Here we describe a case of HEV-3 infection transmitted by a kidney transplant donor. This case is distinguished by the mode of HEV transmission that is classically zoonotic in Europe, mostly foodborne, with pigs and wild boars as the main reservoir.
While HEV transplant transmission had not been documented until 20122, several cases have been described since then. The first case of liver transplant transmission was described in 2012 in Germany27. Liver cirrhosis developed within 15 months and the patient died of septic shock. A second case of liver transplant transmission was described in 2018 in China which was part of an outbreak that affected five organ transplant recipients who shared the same donor and were all diagnosed at the stage of chronic hepatitis E29. The liver transplant recipient developed severe hepatitis with progressive portal hypertension. Regarding HEV kidney transplant transmission, four cases had been reported: two in France in 2017 and two in China in 201828,29. In these four cases, HEV sequences from the transplant recipients were identical with each other and with that of the common donor, indicating donor-derived infection27,28. HEV was of genotype 3 for the European cases and of genotype 4 for the Chinese cases. A case of HEV infection presumed to have been acquired through lung transplantation, was described in the USA in 201730. Supporting evidence included the positive anti-HEV IgG and IgM testing of the donor’s serum and the patient’s persistent transaminitis that began after transplantation, even though the donor was negative for HEV RNA. HEV infection was diagnosed in the lung transplant recipient at the cirrhosis stage, simultaneously to HEV meningoencephalitis, 11 years post-transplantation. Finally, a recent publication by Ushiro-Lumb et al., has further documented transmission by organ donation diagnosed through the UK's systematic donor screening policy31. Between 2017 and 2022, 9500 deceased potential organ donors were screened with nine confirmed viraemic cases identified (incidence of 0.94 per 1000). Among the 20 organ recipients from the 8 proceeding donors, 14 cases of infection were diagnosed: in 5 liver transplant recipients and 9 kidney transplant recipients. As evidence of HEV organ donor transmission accumulates, it is possible that organ donor-derived HEV infections are underestimated in endemic areas, since acute and chronic hepatitis E in immunocompromised patients remain underdiagnosed19,21.
Secondary HEV transmission between humans is rare5 and the scarcity of this event might be notably explained by dose-dependence and a high infectious dose32,33. The organ donor-derived HEV infections raise the question of infectious dose. As liver is the target and the main reservoir of HEV during hepatitis, HEV transmission by liver transplantation is not surprising. In the German study by Schlosser et al., antibody screening and RT-PCR were negative in the donor but HEV RNA was reported to be “in high concentration” in the liver27. In the Chinese study by Sridhar and colleagues, HEV was also detected in the donor liver and viral load was 288 copies/reaction29. In the English series by Ushiro-Lumb et al., all liver transplant recipients from a donor with HEV viremia, even very low at 100 IU/mL, had an infection (except for one recipient who presented a transient viremia in the context of liver graft withdrawal on day 5)31. In the cases of HEV transmission by kidney, lung, and heart transplants, it can be hypothesized that HEV was transmitted by the blood remaining in the different organs after washout. The risk of transfusion-transmitted HEV infection has been found to be closely related to the plasma volume of blood components34,35. In a study performed in southeast England, Tedder et al. reported that the HEV-infected donations associated with transmission exhibited a median viral titer of 4.53 log10IU/ml and a lowest titer leading to infection of 2.61 log10IU/ml36. Significant viremia was retrospectively detected on archived serum from each organ donor collected on the organ retrieval day and exceeded the minimum infectious titer seen in blood products, being 6.5 log10IU/mL for the French kidney donor, 5.3 log10IU/mL for the Chinese organ donor, and 4.9 log10IU/mL for our donor. Among the fourteen patients receiving kidney transplant from HEV positive English donors, five developed no infection, and their donors had a viral load of less than 500 IU/mL. Nevertheless, five developed HEV infections and their donor's viral load ranged significantly, from 111 IU/mL to 4.9 log IU/mL, suggesting the importance of transmission factors other than viral load31. Infectious HEV circulates in peripheral blood as enveloped particles that appear to be the major type of HEV in blood and therefore the primary cause of blood-transmitted HEV infections, while non-enveloped particles excreted in stools are the most infectious37. In the case presented here, tested recipients of tissues remained free of infection. In addition, a recent literature review found no case of HEV infection transmitted through cell and tissue allografts38.
