Comparative Analysis on Clinical Characteristics Among Patients with Acute Hepatitis A Virus (HAV) and Patients with Acute Hepatitis E Virus (HEV): A Single-Center Retrospective Study from Bulgaria

Figures & data

Figure 1 Dynamics of HAV notification rate per 100,000 population in Bulgaria (in red) and EU/EEA (in blue), 2011–2021.

Figure 2 Flow chart showing the selection process of research participants.

Table 1 Clinical Characteristics of Bulgarian Patients with Acute Hepatitis A Virus (HAV) Infection and Acute Hepatitis E Virus (HEV) Infection

Characteristics	HAV (n = 158)	HEV (n = 73)	P-value
Sex, n (%)
Female	72 (45.6)	23 (31.5)	0.043
Male	86 (54.4)	50 (68.5)
Age, years, mean ± SD	40.7 ± 14.8	54.4 ± 14.5	< 0.001
Age groups, n (%)
18–29	42 (26.6)	4 (5.5)	< 0.001
30–39	43 (27.2)	6 (8.2)	0.002
40–49	30 (19.0)	14 (19.2)	0.885
50–59	20 (12.7)	21 (28.8)	0.005
≥ 60	23 (14.5)	28 (38.3)	< 0.001
Length of hospital stay, days, mean ± SD	8.5 ± 3.2	7.9 ± 3.9	0.242
Type of patients, n (%)
Civilians	152 (96.2)	66 (90.4)	0.142
Soldiers	6 (3.8)	7 (9.6)
Exposure history, n (%)
Travel abroad	8 (5.1)	4 (5.5)	0.555
Contact with ill persons	6 (3.8)	0 (0.0)	0.180
Contact with animals	0 (0.0)	1 (1.4)	0.316
Comorbidity, n (%)
Hypertension	18 (11.4)	32 (43.8)	< 0.001
Diabetes mellitus	9 (5.7)	14 (19.2)	0.003
Cardiovascular diseases	8 (5.1)	14 (19.2)	0.002
Malignant diseases	2 (1.3)	7 (9.6)	0.008
Chronic liver diseases	1 (0.6)	6 (8.2)	0.005
COPD	1 (0.6)	3 (4.1)	0.094
Immunodeficiency disorders	0 (0.0)	5 (6.9)	0.003
Clinical signs and symptoms, n (%)
Dark urine	141 (89.2)	61 (83.6)	0.226
Fatigue	123 (77.8)	68 (93.2)	0.004
Abdominal pain	107 (67.7)	53 (72.6)	0.455
Jaundice	103 (65.2)	48 (65.8)	0.933
Nausea / Vomiting	92 (58.2)	39 (53.4)	0.493
Pale stools	91 (57.6)	35 (47.9)	0.171
Muscle pain	86 (54.4)	37 (50.7)	0.596
Malaise	81 (51.3)	47 (64.4)	0.062
Fever	75 (47.5)	19 (26.0)	0.002
Loss of appetite	49 (31.0)	17 (23.3)	0.227
Joint pain	42 (26.6)	4 (5.5)	< 0.001
Skin rash	1 (0.6)	2 (2.7)	0.235
Laboratory parameters (admission), median (IQR)
ALT	1529 (613–2516)	460 (167–1254)	< 0.001
AST	621 (251–1601)	266 (98–951)	< 0.001
GGT	266 (147–409)	313 (169–592)	0.292
AP	190 (145–255)	212 (130–346)	0.280
Total bilirubin	94 (61–138)	67 (20–125)	0.012
Direct bilirubin	64 (36–99)	37 (8–85)	0.012
Total protein	67 (62–71)	69 (62–74)	0.442
Albumin	35 (32–39)	37 (32–42)	0.040
Fibrinogen	3.7 (2.9–4.1)	3.9 (3.2–4.6)	0.077
INR	1.17 (1.04–1.32)	1.07 (1.01–1.15)	0.011
WBC	5.7 (4.7–7.0)	7.4 (5.6–9.5)	< 0.001
Thrombocytes	225 (180–276)	223 (179–288)	0.864
CRP	8.9 (3.6–18.4)	11.2 (1.7–30.2)	0.526
Laboratory parameters (discharge), median (IQR)
ALT	341 (225–462)	202 (102–337)	< 0.001
AST	109 (76–158)	79 (41–127)	0.001
GGT	179 (103–252)	240 (137–418)	0.006
AP	186 (137–232)	172 (131–275)	0.773
Total bilirubin	62 (38–86)	41 (20–84)	0.028
Direct bilirubin	26 (16–43)	18 (6–50)	0.067
Total protein	66 (60–70)	63 (57–67)	0.117
Albumin	33 (30–35)	35 (32–38)	0.114
Fibrinogen	3.8 (3.3–4.0)	3.5 (2.8–3.5)	0.311
INR	1.09 (1.03–1.28)	1.13 (1.03–1.19)	0.940
WBC	6.5 (5.5–7.9)	7.1 (5.8–9.6)	0.229
Thrombocytes	327 (227–373)	234 (187–295)	0.018
CRP	4.2 (2.1–10.3)	5.6 (2.2–22.3)	0.280

