Hepatitis E virus as a transfusion transmitted infection-current status

Epidemiology of HEV

HEV has a worldwide distribution [Figure 1].^[10] Twenty million persons are affected with this virus every year in epidemic and sporadic form with 60,000 mortality.^[11]

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Figure 1:

Distribution of Hepatitis E genotype across the world. (Re-used with permission from Pérez-Gracia^[10]).

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Seroepidemiology shows from around 2–80% positivity of immunoglobulin G (IgG) in different parts of the world with lowest level of 1.4% in a Californian study.^[12] There are eight genotypes of the virus identified of which Genotype 1 and Genotype 2 are associated with acute epidemic form of the disese and are mainly restricted in Indian subcontinent and South-east Asian countries.^[11-13] Genotype 3 and 4 are transmitted through Pork and are sporadically found in European countries and in USA. These genotypes can cause acute hepatitis but has the potential to cause chronic liver disease particularly with Genotype 3 and 4. Genotype 5 and Genotype 6 has been demonstrated in wild Boars and has not been associated with human disease. Genotype 7 and Genotype 8 have been demonstrated in camels and camelids. Recently, this Genotype 7 were reported to cause human transmission and chronic disease in the immunosuppressed.^[14] HEV not only cause hepatitis but in a proportion of cases may cause various extra hepatic pathology [Table 1]^[15] and chronic hepatic pathology.^[16] Epidemiologic characteristic of this infection in developed and developing countries has been presented in [Table 2].

HEV and liver disease

Normally Genotypes 1 and 2 which cause both epidemic and sporadic form of Hepatitis E is largely a water borne disease with faeco-oral route of transmission is the major cause of acute hepatitis.^[17,18] This is self-limited and only 1–2% infected patient develop clinical infection. Hence largely, it is subclinical disease in immunocompetent host.^[18-20] However, the disease becomes very severe in pregnancy leading to acute fulminant hepatitis with 30–40% mortality and increased fetal loss.^[21] In patients who have chronic liver disease, this infection may cause acute decompensation of liver function. With Genotype 3 and Genotype 4 virus, the disease is transmitted through pork meat and a proportion of patient particularly those who are immunocompromised, solid organ transplant patients on immunosuppressive drugs may develop chronic hepatitis and some of them continue to excrete viruses in the stool for indefinite period of time.^[22] Genotype 7 and 8 which cause infection in camels have recently been found to cause chronic liver disease with Genotype 7 in immunocompromised patients.^[23] In cell culture studies, HEV was not found to be cytopathogenic but in autopsied patients with fulminant hepatitis or from liver biopsy specimens in patients with this infection the pathogenic effect of this virus on liver appeared to be immune mediated.^[24,25]

HEV as a transfusion transmitted disease

HEV has a reasonably long incubation period varying between 2 and 10 weeks with a median of 4 weeks when the viruses are demonstrable in blood in asymptomatic individuals. Highest level of viremia is reached just before clinical symptoms and increased transaminases level in the blood. During this asymptomatic period, the viruses could be transmitted if blood is collected during that period. Seroepidemiology of the virus has shown that there is steady increase in seropositivity rate from 15 years to 40 years and males have higher seropositivity than females; this is the age group with which large number of blood donors overlaps. As there are multiple modes of transmission of this virus depending on viral genotype, geographical location of the population and lifestyle, season of the study, food and water hygiene of the area, it has become difficult to assess the transfusion risk of transmission of the virus. Multiple studies across the globe with seroepidemiology and carriage of viral ribonucleic acid (RNA) in asymptomatic blood donors have shown variable frequency of the viral RNA in donor population.^[26-35] On the average one in 2900 donors carry this virus donate it in their blood;^[36] in India it could be as high as one in 36.^[8] As 98–99% of these infections are asymptomatic hence unless looked for with proper tracing records of the blood products it is not possible to quantify the risk. However, data collected so far suggests viral transmission through transfusion definitely occur but the risk is low.^[4,36] Moreover, as the population who receives the blood has antibody to this virus in variable proportion of cases, the risk of virus induced hepatitis is further minimized.^[32] It has often been argued that demonstration of RNA in variable amount does not necessarily mean that the infective virion is present in blood. However, recent study has also shown circulating virus particle in real life donor plasma^[37,38] From the transfusion transmitted Hepatitis E cases, it is now generally understood that the virus withstand refrigeration and freezing for at least 4 weeks and being a non-enveloped and small virus, it is moderately resistant to heat and solvent detergent treatment.^[39] This is a signal to plasma industry that the infectivity of the virus of the plasma pools. However, large pool of plasma does two things to mitigate this from happening - (1) a large pool of plasma dilutes the virus unless many contributors in the pool is infected, (2) presence of IgG antibodies in the population reduce the infectivity of the pool. Virus inactivation studies also showed variation and heterogeneity in the rate of inactivation of the viruses in plasma pools.^[40,41]

In real life virus transmission, it has been shown that presence of IgG antibody to the virus mitigates the risk of infection and there is cross reactivity of the antibody across the genotypes.^[42,43]

Infective dose of the virus

As the virus is associated with the plasma component of the blood, plasma remains the major source of infection. However red cell concentrates which contain small amount of plasma has been shown to transmit the virus. It has generally been shown <19000 iu of the virus does not cause infection and more than 520,000 iu of virus cause infection irrespective of immune status of the host.^[32,44-46] Hence, it can be seen that with low level viremia, red cell concentrate is unlikely to transmit the infection unless the viral load is very high but with plasma containing products, that is, fresh frozen plasma (FFP), concentrates, single donor platelet, pooled random donor platelet, pooled cryoprecipitate all could cause the infection if the recipient is susceptible, that is, IgG negative and immunoglobulin M (IgM) negative.

