quality of life or adverse events reported in any of the trials. AUTHORS' CONCLUSIONS Timing of hypertonic saline inhalation makes little or no difference to lung function (low-certainty evidence). However, inhaling hypertonic saline before or during airway clearance techniques may maximise perceived efficacy and satisfaction. The long-term efficacy of hypertonic saline has only been established for twice-daily inhalations; however, if only one dose per day is tolerated, the time of day at which it is inhaled could be based on convenience or tolerability until evidence comparing these regimens is available. The identified trials were all of very short intervention periods, so longer-term research could be conducted to establish the effects arising from regular use, which would incorporate the influence of changes in adherence with long-term use, as well as generating data on any adverse effects that occur with long-term use.
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Affiliation(s)
- Mark Elkins
- University of SydneySydney Medical SchoolEdward Ford Building A27SydneyAustraliaNSW 2006
| | - Ruth Dentice
- Royal Prince Alfred HospitalDepartment of Respiratory MedicineLevel 11, E BlockMissenden RoadCamperdownNew South WalesAustraliaNSW 2050
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24
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Balfour-Lynn IM. Clinical papers of the year 2018 - Cystic fibrosis. Paediatr Respir Rev 2020; 33:58-61. [PMID: 31053358 DOI: 10.1016/j.prrv.2019.03.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 03/28/2019] [Indexed: 10/27/2022]
Abstract
This paper reviews the most important clinical papers in cystic fibrosis published in 2018, having searched all the literature on Pubmed. Focus is on CFTR modulator therapy, randomised controlled trials, and infection/microbiology issues.
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Affiliation(s)
- I M Balfour-Lynn
- Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, UK.
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25
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Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, Burgel PR, Tullis E, Castaños C, Castellani C, Byrnes CA, Cathcart F, Chotirmall SH, Cosgriff R, Eichler I, Fajac I, Goss CH, Drevinek P, Farrell PM, Gravelle AM, Havermans T, Mayer-Hamblett N, Kashirskaya N, Kerem E, Mathew JL, McKone EF, Naehrlich L, Nasr SZ, Oates GR, O'Neill C, Pypops U, Raraigh KS, Rowe SM, Southern KW, Sivam S, Stephenson AL, Zampoli M, Ratjen F. The future of cystic fibrosis care: a global perspective. THE LANCET. RESPIRATORY MEDICINE 2020; 8:65-124. [PMID: 31570318 PMCID: PMC8862661 DOI: 10.1016/s2213-2600(19)30337-6] [Citation(s) in RCA: 641] [Impact Index Per Article: 128.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 07/19/2019] [Accepted: 08/14/2019] [Indexed: 02/06/2023]
Abstract
The past six decades have seen remarkable improvements in health outcomes for people with cystic fibrosis, which was once a fatal disease of infants and young children. However, although life expectancy for people with cystic fibrosis has increased substantially, the disease continues to limit survival and quality of life, and results in a large burden of care for people with cystic fibrosis and their families. Furthermore, epidemiological studies in the past two decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognised in many regions of the world. The Lancet Respiratory Medicine Commission on the future of cystic fibrosis care was established at a time of great change in the clinical care of people with the disease, with a growing population of adult patients, widespread genetic testing supporting the diagnosis of cystic fibrosis, and the development of therapies targeting defects in the cystic fibrosis transmembrane conductance regulator (CFTR), which are likely to affect the natural trajectory of the disease. The aim of the Commission was to bring to the attention of patients, health-care professionals, researchers, funders, service providers, and policy makers the various challenges associated with the changing landscape of cystic fibrosis care and the opportunities available for progress, providing a blueprint for the future of cystic fibrosis care. The discovery of the CFTR gene in the late 1980s triggered a surge of basic research that enhanced understanding of the pathophysiology and the genotype-phenotype relationships of this clinically variable disease. Until recently, available treatments could only control symptoms and restrict the complications of cystic fibrosis, but advances in CFTR modulator therapies to address the basic defect of cystic fibrosis have been remarkable and the field is evolving rapidly. However, CFTR modulators approved for use to date are highly expensive, which has prompted questions about the affordability of new treatments and served to emphasise the considerable gap in health outcomes for patients with cystic fibrosis between high-income countries, and low-income and middle-income countries (LMICs). Advances in clinical care have been multifaceted and include earlier diagnosis through the implementation of newborn screening programmes, formalised airway clearance therapy, and reduced malnutrition through the use of effective pancreatic enzyme replacement and a high-energy, high-protein diet. Centre-based care has become the norm in high-income countries, allowing patients to benefit from the skills of expert members of multidisciplinary teams. Pharmacological interventions to address respiratory manifestations now include drugs that target airway mucus and airway surface liquid hydration, and antimicrobial therapies such as antibiotic eradication treatment in early-stage infections and protocols for maintenance therapy of chronic infections. Despite the recent breakthrough with CFTR modulators for cystic fibrosis, the development of novel mucolytic, anti-inflammatory, and anti-infective therapies is likely to remain important, especially for patients with more advanced stages of lung disease. As the median age of patients with cystic fibrosis increases, with a rapid increase in the population of adults living with the disease, complications of cystic fibrosis are becoming increasingly common. Steps need to be taken to ensure that enough highly qualified professionals are present in cystic fibrosis centres to meet the needs of ageing patients, and new technologies need to be adopted to support communication between patients and health-care providers. In considering the future of cystic fibrosis care, the Commission focused on five key areas, which are discussed in this report: the changing epidemiology of cystic fibrosis (section 1); future challenges of clinical care and its delivery (section 2); the building of cystic fibrosis care globally (section 3); novel therapeutics (section 4); and patient engagement (section 5). In panel 1, we summarise key messages of the Commission. The challenges faced by all stakeholders in building and developing cystic fibrosis care globally are substantial, but many opportunities exist for improved care and health outcomes for patients in countries with established cystic fibrosis care programmes, and in LMICs where integrated multidisciplinary care is not available and resources are lacking at present. A concerted effort is needed to ensure that all patients with cystic fibrosis have access to high-quality health care in the future.
