Clinical features of acute hepatitis E super-infections on chronic hepatitis B

Table 1 Baseline demographic characteristics, clinical features and laboratory data for hepatitis B virus-hepatitis E virus co-infected patients

Characteristic	Total patients	Cirrhotic patients	Non-cirrhotic patients	P value
	(n = 228)	(n = 94)	(n = 134)
Baseline characteristics
Age (yr) (Q1-Q3)	49 (37-58)	55 (44.8-62.3)	44 (35.0-53.3)	< 0.001
Male sex, n (%)	167 (73.3)	74 (78.7)	93 (69.4)	0.118
Alcohol, n (%)	74 (34.5)	37 (39.4)	37 (27.6)	0.062
Smoker, n (%)	72 (31.6)	30 (31.9)	42 (31.3)	0.927
Clinical features, n (%)
Bilirubin > 10-fold ULN	76 (33.3)	33 (35.1)	43 (32.1)	0.634
Ascites	83 (36.4)	62 (66)	21 (15.7)	< 0.001
Infection	73 (32)	47 (50)	26 (19.4)	< 0.001
HE	39 (17.1)	24 (25.5)	15 (11.2)	< 0.010
GH	11 (4.8)	11 (11.7)	0	< 0.001
Outcomes of disease, n (%)
Severe disease	111 (48.7)	73 (77.7)	38 (28.4)	< 0.001
Mortality	30 (13.2)	20 (21.3)	10 (7.5)	< 0.010
Laboratory parameters
ALT (IU/L)	239.5 (62.5-773.5)	115 (10.8-456.8)	429.5 (89.8-966.8)	< 0.001
AST (IU/L)	144 (63-422.5)	112 (54.5-364.5)	185 (74.5-475.0)	0.077
Tbil (μmol/L)	61.5 (19.0-257.6)	68.1 (22.8-296.5)	59.6 (16.9-246.8)	0.245
ALB (g/dL)	37.8 (32.1-40)	33.1 (28.7-36.7)	38.1 (34.4-40.9)	< 0.001
INR	1.2 (1.0-1.6)	1.4 (1.2-1.8)	1.1 (1.0-1.3)	< 0.001
LEU count (109/L)	5.3 (4.1-7.1)	4.6 (3.3-6.6)	6.0 (4.6-7.2)	< 0.001
Platelet count (109/L)	115 (78-163)	83 (53.8-114.3)	147.5 (97.8-182.3)	< 0.001
NEU count (109/L)	1.4 (1.0-1.9)	1.1 (0.8-1.5)	1.7 (1.2-2.2)	0.080

Data are presented as median (Q1-Q3) and number of patients (%). Severe disease was defined as liver failure and/or liver decompensation. ALB: Albumin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GH: Gastrointestinal hemorrhage; HE: Hepatic encephalopathy; INR: International normalized ratio; LEU: Leukocytes; NEU: Neutrophil; Tbil: Total bilirubin; ULN: Upper limit of normal.

Table 2 Clinical features and laboratory data for hepatitis B virus-hepatitis E virus co-infected patients with underlying decompensated or compensated liver cirrhosis n (%)

Characteristic	Decompensated	Compensated	P value
	(n = 9)	(n = 85)
Baseline characteristics
Age, yr (Q1-Q3)	58 (54.0-62.5)	55 (41.5-62.5)	0.183
Male sex	8 (88.9)	66 (77.7)	0.679
Alcohol	2 (22.2)	35 (41.2)	0.475
Smoker	3 (33.3)	27 (31.8)	0.982
Clinical features
Bilirubin > 10-fold ULN	2 (22.2)	32 (37.7)	0.480
Ascites	8 (88.9)	54 (63.5)	0.160
Infection	6 (66.7)	41 (48.2)	0.486
HE	6 (66.7)	18 (21.2)	< 0.010
GH	1 (11.1)	10 (11.8)	0.982
Outcomes of disease
Severe disease	9 (100)	64 (75.3)	0.200
Mortality	2 (22.2)	18 (21.2)	0.973
Laboratory parameters
ALT ( IU/L)	51 (37.0-114.5)	122 (41.5-545.0)	0.094
AST (IU/L)	81 (49.0-188.5)	118 (53.0-399.5)	0.253
Tbil (μmol/L)	39.5 (22.5-165.8)	85.7 (22.4-322.4)	0.433
ALB (g/dL)	28.7 (26.6-34.9)	33.2 (29.1-37.3)	0.114
INR	1.5 (1.2-1.6)	1.4 (1.2-1.8)	0.995
LEU count (109/L)	3.9 (2.0-7.5)	4.6 (3.5-6.3)	0.516
Platelet count (109/L)	54 (44.0-84.5)	85 (58.8-117.3)	0.080
NEU count (109/L)	2.8 (1.2-6.4)	3.0 (1.8-4.4)	0.933

