Preventive Inhalation of Hypertonic Saline in Infants with Cystic Fibrosis (PRESIS). A Randomized, Double-Blind, Controlled Study.

Rationale: Cystic fibrosis (CF) lung disease starts in early infancy, suggesting that preventive treatment may be most beneficial. Lung clearance index (LCI) and chest magnetic resonance imaging (MRI) have emerged as promising endpoints of early CF lung disease; however, randomized controlled trials testing the safety and efficacy of preventive therapies in infants with CF are lacking. Objectives: To determine the feasibility, safety, and efficacy of preventive inhalation with hypertonic saline (HS) compared with isotonic saline (IS) in infants with CF, including LCI and MRI as outcome measures. Methods: In this randomized, double-blind, controlled trial, 42 infants with CF less than 4 months of age were randomized across five sites to twice-daily inhalation of 6% HS (n = 21) or 0.9% IS (n = 21) for 52 weeks. Measurements and Main Results: Inhalation of HS and IS was generally well tolerated by infants with CF, and the number of adverse events did not differ between groups (P = 0.49). The change in LCI from baseline to Week 52 was larger in infants with CF treated with HS (-0.6) than in those treated with IS (-0.1; P < 0.05). In addition, weight gain was improved in infants with CF treated with HS (P < 0.05), whereas pulmonary exacerbations and chest MRI scores did not differ in the HS group versus the IS group. Conclusions: Preventive inhalation with HS initiated in the first months of life was safe and well tolerated and resulted in improvements in LCI and weight gain in infants with CF. Our results support the feasibility of LCI as an endpoint in randomized controlled trials in infants with CF. Clinical trial registered with www.clinicaltrials.gov (NCT01619657).

[1]  M. Gentzsch,et al.  Ion Channel Modulators in Cystic Fibrosis , 2018, Chest.

[2]  H. Kauczor,et al.  Multicentre standardisation of chest MRI as radiation-free outcome measure of lung disease in young children with cystic fibrosis. , 2018, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[3]  R. Boucher,et al.  The in vitro effect of nebulised hypertonic saline on human bronchial epithelium , 2018, European Respiratory Journal.

[4]  H. Kauczor,et al.  Non-contrast enhanced magnetic resonance imaging detects mosaic signal intensity in early cystic fibrosis lung disease. , 2018, European journal of radiology.

[5]  U. Frey,et al.  Elevated lung clearance index in infants with cystic fibrosis shortly after birth , 2017, European Respiratory Journal.

[6]  C. Meyer,et al.  Hyperpolarized helium-3 magnetic resonance lung imaging of non-sedated infants and young children: a proof-of-concept study. , 2017, Clinical imaging.

[7]  M. Kopp,et al.  Three-center feasibility of lung clearance index in infants and preschool children with cystic fibrosis and other lung diseases. , 2017, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[8]  S. Stanojevic,et al.  Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. , 2017, The Lancet. Respiratory medicine.

[9]  S. Stanojevic,et al.  Progression of Lung Disease in Preschool Patients with Cystic Fibrosis , 2017, American journal of respiratory and critical care medicine.

[10]  M. Wielpütz,et al.  MRI accelerating progress in functional assessment of cystic fibrosis lung disease. , 2017, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[11]  R. Szczesniak,et al.  Ultrashort Echo-Time Magnetic Resonance Imaging Is a Sensitive Method for the Evaluation of Early Cystic Fibrosis Lung Disease. , 2016, Annals of the American Thoracic Society.

[12]  H. Kauczor,et al.  Early detection and sensitive monitoring of CF lung disease: Prospects of improved and safer imaging , 2016, Pediatric pulmonology.

[13]  Hans-Ulrich Kauczor,et al.  Comparison of Lung Clearance Index and Magnetic Resonance Imaging for Assessment of Lung Disease in Children with Cystic Fibrosis , 2016, American journal of respiratory and critical care medicine.

[14]  C. Castellani,et al.  Newborn screening for cystic fibrosis. , 2016, The Lancet. Respiratory medicine.

