Diaphragm Ultrasound is an Imaging Biomarker that Distinguishes Exacerbation Status from Stable Chronic Obstructive Pulmonary Disease

Figures & data

Table 1 Patient Demographics

	Stable (n=33)	AE (n=22)	p-value
Age (years), mean ± SD	73.5 ± 8.3	72.6 ± 11.6	0.897*
Male sex, n (%)	23 (69.7)	18 (81.8)	0.361
mCCI (points), mean ± SD	0.7 ± 0.9	1.4 ± 1.6	0.078*
BMI (kg/m^2), mean ± SD	24.2 ± 3.8	20.9 ± 4.0	0.003
CAT (points), mean ± SD	13.7 ± 6.9	25.4 ± 8.2	< 0.001
mMRC (points), mean ± SD	1.7 ± 1.2	3.1 ± 1.0	< 0.001
Smoking, n (%)
Never	11 (33.3)	11 (50.0)	0.040
Ex-smoker	14 (42.4)	11 (50.0)
Current smoker	8 (24.2)	0 (0.0)
Pack-years, mean ± SD	28.3 ± 24.5	22.3 ± 25.5	0.387
Duration of COPD (years), mean ± SD	5.1 ± 4.4	5.4 ± 6.1	0.839
GOLD group, n (%)
A	14 (42.4)	0 (0.0)	< 0.001
B	10 (30.3)	7 (31.8)
C	5 (15.2)	0 (0.0)
D	4 (12.1)	15 (68.2)
Baseline COPD medication, n (%)
None	2 (6.1)	2 (9.1)	0.255
LABA or LAMA	1 (3.0)	0 (0.0)
ICS/LABA	5 (15.1)	0 (0.0)
LABA/LAMA	12 (36.4)	7 (31.8)
ICS/LABA/LAMA	13 (39.4)	13 (59.1)
DT (mm), mean ± SD
At end-expiration	17.0 ± 6.0	18.9 ± 7.4	0.542*
At tidal inspiration	24.5 ± 7.9	24.9 ± 11.3	0.862*
At maximal deep inspiration	41.8 ± 14.9	35.7 ± 14.1	0.151
TF of diaphragm (%), mean ± SD
At tidal inspiration	51.3 ± 51.0	42.3 ± 45.3	0.523
At maximal deep inspiration	158.4 ± 83.5	94.8 ± 81.4	0.010
DE (mm), mean ± SD
At tidal inspiration	19.6 ± 5.4	20.9 ± 8.7	1.000*
At maximal deep inspiration	40.5 ± 12.5	30.8 ± 11.1	0.007
Lung function test, mean ± SD
FEV1/FVC (%)	52.5 ± 14.9	52.0 ± 17.4	0.922*
FVC (L)	2.82 ± 0.93	2.11 ± 0.81	0.006
FVC (%)	73.2 ± 16.1	55.0 ± 18.6	< 0.001
FEV1 (L)	1.42 ± 0.52	1.00 ± 0.38	0.002
FEV1 (%)	54.6 ± 19.4	40.5 ± 18.1	0.010
RV/TLC (%)	43.7 ± 8.1	51.7 ± 9.4	0.019

Note: *Mann–Whitney U-test.

Abbreviations: SD, standard deviation; mCCI, modified Charlson Comorbidity Index; BMI, body mass index; CAT, COPD assessment test; mMRC, modified Medical Research Council; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; LABA, long-acting β agonist; LAMA, long-acting muscarinic antagonist; ICS, inhaled corticosteroid; DT, diaphragm thickness; TF, thickening fraction; DE, diaphragm excursion; FEV₁, forced expiratory volume in 1 sec; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity.

