Dynamic immune response and its influencing factors in COVID-19 patients with non-alcoholic fatty liver disease: A cohort study

Table 1 Patient characteristics, n (%)/mean ± SD

Characteristic	COVID-19 only (n = 858)	COVID-19 with NAFLD (n = 670)	P value
Age	35.22 ± 12.70	41.23 ± 11.48	< 0.001
Time to negative SARS-CoV-2 nucleic acid test result	11.96 ± 8.96	13.61 ± 11.15	0.002
BMI	22.03 ± 3.02	26.45 ± 3.16	< 0.001
ALT	22.62 ± 20.58	49.60 ± 37.84	< 0.001
AST	22.04 ± 8.58	30.56 ± 17.09	< 0.001
GGT	22.89 ± 19.17	45.10 ± 34.02	< 0.001
TBIL	8.70 ± 4.77	9.48 ± 5.10	0.002
FPG	5.05 ± 1.34	5.89 ± 2.61	< 0.001
HbA1c	5.40 ± 0.67	5.91 ± 1.22	< 0.001
SBP	124.66 ± 14.95	133.95 ± 16.26	< 0.001
DBP	83.60 ± 11.02	90.25 ± 12.01	< 0.001
TC	4.50 ± 0.97	4.83 ± 1.05	< 0.001
TG	1.31 ± 0.83	2.14 ± 1.50	< 0.001
HDL-C	1.27 ± 0.33	1.09 ± 0.26	< 0.001
LDL-C	2.79 ± 2.97	3.05 ± 0.88	< 0.001
Male	509 (59.3)	592 (88.36)	< 0.001
Female	349 (40.7)	78 (11.64)
Cardiopathy	7 (0.81)	15 (2.24)	< 0.001
Hypertension	46 (5.36)	134 (20.00)	< 0.001
Diabetes	10 (1.17)	78 (11.64)	< 0.001
Hyperlipidemia	71 (8.28)	204 (30.45)	< 0.001
Hyperuricemia	22 (2.56)	91 (13.58)	< 0.001
Asymptomatic cases	304 (35.43)	210 (31.34)	< 0.001
Mild cases	229 (26.69)	133 (19.85)
Moderate cases	312 (36.36)	310 (46.27)
Severe cases	4 (0.47)	12 (1.79)
Critical cases	4 (0.47)	4 (0.60)
Liver function abnormalities	247 (28.79)	420 (62.69)	< 0.001

COVID-19: Coronavirus disease 2019; NAFLD: Non-alcoholic fatty liver disease; BMI: Body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase; TBIL: Total bilirubin; FPG: Fasting plasma glucose; HbA1c: Hemoglobin A1c; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; TC: Total cholesterol; TG: Triglycerides; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol.

Table 2 Comparison of lymphocyte subsets and their percentages between obese patients without non-alcoholic fatty liver disease and those with non-alcoholic fatty liver disease, mean ± SD

Variable	Obese patients without NAFLD	Obese patients with NAFLD	P value
LY (cells/μL)	2023.96 ± 790.22	2306.34 ± 946.34	0.117
LY%	21.01 ± 7.14	21.67 ± 7.90	0.377
CD3+ (cells/μL)	1455.32 ± 584.53	1654.04 ± 693.65	0.097
CD3+CD4+ (cells/μL)	842.29 ± 385.28	977.5 ± 436.20	0.064
CD3+CD8+ (cells/μL)	515.00 ± 251.28	585.37 ± 312.55	0.475
CD3+%	72.38 ± 6.71	71.98 ± 7.15	0.939
CD3+CD4+%	41.56 ± 7.26	41.94 ± 7.37	0.550
CD3+CD8+%	27.12 ± 10.30	25.45 ± 7.43	0.067
CD4/CD8	1.81 ± 0.75	1.82 ± 0.74	0.759
CD19+ (cells/μL)	252.04 ± 238.43	361.28 ± 245.29	0.311
CD56+ (cells/μL)	276.14 ± 169.13	237.26 ± 170.36	0.788
CD19+%	10.61 ± 4.51	15.02 ± 6.40	0.019
CD56+%	13.77 ± 8.25	10.49 ± 6.79	0.249

NAFLD: Non-alcoholic fatty liver disease; LY: Lymphocyte counts.