Notes: Reference range: AST / ALT, 5–40 U/L; GGT, 10–50 U/L; AP, 64–300 U/L; Total bilirubin, 5–21 µmol/L; Direct bilirubin, 0–5 µmol/L; Total protein, 66–87 g/L; Albumin, 40–55 g/L; Fibrinogen, 2.0–4.5 g/L; INR, 0.8–1.1; WBC, 3.5–10.5 x 10⁹/L; Thrombocytes, 140–440 x 10⁹/L; CRP, 0.0–5.0 mg/L.

Abbreviations: SD, standard deviation; COPD, chronic obstructive pulmonary disease; IQR, interquartile range; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; AP, alkaline phosphatase; INR, international normalized ratio; WBC, white blood cells; CRP, C-reactive protein.

Figure 3 The monthly incidence rates of acute HAV (in blue) and acute HEV (in red).

Table 2 Univariate Logistic Regression Showing the Association Between the Type of Viral Hepatitis (HAV and HEV) and Various Parameters Among Male and Female

Parameter	Male (n = 136)						Female (n = 95)
	Group	n (%) / Median (IQR)	SE	OR	95% CI	P-value	Group	n (%) / Median (IQR)	SE	OR	95% CI	P-value
Comorbidity, n (%)
Hypertension	HAV	12/86 (13.9)		1.000			HAV	6/72 (8.3)		1.000
	HEV	23/50 (46.0)	0.421	5.523	2.301–11.992	< 0.001	HEV	9/23 (39.1)	0.604	7.071	2.166–23.084	0.001
Diabetes mellitus	HAV	6/86 (6.9)		1.000			HAV	3/72 (4.1)		1.000
	HEV	11/50 (22.0)	0.544	3.761	1.295–10.918	0.015	HEV	3/23 (13.0)	0.855	3.450	0.464–18.436	0.148
Cardiovascular diseases	HAV	6/86 (6.9)		1.000			HAV	2/72 (2.7)		1.000
	HEV	12/50 (24.0)	0.537	4.211	1.469–12.072	0.007	HEV	2/23 (8.6)	1.030	3.333	0.442–25.121	0.243
Clinical signs and symptoms, n (%)
Dark urine	HAV	80/86 (93.0)		1.000			HAV	61/72 (84.7)		1.000
	HEV	42/50 (84.0)	0.573	0.696	0.128–1.210	0.394	HEV	19/23 (82.6)	0.640	0.857	0.244–3.004	0.809
Fatigue	HAV	68/86 (79.0)		1.000			HAV	55/72 (76.3)		1.000
	HEV	46/50 (92.0)	0.585	3.044	0.968–9.577	0.057	HEV	22/23 (95.6)	1.059	6.800	0.852–54.241	0.070
Abdominal pain	HAV	57/86 (66.2)		1.000			HAV	50/72 (69.4)		1.000
	HEV	37/50 (74.0)	0.395	1.448	0.668–3.140	0.349	HEV	16/23 (69.5)	0.520	1.006	0.363–2.789	0.991
Jaundice	HAV	60/86 (69.7)		1.000			HAV	43/72 (59.7)		1.000
	HEV	35/50 (70.0)	0.388	1.011	0.473–2.162	0.977	HEV	13/23 (56.5)	0.484	0.877	0.339–2.266	0.786
Nausea / Vomiting	HAV	50/86 (58.1)		1.000			HAV	42/72 (58.3)		1.000
	HEV	27/50 (54.0)	0.358	0.845	0.419–1.706	0.639	HEV	12/23 (52.1)	0.481	0.779	0.304–2.000	0.604
Pale stools	HAV	53/86 (61.6)		1.000			HAV	38/72 (52.7)		1.000
	HEV	23/50 (46.0)	0.360	0.530	0.262–1.074	0.078	HEV	12/23 (52.1)	0.480	0.976	0.381–2.498	0.960
Muscle pain	HAV	44/86 (51.1)		1.000			HAV	42/72 (58.3)		1.000