Data are presented as median (Q1-Q3) and number of patients (%). Severe disease was defined as liver failure and/or liver decompensation. ALB: Albumin; ALT: Alanine aminotransferase; AST; Aspartate aminotransferase; GH: Gastrointestinal hemorrhage; HE: Hepatic encephalopathy; INR: International normalized ratio; LEU: Leukocytes; NEU: Neutrophil; Tbil: Total bilirubin; ULN: Upper limit of normal.

Table 3 Previous comorbidities, chronic hepatitis B-related status and disease severity for co-infected cirrhotic patients n (%)

	Cirrhotic	Severe	Mild	P value
	(n = 94)	(n = 73)	(n = 21)
Baseline characteristics
Age (yr) (Q1-Q3)	55 (44.8-62.3)	56 (45.5-62.5)	52 (38-62)	0.254
Male sex	74 (78.7)	61 (83.6)	13 (61.9)	0.065
Smoker	30 (31.9)	27 (37)	3 (14.3)	< 0.050
Alcohol	37 (39.4)	31 (42.5)	6 (28.6)	0.251
Potential hepatoxic medications	8 (8.5)	8 (11)	0	0.192
Pre-existing comorbidities, n (%)
Hypertension	12 (12.8)	8 (11)	4 (19.1)	0.456
Diabetes	10 (10.6)	9 (12.3)	1 (4.8)	0.448
Respiratory diseases	4 (4.3)	4 (5.5)	0	0.572
Kidney diseases	10 (10.6)	9 (12.3)	1 (4.8)	0.448
Other liver diseases	24 (25.5)	21 (28.8)	3 (14.3)	0.180
HBeAg positivity	32 (34)	22 (30.1)	10 (47.6)	0.136
HBV DNA positivity	69 (73.4)	52 (71.2)	17 (81)	0.374
HBV DNA < 500 IU/mL	25 (26.6)	21 (28.8)	4 (19.1)	0.374
500 ≤ HBV DNA < 5 × 105 IU/mL	31 (33)	22 (30.1)	9 (42.9)	0.275
HBV DNA ≥ 5 × 105 IU/mL	38 (40.4)	30 (41.1)	8 (38.1)	0.805
Pre-anti-HBV therapy	27 (28.7)	19 (26)	8 (38.1)	0.281
Effective	11 (11.7)	9 (12.3)	2 (9.5)	0.982
Post-anti-HBV therapy	40 (42.6)	34 (46.6)	6 (28.6)	0.141

Data are presented as median (Q1-Q3) or number of patients (%). The severe cases included patients with liver failure, liver decompensation or both; The remaining were regarded as mild cases. Respiratory diseases: chronic obstructive pulmonary disease, bronchial asthma, bronchiectasis, tuberculosis, phthisis; Kidney diseases: kidney stone, renal cyst, chronic renal insufficiency, chronic glomerulonephritis; Other liver diseases: chronic hepatitis C, alcoholic liver disease, fatty liver, autoimmune liver diseases, schistosomiasis, primary hepatic carcinoma, hepatic cyst, hepatic hemangioma. Pre-anti-hepatitis B virus (HBV) therapy consisted of nucleos/tide analogues for more than 3 mo before the disease onset; Post-anti-HBV therapy consisted of IFNα within 3 mo from the disease onset; Therapeutic efficacy was defined as HBV DNA reduction by 2 log after stable antiviral treatment for 3 mo.