Table 3 Linear trend analysis of lymphocyte subsets and their percentages in association with the time to negative severe acute respiratory syndrome coronavirus 2 nucleic acid test result in patients with coronavirus disease 2019 and non-alcoholic fatty liver disease

Variable	F	P value
LY (cells/μL)	53.817	< 0.001
LY%	27.065	< 0.001
CD3+ (cells/μL)	54.778	< 0.001
CD3+CD4+ (cells/μL)	50.838	< 0.001
CD3+CD8+ (cells/μL)	29.331	< 0.001
CD3+%	3.251	0.072
CD3+CD4+%	0.003	0.955
CD3+CD8+%	0.001	0.972
CD4/CD8	0.459	0.499
CD19+ (cells/μL)	8.599	0.008
CD56+ (cells/μL)	3.501	0.076
CD19+%	1.673	0.211
CD56+%	0.114	0.739

LY: Lymphocyte counts.

Table 4 Pearson correlation analysis of lymphocyte subsets and their percentages with the Time to negative severe acute respiratory syndrome coronavirus 2 nucleic acid test result in patients with coronavirus disease 2019 and non-alcoholic fatty liver disease

Variable	Time to negative severe acute respiratory syndrome coronavirus 2 nucleic acid test result
	r	P value
LY (cells/μL)	-0.270	< 0.001
LY%	-0.193	< 0.001
CD3+ (cells/μL)	-0.274	< 0.001
CD3+CD4+ (cells/μL)	-0.264	< 0.001
CD3+CD8+ (cells/μL)	-0.204	< 0.001
CD3+%	-0.062	0.111
CD3+CD4+%	0.002	0.961
CD3+CD8+%	0.001	0.987
CD4/CD8	0.028	0.475
CD19+ (cells/μL)	-0.186	< 0.001
CD56+ (cells/μL)	-0.093	0.018
CD19+%	-0.014	0.726
CD56+%	0.081	0.039

LY: Lymphocyte counts.

Table 5 Linear trend analysis of lymphocyte subsets and their percentages in relation to clinical disease severity in coronavirus disease 2019 patients with non-alcoholic fatty liver disease

Variable	χ2 value	P value
LY (cells/μL)	24.995	< 0.001
LY%	22.745	< 0.001
CD3+ (cells/μL)	24.038	< 0.001
CD3+CD4+ (cells/μL)	18.591	< 0.001
CD3+CD8+ (cells/μL)	17.564	< 0.001
CD3+%	0.545	0.461
CD3+CD4+%	0.031	0.861
CD3+CD8+%	0.051	0.822
CD4/CD8	0.108	0.742
CD19+ (cells/μL)	8.839	0.003
CD56+ (cells/μL)	5.444	0.02
CD19+%	0.165	0.685
CD56+%	1.404	0.236

LY: Lymphocyte counts.

Table 6 Pearson correlation analysis between lymphocyte subsets and their percentages and clinical disease severity in coronavirus disease 2019 patients with non-alcoholic fatty liver disease

Variable	Clinical disease severity
	r	P value
LY (cells/μL)	-0.193	< 0.001
LY%	-0.185	< 0.001
CD3+ (cells/μL)	-0.190	< 0.001
CD3+CD4+ (cells/μL)	-0.167	< 0.001
CD3+CD8+ (cells/μL)	-0.162	< 0.001
CD3+%	-0.029	0.461
CD3+CD4+%	-0.007	0.861
CD3+CD8+%	-0.009	0.822
CD4/CD8	0.013	0.743
CD19+ (cells/μL)	-0.115	0.003
CD56+ (cells/μL)	-0.090	0.02
CD19+%	0.016	0.685
CD56+%	0.046	0.236

LY: Lymphocyte counts.

Table 7 Multivariable linear regression analysis of factors influencing lymphocyte subset counts in coronavirus disease 2019 patients with non-alcoholic fatty liver disease