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Affiliation(s)
- Scott C Bell
- Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia; QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
| | - Marcus A Mall
- Charité - Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany; German Center for Lung Research, Berlin, Germany
| | | | - Milan Macek
- Department of Biology and Medical Genetics, Second Faculty of Medicine, Motol University Hospital, Charles University, Prague, Czech Republic
| | - Susan Madge
- Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Jane C Davies
- Royal Brompton and Harefield NHS Foundation Trust, London, UK; National Heart and Lung Institute, Imperial College, London, UK
| | - Pierre-Régis Burgel
- Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France; Université Paris Descartes, Institut Cochin, Paris, France
| | - Elizabeth Tullis
- St Michael's Hospital, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada
| | - Claudio Castaños
- Hospital de Pediatria "Juan P Garrahan", Buenos Aires, Argentina
| | - Carlo Castellani
- Cystic Fibrosis Centre, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Catherine A Byrnes
- Starship Children's Hospital, Auckland, New Zealand; University of Auckland, Auckland, New Zealand
| | - Fiona Cathcart
- Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Sanjay H Chotirmall
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | | | | | - Isabelle Fajac
- Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France; Université Paris Descartes, Institut Cochin, Paris, France
| | | | - Pavel Drevinek
- Department of Medical Microbiology, Second Faculty of Medicine, Motol University Hospital, Charles University, Prague, Czech Republic
| | | | - Anna M Gravelle
- Cystic Fibrosis Clinic, British Columbia Children's Hospital, Vancouver, BC, Canada
| | - Trudy Havermans
- Cystic Fibrosis Centre, University Hospital Leuven, Leuven, Belgium
| | - Nicole Mayer-Hamblett
- University of Washington, Seattle, WA, USA; Seattle Children's Research Institute, Seattle, WA, USA
| | | | | | - Joseph L Mathew
- Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Edward F McKone
- School of Medicine, St Vincent's University Hospital, Dublin, Ireland; University College Dublin School of Medicine, Dublin, Ireland
| | - Lutz Naehrlich
- Universities of Giessen and Marburg Lung Center, German Center of Lung Research, Justus-Liebig-University Giessen, Giessen, Germany
| | - Samya Z Nasr
- CS Mott Children's Hospital, Ann Arbor, MI, USA; University of Michigan, Ann Arbor, MI, USA
| | | | | | | | | | - Steven M Rowe
- University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kevin W Southern
- Alder Hey Children's Hospital, Liverpool, UK; University of Liverpool, Liverpool, UK
| | - Sheila Sivam
- Royal Prince Alfred Hospital, Sydney, NSW, Australia; Woolcock Institute of Medical Research, Sydney, NSW, Australia
| | - Anne L Stephenson
- St Michael's Hospital, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada
| | - Marco Zampoli
- Division of Paediatric Pulmonology and MRC Unit for Child and Adolescent Health, University of Cape Town, Cape Town, South Africa; Red Cross War Memorial Children's Hospital, Cape Town, South Africa
| | - Felix Ratjen
- University of Toronto, Toronto, ON, Canada; Division of Respiratory Medicine, Department of Paediatrics, Translational Medicine Research Program, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
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26
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Kasi AS, Wee CP, Keens TG, Salinas DB. Abnormal Lung Clearance Index in Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID) Children with Otherwise Normal FEV1. Lung 2019; 198:163-167. [DOI: 10.1007/s00408-019-00307-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 12/09/2019] [Indexed: 10/25/2022]
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27
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Ratjen F, Klingel M, Black P, Powers MR, Grasemann H, Solomon M, Sagel SD, Donaldson SH, Rowe SM, Rosenfeld M. Changes in Lung Clearance Index in Preschool-aged Patients with Cystic Fibrosis Treated with Ivacaftor (GOAL): A Clinical Trial. Am J Respir Crit Care Med 2019; 198:526-528. [PMID: 29614238 DOI: 10.1164/rccm.201802-0243le] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Affiliation(s)
- Felix Ratjen
- 1 University of Toronto Toronto, Ontario, Canada
| | | | - Philip Black
- 2 Children's Mercy Hospital Kansas City, Missouri
| | | | | | | | - Scott D Sagel
- 4 University of Colorado School of Medicine Aurora, Colorado
| | | | - Steven M Rowe
- 6 University of Alabama at Birmingham Birmingham, Alabama and
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28
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Ellemunter H, Steinkamp G. Lung clearance index to detect the efficacy of Aztreonam lysine inhalation in patients with cystic fibrosis and near normal spirometry - A single-centre feasibility study. PLoS One 2019; 14:e0221673. [PMID: 31498805 PMCID: PMC6733506 DOI: 10.1371/journal.pone.0221673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 08/10/2019] [Indexed: 12/29/2022] Open
Abstract
Comparing the efficacy of inhaled antibiotics can be difficult in small groups of patients with cystic fibrosis and mild lung disease. In a feasibility study we compared Aztreonam lysine for inhalation solution (AZLI; Cayston®) to standard inhaled antibiotic therapy in patients with cystic fibrosis and near normal spirometry. To detect treatment responses we used both lung clearance index (LCI) and forced expiratory volume in one second (FEV1). At baseline, median FEV1 was 87% pred. and median LCI was 8.6 (upper limit of normal: 7.0). After 4 weeks, LCI improved by -0.36 after AZLI and deteriorated by +0.12 after tobramycin treatment (p = 0.039). No significant differences between treatments (p = 0.195) were observed using FEV1. These results suggest that lung clearance index can be used to detect treatment induced changes in subjects with mild lung disease.
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Affiliation(s)
- Helmut Ellemunter
- Cystic Fibrosis (CF) Centre at the Medical University of Innsbruck, Innsbruck, Austria
| | - Gratiana Steinkamp
- Cystic Fibrosis (CF) Centre at the Medical University of Innsbruck, Innsbruck, Austria
- Clinical Research and Medical Scientific Writing, Schwerin, Germany
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29
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Hardaker K, Panda H, Hulme K, Wong A, Coward E, Cooper P, Fitzgerald D, Pandit C, Towns S, Selvadurai H, Robinson P. Abnormal preschool Lung Clearance Index (LCI) reflects clinical status and predicts lower spirometry later in childhood in cystic fibrosis. J Cyst Fibros 2019; 18:721-727. [DOI: 10.1016/j.jcf.2019.02.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 02/11/2019] [Accepted: 02/12/2019] [Indexed: 11/26/2022]
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Couch MJ, Thomen R, Kanhere N, Hu R, Ratjen F, Woods J, Santyr G. A two-center analysis of hyperpolarized 129Xe lung MRI in stable pediatric cystic fibrosis: Potential as a biomarker for multi-site trials. J Cyst Fibros 2019; 18:728-733. [PMID: 30922812 PMCID: PMC7054852 DOI: 10.1016/j.jcf.2019.03.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 02/25/2019] [Accepted: 03/11/2019] [Indexed: 12/23/2022]
Abstract
BACKGROUND The ventilation defect percent (VDP), measured from hyperpolarized (HP) 129Xe 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 129Xe 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, N2 multiple breath washout (to measure lung clearance index, LCI), and HP 129Xe 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 (FEV1) 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 FEV1 (R2 = 0.33, p = .003; and R2 = 0.26, p = .009 for Analysts 1 and 2, respectively) and LCI (R2 = 0.76, p < .0001; and R2 = 0.77, p < .0001 for Analysts 1 and 2, respectively). CONCLUSION HP 129Xe 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.
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Affiliation(s)
- Marcus J Couch
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Robert Thomen
- School of Medicine, University of Missouri, Columbia, MO, USA
| | - Nikhil Kanhere
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Raymond Hu
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Felix Ratjen
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada; Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Jason Woods
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Giles Santyr
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada..