Table 2 Results of the Receiver Operating Characteristic Curve Analysis for COPD Exacerbation

	AUC	95% CI	Cut-Off Values	p-value	Sensitivity	Specificity
TFmax	0.745	0.605–0.856	≤ 93.8%	0.001	68.4%	78.8%
DEmax	0.721	0.576–0.838	≤44.9 mm	0.003	95.2%	44.8%
FEV1/FVC	0.508	0.368–0.647	≤64%	0.927	57.1%	21.2%
FVC	0.709	0.570–0.825	≤1.78 L	0.003	47.6%	87.9%
FEV1	0.747	0.610–0.855	≤1.21 L	< 0.001	85.7%	57.6%
BMI	0.729	0.592–0.840	≤22.5 kg/m^2	0.002	77.3%	66.7%

Abbreviations: COPD, chronic obstructive pulmonary disease; AUC, area under curve; CI, confidence interval; TF_max, thickening fraction at maximal inspiration; DE_max, diaphragm excursion at maximal inspiration; FEV₁, forced expiratory volume in 1 sec; FVC, forced vital capacity; BMI, body mass index.

Figure 1 Receiver operating characteristic (ROC) curve analysis for determining chronic obstructive pulmonary disease exacerbation status using diaphragm ultrasound findings. The ROC curve for distinguishing exacerbation from a stable status indicated that the outcomes were fair. The area under the curve (AUC) of the thickening fraction during maximal deep breathing (TF_max) was 0.745. The AUC of diaphragm excursion during maximal deep breathing (DE_max) was 0.721. No significant difference was observed between TF_max and DE_max for distinguishing exacerbation status (p = 0.608).

Abbreviations: TF, thickening fraction at maximal inspiration; DE, diaphragm excursion at maximal inspiration.

Figure 2 Multiple comparative analysis of the receiver operating characteristic (ROC) curve between diaphragm thickening, diaphragm excursion, lung function, and body mass index (BMI). The ROC curve of thickening fraction of diaphragm during maximal breathing (TF_max) (A) and diaphragm excursion during maximal breathing (DE_max) (B) showed in Figure 2. (C) There was no significant difference for distinguishing exacerbation both in TF_max and DE_max compared to those of forced vital capacity (FVC), forced expiratory volume in 1 second (FEV₁), and BMI in multiple comparative analysis of the ROC curve analysis.

Abbreviations: BMI, body mass index; TF_max, thickening fraction at maximal inspiration; DE_max, diaphragm excursion at maximal inspiration; FVC, forced vital capacity; FEV₁, forced expiratory volume in 1 sec.

Table 3 Clinical Characteristics of COPD Patients According to Diaphragm Ultrasound Findings