[15]  M Puderbach,et al.  Imaging of Cystic Fibrosis Lung Disease and Clinical Interpretation , 2016, RöFo - Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren.

[16]  S. Stick,et al.  Lung Clearance Index and Structural Lung Disease on Computed Tomography in Early Cystic Fibrosis. , 2015, American journal of respiratory and critical care medicine.

[17]  I. Korten,et al.  False normal Lung Clearance Index in infants with cystic fibrosis due to software algorithms , 2015, Pediatric pulmonology.

[18]  S. Stick,et al.  Progressive ventilation inhomogeneity in infants with cystic fibrosis after pulmonary infection , 2015, European Respiratory Journal.

[19]  P. Sly,et al.  Early respiratory infection is associated with reduced spirometry in children with cystic fibrosis. , 2014, American journal of respiratory and critical care medicine.

[20]  M. Mall,et al.  Early cystic fibrosis lung disease: Role of airway surface dehydration and lessons from preventive rehydration therapies in mice. , 2014, The international journal of biochemistry & cell biology.

[21]  D. Hartl,et al.  CFTR: cystic fibrosis and beyond , 2014, European Respiratory Journal.

[22]  H. Kauczor,et al.  Magnetic resonance imaging detects changes in structure and perfusion, and response to therapy in early cystic fibrosis lung disease. , 2014, American journal of respiratory and critical care medicine.

[23]  O. Sommerburg,et al.  Multiple Breath Washout Is Feasible in the Clinical Setting and Detects Abnormal Lung Function in Infants and Young Children with Cystic Fibrosis , 2014, Respiration.

[24]  P. Lee,et al.  Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial. , 2013, The Lancet. Respiratory medicine.

[25]  R. Boucher,et al.  Hypertonic saline is effective in the prevention and treatment of mucus obstruction, but not airway inflammation, in mice with chronic obstructive lung disease. , 2013, American journal of respiratory cell and molecular biology.

[26]  S. Stanojevic,et al.  Lung clearance index as an outcome measure for clinical trials in young children with cystic fibrosis. A pilot study using inhaled hypertonic saline. , 2013, American journal of respiratory and critical care medicine.

[27]  Peter D Sly,et al.  Risk factors for bronchiectasis in children with cystic fibrosis. , 2013, The New England journal of medicine.

[28]  F. Ratjen,et al.  Early lung disease in cystic fibrosis. , 2013, The Lancet. Respiratory medicine.

[29]  M. Rosenfeld,et al.  Early intervention studies in infants and preschool children with cystic fibrosis: are we ready? , 2013, European Respiratory Journal.

[30]  Janet Stocks,et al.  Consensus statement for inert gas washout measurement using multiple- and single- breath tests , 2013, European Respiratory Journal.

[31]  A. Numa,et al.  Early cystic fibrosis lung disease detected by bronchoalveolar lavage and lung clearance index. , 2012, American journal of respiratory and critical care medicine.

[32]  S. Stanojevic,et al.  Age and height dependence of lung clearance index and functional residual capacity , 2012, European Respiratory Journal.

[33]  K. Rabe,et al.  Das Deutsche Zentrum für Lungenforschung – Translationale Forschung für Prävention, Diagnose und Therapie von Atemwegserkrankungen , 2012, Pneumologie.

[34]  A. Wade,et al.  Lung function is abnormal in 3-month-old infants with cystic fibrosis diagnosed by newborn screening , 2012, Thorax.

[35]  R. Kronmal,et al.  Inhaled hypertonic saline in infants and children younger than 6 years with cystic fibrosis: the ISIS randomized controlled trial. , 2012, JAMA.

[36]  Annette Kopp-Schneider,et al.  Morphologic and functional scoring of cystic fibrosis lung disease using MRI. , 2012, European journal of radiology.

[37]  M. Welsh,et al.  Future directions in early cystic fibrosis lung disease research: an NHLBI workshop report. , 2012, American journal of respiratory and critical care medicine.

[38]  P. Sly,et al.  Air Trapping on Chest CT Is Associated with Worse Ventilation Distribution in Infants with Cystic Fibrosis Diagnosed following Newborn Screening , 2011, PloS one.

