Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 147 No. 3334 (2017)

Inert gas washout: background and application in various lung diseases

DOI
https://doi.org/10.4414/smw.2017.14483
Cite this as:
Swiss Med Wkly. 2017;147:w14483
Published
16.08.2017

Abstract

Multiple breath inert gas washout (MBW) is a lung function technique to measure ventilation inhomogeneity. The technique was developed more than 60 years ago, but not much used for many decades. Technical improvements, easy protocols and higher sensitivity compared with standard lung function tests in some disease groups have led to a recent renaissance of MBW.

The lung clearance index (LCI) is a common measure derived from MBW tests, and offers information on lung pathology complementary to that from conventional lung function tests such as spirometry. The LCI measures the overall degree of pulmonary ventilation inhomogeneity. There are other MBW-derived parameters, which describe more regional airway ventilation and enable specific information on conductive or acinar ventilation inhomogeneity. How this specific ventilation distribution is exactly related to different disease processes has not entirely been examined yet.

MBW measurements are performed during tidal breathing, making this technique attractive for children, even young children and infants. These benefits and the additional physiological information on ventilation inhomogeneity early in the course of lung diseases have led to increasing research activities and clinical application of MBW, especially in paediatric lung diseases such as cystic fibrosis (CF). In these patients, LCI detects early airway damage and enables monitoring of disease progression and treatment response. Guidelines for the standardisation of the MBW technique were recently published. These guidelines will, hopefully, increase comparability of LCI data obtained in different centres or intervention trials in children and adults.

In this non-systematic review article, we provide an overview of recent developments in MBW, with a special focus on children. We first explain the physiological and technical background to this technique with a short explanation of several methodological aspects that are important for understanding the principle behind the technique and enable high quality measurements. We then provide examples of MBW application in different lung diseases of children and adults, with regards to both clinical application and research activities. Lastly, we report on ongoing clinical trials using MBW as outcome and give an outlook on possible future developments.

References

  1. Aurora P, Bush A, Gustafsson P, Oliver C, Wallis C, Price J, et al.; London Cystic Fibrosis Collaboration. Multiple-breath washout as a marker of lung disease in preschool children with cystic fibrosis. Am J Respir Crit Care Med. 2005;171(3):249–56. doi:.https://doi.org/10.1164/rccm.200407-895OC
  2. Hjalmarson O, Sandberg K. Abnormal lung function in healthy preterm infants. Am J Respir Crit Care Med. 2002;165(1):83–7. doi:.https://doi.org/10.1164/ajrccm.165.1.2107093
  3. Fowler WS, Cornish ER, Jr, Kety SS. Lung function studies. VIII. Analysis of alveolar ventilation by pulmonary N2 clearance curves. J Clin Invest. 1952;31(1):40–50. doi:.https://doi.org/10.1172/JCI102575
  4. Kraemer R, Meister B. Fast real-time moment-ratio analysis of multibreath nitrogen washout in children. J Appl Physiol (1985). 1985;59(4):1137–44.
  5. Robinson PD, Goldman MD, Gustafsson PM. Inert gas washout: theoretical background and clinical utility in respiratory disease. Respiration. 2009;78(3):339–55. doi:.https://doi.org/10.1159/000225373
  6. Subbarao P, Milla C, Aurora P, Davies JC, Davis SD, Hall GL, et al. Multiple-Breath Washout as a Lung Function Test in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report. Ann Am Thorac Soc. 2015;12(6):932–9. doi:.https://doi.org/10.1513/AnnalsATS.201501-021FR
  7. Robinson PD, Latzin P, Verbanck S, Hall GL, Horsley A, Gappa M, et al. Consensus statement for inert gas washout measurement using multiple- and single- breath tests. Eur Respir J. 2013;41(3):507–22. doi:.https://doi.org/10.1183/09031936.00069712
  8. Ramsey KA, McGirr C, Stick SM, Hall GL, Simpson SJ ; AREST CF. Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis. J Cyst Fibros. 2017;S1569-1993(17)30020-6.
  9. Aurora P, Gustafsson P, Bush A, Lindblad A, Oliver C, Wallis CE, et al. Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis. Thorax. 2004;59(12):1068–73. doi:.https://doi.org/10.1136/thx.2004.022590
  10. Horsley AR, Gustafsson PM, Macleod KA, Saunders C, Greening AP, Porteous DJ, et al. Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis. Thorax. 2008;63(2):135–40. doi:.https://doi.org/10.1136/thx.2007.082628
  11. Yammine S, Singer F, Abbas C, Roos M, Latzin P. Multiple-breath washout measurements can be significantly shortened in children. Thorax. 2013;68(6):586–7. doi:.https://doi.org/10.1136/thoraxjnl-2012-202345
  12. Robinson PD, Stocks J, Aurora P, Lum S. Abbreviated multi-breath washout for calculation of lung clearance index. Pediatr Pulmonol. 2013;48(4):336–43. doi:.https://doi.org/10.1002/ppul.22618
  13. Yammine S, Lenherr N, Nyilas S, Singer F, Latzin P. Using the same cut-off for sulfur hexafluoride and nitrogen multiple-breath washout may not be appropriate. J Appl Physiol (1985). 2015;119(12):1510–2. doi:.https://doi.org/10.1152/japplphysiol.00333.2015
  14. Saidel GM, Salmon RB, Chester EH. Moment analysis of multibreath lung washout. J Appl Physiol. 1975;38(2):328–34.
  15. Fleming GM, Chester EH, Saniie J, Saidel GM. Ventilation inhomogeneity using multibreath nitrogen washout: comparison of moment ratios and other indexes. Am Rev Respir Dis. 1980;121(5):789–94.
