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The clinical utility of lung clearance index in early cystic fibrosis lung disease is not impacted by the number of multiple-breath washout trials

Rachel E. Foong, Alana J. Harper, Billy Skoric, Louise King, Lidija Turkovic, Miriam Davis, Charles C. Clem, Tim Rosenow, Stephanie D. Davis, Sarath Ranganathan, Graham L. Hall, Kathryn A. Ramsey on behalf of AREST CF
ERJ Open Research 2018 4: 00094-2017; DOI: 10.1183/23120541.00094-2017
Rachel E. Foong
1Telethon Kids Institute, Subiaco, Australia
2The Hospital for Sick Children, Toronto, ON, Canada
3School of Physiotherapy and Exercise Science, Curtin University, Bentley, Australia
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Alana J. Harper
1Telethon Kids Institute, Subiaco, Australia
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Billy Skoric
4Murdoch Children's Research Institute, Parkville, Australia
5Dept of Respiratory Medicine, The Royal Children's Hospital, Parkville, Australia
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Louise King
4Murdoch Children's Research Institute, Parkville, Australia
5Dept of Respiratory Medicine, The Royal Children's Hospital, Parkville, Australia
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Lidija Turkovic
1Telethon Kids Institute, Subiaco, Australia
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Miriam Davis
6Section of Pediatric Pulmonology, Allergy and Sleep Medicine, Dept of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA
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Charles C. Clem
6Section of Pediatric Pulmonology, Allergy and Sleep Medicine, Dept of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA
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Tim Rosenow
1Telethon Kids Institute, Subiaco, Australia
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Stephanie D. Davis
6Section of Pediatric Pulmonology, Allergy and Sleep Medicine, Dept of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA
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Sarath Ranganathan
5Dept of Respiratory Medicine, The Royal Children's Hospital, Parkville, Australia
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Graham L. Hall
1Telethon Kids Institute, Subiaco, Australia
3School of Physiotherapy and Exercise Science, Curtin University, Bentley, Australia
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  • For correspondence: Graham.Hall@telethonkids.org.au
Kathryn A. Ramsey
1Telethon Kids Institute, Subiaco, Australia
7Paediatric Respiratory Medicine, Inselspital, University of Bern, Bern, Switzerland
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  • FIGURE 1
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    FIGURE 1

    Flowchart of children with cystic fibrosis and healthy children enrolled in this study. MBW: multiple-breath washout.

  • FIGURE 2
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    FIGURE 2

    Differences in a) functional residual capacity (FRC) and b) lung clearance index (LCI) when using all trials in comparison with only the first two trials from children who completed three or more acceptable trials. A paired t-test was performed to compare the differences in FRC and LCI values.

Tables

  • Figures
  • Supplementary Materials
  • TABLE 1

    Demographics of children with cystic fibrosis (CF) and healthy children for all visits with two or more acceptable multiple-breath washout (MBW) trials, visits with three or more acceptable MBW trials and visits with only two acceptable MBW trials obtained within a single testing session

    All visits (two or more acceptable trials)Three or more acceptable trialsTwo acceptable trials
    CFHealthyCFHealthyCFHealthy
    Subjects714749362211
    Test occasions1046166423819
    Age years5.1±1.04.8±1.15.0±1.04.8±1.15.1±1.05.0±0.8
    Male31 (44)22 (54)27 (43)19 (53)15 (39)6 (55)
    Height cm109.9±8.8108.8±8.2109.7±8.8108.8±8.2108.4±8.9111.1±7.1
    Weight kg19.4±3.719.2±3.919.7±3.819.2±3.918.9±3.521.0±5.1
    Height z-score−0.08±1.00.17±1.00.04±1.10.09±1.1−0.27±0.950.34±0.95
    Weight z-score0.32±0.890.51±1.20.44±0.930.34±1.00.12±0.780.84±1.5
    Multiple-breath washout test
     Functional residual capacity L0.88±0.230.85±0.180.87±0.250.87±0.170.89±0.210.94±0.17
     Lung clearance index8.13±1.547.10±0.60***8.19±1.506.84±0.63***8.05±1.666.69±0.48***
     First moment ratio1.78±0.311.65±0.12***1.81±0.311.58±0.14***1.75±0.321.52±0.10**
     Second moment ratio6.91±2.795.54±0.87***7.11±2.835.07±0.97***6.63±2.824.62±0.59**
    Respiratory infection
     Any infection47/97 (48)24/60 (40)23/37 (62)*
     Infection with a pro-inflammatory pathogen32/97 (33)17/60 (28)15/38 (39)
    Inflammation      
     Total cell count ×106 mL−18.13±14.0 8.93±17.2 6.32±5.16 
     Macrophages %75.1±23.4 76.2±23.1 79.8±18.3 
     Neutrophils %23.3±23.0 23.0±23.1 19.3±18.8 
     Neutrophil elastase present32/92 (35) 18/55 (33) 14/37 (38) 
     Neutrophil elastase ng·mL−1874.4±2155.0 904.7±2067.6 1231.1±3127.9 
     Interleukin-8 pg·mL−13227.34±7826.1 4228.2±9674.7 1454.7±2118.0 
    Structural lung disease      
     Bronchiectasis present46/65 (71) 33/49 (67) 13/16 (81) 
     Bronchiectasis extent %1.25±2.89 1.11±2.51 1.67±4.09 
     Air trapping present52/65 (80) 35/49 (71) 13/16 (81) 
     Air trapping extent %5.10±10.1 4.65±8.04 6.14±15.5 
     Structural lung disease extent %4.04±3.56 3.96±2.69 3.91±5.68 

