TRANSFUSION COMPLICATIONS Declining prevalence of hepatitis E antibodies among Danish blood donors Dorte K. Holm,1 Belinda K. Moessner,2 Ronald E. Engle,3 Hans L. Zaaijer,4 Jørgen Georgsen,1 Robert H. Purcell,3 and Peer B. Christensen2

BACKGROUND: The increasing incidence of reported hepatitis E cases in Europe has focused attention on hepatitis E virus (HEV) and the risk of transfusiontransmitted hepatitis E. The aim of this study was to investigate the prevalence of antibodies to HEV (antiHEV) among Danish blood donors in 2013 and to compare it to previous studies in Denmark. In addition we wanted to compare the relative reactivity of two different assays. STUDY DESIGN AND METHODS: Samples from 504 blood donors were collected and analyzed for anti-HEV with an in-house assay developed at the National Institutes of Health (NIH). In addition the samples were analyzed with the Wantai anti-HEV assay. Demographic information and possible HEV exposure was collected by self-administered questionnaire. RESULTS: Using the NIH assay the prevalence of antiHEV among Danish blood donors was 10.7% and with the Wantai assay the prevalence of anti-HEV was 19.8% (p < 0.001). In both cases the presence of anti-HEV was significantly correlated with increasing age. In addition, anti-HEV as measured by the Wantai test was significantly associated with contact with children (p 5 0.01), but in multivariate analysis only age was associated with anti-HEV in both assays. By the NIH assay, the prevalence had declined from 20.6% in 2003 to 10.7% in 2013. CONCLUSIONS: Anti-HEV prevalence had decreased by half among Danish blood donors over 10 years, but was still highly prevalent. The difference in reactivity of the two assays demonstrates the importance of using the same assay when comparing the anti-HEV prevalence in populations over time.

H

epatitis E is the most common cause of acute hepatitis and jaundice worldwide.1 The virus of hepatitis E is a small nonenveloped RNA virus belonging to the Hepeviridae family.2 HEV consists of multiple genotypes and its classification is being revised.3,4 Genotypes 1 and 2 are human viruses and the most common cause of epidemic hepatitis E in developing countries. Genotypes 1 and 2 are often associated with contaminated drinking water and fecal-oral transmission. Genotypes 3 and 4 are associated with zoonotic infections with a porcine reservoir and other genotypes have been found in birds.5 Genotypes 1 and 2 appear to be more virulent than Genotypes 3 and 4 in humans and infect younger people than Genotypes 3 and 4. Based on the high prevalence of anti-HEV in Western populations, infections with Genotypes 3 and 4 must be subclinical in the vast majority of cases.6 It may have a more serious course in elderly men and can lead to chronic infection in immunocompromised patients.7

ABBREVIATION: S/CO 5 signal to cutoff. From the 1Department of Clinical Immunology and the 2

Department of Infectious Diseases, Odense University Hospital, Odense, Denmark; 3Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and the 4Department of Blood-Borne Infections, Sanquin Blood Supply Foundation, Amsterdam, the Netherlands Address reprint requests to: Dorte Kinggaard Holm, M.Sc., Ph.D., Department of Clinical Immunology, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark; e-mail: [email protected] This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. Received for publication

August

10,

2014;

revision

received December 23, 2014; and accepted December 26, 2014. doi:10.1111/trf.13028 C 2015 AABB V