  16. Wall MA. Moment analysis of multibreath nitrogen washout in young children. J Appl Physiol (1985). 1985;59(1):274–9.
  17. Hutchison AA, Sum AC, Demis TA, Erben A, Landau LI. Moment analysis of multiple breath nitrogen washout in children. Am Rev Respir Dis. 1982;125(1):28–32.
  18. Kraemer R, Zehnder M, Meister B. Intrapulmonary gas distribution in healthy children. Respir Physiol. 1986;65(2):127–37. doi:.https://doi.org/10.1016/0034-5687(86)90045-9
  19. Habib RH, Lutchen KR. Moment analysis of a multibreath nitrogen washout based on an alveolar gas dilution number. Am Rev Respir Dis. 1991;144(3 Pt 1):513–9. doi:.https://doi.org/10.1164/ajrccm/144.3_Pt_1.513
  20. Schibler A, Hall GL, Businger F, Reinmann B, Wildhaber JH, Cernelc M, et al. Measurement of lung volume and ventilation distribution with an ultrasonic flow meter in healthy infants. Eur Respir J. 2002;20(4):912–8. doi:.https://doi.org/10.1183/09031936.02.00226002
  21. Aurora P, Kozlowska W, Stocks J. Gas mixing efficiency from birth to adulthood measured by multiple-breath washout. Respir Physiol Neurobiol. 2005;148(1-2):125–39. doi:.https://doi.org/10.1016/j.resp.2005.05.027
  22. Singer F, Yammine S, Schmidt A, Proietti E, Kieninger E, Barben J, et al. Ventilatory response to nitrogen multiple-breath washout in infants. Pediatr Pulmonol. 2014;49(4):342–7. doi:.https://doi.org/10.1002/ppul.22841
  23. Egger B, Jost K, Anagnostopoulou P, Yammine S, Singer F, Casaulta C, et al. Lung clearance index and moment ratios at different cut-off values in infant multiple-breath washout measurements. Pediatr Pulmonol. 2016;51(12):1373–81. doi:.https://doi.org/10.1002/ppul.23483
  24. Verbanck S, Paiva M. Model simulations of gas mixing and ventilation distribution in the human lung. J Appl Physiol (1985). 1990;69(6):2269–79.
  25. Gonem S, Hardy S, Buhl N, Hartley R, Soares M, Kay R, et al. Characterization of acinar airspace involvement in asthmatic patients by using inert gas washout and hyperpolarized (3)helium magnetic resonance. J Allergy Clin Immunol. 2016;137(2):417–25. doi:.https://doi.org/10.1016/j.jaci.2015.06.027
  26. Bauman G, et al. Pulmonary Fourier decomposition MRI compared to multiple breath washout and spirometry: A preliminary study in Primary Ciliary Dyskinesia. ISMRM 24th Annual Meeting & Exhibition; 2016,7–13 May; Singapore. Available at: http://dev.ismrm.org/2016/2924.html
  27. Arieli R. Mass spectrometer for respiratory research. Respir Physiol Neurobiol. 2010;170(2):183–4. doi:.https://doi.org/10.1016/j.resp.2009.12.013
  28. Fuchs SI, Sturz J, Junge S, Ballmann M, Gappa M. A novel sidestream ultrasonic flow sensor for multiple breath washout in children. Pediatr Pulmonol. 2008;43(8):731–8. doi:.https://doi.org/10.1002/ppul.20825
  29. Schmidt A, Yammine S, Proietti E, Frey U, Latzin P, Riedel T, et al. Validation of multiple-breath washout equipment for infants and young children. Pediatr Pulmonol. 2015;50(6):607–14. doi:.https://doi.org/10.1002/ppul.23010
  30. Gustafsson PM, Robinson PD, Lindblad A, Oberli D. Novel methodology to perform sulfur hexafluoride (SF6)-based multiple-breath wash-in and washout in infants using current commercially available equipment. J Appl Physiol (1985). 2016;121(5):1087–97. doi:.https://doi.org/10.1152/japplphysiol.00115.2016
  31. Singer F, Houltz B, Latzin P, Robinson P, Gustafsson P. A realistic validation study of a new nitrogen multiple-breath washout system. PLoS One. 2012;7(4):e36083. doi:.https://doi.org/10.1371/journal.pone.0036083
  32. Gonem S, Singer F, Corkill S, Singapuri A, Siddiqui S, Gustafsson P. Validation of a photoacoustic gas analyser for the measurement of functional residual capacity using multiple-breath inert gas washout. Respiration. 2014;87(6):462–8. doi:.https://doi.org/10.1159/000357786
  33. Anagnostopoulou P, Egger B, Lurà M, Usemann J, Schmidt A, Gorlanova O, et al. Multiple breath washout analysis in infants: quality assessment and recommendations for improvement. Physiol Meas. 2016;37(3):L1–15. doi:.https://doi.org/10.1088/0967-3334/37/3/L1
  34. Latzin P, Sauteur L, Thamrin C, Schibler A, Baldwin D, Hutten GJ, et al. Optimized temperature and deadspace correction improve analysis of multiple breath washout measurements by ultrasonic flowmeter in infants. Pediatr Pulmonol. 2007;42(10):888–97. doi:.https://doi.org/10.1002/ppul.20674
  35. Jensen R, Stanojevic S, Gibney K, Salazar JG, Gustafsson P, Subbarao P, et al. Multiple breath nitrogen washout: a feasible alternative to mass spectrometry. PLoS One. 2013;8(2):e56868. doi:.https://doi.org/10.1371/journal.pone.0056868