Table 4 Clinical features and laboratory data for patients with non-cirrhotic hepatitis B virus-hepatitis E virus co-infections n (%)

Characteristic	IT	IC	LC	RA	P value
	(n = 38)	(n = 27)	(n = 16)	(n = 53)
Baseline characteristics
Age (yr ) (Q1-Q3)	43 (30-52)	42 (34-51)	48 (39.3-58.8)	47 (36.0-56.5)	0.134
Male sex	17 (44.7)	22 (81.5)	13 (81.3)	41 (77.4)	< 0.010
Alcohol	7 (18.4)	5 (18.5)	5 (31.3)	20 (37.7)	0.136
Smoker	8 (21.1)	8 (29.6)	4 (25)	22 (41.5)	0.191
Clinical features
Jaundice > 10 ULN	6 (15.8)	6 (22.2)	6 (37.5)	25 (47.2)	< 0.010
Ascites	4 (10.5)	3 (11.1)	0	14 (26.4)	< 0.050
Infection	4 (10.5)	2 (7.4)	4 (25)	16 (30.2)	< 0.050
HE	1 (2.6)	1 (3.7)	0	13 (24.5)	< 0.010
Outcomes of disease
Severe disease	5 (13.2)	6 (22.2)	5 (31.3)	22 (41.5)	< 0.050
Mortality	1 (2.6)	0	0	9 (17)	< 0.010
Laboratory parameters
ALT (IU/L)	276.5 (77.5-520.5)	454 (214-822)	597.5 (156.75-1188.5)	447 (70-1034.5)	0.231
AST (IU/L)	162 (66.3-471.0)	186 (108-527)	266 (55.5-841.0)	200 (70.5-421.0)	0.854
Tbil (μmol/L)	22.1 (10.5-42.9)	38.8 (15.0-162.3)	160.3 (63.9-205.5)	148.4 (29.8-339.0)	< 0.001
ALB (g/dL)	38.4 (35.0-40.8)	39.4 (35.1-42.0)	36.5 (32.9-39.4)	36.5 (33.5-41.2)	0.199
INR	1.1 (1.0-1.2)	1.1 (1.0-1.2)	1.1 (0.9-1.3)	1.1 (1-2)	< 0.050
LEU count (109/L)	5 (4.3-6.5)	6.2 (5.0-6.9)	7.2 (5.4-9.0)	6.1 (4.4-7.1)	< 0.050
Platelet count (109/L)	155 (102.3-205.3)	149 (103-190)	177.5 (124.3-200.0)	126 (93-159)	0.072
NEU count (109/L)	2.7 (2.3-3.7)	3.4 (2.8-4.2)	3.9 (2.8-5.5)	3.7 (2.1-4.8)	0.144

Data are presented as median (Q1-Q3) and number of patients (%). Severe disease was defined as liver failure and/or liver decompensation. ALB: Albumin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HE: Hepatic encephalopathy; INR: International normalized ratio; LEU: Leukocytes; NEU: Neutrophil; Tbil: Total bilirubin; ULN: Upper limit of normal.

Table 5 Previous comorbidities, chronic hepatitis B related status and disease severity for co-infected non-cirrhotic patients n (%)

Characteristic	Non-cirrhotic (n = 134)	Severe (n = 38)	Mild (n = 96)	P value
Baseline characteristics
Age (yr) (Q1-Q3)	44 (35-53.3)	47.5 (36-56.3)	44 (32.5-53)	0.167
Male sex	93 (69.4)	30 (80.0)	63 (65.6)	0.131
Alcohol	37 (27.6)	18 (47.4)	19 (19.8)	< 0.010
Smoker	42 (31.3)	16 (42.1)	26 (27.1)	0.091
Potential hepatoxic medications	18 (13.4)	9 (23.7)	9 (9.4)	< 0.050
Pre-existing comorbidities
Hypertension	13 (9.7)	4 (10.5)	9 (9.4)	0.986
Diabetes	15 (11.2)	9 (23.7)	6 (6.3)	< 0.050
Respiratory diseases	9 (6.7)	3 (7.9)	6 (6.3)	0.713
Kidney diseases	10 (7.5)	8 (21.1)	2 (2.1)	< 0.010
Extrahepatic tumors	2 (1.5)	1 (2.6)	1 (1.0)	0.488
Other liver diseases	24 (17.9)	6 (15.8)	18 (18.8)	0.687
HBeAg positive	65 (48.5)	11 (29.0)	54 (56.3)	< 0.010
HBV DNA positivity	98 (73.1)	29 (76.3)	69 (71.9)	0.601
HBV DNA < 500 IU/mL	36 (26.9)	9 (23.7)	27 (28.1)	0.556
500 ≤ HBV DNA < 5 × 105 IU/mL	36 (26.9)	18 (47.4)	18 (18.8)	< 0.010
HBV DNA ≥ 5 × 105 IU/mL	62 (46.3)	11 (29.0)	51 (53.1)	< 0.050
Pre-anti-HBV therapy	12 (9)	2 (5.3)	10 (10.4)	0.508
Effective	3 (2.2)	1 (2.6)	2 (2.1)	0.991
Post-anti-HBV therapy	30 (22.4)	10 (26.3)	20 (20.8)	0.493