    Data are presented as n, mean±sd, n (%) or n/N (%). z-scores for height and weight were calculated using World Health Organization Child Growth Standards [16, 17]. Demographics and MBW outcomes were compared between children with CF and healthy children; MBW outcomes, demographics and clinical data were compared between visits with three or more acceptable trials and visits with only two acceptable trials. *: p<0.05; **: p<0.01; ***: p<0.001.

    • TABLE 2

      Success rates of obtaining acceptable and repeatable multiple-breath washout measurements in pre-school-aged children when three or more trials or two or more trials were deemed acceptable

      Age yearsCystic fibrosisHealthy
      Three or more acceptable trialsTwo or more acceptable trialsThree or more acceptable trialsTwo or more acceptable trials
      37/21 (33)14/21 (67)*10/14 (71)13/14 (93)
      418/38 (47)27/38 (71)*9/17 (53)15/17 (88)*
      522/49 (45)35/49 (71)**14/26 (54)22/26 (85)*
      628/41 (68)*9/15 (60)11/15 (73)
      Overall66/149 (44)104/149 (70)***42/72 (58)61/72 (85)***

      Data are presented as n/N (%). The Chi-squared test was used to compare differences in proportions between visits with three or more acceptable trials and two or more acceptable trials. *: p<0.05; **: p<0.01; ***: p<0.001.

      • TABLE 3

        Relationship between multiple-breath washout (MBW) test outcomes with inflammation and structural lung disease in children with cystic fibrosis when MBW outcomes were calculated from all trials obtained compared with the first two trials obtained in visits with three or more acceptable trials

        Lung clearance indexFirst moment ratioSecond moment ratio
        All trialsFirst two trialsAll trialsFirst two trialsAll trialsFirst two trials
        MBW outcomes8.19±1.508.19±1.461.81±0.311.80±0.307.11±2.837.04±2.84
        Pulmonary inflammation
         Total cell count0.35 (−0.04–0.75)0.40 (−0.01–0.80)0.06 (−0.02–0.14)0.08 (−0.01–0.17)0.50 (−0.21–1.22)0.65 (−0.11–1.41)
         Neutrophil cells0.38 (0.12–0.63)*0.40 (0.14–0.66)*0.07 (0.01–0.12)*0.07 (0.01–0.13)*0.55 (0.07–1.03)*0.58 (0.06–1.10)*
         Neutrophil elastase concentration0.28 (0.04–0.53)*0.29 (0.04–0.54)*0.06 (0.01–0.11)*0.07 (0.01–0.12)*0.49 (0.05–0.93)*0.56 (0.08–1.03)*
         Interleukin-8 concentration0.31 (0.08–0.53)*0.32 (0.09–0.55)*0.05 (0.01–0.10)*0.06 (0.01–0.11)*0.45 (0.04–0.87)*0.48 (0.04–0.93)*
        Structural lung disease
         %Dis0.08 (−0.06–0.23)0.07 (−0.08–0.22)0.02 (−0.01–0.05)0.02 (−0.02–0.05)0.13 (−0.14–0.39)0.12 (−0.17–0.41)
         %Bx0.07 (−0.09–0.23)0.06 (−0.10–0.22)0.01 (−0.02–0.04)0.01 (−0.02–0.05)0.10 (−0.19–0.39)0.08 (−0.23–0.40)
         %TA0.03 (−0.02–0.08)0.04 (−0.01–0.09)0.01 (−0.01–0.01)0.01 (−0.01–0.02)0.05 (−0.04–0.14)0.06 (−0.03–0.16)

        The raw MBW outcomes are presented, and the coefficients for the linear mixed effects model (adjusted for test centre) for associations with markers of pulmonary inflammation and structural lung disease are presented with 95% confidence intervals. %Dis: volume proportion of the lung with airway disease; %Bx: volume proportion of the lung with bronchiectasis; %TA: volume proportion of the lung with trapped air. *: p<0.05.