  36. Summermatter S, Singer F, Latzin P, Yammine S. Impact of Software Settings on Multiple-Breath Washout Outcomes. PLoS One. 2015;10(7):e0132250. doi:.https://doi.org/10.1371/journal.pone.0132250
  37. Horsley A, Macleod K, Gupta R, Goddard N, Bell N. Enhanced photoacoustic gas analyser response time and impact on accuracy at fast ventilation rates during multiple breath washout. PLoS One. 2014;9(6):e98487. doi:.https://doi.org/10.1371/journal.pone.0098487
  38. Downing B, Irving S, Bingham Y, Fleming L, Bush A, Saglani S. Feasibility of lung clearance index in a clinical setting in pre-school children. Eur Respir J. 2016;48(4):1074–80. doi:.https://doi.org/10.1183/13993003.00374-2016
  39. Grønbæk J, Hallas HW, Arianto L, Pedersen K, Thomsen A, Chawes BL, et al. New time-saving predictor algorithm for multiple breath washout in adolescents. Pediatr Res. 2016;80(1):49–53. doi:.https://doi.org/10.1038/pr.2016.57
  40. Nielsen N, Nielsen JG, Horsley AR. Evaluation of the impact of alveolar nitrogen excretion on indices derived from multiple breath nitrogen washout. PLoS One. 2013;8(9):e73335. doi:.https://doi.org/10.1371/journal.pone.0073335
  41. Shawcross A, Murray CS, Goddard N, Gupta R, Watson S, Horsley A. Accurate lung volume measurements in vitro using a novel inert gas washout method suitable for infants. Pediatr Pulmonol. 2016;51(5):491–7. doi:.https://doi.org/10.1002/ppul.23348
  42. Fuchs O, Latzin P, Thamrin C, Stern G, Frischknecht P, Singer F, et al. Normative data for lung function and exhaled nitric oxide in unsedated healthy infants. Eur Respir J. 2011;37(5):1208–16. doi:.https://doi.org/10.1183/09031936.00125510
  43. Gray D, Willemse L, Visagie A, Smith E, Czövek D, Sly PD, et al. Lung function and exhaled nitric oxide in healthy unsedated African infants. Respirology. 2015;20(7):1108–14. doi:.https://doi.org/10.1111/resp.12579
  44. Gray DM, Turkovic L, Willemse L, Visagie A, Vanker A, Stein DJ, et al. Lung Function in African Infants in the Drakenstein Child Health Study. Impact of Lower Respiratory Tract Illness. Am J Respir Crit Care Med. 2017;195(2):212–20. doi:.https://doi.org/10.1164/rccm.201601-0188OC
  45. Belessis Y, Dixon B, Hawkins G, Pereira J, Peat J, MacDonald R, et al. Early cystic fibrosis lung disease detected by bronchoalveolar lavage and lung clearance index. Am J Respir Crit Care Med. 2012;185(8):862–73. doi:.https://doi.org/10.1164/rccm.201109-1631OC
  46. Simpson SJ, Ranganathan S, Park J, Turkovic L, Robins-Browne RM, Skoric B, et al.; AREST CF. Progressive ventilation inhomogeneity in infants with cystic fibrosis after pulmonary infection. Eur Respir J. 2015;46(6):1680–90. doi:.https://doi.org/10.1183/13993003.00622-2015
  47. Hall GL, Logie KM, Parsons F, Schulzke SM, Nolan G, Murray C, et al.; AREST CF. Air trapping on chest CT is associated with worse ventilation distribution in infants with cystic fibrosis diagnosed following newborn screening. PLoS One. 2011;6(8):e23932. doi:.https://doi.org/10.1371/journal.pone.0023932
  48. Stanojevic S, Davis SD, Retsch-Bogart G, Webster H, Davis M, Johnson RC, et al. Progression of Lung Disease in Preschool Patients with Cystic Fibrosis. Am J Respir Crit Care Med. 2017;195(9):1216–25.
  49. Stahl M, Wielpütz MO, Graeber SY, Joachim C, Sommerburg O, Kauczor HU, et al. Comparison of Lung Clearance Index and Magnetic Resonance Imaging for Assessment of Lung Disease in Children with Cystic Fibrosis. Am J Respir Crit Care Med. 2017;195(3):349–59.
  50. Amin R, Stanojevic S, Kane M, Webster H, Ratjen F. A randomized controlled trial to evaluate the lung clearance index as an outcome measure for early phase studies in patients with cystic fibrosis. Respir Med. 2016;112:59–64. doi:.https://doi.org/10.1016/j.rmed.2016.01.020
  51. Ramsey KA, Rosenow T, Turkovic L, Skoric B, Banton G, Adams AM, et al.; AREST CF. Lung Clearance Index and Structural Lung Disease on Computed Tomography in Early Cystic Fibrosis. Am J Respir Crit Care Med. 2016;193(1):60–7. doi:.https://doi.org/10.1164/rccm.201507-1409OC
  52. Davies J, Sheridan H, Bell N, Cunningham S, Davis SD, Elborn JS, 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. Lancet Respir Med. 2013;1(8):630–8. doi:.https://doi.org/10.1016/S2213-2600(13)70182-6
  53. Singer F, Kieninger E, Abbas C, Yammine S, Fuchs O, Proietti E, et al. Practicability of nitrogen multiple-breath washout measurements in a pediatric cystic fibrosis outpatient setting. Pediatr Pulmonol. 2013;48(8):739–46. doi:.https://doi.org/10.1002/ppul.22651
  54. Poncin W, Singer F, Aubriot AS, Lebecque P. Agreement between multiple-breath nitrogen washout systems in children and adults. J Cyst Fibros. 2017;16(2):258–66.
