Chronic hepatitis E in the immunosuppressed: A new source of trouble?
2008; Elsevier BV; Volume: 50; Issue: 2 Linguagem: Inglês
10.1016/j.jhep.2008.11.007
ISSN1600-0641
AutoresFlorian Bihl, Francesco Negro,
Tópico(s)Liver Disease and Transplantation
ResumoChronic hepatitis E virus infection in liver transplant recipients. Haagsma EB, van den Berg AP, Porte RJ, Benne CA, Vennema H, Reimerink JH, Koopmans MP.Hepatitis E virus (HEV) infection is known to run a self-limiting course. Sporadic cases of acute hepatitis due to infection with HEV genotype 3, present in pig populations, are increasingly recognized. Zoonotic transmission seems infrequent. The entity of unexplained chronic hepatitis after liver transplantation has been recognized. Detection of HEV in 2 liver transplant recipients triggered a review of these cases. Freeze-stored sera were available for retrospective analysis. HEV antibodies were determined. For virus detection and identification, a fragment of the gene encoding the major capsid protein (open reading frame 2) was amplified by reverse-transcription polymerase chain reaction and sequenced to identify the genotype. Two months after liver transplantation, case A developed unexplained chronic hepatitis, which developed into cirrhosis. Retransplantation followed 7 years later, after which chronic hepatitis recurred. In retrospect, HEV RNA was present in serum 3 weeks after the first transplantation and remained present afterwards. HEV RNA was also present in retransplant liver tissue. HEV antibodies appeared late after retransplantation. Case B developed unexplained chronic hepatitis 7 years after transplantation. Retransplantation was needed 5 years later, after which no signs of hepatitis recurred. In retrospect, the period of chronic hepatitis up to the retransplantation coincided with HEV RNA in serum. In case B, antibodies developed, the viral load was much lower than in case A, and the virus seemed to be cleared after retransplantation. Genotyping in both cases revealed 2 unique strains of genotype 3. In conclusion, chronic HEV infection may develop in immunosuppressed patients, who may then serve as long-term carriers of the virus. We hypothesize that HEV may be the cause of chronic hepatitis in liver transplant recipients. (c) 2008 AASLD.[Abstract reproduced by permission of Liver Transpl 2008;14:547–553].Hepatitis E virus and chronic hepatitis in organ-transplant recipients. Kamar N, Selves J, Mansuy JM, Ouezzani L, Péron JM, Guitard J, Cointault O, Esposito L, Abravanel F, Danjoux M, Durand D, Vinel JP, Izopet J, Rostaing L.Hepatitis E virus (HEV) is considered an agent responsible for acute hepatitis that does not progress to chronic hepatitis. We identified 14 cases of acute HEV infection in three patients receiving liver transplants, nine receiving kidney transplants, and two receiving kidney and pancreas transplants. All patients were positive for serum HEV RNA. Chronic hepatitis developed in eight patients, as confirmed by persistently elevated aminotransferase levels, serum HEV RNA, and histologic features of chronic hepatitis. The time from transplantation to diagnosis was significantly shorter and the total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed.[Abstract reproduced by permission of N Engl J Med 2008;358:811–817]. Chronic hepatitis E virus infection in liver transplant recipients. Haagsma EB, van den Berg AP, Porte RJ, Benne CA, Vennema H, Reimerink JH, Koopmans MP. Hepatitis E virus (HEV) infection is known to run a self-limiting course. Sporadic cases of acute hepatitis due to infection with HEV genotype 3, present in pig populations, are increasingly recognized. Zoonotic transmission seems infrequent. The entity of unexplained chronic hepatitis after liver transplantation has been recognized. Detection of HEV in 2 liver transplant recipients triggered a review of these cases. Freeze-stored sera were available for retrospective analysis. HEV antibodies were determined. For virus detection and identification, a fragment of the gene encoding the major capsid protein (open reading frame 2) was amplified by reverse-transcription polymerase chain reaction and sequenced to identify the genotype. Two months after liver transplantation, case A developed unexplained chronic hepatitis, which developed into cirrhosis. Retransplantation followed 7 years later, after which chronic hepatitis recurred. In retrospect, HEV RNA was present in serum 3 weeks after the first transplantation and remained present afterwards. HEV RNA was also present in retransplant liver tissue. HEV antibodies appeared late after retransplantation. Case B developed unexplained chronic hepatitis 7 years after transplantation. Retransplantation was needed 5 years later, after which no signs of hepatitis recurred. In retrospect, the period of chronic hepatitis up to the retransplantation coincided with HEV RNA in serum. In case B, antibodies developed, the viral load was much lower than in case A, and the virus seemed to be cleared after retransplantation. Genotyping in both cases revealed 2 unique strains of genotype 3. In conclusion, chronic HEV infection may develop in immunosuppressed patients, who may then serve as long-term carriers of the virus. We hypothesize that HEV may be the cause of chronic hepatitis in liver transplant recipients. (c) 2008 AASLD. [Abstract reproduced by permission of Liver Transpl 2008;14:547–553]. