Respiratory parameters predict poor outcome in COPD patients, category GOLD 2017 B

Figures & data

Figure 1 Flow chart of patients.

Notes: *Self-reported history of sleep apnea. **Self-reported history of pulmonary hypertension.
Abbreviation: CMRD, Czech Multicentre Research Database.

Table 1 Basic characteristics of the study cohort – COPD patients (n=725)

Demography
Sex – men	520 (71.7%)
Age at inclusion	n=725; 66.7 (9.4)
BMI	n=725; 26.9 (5.8)
Smoking status
Ex-smoker	491 (67.7%)
Nonsmoker	79 (10.9%)
Current smoker	155 (21.4%)
Symptoms
Dyspnea – mMRC
0	36 (5.0%)
1	141 (19.4%)
2	289 (39.9%)
3	150 (20.7%)
4	109 (15.0%)
CAT	n=715; 16.0 (7.8)
Fatigue	331 (46.8%)
Cough	521 (71.9%)
Expectoration	423 (58.3%)
Atopy	86 (11.9%)
Asthma	75 (10.3%)
Exacerbations in the last 12 months
Treated at home	n=725; 0.8 (1.3)
Requiring hospitalization	n=725; 0.4 (0.8)
Total	n=725; 1.2 (1.6)
Lung functions
FEV1 (% pred)	n=725; 44.9 (11.6)
FVC (% pred)	n=725; 69.2 (17.7)
FEV1/FVC (%)	n=725; 0.5 (0.1)
RV (% pred)	n=587; 189.0 (58.7)
TLC (% pred)	n=583; 112.1 (25.8)
IC/TLC (%)	n=422; 42.1 (24.6)
TLCO (% pred)	n=473; 52.5 (22.1)
FeNO (ppb)	n=267; 18.6 (19.4)
6-MWD (m)	n=552; 334.9 (131.7)
Phenotypes
Czech approach (one COPD subject = one or more “phenotypical labels – treatable traits”)
Bronchitic	423 (58.3%)
Emphysematous	263 (78.0%)
BCOS	105 (31.9%)
ACOS*	23 (4.1%)
Frequent exacerbators	225 (31.0%)
Cachexia	111 (15.3%)
Spanish approach (one COPD subject = one “clinical phenotype”)
ACOS**	85 (11.7%)
Non-AE	451 (62.2%)
AE CB	126 (17.4%)
AE non-CB	63 (8.7%)
GOLD
GOLD 2016 (A–D)
A	34 (4.9%)
B	140 (20.2%)
C	37 (5.3%)
D	483 (69.6%)
GOLD 2017 (A–D)
A	60 (8.3%)
B	383 (53.0%)
C	14 (1.9%)
D	265 (36.7%)

Notes: Categorical parameters are described by absolute (relative) frequencies. Relative frequencies are calculated from valid data. Continuous parameters are described by valid N, mean (SD).

* Czech approach has used more restrictive criteria¹³ than simplified.

** Spanish approach.¹⁵

Abbreviations: 6-MWD, 6 minute walking distance; ACOS (ACO), asthma COPD overlap syndrome; AE CB, frequent exacerbators with chronic bronchitis; AE non-CB, frequent exacerbators without chronic bronchitis; BCOS, bronchiectases COPD overlap syndrome; BMI, body mass index; CAT, COPD Assessment Test; FeNO, fractional exhaled nitric oxide; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Obstructive Lung Disease; IC/TLC, inspiratory capacity to total lung capacity ratio; mMRC, modified Medical Research Council dyspnea scale; ppb, part per billion; pred, predicted value; RV, residual volume; TLC, total lung capacity; TL_CO, transfer factor for carbon monoxide.

Table 2 Respiratory parameters (n=725)

Respiratory parameters
PaO2 (kPa)	n=391; 8.8 (1.6)
PaCO2 (kPa)	n=391; 5.2 (0.9)
pH	n=391; 7.42 (0.43)
Basal SpO2 (%)	n=552; 94.5 (3.6)
Minimal SpO2 during (after) 6-MWT (%)	n=552; 89.6 (7.0)
Greatest decrease of SpO2 during 6-MWT (%)	n=552; 4.8 (4.7)

Note: Continuous parameters are described by valid N, mean (SD).

