Transmission of hepatitis E virus by transfusion: what is the risk?

Hepatitis E virus (HEV) was identified in 1983 as the cause of recurrent large epidemics of hepatitis that occurred regularly during monsoon rains in countries in Southern Asia.1 Subsequently the virus was sequenced and found to cause large epidemics among refugee populations in Africa and Asia, whose drinking water was fecally contaminated.2, 3 More recently, sporadic cases of hepatitis from HEV infection have been reported among persons living in higher income countries in Western Europe, Japan, China, and North and South America.4 Genetic analysis of the nucleotide sequences has shown that the viruses causing these sporadic infections differ from the epidemic strains. Although both HEV strains causing epidemics and sporadic cases can be diagnosed serologically, the epidemic strains are classified into Genotypes 1 and 2, while those causing sporadic infections are Genotypes 3 and 4. Genotypes 1 and 2 only affect humans naturally, whereas Genotypes 3 and 4 have been found in many animals, especially domestic swine, but also wild boar, deer, rabbits, muskrats, shellfish, and other animals. Transmission of those genotypes that have a zoonotic reservoir occurs by ingesting inadequately cooked food or direct contact with an infected animal. However, the source of infection among sporadic cases is often not documented. Since HEV viruses do not have a lipid envelope, they are transmissible by the ingestion of contaminated food or water and may be difficult to eliminate by pathogen reduction methods to prevent transmission of blood products.4 Infection with HEV most commonly occurs among adults and is usually asymptomatic. Seroprevalence studies in industrialized countries in Western Europe, North America, and Japan have reported that 6.25% of the healthy population have antibodies to HEV.4 A study of 18,695 enrolled in the third National Health and Nutrition Examination Survey in the United States in 1988 to 1994 found HEV antibody prevalence of 21%.5 Despite the very high prevalence of antibodies to HEV, very few patients with clinical hepatitis have been documented to be infected with HEV. In part this low level of reporting may be due to the lack of an FDA-approved serologic assay for antibody detection that is available to clinicians in the United States. However, the Centers for Disease Control and Prevention has documented 26 cases of clinical hepatitis from HEV infection between 2005 and 2012.6 Fifteen of these infections were acquired in the United States and 11 were among travelers to endemic countries. These data indicate that most HEV infections in industrialized countries occur among adults who are asymptomatic and, therefore, could qualify as acceptable blood donors. Although the incidence and clinical consequences of transmission of HEV by transfusion have not been systematically evaluated, several case reports from Europe and Japan have documented clinical hepatitis in patients after being transfused with blood products from an HEV-infected donor.7-14 This issue of TRANSFUSION includes a report by Juhl and colleagues15 from Germany of a study of 1019 whole blood donors who were evaluated for HEV infection. The anti-HEV immunoglobulin (Ig)G seroprevalence was 6.8% and seroconversion occurred in seven of 69 donors during a 2-year interval, an annual incidence of 0.35%. Among seven donors who had seroconverted, three had HEV RNA detectable in an archived sample. One recipient of a donation that contained HEV RNA was traceable and was anti-HEV IgG, IgM, and RNA negative after a 41-day follow-up. The authors speculated that the viremic donor may have had levels of HEV lower than required for transmission and that transmission by transfusion may often be subclinical, as may have occurred in the recipients who were not followed. However, the unit that was transfused also contained IgM antibodies to HEV, which could have neutralized infectivity, and the follow-up period was short. Nevertheless, this report confirms the fact that asymptomatic donors who are HEV RNA positive may not be unusual. Another study, which has been published electronically in TRANSFUSION, evaluated 1939 whole blood donors at the National Institutes of Health.16 The prevalence of anti-HEV IgG in donors was 21.8% in 2006 and 16.0% in 2012. Eight donors (0.4%) were anti-HEV IgM positive but none was HEV RNA positive. None of 362 transfused patients who could be followed seroconverted after their transfusion. Despite the lack of documented transmission of HEV found