	HEV	24/50 (48.0)	0.356	0.881	0.439–1.770	0.722	HEV	13/23 (56.5)	0.484	0.929	0.360–2.397	0.878
Malaise	HAV	47/86 (54.6)		1.000			HAV	34/72 (47.2)		1.000
	HEV	31/50 (62.0)	0.363	1.354	0.665–2.758	0.404	HEV	16/23 (69.5)	0.511	2.555	0.938–6.954	0.066
Fever	HAV	41/86 (47.6)		1.000			HAV	34/72 (47.2)		1.000
	HEV	10/50 (20.0)	0.414	0.274	0.122–0.618	0.002	HEV	9/23 (39.1)	0.488	0.718	0.276–1.870	0.498
Loss of appetite	HAV	25/86 (29.0)		1.000			HAV	24/72 (33.3)		1.000
	HEV	13/50 (26.0)	0.400	0.857	0.391–1.879	0.701	HEV	4/23 (17.3)	0.604	0.421	0.129–1.376	0.152
Laboratory parameters (admission), median (IQR)
ALT	HAV	1890 (731–3100)		1.000			HAV	912 (524–2070)		1.000
	HEV	464 (153–1088)	0.0002	1.010	1.001–1.020	< 0.001	HEV	268 (185–1403)	0.001	1.001	1.000–1.003	0.033
AST	HAV	809 (267–1710)		1.000			HAV	448 (245–1177)		1.000
	HEV	241 (107–887)	0.0002	1.002	1.001–1.004	0.002	HEV	287 (82–1127)	0.0004	0.999	0.999–1.000	0.145
GGT	HAV	306 (186–504)		1.000			HAV	197 (130–321)		1.000
	HEV	306 (164–526)	0.0004	1.000	0.999–1.001	0.543	HEV	317 (135–570)	0.001	1.002	1.000–1.005	0.037
Total bilirubin	HAV	107 (78–150)		1.000			HAV	83 (47–122)		1.000
	HEV	69 (25–146)	0.002	0.999	0.995–1.003	0.614	HEV	28 (13–91)	0.004	0.996	0.989–1.004	0.306
Direct bilirubin	HAV	79 (50–102)		1.000			HAV	54 (27–89)		1.000
	HEV	38 (10–105)	0.004	0.997	0.990–1.004	0.380	HEV	28 (4–60)	0.006	0.995	0.984–1.006	0.351
CRP	HAV	12.9 (5.2–23.8)		1.000			HAV	6.2 (2.6–15.7)		1.000
	HEV	10.7 (1.4–30.0)	0.007	1.008	0.994–1.022	0.277	HEV	12.5 (2.2–31.4)	0.010	1.021	1.001–1.042	0.039
Laboratory parameters (discharge), median (IQR)
ALT	HAV	378 (242–504)		1.000			HAV	300 (198–400)		1.000
	HEV	218 (115–444)	0.001	0.998	0.997–1.000	0.060	HEV	173 (89–309)	0.002	0.992	0.988–0.997	0.002
AST	HAV	103 (68–136)		1.000			HAV	116 (81–194)		1.000
	HEV	90 (43–127)	0.002	0.997	0.992–1.001	0.174	HEV	67 (39–98)	0.004	0.992	0.984–1.000	0.040
GGT	HAV	203 (128–274)		1.000			HAV	144 (86–241)		1.000
	HEV	234 (168–418)	0.001	1.002	1.000–1.003	0.059	HEV	245 (83–396)	0.002	1.004	1.000–1.007	0.031
Total bilirubin	HAV	64 (40–86)		1.000			HAV	60 (35–84)		1.000
	HEV	49 (25–125)	0.003	0.999	0.993–1.005	0.795	HEV	23 (12–57)	0.009	0.985	0.967–1.003	0.098
Direct bilirubin	HAV	26 (16–42)		1.000			HAV	25 (15–45)		1.000
	HEV	21 (7–70)	0.005	0.999	0.989–1.008	0.803	HEV	11 (4–38)	0.015	0.983	0.953–1.013	0.253
CRP	HAV	5.4 (2.2–10.5)		1.000			HAV	3.3 (0.9–7.1)		1.000
	HEV	5.1 (2.3–20.0)	0.016	1.017	0.987–1.108	0.263	HEV	7.9 (1.3–31.7)	0.029	1.046	0.987–1.108	0.128