        • TABLE 4

          Group comparisons for the relationship between multiple-breath washout test outcomes with inflammation and structural lung disease in children with cystic fibrosis when results from the first two trials of children who could perform three or more acceptable trials# were compared with children who could perform two or more acceptable trials¶

          Lung clearance indexFirst moment ratioSecond moment ratio
          Three or more acceptable trialsTwo or more acceptable trialsThree or more acceptable trialsTwo or more acceptable trialsThree or more acceptable trialsTwo or more acceptable trials
          Pulmonary inflammation
           Total cell counts0.40 (−0.01–0.80)0.66 (0.34–0.98)***0.08 (−0.01–0.17)0.13 (0.06–0.20)***0.65 (−0.11–1.41)1.08 (0.49–1.68)***
           Neutrophil cells0.40 (0.14–0.66)*0.44 (0.21–0.67)***0.07 (0.01–0.13)*0.08 (0.03–0.13)**0.58 (0.06–1.10)*0.72 (0.30–1.14)**
           Neutrophil elastase concentration0.29 (0.04–0.54)*0.29 (0.10–0.48)***0.07 (0.01–0.12)*0.06 (0.02–0.10)**0.56 (0.08–1.03)*0.53 (0.19–0.86)**
           Interleukin-8 concentration0.32 (0.09–0.55)*0.25 (0.08–0.42)**0.06 (0.01–0.11)*0.05 (0.01–0.08)**0.48 (0.04–0.93)*0.40 (0.10–0.71)**
          Structural lung disease
           %Dis0.07 (−0.08–0.22)0.09 (−0.01–0.19)0.02 (−0.02–0.05)0.02 (−0.01–0.04)0.12 (−0.17–0.41)0.14 (−0.05–0.33)
           %Bx0.06 (−0.10–0.22)0.07 (−0.06–0.20)0.01 (−0.02–0.05)0.01 (−0.01–0.04)0.08 (−0.23–0.40)0.10 (−0.13–0.34)
           %TA0.04 (−0.01–0.09)0.03 (−0.01–0.07)0.01 (−0.01–0.02)0.01 (−0.01–0.01)0.06 (−0.03–0.16)0.05 (−0.01–0.12)

          The coefficient for the linear mixed effects model (adjusted for test centre) is presented with 95% confidence intervals. %Dis: volume proportion of the lung with airway disease; %Bx: volume proportion of the lung with bronchiectasis; %TA: volume proportion of the lung with trapped air. #: n=49; ¶: n=71. *: p<0.05; **: p<0.01; ***: p<0.001.

          • TABLE 5

            Ability of the multiple-breath washout test to detect the presence of neutrophil elastase, respiratory infections and structural lung disease in pre-school children with cystic fibrosis who achieved three or more and two or more acceptable trials

            Lung clearance indexFirst moment ratioSecond moment ratio
            Three or more acceptable trialsTwo or more acceptable trialsThree or more acceptable trialsTwo or more acceptable trialsThree or more acceptable trialsTwo or more acceptable trials
            Neutrophil elastase
             Sensitivity %83 (59–96)83 (59–96)89 (65–99)89 (65–99)89 (65–99)89 (65–99)
             Specificity %61 (43–76)64 (46–79)61 (43–76)64 (46–79)47 (31–64)47 (30–65)
            Respiratory infection
             Sensitivity %67 (43–85)70 (47–87)67 (43–85)74 (54–87)71 (48–89)83 (63–93)
             Specificity %58 (39–75)56 (38–72)58 (39–75)53 (37–68)42 (25–61)42 (27–58)
            Bronchiectasis
             Sensitivity %66 (46–82)70 (51–85)65 (46–82)69 (50–84)83 (64–94)84 (67–95)
             Specificity %59 (33–82)69 (41–89)59 (33–82)63 (35–85)53 (28–77)63 (35–85)

            Data are presented as median (range).

            Supplementary Materials

            • Figures
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            • Supplementary Material

              S.D. Davis 00094-2017_Davis

              R.E. Foong 00094-2017_Foong

              G.L. Hall 00094-2017_Hall

              T. Rosenow 00094-2017_Rosenow

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            The clinical utility of lung clearance index in early cystic fibrosis lung disease is not impacted by the number of multiple-breath washout trials
            Rachel E. Foong, Alana J. Harper, Billy Skoric, Louise King, Lidija Turkovic, Miriam Davis, Charles C. Clem, Tim Rosenow, Stephanie D. Davis, Sarath Ranganathan, Graham L. Hall, Kathryn A. Ramsey
            ERJ Open Research Jan 2018, 4 (1) 00094-2017; DOI: 10.1183/23120541.00094-2017

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            The clinical utility of lung clearance index in early cystic fibrosis lung disease is not impacted by the number of multiple-breath washout trials
            Rachel E. Foong, Alana J. Harper, Billy Skoric, Louise King, Lidija Turkovic, Miriam Davis, Charles C. Clem, Tim Rosenow, Stephanie D. Davis, Sarath Ranganathan, Graham L. Hall, Kathryn A. Ramsey
            ERJ Open Research Jan 2018, 4 (1) 00094-2017; DOI: 10.1183/23120541.00094-2017
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