TRANSFUSION 2015;55;1662–1667 1662 TRANSFUSION Volume 55, July 2015

PREVALENCE OF ANTI-HEV AMONG DONORS

In Europe and other Western countries the focus on hepatitis E virus (HEV) has increased within the past decade because of an increasing number of reported cases of HEV infections. HEV transmission by blood transfusion is well documented.8-11 Recently, a British study found 0.04% of blood donors to be HEV RNA positive and that 42% of these transmitted the infection to their recipients.12 Since HEV is a nonenveloped virus, it is resistant to inactivation methods including solvent/detergent treatment of plasma.13 Similarly, HEV transfusion transmission from INTERCEPT Blood System-treated plasma was recently shown in France.14 Several studies in Europe and the United States have found not only a surprisingly high prevalence of anti-HEV in the general population, but also a 10-fold difference in prevalence depending on which assay was used.15,16 In the Netherlands, among 5239 donors, the anti-HEV immunoglobulin (Ig)G prevalence was 27% using the Wantai assay (Beijing Wantai Biological Pharmacy Enterprise Ltd., Beijing, China).16 A study among Scottish blood donors using the same assay reported 4.7% antiHEV IgG prevalence.17 In France HEV IgG antibodies were found in 52.2% of the blood donors (Wantai assay).18 In children, only 3.7% were anti-HEV positive. In Denmark an anti-HEV prevalence study was performed in 2003 using an in-house assay developed at the National Institutes of Health (NIH; Bethesda, MD).19 Among 461 blood donors the prevalence of anti-HEV was 20.6% in 2003 and had decreased from 32.9% in 1983. The objectives of this study were to investigate the prevalence of anti-HEV of Danish blood donors in 2013 and to compare this to the prevalence in 2003.

MATERIALS AND METHODS Study population Unpaid, volunteer Danish blood donors (n 5 504) whose records were collected in 2013 from the blood bank of Odense University Hospital were recruited, and written consent for the research was obtained. In addition to the health history questionnaire completed for each donation, the blood donors completed an additional questionnaire with demographic information; hepatitis A vaccination status; employment; and contact with animals, children, and farming.

protein of HEV was coated on microtiter plates, and specific antibodies against this antigen were detected with horseradish peroxidase (HRP)-labeled goat anti-human IgG22 (KPL, 074-1006, 1.0 mg) used at 1 mg/mL. Samples were tested at a 1:100 dilution (1% bovine serum albumin/0.5% gelatin). The assay was calibrated with a World Health Organization anti-HEV standard to a detection limit of 1.6 U/mL. The assay was found to have a sensitivity of 96% and a specificity of 98% and to be superior to available commercial and in-house assays in a blinded evaluation of serum panels in 1998.23 The NIH tests performed in 2003 and 2013 were carried out with the same capture antigen (two calibrated lots), reagents, standards, and controls. The WHO anti-HEV standard (95/584) was used to qualify an in-house secondary standard and serial dilutions of this secondary standard were included in every test. Routine evaluation of the secondary standard revealed very little drift between 2003 and 2013. At the Sanquin Blood Bank in Amsterdam, the plasma samples were analyzed with the Wantai hepatitis E IgG enzyme-linked immunosorbent assay (ELISA) kit (Beijing Wantai Biological Pharmacy Enterprise Ltd.) according to the manufacturer’s instructions. The Wantai HEV IgG assay is an indirect ELISA method using synthetic HEV ORF2 and three peptides precoated on a polystyrene microtiter plate. Anti-HEV–specific antibodies were bound to the solidphase precoated HEV antigens. The wells were washed to remove unbound serum proteins, and rabbit anti-human IgG antibodies (anti-IgG) conjugated to HRP (HRP-conjugate) were then added. HRP-conjugated antibodies then bound to any antigen–antibody (IgG) complexes previously formed, and the unbound HRP-conjugate was removed by washing. For the Wantai assay the analytical sensitivity was 99.08% (package insert) and the specificity was 99.6%.24 At the Department of Clinical Immunology Odense University Hospital Denmark the plasma samples were tested for the presence of anti-hepatitis A virus (HAV) with use of a commercial assay (Architect HAV IgG, Abbott Diagnostics Division, Wiesbaden, Germany). The donor samples were also tested for the presence of antibody to human immunodeficiency virus (anti-HIV), hepatitis B surface antigen, antibody to hepatitis C virus (anti-HCV), HIV RNA, HBV DNA, and HCV RNA (and found to be negative).

Ethics Laboratory analysis Plasma samples from the blood donors were analyzed with the two different HEV IgG assays. Anti-HEV was analyzed at the NIH with an in-house assay, as described elsewhere.20,21 Briefly, a baculovirus vector containing a cDNA fragment corresponding to the major part of ORF2 of the Pakistani HEV strain SAR-55 was expressed in insect cells. A purified 55-kDa antigen representing a truncated form (Amino Acids 112-607) of the 660-amino-acid capsid

Ethical approval for the study was granted by The Regional Scientific Ethical Committees for Southern Denmark (ID S-20130016).