Abbreviations: SE, standard error; OR, odds ratio; CI, confidence interval.

Table 3 Multivariable Logistic Regression Showing the Relationship Between the Type of Viral Hepatitis and Some Parameters Among Male and Female

Parameter	Group	SE	P-value	OR	95% CI
Male
Hypertension	HAV			1.000
	HEV	0.527	0.032	3.091	1.100–8.689
Diabetes mellitus	HAV			1.000
	HEV	0.679	0.489	1.600	0.423–6.048
Cardiovascular diseases	HAV			1.000
	HEV	0.648	0.227	2.186	0.614–7.780
Fever	HAV			1.000
	HEV	0.488	0.148	0.494	0.190–1.284
ALT	HAV			1.000
	HEV	< 0.001	0.003	0.999	0.998–0.999
AST	HAV			1.000
	HEV	< 0.001	0.797	1.000	1.000–1.001
Female
Hypertension	HAV			1.000
	HEV	0.835	0.049	5.161	1.004–26.529
ALT	HAV			1.000
	HEV	< 0.001	0.025	0.999	0.998–0.999
GGT	HAV			1.000
	HEV	0.001	0.128	1.002	0.999–1.005
CRP	HAV			1.000
	HEV	0.012	0.274	1.014	0.989–1.038

Table 4 Univariate Logistic Regression Showing the Association Between the Type of Viral Hepatitis (HAV and HEV) and Various Parameters Among Age Groups (Non-Elderly and Elderly)