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Ratjen F, Davis SD, Stanojevic S, Kronmal RA, Hinckley Stukovsky KD, Jorgensen N, Rosenfeld M, Kerby G, Kopecky C, Anthony M, Mogayzel P, Walker D, Zeglin B, Hoover W, Hathorne H, Slaten K, Dorkin H(H, Fowler R, Fenton C(N, Ulles M, Goetz D, Caci N, Cahill B, Roach C, Retsch-Bogart G, Johnson R, Cunnion R, McColley S, Ward S, Bell E, McPhail G, Keller K, Thornton K, Parsons A, Chmiel J, Schaefer C, Tribout M, Consiglio B, Tribout H, McCoy K, Johnson T, Olson P, Raterman L, Hiatt P, Walker B, Schaap N, Davis M, Davis S, Clem C, Bendy L, Starner T, Lux C, Carver T, Thompson R, Williams A, Schmoll C, Hastings PM, Noe J, Roth L, Kump T, McNamara J, Franck Thompson E, Yousef S, Wezel G(G, Oquendo O, Darling A, Valencia W, Milla C, Zirbes J, Rubenstein R, Donnelly E, Malpass J, Weiner D, Agostini B, Hartigan E, Cornell A, Klein B, Bucher J, Nusbaum P, Rosenfeld M, McNamara S, Genatossio A, Pittman J, Hicks T, Bauer I, Siegel M, Isaac S, Jensen R, Au J, Stanojevic S, Ratjen F, McDonald N, Prentice C, Chilvers M, Richmond M. Inhaled hypertonic saline in preschool children with cystic fibrosis (SHIP): a multicentre, randomised, double-blind, placebo-controlled trial. THE LANCET RESPIRATORY MEDICINE 2019; 7:802-809. [DOI: 10.1016/s2213-2600(19)30187-0] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 04/25/2019] [Accepted: 04/30/2019] [Indexed: 01/25/2023]
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Robinson PD, Latzin P, Ramsey KA, Stanojevic S, Aurora P, Davis SD, Gappa M, Hall GL, Horsley A, Jensen R, Lum S, Milla C, Nielsen KG, Pittman JE, Rosenfeld M, Singer F, Subbarao P, Gustafsson PM, Ratjen F. Preschool Multiple-Breath Washout Testing. An Official American Thoracic Society Technical Statement. Am J Respir Crit Care Med 2019; 197:e1-e19. [PMID: 29493315 DOI: 10.1164/rccm.201801-0074st] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Obstructive airway disease is nonuniformly distributed throughout the bronchial tree, although the extent to which this occurs can vary among conditions. The multiple-breath washout (MBW) test offers important insights into pediatric lung disease, not available through spirometry or resistance measurements. The European Respiratory Society/American Thoracic Society inert gas washout consensus statement led to the emergence of validated commercial equipment for the age group 6 years and above; specific recommendations for preschool children were beyond the scope of the document. Subsequently, the focus has shifted to MBW applications within preschool subjects (aged 2-6 yr), where a "window of opportunity" exists for early diagnosis of obstructive lung disease and intervention. METHODS This preschool-specific technical standards document was developed by an international group of experts, with expertise in both custom-built and commercial MBW equipment. A comprehensive review of published evidence was performed. RESULTS Recommendations were devised across areas that place specific age-related demands on MBW systems. Citing evidence where available in the literature, recommendations are made regarding procedures that should be used to achieve robust MBW results in the preschool age range. The present work also highlights the important unanswered questions that need to be addressed in future work. CONCLUSIONS Consensus recommendations are outlined to direct interested groups of manufacturers, researchers, and clinicians in preschool device design, test performance, and data analysis for the MBW technique.
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Sanders DB, Nichols DP. Developmental Milestones in Pediatric Research: A Case for Including Efficacy as Part of Interventional Trials in Infants with Cystic Fibrosis. Am J Respir Crit Care Med 2019; 199:1181-1182. [PMID: 30422678 PMCID: PMC6519866 DOI: 10.1164/rccm.201811-2103ed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Affiliation(s)
- Don B Sanders
- 1 Section of Pediatric Pulmonology, Allergy, and Sleep Medicine Indiana University Indianapolis, Indiana and
| | - Dave P Nichols
- 2 Seattle Children's Hospital University of Washington Seattle, Washington
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Stahl M, Wielpütz MO, Ricklefs I, Dopfer C, Barth S, Schlegtendal A, Graeber SY, Sommerburg O, Diekmann G, Hüsing J, Koerner-Rettberg C, Nährlich L, Dittrich AM, Kopp MV, Mall MA. Preventive Inhalation of Hypertonic Saline in Infants with Cystic Fibrosis (PRESIS). A Randomized, Double-Blind, Controlled Study. Am J Respir Crit Care Med 2019; 199:1238-1248. [DOI: 10.1164/rccm.201807-1203oc] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Mirjam Stahl
- Department of Translational Pulmonology
- Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Pediatrics, and
- Translational Lung Research Center Heidelberg, German Center for Lung Research, Heidelberg, Germany
| | - Mark O. Wielpütz
- Department of Diagnostic and Interventional Radiology, University of Heidelberg, Heidelberg, Germany
- Translational Lung Research Center Heidelberg, German Center for Lung Research, Heidelberg, Germany
- Department of Radiology, German Cancer Research Center, Heidelberg, Germany
| | - Isabell Ricklefs
- Division of Pediatric Allergology and Pneumology, Department of Pediatrics, Medical University of Lübeck, Lübeck, Germany
- Airway Research Center North, German Center for Lung Research, Lübeck, Germany
| | - Christian Dopfer
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease, German Center for Lung Research, Hannover, Germany
| | - Sandra Barth
- Department of Pediatrics, Justus-Liebig-University Giessen, Giessen, Germany
- Universities Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany
| | - Anne Schlegtendal
- Department of Pediatric Pulmonology, University Children’s Hospital of Ruhr University Bochum at St. Josef-Hospital, Bochum, Germany
| | - Simon Y. Graeber
- Department of Translational Pulmonology
- Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Pediatrics, and
- Translational Lung Research Center Heidelberg, German Center for Lung Research, Heidelberg, Germany
- Department of Pediatric Pulmonology, Immunology and Intensive Care Medicine, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany; and
| | - Olaf Sommerburg
- Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Pediatrics, and
- Translational Lung Research Center Heidelberg, German Center for Lung Research, Heidelberg, Germany
| | - Gesa Diekmann
- Division of Pediatric Allergology and Pneumology, Department of Pediatrics, Medical University of Lübeck, Lübeck, Germany
- Airway Research Center North, German Center for Lung Research, Lübeck, Germany
| | - Johannes Hüsing
- Coordination Center for Clinical Trials, Heidelberg University Hospital, Heidelberg, Germany
| | - Cordula Koerner-Rettberg
- Department of Pediatric Pulmonology, University Children’s Hospital of Ruhr University Bochum at St. Josef-Hospital, Bochum, Germany
| | - Lutz Nährlich
- Department of Pediatrics, Justus-Liebig-University Giessen, Giessen, Germany
- Universities Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany
| | - Anna-Maria Dittrich
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease, German Center for Lung Research, Hannover, Germany
| | - Matthias V. Kopp
- Division of Pediatric Allergology and Pneumology, Department of Pediatrics, Medical University of Lübeck, Lübeck, Germany
- Airway Research Center North, German Center for Lung Research, Lübeck, Germany
| | - Marcus A. Mall
- Department of Translational Pulmonology
- Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Pediatrics, and
- Translational Lung Research Center Heidelberg, German Center for Lung Research, Heidelberg, Germany
- Department of Pediatric Pulmonology, Immunology and Intensive Care Medicine, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany; and
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Lombardi E, Gambazza S, Pradal U, Braggion C. Lung clearance index in subjects with cystic fibrosis in Italy. Ital J Pediatr 2019; 45:56. [PMID: 31046783 PMCID: PMC6498565 DOI: 10.1186/s13052-019-0647-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 04/16/2019] [Indexed: 02/06/2023] Open
Abstract
The Lung Clearance Index (LCI) is an index derived from washout recordings, able to detect early peripheral airway damage in subjects with cystic fibrosis (CF) with a greater sensitivity than spirometry. LCI is a marker of overall lung ventilation inhomogeneity; in fact, as pulmonary ventilation worsens, the number of tidal breaths and the expiratory volumes required to clear the lungs of a marker gas are increased, as documented by a greater value. In the field of CF, LCI allows indirect investigation of the small airways (< 2 mm) the site where, from a pathophysiologic point of view, the disease begins due to the defect of the CF transmembrane-conductance regulator (CFTR) protein. Infant pulmonary function changes seem to occur before clinically overt symptoms of lower respiratory illness occur. When performing the test, it is important to refer to the American Thoracic Society and European Respiratory Society consensus statements and apply a strict standardization. In Italy the first tests were carried out in 2014 for research purpose and now approximately 10 centers are collecting data and are experiencing a consistency in repeating exams. Currently in Italian centers children at pre-school age are the main target: in this population it is important to have a sensitive and feasible test, non-invasive, that can be performed at tidal volume without sedation, and requiring minimal cooperation and coordination, and that can be used longitudinally over time. Another target could be the transplanted subjects to detect early signs of lung function decline. The content of this paper captures the experience and discussions among some of the Italian centers where LCI is currently used for research and/or in clinical practice about the method and the need to have a common approach. The aim of this paper is not to describe the methodology of MBW, but to inform the pediatric community about the possible application of LCI in CF.
