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

doi:10.1183/23120541.00094-2017

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FIGURE 1
Flowchart of children with cystic fibrosis and healthy children enrolled in this study. MBW: multiple-breath washout.
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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.

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 trials		Two acceptable trials
	CF	Healthy	CF	Healthy	CF	Healthy
Subjects	71	47	49	36	22	11
Test occasions	104	61	66	42	38	19
Age years	5.1±1.0	4.8±1.1	5.0±1.0	4.8±1.1	5.1±1.0	5.0±0.8
Male	31 (44)	22 (54)	27 (43)	19 (53)	15 (39)	6 (55)
Height cm	109.9±8.8	108.8±8.2	109.7±8.8	108.8±8.2	108.4±8.9	111.1±7.1
Weight kg	19.4±3.7	19.2±3.9	19.7±3.8	19.2±3.9	18.9±3.5	21.0±5.1
Height z-score	−0.08±1.0	0.17±1.0	0.04±1.1	0.09±1.1	−0.27±0.95	0.34±0.95
Weight z-score	0.32±0.89	0.51±1.2	0.44±0.93	0.34±1.0	0.12±0.78	0.84±1.5
Multiple-breath washout test
Functional residual capacity L	0.88±0.23	0.85±0.18	0.87±0.25	0.87±0.17	0.89±0.21	0.94±0.17
Lung clearance index	8.13±1.54	7.10±0.60***	8.19±1.50	6.84±0.63***	8.05±1.66	6.69±0.48***
First moment ratio	1.78±0.31	1.65±0.12***	1.81±0.31	1.58±0.14***	1.75±0.32	1.52±0.10**
Second moment ratio	6.91±2.79	5.54±0.87***	7.11±2.83	5.07±0.97***	6.63±2.82	4.62±0.59**
Respiratory infection
Any infection	47/97 (48)		24/60 (40)		23/37 (62)*
Infection with a pro-inflammatory pathogen	32/97 (33)		17/60 (28)		15/38 (39)
Inflammation
Total cell count ×10⁶ mL⁻¹	8.13±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 present	32/92 (35)		18/55 (33)		14/37 (38)
Neutrophil elastase ng·mL⁻¹	874.4±2155.0		904.7±2067.6		1231.1±3127.9
Interleukin-8 pg·mL⁻¹	3227.34±7826.1		4228.2±9674.7		1454.7±2118.0
Structural lung disease
Bronchiectasis present	46/65 (71)		33/49 (67)		13/16 (81)
Bronchiectasis extent %	1.25±2.89		1.11±2.51		1.67±4.09
Air trapping present	52/65 (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 years	Cystic fibrosis		Healthy
Age years	Three or more acceptable trials	Two or more acceptable trials	Three or more acceptable trials	Two or more acceptable trials
3	7/21 (33)	14/21 (67)*	10/14 (71)	13/14 (93)
4	18/38 (47)	27/38 (71)*	9/17 (53)	15/17 (88)*
5	22/49 (45)	35/49 (71)**	14/26 (54)	22/26 (85)*
6		28/41 (68)*	9/15 (60)	11/15 (73)
Overall	66/149 (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 index		First moment ratio		Second moment ratio
	All trials	First two trials	All trials	First two trials	All trials	First two trials
MBW outcomes	8.19±1.50	8.19±1.46	1.81±0.31	1.80±0.30	7.11±2.83	7.04±2.84
Pulmonary inflammation
Total cell count	0.35 (−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 cells	0.38 (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 concentration	0.28 (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 concentration	0.31 (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
%Dis	0.08 (−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)
%Bx	0.07 (−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)
%TA	0.03 (−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 index		First moment ratio		Second moment ratio
	Three or more acceptable trials	Two or more acceptable trials	Three or more acceptable trials	Two or more acceptable trials	Three or more acceptable trials	Two or more acceptable trials
Pulmonary inflammation
Total cell counts	0.40 (−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 cells	0.40 (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 concentration	0.29 (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 concentration	0.32 (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
%Dis	0.07 (−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)
%Bx	0.06 (−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)
%TA	0.04 (−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 index		First moment ratio		Second moment ratio
	Three or more acceptable trials	Two or more acceptable trials	Three or more acceptable trials	Two or more acceptable trials	Three or more acceptable trials	Two 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)