Hepatitis E virus infection

Joe Sasadeusz: Victorian Infectious Diseases Service, Royal Melbourne Hospital and Infectious Diseases Unit, The Alfred Hospital, Melbourne VIC

Hepatitis E virus (HEV) infection is an important cause of acute hepatitis, predominantly in residents of, and returned travellers from, countries where HEV infection is endemic. It has a high mortality rate in pregnant women. It is also rarely a cause of chronic infection in immunocompromised hosts.

Virology HEV is a small non-enveloped, single-stranded RNA virus approximately 27-34 nm in diameter with a genome that is approximately 7.2 kb in length. It is the only member in the Hepevirdae family and is closely related to members of the Calicivirus family.[1] HEV was previously known as enterically-transmitted non-A, non-B hepatitis.[2] There are four recognised genotypes which fall into two groups. Genotypes 1 and 2 are confined to humans and cause epidemic hepatitis associated with faecal-oral transmission while genotypes 3 and 4 are swine viruses which are common in domestic and wild pigs and infect humans as an accidental host and therefore are considered as zoonoses.[3]

Epidemiology and pathogenesis

HEV is the most common cause of acute hepatitis and jaundice in the world, although it is uncommon in the developed world. It has been estimated to cause at least 3.3 million cases of hepatitis per year and result in approximately 70,000 deaths.[4] In endemic areas, seroprevalence rates of HEV infection range between 30-80% usually due to genotypes 1 and 2.[5] In these areas HEV infection occurs both sporadically and in epidemics and is predominantly spread by faecally-contaminated water while person-to-person spread is uncommon. HEV can also be transmitted by blood transfusion, particularly in endemic areas.[6][7] The highest incidence of HEV infection occurs in Asia, Africa, the Middle East, and Central America. HEV is the second most common cause of sporadic hepatitis in North Africa and the Middle East.[8] High attack rates are found in adults between 15 and 40 years of age.[9] Secondary attack rates from person-to-person transmission in susceptible households are uncommon but have been documented.[10]

Seroprevalence rates of HEV infection in resource-rich areas of the world, such as Europe and the United States of America (USA), are lower than in countries where HEV infection is endemic, with the USA reporting rates of 21%.[11] However, this rate is surprisingly high and suggests a high rate of subclinical HEV infection. In these regions cases are sporadic and have been predominantly described in people who have travelled to areas of the world where HEV infection is endemic.[12] However, sporadic cases that were not associated with travel have also been reported.[13] HEV can infect pigs, suggesting that some cases of human transmission may be due to transmission across species.[14][15] This assumption is further supported by the identification of HEV RNA in a high percentage of pig liver and sausage in commercial settings.[16] Zoonotic transmission is also supported by the observation of high seroprevalence rate for HEV infection among people with occupational contact with animals.[17] There is also evidence that infection can be associated with exposure to other animals such as game[18] as well as shellfish.[19]

There is also some limited information that vertical transmission of HEV from mothers with HEV infection to their infants can occur. In one report, eight babies were born to mothers with HEV in the third trimester of pregnancy. Six infants had clinical, serological, or virological evidence of HEV infection. Two infants died within 24 hours of birth, one of whom had massive hepatic necrosis at autopsy.[20] This finding suggests that HEV infection can be transmitted from mother to newborn with significant perinatal morbidity and mortality.

Diagnosis

The diagnosis of HEV infection is based upon the direct detection HEV RNA in serum or stool by polymerase chain reaction (PCR) or by the detection of antibodies to HEV. Serological and nucleic acid tests (qualitative and quantitative HEV RNA) currently form the basis of HEV testing and have been used for both epidemiological and diagnostic purposes. HEV can be detected in stool during the incubation period before symptomatic illness, during the illness, and persists for as long as 2 weeks thereafter. Because HEV is enterically transmitted, patients are infectious during faecal shedding. Both IgG and IgM antibodies appear at the time of clinical onset of hepatitis, just before symptoms and elevations of liver function tests (Figure 1). Following clinical recovery, serum levels of IgG antibodies to HEV increase and usually persist lifelong while IgM antibodies wane and disappear over 3-12 months.[21] Real-time PCR is the assay of choice to detect HEV RNA and can detect all known genotypes, and is suitable for testing faecal as well as tissue samples.[22] PCR assays are still largely experimental and not widely available for routine diagnostic use.

