Literature search
In the initial search, 615 articles were identified from five electronic international databases. A total of 277 duplicates was excluded, and then 338 articles were screened by title and abstract, which led to the elimination of 260 articles. The remaining 78 articles were checked for agreement with the inclusion and exclusion criteria by the full-text review. After full-text screening, 28 articles were excluded due to the following: 12 articles were not relevant to the subject, 10 articles were included duplicated data, four articles had no full-text available, one article was determined the incidence of HEV among HD patients, and one article was not presented sufficient data. In addition, six relevant articles were found and included by a manual search of the reference lists of the identified articles. Finally, 56 articles were included in this systematic review and meta-analysis. Figure 1 represents the process of literature retrieval and screening using a flow chart.
Study characteristics
In this meta-analysis, a total of 56 studies, including a total of 9483 patients from 20 countries were included. Publication date of articles was ranged from 1994 to 2020. The characteristics of eligible studies in this systematic review and meta-analysis are summarized in Table 2. The largest study [18] included 420 and the smallest [19] included 30 HD patients. Most studies investigating the seroprevalence of HEV among patients undergoing HD were from Iran (n=11), Italy (n=7), and Turkey (n=6). Of the 56 studies included, 17 provided information on patients’ sex, 7 studies provided information on patients’ sex, 4 had information on duration of HD, and 6 studies presented data on history of blood transfusion. In total, 53.5% of the studies (n=30) were performed before 2010, and 46.5% of the studies (n=26) were performed after 2010.
Table 2. Characteristics of studies included in the systematic review and meta-analysis
Author (Ref.)
|
Year
|
Study Location
|
Sample size
|
Mean age (year)
|
Detection method
|
No. of HEV seropositive cases
|
Mean duration of HD (Month)
|
Halfon [23]
|
1994
|
France
|
147
|
62.3
|
ELISA/Western blot
|
16
|
-
|
Knödler [24]
|
1994
|
Germany
|
150
|
-
|
ELISA/Western blot
|
5
|
-
|
Buti [25]
|
1995
|
Spain
|
50
|
-
|
ELISA/Western blot
|
3
|
-
|
Cengiz [26]
|
1996
|
Turkey
|
72
|
45.5
|
ELISA
|
10
|
56.4
|
Fabrizi [27]
|
1996
|
Italy
|
204
|
-
|
ELISA
|
6
|
-
|
Gessoni [28]
|
1996
|
Italy
|
193
|
59.5
|
ELISA
|
18
|
-
|
Guiserix [29]
|
1996
|
France
|
62
|
-
|
ELISA
|
2
|
-
|
Psichogiou [18]
|
1996
|
Greece
|
420
|
57.3
|
ELISA
|
27
|
61.4
|
Fabrizi [30]
|
1997
|
Italy
|
204
|
61.1
|
ELISA
|
6
|
39
|
Parana [22]
|
1997
|
Brazil
|
392
|
-
|
ELISA
|
0
|
-
|
Abdel Hady [31]
|
1998
|
Egypt
|
96
|
-
|
ELISA
|
38
|
-
|
Arinsoy [32]
|
1998
|
Turkey
|
52
|
-
|
ELISA
|
9
|
-
|
Gessoni [33]
|
1998
|
Italy
|
247
|
-
|
ELISA
|
23
|
-
|
Dalekos [34]
|
1998
|
Greece
|
211
|
-
|
ELISA/Western blot
|
7
|
-
|
Sylvan [35]
|
1998
|
Sweden
|
182
|
-
|
ELISA
|
11
|
-
|
Agarwal [36]
|
1999
|
India
|
64
|
38
|
ELISA
|
26
|
-
|
Kilic [37]
|
1999
|
Turkey
|
70
|
-
|
ELISA
|
4
|
-
|
Mateos [38]
|
1999
|
Spain
|
63
|
-
|
ELISA/Western blot
|
4
|
62
|
Trinta [39]
|
2001
|
Brazil
|
65
|
65.1
|
ELISA
|
4
|
-
|
Irshad [40]
|
2002
|
India
|
58
|
-
|
ELISA
|
21
|
-
|
Ayoola [41]
|
2002
|
Saudi Arabia
|
83
|
39
|
ELISA
|
6
|
-
|
Kiesslich [42]
|
2002
|
Brazil
|
192
|
-
|
ELISA
|
1
|
-
|
Ding [43]
