U-Shaped Relationship Between Serum Lactate Dehydrogenase with All-Cause Mortality in Patients with Chronic Obstructive Pulmonary Disease

Figures & data

Figure 1 Study flowchart.

Abbreviations: NHANES, National Survey of the National Center for Health Statistics; FVC, forced vital capacity; FEV1, forced expiratory volume in the first 1 second; LDH, serum lactate dehydrogenase; BMI, body mass index; CVD, cardiovascular diseases; MCV, mean corpuscular volume; FEV1% predicted, forced expiratory volume in 1 second percent of predicted.

Table 1 Baseline Characteristics of the Study Participants

Variables	Serum LDH Levels
	Total	59–111 (U/L)	112–123 (U/L)	124–135 (U/L)	136–150 (U/L)	151–344 (U/L)	P-value
	(n = 1320)	T1 (n = 253)	T2 (n = 267)	T3 (n = 278)	T4 (n = 266)	T5 (n = 256)
Age, years, n (%)							< 0.001
<65	814 (61.7)	184 (72.7)	172 (64.4)	180 (64.7)	148 (55.6)	130 (50.8)
≥65	506 (38.3)	69 (27.3)	95 (35.6)	98 (35.3)	118 (44.4)	126 (49.2)
Mean ± SD	57.9 ± 14.2	52.9 ± 15.3	56.4 ± 14.7	58.6 ± 12.7	60.0 ± 13.4	61.4 ± 13.4	< 0.001
Sex, n (%)							0.133
Male	823 (62.3)	153 (60.5)	182 (68.2)	172 (61.9)	169 (63.5)	147 (57.4)
Female	497 (37.7)	100 (39.5)	85 (31.8)	106 (38.1)	97 (36.5)	109 (42.6)
Race-ethnicity, n (%)							0.027
Mexican American	90 (6.8)	16 (6.3)	23 (8.6)	22 (7.9)	12 (4.5)	17 (6.6)
Other Hispanic	90 (6.8)	13 (5.1)	25 (9.4)	17 (6.1)	22 (8.3)	13 (5.1)
Non-Hispanic White	836 (63.3)	169 (66.8)	172 (64.4)	185 (66.5)	166 (62.4)	144 (56.2)
Non-Hispanic Black	240 (18.2)	43 (17)	35 (13.1)	42 (15.1)	55 (20.7)	65 (25.4)
Other Race-Including Multi Racial	64 (4.8)	12 (4.7)	12 (4.5)	12 (4.3)	11 (4.1)	17 (6.6)
Education Level, n (%)							0.007
Low (<9 years)	128 (9.7)	13 (5.1)	22 (8.2)	35 (12.6)	28 (10.5)	30 (11.7)
Medium (9–13 years)	576 (43.6)	125 (49.4)	97 (36.3)	122 (43.9)	115 (43.2)	117 (45.7)
High (≥13 years)	616 (46.7)	115 (45.5)	148 (55.4)	121 (43.5)	123 (46.2)	109 (42.6)
Poverty Income Ratio,(%) Mean ± SD	2.6 ± 1.6	2.5 ± 1.6	2.7 ± 1.7	2.6 ± 1.6	2.6 ± 1.6	2.6 ± 1.6	0.661
BMI, kg/m2, n (%)							0.044
Under weight (<18.5)	25 (1.9)	9 (3.6)	1 (0.4)	6 (2.2)	6 (2.3)	3 (1.2)
Normal weight (18.5–24.9)	447 (33.9)	98 (38.7)	82 (30.7)	101 (36.3)	89 (33.5)	77 (30.1)
Over wight (25–29.9)	463 (35.1)	85 (33.6)	108 (40.4)	96 (34.5)	89 (33.5)	85 (33.2)
Obese (>30)	385 (29.2)	61 (24.1)	76 (28.5)	75 (27)	82 (30.8)	91 (35.5)
Mean ± SD	27.8 ± 6.1	27.1 ± 6.3	28.0 ± 5.6	27.5 ± 5.7	28.0 ± 6.2	28.6 ± 6.4	0.066
Smoking Status, n (%)							0.004