Abbreviations: 6-MWT, 6-minute walking test; PaCO₂, partial pressure of arterial carbon dioxide; PaO₂, partial pressure of arterial oxygen; pH, arterial potential of hydrogen; SpO₂, peripheral capillary oxygen saturation.

Table 3 Correlation of respiratory parameters (all patients and GOLD 2017 B patients)

All patients	PaO2 (kPa)	PaCO2 (kPa)	Basal SpO2 (%)	Minimal SpO2 (%)	Greatest decrease of SpO2 (%)
PaO2 (kPa)	–	n=391 −0.306 (<0.001)	n=351 0.552 (<0.001 )	n=351 0.535 (<0.001)	n=351 −0.367 (<0.001)
PaCO2 (kPa)	n=391 −0.306 (<0.001)	–	n=351 −0.274 (<0.001)	n=351 −0.298 (<0.001)	n=351 0.219 (<0.001)
Basal SpO2 (%)	n=351 0.552 (<0.001)	n=351 −0.274 (<0.001)	–	n=552 0.742 (<0.001)	n=552 −0.350 (<0.001)
Minimal SpO2 (%)	n=351 0.535 (<0.001)	n=351 −0.298 (<0.001)	n=552 0.742 (<0.001)	–	n=552 −0.860 (<0.001)
Greatest decrease of SpO2 (%)	n=351 −0.367 (<0.001)	n=351 0.219 (<0.001)	n=552 −0.350 (<0.001)	n=552 −0.860 (<0.001)	–
GOLD 2017 B patients
PaO2 (kPa)	–	n=181 −0.345 (<0.001)	n=168 0.462 (<0.001)	n=168 0.477 (<0.001)	n=168 −0.338 (<0.001)
PaCO2 (kPa)	n=181 −0.345 (<0.001)	–	n=168 −0.303 (<0.001)	n=168 −0.279 (<0.001)	n=168 0.167 (0.030)
Basal SpO2 (%)	n=168 0.462 (<0.001)	n=168 −0.303 (<0.001)	–	n=287 0.738 (<0.001)	n=287 −0.351 (<0.001)
Minimal SpO2 (%)	n=168 0.477 (<0.001)	n=168 −0.279 (<0.001)	n=287 0.738 (<0.001)	–	n=287 −0.853 (<0.001)
Greatest decrease of SpO2 (%)	n=168 −0.338 (<0.001)	n=168 0.167 (0.030)	n=287 −0.351 (<0.001)	n=287 −0.853 (<0.001)	–

Notes: Spearman’s coefficient of correlation. Significant differences are indicated in bold.

Abbreviations: PaCO₂, partial pressure of arterial carbon dioxide; PaO₂, partial pressure of arterial oxygen; SpO₂, peripheral capillary oxygen saturation.

Table 4 Prediction of all-cause mortality by respiratory parameters

Respiratory parameters	AUC (95% CI)	p-value
PaO2 (kPa)	0.590 (0.507; 0.673)	0.020
PaCO2 (kPa)	0.600 (0.521; 0.679)	0.010
Basal SpO2 (%)	0.607 (0.537; 0.676)	0.002
Minimal SpO2 during 6-MWT (%)	0.631 (0.569; 0.693)	<0.001
Greatest decrease of SpO2 (%)	0.610 (0.548; 0.671)	0.001

Notes: Receiver operating characteristic analysis was used to determine parameter ability to predict mortality of COPD patients. AUC with p-value illustrated the power of this ability. Significant differences are indicated in bold.

Abbreviations: 6-MWT, 6-minute walking test; AUC, area under curve; PaCO₂, partial pressure of arterial carbon dioxide; PaO₂, partial pressure of arterial oxygen; SpO₂, peripheral capillary oxygen saturation.

Figure 2 (A) Long-term survival according to PaO₂ (all patients); (B) long-term survival according to PaO₂ (GOLD 2017 group B COPD subjects); (C) long-term survival according to PaO₂ (GOLD 2017 group D COPD subjects).