Figure 1. The course of acute hepatitis E infection showing the timeframes for the detection of HEV RNA, the rise of transaminases and the evolution of IgM and If G antibod. Adapted from Hoofnagle et al. N Engl J Med 2012;367:1237-44.[23]

Progression of hepatitis E infection Tests for anti-HEV antibody are commercially available but the sensitivity and specificity vary widely between assays, which probably explains the wide variation in the seroprevalence of HEV infection in different populations and the differing sensitivities between different assays in the diagnosis of PCR-proven acute HEV infection.[24] This mandates that physicians know the performance characteristics of the local assays available to them.

Clinical manifestations

The incubation period of HEV infection ranges from 3-8 weeks. It generally has a short prodromal phase and a symptomatic period, which is usually associated with jaundice, lasting several days to weeks. Acute HEV infection is usually self-limited, although fulminant hepatitis can develop. Case fatality averages 5% but ranges between 0-10%.[25] Chronic HEV infection does not usually develop after acute HEV infection, except rarely in immunosuppressed individuals (see below). The clinical signs and symptoms in patients with typical HEV infection are similar to those seen with other forms of acute viral hepatitis and jaundice is usually accompanied by malaise, anorexia, nausea, vomiting, abdominal pain, fever and hepatomegaly. Laboratory findings include elevated serum concentrations of bilirubin, as well as alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Resolution of the abnormal biochemical tests generally occurs within 1 to 6 weeks after the onset of the illness.

HEV infection tends to be more severe than hepatitis A virus infection and prolonged cholestasis has been described in up to 60% of patients.[26] An association between HEV infection and Guillain-Barré syndrome has also been reported[27] as well as a number of other neurological manifestations including Bell palsy, peripheral neuropathy, ataxia and confusion.[28]

A striking feature of HEV infection is that for reasons that are not fully understood, fulminant hepatic failure occurs more frequently during pregnancy, resulting in a mortality rate of 15-25%, primarily in women in the third trimester.[29] This high rate may be at least partly due to increased viral replication.[30] Pregnant women with jaundice and acute viral hepatitis caused by HEV infection also appear to have worse obstetric and foetal outcomes compared to pregnant women who have jaundice and acute viral hepatitis due to other causes.[31]

Infection with HEV can also lead to hepatic decompensation in patients with pre-existing liver disease and those who are malnourished, a phenomenon called ‘acute-on-chronic liver failure’.[32]

The differential diagnosis of acute HEV infection mainly includes other forms of acute hepatitis including viral hepatitis due to other hepatitis viruses as well as herpesviruses such as herpes simplex virus, cytomegalovirus and Epstein-Barr virus; drug induced liver disease; ischaemic hepatitis; autoimmune hepatitis and other infectious diseases, such as leptospirosis, dengue, malaria and typhoid.

The basis of acute HEV infection management is supportive, as the disease appears to be self-limiting in non-immunocompromised patients The exception is chronic HEV in immunocompromised individuals as detailed below.