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Affiliation(s)
- Enrico Lombardi
- Azienda Ospedaliero-Universitaria Meyer, Pediatric University Hospital, Viale Pieraccini 24, 50139, Florence, Italy.
| | - Simone Gambazza
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Cystic Fibrosis Centre, Milan, Italy.,Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.,Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, U.O.C. Direzione delle Professioni Sanitarie, Milan, Italy
| | - Ugo Pradal
- UO Pediatria Ospedale di Rovereto, APSS Trento, Trento, Italy
| | - Cesare Braggion
- Azienda Ospedaliero-Universitaria Meyer, Pediatric University Hospital, Viale Pieraccini 24, 50139, Florence, Italy
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36
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Fretzayas A, Douros K, Moustaki M, Loukou I. Applications of lung clearance index in monitoring children with cystic fibrosis. World J Clin Pediatr 2019; 8:15-22. [PMID: 31041164 PMCID: PMC6477151 DOI: 10.5409/wjcp.v8.i2.15] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 02/03/2019] [Accepted: 02/19/2019] [Indexed: 02/06/2023] Open
Abstract
A sensitive, reproducible and feasible measure of lung function for monitoring the respiratory health is a prerequisite for the optimization of management of the patients with cystic fibrosis (CF). Spirometry has been considered the method of choice, although it is applicable only in children older than 6 years of age, as good cooperation is necessary for its proper performance. However, over the last 15 years, scientific interest in gas dilution techniques and particularly in multiple breath wash out (MBW) method has been revived. The most commonly reported index of MBW is lung clearance index (LCI). The aim of this review is to present the most recent developments in the application of LCI as a monitoring index of respiratory status of CF patients. LCI is a sensitive and reproducible marker of ventilation inhomogeneity. It is more sensitive than spirometry and, unlike spirometry; it can be performed across the whole pediatric age range. Since it is dependent on body size, until at least the age of 6 years, the relative and not the absolute changes are more appropriate for providing clinically meaningful conclusion on ventilation inhomogeneity. Until now, MBW has been mainly used as a research tool. Based on the currently available data LCI cannot safely predict high-resolution computed tomography findings in children with CF, especially in infants. It can be used as an end-point measure for the assessment of beneficial effect of interventions. However, its utility as an outcome measure for the efficacy of therapeutic interventions seems to be dependent on the pathophysiologic mechanisms that underlie each intervention. It seems that more studies, especially longitudinal ones, are required in order to fully clarify the clinical usefulness of LCI, not only in the research setting, but also in every day practice of CF clinic.
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Affiliation(s)
- Andrew Fretzayas
- School of Medicine, University of Athens, Athens 11527, Greece
- Department of Pediatrics, Athens Medical Center, Athens University Medical School, Maroussi 15125, Greece
| | - Konstantinos Douros
- Respiratory Unit, Third Department of Pediatrics, Athens University Medical School, “Attikon” University Hospital, Haidari 12464, Greece
| | - Maria Moustaki
- Department of Cystic Fibrosis, “Agia Sofia”, Children’s Hospital, Athens 11527, Greece
| | - Ioanna Loukou
- Department of Cystic Fibrosis, “Agia Sofia”, Children’s Hospital, Athens 11527, Greece
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Poncin W, Lebecque P. [Lung clearance index in cystic fibrosis]. Rev Mal Respir 2019; 36:377-395. [PMID: 30686561 DOI: 10.1016/j.rmr.2018.03.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 03/28/2018] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Small airways' involvement in cystic fibrosis (CF) pulmonary disease is a very early event, which can progress sub-clinically and insidiously since it is poorly reflected by commonly used lung function tests. STATE OF ART Sensitive and discriminative tools are available to investigate small airways function. However their complexity and/or invasiveness has confined their use to research purposes and to some specialized research teams. By contrast, the multiple breath washout (MBW) test is more affordable and non-invasive. Lung clearance index (LCI), which is the most used derived parameter, is reproducible and much more sensitive than spirometry in detecting small airways disease. However, MBW is operator dependent. PERSPECTIVES The recent commercialization of devices assessing LCI launches MBW as a potential tool in routine clinical care, although its use currently remains mostly dedicated to research purposes. However, important differences in LCI between various equipment settings raise a number of theoretical questions. Specific algorithms should be refined and more transparent. Standardization of MBW is still an ongoing process. Whether other MBW derived indices can prove superior over LCI deserves further study. CONCLUSIONS In CF, LCI is now a well-established outcome in research settings to detect early lung function abnormalities and new treatment effects, especially in patients with mild lung disease. In these patients, LCI seems an attractive tool for clinicians too. Yet, further investigation is needed to define clinically significant changes in LCI and to which extent this index can be useful in guiding clinical decisions remains to be studied.
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Affiliation(s)
- W Poncin
- Pôle de pneumologie, ORL et dermatologie, université Catholique de Louvain, institut de recherche expérimentale et clinique (IREC), 1200 Bruxelles, Belgique; Service de médecine physique et réadaptation, cliniques universitaires Saint-Luc, 1200 Bruxelles, Belgique.
| | - P Lebecque
- Pneumologie pédiatrique & centre de référence pour la mucoviscidose, cliniques universitaires Saint-Luc, 1200 Bruxelles, Belgique
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Dobra R, Edmondson C, Hughes D, Martin I, Davies JC. Potentiators and Correctors in Paediatric Cystic Fibrosis Patients: A Narrative Review. Paediatr Drugs 2018; 20:555-566. [PMID: 30328089 DOI: 10.1007/s40272-018-0315-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Cystic fibrosis is the most common inherited condition in the Caucasian population and is associated with significantly reduced life expectancy. Recent advances in treatment have focussed on addressing the underlying cause of the condition, the defective production, expression and function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Several drugs with different modes of action have produced promising results in clinical trials, and some have been incorporated into routine clinical care for specific patients in many countries worldwide. Further trials continue to explore the safety and efficacy of these drugs in the youngest age groups and to search for more effective therapies to treat the most common disease-causing gene mutations in an ever-expanding drug pipeline. As evidence mounts for the early onset of disease in young patients, the prospect of introducing disease-modifying therapy in early life becomes more pertinent, although the cost implications of these expensive drugs are significant. In this review, we summarise these new therapy advances and review those currently being explored in clinical trials.
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Affiliation(s)
- R Dobra
- The Department of Cystic Fibrosis and Chronic Lung Infection, National Heart and Lung Institute, Imperial College London, Emmanuel Kaye Building, 1B Manresa Road, London, SW36LR, UK
| | - C Edmondson
- The Department of Cystic Fibrosis and Chronic Lung Infection, National Heart and Lung Institute, Imperial College London, Emmanuel Kaye Building, 1B Manresa Road, London, SW36LR, UK
| | - D Hughes
- The Department of Cystic Fibrosis and Chronic Lung Infection, National Heart and Lung Institute, Imperial College London, Emmanuel Kaye Building, 1B Manresa Road, London, SW36LR, UK
| | - I Martin
- The Department of Cystic Fibrosis and Chronic Lung Infection, National Heart and Lung Institute, Imperial College London, Emmanuel Kaye Building, 1B Manresa Road, London, SW36LR, UK
| | - J C Davies
- The Department of Cystic Fibrosis and Chronic Lung Infection, National Heart and Lung Institute, Imperial College London, Emmanuel Kaye Building, 1B Manresa Road, London, SW36LR, UK.