[39]  M. Rosenfeld,et al.  Inhaled hypertonic saline in infants and toddlers with cystic fibrosis: short‐term tolerability, adherence, and safety , 2011, Pediatric pulmonology.

[40]  T. Riedel,et al.  Normative data for lung function and exhaled nitric oxide in unsedated healthy infants , 2010, European Respiratory Journal.

[41]  F. Ratjen,et al.  Hypertonic saline improves the LCI in paediatric patients with CF with normal lung function , 2010, Thorax.

[42]  P. Sly,et al.  Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening. , 2009, American journal of respiratory and critical care medicine.

[43]  M. Goldman,et al.  Inert Gas Washout: Theoretical Background and Clinical Utility in Respiratory Disease , 2009, Respiration.

[44]  Margaret Rosenfeld,et al.  Early anti-pseudomonal acquisition in young patients with cystic fibrosis: rationale and design of the EPIC clinical trial and observational study'. , 2009, Contemporary clinical trials.

[45]  R. Boucher,et al.  Preventive but not late amiloride therapy reduces morbidity and mortality of lung disease in betaENaC-overexpressing mice. , 2008, American journal of respiratory and critical care medicine.

[46]  S. Donaldson,et al.  Safety and tolerability of inhaled hypertonic saline in young children with cystic fibrosis , 2008, Pediatric pulmonology.

[47]  D. Baldwin,et al.  Optimized temperature and deadspace correction improve analysis of multiple breath washout measurements by ultrasonic flowmeter in infants , 2007, Pediatric pulmonology.

[48]  F. Ratjen,et al.  Pilot study of safety and tolerability of inhaled hypertonic saline in infants with cystic fibrosis , 2007, Pediatric pulmonology.

[49]  A. Wade,et al.  Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests , 2007, Thorax.

[50]  R. Boucher Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. , 2007, Annual review of medicine.

[51]  Janet Stocks,et al.  Multiple-breath washout as a marker of lung disease in preschool children with cystic fibrosis. , 2005, American journal of respiratory and critical care medicine.

[52]  J. Stocks,et al.  Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis , 2004, Thorax.

[53]  M. Van Winckel,et al.  Percutaneous endoscopic gastrostomy in cystic fibrosis: patient acceptance and effect of overnight tube feeding on nutritional status. , 2004, Acta gastro-enterologica Belgica.

[54]  P. Gustafsson,et al.  Evaluation of ventilation maldistribution as an early indicator of lung disease in children with cystic fibrosis , 2003, European Respiratory Journal.

[55]  J. Wit,et al.  Catch-Up Growth and Endocrine Changes in Childhood Celiac Disease , 2002, Hormone Research in Paediatrics.

[56]  J. Müller,et al.  Perzentile für den Body-mass-Index für das Kindes- und Jugendalter unter Heranziehung verschiedener deutscher Stichproben , 2001, Monatsschrift Kinderheilkunde.

[57]  M. Hofbeck,et al.  Percutaneous endoscopic gastrostomy in children and adolescents. , 1997, Journal of pediatric gastroenterology and nutrition.

[58]  H. Fuchs,et al.  Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. , 1994, The New England journal of medicine.

[59]  R. Kauffman,et al.  American Academy of Pediatrics Committee on Drugs and Committee on Environmental Health: Use of chloral hydrate for sedation in children. , 1993, Pediatrics.

[60]  Zusammenfassung,et al.  Longitudinale Körperentwicklung gesunder Kinder von 0 bis 18 Jahren , 1992 .

[61]  L. Rees,et al.  Chronic renal failure and growth. , 1989, Archives of disease in childhood.

[62]  A. Prader,et al.  Dedicated to Dr. Guido Fanconi on the occasion of his 80th birthday Catch-up Growth in Malnutrition, Studied in Celiac Disease After Institution of Gluten-free Diet , 1972, Pediatric Research.

[63]  J. Tanner,et al.  Catch-up growth following illness or starvation. An example of developmental canalization in man. , 1963, The Journal of pediatrics.