Early intervention studies in infants and preschool children with cystic fibrosis: are we ready?

Cystic fibrosis (CF) lung disease starts early in life and progresses even in the absence of clinical symptoms. Therefore, sensitive outcome measures to quantify and track these early abnormalities in infants and young children are needed; both for clinical care and interventional trials. Currently, the efficacy of most therapeutic interventions in CF has not been tested in children under the age of 6 years and drug development programmes have focused on assessing safety rather than efficacy in this age group. This article summarises the current status for outcome measures that can be utilised in clinical trials in infants and children with CF. Two methodologies are specifically highlighted in this review; chest computed tomography to assess structural damage of the lung and multiple breath washout as a technique to quantify ventilation inhomogeneity. While not all questions regarding the utility of these outcome measures in infants and young children have been resolved, significant advances have been made and it now appears feasible to design and conduct adequately powered efficacy studies in this age group. This could be a crucial step to further improve outcomes in CF patients as initiating effective treatment early is considered essential to prevent permanent lung damage.

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

[2]  Marleen de Bruijne,et al.  Chest computed tomography scores are predictive of survival in patients with cystic fibrosis awaiting lung transplantation. , 2012, American journal of respiratory and critical care medicine.

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

[4]  L. Saiman,et al.  Effect of azithromycin on systemic markers of inflammation in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa. , 2012, Chest.

[5]  P. Gustafsson,et al.  Tidal N2 washout ventilation inhomogeneity indices in a reference population aged 7-70 years , 2012 .

[6]  M. Gappa,et al.  Feasibility and Variability of Measuring the Lung Clearance Index in a Multi‐Center Setting , 2012, Pediatric pulmonology.

[7]  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.

[8]  M. Rosenfeld,et al.  Lung function distinguishes preschool children with CF from healthy controls in a multi‐center setting , 2012, Pediatric pulmonology.

[9]  S. Davis,et al.  Improvement in pulmonary function following antibiotics in infants with cystic fibrosis , 2012, Pediatric pulmonology.

[10]  Florian Singer,et al.  A Realistic Validation Study of a New Nitrogen Multiple-Breath Washout System , 2012, PloS one.

[11]  P. Aurora,et al.  Alveolar LCI vs. standard LCI in detecting early CF lung disease , 2012, Respiratory Physiology & Neurobiology.

[12]  P. Sly,et al.  Progression of early structural lung disease in young children with cystic fibrosis assessed using CT , 2011, Thorax.

[13]  U. Frey,et al.  Long-term course of lung clearance index between infancy and school-age in cystic fibrosis subjects. , 2011, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[14]  M. Gappa,et al.  Lung clearance index: clinical and research applications in children. , 2011, Paediatric respiratory reviews.

[15]  Matthias Griese,et al.  A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. , 2011, The New England journal of medicine.

[16]  P. Gustafsson,et al.  Ventilation inhomogeneity in children with primary ciliary dyskinesia , 2011, Thorax.

[17]  Umer Khan,et al.  Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. , 2011, Archives of pediatrics & adolescent medicine.

[18]  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.

[19]  J. Carlin,et al.  Effect of bronchoalveolar lavage-directed therapy on Pseudomonas aeruginosa infection and structural lung injury in children with cystic fibrosis: a randomized trial. , 2011, JAMA.

[20]  P. Sly,et al.  Infection, inflammation, and lung function decline in infants with cystic fibrosis. , 2011, American journal of respiratory and critical care medicine.

[21]  C. Anastassopoulou,et al.  Caenorhabditis elegans-based model systems for antifungal drug discovery. , 2011, Current pharmaceutical design.

[22]  J. Stocks,et al.  Re: Lum S, Hoo AF, Hulskamp G, Wade A, Stocks J. Potential Misinterpretation of Infant Lung Function Unless Prospective Healthy Controls Are Studied. Pediatr Pulmonol 2010;45:906-913 Reply , 2011 .

[23]  S. Stanojevic,et al.  Lung Clearance Index and HRCT are complementary markers of lung abnormalities in young children with CF , 2011, Thorax.

[24]  S. Stanojevic,et al.  Lung clearance index at 4 years predicts subsequent lung function in children with cystic fibrosis. , 2011, American journal of respiratory and critical care medicine.

[25]  M. Rosenfeld,et al.  Multicenter evaluation of infant lung function tests as cystic fibrosis clinical trial endpoints. , 2010, American journal of respiratory and critical care medicine.