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Comparison of lung clearance index determined by washout of N 2 and SF 6 in infants and preschool children with cystic fibrosis. J Cyst Fibros 2018; 18:399-406. [PMID: 30420236 DOI: 10.1016/j.jcf.2018.11.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 10/30/2018] [Accepted: 11/02/2018] [Indexed: 12/29/2022]
Abstract
BACKGROUND Multiple-breath washout (MBW) has been shown to detect early impairment of lung function in children with cystic fibrosis (CF). Nitrogen (N2) or sulfur hexafluoride (SF6) can be used as tracer gas for MBW. Recent data indicated higher lung clearance index (LCI) values measured with N2-MBW than concurrent SF6-MBW in older children and adults, however, a comparison in infants and younger children, as well as to other outcome measures of CF lung disease is pending. METHODS N2- and SF6-MBW were performed consecutively in 31 sedated infants and preschool children with CF (mean age, 2.3 ± 0.8 years) and 20 controls (mean age, 2.3 ± 1.1 years) using the Exhalyzer D system. Children with CF also underwent chest magnetic resonance imaging (MRI). RESULTS Mean difference (95% CI) in LCI between N2- and SF6-MBW was 1.1 ± 0.4 (0.9 to 1.3) in controls and 2.1 ± 1.9 (1.4 to 2.8) in CF. Agreement between N2- and SF6-LCI was poor in children with CF. N2-LCI and SF6-LCI correlated with MRI, however N2-LCI showed a higher concordance with MRI than SF6-LCI. The absolute difference between N2- and SF6-LCI values increased with the severity of CF lung disease as determined by MRI scores. CONCLUSION N2-LCI values were higher than SF6-LCI values in infants and preschool children with CF and controls. Better concordance of N2-LCI than SF6-LCI with chest MRI scores point towards of a higher sensitivity of N2-LCI to detect early lung disease in children with CF.
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Guglani L, Kasi A, Starks M, Pedersen KE, Nielsen JG, Weiner DJ. Difference between SF6 and N2 multiple breath washout kinetics is due to N2 back diffusion and error in N2 offset. J Appl Physiol (1985) 2018; 125:1257-1265. [DOI: 10.1152/japplphysiol.00326.2018] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Measurement of lung clearance index (LCI) by multiple breath washout (MBW) is a sensitive method for monitoring lung disease in patients with cystic fibrosis (CF). To compare nitrogen MBW (N2-MBW) and sulfur hexafluoride MBW (SF6-MBW), we connected these two gas analysis systems in series to obtain truly simultaneous measurements, with no differences other than the gas used. Nonsmoking healthy controls (HC) and subjects with CF were recruited at two institutions. The Exhalyzer-D (for N2-MBW measurement) was connected in series with the Innocor (for SF6-MBW measurement). Subjects washed in SF6 from a Douglas bag with tidal breathing and washed out SF6 and nitrogen with 100% oxygen provided as bias flow. Washout of both gases was continued past the LCI point (1/40th of equilibration concentration) in triplicate. N2-MBW resulted in higher cumulative exhaled volume, functional residual capacity (FRC), and LCI when compared with SF6-derived parameters in HC subjects ( P < 0.0001 for all comparisons). All N2-MBW parameters were also significantly higher than SF6-MBW parameters in subjects with CF ( P < 0.01 for all comparisons). After recalculation with a common FRC, N2-MBW LCI was higher than SF6-MBW LCI in subjects with CF (19.73 vs. 11.39; P < 0.0001) and in HC (8.12 vs. 6.78; P < 0.0001). Adjusting for N2 back diffusion and an offset error in the nitrogen measurement resulted in near complete agreement between the two methodologies. We found significant differences in LCI and FRC measurements using two different gases for MBW. This may have significant implications for the future use and interpretation of LCI data in clinical trials and routine clinical care. NEW & NOTEWORTHY This study provides important insights into the differences between the two techniques used for measuring lung clearance index (LCI): N2 and SF6 multiple breath washout. Differences between measurements made by these two methods in subjects with cystic fibrosis and healthy controls could be explained by nitrogen back diffusion and N2 offset error. This is important for use and interpretation of LCI data as an outcome measure for clinical trials and in routine clinical care.
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Affiliation(s)
- Lokesh Guglani
- Center for Cystic Fibrosis and Airways Disease Research, Emory University, Atlanta, Georgia
| | - Ajay Kasi
- Center for Cystic Fibrosis and Airways Disease Research, Emory University, Atlanta, Georgia
| | - Miah Starks
- Center for Cystic Fibrosis and Airways Disease Research, Emory University, Atlanta, Georgia
| | | | | | - Daniel J. Weiner
- Division of Pulmonary Medicine, Allergy & Immunology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania
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Wark P, McDonald VM, Cochrane Cystic Fibrosis and Genetic Disorders Group. Nebulised hypertonic saline for cystic fibrosis. Cochrane Database Syst Rev 2018; 9:CD001506. [PMID: 30260472 PMCID: PMC6513595 DOI: 10.1002/14651858.cd001506.pub4] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
BACKGROUND Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review. OBJECTIVES To investigate efficacy and tolerability of treatment with nebulised hypertonic saline on people with CF compared to placebo and or other treatments that enhance mucociliary clearance. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also searched ongoing trials databases.Date of most recent searches: 08 August 2018. SELECTION CRITERIA Randomised and quasi-randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity). DATA COLLECTION AND ANALYSIS Two authors independently reviewed all identified trials and data, and assessed trial quality. The quality of the evidence was assessed using GRADE. MAIN RESULTS A total of 17 trials (966 participants, aged 4 months to 63 years) were included; 19 trials were excluded, three trials are ongoing and 16 are awaiting classification. We judged 14 of the 17 included trials to have a high risk of bias due to participants ability to discern the taste of the solutions.Hypertonic saline 3% to 7% versus placeboAt four weeks, we found very low-quality evidence from three placebo-controlled trials (n = 225) that hypertonic saline (3% to 7%, 10 mL twice-daily) increased the mean change from baseline of the forced expiratory volume at one second (FEV1) (% predicted) by 3.44% (95% confidence interval (CI) 0.67 to 6.21), but there was no difference between groups in lung clearance index in one small trial (n = 10). By 48 weeks the effect was slightly smaller in one trial (n = 134), 2.31% (95% CI -2.72 to 7.34) (low-quality evidence). No deaths occurred in the trials. Two trials reporting data on exacerbations were not combined as the age difference between the participants in the trials was too great. One trial (162 adults) found 0.5 fewer exacerbations requiring antibiotics per person in the hypertonic saline group; the second trial (243 children, average age of two years) found no difference between groups (low-quality evidence). There was insufficient evidence reported across the trials to determine the rate of different adverse events such as cough, chest tightness, tonsillitis and vomiting (very low-quality evidence). Four trials (n = 80) found very low-quality evidence that sputum clearance was better with hypertonic saline.A further trial was performed in adults with an acute exacerbation of lung disease (n = 132). The effects of hypertonic saline on short-term lung function, 5.10% higher (14.67% lower to 24.87% higher) and the time to the subsequent exacerbation post-discharge, hazard ratio 0.86 (95% CI 0.57 to 1.30) are uncertain (low-quality evidence). No deaths were reported. Cough and wheeze were reported but no serious adverse events (very low-quality evidence).Hypertonic saline versus mucus mobilising treatments Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two (61 participants) provided data for inclusion in the review. There was insufficient evidence from one three-week trial (14 participants) to determine the effects of hypertonic saline on FEV1 % predicted, mean difference (MD) 1.60% (95% CI -7.96 to 11.16) (very low-quality evidence). In the second trial, rhDNase led to a greater increase in FEV1 % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease, MD 8.00% (95% CI 2.00 to 14.00) (low-quality evidence). One cross-over trial (47 participants) reported 15 exacerbations during treatment with hypertonic saline and 18 exacerbations in the rhDNase group (low-quality evidence). Increased cough was reported in 13 participants using hypertonic saline and 17 on daily rhDNase in one cross-over trial of 47 people (low-quality evidence). There was insufficient evidence to assess rates of other adverse events reported. No deaths were reported.One trial (12 participants) compared hypertonic saline to amiloride and one (29 participants) to sodium-2-mercaptoethane sulphonate. Neither trial found a difference between treatments in any measures of sputum clearance; additionally the comparison of hypertonic saline and sodium-2-mercaptoethane sulphonate reported no differences in courses of antibiotics or adverse events (very low-quality evidence).One trial (12 participants) compared hypertonic saline to mannitol but did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' (very low-quality evidence). AUTHORS' CONCLUSIONS Regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (very low-quality evidence from three trials), but this was not sustained at 48 weeks (low-quality evidence from one trial). The review did show that nebulised hypertonic saline reduced the frequency of pulmonary exacerbations (although we found insufficient evidence for this outcome in children under six years of age) and may have a small effect on improvement in quality of life in adults.Evidence from one small cross-over trial in children indicates that rhDNase may lead to better lung function at three months; qualifying this we highlight that while the study did demonstrate that the improvement in FEV1 was greater with daily rHDNase, there were no differences seen in any of the secondary outcomes.Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the quality of the evidence ranged from very low to at best moderate, according to the GRADE criteria.