Statistical analysis Data processing and statistical analysis were performed with the use of computer software (STATA, Version 13.0, StataCorp, College Station, TX). Nonparametric tests were used for univariate analysis; the chi-square test and Fisher’s Volume 55, July 2015 TRANSFUSION 1663

HOLM ET AL.

TABLE 2. S/CO values of the three donors represented in both studies Donor 1 2 3

Fig. 1. Prevalence of anti-HEV IgG in 504 Danish blood donors in 2013 when tested in the NIH assay (䊏) and the Wantai assay (䊏).

TABLE 1. 2 3 2 table showing reactive comparisons between the assays* Wantai NIH Negative Positive Total Percent

Negative

Positive

Total

Percent

404 0 404 80.2

46† 54 100 19.8

450 54 504

89.3 10.7

* Fisher’s exact < 0.0001. † S/CO range: minimum, 1.12; maximum, 11.64; mean, 3.2.

exact test were used as appropriate. Statistical significance was set at p values of less than 0.05. Independent factors associated with anti-HEV were identified by logistic regression analysis in separate analysis for the NIH and Wantai assays. From a full model we eliminated insignificant variables based on the Wald statistic (backward elimination), until all variables remaining in the model were significant.

RESULTS Blood samples and questionnaire information were obtained from the 504 consecutive blood donors. All were tested for anti-HEV in both the NIH assay and the Wantai assay. Using the NIH assay a total of 54 of 504 donors (10.7%; 95% confidence interval [CI], 8.2-13.7) were reactive for anti-HEV IgG. In univariate analysis anti-HEV IgG was only associated with increasing age (p 5 0.001; Fig. 1). In the full model anti-HEV was positively associated with increasing age and anti-HAV positivity and negatively associated with travel outside the European Union. This 1664 TRANSFUSION Volume 55, July 2015

NIH 2003

NIH 2013

Wantai 2013

1.19 3.0 1.6

0.62 1.14 0.92

1.51 4.95 1.29

was not changed by backward stepwise elimination of insignificant variables (data not shown). Using the Wantai assay a total of 100 of the 504 donors (19.8%; 95% CI, 16.4-23.6) were reactive for anti-HEV IgG. All 54 anti-HEV–positive donors in the NIH assay were reactive when using the Wantai assay (Tables 1 and 2). The signal-to-cutoff (S/CO) range for the samples only reactive in the Wantai assay is shown in Table 1. The presence of anti-HEV IgG in the Wantai assay was associated with increasing age (p < 0.001) and contact with children (p 5 0.01). The prevalence of anti-HEV was numerically higher among donors living in the countryside, but did not reach significance (Table 3 and Fig. 1). However, both of these factors were significantly associated with increasing age. In multivariate analysis Wantai anti-HEV was associated with increasing age and negatively associated with contact to sheep in the full model. By backward elimination only age remained independently associated (data not shown). Among the 504 donors from the current study, 13 had been tested in 2003.19 Three of the 13 reactive in 2003 remained reactive in 2013 using the Wantai assay, whereas only one of the three was weakly reactive (borderline) using the NIH assay. The initial S/CO values of the three samples (2003) as well as the current S/CO values (2013) are shown in Table 2. Earlier anti-HEV prevalence studies among Danish blood donors have shown a strong birth cohort effect. This cohort effect was still present and explains the overall decline in NIH anti-HEV prevalence over the past decade (Fig. 2). The median birth year of the 2013 donors was 1969 and had increased 1 year compared to the 2003 donors (1958). We compared the anti-HEV prevalence of blood donors in Denmark based on the results obtained from the Wantai assay with recently reported anti-HEV prevalences of blood donors in other Western countries also obtained from analysis using the Wantai assay (Table 4). The anti-HEV prevalence of Danish blood donors was similar to that of England and Wales, the Netherlands, and the United States; higher than in Scotland; and lower than in Southwest France.