|
2003
|
Japan
|
60
|
46.2
|
ELISA
|
18
|
-
|
Mitsui [44]
|
2004
|
Japan
|
416
|
60.1
|
ELISA
|
39
|
91.2
|
Stefanidis [45]
|
2004
|
Greece
|
351
|
60
|
ELISA
|
17
|
49
|
Lee [46]
|
2005
|
Taiwan
|
400
|
57
|
ELISA
|
124
|
32
|
Taremi [47]
|
2005
|
Iran
|
324
|
53.5
|
ELISA
|
24
|
53.45
|
Kikuchi [48]
|
2006
|
Japan
|
300
|
60.1
|
ELISA
|
57
|
116.4
|
Pourahmad [49]
|
2009
|
Iran
|
43
|
59.3
|
ELISA
|
3
|
108
|
Uçar [50]
|
2009
|
Turkey
|
92
|
55
|
ELISA
|
19
|
66
|
Mina [51]
|
2010
|
Greece
|
366
|
60.5
|
ELISA
|
15
|
49.2
|
Khameneh [52]
|
2011
|
Iran
|
65
|
-
|
ELISA
|
22
|
-
|
El Sayed Zaki [19]
|
2013
|
Egypt
|
30
|
-
|
ELISA
|
0
|
-
|
Harrison [53]
|
2013
|
United Kingdom
|
76
|
-
|
ELISA
|
28
|
-
|
Mobaien [54]
|
2013
|
Iran
|
93
|
57
|
ELISA
|
25
|
-
|
Scotto [55]
|
2013
|
Italy
|
104
|
65.1
|
ELISA/Western blot
|
10
|
-
|
Zekavat [56]
|
2013
|
Iran
|
80
|
55.69
|
ELISA
|
5
|
15.6
|
Ben-Ayed [57]
|
2014
|
Tunisia
|
286
|
54.86
|
ELISA
|
29
|
-
|
Kelishadi [21]
|
2014
|
Iran
|
149
|
56
|
ELISA
|
0
|
-
|
Mousavi [58]
|
2014
|
Iran
|
47
|
55.27
|
ELISA
|
5
|
-
|
Alavian [59]
|
2015
|
Iran
|
274
|
59.9
|
ELISA
|
78
|
34.6
|
El Sayed Zaki [60]
|
2015
|
Egypt
|
96
|
46.6
|
ELISA
|
22
|
-
|
Eini [61]
|
2015
|
Iran
|
153
|
-
|
ELISA
|
30
|
33
|
Scotto [62]
|
2015
|
Italy
|
231
|
-
|
ELISA/Western blot
|
14
|
-
|
Debes [63]
|
2016
|
Argentina
|
81
|
-
|
ELISA
|
8
|
-
|
Hajiahmadi [64]
|
2016
|
Iran
|
149
|
55.09
|
ELISA
|
6
|
-
|
Pisano [65]
|
2016
|
Argentina
|
82
|
60
|
ELISA
|
8
|
-
|
Naziri [66]
|
2016
|
Iran
|
300
|
54
|
ELISA
|
12
|
-
|
Ricco [67]
|
2016
|
Italy
|
88
|
74.3
|
ELISA
|
22
|
-
|
Yılmaz [68]
|
2017
|
Turkey
|
66
|
-
|
ELISA
|
28
|
-
|
Sheng [20]
|
2017
|
China
|
170
|
-
|
ELISA
|
82
|
-
|
Altuǧlu [69]
|
2018
|
Turkey
|
68
|
49.2
|
ELISA
|
1
|
37.9
|
de Oliveira [70]
|
2018
|
Brazil
|
310
|
-
|
ELISA/Western blot
|
8
|
-
|
Kuznetsova [71]
|
2018
|
Estonia
|
176
|
50.9
|
ELISA/Western blot
|
7
|
-
|
Lemos [72]
|
2019
|
Brazil
|
286
|
-
|
ELISA
|
70
|
-
|
Mrzljak [73]
|
2020
|
Croatia
|
394
|
70.5
|
ELISA
|
110
|
-
|
Seroprevalence of HEV infection among HD patients
The pooled estimated seroprevalence of HEV infection in HD patients around the world was 9.31 % (95% CI: 6.83%-12.57%), and the range was from 48.24% [20] to 0% [19, 21, 22] of the selected individual studies. The results of the heterogeneity test indicated a significant heterogeneity among all studies that were analyzed in this meta-analysis, so the random-effects model was used for pooling the data. The highest and lowest seroprevalence of HEV were found in HD patients from China and Brazil, respectively (48.24%, 95%CI: 40.82%–55.73% vs 1.77%, 95%CI: 0.23%–12.31%). To explore responsible factors for heterogeneity, subgroup analysis was conducted. This analysis showed that diagnostic method, duration of HD, age, study year, and study location are responsible for heterogeneity.
We divided the individual studies into two time periods of publication, before and after 2010. The polled estimated seroprevalence of HEV infection before and after 2010 were different, 8.1% (95% CI: 5.36%-12.05%) and 10.94% (95% CI: 6.91%-16.89%), respectively (Figure 2). However, the difference was not statistically significant (P=0.3). Among studies performed after 2010, the maximum and minimum seroprevalence of HEV among HD patients were found in China and Estonia, respectively (48.24%, 95%CI: 40.82%–55.73% vs 3.98%, 95%CI: 1.91%–8.11%).