	TFmax			DEmax
	Low (n=19)	High (n=34)	p-value	Low (n=36)	High (n=14)	p-value
Age (years), mean ± SD	71.3 ± 12.9	74.2 ± 7.7	0.315	72.9 ± 10.0	73.9 ± 9.4	0.755
Male sex, n (%)	15 (78.9)	24 (70.6)	0.746	25 (69.4)	12 (85.7)	0.303
mCCI (points), mean ± SD	1.1 ± 1.5	0.8 ± 1.0	0.411	0.9 ± 1.1	0.5 ± 0.9	0.389
BMI (kg/m^2), mean ± SD	22.4 ± 4.9	22.9 ± 3.8	0.689	22.1 ± 4.4	24.3 ± 3.4	0.237
CAT (points), mean ± SD	20.5 ± 7.1	16.2 ± 9.7	0.167	19.2 ± 9.6	13.9 ± 8.2	0.089
mMRC (points), mean ± SD	2.7 ± 1.2	2.0 ± 1.3	0.061	2.5 ± 1.2	1.7 ± 1.4	0.055
Smoking, n (%)
Never	9 (47.4)	13 (38.2)	0.325	18 (50.0)	2 (14.3)	0.052
Ex-smoker	9 (47.4)	14 (41.2)		14 (38.9)	8 (57.1)
Current smoker	1 (5.3)	7 (20.6)		4 (11.1)	4 (28.6)
Pack-years, mean ± SD	23.2 ± 27.5	25.7 ± 23.2	0.727	23.9 ± 27.5	32.3 ± 17.4	0.209
Duration of COPD (years), mean ± SD	6.7 ± 5.9	4.7 ± 4.5	0.190	5.4 ± 5.3	5.1 ± 5.3	0.838
GOLD group, n (%)
A	1 (5.3)	13 (38.2)	0.044	6 (16.7)	7 (50.0)	0.009
B	6 (31.6)	10 (29.4)		11 (30.6)	3 (21.4)
C	2 (10.5)	3 (8.8)		2 (5.6)	3 (21.4)
D	10 (52.6)	8 (23.5)		17 (47.2)	1 (7.1)
Baseline COPD medication, n (%)
None	0 (0.0)	3 (8.8)	0.111	3 (8.3)	0 (0.0)	0.005
LABA or LAMA	1 (5.3)	0 (0.0)		0 (0.0)	1 (7.1)
ICS/LABA	0 (0.0)	5 (14.7)		0 (0.0)	4 (28.6)
LABA/LAMA	6 (31.6)	12 (35.3)		14 (38.9)	4 (28.6)
ICS/LABA/LAMA	12 (63.2)	14 (41.2)		19 (52.8)	5 (35.7)
Lung function test, mean ± SD
FEV1/FVC (%)	53.9 ± 15.4	51.3 ± 16.4	0.569	51.0 ± 16.4	53.6 ± 15.9	0.619
FVC (L)	2.20 ± 0.92	2.72 ± 0.94	0.060	2.20 ± 0.83	3.08 ± 0.83	0.002
FVC (%)	55.8 ± 17.7	71.6 ± 18.4	0.004	59.7 ± 18.9	77.3 ± 14.7	0.003
FEV1 (L)	1.13 ± 0.50	1.31 ± 0.51	0.232	1.026 ± 0.32	1.60 ± 0.59	< 0.001
FEV1 (%)	44.6 ± 21.2	51.4 ± 19.7	0.254	41.9 ± 15.7	60.9 ±23.2	0.002
RV/TLC (%)	51.9 ± 10.8	44.8 ± 7.0	0.044	50.4 ± 8.1	41.5 ± 7.7	0.014
Exacerbation status, n (%)	12 (63.2)	8 (23.5)	0.007	20 (55.6)	1 (7.1)	0.003

Abbreviations: COPD, chronic obstructive pulmonary disease; AUC, area under curve; CI, confidence interval; TF_max, thickening fraction at maximal inspiration; DE_max, diaphragm excursion at maximal inspiration; mCCI, modified Charlson Comorbidity Index; BMI, body mass index; CAT, COPD assessment test; mMRC, modified Medical Research Council; GOLD, Global Initiative for Chronic Obstructive Lung Disease; LABA, long-acting β agonist; LAMA, long-acting muscarinic antagonist; ICS, inhaled corticosteroid; FEV₁, forced expiratory volume in 1 sec; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity.

Table 4 Logistic Regression Analysis for Estimating Exacerbation of Chronic Obstructive Pulmonary Diseases

Model 1	Univariate		Multivariate
	p-value	OR (95% CI)	p-value	OR (95% CI)
Age	0.722	0.99 (0.94–1.05)	0.682	0.98 (0.91–1.06)
Male sex	0.317	1.96 (0.53–7.28)	0.544	1.74 (0.29–10.34)
mCCI	0.049	1.62 (1.00–2.62)	0.157	1.73 (0.81–3.70)
BMI	0.007	0.80 (0.68–0.94)	0.002	0.70 (0.56–0.88)
Low TFmax	0.006	5.57 (1.64–18.94)	0.014	8.40 (1.55–45.56)
Model 2	Univariate		Multivariate
Age	0.722	0.99 (0.94–1.05)	0.233	0.95 (0.88–1.03)
Male sex	0.317	1.957 (0.53–7.28)	0.393	2.16 (0.37–12.67)
mCCI	0.049	1.62 (1.00–2.62)	0.032	2.68 (1.09–6.60)
BMI	0.007	0.80 (0.68–0.94)	0.022	0.79 (0.64–0.97)
Low DEmax	0.011	16.25 (1.92–137.78)	0.038	11.51 (1.15–115.56)

Abbreviations: mCCI, modified Charlson Comorbidity Index; BMI, body mass index; TF_max, diaphragm thickening fraction during maximal deep breathing; DE_max, diaphragm excursion during maximal deep breathing.