Chronic HEV infection

A subset of patients who undergo solid organ transplantation develop chronic HEV infection as evidenced by the presence of persistently elevated transaminase levels, detectable serum HEV RNA, histologic findings compatible with chronic viral hepatitis and absence of other viral causes.[33] In one study of solid organ transplant recipients, 5% acquired HEV infection of whom half developed chronic infection.[34] Chronic infection has also been reported in patients undergoing cancer chemotherapy as well as HIV patients.[35][36]

The natural history of transplant recipients with chronic infection is incompletely understood but progressive disease with the development of cirrhosis has been reported.[37] Therapy consists of a reduction in immunosuppression which leads to spontaneous clearance in a third of individuals. In addition interferon-alpha and ribavirin or a combination of both have been reported to clear HEV infection in a majority of patients.[38]

Prevention

Basic sanitation is the cornerstone of HEV prevention in resource-poor countries however standard interventions in recent outbreaks have not been successful, highlighting the need for more specific preventative measures such as vaccines.[39] Travellers to endemic areas should practise preventive measures, such as avoiding drinking water of unknown purity, eating uncooked shellfish and uncooked fruits or vegetables. In developed countries an approach to contain infection in animals, especially pigs, would seem logical but has not yet gained acceptance

HEV vaccines

Two HEV vaccines are in development. A recombinant vaccine developed in China has proven to be 87% protective over 4.5 years of follow-up. It uses a 30 μg dose in a 3 dose schedule administered at 0, 1 and 6 months and was also found to be safe.[40] A second recombinant vaccine, evaluated in the Nepalese army and given at a dose of 20 μg at 0, 1 and 6 months, showed a vaccine efficacy of 96% over a shorter period of time.[41]

Little information exists regarding the efficacy of pre- or post-exposure immune globulin prophylaxis for the prevention of HEV infection. There is at present no proof that immune globulin, including lots produced in countries where HEV infection is endemic, confers protection against HEV infection.[42]

References

1. Hoofnagle JH, Nelson KE, Purcell RH. Hepatitis E. N Engl J Med 2012;367:1237-44.

2. Wong DC, Purcell RH, Sreenivasan MA, et al. Epidemic and endemic hepatitis in India: evidence for a non-A, non-B hepatitis virus aetiology. Lancet 1980;2:876-9.

3. 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.

4. Rein DB, Stevens GA, Theaker J, et al. The global burden of hepatitis E virus genotypes 1 and 2 in 2005. Hepatology 2012;55:988-97.

5. Purcell RH, Emerson SU. Hepatitis E: an emerging awareness of an old disease. J Hepatology 2008;48:494-503.

6. Naik SR, Aggarwal R, Salunke PN, et al. A large waterborne viral hepatitis E epidemic in Kanpur, India. Bull World Health Organ1992;70:597-604.

7. Khuroo MS, Kamili S, Yattoo GN. Hepatitis E virus infection may be transmitted through blood transfusions in an endemic area. J Gastroenterol Hepatol 2004;19:778-84.

8. Emerson SU, Purcell RH. Running like water--the omnipresence of hepatitis E. N Engl J Med 2004;351:2367-8.

9. Arankalle VA, Tsarev SA, Chadha MS, et al. Age-specific prevalence of antibodies to hepatitis A and E viruses in Pune, India, 1982 and 1992. J Infect Dis 1995;171:447-50.

10. Howard CM, Handzel T, Hill VR, et al. Novel risk factors associated with hepatitis E virus infection in a large outbreak in northern Uganda: results from a case-control study and environmental analysis. Am J Trop Med Hyg 2010;83:1170-3.

11. 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.

12. From the Centers for Disease Control and Prevention. Hepatitis E among US travelers, 1989-1992.JAMA 1993;269:845-6.

13. Ijaz S, Arnold E, Banks M, et al. Non-travel-associated hepatitis E in England and Wales: demographic, clinical, and molecular epidemiological characteristics. J Infect Dis2005;192:1166-72.

14. Bouwknegt M, Rutjes SA, Reusken CB, et al. The course of hepatitis E virus infection in pigs after contact-infection and intravenous inoculation. BMC Vet Res 2009;5:7.

15. Colson P, Borentain P, Queyriaux B, et al. Pig liver sausage as a source of hepatitis E virus transmission to humans. J Infect Dis 2010;202:825-34.

16. Meng XJ, Wiseman B, Elvinger F, et al. Prevalence of antibodies to hepatitis E virus in veterinarians working with swine and in normal blood donors in the United States and other countries. J Clin Microbiol 2002;40:117-22.