Notes: *Number of patients with known follow-up. p-values <0.001, 0.001 respectively in bold represent significant survival difference between presence of severe hypoxemia and absence of severe hypoxemia in total COPD cohort, and in GOLD 2017 B category.

Abbreviations: GOLD, Global Initiative for Obstructive Lung Disease; PaCO₂, partial pressure of arterial carbon dioxide.

Figure 3 (A) Long-term survival according to PaCO₂ (all patients); (B) long-term survival according to PaCO₂ (GOLD 2017 group B COPD subjects); (C) long-term survival according to PaCO₂ (GOLD 2017 group D COPD subjects).

Note: p-value <0.001 in bold represents significant survival difference between hypocapnic, normocapnic, and hypercapnic patients in GOLD 2017 B category only.

Abbreviations: GOLD, Global Initiative for Obstructive Lung Disease; PaCO₂, partial pressure of arterial carbon dioxide.

Figure 4 (A) Long-term survival according to desaturation (all patients); (B) long-term survival according to desaturation (GOLD 2017 group B COPD subjects); (C) long-term survival according to desaturation (GOLD 2017 group D COPD subjects).

Notes: *Number of patients with known follow-up. p-values 0.004, 0.022 respectively in bold represent significant survival difference between presence of desaturation and absence of desaturation in total COPD cohort, and in GOLD 2017 B category.
Abbreviation: GOLD, Global Initiative for Obstructive Lung Disease.

Table 5A Prediction of all-cause mortality by respiratory parameters – all patients

Respiratory parameter	Cox model of proportional risk
	HR (95% CI)	p-value
PaO2 (kPa)
Continuously*	1.304 (1.108–1.534)	0.001
<7.3	3.064 (1.840–5.103)	<0.001
<8.0	1.700 (1.040–2.779)	0.034
PaCO2 (kPa)
Continuously**	1.484 (1.177–1.870)	0.001
5.0–7.0	Reference category
<5.0	0.805 (0.482–1.345)	0.407
>7.0	1.813 (0.648–5.071)	0.257
Desaturation
Yes	1.883 (1.217–2.911)	0.004

Notes:

* HR represents change of risk of mortality, if parameter decreases by unit (lower values are risk).

** HR represents change of risk of mortality, if parameter increases by unit (higher values are risk). Desaturation, greatest decrease of SpO₂ during 6-MWT (%)>4% and/or minimal SpO₂ during (after) 6-MWT (%)<90%. p-values in bold represent significant change of mortality risk (expressed as hazard ratio).

Abbreviations: 6-MWT, 6-minute walking test; HR, hazard ratio; PaCO₂, partial pressure of arterial carbon dioxide; PaO₂, partial pressure of arterial oxygen; SpO₂, peripheral capillary oxygen saturation.

Table 5B Prediction of all-cause mortality by respiratory parameters – GOLD 2017 B patients

	Cox model of proportional risk
	HR (95% CI)	p-value
PaO2 (kPa)
Continuously*	1.282 (0.997–1.647)	0.052
<7.3	3.532 (1.628–7.662)	0.001
<8.0	1.462 (0.675–3.169)	0.336
PaCO2 (kPa)
Continuously**	1.723 (1.085–2.734)	0.021
5.0–7.0	Reference category
<5.0	1.564 (0.712–3.438)	0.265
.7.0	10.185 (2.719–38.158)	0.001
Desaturation
Yes	2.001 (1.090–3.672)	0.025

Notes:

* HR represents change of risk of mortality, if parameter decreases by unit (lower values are risk).

** HR represents change of risk of mortality, if parameter increases by unit (higher values are risk). Desaturation, greatest decrease of SpO₂ during 6-MWT (%) >4% and/or minimal SpO₂ during (after) 6-MWT (%)<90%. p-values in bold represent significant change of mortality risk (expressed as hazard ratio).

Abbreviations: 6-MWT, 6-minute walking test; HR, hazard ratio; PaCO₂, partial pressure of arterial carbon dioxide; PaO₂, partial pressure of arterial oxygen; SpO₂, peripheral capillary oxygen saturation.