[26]  I. Sermet-Gaudelus,et al.  Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening. , 2010, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[27]  A. Wade,et al.  Potential misinterpretation of infant lung function unless prospective healthy controls are studied , 2010, Pediatric pulmonology.

[28]  E. Sakmar,et al.  The use of high resolution computerized tomography (HRCT) of the chest in evaluating the effect of tobramycin solution for inhalation in cystic fibrosis lung disease , 2010, Pediatric pulmonology.

[29]  A. Wade,et al.  Potential Mis-diagnosis Of Lung Disease In Infants: Need For Equipment-specific Reference Values , 2010, ATS 2010.

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

[31]  P. Sly,et al.  Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after newborn screening. , 2009, The Journal of pediatrics.

[32]  S. Stanojevic,et al.  Spirometry centile charts for young Caucasian children: the Asthma UK Collaborative Initiative. , 2009, American journal of respiratory and critical care medicine.

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

[34]  W. T. Harris,et al.  Association of lower airway inflammation with physiologic findings in young children with cystic fibrosis , 2009, Pediatric pulmonology.

[35]  W. Regelmann,et al.  Longitudinal assessment of lung function from infancy to childhood in patients with cystic fibrosis , 2009, Pediatric pulmonology.

[36]  P. Sly,et al.  Lung function in infants with cystic fibrosis diagnosed by newborn screening. , 2008, American journal of respiratory and critical care medicine.

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

[38]  M. Gappa,et al.  A novel sidestream ultrasonic flow sensor for multiple breath washout in children , 2008, Pediatric pulmonology.

[39]  H. Tiddens,et al.  Estimation of the radiation dose from CT in cystic fibrosis. , 2008, Chest.

[40]  S. Stanojevic,et al.  Reference ranges for spirometry across all ages: a new approach. , 2008, American journal of respiratory and critical care medicine.

[41]  H. Tiddens,et al.  Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis , 2007, Thorax.

[42]  F. Long.  High-resolution computed tomography of the lung in children with cystic fibrosis: technical factors. , 2007, Proceedings of the American Thoracic Society.

[43]  Janet Stocks,et al.  An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children. , 2007, American journal of respiratory and critical care medicine.

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

[45]  B. Yankaskas,et al.  Computed tomography reflects lower airway inflammation and tracks changes in early cystic fibrosis. , 2007, American journal of respiratory and critical care medicine.

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

[47]  Sylvia Verbanck,et al.  Ventilation heterogeneity is a major determinant of airway hyperresponsiveness in asthma, independent of airway inflammation , 2007, Thorax.

[48]  E. Picard,et al.  Spirometry in early childhood in cystic fibrosis patients. , 2007, Chest.

[49]  P. Gustafsson.  Peripheral airway involvement in CF and asthma compared by inert gas washout , 2007, Pediatric pulmonology.

[50]  E. Sakmar,et al.  High resolution computerized tomography of the chest and pulmonary function testing in evaluating the effect of tobramycin solution for inhalation in cystic fibrosis patients , 2006, Pediatric pulmonology.

[51]  P. Devos,et al.  Spirometry in 3–5‐year‐old children with asthma , 2006, Pediatric pulmonology.

[52]  D. Sin,et al.  Estimation of cancer mortality associated with repetitive computed tomography scanning. , 2006, American journal of respiratory and critical care medicine.

[53]  W. Hop,et al.  Progression of lung disease on computed tomography and pulmonary function tests in children and adults with cystic fibrosis , 2005, Thorax.

[54]  M. Goris,et al.  Dornase alfa reduces air trapping in children with mild cystic fibrosis lung disease: a quantitative analysis. , 2005, Chest.

[55]  J. Hankinson,et al.  Standardisation of spirometry , 2005, European Respiratory Journal.

[56]  R. Castile,et al.  Comparison of quiet breathing and controlled ventilation in the high-resolution CT assessment of airway disease in infants with cystic fibrosis , 2005, Pediatric Radiology.

[57]  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.

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

[59]  P. Molina,et al.  High-resolution computed tomography in young patients with cystic fibrosis: distribution of abnormalities and correlation with pulmonary function tests. , 2004, The Journal of pediatrics.

[60]  A. Wade,et al.  The evolution of airway function in early childhood following clinical diagnosis of cystic fibrosis. , 2004, American journal of respiratory and critical care medicine.

[61]  J. Mayo,et al.  Progressive damage on high resolution computed tomography despite stable lung function in cystic fibrosis , 2004, European Respiratory Journal.