  55. Hülskamp G, Lum S, Stocks J, Wade A, Hoo AF, Costeloe K, et al. Association of prematurity, lung disease and body size with lung volume and ventilation inhomogeneity in unsedated neonates: a multicentre study. Thorax. 2009;64(3):240–5. doi:.https://doi.org/10.1136/thx.2008.101758
  56. Latzin P, Roth S, Thamrin C, Hutten GJ, Pramana I, Kuehni CE, et al. Lung volume, breathing pattern and ventilation inhomogeneity in preterm and term infants. PLoS One. 2009;4(2):e4635. doi:.https://doi.org/10.1371/journal.pone.0004635
  57. Yammine S, Schmidt A, Sutter O, Fouzas S, Singer F, Frey U, et al. Functional evidence for continued alveolarisation in former preterms at school age? Eur Respir J. 2016;47(1):147–55. doi:.https://doi.org/10.1183/13993003.00478-2015
  58. Boon M, Vermeulen FL, Gysemans W, Proesmans M, Jorissen M, De Boeck K. Lung structure-function correlation in patients with primary ciliary dyskinesia. Thorax. 2015;70(4):339–45. doi:.https://doi.org/10.1136/thoraxjnl-2014-206578
  59. Nyilas S, Schlegtendal A, Singer F, Goutaki M, Kuehni CE, Casaulta C, et al. Alternative inert gas washout outcomes in patients with primary ciliary dyskinesia. Eur Respir J. 2017;49(1):1600466. doi:.https://doi.org/10.1183/13993003.00466-2016
  60. Madsen A, Green K, Buchvald F, Hanel B, Nielsen KG. Aerobic fitness in children and young adults with primary ciliary dyskinesia. PLoS One. 2013;8(8):e71409. doi:.https://doi.org/10.1371/journal.pone.0071409
  61. Jarenbäck L, Ankerst J, Bjermer L, Tufvesson E. Acinar ventilation heterogeneity in COPD relates to diffusion capacity, resistance and reactance. Respir Med. 2016;110:28–33. doi:.https://doi.org/10.1016/j.rmed.2015.11.005
  62. Fuchs SI, Schwerk N, Pittschieler K, Ahrens F, Baden W, Bals R, et al. Lung clearance index for monitoring early lung disease in alpha-1-antitrypsin deficiency. Respir Med. 2016;116:93–9. doi:.https://doi.org/10.1016/j.rmed.2016.04.015
  63. Macleod KA, Horsley AR, Bell NJ, Greening AP, Innes JA, Cunningham S. Ventilation heterogeneity in children with well controlled asthma with normal spirometry indicates residual airways disease. Thorax. 2009;64(1):33–7. doi:.https://doi.org/10.1136/thx.2007.095018
  64. Fuchs SI, Buess C, Lum S, Kozlowska W, Stocks J, Gappa M. Multiple breath washout with a sidestream ultrasonic flow sensor and mass spectrometry: a comparative study. Pediatr Pulmonol. 2006;41(12):1218–25. doi:.https://doi.org/10.1002/ppul.20524
  65. Fuchs SI, Eder J, Ellemunter H, Gappa M. Lung clearance index: normal values, repeatability, and reproducibility in healthy children and adolescents. Pediatr Pulmonol. 2009;44(12):1180–5. doi:.https://doi.org/10.1002/ppul.21093
  66. Ellemunter H, Fuchs SI, Unsinn KM, Freund MC, Waltner-Romen M, Steinkamp G, et al. Sensitivity of Lung Clearance Index and chest computed tomography in early CF lung disease. Respir Med. 2010;104(12):1834–42. doi:.https://doi.org/10.1016/j.rmed.2010.06.010
  67. Verbanck S, Paiva M, Schuermans D, Malfroot A, Vincken W, Vanderhelst E. Acinar and conductive ventilation heterogeneity in severe CF lung disease: back to the model. Respir Physiol Neurobiol. 2013;188(2):124–32. doi:.https://doi.org/10.1016/j.resp.2013.05.011
  68. Yammine S, Singer F, Gustafsson P, Latzin P. Impact of different breathing protocols on multiple-breath washout outcomes in children. J Cyst Fibros. 2014;13(2):190–7. doi:.https://doi.org/10.1016/j.jcf.2013.08.010
  69. Banton GL, Hall GL, Tan M, Skoric B, Ranganathan SC, Franklin PJ, et al. Multiple breath washout cannot be used for tidal breath parameter analysis in infants. Pediatr Pulmonol. 2016;51(5):531–40. doi:.https://doi.org/10.1002/ppul.23326
  70. Jost K, Egger B, Kieninger E, Singer F, Frey U, Latzin P. Changes in minute ventilation after exposure to 4% sulfur hexafluoride (SF6 ) in infants. Pediatr Pulmonol. 2017;52(2):151–3. doi:.https://doi.org/10.1002/ppul.23557
  71. Jost K, Lenherr N, Singer F, Schulzke SM, Frey U, Latzin P, et al. Changes in breathing pattern upon 100% oxygen in children at early school age. Respir Physiol Neurobiol. 2016;228:9–15. doi:.https://doi.org/10.1016/j.resp.2016.03.006
  72. Schmalisch G, Wilitzki S, Bührer C, Fischer HS. The lung clearance index in young infants: impact of tidal volume and dead space. Physiol Meas. 2015;36(7):1601–13. doi:.https://doi.org/10.1088/0967-3334/36/7/1601
  73. Frey U, Stocks J, Sly P, Bates J ; European Respiratory Society/American Thoracic Society. Specification for signal processing and data handling used for infant pulmonary function testing. ERS/ATS Task Force on Standards for Infant Respiratory Function Testing. Eur Respir J. 2000;16(5):1016–22. doi:.https://doi.org/10.1183/09031936.00.16510160
  74. Foong RE, Rosenow T, Simpson SJ, Stöklin B, Gray D, Pillow JJ, et al. End-inspiratory molar mass step correction for analysis of infant multiple breath washout tests. Pediatr Pulmonol. 2017;52(1):10–3. doi:.https://doi.org/10.1002/ppul.23499
  75. Raaijmakers L, Jensen R, Stanojevic S, Ratjen F. Validation of multiple breath washout devices. J Cyst Fibros. 2017;S1569-1993(17)30018-8.