Never Smoker	389 (29.5)	66 (26.1)	80 (30)	81 (29.1)	76 (28.6)	86 (33.6)
Former Smoker	463 (35.1)	73 (28.9)	88 (33)	95 (34.2)	108 (40.6)	99 (38.7)
Current Smoker	468 (35.5)	114 (45.1)	99 (37.1)	102 (36.7)	82 (30.8)	71 (27.7)
Comorbidity
CVD, n (%)	212 (16.1)	30 (11.9)	38 (14.2)	33 (11.9)	56 (21.1)	55 (21.5)	0.001
Hypertension, n (%)	689 (52.2)	107 (42.3)	134 (50.2)	126 (45.3)	156 (58.6)	166 (64.8)	< 0.001
Diabetes, n (%)	280 (21.2)	51 (20.2)	59 (22.1)	45 (16.2)	63 (23.7)	62 (24.2)	0.144
Stroke, n (%)	62 (4.7)	15 (5.9)	12 (4.5)	7 (2.5)	15 (5.6)	13 (5.1)	0.350
Cancer, n (%)	202 (15.3)	37 (14.6)	40 (15)	47 (16.9)	38 (14.3)	40 (15.6)	0.925
Follow-up in years Median (IQR)	9.7 (7.8, 11.2)	9.6 (7.8, 10.9)	9.7 (7.8, 11.0)	10.0 (8.4, 11.3)	9.6 (7.9, 11.2)	9.6 (7.6, 11.1)	0.205
Mortality, n (%)	252 (19.1)	40 (15.8)	50 (18.7)	41 (14.7)	62 (23.3)	59 (23)	0.028
Pulmonary function test
FVC, (mL) Median (IQR)	3650.0 (2886.0, 4612.0)	3910.0 (3074.0, 4751.0)	3877.0 (3094.0, 4891.0)	3605.0 (3059.0, 4587.0)	3528.0 (2768.0, 4423.0)	3074.0 (2535.0, 4201.0)	< 0.001
FEV1, (mL) Median (IQR)	2282.0 (1846.0, 2992.0)	2428.0 (1900.0, 3044.0)	2321.0 (1902.0, 3076.0)	2330.0 (1874.0, 3066.0)	2210.0 (1848.0, 2938.0)	2116.0 (1628.0, 2658.0)	0.023
FEV1/FVC,(%) Mean ± SD	0.64 ± 0.07	0.63 ± 0.08	0.64 ± 0.06	0.64 ± 0.06	0.63 ± 0.07	0.64 ± 0.06	0.621
FEV1% predicted,(%) Mean ± SD	0.81 ± 0.18	0.79 ± 0.18	0.83 ± 0.17	0.83 ± 0.18	0.81 ± 0.17	0.81 ± 0.19	0.077
GOLD stage, n (%)							0.512
GOLD stage (I)	715 (54.2)	130 (51.4)	149 (55.8)	153 (55)	145 (54.5)	138 (53.9)
GOLD stage (II)	541 (41.0)	105 (41.5)	112 (41.9)	112 (40.3)	107 (40.2)	105 (41)
GOLD stage (III–IV)	64 (4.8)	18 (7.1)	6 (2.2)	13 (4.7)	14 (5.3)	13 (5.1)
Laboratory
WBC,(×10^9/L) Mean ± SD	7.25 ± 2.05	7.48 ± 1.93	7.19 ± 1.92	7.54 ± 2.18	7.17 ± 2.19	6.84 ± 1.96	< 0.001
Neutrophil,(×10^9/L) Mean ± SD	4.38 ± 1.64	4.50 ± 1.56	4.32 ± 1.56	4.59 ± 1.74	4.37 ± 1.76	4.08 ± 1.51	0.004
Hemoglobin,(g/dL) Mean ± SD	14.42 ± 1.48	14.37 ± 1.48	14.62 ± 1.46	14.56 ± 1.46	14.41 ± 1.46	14.15 ± 1.52	0.003
MCV, (fL) Mean ± SD	90.77 ± 5.57	90.84 ± 5.67	90.68 ± 5.69	90.59 ± 5.25	91.27 ± 5.30	90.46 ± 5.94	0.5
ALT,(U/L) Median (IQR)	20.0 (16.0, 27.0)	18.0 (15.0, 23.0)	19.0 (15.0, 25.0)	21.0 (17.0, 28.0)	21.0 (17.0, 27.0)	23.0 (18.8, 31.0)	< 0.001
ALB,(g/L) Mean ± SD	42.4 ± 3.1	42.3 ± 3.4	42.6 ± 3.1	42.7 ± 2.9	42.3 ± 2.8	42.0 ± 3.1	0.106
LDH, (U/L) Mean±SD	132.5 ± 27.0	100.9 ± 9.2	118.0 ± 3.5	129.1 ± 3.4	142.3 ± 4.1	172.2 ± 27.2	< 0.001