17. Masuda J, Yano K, Tamada Y, et al. Acute hepatitis E of a man who consumed wild boar meat prior to the onset of illness in Nagasaki, Japan. Hepatol Res 2005;31:178-83.

18. Amri I, Hmaied F, Loisy F, et al. Hepatitis A virus detection in shellfish from Tunisia by reverse transcription-nested PCR--investigation of a correlation between viral and bacterial contamination. [Article in French]. Pathol Biol (Paris) 2011;59:217-21.

19. Chandra NS, Sharma A, Malhotra B, et al. Dynamics of HEV viremia, fecal shedding and its relationship with transaminases and antibody response in patients with sporadic acute hepatitis E. Virol J 2010;7:213.

20. Gyarmati P, Mohammed N, Norder H, et al. Universal detection of hepatitis E virus by two real-time PCR assays: TaqMan and Primer-Probe Energy Transfer. J Virol Methods 2007;146:226-35.

21. Mast EE, Alter MJ, Holland PV, et al. Evaluation of assays for antibody to hepatitis E virus by a serum panel. Hepatitis E Virus Antibody Serum Panel Evaluation Group. Hepatology 1998;27:857-61.

22. Chau TN, Lai ST, Tse C, et al. Epidemiology and clinical features of sporadic hepatitis E as compared with hepatitis A. Am J Gastroenterol 2006;101:292-6. 23. Geurtsvankessel CH, Islam Z, Mohammad QD, et al. Hepatitis E and Guillain-Barre syndrome. Clin Infect Dis2013;57:1369-70.

23. Geurtsvankessel CH, Islam Z, Mohammad QD, et al. Hepatitis E and Guillain-Barre syndrome. Clin Infect Dis2013;57:1369-70.

24. Daude M, Rostaing L, Saune K, et al. Tenofovir therapy in hepatitis B virus-positive solid-organ transplant recipients. Transplantation 2011;91:916-20.

25. Khuroo MS, Teli MR, Skidmore S,et al. Incidence and severity of viral hepatitis in pregnancy. Am J Med 1981;70:252-5.

26. Kar P, Jilani N, Husain SA, et al. Does hepatitis E viral load and genotypes influence the final outcome of acute liver failure during pregnancy? Am J Gastroenterol 2008;103:2495-501.

27. Patra S, Kumar A, Trivedi SS, et al. Maternal and fetal outcomes in pregnant women with acute hepatitis E virus infection. Ann Intern Med 2007;147:28-33.

28. Hamid SS, Atiq M, Shehzad F, et al. Hepatitis E virus superinfection in patients with chronic liver disease. Hepatology 2002;36:474-8.

29. Izopet J, Kamar N. Hepatitis E: from zoonotic transmission to chronic infection in immunosuppressed patients. [Article in French]. Med Sci (Paris). 2008;24:1023-5.

30. Legrand-Abravanel F, Kamar N, Sandres-Saune K, et al. Hepatitis E virus infection without reactivation in solid-organ transplant recipients, France. Emerg Infect Dis 2011;17:30-7.

31. Ollier L, Tieulie N, Sanderson F, et al. Chronic hepatitis after hepatitis E virus infection in a patient with non-Hodgkin lymphoma taking rituximab. Ann Intern Med 2009;150:430-1.

32. Dalton HR, Bendall RP, Keane FE, et al. Persistent carriage of hepatitis E virus in patients with HIV infection. N Engl J Med 2009;361:1025-7.

33. Gerolami R, Moal V, Colson P. Chronic hepatitis E with cirrhosis in a kidney-transplant recipient. N Engl J Med 2008;358:859-60.

34. Chen S, Zhou Z, Wei FX, et al. Modeling the long-term antibody response of a hepatitis E vaccine. Vaccine 2015;33:4124-9.