  76. Mahar RK, Vukcevic D, King L, Carlin JB, Ranganathan S. Lack of transparency in software used to analyze multiple breath washout data. Pediatr Pulmonol. 2016;51(11):1108–10. doi:.https://doi.org/10.1002/ppul.23420
  77. Anagnostopoulou P, Yammine S, Schmidt A, Korten I, Kieninger E, Mack I, et al. False normal Lung Clearance Index in infants with cystic fibrosis due to software algorithms. Pediatr Pulmonol. 2015;50(10):970–7. doi:.https://doi.org/10.1002/ppul.23256
  78. Lum S, Stocks J, Stanojevic S, Wade A, Robinson P, Gustafsson P, et al. Age and height dependence of lung clearance index and functional residual capacity. Eur Respir J. 2013;41(6):1371–7. doi:.https://doi.org/10.1183/09031936.00005512
  79. Benseler A, Stanojevic S, Jensen R, Gustafsson P, Ratjen F. Effect of equipment dead space on multiple breath washout measures. Respirology. 2015;20(3):459–66. doi:.https://doi.org/10.1111/resp.12470
  80. Subbarao P, Lu Z, Kowalik K, Brown M, Balkovec S, Gustafsson P, et al. Changes in multiple breath washout measures after raised volume rapid thoracoabdominal compression maneuvers in infants. Pediatr Pulmonol. 2016;51(2):183–8. doi:.https://doi.org/10.1002/ppul.23220
  81. Fuchs SI, Toussaint S, Edlhaimb B, Ballmann M, Gappa M. Short-term effect of physiotherapy on variability of the lung clearance index in children with cystic fibrosis. Pediatr Pulmonol. 2010;45(3):301–6.
  82. Pfleger A, Steinbacher M, Schwantzer G, Weinhandl E, Wagner M, Eber E. Short-term effects of physiotherapy on ventilation inhomogeneity in cystic fibrosis patients with a wide range of lung disease severity. J Cyst Fibros. 2015;14(5):627–31. doi:.https://doi.org/10.1016/j.jcf.2014.12.017
  83. Grosse-Onnebrink J, Mellies U, Olivier M, Werner C, Stehling F. Chest physiotherapy can affect the lung clearance index in cystic fibrosis patients. Pediatr Pulmonol. 2017;52(5):625–31. doi:.https://doi.org/10.1002/ppul.23670
  84. Singer F, Stern G, Thamrin C, Abbas C, Casaulta C, Frey U, et al. A new double-tracer gas single-breath washout to assess early cystic fibrosis lung disease. Eur Respir J. 2013;41(2):339–45. doi:.https://doi.org/10.1183/09031936.00044312
  85. Abbas C, Singer F, Yammine S, Casaulta C, Latzin P. Treatment response of airway clearance assessed by single-breath washout in children with cystic fibrosis. J Cyst Fibros. 2013;12(6):567–74. doi:.https://doi.org/10.1016/j.jcf.2013.05.010
  86. Singer F, Abbas C, Yammine S, Casaulta C, Frey U, Latzin P. Abnormal small airways function in children with mild asthma. Chest. 2014;145(3):492–9. doi:.https://doi.org/10.1378/chest.13-0784
  87. Verbanck S, Schuermans D, Meysman M, Paiva M, Vincken W. Noninvasive assessment of airway alterations in smokers: the small airways revisited. Am J Respir Crit Care Med. 2004;170(4):414–9. doi:.https://doi.org/10.1164/rccm.200401-037OC
  88. Mikamo M, Shirai T, Mori K, Shishido Y, Akita T, Morita S, et al. Predictors of phase III slope of nitrogen single-breath washout in COPD. Respir Physiol Neurobiol. 2013;189(1):42–6. doi:.https://doi.org/10.1016/j.resp.2013.06.018
  89. Husemann K, Berg N, Engel J, Port J, Joppek C, Tao Z, et al. Double tracer gas single-breath washout: reproducibility in healthy subjects and COPD. Eur Respir J. 2014;44(5):1210–22. doi:.https://doi.org/10.1183/09031936.00085713
  90. Boeck L, Gensmer A, Nyilas S, Stieltjes B, Re TJ, Tamm M, et al. Single-Breath Washout Tests to Assess Small Airway Disease in COPD. Chest. 2016;150(5):1091–100. doi:.https://doi.org/10.1016/j.chest.2016.05.019
  91. Nyilas S, Singer F, Kumar N, Yammine S, Meier-Girard D, Koerner-Rettberg C, et al. Physiological phenotyping of pediatric chronic obstructive airway diseases. J Appl Physiol (1985). 2016;121(1):324–32. doi:.https://doi.org/10.1152/japplphysiol.00086.2016
  92. Van Muylem A, Antoine M, Yernault JC, Paiva M, Estenne M. Inert gas single-breath washout after heart-lung transplantation. Am J Respir Crit Care Med. 1995;152(3):947–52. doi:.https://doi.org/10.1164/ajrccm.152.3.7663808
  93. Van Muylem A, Verbanck S, Estenne M. Monitoring the lung periphery of transplanted lungs. Respir Physiol Neurobiol. 2005;148(1-2):141–51. doi:.https://doi.org/10.1016/j.resp.2005.05.010
  94. Riise GC, Mårtensson G, Houltz B, Bake B. Prediction of BOS by the single-breath nitrogen test in double lung transplant recipients. BMC Res Notes. 2011;4(1):515. doi:.https://doi.org/10.1186/1756-0500-4-515
  95. Latzin P, Thompson B. Double tracer gas single-breath washout: promising for clinics or just a toy for research? Eur Respir J. 2014;44(5):1113–5. doi:.https://doi.org/10.1183/09031936.00111114
  96. Verbanck S, Paiva M. Dual gas techniques for peripheral airway function: diffusing the issues. Eur Respir J. 2015;45(5):1491–4. doi:.https://doi.org/10.1183/09031936.00207514