Abbreviations: FVC, forced vital capacity; FEV1, forced expiratory volume in the first 1 second; LDH, serum lactate dehydrogenase; BMI, body mass index; CVD, cardiovascular disease; FEV1% predicted, FEV in 1 second percent of predicted ratio of FEV1 to FVC; MCV, mean corpuscular volume; ALT, alanine aminotransferase; ALB, albumin.

Table 2 Univariate Analysis of Risk Factor Associated with All-Cause Mortality in Patients with COPD

Variables	HR (95% CI)	P-value
Age, n (%)
<65	Ref.
≥65	3.61 (2.78, 4.69)	< 0.001
Age (years)	1.07 (1.05, 1.08)	< 0.001
Sex, n (%)
Male	Ref.
Female	0.77 (0.59, 1)	0.046
Race-ethnicity, n (%)
Mexican American	Ref.
Other Hispanic	1.51 (0.68, 3.37)	0.311
Non-Hispanic White	1.93 (1.02, 3.65)	0.043
Non-Hispanic Black	1.88 (0.95, 3.72)	0.071
Other Race-Including Multi-Racial	1.13 (0.43, 2.96)	0.809
Education Level, n (%)
Low (≤9 years)	Ref.
Medium (9–13 years)	1.02 (0.68, 1.53)	0.92
High (≥13 years)	0.65 (0.42, 0.99)	0.045
Poverty Income Ratio, (%)	0.76 (0.7, 0.83)	< 0.001
BMI, kg/m^2, n (%)
Under weight (<18.5)	0.78 (0.36, 1.69)	0.533
Normal weight (18.5–24.9)	Ref.
Over wight (25–29.9)	0.77 (0.36, 1.67)	0.509
Obese (>30)	0.78 (0.36, 1.69)	0.533
BMI (kg/m^2)	0.9956 (0.9747, 1.0169)	0.681
Smoking Status, n (%)
Never Smoker	Ref.
Former Smoker	1.81 (1.3, 2.53)	< 0.001
Current Smoker	1.63 (1.16, 2.29)	0.005
Comorbidity
CVD (YES vs NO), n (%)	2.62 (2.01, 3.43)	< 0.001
Hypertension (YES vs NO), n (%)	2.08 (1.59, 2.7)	< 0.001
Diabetes (YES vs NO), n (%)	2.15 (1.66, 2.79)	< 0.001
Stroke (YES vs NO), n (%)	2.26 (1.47, 3.48)	< 0.001
Cancer (YES vs NO), n (%)	1.44 (1.06, 1.95)	0.02
Pulmonary function test
FVC, (mL)	0.9996 (0.9995, 0.9997)	< 0.001
FEV1, (mL)	0.9992 (0.9991, 0.9994)	< 0.001
FEV1/FVC, (%)	0.004 (0.001, 0.014)	< 0.001
FEV1% predicted,(%)	0.08 (0.04, 0.16)	< 0.001
GOLD stage, n (%)
GOLD stage (I)	Ref.
GOLD stage (II)	1.77 (1.35, 2.31)	< 0.001
GOLD stage (III or IV)	5.05 (3.4, 7.51)	< 0.001
Laboratory
WBC,(×10^9/L)	1.10 (1.04, 1.17)	0.002
Neutrophil,(×10^9/L)	1.16 (1.08, 1.25)	< 0.001
Hemoglobin,(g/dL)	0.9 (0.82, 0.97)	0.01
MCV,(fL)	1.06 (1.03, 1.09)	< 0.001
ALT,(U/L)	0.9993 (0.9922, 1.0064)	0.839
ALB,(g/L)	0.9 (0.87, 0.94)	< 0.001
LDH,(U/L)	1.0069 (1.0028, 1.011)	0.001

Abbreviations: FVC, forced vital capacity; FEV1, forced expiratory volume in the first 1 second; LDH, serum lactate dehydrogenase; BMI, body mass index; CVD, cardiovascular disease; FEV1% predicted, forced expiratory volume in 1 second percent of predicted; MCV, mean corpuscular volume; ALT, alanine aminotransferase; ALB, albumin.