Data are presented as median (Q1-Q3) or number of patients (%). P value was derived from comparisons between mild and severe cases. The severe cases included patients with liver failure, liver decompensation or both; The remaining were regarded as mild cases. Respiratory diseases: chronic obstructive pulmonary disease, bronchial asthma, bronchiectasis, tuberculosis, phthisis; Kidney diseases: kidney stone, renal cyst, chronic renal insufficiency, chronic glomerulonephritis; Other liver diseases: chronic hepatitis C, alcoholic liver disease, fatty liver, autoimmune liver diseases, schistosomiasis, primary hepatic carcinoma, hepatic cyst, hepatic hemangioma. Pre-anti-hepatitis B virus (HBV) therapy consisted of nucleos/tide analogues for more than 3 mo before the disease onset; Post-anti-HBV therapy consisted of IFNα within 3 mo from the disease onset; Therapeutic efficacy was defined as HBV DNA reduction by 2 log after stable antiviral treatment for 3 mo.

Table 6 Risk factors for disease severity in non-cirrhotic hepatitis B virus-hepatitis E virus co-infection

Risk factors	Odds ratio for severe liver diseases
	Odds ratio (95%CI)1	P value1	Odds ratio (95%CI)2	P value2
Non-cirrhotic patients (n = 134)
Male sex	2 (0.8-4.8)	0.135
Age	1 (0.9-1.1)	0.135
Alcohol	3.7 (1.6-8.2)	< 0.01	6.4 (1.3-31.4)	< 0.05
Smoker	2.8 (1.2-6.7)	< 0.05	0.4 (0.1-2.4)	0.341
Potential hepatoxic medications	3 (1.1-8.3)	< 0.05	2 (0.56-7.2)	0.296
Diabetes	4.7 (1.5-14.2)	< 0.01	7.5 (2-28.5)	< 0.01
Hypertension	1.1 (0.3-3.9)	0.839
Respiratory diseases	1.3 (0.3-5.4)	0.732
Kidney diseases	12.5 (2.5-62.3)	< 0.01	12.7 (2.1-76)	< 0.01
Extrahepatic tumors	2.6 (0.2-42.1)	0.509
Other liver disease	0.8 (0.3-2.2)	0.687
HBeAg positive	0.3 (0.1-0.7)	< 0.01	0.4 (0.1-1.3)	0.118
HBV DNA status
HBV DNA < 500 IU/mL	Reference	< 0.01	Reference	< 0.05
500 ≤ HBV DNA < 5 × 105 IU/mL	3 (1.1-8.1)	< 0.05	5.1 (1.4-18.2)	< 0.05
HBV DNA ≥ 5 × 105 IU/mL	0.7 (0.2-1.8)	0.392	2 (0.5-8.6)	0.347
Pre-anti-HBV therapy	0.5 (0.1-2.3)	0.356
Effective	1.3 (0.1-14.4)	0.847
Post-anti-HBV therapy	1.4 (0.6-3.3)	0.493

¹Odds ratio (95%CI) and P value refer to single factor analysis;

²Odds ratio (95%CI) and P value correspond to multivariate logistic regression results. With hepatitis B virus (HBV) DNA < 500 IU/mL as reference category respectively. Multivariate logistic regression models were used to assess the association between various risk factors and severe disease. The severe cases included patients with liver failure, liver decompensation or both; The remaining were regarded as mild cases. Respiratory diseases: chronic obstructive pulmonary disease, bronchial asthma, bronchiectasis, tuberculosis, phthisis; Kidney diseases: kidney stone, renal cyst, chronic renal insufficiency, chronic glomerulonephritis; Other liver diseases: chronic hepatitis C, alcoholic liver disease, fatty liver, autoimmune liver diseases, schistosomiasis, primary hepatic carcinoma, hepatic cyst, hepatic hemangioma. Pre-anti-HBV therapy consisted of nucleos/tide analogues for more than 3 mo before the disease onset; Post-anti-HBV therapy consisted of IFNα within 3 mo from the disease onset; Therapeutic efficacy was defined as HBV DNA reduction by 2 log after stable antiviral treatment for 3 mo.