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

[63]  R. Gibson,et al.  Pathophysiology and management of pulmonary infections in cystic fibrosis. , 2003, American journal of respiratory and critical care medicine.

[64]  A. Leung,et al.  Composite spirometric-computed tomography outcome measure in early cystic fibrosis lung disease. , 2003, American journal of respiratory and critical care medicine.

[65]  A. Wade,et al.  Relative ability of full and partial forced expiratory maneuvers to identify diminished airway function in infants with cystic fibrosis. , 2002, American journal of respiratory and critical care medicine.

[66]  R. Tepper,et al.  Spirometry in 3- to 6-year-old children with cystic fibrosis. , 2002, American journal of respiratory and critical care medicine.

[67]  J. Stocks,et al.  Exploring the relationship between forced maximal flow at functional residual capacity and parameters of forced expiration from raised lung volume in healthy infants , 2002, Pediatric pulmonology.

[68]  J. Stocks,et al.  Lung function testing in infants with cystic fibrosis: Lessons from the past and future directions , 2001, Pediatric pulmonology.

[69]  L. Kuhns,et al.  Use of computerized tomography and chest X‐rays in evaluating efficacy of aerosolized recombinant human DNase in cystic fibrosis patients younger than age 5 years: A preliminary study * , 2001, Pediatric pulmonology.

[70]  J. Emerson,et al.  Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis , 1999, Pediatric pulmonology.

[71]  Maya Ramagopal,et al.  High-resolution computed tomography of the chest in children with cystic fibrosis: support for use as an outcome surrogate , 1999, Pediatric Radiology.

[72]  A. Friedman,et al.  High-resolution CT in the acute exacerbation of cystic fibrosis: evaluation of acute findings, reversibility of those findings, and clinical correlation. , 1997, AJR. American journal of roentgenology.

[73]  R R Miller,et al.  Bronchiectasis: comparison of preoperative thin-section CT and pathologic findings in resected specimens. , 1995, Radiology.

[74]  P. Sly,et al.  A new technique to generate and assess forced expiration from raised lung volume in infants. , 1995, American journal of respiratory and critical care medicine.

[75]  S. Greenberg,et al.  The lung in cystic fibrosis. A quantitative study including prevalence of pathologic findings among different age groups. , 1976, Human pathology.

[76]  A. M. Deall.  Diagnosis of Cystic Fibrosis , 1971 .

[77]  E. Goodwin.  For Children with Cystic Fibrosis , 1963 .

[78]  J. Stockman.  Effect of Azithromycin on Pulmonary Function in Patients With Cystic Fibrosis Uninfected With Pseudomonas aeruginosa: A Randomized Controlled Trial , 2012 .

[79]  S. Willsie.  Lung Disease at Diagnosis in Infants with Cystic Fibrosis Detected by Newborn Screening , 2010 .

[80]  S. Jones.  Lung Function from Infancy to the Preschool Years after Clinical Diagnosis of Cystic Fibrosis , 2009 .

[81]  H. Bisgaard,et al.  Feasibility of repetitive lung function measurements by raised volume rapid thoracoabdominal compression during methacholine challenge in young infants. , 2008, Chest.

[82]  A. Oestreich.  High-Resolution Computed Tomography Imaging of Airway Disease in Infants with Cystic Fibrosis , 2007 .

[83]  G. Wandalsen,et al.  Variability of the raised volume rapid thoracic compression technique in infants with recurrent wheezing. , 2005, Allergologia et immunopathologia.

[84]  W. Ambrosius,et al.  Forced expiratory flows and volumes in infants. Normative data and lung growth. , 2000, American journal of respiratory and critical care medicine.

[85]  A. B. A. C. I. D. F. Midulla.  Bronchoalveolar lavage in children , 2000 .

[86]  F. Ratjen,et al.  Bronchoalveolar lavage in children , 2000 .

[87]  A. Clément,et al.  Bronchoalveolar lavage in children. ERS Task Force on bronchoalveolar lavage in children. European Respiratory Society. , 2000 .

[88]  M. Zach.  Lung disease in cystic fibrosis—an updated concept , 1990 .

[89]  P. Hiatt,et al.  Infants with cystic fibrosis: Pulmonary function at diagnosis , 1988, Pediatric pulmonology.

[90]  J. Gustafson,et al.  Cystic Fibrosis , 2009, Journal of the Iowa Medical Society.