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Affiliation(s)
- Peter Wark
- Hunter Medical Research Institute, University of NewcastleCentre for Healthy Lungs1 Kookaburra CloseNew LambtonNew South WalesAustralia2305
| | - Vanessa M McDonald
- The University of NewcastleSchool of Nursing and Midwifery, Priority Reseach Centre for Asthma and Respiratory DiseaseLocked Bag 1000New LambtionNewcastleNSWAustralia2305
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42
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Fainardi V, Lombardi E. Lung function tests to monitor respiratory disease in preschool children. ACTA BIO-MEDICA : ATENEI PARMENSIS 2018; 89:148-156. [PMID: 29957746 PMCID: PMC6179029 DOI: 10.23750/abm.v89i2.7155] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 04/06/2018] [Indexed: 01/22/2023]
Abstract
Pulmonary function tests are routinely used in the diagnosis and follow-up of respiratory diseases. In preschool children assessment and evaluation of lung function has always been challenging but improved techniques that require only minimal collaboration allowed obtaining reliable and useful results even in this group of patients. In this review we will describe the different techniques used in clinical practice to measure lung function in preschool children.(www.actabiomedica.it)
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Affiliation(s)
| | - Enrico Lombardi
- Paediatric Pulmonary Unit, "Anna Meyer" Paediatric University Hospital, Florence, Italy.
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43
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Kentgens AC, Guidi M, Korten I, Kohler L, Binggeli S, Singer F, Latzin P, Anagnostopoulou P. Infant multiple breath washout using a new commercially available device: Ready to replace the previous setup? Pediatr Pulmonol 2018; 53:628-635. [PMID: 29418075 DOI: 10.1002/ppul.23959] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 01/08/2018] [Indexed: 11/11/2022]
Abstract
INTRODUCTION Multiple breath washout (MBW) is a sensitive test to measure lung volumes and ventilation inhomogeneity from infancy on. The commonly used setup for infant MBW, based on ultrasonic flowmeter, requires extensive signal processing, which may reduce robustness. A new setup may overcome some previous limitations but formal validation is lacking. AIM We assessed the feasibility of infant MBW testing with the new setup and compared functional residual capacity (FRC) values of the old and the new setup in vivo and in vitro. METHODS We performed MBW in four healthy infants and four infants with cystic fibrosis, as well as in a Plexiglas lung simulator using realistic lung volumes and breathing patterns, with the new (Exhalyzer D, Spiroware 3.2.0, Ecomedics) and the old setup (Exhalyzer D, WBreath 3.18.0, ndd) in random sequence. RESULTS The technical feasibility of MBW with the new device-setup was 100%. Intra-subject variability in FRC was low in both setups, but differences in FRC between the setups were considerable (mean relative difference 39.7%, range 18.9; 65.7, P = 0.008). Corrections of software settings decreased FRC differences (14.0%, -6.4; 42.3, P = 0.08). Results were confirmed in vitro. CONCLUSION MBW measurements with the new setup were feasible in infants. However, despite attempts to correct software settings, outcomes between setups were not interchangeable. Further work is needed before widespread application of the new setup can be recommended.
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Affiliation(s)
- Anne-Christianne Kentgens
- Pediatric Respiratory Medicine, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Department of Respiratory Medicine and Allergy, Radboud University Medical Centre, Amalia Children's Hospital, Nijmegen, The Netherlands
| | - Marisa Guidi
- Pediatric Respiratory Medicine, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Insa Korten
- Pediatric Respiratory Medicine, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Lena Kohler
- Pediatric Respiratory Medicine, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Severin Binggeli
- Pediatric Respiratory Medicine, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Florian Singer
- Pediatric Respiratory Medicine, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Division of Respiratory Medicine, University Children's Hospital of Zurich, Zurich, Switzerland
| | - Philipp Latzin
- Pediatric Respiratory Medicine, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Pinelopi Anagnostopoulou
- Pediatric Respiratory Medicine, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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44
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Stahl M, Graeber SY, Joachim C, Barth S, Ricklefs I, Diekmann G, Kopp MV, Naehrlich L, Mall MA. Three-center feasibility of lung clearance index in infants and preschool children with cystic fibrosis and other lung diseases. J Cyst Fibros 2018; 17:249-255. [PMID: 28811149 DOI: 10.1016/j.jcf.2017.08.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 07/28/2017] [Accepted: 08/01/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Lung clearance index (LCI) detects early ventilation inhomogeneity and has been suggested as sensitive endpoint in multicenter intervention trials in infants and preschoolers with cystic fibrosis (CF). However, the feasibility of multicenter LCI in this age group has not been determined. We, therefore, investigated the feasibility of LCI in infants and preschoolers with and without CF in a three-center setting. METHODS Following central training, standardized SF6-MBW measurements were performed in 73 sedated children (10 controls, 49 with CF and 14 with other lung diseases), mean age 2.3±1.2years across three centers, and data were analyzed centrally. RESULTS Overall success rate of LCI measurements was 91.8% ranging from 78.9% to 100% across study sites. LCI was increased in patients with CF (P<0.05) and with other lung diseases (P<0.05) compared to controls. CONCLUSION Our results support feasibility of LCI as multicenter endpoint in clinical trials in infants and preschoolers with CF.