Table 6 Prediction of all-cause mortality – multivariate analysis containing PaO₂ (kPa) ≤7.3

Prognostic parameter	Cox model of proportional risk
	HR (95% CI)	p-value
6-MWD (m)*	0.996 (0.993–0.999)	0.003
PaO2 (kPa) ≤7.3	2.398 (1.245–4.630)	0.009

Notes:

* HR represents change of risk of mortality, if parameter increases by unit. p-values in bold represent significant change of mortality risk (expressed as hazard ratio).

Abbreviations: 6-MWD, 6-minute walking distance; HR, hazard ratio; PaO₂, partial pressure of arterial oxygen.

Table S1 Frequency of desaturation (n=552)

Desaturation	n=552
No	296 (53.6%)
Yes	256 (46.4%)

Note: Desaturation means greatest decrease of SpO₂ during 6-MWT (%) >4% and/or minimal SpO₂ during (after) 6-MWT (%)<90%.

Abbreviations: 6-MWT, 6-minute walking test; SpO₂, basal peripheral capillary oxygen saturation.

Table S2 (A) Prediction of all-cause mortality – multivariate analysis containing PaCO₂ (kPa) – categories (<5; 5–7 – reference; >7). (B) Prediction of all-cause mortality – multivariate analysis containing desaturation. (C) Prediction of mortality by parameters of blood gases – ideal cutoff values. (D) Prediction of mortality – multivariate analysis containing PaO₂ (kPa) ≤7.1.

Prognostic parameter		Cox model of proportional risk
		HR (95% CI)			p-value
A
TLCO (%)*		0.979 (0.961–0.998)			0.032
6-MWD (m)*		0.996 (0.993–0.998)			0.001
PaCO2 (kPa)		–			–
B
BODE*		1.310 (1.168–1.470)			<0.001
TLC (%)*		0.985 (0.975–0.995)			0.004
Desaturation		–			–
	AUC (95% CI)	p-value	Cutoff	Sensitivity	Specificity
C
PaO2 (kPa)	0.590 (0.507; 0.673)	0.020	≤7.1	0.313	0.914
PaCO2 (kPa)	0.600 (0.521; 0.679)	0.010	≥0.54	0.537	0.654
Basal SpO2 (%)	0.607 (0.537; 0.676)	0.002	≤95.5	0.701	0.473
Minimal SpO2 during 6-MWT (%)	0.631 (0.569; 0.693)	<0.001	≤93.5	0.851	0.366
Greatest decrease in SpO2 (%)	0.610 (0.548; 0.671)	0.001	≥4.5	0.552	0.626
		Cox model of proportional risk
		HR (95% CI)			p-value
D
BMI*	0.921 (0.865–0.982)			0.012
RV (%)*		0.993 (0.987–1.000)			0.038
6-MWD*		0.994 (0.991–0.998)			<0.001
PaO2 (kPa) ≤7.1		5.135 (2.415–10.917)			<0.001

Notes:

* HR represents change of risk of mortality, if parameter increases by unit. Desaturation, greatest decrease of SpO₂ during 6-MWT (%) >4% and/or minimal SpO₂ during (after) 6-MWT (%)<90%. Bold p-values represent statistically significant differences in mortality between tested end-points.

Abbreviations: AUC, area under curve; 6-MWT, 6-minute walking test; BMI, body mass index; BODE, body-mass index, airflow obstruction, dyspnea, and exercise; HR, hazard ratio; TLC, total lung capacity; SpO₂, basal peripheral capillary oxygen saturation; PaO₂, partial pressure of oxygen in arterial blood; PaCO₂, partial pressure of arterial carbon dioxide; TL_CO, transfer factor for carbon monoxide; RV, residual volume.