DISCUSSION In this study we found that anti-HEV was still very prevalent among Danish blood donors. Using the same NIH assay among Danish blood donors the prevalences of

PREVALENCE OF ANTI-HEV AMONG DONORS

TABLE 3. Prevalence of anti-HEV IgG in Danish blood donors related to activities* HEV IgG positive by NIH Yes Activity Traveling out of Europe Daily contact with small children Contact with mentally disabled Contact with cats Contact with dogs Contact with pigs Contact with horses Contact with cows Contact with sheep Living in the countryside Working in the countryside Working with raw meat HAV IgG positive

HEV IgG positive by Wantai

No

Yes

No

Percent

n/N

Percent

n/N

p value

Percent

n/N

Percent

n/N

p value

10 11.5 7 11.5 11.4 16.7 11.2 13.6 7.7 11.3 14.6 13.4 12.8

33/329 45/393 4/57 38/330 42/367 10/60 10/89 9/66 3/39 33/291 12/82 25/187 21/164

12.2 9.3 11.4 9.8 9.6 10.2 11 10.6 11.3 10.5 10.3 9.7 10

20/164 10/108 51/446 17/173 13/135 45/440 45/411 46/434 52/460 22/209 43/419 30/311 34/339

0.537 0.604 0.376 0.653 0.631 0.183 1 0.525 0.789 0.885 0.249 0.237 0.363

19.5 22.3 19.3 22.1 21.3 25.4 22.5 24.6 10.3 23 24.4 23.1 18.9

64/329 88/394 11/57 73/330 78/367 15/59 20/89 16/65 4/39 67/291 20/82 43/186 31/164

20 11.2 20 15.6 16.3 19.3 19.2 19.1 20.4 15.8 19.1 18.3 20.1

33/165 12/107 89/446 27/173 22/135 85/441 79/411 83/435 94/460 33/209 80/419 57/312 68/339

0.905 0.010 1 0.099 0.257 0.298 0.467 0.317 0.145 0.054 0.291 0.204 0.812

* A nonparametric test was used for univariate analysis of donor activities associated with HEV IgG. n 5 number of donors; N 5 total number of donors.

Fig. 2. Prevalence of HEV IgG in Danish blood donors, who had samples obtained in 2013, compared with donors and farmers, who had samples obtained in 2003 and 1983. In 2013 the HEV IgG assay from NIH and the Wantai IgG HEV assay were used in parallel. The NIH HEV IgG assay was the only assay used in 2003 and 1998.

anti-HEV were 32.9% in 1983, 20.6% in 2003, and 10.7% in 2013.19 This indicates a strong birth cohort effect in antiHEV prevalence and suggests that the exposure to antiHEV has continued to decline over the past 30 years. A similar decrease was found in a study performed in the United States, where the anti-HEV prevalences were 21.8% in 2006 and 16% in 2012.25 In the general US population the anti-HEV prevalence decreased from 21% in the 1988 to 1994 NHANES survey to 6% in the 2009 to 2010 survey, comparable to the decrease observed in our study.26,27 However, the results may not be directly comparable, as the 1988 to 1994 study and our study used the

NIH assay, while the 2009 to 2010 survey used a commercial assay (Diagnostic Systems, Soronno, Italy). In England,28 a similar cohort effect was found. We do not know how long anti-HEV persists in the absence of new exposure, but our finding that two of three donors who tested positive in 2003 were no longer anti-HEV positive 10 years later using the NIH assay indicates that antiHEV levels may decay over time. The inability of the NIH assay to detect all three anti-HEV IgG–positive donors from 2003 could not be explained by migration of the performance of the assay, since serial dilutions of an inhouse secondary standard were included in every test. However, some IgG assays lack the ability to detect mature antibodies from distant infections,24 and this may be an explanation why anti-HEV IgG was not detected in those three donors. The difference in the prevalence of anti-HEV between the two assays indicated that the sensitivity of the Wantai assay, compared to the NIH assay, is much higher, or— theoretically—that the specificity of the Wantai assay is much lower. If we had used only the Wantai assay in this study, we would have concluded that the prevalence was stable the past 10 years, instead of the 48% decline observed with the NIH assay. This suggests that comparisons between different populations and different points in time require the same assay used in both populations. We speculate whether the variation could be solved by specifying a detection limit in WHO anti-HEV units, when used in population surveys. In a recent study comparing the diagnostic performance of eight different commercial assays,29 the Wantai assay was the most sensitive assay. However, we acknowledge that as a gold standard confirmatory test for anti-HEV is not available, interassay comparison is difficult and reactivity may not reflect hepatitis E exposure in all cases. Volume 55, July 2015 TRANSFUSION 1665

HOLM ET AL.