In modern transfusion medicine set up, many patients who are pregnant, immunosuppressed due to their disease, on medication with immunosuppressing agents due to various reasons or had solid organ transplantation and related pathology, very small sized neonates, and chronic liver disease patients receive blood or plasma products due to various reasons. In these patients, HEV can cause serious acute and chronic liver disorder and many non-hepatic symptoms already referred to.^[21,28]

Moreover, due to globalization of food industry, increased international travel and massive population displacement in different parts of the world created situations where this virus transmission in healthy donors can only increase. Hence, hepatitis E screening of some type in blood products needs to be initiated sooner than later.

HEV in blood donors

HEV antibody has been demonstrated in variable number of populations from different parts of the world. It is usually much lower in developed European Countries and in United states. However, here, autochthonous transmission of Genotype 3 and Genotype 4 virus in asymptomatic donors pose a different kind of problem. Because if transmitted in susceptible immune compromised host, it has higher propensity to cause persistent infection, chronic liver disease and extrahepatic symptoms, transfusion of blood, and blood products surely pose a risk of hepatitis E infection in these patients. Evaluation of donors for RNA and serology in these donors show different prevalence of circulating RNA in these donors^[16,44] [Tables 2 and 3]. With increase in age the RNA positivity as well as seropositivity of the donors also increases [Table 4].^[45]

Should we screen our donors or recipients for HEV and susceptibility to infection on transfusion?

There is definite evidence of circulating RNA as well as virus particle in donors blood, a good number of evidence from different countries that the transmission of the hepatitis do happen through transfusion of infected blood products and risk of severe disease increases in pregnancy and in immunosuppressed patients. There is also evidence unlike some of the transfusion transmitted hepatitis viruses suh as Hepatitis B and Hepatitis C, presence of IgG in blood of a immunocompetent person gives him partial immunity and in acute epidemic setting majority of the population have asymptomatic infection; hence capable of transmission through blood donation. If hepatitis does happen it is mostly mild and recovers on its own except in pregnant ladies in third trimester of pregnancy. Fairly effective hepatitis E vaccine is likely to be available soon.^[48] Evaluating all these parameters HEV-RNA screening of blood units either as Individual Donor-NAT (ID-NAT) or Minipool NAT has already been initiated in several European countries.^[44,45]

However, in large part of the world, Hepatitis E related transfusion risk is considered to be low, negligible or a debatable issue.^[41,49-51] However, a variable number of donors on the average across the world carries HEV RNA without associated antibody. They are at greatest risk of transmitting the virus and cause disease in non-immunized, immune suppressed and pregnant patients who also receives a substantial amount of red cell and other blood product transfusion with high plasma content risking them for real infection.

What then should be the strategy for screening?

Straight forward and democratic way of screening without raising any conflicts of interest should be NAT screening of all blood units as we do for other transfusion transmitted viruses i.e. HIV-1&2, HBV and HCV. Then of course, a major discussion will be whether it should be ID-NAT or minipool NAT of different sample sizes depending on perception of virus load and frequency of positivity in the population. In general, studies have shown ID- NAT detects this virus in 50% more donors^[49] than minipool NAT particularly those who have low viral load yet may be able to transmit the infection if high volume plasma infusion is given. Both the techniques are currently employed in several European countries^[49] As plasma is the main source of transfusion transmitted hepatitis E infection, plasma containing products such as platelet concentrates, FFP, Cryo poor plasma, cryoprecipitates, and plasma-based concentrates all can transmit the infection even when the viral load in these products are low. Red cell concentrates which contains minimum amount of plasma (<15 mL) have also transmitted HEV.^[50] As this virus is a non-enveloped one and in plasma a proportion of these viruses remains non-enveloped, solvent detergent technology does not inactivate the virus easily.^[41] Similarly, heat sensitivity of this virus in usual plasma heat treatment condition has not been established with certainty making screening for this virus is essential at least for some blood products.

So what are the ways HEV transmission causing serious damage to recipients can be minimized? (1) testing every unit of blood using NAT based or loop mediated amplification^[51] or using ID-NAT format or minipool format. Pool size may be decided on past data on frequency of this infection in voluntary donors; (2) testing all blood units for IgG/IgM as positive units even if they transmit infection the infection is likely to be subclinical or mild; (3) combine option 1 and 2; and (4) surrogate liver function test (alanine transaminase, ALT) may be added as used to be done before because the peak viremia in this disease closely corresponds with ALT levels. Moreover, donors with high ALT are at risk of transmitting other infections and provides the opportunity of counseling the donor for other liver disorders and subsequently referring the donor to competent clinical center; (5) if sensitive antigen testing serology is developed they may be combined with other modes or may be used alone; (6) testing the susceptible/pregnant/ immunosuppressed recipient for seroimmune status against HEV before transfusing the product. Here, the donors may/ may not be tested for the virus or serostatus. The menu as described above can be combined in a different ways to suit the country’s finance and risk of transfusion transmitted Hepatitis E as well as the number of susceptible recipient population in the country. Suitable algorithm for testing can be developed and improved over time in each country. Here, artificial intelligence-based decision-making and algorithm for donor recipient testing may optimize the risk-benefit of such decision-making process.