The seroprevalence of HEV among patients with hemodialysis duration more than 60 months was significantly higher than those with hemodialysis duration less than 60 months (27.69%, 95%CI: 20.69%–35.99% vs 15.78%, 95%CI: 8.85%–26.57%, respectively) (P= 0.06). Furthermore, the proportion of HEV seropositivity among male cases undergoing HD was slightly higher than female cases (10.86%, 95%CI: 6.66%–17.20% vs 9.54%, 95%CI: 5.62%–15.74%, respectively) (P=0.7). With respect to HEV serodetection techniques in blood samples of HD patients, ELISA with or without western blot assay as a confirmatory test was used. HEV seroprevalences were 10.37% (95%CI: 7.30%–14.54%) and 5.14% (95%CI: 3.62%–7.25%) when ELISA and ELISA/western blot assays were used, respectively, and the difference was statistically significant (P= 0.005). Table 3 indicates more detailed information on the seroprevalence of HEV infection among HD patients for subgroups. In addition, our results showed that blood transfusion is associated with a nearly two-fold increase in the rate of HEV seropositivity (OR=1.99; 95%CI: 1.50-2.63, P value < 0.0001, I2=6.5%) (Figure 3).
Table 3. Subgroup analysis of the seroprevalence of HEV infection in HD patients
NA: Not applicable; ELISA: enzyme-linked immunosorbent assay;
† Statistical significant
Characteristics
|
Categories
|
No. of Studies
|
Pooled prevalence (%) (95% CI)
|
Heterogeneity test
I2 %, p-value
|
Differences between subgroups; χ2 test
(p-value)
|
Overall
|
|
56
|
9.31 (6.83-12.57)
|
95.9%, P<0.01
|
|
Diagnostic method
|
ELISA
|
47
|
10.37 (7.30-14.54)
|
96.6%, P<0.01
|
P=0.005†
|
ELISA/Western blot
|
9
|
5.14 (3.62-7.25)
|
55.4%, P=0.01
|
Duration of HD (Month)
|
60>
|
4
|
15.78 (8.85-26.57)
|
87.8%, P<0.01
|
P=0.06
|
60<
|
2
|
27.69 (20.69-35.99)
|
0%, P=0.1
|
Age (Year)
|
40>
|
6
|
4.91 (1.76-12.97)
|
52.9%, P=0.09
|
P=0.1
|
40<
|
7
|
12.19 (6.42-21.93)
|
94.9%, P<0.01
|
Gender
|
Male
|
17
|
10.86 (6.66-17.20)
|
94.0%, P=0.01
|
P=0.7
|
Female
|
17
|
9.54 (5.62-15.74)
|
91.5%, P=0.01
|
Study year
|
1994-2000
|
18
|
6.60 (3.82-11.16)
|
92.9%, P<0.01
|
P=0.6
|
2001-2005
|
9
|
9.81 (4.54-19.93)
|
96.4%, P<0.01
|
2006-2010
|
4
|
10.77 (5.16-21.12)
|
89.4%, P<0.01
|
2011-2015
|
13
|
11.70 (6.15-21.15)
|
95.5%, P<0.01
|
2016-2020
|
12
|
11.13 (5.59-20.94)
|
96.8%, P<0.01
|
Study location
|
Argentina
|
2
|
9.82 (6.10-15.42)
|
0%, P=0.98
|
P<0.0001†
|
Brazil
|
5
|
1.77 (0.23-12.31)
|
96.2%, P<0.01
|
China
|
1
|
48.24 (40.82-55.73)
|
NA, NA
|
Croatia
|
1
|
27.92 (23.71-32.55)
|
NA, NA
|
Egypt
|
3
|
12.78 (1.54-57.82)
|
96.6%, P=0.05
|
Estonia
|
1
|
3.98 (1.91-8.11)
|
NA, NA
|
France
|
2
|
7.63 (3.29-16.72)
|
28.2%, P=0.09
|
Germany
|
1
|
3.33 (1.39-7.76)
|
NA, NA
|
Greece
|
4
|
4.90 (3.86-6.19)
|
0%, P=0.30
|
India
|
2
|
38.52 (30.32-47.43)
|
0%, P=0.62
|
Iran
|
11
|
9.11 (4.53-17.49)
|
95.0%, P<0.01
|
Italy
|
7
|
7.52 (4.39-12.58)
|
85.8%, P<0.01
|
Japan
|
3
|
17.26 (9.87-28.44)
|
88.7%, P<0.01
|
Saudi Arabia
|
1
|
7.23 (3.28-15.17)
|
NA, NA
|
Spain
|
2
|
6.19 (2.98-12.43)
|
0%, P=0.94
|
Sweden
|
1
|
6.04 (3.38-10.58)
|
NA, NA
|
Taiwan
|
1
|
31.00 (26.66-35.70)
|
NA, NA
|
Tunisia
|
1
|
10.14 (7.14-14.21)
|
NA, NA
|
Turkey
|
6
|
12.92 (5.65-26.87)
|
89.6%, P<0.01
|
United Kingdom
|
1
|
36.84 (26.79-48.18)
|
NA, NA
|
Time trend analysis
Time trend analysis was performed to investigate changes in the seroprevalence of HEV infection over time in the world (Figure 4). According to this analysis, the seroprevalence of HEV was the lowest (6.6%; 95% CI: 3.82%-11.16%) between the years of 1994 and 2000. Since 2001 until 2020, the number of HEV-seropositive cases among HD patients dramatically was increased, and the seroprevalence was 11.13% (95% CI: 5.59%-20.94%) between the years of 2016 and 2020 (Table 3).