35. Shrestha MP, Scott RM, Joshi DM, et al. Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med 2007;356:895-903.

36. Khuroo MS, Dar MY. Hepatitis E: evidence for person-to-person transmission and inability of low dose immune serum globulin from an Indian source to prevent it. Indian J Gastroenterol 1992;11:113-6.

1.
Hoofnagle JH, Nelson KE, Purcell RH. Hepatitis E. N Engl J Med 2012;367:1237-44 
2.
Wong DC, Purcell RH, Sreenivasan MA, et al. Epidemic and endemic hepatitis in India: evidence for a non-A, non-B hepatitis virus aetiology. Lancet 1980;2:876-9 
3.
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 
4.
Rein DB, Stevens GA, Theaker J, et al. The global burden of hepatitis E virus genotypes 1 and 2 in 2005. Hepatology 2012;55:988-97 
5.
Purcell RH, Emerson SU. Hepatitis E: an emerging awareness of an old disease. J Hepatology 2008;48:494-503 
6.
Naik SR, Aggarwal R, Salunke PN, et al. A large waterborne viral hepatitis E epidemic in Kanpur, India. Bull World Health Organ1992;70:597-604 
7.
Khuroo MS, Kamili S, Yattoo GN. Hepatitis E virus infection may be transmitted through blood transfusions in an endemic area. J Gastroenterol Hepatol 2004;19:778-84 
8.
Emerson SU, Purcell RH. Running like water--the omnipresence of hepatitis E. N Engl J Med 2004;351:2367-8 
9.
Arankalle VA, Tsarev SA, Chadha MS, et al. Age-specific prevalence of antibodies to hepatitis A and E viruses in Pune, India, 1982 and 1992. J Infect Dis 1995;171:447-50 
10.
Howard CM, Handzel T, Hill VR, et al. Novel risk factors associated with hepatitis E virus infection in a large outbreak in northern Uganda: results from a case-control study and environmental analysis. Am J Trop Med Hyg 2010;83:1170-3 
11.
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 
12.
From the Centers for Disease Control and Prevention. Hepatitis E among US travelers, 1989-1992.JAMA 1993;269:845-6 
13.
Ijaz S, Arnold E, Banks M, et al. Non-travel-associated hepatitis E in England and Wales: demographic, clinical, and molecular epidemiological characteristics. J Infect Dis2005;192:1166-72 
14.
Ijaz S, Arnold E, Banks M, et al. Non-travel-associated hepatitis E in England and Wales: demographic, clinical, and molecular epidemiological characteristics. J Infect Dis2005;192:1166-72 
15.
Bouwknegt M, Rutjes SA, Reusken CB, et al. The course of hepatitis E virus infection in pigs after contact-infection and intravenous inoculation. BMC Vet Res 2009;5:7 
16.
Colson P, Borentain P, Queyriaux B, et al. Pig liver sausage as a source of hepatitis E virus transmission to humans. J Infect Dis 2010;202:825-34 
17.
Meng XJ, Wiseman B, Elvinger F, et al. Prevalence of antibodies to hepatitis E virus in veterinarians working with swine and in normal blood donors in the United States and other countries. J Clin Microbiol 2002;40:117-22 
18.
Masuda J, Yano K, Tamada Y, et al. Acute hepatitis E of a man who consumed wild boar meat prior to the onset of illness in Nagasaki, Japan. Hepatol Res 2005;31:178-83 
19.
Amri I, Hmaied F, Loisy F, et al. Hepatitis A virus detection in shellfish from Tunisia by reverse transcription-nested PCR--investigation of a correlation between viral and bacterial contamination. [Article in French]. Pathol Biol (Paris) 2011;59:217-21 
20.
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 
21.