Table 3 Multivariate Cox Regression for LDH on All-Cause Mortality of COPD

Variable	Total	Non-Adjusted Model	p value	Model I	p value	Model II	p value	Model III	p value
	n	HR (95% CI)		HR (95% CI)		HR (95% CI)		HR (95% CI)
Continuous variable
LDH (per SD)	1320	1.2 (1.08~1.34)	0.001	1.15 (1.02~1.3)	0.023	1.16 (1.03~1.3)	0.016	1.17 (1.03~1.32)	0.013
Binary variable
T1 LDH 59–111 (U/L)	253	1.14 (0.74~1.76)	0.558	1.46 (0.94~2.26)	0.094	1.32 (0.84~2.05)	0.225	1.22 (0.78~1.92)	0.386
T2 LDH 112–123 (U/L)	267	1.34 (0.88~2.02)	0.168	1.61 (1.06~2.44)	0.026	1.48 (0.98~2.26)	0.065	1.60 (1.05~2.44)	0.030
T3 LDH 124–135 (U/L)	278	Ref.		Ref.		Ref.		Ref.
T4 LDH 136–150 (U/L)	266	1.66 (1.12~2.47)	0.011	1.65 (1.11~2.45)	0.013	1.54 (1.03~2.29)	0.035	1.52 (1.01~2.27)	0.043
T5 LDH 151–344 (U/L)	256	1.68 (1.13~2.51)	0.01	1.66 (1.11~2.48)	0.013	1.60 (1.06~2.40)	0.024	1.64 (1.08~2.47)	0.020
P for trend			0.022		0.420		0.316		0.247

Notes: Model I: adjusted for age + sex + race + education + poverty income ratio; Model II: adjusted for Model I+ BMI + smoking status + diabetes + hypertension + CVD + stroke + cancer; Model III: adjusted for Model II+ ALT+ ALB + neutrophil + hemoglobin + MCV + FEV1% predicted. FVC, FEV1, and FEV1/FVC were not included in the final model due to collinearity with the FEV1% predicted; WBC was not included in the final model due to collinearity with neutrophils.

Abbreviations: FVC, forced vital capacity; FEV1, forced expiratory volume in the first 1 second; LDH, serum lactate dehydrogenase; BMI, body mass index; CVD, cardiovascular disease; FEV1% predicted, forced expiratory volume in 1 second percent of predicted; MCV, mean corpuscular volume; ALT, alanine aminotransferase; ALB, albumin.

Table 4 The Non-Linear Relationship Between Serum LDH and All-Cause Mortality

Two-Piecewise Linear Regression Model	HR	95% CI	P-value
LDH<110 (U/L)(per sd)	0.32	0.13~0.81	0.016
LDH≥110 (U/L)(per sd)	1.23	1.08~1.41	0.002
Non-linear test			0.005
Likelihood Ratio test			0.004

Notes: Adjusted for age + sex + race + education + poverty income ratio + BMI + smoking status + diabetes + hypertension + CVD + stroke + cancer + ALT + ALB + neutrophil + hemoglobin + MCV + FEV1% predicted.

Abbreviations: FVC, forced vital capacity; FEV1, forced expiratory volume in the first 1 second; LDH, serum lactate dehydrogenase; BMI, body mass index; CVD, cardiovascular disease; FEV1% predicted, forced expiratory volume in 1 second percent of predicted; MCV, mean corpuscular volume; ALT, alanine aminotransferase; ALB, albumin.

Figure 2 Association between serum LDH levels and all-cause mortality after adjusted for Model III. Adjusted for age + sex + race + education + poverty income ratio + BMI + smoking status + diabetes + hypertension + CVD + stroke + cancer + ALT + ALB + neutrophil + hemoglobin + MCV + FEV1% predicted.

Note: The black and dotted lines represent the estimated values and their corresponding 95% confidence intervals, respectively.

Abbreviations: BMI, body mass index; CVD, cardiovascular disease; MCV, mean corpuscular volume; FEV1% predicted, forced expiratory volume in 1 second percent of predicted; ALT, alanine aminotransferase; ALB, albumin.