		Β	SD	Beta	t	P value
CD3+ (cells/μL)	Age	-4.908	2.731	-0.088	-1.797	0.073
	COVID-19 severity	-450.591	175.134	-0.101	-2.573	0.01
	BMI	20.825	7.259	0.107	2.869	0.004
	IFG	-227.875	81.150	-0.152	-2.808	0.005
	Liver fibrosis	-324.154	71.100	-0.200	-4.599	< 0.001
CD3+CD4+ (cells/μL)	Age	0.507	1.778	0.014	0.285	0.776
	COVID-19 severity	-242.804	114.044	-0.085	-2.129	0.034
	BMI	11.363	4.690	0.091	2.423	0.016
	IFG	-138.203	52.844	-0.144	-2.615	0.009
	Liver fibrosis	-211.795	46.299	-0.204	-4.574	< 0.001
CD3+CD8+ (cells/μL)	Age	-4.062	1.201	-0.169	-3.381	< 0.001
	COVID-19 severity	-171.379	77.042	-0.089	-2.224	0.027
	BMI	9.546	3.197	0.113	2.986	0.003
	IFG	-80.441	35.698	-0.124	-2.253	0.025
	Liver fibrosis	-100.665	31.227	-0.144	-3.218	0.001
LY (cells/μL)	Age	-7.529	3.715	-0.100	-2.027	0.043
	COVID-19 severity	-696.257	238.256	-0.116	-2.922	0.004
	BMI	33.191	9.801	0.126	3.386	< 0.001
	IFG	-233.764	110.399	-0.116	-2.117	0.035
	Liver fibrosis	-390.922	128.213	-0.267	-2.570	< 0.001
CD19+ (cells/μL)	Age	-0.690	0.967	-0.037	-0.714	0.476
	COVID-19 severity	-98.248	62.003	-0.065	-1.585	0.114
	BMI	7.508	2.517	0.113	2.983	0.003
	IFG	-23.139	28.730	-0.046	-0.805	0.421
	Liver fibrosis	-46.090	25.172	-0.084	-1.831	0.068
CD56+ (cells/μL)	Age	-1.478	0.733	-0.106	-1.880	0.044
	COVID-19 severity	-88.335	46.978	-0.080	-1.880	0.061
	BMI	5.588	1.869	0.116	2.990	0.003
	IFG	-24.824	21.768	-0.066	-1.140	0.255
	Liver fibrosis	-3.042	19.072	-0.008	-0.159	0.873

Liver fibrosis: < F2: Non-significant liver fibrosis; ≥ F2: Significant liver fibrosis; ≥ F4: Cirrhosis. The number of comorbidities (0, 1, 2, 3 and more). LY: Lymphocyte counts; COVID-19: Coronavirus disease 2019; BMI: Body mass index; IFG: Impaired fasting glucose.

Table 8 Multivariable linear regression analysis of association between plasma glucose and lipid profiles with lymphocyte subsets in coronavirus disease 2019 patients with non-alcoholic fatty liver disease

		Β	SD	Beta	t	P value
CD3+ (cells/μL)	TC	16.645	97.254	0.029	0.171	0.864
	TG	-2.000	26.365	-0.005	-0.076	0.940
	HDL-C	390.391	359.852	0.154	1.085	0.278
	LDL-C	256.168	67.826	0.371	3.777	< 0.001
	FPG	46.102	27.497	0.194	1.677	0.094
	HbA1c	106.171	27.755	0.205	3.825	< 0.001
CD3+CD4+ (cells/μL)	TC	-0.291	62.833	-0.001	-0.005	0.996
	TG	-8.329	17.034	-0.035	-0.489	0.625
	HDL-C	191.088	232.492	0.118	0.822	0.411
	LDL-C	151.638	43.821	0.343	3.460	< 0.001
	FPG	20.552	17.765	0.135	1.157	0.248
	HbA1c	56.037	17.932	0.169	3.125	0.002
CD3+CD8+ (cells/μL)	TC	15.817	42.833	0.064	0.369	0.712
	TG	6.168	11.612	0.038	0.531	0.595
	HDL-C	184.052	158.486	0.169	1.161	0.246
	LDL-C	97.151	29.872	0.372	3.252	0.001
	FPG	24.161	12.110	0.236	1.995	0.046
	HbA1c	49.049	12.224	0.220	4.013	< 0.001
LY (cells/μL)	TC	-22.561	131.308	-0.029	-0.172	0.864
	TG	-0.236	35.598	0.000	-0.007	0.995
	HDL-C	569.767	485.859	0.167	1.173	0.241
	LDL-C	348.534	91.576	0.375	3.806	< 0.001
	FPG	43.050	37.125	0.134	1.160	0.247
	HbA1c	136.512	37.474	0.196	3.643	< 0.001
CD19+ (cells/μL)	TC	4.811	33.715	0.025	0.143	0.887
	TG	1.366	9.140	0.011	0.149	0.881
	HDL-C	81.301	124.749	0.095	0.652	0.515
	LDL-C	41.076	23.513	0.176	1.747	0.081
	FPG	7.725	9.532	0.096	0.810	0.418
	HbA1c	23.790	9.622	0.136	2.472	0.014
CD56+ (cells/μL)	TC	15.622	25.037	0.110	0.624	0.533
	TG	-5.151	6.787	-0.056	-0.759	0.448
	HDL-C	114.812	92.639	0.185	1.239	0.216
	LDL-C	18.185	17.461	0.107	1.041	0.298
	FPG	18.366	7.079	0.314	2.595	0.01
	HbA1c	-4.433	7.145	-0.035	-0.620	0.535

TC: Total cholesterol; TG: Triglycerides; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; FPG: Fasting plasma glucose; HbA1c: Hemoglobin A1c; LY: Lymphocyte counts.