Table S3 Relationship between comorbidities and all-cause mortality (A); relationship between comorbidity and PaO₂ (B); relationship between comorbidity and PaCO₂ (C)

Comorbidity	Death		p-value
	No	Yes
A
Atopy	75 (12.4%)	11 (9.2%)	0.357
Asthma	66 (10.9%)	9 (7.5%)	0.325
Coronary artery disease	149 (24.6%)	39 (32.5%)	0.087
Heart failure	88 (14.5%)	27 (22.5%)	0.039
Atrial fibrillation	74 (12.2%)	16 (13.3%)	0.762
Hypertension	341 (56.4%)	72 (60.0%)	0.481
Syncope	29 (4.8%)	7 (5.8%)	0.645
Tumor	79 (13.1%)	27 (22.5%)	0.011
Osteoporosis	85 (14.0%)	15 (12.6%)	0.772
Diabetes mellitus	129 (21.3%)	26 (21.7%)	0.904
Anemia	68 (11.2%)	21 (17.5%)	0.067
Depression	109 (18.0%)	35 (29.2%)	0.008
Ulcer disease	118 (19.5%)	22 (18.3%)	0.899
	Comorbidity		p-value
	No	Yes
B
Atopy	8.8 (1.6); 8.7 (6.3–11.7)	9.4 (1.7); 9.4 (7.1–11.8)	0.020
Asthma	8.8 (1.6); 8.8 (6.3–11.8)	9.1 (1.5); 9.3 (6.3–11.7)	0.262
Coronary artery disease	8.9 (1.6); 8.9 (6.3–11.8)	8.6 (1.7); 8.4 (6.1–11.2)	0.036
Heart failure	9.0 (1.6); 8.9 (6.6–11.8)	8.0 (1.7); 7.8 (5.3–10.9)	<0.001
Atrial fibrillation	8.8 (1.6); 8.8 (6.3–11.8)	8.9 (1.6); 8.9 (6.1–11.2)	0.644
Hypertension	8.9 (1.6); 9.0 (6.4–11.3)	8.8 (1.7); 8.7 (6.1–11.9)	0.339
Syncope	8.8 (1.6); 8.8 (6.3–11.7)	9.4 (1.9); 9.0 (6.5–12.5)	0.201
Tumor	8.8 (1.6); 8.8 (6.4–11.7)	8.9 (1.8); 9.0 (5.9–12.2)	0.708
Osteoporosis	8.8 (1.6); 8.9 (6.4–11.7)	8.8 (1.9); 8.6 (6.0–12.0)	0.808
Diabetes mellitus	8.9 (1.7); 8.9 (6.3–11.9)	8.6 (1.5); 8.6 (6.4–11.3)	0.038
Anemia	8.9 (1.6); 8.9 (6.4–11.7)	8.6 (1.9); 8.4 (5.5–12.2)	0.307
Depression	8.8 (1.6); 8.8 (6.3–11.7)	9.1 (1.8); 9.1 (6.4–12.2)	0.197
Ulcer disease	8.8 (1.6); 8.7 (6.4–11.7)	9.1 (1.7); 9.3 (6.0–11.9)	0.067
C
Atopy	5.3 (0.9); 5.2 (4.0–6.8)	5.0 (0.6); 5.0 (4.1–6.2)	0.046
Asthma	5.3 (0.9); 5.2 (4.0–6.8)	5.0 (0.8); 4.9 (3.8–5.7)	0.025
Coronary artery disease	5.2 (0.9); 5.2 (4.0–6.8)	5.3 (0.9); 5.2 (4.2–6.8)	0.918
Heart failure	5.2 (0.8); 5.1 (3.9–6.4)	5.6 (0.9); 5.4 (4.4–7.2)	<0.001
Atrial fibrillation	5.2 (0.9); 5.1 (4.0–6.8)	5.3 (0.8); 5.2 (3.9–6.7)	0.089
Hypertension	5.2 (0.8); 5.2 (3.9–6.8)	5.2 (0.9); 5.2 (4.2–6.7)	0.871
Syncope	5.2 (0.9); 5.2 (4.0–6.8)	5.2 (0.9); 5.1 (3.9–6.9)	0.614
Presyncope	5.2 (0.9); 5.2 (4.0–6.8)	5.2 (0.7); 5.2 (3.9–6.2)	0.974
Tumor	5.3 (0.8); 5.2 (4.2–6.8)	5.1 (1.0); 5.2 (3.9–6.8)	0.538
Osteoporosis	5.3 (0.8); 5.2 (4.2–6.8)	5.1 (0.9); 5.1 (3.7–6.8)	0.153
Diabetes mellitus	5.2 (0.9); 5.1 (3.9–6.8)	5.4 (0.8); 5.3 (4.3–6.8)	0.010
Anemia	5.2 (0.8); 5.1 (4.0–6.8)	5.4 (0.9); 5.4 (3.9–6.9)	0.122
Depression	5.2 (0.8); 5.2 (4.0–6.7)	5.4 (1.1); 5.2 (3.9–7.0)	0.302
Ulcer disease	5.3 (0.8); 5.2 (4.1–6.8)	5.2 (1.1); 5.0 (3.9–6.8)	0.102