Parameter	Non-Elderly (<60-Year-Old) (n = 180)						Elderly (≥60-Year-Old) (n = 51)
	Group	n (%) / Median (IQR)	SE	OR	95% CI	P-value	Group	n (%) / Median (IQR)	SE	OR	95% CI	P-value
Comorbidity, n (%)
Hypertension	HAV	9/135 (6.6)		1.000			HAV	9/23 (39.1)		1.000
	HEV	13/45 (28.8)	0.477	5.687	2.234–14.477	< 0.001	HEV	19/28 (67.8)	0588	3.284	1.036–10.406	0.043
Diabetes mellitus	HAV	4/135 (2.9)		1.000			HAV	5/23 (21.7)		1.000
	HEV	5/45 (11.1)	0.695	4.094	1.049–15.976	0.042	HEV	9/28 (32.1)	0.648	1.705	0.479–6.067	0.410
Cardiovascular diseases	HAV	4/135 (2.9)		1.000			HAV	4/23 (17.3)		1.000
	HEV	5/45 (11.1)	0.695	4.094	1.049–15.976	0.042	HEV	9/28 (32.1)	0.683	2.250	0.590–8.580	0.235
Clinical signs and symptoms, n (%)
Dark urine	HAV	119/135 (88.1)		1.000			HAV	22/23 (95.6)		1.000
	HEV	37/45 (82.2)	0.472	0.622	0.246–1.569	0.314	HEV	24/28 (85.7)	1.156	0.273	0.028–2.630	0.261
Fatigue	HAV	108/135 (80.0)		1.000			HAV	15/23 (65.2)		1.000
	HEV	41/45 (91.1)	0.566	2.562	0.845–7.775	0.097	HEV	27/28 (96.4)	1.108	14.400	1.640–126.443	0.016
Abdominal pain	HAV	92/135 (68.1)		1.000			HAV	15/23 (65.2)		1.000
	HEV	31/45 (68.8)	0.371	1.035	0.500–2.142	0.936	HEV	22/28 (78.5)	0.635	1.956	0.563–6.795	0.291
Jaundice	HAV	87/135 (64.4)		1.000			HAV	16/23 (69.5)		1.000
	HEV	26/45 (57.7)	0.351	0.755	0.379–1.503	0.424	HEV	22/28 (78.5)	0.646	1.604	0.452–5.692	0.465
Nausea / Vomiting	HAV	79/135 (58.5)		1.000			HAV	13/23 (56.5)		1.000
	HEV	24/45 (53.3)	0.346	0.810	0.411–1.597	0.543	HEV	15/28 (53.5)	0.566	0.888	0.293–2.692	0.833
Pale stools	HAV	73/135 (54.0)		1.000			HAV	18/23 (78.2)		1.000
	HEV	21/45 (46.6)	0.345	0.743	0.378–1.462	0.390	HEV	14/28 (50.0)	0.631	0.278	0.081–0.957	0.042
Muscle pain	HAV	73/135 (54.0)		1.000			HAV	13/23 (56.5)		1.000
	HEV	25/45 (55.5)	0.346	1.062	0.539–2.092	0.863	HEV	12/28 (42.8)	0.568	0.577	0.189–1.757	0.333
Malaise	HAV	69/135 (51.1)		1.000			HAV	12/23 (52.1)		1.000
	HEV	31/45 (68.8)	0.365	2.118	1.035–4.333	0.040	HEV	16/28 (57.1)	0.566	1.222	0.403–3.704	0.723
Fever	HAV	68/135 (50.3)		1.000			HAV	7/23 (30.4)		1.000
	HEV	15/45 (33.3)	0.360	0.493	0.243–0.998	0.049	HEV	4/28 (14.2)	0.705	0.381	0.096–1.517	0.171
Loss of appetite	HAV	42/135 (31.1)		1.000			HAV	7/23 (30.4)		1.000
	HEV	8/45 (17.7)	0.432	0.479	0.205–1.116	0.088	HEV	9/28 (32.1)	0.608	1.083	0.329–3.562	0.869
Laboratory parameters (admission), median (IQR)
ALT	HAV	1688 (709–2771)		1.000			HAV	629 (357–1106)		1.000
	HEV	372 (150–974)	<0.001	1.002	1.001–1.003	< 0.001	HEV	572 (242–1318)	0.001	1.000	0.999–1.001	0.830
AST	HAV	691 (274–1629)		1.000			HAV	328 (147–599)		1.000
	HEV	210 (94–846)	0.001	1.002	1.000–1.004	0.001	HEV	317 (149–1105)	0.001	1.000	0.999–1.001	0.565
GGT	HAV	268 (156–409)		1.000			HAV	195 (134–400)		1.000
	HEV	244 (111–490)	0.001	1.001	1.000–1.002	0.142	HEV	334 (289–679)	0.001	1.001	0.999–1.002	0.345
Total bilirubin	HAV	92 (64–125)		1.000			HAV	156 (34–203)		1.000
	HEV	49 (14–98)	0.004	0.989	0.982–0.997	0.005	HEV	121 (37–248)	0.003	0.002	0.996–1.007	0.559
Direct bilirubin	HAV	62 (36–89)		1.000			HAV	104 (36–130)		1.000
	HEV	26 (3–60)	0.006	0.984	0.973–0.994	0.003	HEV	81 (35–141)	0.004	1.002	0.993–1.011	0.683
CRP	HAV	7.9 (3.1–17.1)		1.000			HAV	13.3 (7.8–21.2)		1.000
	HEV	7.9 (1.4–28.2)	0.008	1.008	0.991–1.024	0.354	HEV	19.5 (7.1–31.8)	0.010	1.013	0.993–1.033	0.208
Laboratory parameters (discharge), median (IQR)
ALT	HAV	348 (238–476)		1.000			HAV	273 (167–397)		1.000
	HEV	199 (90–324)	0.001	0.997	0.995–0.999	0.008	HEV	266 (175–395)	0.002	1.000	0.996–1.004	0.952
AST	HAV	108 (76–155)		1.000			HAV	136 (76–165)		1.000
	HEV	71 (36–123)	0.003	0.993	0.987–0.999	0.024	HEV	85 (56–131)	0.004	0.996	0.989–1.003	0.244
GGT	HAV	173 (99–240)		1.000			HAV	229 (139–331)		1.000
	HEV	212 (90–393)	0.001	1.002	1.000–1.004	0.067	HEV	287 (219–512)	0.001	1.001	0.999–1.003	0.332
Total bilirubin	HAV	60 (36–82)		1.000			HAV	71 (52–113)		1.000
	HEV	31 (14–56)	0.006	0.987	0.975–0.999	0.041	HEV	68 (29–145)	0.006	1.003	0.991–1.014	0.648
Direct bilirubin	HAV	24 (15–41)		1.000			HAV	32 (23–57)		1.000
	HEV	11 (3–25)	0.011	0.979	0.958–1.000	0.054	HEV	44 (14–81)	0.011	1.009	0.988–1.030	0.396
CRP	HAV	3.4 (1.6–7.7)		1.000			HAV	11.3 (7.4–22.6)		1.000
	HEV	2.7 (1.0–20.0)	0.024	1.040	0.993–1.090	0.096	HEV	14.3 (3.4–24.2)	0.017	1.003	0.971–1.037	0.853