  97. Farrell PM. The prevalence of cystic fibrosis in the European Union. J Cyst Fibros. 2008;7(5):450–3. doi:.https://doi.org/10.1016/j.jcf.2008.03.007
  98. Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis. Thorax. 2008;63(2):129–34. doi:.https://doi.org/10.1136/thx.2007.077784
  99. Bush A, Sly PD. Evolution of cystic fibrosis lung function in the early years. Curr Opin Pulm Med. 2015;21(6):602–8. doi:.https://doi.org/10.1097/MCP.0000000000000209
  100. Gustafsson PM, Aurora P, Lindblad A. Evaluation of ventilation maldistribution as an early indicator of lung disease in children with cystic fibrosis. Eur Respir J. 2003;22(6):972–9. doi:.https://doi.org/10.1183/09031936.03.00049502
  101. Owens CM, Aurora P, Stanojevic S, Bush A, Wade A, Oliver C, et al.; London Cystic Fibrosis Collaboration. Lung Clearance Index and HRCT are complementary markers of lung abnormalities in young children with CF. Thorax. 2011;66(6):481–8. doi:.https://doi.org/10.1136/thx.2010.150375
  102. Hoo AF, Thia LP, Nguyen TT, Bush A, Chudleigh J, Lum S, et al.; London Cystic Fibrosis Collaboration. Lung function is abnormal in 3-month-old infants with cystic fibrosis diagnosed by newborn screening. Thorax. 2012;67(10):874–81. doi:.https://doi.org/10.1136/thoraxjnl-2012-201747
  103. Aurora P, Stanojevic S, Wade A, Oliver C, Kozlowska W, Lum S, et al.; London Cystic Fibrosis Collaboration. Lung clearance index at 4 years predicts subsequent lung function in children with cystic fibrosis. Am J Respir Crit Care Med. 2011;183(6):752–8. doi:.https://doi.org/10.1164/rccm.200911-1646OC
  104. Kieninger E, Singer F, Fuchs O, Abbas C, Frey U, Regamey N, et al. Long-term course of lung clearance index between infancy and school-age in cystic fibrosis subjects. J Cyst Fibros. 2011;10(6):487–90. doi:.https://doi.org/10.1016/j.jcf.2011.07.006
  105. O’Neill K, Bradley JM, Johnston E, McGrath S, McIlreavey L, Rowan S, et al. Reduced bacterial colony count of anaerobic bacteria is associated with a worsening in lung clearance index and inflammation in cystic fibrosis. PLoS One. 2015;10(5):e0126980. doi:.https://doi.org/10.1371/journal.pone.0126980
  106. Sonneveld N, Stanojevic S, Amin R, Aurora P, Davies J, Elborn JS, et al. Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations. Eur Respir J. 2015;46(4):1055–64. doi:.https://doi.org/10.1183/09031936.00211914
  107. Yammine S, Bigler A, Casaulta C, Singer F, Latzin P. Reasons for heterogeneous change in LCI in children with cystic fibrosis after antibiotic treatment. Thorax. 2014;69(2):183. doi:.https://doi.org/10.1136/thoraxjnl-2013-204283
  108. Kent L, Reix P, Innes JA, Zielen S, Le Bourgeois M, Braggion C, et al.; European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) Standardisation Committee. Lung clearance index: evidence for use in clinical trials in cystic fibrosis. J Cyst Fibros. 2014;13(2):123–38. doi:.https://doi.org/10.1016/j.jcf.2013.09.005
  109. Milla CE, Ratjen F, Marigowda G, Liu F, Waltz D, Rosenfeld M ; VX13-809-011 Part B Investigator Group. Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017;195(7):912–20.
  110. Subbarao P, Stanojevic S, Brown M, Jensen R, Rosenfeld M, Davis S, 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. Am J Respir Crit Care Med. 2013;188(4):456–60. doi:.https://doi.org/10.1164/rccm.201302-0219OC
  111. Amin R, Subbarao P, Jabar A, Balkovec S, Jensen R, Kerrigan S, et al. Hypertonic saline improves the LCI in paediatric patients with CF with normal lung function. Thorax. 2010;65(5):379–83. doi:.https://doi.org/10.1136/thx.2009.125831
  112. Amin R, Subbarao P, Lou W, Jabar A, Balkovec S, Jensen R, et al. The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis. Eur Respir J. 2011;37(4):806–12. doi:.https://doi.org/10.1183/09031936.00072510
  113. Panettieri RA, Jr, Covar R, Grant E, Hillyer EV, Bacharier L. Natural history of asthma: persistence versus progression-does the beginning predict the end? J Allergy Clin Immunol. 2008;121(3):607–13. doi:.https://doi.org/10.1016/j.jaci.2008.01.006
  114. Sonnappa S, Bastardo CM, Saglani S, Bush A, Aurora P. Relationship between past airway pathology and current lung function in preschool wheezers. Eur Respir J. 2011;38(6):1431–6. doi:.https://doi.org/10.1183/09031936.00164910
  115. Fischer HS, Puder LC, Wilitzki S, Usemann J, Bührer C, Godfrey S, et al. Relationship between computerized wheeze detection and lung function parameters in young infants. Pediatr Pulmonol. 2016;51(4):402–10. doi:.https://doi.org/10.1002/ppul.23310
  116. Sonnappa S, Bastardo CM, Wade A, Bush A, Stocks J, Aurora P. Repeatability and bronchodilator reversibility of lung function in young children. Eur Respir J. 2013;42(1):116–24. doi:.https://doi.org/10.1183/09031936.00076012
  117. From the Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA) 2016 [cited 2017 23 Feb.]; Available from: http://www.ginasthma.org/.