TABLE 4. Anti-HEV IgG prevalence of different donor populations in Europe and the United States tested by the Wantai HEV IgG assay

Country Scotland United States England and Wales Denmark Netherlands Southwest France

Number of samples Anti-HEV tested IgG positive (%) 1559 1023 500 505 5239 512

4.7 16.0 16.0 19.8 26.7 52.2

dating back at least four decades. Furthermore, our findings suggest that studies of anti-HEV prevalence should correct for the different sensitivity in available anti-HEV assays, and ideally studies comparing populations over space and time should use the same assay.

References Cleland et al.17 Xu et al.25 Dalton et al. This study Slot et al.16 Mansuy et al.18

CONFLICT OF INTEREST The authors have disclosed no conflicts of interest.

REFERENCES Although the seroprevalence of anti-HEV seems to be decreasing in Denmark, it is still high compared to the number of clinical cases seen per year. Our current hypothesis suggests that HEV infection is a zoonotic infection transmitted to humans from domestic animals. However, like in the 2003 study, we found no indication that direct contact with the animals is the route of transmission. We found that anti-HEV IgG seroprevalence was numerically higher among donors living in the countryside. An unpublished study from Denmark has recently shown that HEV was found in the drain water from fields spread with swine manure,30 which indicates that there is a potential risk of contamination of water reservoirs connected to the drainage runoff. In the same study, HEV was also found in the feces of pigs, as well as in organs such as the liver and lungs. In the Netherlands, there was no association between anti-HEV positivity and living in the countryside and contact with pig farms,16 whereas in Southwest France living in the countryside (rural) and hunting were highly associated with anti-HEV positivity. Studies in several countries including France and the United States have found HEV RNA in pig liver from commercial butcher shops.31,32 This was recently also confirmed in a Danish study,30 but we found no association between the handling of raw meat and anti-HEV presence (Table 3). If infection took place in the kitchen, during  (a Danish national dish), we preparation of pork pate would have expected the anti-HEV prevalence to be higher among women than men. However, if both preparing raw liver and outdoor activities are routes of transmission, this could produce an equal sex distribution. In England, HEV infection recently has been documented in 42% of recipients of HEV RNA–positive donations, of whom several developed chronic infection. Interestingly, 71% of the implicated donors were negative for HEV antibodies by the Wantai assay at the time of donation, suggesting recent infection.12 Thus, transfusiontransmitted HEV appears to be a significant issue requiring consideration of an intervention. In conclusion, our study shows that the HEV prevalence in Denmark has been rapidly decreasing over the past decade, but remains high. This continues a trend 1666 TRANSFUSION Volume 55, July 2015

1. Hoofnagle JH, Nelson KE, Purcell RH. Hepatitis E. N Engl J Med 2012; 367:1237-44. 2. Purcell RH, Emerson SU. Hepatitis E: an emerging awareness of an old disease. J Hepatol 2008; 48:494-503. 3. Meng XJ, Purcell RH, Halbur PG, et al. A novel virus in swine is closely related to the human hepatitis E virus. Proc Natl Acad Sci U S A 1997; 94:9860-5. 4. Meng XJ. From barnyard to food table: the omnipresence of hepatitis E virus and risk for zoonotic infection and food safety. Virus Res 2011; 161:23-30. 5. Huang FF, Sun ZF, Emerson SU, et al. Determination and analysis of the complete genomic sequence of avian hepatitis E virus (avian HEV) and attempts to infect rhesus monkeys with avian HEV. J Gen Virol 2004; 85:1609-18. 6. Mansuy JM, Legrand-Abravanel F, Calot JP, et al. High prevalence of anti-hepatitis E virus antibodies in blood donors from South West France. J Med Virol 2008; 80:289-93. 7. Kamar N, Selves J, Mansuy JM, et al. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med 2008; 358:811-7. 8. Colson P, Coze C, Gallian P, et al. Transfusion-associated hepatitis E, France. Emerg Infect Dis 2007; 13:648-9. 9. Matsubayashi K, Kang JH, Sakata H, et al. A case of transfusion-transmitted hepatitis E caused by blood from a donor infected with hepatitis E virus via zoonotic foodborne route. Transfusion 2008; 48:1368-75. 10. Boxall E, Herborn A, Kochethu G, et al. Transfusion-transmitted hepatitis E in a ‘nonhyperendemic’ country. Transfus Med 2006; 16:79-83. 11. Engle RE, Bukh J, Alter HJ, et al. Transfusion-associated hepatitis before the screening of blood for hepatitis risk factors. Transfusion 2014;54:2833-41. 12. Hewitt PE, Ijaz S, Brailsford SR, et al. Hepatitis E virus in blood components: a prevalence and transmission study in southeast England. Lancet 2014;384:1766-73. 13. Hellstern P, Solheim BG. The use of solvent/detergent treatment in pathogen reduction of plasma. Transfus Med Hemother 2011; 38:65-70.  A, et al. Hepatitis E 14. Hauser L, Roque-Afonso AM, Beyloune transmission by transfusion of Intercept blood systemtreated plasma. Blood 2014; 123:796-7. 15. Verhoef L, Koopmans M, Duizer E, et al. Seroprevalence of hepatitis E antibodies and risk profile of HEV seropositivity