Table 5 Multivariable Logistic Regression Showing the Relationship Between the Type of Viral Hepatitis and Some Parameters Among Age Groups (Non-Elderly and Elderly)

Parameter	Group	SE	P-value	OR	95% CI
Non-elderly (<60-year-old)
Hypertension	HAV			1.000
	HEV	0.593	0.011	4.544	1.420–14.534
Diabetes mellitus	HAV			1.000
	HEV	0.866	0.690	1.413	0.259–7.710
Cardiovascular diseases	HAV			1.000
	HEV	0.920	0.010	10.560	1.740–64.079
Malaise	HAV			1.000
	HEV	0.437	0.319	1.545	0.656–3.639
Fever	HAV			1.000
	HEV	0.442	0.147	0.527	0.221–1.254
ALT	HAV			1.000
	HEV	< 0.001	0.002	0.998	0.997–0.999
GGT	HAV			1.000
	HEV	0.001	0.276	1.001	1.000–1.002
Elderly (≥60-year-old)
Hypertension	HAV			1.000
	HEV	0.661	0.069	3.323	0.911–12.128
Fatigue	HAV			1.000
	HEV	1.162	0.029	12.592	1.291–122.848
Pale stools	HAV			1.000
	HEV	0.687	0.178	0.396	0.103–1.523