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Affiliation(s)
- Mirjam Stahl
- Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Pediatrics, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany; Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), German Centre for Lung Research (DZL), University of Heidelberg, Im Neuenheimer Feld 156, 69120 Heidelberg, Germany.
| | - Simon Y Graeber
- Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Pediatrics, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany; Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), German Centre for Lung Research (DZL), University of Heidelberg, Im Neuenheimer Feld 156, 69120 Heidelberg, Germany
| | - Cornelia Joachim
- Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Pediatrics, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany; Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), German Centre for Lung Research (DZL), University of Heidelberg, Im Neuenheimer Feld 156, 69120 Heidelberg, Germany
| | - Sandra Barth
- Department of Pediatrics, Justus-Liebig-University Giessen, Feulgenstrasse 10-12, 35392 Giessen, Germany; Universities Giessen and Marburg Lung Centre (UGMLC), German Centre for Lung Research (DZL), Aulweg 130, 35392 Giessen, Germany
| | - Isabell Ricklefs
- Department of Pediatric Allergology and Pneumology, Medical University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; Airway Research Centre North (ARCN), German Centre for Lung Research (DZL), Ratzeburger Allee 160, 23538 Lübeck, Germany
| | - Gesa Diekmann
- Department of Pediatric Allergology and Pneumology, Medical University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; Airway Research Centre North (ARCN), German Centre for Lung Research (DZL), Ratzeburger Allee 160, 23538 Lübeck, Germany
| | - Matthias V Kopp
- Department of Pediatric Allergology and Pneumology, Medical University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; Airway Research Centre North (ARCN), German Centre for Lung Research (DZL), Ratzeburger Allee 160, 23538 Lübeck, Germany
| | - Lutz Naehrlich
- Department of Pediatrics, Justus-Liebig-University Giessen, Feulgenstrasse 10-12, 35392 Giessen, Germany; Universities Giessen and Marburg Lung Centre (UGMLC), German Centre for Lung Research (DZL), Aulweg 130, 35392 Giessen, Germany
| | - Marcus A Mall
- Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Pediatrics, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany; Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), German Centre for Lung Research (DZL), University of Heidelberg, Im Neuenheimer Feld 156, 69120 Heidelberg, Germany; Department of Pediatric Pulmonology and Immunology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
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45
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Lenherr N, Ramsey KA, Jost K, Hornwall L, Singer F, Yammine S, Latzin P. Leaks during multiple-breath washout: characterisation and influence on outcomes. ERJ Open Res 2018; 4:00012-2017. [PMID: 29497618 PMCID: PMC5827412 DOI: 10.1183/23120541.00012-2017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Accepted: 12/13/2017] [Indexed: 11/19/2022] Open
Abstract
Nitrogen multiple-breath washout (N2MBW) is increasingly used in patients with cystic fibrosis. The current European Respiratory Society/American Thoracic Society consensus statement for MBW recommends the rejection of measurements with leaks. However, it is unclear whether this is necessary for all types of leaks. Here, our aim was to 1) model and 2) apply air leaks, and 3) to assess their influence on the primary MBW outcomes of lung clearance index and functional residual capacity. We investigated the influence of air leaks at various locations (pre-, intra- and post-capillary), sizes, durations and stages of the washout. Modelled leaks were applied to existing N2MBW data from 10 children by modifying breath tables. In addition, leaks were applied to the equipment during N2MBW measurements performed by one healthy adolescent. All modelled and applied leaks resulted in statistically significant but heterogeneous effects on lung clearance index and functional residual capacity. In all types of continuous inspiratory leaks exceeding a certain size, the end of the washout was not reached. For practical application, we illustrated six different “red flags”, i.e. signs that enable easy identification of leaks during measurements. Air leaks during measurement significantly influence N2MBW outcomes. The influence of leaks on MBW outcomes is dependent on the location, relation to breath cycle, duration, stage of washout and size of the leak. We identified a range of signs to help distinguish leaks from physiological noise. The influence of leaks on nitrogen MBW outcomes is complex, dynamic and dependent on the size, duration, location and position of leaks during the washout and breathing cyclehttp://ow.ly/PbHV30hB91H
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Affiliation(s)
- Nina Lenherr
- Dept of Pediatric Pneumology, University Children's Hospital Basel (UKBB), Basel, Switzerland
| | - Kathryn A Ramsey
- Pediatric Respiratory Medicine, Dept of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Kerstin Jost
- Dept of Pediatric Pneumology, University Children's Hospital Basel (UKBB), Basel, Switzerland
| | - Linn Hornwall
- Dept of Pediatric Pneumology, University Children's Hospital Basel (UKBB), Basel, Switzerland
| | - Florian Singer
- Pediatric Respiratory Medicine, Dept of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Division of Respiratory Medicine, University Children's Hospital Zurich, Zurich, Switzerland
| | - Sophie Yammine
- Pediatric Respiratory Medicine, Dept of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Philipp Latzin
- Pediatric Respiratory Medicine, Dept of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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46
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Birket SE, Davis JM, Fernandez CM, Tuggle KL, Oden AM, Chu KK, Tearney GJ, Fanucchi MV, Sorscher EJ, Rowe SM. Development of an airway mucus defect in the cystic fibrosis rat. JCI Insight 2018; 3:97199. [PMID: 29321377 DOI: 10.1172/jci.insight.97199] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 11/30/2017] [Indexed: 12/11/2022] Open
Abstract
The mechanisms underlying the development and natural progression of the airway mucus defect in cystic fibrosis (CF) remain largely unclear. New animal models of CF, coupled with imaging using micro-optical coherence tomography, can lead to insights regarding these questions. The Cftr-/- (KO) rat allows for longitudinal examination of the development and progression of airway mucus abnormalities. The KO rat exhibits decreased periciliary depth, hyperacidic pH, and increased mucus solid content percentage; however, the transport rates and viscoelastic properties of the mucus are unaffected until the KO rat ages. Airway submucosal gland hypertrophy develops in the KO rat by 6 months of age. Only then does it induce increased mucus viscosity, collapse of the periciliary layer, and delayed mucociliary transport; stimulation of gland secretion potentiates this evolution. These findings could be reversed by bicarbonate repletion but not pH correction without counterion donation. These studies demonstrate that abnormal surface epithelium in CF does not cause delayed mucus transport in the absence of functional gland secretions. Furthermore, abnormal bicarbonate transport represents a specific target for restoring mucus clearance, independent of effects on periciliary collapse. Thus, mature airway secretions are required to manifest the CF defect primed by airway dehydration and bicarbonate deficiency.