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in The Netherlands, 2006-2007. Epidemiol Infect 2012; 140: 1838-47. 16. Slot E, Hogema BM, Riezebos-Brilman A, et al. Silent hepatitis E virus infection in Dutch blood donors, 2011 to 2012. Euro Surveill 2013;18. 17. Cleland A, Smith L, Crossan C, et al. Hepatitis E virus in Scottish blood donors. Vox Sang 2013; 105:283-9. 18. Mansuy JM, Bendall R, Legrand-Abravanel F, et al. Hepatitis E virus antibodies in blood donors, France. Emerg Infect Dis 2011; 17:2309-12. 19. Christensen PB, Engle RE, Hjort C, et al. Time trend of the prevalence of hepatitis E antibodies among farmers and blood donors: a potential zoonosis in Denmark. Clin Infect Dis 2008; 47:1026-31. 20. Christensen PB, Engle RE, Jacobsen SE, et al. High prevalence of hepatitis E antibodies among Danish prisoners and drug users. J Med Virol 2002; 66:49-55. 21. Engle RE, Yu C, Emerson SU, et al. Hepatitis E virus (HEV) capsid antigens derived from viruses of human and swine origin are equally efficient for detecting anti-HEV by enzyme immunoassay. J Clin Microbiol 2002; 40:4576-80. 22. Tsarev SA, Tsareva TS, Emerson SU, et al. ELISA for anti-

HEV IgG seroprevalence data in developed countries. J Med Virol 2010; 82:799-805. 25. Xu C, Wang RY, Schechterly CA, et al. An assessment of hepatitis E virus (HEV) in US blood donors and recipients: no detectable HEV RNA in 1939 donors tested and no evidence for HEV transmission to 362 prospectively followed recipients. Transfusion 2013; 53:2505-11. 26. Kuniholm MH, Purcell RH, McQuillan GM, et al. Epidemiology of hepatitis E virus in the United States: results from the Third National Health and Nutrition Examination Survey, 1988-1994. J Infect Dis 2009; 200:48-56. 27. Ditah I, Ditah F, Devaki P, et al. Current epidemiology of hepatitis E virus infection in the United States: low seroprevalence in the National Health and Nutrition Evaluation Survey. Hepatology 2014; 60:815-22. 28. Ijaz S, Vyse AJ, Morgan D, et al. Indigenous hepatitis E virus infection in England: more common than it seems. J Clin Virol 2009; 44:272-6. 29. Pas SD, Streefkerk RH, Pronk M, et al. Diagnostic performance of selected commercial HEV IgM and IgG ELISAs for immunocompromised and immunocompetent patients. J Clin Virol 2013; 58:629-34.

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31. Berto A, Grierson S, Hakze-van der Honing R, et al. Hepatitis E virus in pork liver sausage, France. Emerg Infect Dis 2013; 19:264-6. 32. Feagins AR, Opriessnig T, Guenette DK, et al. Detection and characterization of infectious hepatitis E virus from commercial pig livers sold in local grocery stores in the USA. J Gen Virol 2007; 88:912-7.

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Declining prevalence of hepatitis E antibodies among Danish blood donors.

The increasing incidence of reported hepatitis E cases in Europe has focused attention on hepatitis E virus (HEV) and the risk of transfusion-transmit...
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