Considering the clinical presentation of the nine cases of organ donor-derived HEV infections without systematic screening published in the literature and found in our case, HEV infection was diagnosed at the chronic hepatitis stage in all patients, at post-mortem for two (27,29, present case) and after a mean of 211 days after transplantation for seven (28,29, present case). HEV RNA positivity determined retrospectively has been reported after a mean time of 57 days and as soon as 21 days after transplantation on available sera for four patients (27,29, present case). Two cases developed liver cirrhosis27,30, and one presented severe hepatitis with progressive portal hypertension29. Although the rate of progression to chronicity varied between the different studies, HEV infections overall became chronic in about two-thirds of SOTRs21,22,24, while almost all the cases of organ donor-transmitted HEV infection in SOTRs are described as having become chronic. Furthermore, we observed a relapse of chronic hepatitis despite ribavirin treatment and sero-conversion in our case.
Organ donor-transmitted HEV infection in SOTRs is characterized by an infection on the day of transplantation, probably at the worst juncture for achieving an immune response against HEV. In fact, in previous studies in SOTRs, there was no trend for an association between initial viral load and chronic HEV infection19,21. Such an observation, however, largely depends on the clinical samples available for testing. It is possible that the temporality between HEV infection and organ transplantation and the introduction of immunosuppressive treatment in organ donor-transmitted HEV infection challenges this result. There have been studies on the implications of immunosuppressive drugs (apart from anti-T polyclonal antibodies) for treatment in chronic hepatitis E39,40. Immunosuppressive induction treatment led as expected to the quasi-complete depletion of lymphocytes in our patient (total lymphocyte count of 0.97 G/L before and 0.06 G/L several hours after transplant). This highlights an inadequate defense against HEV provided by innate immunity. It should be noted that clinical presentation as mild hepatitis then moderate chronic hepatitis looks like the HEV infection of athymic nude rats, resulting in mild alterations of liver enzyme levels, lack of hepatic injury, and persistent hepatitis, as reported by Debing et al.41.
All the cases of organ donor-transmitted HEV infection have been diagnosed at the chronic hepatitis stage. If this evolution was undoubtedly favored by immunosuppression, the lack of attention to mild or moderate liver function test impairment at the beginning of the hepatitis course should also be highlighted, because it is typical of E hepatitis in SOTRs compared to immunocompetent patients, and has been associated with chronic HEV infection development19,21,42. Two French SOTR cohorts estimated that 6 to 8% of patients with biological liver abnormalities had hepatitis E, which reflects the high HEV endemicity level in France16,43. In view of the potential severity of liver damage, any biological liver abnormalities in SOTRs should be investigated for HEV by qPCR, the diagnostic method of preference for on-going HEV infection19,21,43. When considering the time to diagnosis, any diagnosis of HEV infection in SOTRs within the first year of transplantation should raise the possibility of transmission from the organ donor.
The hope for a better prevention of HEV infection in immunocompromised patients may notably depend on the availability of safe and effective vaccines. The only approved vaccine (Hecolin) was licensed in China in 20115. Because neutralizing anti-HEV antibodies produced in response to a natural infection mainly target the capsid protein, it has been suggested that neither pre-exposure to HEV nor ORF2-based HEV vaccines such as Hecolin confer protection against enveloped HEV virions37. However, vaccination with Hecolin in rabbits prior to administration of immunosuppressants fully protected them against HEV genotype 3 and 4 infections, whereas only partial protection was achieved when the animals were already receiving immunosuppressants44. These data could argue in favor of preferentially vaccinating patients on the waiting list for organ transplantation39. As HEV vaccines are not commercialized worldwide, as evidence of HEV organ donor transmission accumulates in endemic areas, and as mild liver function test impairment potentially related to hepatitis E in immunocompromised are insufficiently considered, we think that systematic screening of organ donors – at least in HEV hyperendemic areas such as ours45 – should be implemented independently of liver function abnormalities. This would be in line with screening already performed in the UK and Spain for deceased and living donors, regardless of HEV incidence, 46–48. Recommendations from The British Transplantation Society and the UK Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO), in place since 2017, state that all organ donors must be screened for hepatitis E viremia using HEV-Nucleic Acid Amplification Testing. In France, a similar policy has been implemented no later than January 2024. In this context, the detection of viremia is unlikely to be an absolute contra-indication to use of an organ from a donor but will certainly inform clinical management decisions post-transplant.