in these two studies, the transmission of HEV by transfusion has been reported on several occasions from Europe and Japan.7-14 Four patients who acquired HEV infection by transfusion have been reported from Japan. However, a total of 12 transfusion-transmitted cases have been diagnosed in Japan (K. Mitsubayashi, personal communication, 2013). Blood donors in Japan are screened for elevated alanine aminotransferase (ALT) levels. A donor who was disqualified because of an ALT of 236 IU/L was found to be HEV RNA positive. He had donated platelets (PLTs) 2 weeks earlier. The PLTs were given to a patient with non-Hodgkin's lymphoma, who became infected with the HEV strain that was genetically identical to that in the infected donor.11 Another study in Japan found 15 (1.1%) donors with an ALT over 200 IU/L to be HEV RNA positive.17 An additional study from Japan found nine voluntary blood donors who were HEV RNA positive among 6700 with elevated ALT levels.18 The prevalence of HEV RNA was 2.8% in those whose ALT was more than 201 IU/L and 0.1% in those with ALT of 61 to 200 IU/L. Because the prevalence of HEV-infected donors has been higher in the Hokkaido area in Japan, all donors have been screened for HEV RNA since 2005 in minipools of 20 specimens. Among nearly 2 million donors 231 HEV viremic donors have been identified, a prevalence of 0.012% (K. Mitsubayashi, personal communication, 2013). A study of 44,816 blood donors from six urban blood collection centers in China detected HEV RNA in 30 (0.07%) otherwise eligible donors.19 The results of a study of 45,415 Dutch blood donors who donated in 2011 and 2012 was reported recently.20 This study detected 17 donors who were HEV RNA positive, a prevalence of 0.037%. In this study 459 pools of either 48 or 480 samples were tested for HEV RNA. Among the 5239 donations that were tested for antibodies to HEV, 1401 (27%) tested positive for anti-HEV IgG and 40 (3.5%) for anti-HEV IgM, of which four of the latter were also HEV RNA positive. The level of HEV RNA ranged from near the detection limit (<25 IU/mL) to more than 100,000 IU/mL. In seven donors HEV viremia occurred in up to five serial donations, with a maximum documented positivity of 58 days. The incidence of HEV infection among repeat donors was 1.1% per person year. This publication did not report on whether or not the infected units were transfused or whether they transmitted HEV. A study of minipools containing 48 samples from 16,125 individual donors in Germany using a sensitive assay detected 13 HEV RNA–positive donors, a prevalence of 0.08%.21 Only three of the HEV RNA–positive samples were also anti-HEV IgM positive. A study of plasma pools from North America, Europe, and Southeast Asia found approximately 10% to contain HEV RNA. However, there have been no reports of the transmission of HEV by pooled plasma.22, 23 One can arrive at several conclusions about the possible risk of transmission of HEV by transfusion from data published to date. First, the fact that transmission of HEV by transfusion has occurred and caused clinical hepatitis in the recipient has been established. Second, although only a few cases of HEV hepatitis among transfused patients have been reported, it is likely that many have gone unrecognized. Clinical symptoms from HEV infection are often self-limited and follow after an incubation period of about 30 days. In addition testing for infection is only available from special reference laboratories in the United States. Third, anti-HEV IgM or HEV RNA have been reported commonly among blood donors in many countries. The seroprevalence data in healthy populations in industrialized countries suggest that asymptomatic HEV infections among adults may be common. Clearly more data are needed to better quantify the risk of transmission by transfusion. These data might be obtained by surveillance screening of donors and recipients for markers of recent or active infection, testing repeat donors and lookback tracing of recipients of the blood transfused from seroconverters or testing donor-recipient repositories, such as RADAR.24 If these studies or other data indicate that HEV transmission is more frequent than is currently recognized, routine testing of donors for HEV RNA would be important. Patients who are immunosuppressed, pregnant, or have chronic liver disease commonly receive blood transfusions. These patients are at risk of fulminant hepatitis or chronic rapidly progressive liver disease from an HEV infection.4, 25-28 The author reports no conflicts of interest or funding sources.