Notes:

Parameters are described by absolute (relative) frequencies and tested by Fisher’s exact test (A). Parameters are described by mean (SD); median (5th and 95th percentiles) and tested by Mann–Whitney test (B, C). Bold p-values represent statistically significant differences in mortality between tested end-points.

Abbreviation: PaCO₂, partial pressure of arterial carbon dioxide.

Table S4 Comparison of parameters between groups according to valid data (n=725)

Tested parameter	Without 6-MWT and ABG (n=133)	Only with 6-MWT (n=201)	Only with ABG (n=40)	With 6-MWT and ABG (n=351)	p-value
Demography
Sex – men	97 (72.9%)	146 (72.6%)	25 (62.5%)	252 (71.8%)	0.597
Age at inclusion	67.4 (10.3)	65.3 (10.0)	69.4 (9.3)	67.0 (8.5)	0.078
BMI	26.7 (5.6)	27.1 (5.4)	25.9 (4.7)	26.9 (6.1)	0.553
Symptoms
mMRC	2.0 (1.1)	2.3 (0.9)	2.5 (1.1)	2.2 (1.2)	0.007
CAT	17.3 (8.2)	15.5 (7.2)	17.5 (8.0)	15.5 (7.9)	0.067
Exacerbations
Treated at home (moderate)	0.6 (1.1)	0.8 (1.2)	0.9 (1.1)	0.9 (1.5)	0.223
Requiring hospitalization (severe)	0.2 (0.6)	0.2 (0.5)	0.7 (0.8)	0.5 (0.9)	<0.001
Total	0.8 (1.4)	1.0 (1.4)	1.6 (1.4)	1.4 (1.9)	<0.001
Lung function
FEV1 (%)	45.3 (11.2)	47.7 (11.6)	44.8 (12.9)	43.2 (11.4)	<0.001
FVC (%)	71.8 (16.8)	69.1 (15.2)	71.3 (15.5)	68.0 (19.5)	0.057
TLCO (% pred)	52.1 (21.9)	62.1 (24.1)	48.6 (16.2)	49.4 (21.0)	<0.001

Notes:

Categorical parameters are described by absolute (relative) frequency. Differences are tested by Fisher’s exact test. Continuous parameters are described by mean (SD). Differences are tested by Kruskal–Wallis test. Significant differences are indicated in bold.

Abbreviations: 6-MWT, 6-minute walking test; ABG, arterial blood gas; BMI, body mass index; CAT, COPD Assessment Test; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; mMRC, modified Medical Research Council dyspnea scale; pred, predicted value; TL_co, transfer factor for carbon monoxide.

Table S5 SpO₂ according to physical examination (n=725) (A), correlation between SpO₂ (physical examination*) and SpO₂ (6-MWT°) (n=552) (B)

	Valid N, mean (SD), median (5th and 95th percentile)
A
SpO2 (physical examination*)	n=725; 93.8 (4.6); 95.0 (87.0; 98.0)
SpO2 (6-MWT°)	n=552; 94.5 (3.6); 95.0 (88.0; 98.0)
	Spearman’s coefficient of correlation (p-value)
B
SpO2	n=552; 0.779 (<0.001)

Note:

* Mandatory parameter available in all COPD subjects,

° optional (nonmandatory) parameter used in our analysis.

Abbreviations: 6-MWT, 6-minute walking test; SpO₂, peripheral capillary oxygen saturation.

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