  118. Moeller A, Carlsen KH, Sly PD, Baraldi E, Piacentini G, Pavord I, et al.; ERS Task Force Monitoring Asthma in Children. Monitoring asthma in childhood: lung function, bronchial responsiveness and inflammation. Eur Respir Rev. 2015;24(136):204–15. doi:.https://doi.org/10.1183/16000617.00003914
  119. Horsley A. Lung clearance index in the assessment of airways disease. Respir Med. 2009;103(6):793–9. doi:.https://doi.org/10.1016/j.rmed.2009.01.025
  120. Verbanck S, Paiva M, Schuermans D, Hanon S, Vincken W, Van Muylem A. Relationships between the lung clearance index and conductive and acinar ventilation heterogeneity. J Appl Physiol (1985). 2012;112(5):782–90. doi:.https://doi.org/10.1152/japplphysiol.01221.2011
  121. Zwitserloot A, Fuchs SI, Müller C, Bisdorf K, Gappa M. Clinical application of inert gas Multiple Breath Washout in children and adolescents with asthma. Respir Med. 2014;108(9):1254–9. doi:.https://doi.org/10.1016/j.rmed.2014.07.003
  122. Hardaker KM, Downie SR, Kermode JA, Berend N, King GG, Salome CM. Ventilation heterogeneity is associated with airway responsiveness in asthma but not COPD. Respir Physiol Neurobiol. 2013;189(1):106–11. doi:.https://doi.org/10.1016/j.resp.2013.07.009
  123. Downie SR, Salome CM, Verbanck S, Thompson B, Berend N, King GG. Ventilation heterogeneity is a major determinant of airway hyperresponsiveness in asthma, independent of airway inflammation. Thorax. 2007;62(8):684–9. doi:.https://doi.org/10.1136/thx.2006.069682
  124. Farah CS, King GG, Brown NJ, Peters MJ, Berend N, Salome CM. Ventilation heterogeneity predicts asthma control in adults following inhaled corticosteroid dose titration. J Allergy Clin Immunol. 2012;130(1):61–8. doi:.https://doi.org/10.1016/j.jaci.2012.02.015
  125. Gustafsson PM. Peripheral airway involvement in CF and asthma compared by inert gas washout. Pediatr Pulmonol. 2007;42(2):168–76. doi:.https://doi.org/10.1002/ppul.20554
  126. Fuchs SI, Gappa M. Lung clearance index: clinical and research applications in children. Paediatr Respir Rev. 2011;12(4):264–70. doi:.https://doi.org/10.1016/j.prrv.2011.05.001
  127. Pillow JJ, Frerichs I, Stocks J. Lung function tests in neonates and infants with chronic lung disease: global and regional ventilation inhomogeneity. Pediatr Pulmonol. 2006;41(2):105–21. doi:.https://doi.org/10.1002/ppul.20319
  128. Hülskamp G, Pillow JJ, Dinger J, Stocks J. Lung function tests in neonates and infants with chronic lung disease of infancy: functional residual capacity. Pediatr Pulmonol. 2006;41(1):1–22. doi:.https://doi.org/10.1002/ppul.20318
  129. Lum S, Kirkby J, Welsh L, Marlow N, Hennessy E, Stocks J. Nature and severity of lung function abnormalities in extremely pre-term children at 11 years of age. Eur Respir J. 2011;37(5):1199–207. doi:.https://doi.org/10.1183/09031936.00071110
  130. Simpson SJ, Logie KM, O’Dea CA, Banton GL, Murray C, Wilson AC, et al. Altered lung structure and function in mid-childhood survivors of very preterm birth. Thorax. 2017;thoraxjnl-2016-208985. doi:.https://doi.org/10.1136/thoraxjnl-2016-208985
  131. Lucas JS, Barbato A, Collins SA, Goutaki M, Behan L, Caudri D, et al. European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia. Eur Respir J. 2017;49(1):1601090. doi:.https://doi.org/10.1183/13993003.01090-2016
  132. Marthin JK, Petersen N, Skovgaard LT, Nielsen KG. Lung function in patients with primary ciliary dyskinesia: a cross-sectional and 3-decade longitudinal study. Am J Respir Crit Care Med. 2010;181(11):1262–8. doi:.https://doi.org/10.1164/rccm.200811-1731OC
  133. Green K, Buchvald FF, Marthin JK, Hanel B, Gustafsson PM, Nielsen KG. Ventilation inhomogeneity in children with primary ciliary dyskinesia. Thorax. 2012;67(1):49–53. doi:.https://doi.org/10.1136/thoraxjnl-2011-200726
  134. Irving SJ, Ives A, Davies G, Donovan J, Edey AJ, Gill SS, et al. Lung clearance index and high-resolution computed tomography scores in primary ciliary dyskinesia. Am J Respir Crit Care Med. 2013;188(5):545–9. doi:.https://doi.org/10.1164/rccm.201304-0800OC
  135. Tai A, Tran H, Roberts M, Clarke N, Wilson J, Robertson CF. The association between childhood asthma and adult chronic obstructive pulmonary disease. Thorax. 2014;69(9):805–10. doi:.https://doi.org/10.1136/thoraxjnl-2013-204815