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Affiliation(s)
- Susan E Birket
- Department of Medicine and.,Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | | | | | - Katherine L Tuggle
- Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | | | - Kengyeh K Chu
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Guillermo J Tearney
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA.,Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts, USA
| | - Michelle V Fanucchi
- Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Eric J Sorscher
- Department of Pediatrics, Emory University, Atlanta, Georgia, USA
| | - Steven M Rowe
- Department of Medicine and.,Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.,Department of Cellular, Developmental, and Integrative Biology and.,Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Kanhere N, Couch MJ, Kowalik K, Zanette B, Rayment JH, Manson D, Subbarao P, Ratjen F, Santyr G. Correlation of Lung Clearance Index with Hyperpolarized 129Xe Magnetic Resonance Imaging in Pediatric Subjects with Cystic Fibrosis. Am J Respir Crit Care Med 2017; 196:1073-1075. [DOI: 10.1164/rccm.201611-2228le] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Nikhil Kanhere
- The Hospital for Sick ChildrenToronto, Ontario, Canadaand
| | | | | | - Brandon Zanette
- The Hospital for Sick ChildrenToronto, Ontario, Canadaand
- University of TorontoToronto, Ontario, Canada
| | | | - David Manson
- The Hospital for Sick ChildrenToronto, Ontario, Canadaand
- University of TorontoToronto, Ontario, Canada
| | - Padma Subbarao
- The Hospital for Sick ChildrenToronto, Ontario, Canadaand
- University of TorontoToronto, Ontario, Canada
| | - Felix Ratjen
- The Hospital for Sick ChildrenToronto, Ontario, Canadaand
- University of TorontoToronto, Ontario, Canada
| | - Giles Santyr
- The Hospital for Sick ChildrenToronto, Ontario, Canadaand
- University of TorontoToronto, Ontario, Canada
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48
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Cox NS, Holland AE. Exercise assessment and training in cystic fibrosis: Can less achieve more? J Cyst Fibros 2017; 16:649-650. [PMID: 29032177 DOI: 10.1016/j.jcf.2017.09.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 09/26/2017] [Accepted: 09/26/2017] [Indexed: 10/18/2022]
Affiliation(s)
- Narelle S Cox
- Discipline of Physiotherapy, La Trobe University, 99 Commercial Road Melbourne, 3004 Victoria, Australia; Institute for Breathing and Sleep, 145 Studley Rd, Heidelberg 3084, Victoria, Australia; Youth Activity Unlimited, A Strategic Research Centre of the UK Cystic Fibrosis Trust.
| | - Anne E Holland
- Discipline of Physiotherapy, La Trobe University, 99 Commercial Road Melbourne, 3004 Victoria, Australia; Institute for Breathing and Sleep, 145 Studley Rd, Heidelberg 3084, Victoria, Australia; Youth Activity Unlimited, A Strategic Research Centre of the UK Cystic Fibrosis Trust; Department of Physiotherapy, Alfred Hospital, 55 Commercial Road Melbourne, 3004 Victoria, Australia
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49
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Gauthier R, Cabon Y, Giroux-Metges MA, Du Boisbaudry C, Reix P, Le Bourgeois M, Chiron R, Molinari N, Saguintaah M, Amsallem F, Matecki S. Early follow-up of lung disease in infants with cystic fibrosis using the raised volume rapid thoracic compression technique and computed tomography during quiet breathing. Pediatr Pulmonol 2017; 52:1283-1290. [PMID: 28861941 DOI: 10.1002/ppul.23786] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 07/06/2017] [Indexed: 11/07/2022]
Abstract
BACKGROUND Among the different techniques used to monitor lung disease progression in infants with CF diagnosed by Newborn screening (NBS), raised volume-rapid thoracic compression (RVRTC) remains a promising tool. However, the need of sedation and positive pressure ventilation considerably limits its clinical use. We recently described a semi-quantitative method to evaluate air trapping by chest tomography during quite breathing without sedation (CTqb score). This parameter is the radiological sign of airway obstruction and could be also used for lung disease follow-up in infants with CF. However, its discriminative power compared with RVRTC and correlation with lung function parameters are not known. OBJECTIVES To compare the discriminative powers of the CTqb score and RVRTC parameters and to determine their correlation during the first year of life of infants with CF. METHODS In this multicenter longitudinal study, infants with CF diagnosed by NBS underwent RVRTC and CT during quite breathing at 10 ± 4 weeks (n = 30) and then at 13 ± 1 months of age (n = 28). RESULTS All RVRTC parameters and the CTqb score remained stable between evaluations. The CTqb score showed a higher discriminative power than forced expiratory volume in 0.5 s (FEV0.5 ; the main RVRTC parameter) at both visits (66% and 50% of abnormal values vs 30% and 28%, respectively). No correlation was found between CTqb score and, the different RVRTC parameters or the plethysmographic functional residual capacity, indicating that they evaluate different aspect of CF lung disease.
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Affiliation(s)
- Rémi Gauthier
- Pediatric Functional Exploration Unit, Hôpital Nord, Amiens University Hospital, Amiens, France
| | - Yann Cabon
- Medical Informatics Department, Montpellier University Hospital, Montpellier, France
| | | | | | - Phillipe Reix
- Pediatric Functional Exploration Unit, CF Center Lyon University Hospital, Paris, France
| | - Muriel Le Bourgeois
- Pediatric Functional Exploration Unit and CF Center, Necker University Hospital, Paris, France
| | - Raphael Chiron
- Cystic Fibrosis Center, Montpellier University Hospital, France
| | - Nicolas Molinari
- Medical Informatics Department, Montpellier University Hospital, Montpellier, France
| | - Magali Saguintaah
- Pediatric Imaging Department, Montpellier University Hospital, France
| | - Francis Amsallem
- Pediatric Functional Exploration Unit, UMR CNRS 9214-Inserm, U1046, Montpellier University Hospital, Montpellier, France
| | - Stefan Matecki
- Pediatric Functional Exploration Unit, UMR CNRS 9214-Inserm, U1046, Montpellier University Hospital, Montpellier, France
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50
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Gustafsson PM, Bengtsson L, Lindblad A, Robinson PD. The effect of inert gas choice on multiple breath washout in healthy infants: differences in lung function outcomes and breathing pattern. J Appl Physiol (1985) 2017; 123:1545-1554. [PMID: 28860172 DOI: 10.1152/japplphysiol.00524.2017] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The detrimental effects on breathing pattern during multiple breath inert gas washout (MBW) have been described with different inhaled gases [100% oxygen (O2) and sulfur hexafluoride (SF6)] but detailed comparisons are lacking. N2- and SF6-based tests were performed during spontaneous quiet sleep in 10 healthy infants aged 0.7-1.3 yr using identical hardware. Differences in breathing pattern pre and post 100% O2 and 4% SF6 exposure were investigated, and the results obtained were compared [functional residual capacity (FRC) and lung clearance index (LCI)]. During 100% O2 exposure. mean inspiratory flow ("respiratory drive") decreased transiently by mean (SD) 28 (9)% ( P < 0.001), and end-tidal CO2 (carbon dioxide) increased by mean (SD) 0.3 (0.4)% units ( P < 0.05) vs. air breathing prephase. During subsequent N2 washin (i.e., recovery phase), the pattern of change reversed. No significant effect on breathing pattern was observed during SF6 testing. In vitro testing confirmed that technical artifacts did not explain these changes. Mean (SD) FRC and LCI in vivo were significantly higher with N2 vs. SF6 washout: 216 (33) vs. 186 (22) ml ( P < 0.001) and 8.25 (0.85) vs. 7.55 (0.57) turnovers ( P = 0.021). Based on these results, SF6 based MBW is the preferred methodology for tests in this age range. NEW & NOTEWORTHY Inert gas choice for multiple breath inert gas washout (MBW) in infants has important consequences on both breathing pattern during test performance and the functional residual capacity and lung clearance index values obtained. Data suggest the detrimental effect of breathing pattern of 100% O2 and movement of O2 across the alveolar capillary membrane, with direct effects on MBW outcomes. SF6 MBW during infancy avoids this and can be further optimized by addressing the sources of technical artifact identified in this work.
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Affiliation(s)
- Per M Gustafsson
- Department of Pediatrics, Central Hospital , Skövde , Sweden.,The Sahlgrenska Academy at the University of Gothenburg , Gothenburg , Sweden
| | | | - Anders Lindblad
- The Sahlgrenska Academy at the University of Gothenburg , Gothenburg , Sweden.,CF Centre, Queen Silvia Children's Hospital , Gothenburg , Sweden
| | - Paul D Robinson
- Department of Respiratory Medicine, The Children's Hospital at Westmead , Sydney, New South Wales , Australia.,Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney , Australia
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