Chandra NS, Sharma A, Malhotra B, et al. Dynamics of HEV viremia, fecal shedding and its relationship with transaminases and antibody response in patients with sporadic acute hepatitis E. Virol J 2010;7:213 
22.
Gyarmati P, Mohammed N, Norder H, et al. Universal detection of hepatitis E virus by two real-time PCR assays: TaqMan and Primer-Probe Energy Transfer. J Virol Methods 2007;146:226-35 
23.
Hoofnagle JH, Nelson KE, Purcell RH. Hepatitis E. N Engl J Med 2012;367:1237-44 
24.
Mast EE, Alter MJ, Holland PV, et al. Evaluation of assays for antibody to hepatitis E virus by a serum panel. Hepatitis E Virus Antibody Serum Panel Evaluation Group. Hepatology 1998;27:857-61 
25.
Hoofnagle JH, Nelson KE, Purcell RH. Hepatitis E. N Engl J Med 2012;367:1237-44 
26.
Chau TN, Lai ST, Tse C, et al. Epidemiology and clinical features of sporadic hepatitis E as compared with hepatitis A. Am J Gastroenterol 2006;101:292-6. 23. Geurtsvankessel CH, Islam Z, Mohammad QD, et al. Hepatitis E and Guillain-Barre syndrome. Clin Infect Dis2013;57:1369-70 
27.
Geurtsvankessel CH, Islam Z, Mohammad QD, et al. Hepatitis E and Guillain-Barre syndrome. Clin Infect Dis2013;57:1369-70 
28.
Daude M, Rostaing L, Saune K, et al. Tenofovir therapy in hepatitis B virus-positive solid-organ transplant recipients. Transplantation 2011;91:916-20 
29.
Khuroo MS, Teli MR, Skidmore S,et al. Incidence and severity of viral hepatitis in pregnancy. Am J Med 1981;70:252-5 
30.
Kar P, Jilani N, Husain SA, et al. Does hepatitis E viral load and genotypes influence the final outcome of acute liver failure during pregnancy? Am J Gastroenterol 2008;103:2495-501 
31.
Patra S, Kumar A, Trivedi SS, et al. Maternal and fetal outcomes in pregnant women with acute hepatitis E virus infection. Ann Intern Med 2007;147:28-33 
32.
Hamid SS, Atiq M, Shehzad F, et al. Hepatitis E virus superinfection in patients with chronic liver disease. Hepatology 2002;36:474-8 
33.
Izopet J, Kamar N. Hepatitis E: from zoonotic transmission to chronic infection in immunosuppressed patients. [Article in French]. Med Sci (Paris). 2008;24:1023-5 
34.
Legrand-Abravanel F, Kamar N, Sandres-Saune K, et al. Hepatitis E virus infection without reactivation in solid-organ transplant recipients, France. Emerg Infect Dis 2011;17:30-7 
35.
Ollier L, Tieulie N, Sanderson F, et al. Chronic hepatitis after hepatitis E virus infection in a patient with non-Hodgkin lymphoma taking rituximab. Ann Intern Med 2009;150:430-1 
36.
Dalton HR, Bendall RP, Keane FE, et al. Persistent carriage of hepatitis E virus in patients with HIV infection. N Engl J Med 2009;361:1025-7 
37.
Gerolami R, Moal V, Colson P. Chronic hepatitis E with cirrhosis in a kidney-transplant recipient. N Engl J Med 2008;358:859-60 
38.
Hoofnagle JH, Nelson KE, Purcell RH. Hepatitis E. N Engl J Med 2012;367:1237-44 
39.
Howard CM, Handzel T, Hill VR, et al. Novel risk factors associated with hepatitis E virus infection in a large outbreak in northern Uganda: results from a case-control study and environmental analysis. Am J Trop Med Hyg 2010;83:1170-3 
40.
Chen S, Zhou Z, Wei FX, et al. Modeling the long-term antibody response of a hepatitis E vaccine. Vaccine 2015;33:4124-9 
41.
Shrestha MP, Scott RM, Joshi DM, et al. Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med 2007;356:895-903 
42.
Khuroo MS, Dar MY. Hepatitis E: evidence for person-to-person transmission and inability of low dose immune serum globulin from an Indian source to prevent it. Indian J Gastroenterol 1992;11:113-6