  136. McGeachie MJ, Yates KP, Zhou X, Guo F, Sternberg AL, Van Natta ML, et al.; CAMP Research Group. Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma. N Engl J Med. 2016;374(19):1842–52. doi:.https://doi.org/10.1056/NEJMoa1513737
  137. Swanney MP, Ruppel G, Enright PL, Pedersen OF, Crapo RO, Miller MR, et al. Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction. Thorax. 2008;63(12):1046–51. doi:.https://doi.org/10.1136/thx.2008.098483
  138. Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary. Eur Respir J. 2017;49(3):1700214. doi:.https://doi.org/10.1183/13993003.00214-2017
  139. Verbanck S, Schuermans D, Paiva M, Meysman M, Vincken W. Small airway function improvement after smoking cessation in smokers without airway obstruction. Am J Respir Crit Care Med. 2006;174(8):853–7. doi:.https://doi.org/10.1164/rccm.200603-422OC
  140. Brusasco V, Barisione G, Crimi E. Pulmonary physiology: future directions for lung function testing in COPD. Respirology. 2015;20(2):209–18. doi:.https://doi.org/10.1111/resp.12388
  141. Reynaud-Gaubert M, Thomas P, Badier M, Cau P, Giudicelli R, Fuentes P. Early detection of airway involvement in obliterative bronchiolitis after lung transplantation. Functional and bronchoalveolar lavage cell findings. Am J Respir Crit Care Med. 2000;161(6):1924–9. doi:.https://doi.org/10.1164/ajrccm.161.6.9905060
  142. Thompson BR, Ellis MJ, Stuart-Andrews C, Lopez M, Kedarisetty S, Snell GI, et al. Early bronchiolitis obliterans syndrome shows an abnormality of perfusion not ventilation in lung transplant recipients. Respir Physiol Neurobiol. 2015;216:28–34. doi:.https://doi.org/10.1016/j.resp.2015.05.003
  143. Lahzami S, Schoeffel RE, Pechey V, Reid C, Greenwood M, Salome CM, et al. Small airways function declines after allogeneic haematopoietic stem cell transplantation. Eur Respir J. 2011;38(5):1180–8. doi:.https://doi.org/10.1183/09031936.00018311
  144. Stafler P, Weinreb S, Mussaffi H, Mei-Zahav M, Prais D, Steuer G, et al. Feasibility of multiple breath washout measurements in infants with bronchiolitis: A pilot study. Pediatr Pulmonol. 2017;52(6):763–70. doi:.https://doi.org/10.1002/ppul.23674
  145. Sigurs N, Aljassim F, Kjellman B, Robinson PD, Sigurbergsson F, Bjarnason R, et al. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax. 2010;65(12):1045–52. doi:.https://doi.org/10.1136/thx.2009.121582
  146. ClinicalTrials.gov. [cited 2017 23 February]; Available from: https://clinicaltrials.gov.
  147. EU Clinical Trials Register. [cited 2017 23 February]; Available from: https://www.clinicaltrialsregister.eu.
  148. A Study to Evaluate the Efficacy and Safety of Lumacaftor in Combination With Ivacaftor in Subjects With CF, Homozygous for the F508del-CFTR Mutation. [cited 2017 06 March]; Available from: https://clinicaltrials.gov/ct2/show/NCT02514473.
  149. A Study to Evaluate Efficacy and Safety of Ivacaftor in Subjects With Cystic Fibrosis Aged 3 Through 5 Years Who Have a Specified CFTR Gating Mutation. [cited 2017 07 March]; Available from: https://clinicaltrials.gov/ct2/show/NCT02742519.
  150. A Study to Evaluate Efficacy of Ivacaftor in Subjects With Cystic Fibrosis Who Have a 3849 + 10KB C→T or D1152H CFTR Mutation. [cited 2017 07 March]; Available from: https://clinicaltrials.gov/ct2/show/NCT03068312.
  151. Kobbernagel HE, Buchvald FF, Haarman EG, Casaulta C, Collins SA, Hogg C, et al. Study protocol, rationale and recruitment in a European multi-centre randomized controlled trial to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in primary ciliary dyskinesia. BMC Pulm Med. 2016;16(1):104. doi:.https://doi.org/10.1186/s12890-016-0261-x
  152. Effects of QVAR in Smokers With Asthma (OLiVIA). [cited 2017 23 February]; Available from: https://clinicaltrials.gov/ct2/show/NCT01741285
  153. Changes in the Lung Clearance Index in Pediatric Patients With Asthma. [cited 2017 23 February]; Available from: https://clinicaltrials.gov/ct2/show/NCT02678949.
  154. A Randomized-Controlled Trial of Inhaled Hypertonic Saline (7%) to Evaluate the Lung Clearance Index. [cited 2017 23 February]; Available from: https://clinicaltrials.gov/ct2/show/NCT02276898.
  155. Measures of Respiratory Health (MRH). [cited 2017 23 February]; Available from: https://clinicaltrials.gov/ct2/show/NCT02657837.
  156. Evaluation of Novel Lung Function Parameters in Patients With Interstitial Lung Disease (ILD). [cited 2017 23 February]; Available from: https://clinicaltrials.gov/ct2/show/NCT02827734.

Most read articles by the same author(s)