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. Kamar N, Selves J, Mansuy JM, Ouezzani L, Péron JM, Guitard J, Cointault O, Esposito L, Abravanel F, Danjoux M, Durand D, Vinel JP, Izopet J, Rostaing L. Hepatitis E virus (HEV) is considered an agent responsible for acute hepatitis that does not progress to chronic hepatitis. We identified 14 cases of acute HEV infection in three patients receiving liver transplants, nine receiving kidney transplants, and two receiving kidney and pancreas transplants. All patients were positive for serum HEV RNA. Chronic hepatitis developed in eight patients, as confirmed by persistently elevated aminotransferase levels, serum HEV RNA, and histologic features of chronic hepatitis. The time from transplantation to diagnosis was significantly shorter and the total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed. [Abstract reproduced by permission of N Engl J Med 2008;358:811–817]. Until recently, hepatitis E virus (HEV) infection was believed to be associated with a self-limited acute hepatitis without long-term sequelae. Usually after an incubation period of 3–6 weeks, acute hepatitis E is characterized by a subclinical to severe clinical picture that includes jaundice, dark urine, anorexia, nausea, vomiting and fever, lasting for 1–6 weeks. Typically, young adults and patients with underlying chronic liver disease of diverse etiology are affected with an overall low case fatality rate. However, pregnant women, especially in their third trimester, are at risk of developing more severe disease, which may proceed to liver failure, with a significant mortality rate (up to 20%) [1Purcell R.H. Emerson S.U. Hepatitis E: an emerging awareness of an old disease.J Hepatol. 2008; 48: 494-503Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar, 2Mushahwar I.K. Hepatitis E virus: molecular virology, clinical features, diagnosis, transmission, epidemiology, and prevention.J Med Virol. 2008; 80: 646-658Crossref PubMed Scopus (210) Google Scholar].HEV, the causative agent of hepatitis E, is a non-enveloped, single-stranded RNA virus of the Hepevirus genus. HEV is mainly transmitted enterically through contaminated water. Nevertheless, parenteral transmission (blood-borne) or vertical transmission (mother-to-child) have been reported [[2]Mushahwar I.K. Hepatitis E virus: molecular virology, clinical features, diagnosis, transmission, epidemiology, and prevention.J Med Virol. 2008; 80: 646-658Crossref PubMed Scopus (210) Google Scholar].The epidemiology of HEV is mostly unknown; the disease is worldwide endemic with a predominance in developing countries with tropical or subtropical climate. Thus, HEV accounts for the majority of acute hepatitis cases among adults in some areas of the Middle East, North Africa, and Central and Southeast Asia [[1]Purcell R.H. Emerson S.U. Hepatitis E: an emerging awareness of an old disease.J Hepatol. 2008; 48: 494-503Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar].In industrialized countries, hepatitis E is considered an emerging disease, formerly associated with travel to highly endemic regions. However, a worrying observation is the accumulating evidence of sporadic cases of HEV infection in developed countries due to spread of autochthonous viral strains [3Borgen K. Herremans T. Duizer E. Vennema H. Rutjes S. Bosman A. et al.Non-travel related Hepatitis E virus genotype 3 infections in the Netherlands; a case series 2004–2006.BMC Infect Dis. 2008; 8: 61Crossref PubMed Scopus (103) Google Scholar, 4Dalton H.R. Stableforth W. Hazeldine S. Thurairajah P. Ramnarace R. Warshow U. et al.Autochthonous hepatitis E in Southwest England: a comparison with hepatitis A.Eur J Clin Microbiol Infect Dis. 2008; 27: 579-585Crossref PubMed Scopus (56) Google Scholar]. Indeed, epidemiologic studies conducted among blood donors showed a 1–9.3% prevalence of anti-HEV antibodies in Europe (1–3% Spain; 3.2% France; 9.3% Sweden) [5Clemente-Casares P. Pina S. Buti M. Jardi R. Martin M. Bofill-Mas S. et al.Hepatitis E virus epidemiology in industrialized countries.Emerg Infect Dis. 2003; 9: 448-454Crossref PubMed Scopus (250) Google Scholar, 6Boutrouille A. Bakkali-Kassimi L. Cruciere C. Pavio N. Prevalence of anti-hepatitis E virus antibodies in French blood donors.J Clin Microbiol. 2007; 45: 2009-2010Crossref PubMed Scopus (120) Google Scholar, 7Olsen B. Axelsson-Olsson D. Thelin A. Weiland O. Unexpected high prevalence of IgG-antibodies to hepatitis E virus in Swedish pig farmers and controls.Scand J Infect Dis. 2006; 38: 55-58Crossref PubMed Scopus (111) Google Scholar] and 3.7–7.9% in Japan and a not negligible number of blood donors with detectable HEV RNA (0.05–0.13% in Japan) [8Fukuda S. Sunaga J. Saito N. Fujimura K. Itoh Y. Sasaki M. et al.Prevalence of antibodies to hepatitis E virus among Japanese blood donors: identification of three blood donors infected with a genotype 3 hepatitis E virus.J Med Virol. 2004; 73: 554-561Crossref PubMed Scopus (60) Google Scholar, 9Gotanda Y. Iwata A. Ohnuma H. Yoshikawa A. Mizoguchi H. Endo K. et al.Ongoing subclinical infection of hepatitis E virus among blood donors with an elevated alanine aminotransferase level in Japan.J Med Virol. 2007; 79: 734-742Crossref PubMed Scopus (61) Google Scholar].In addition, increasing evidence suggests that HEV might be a zoonosis and viral spread in humans involves consumption of edible wild animals, like wild boar and deer, or domestic pigs. The meat of the latter constitutes a substantial part in the human food chain and viral spread in developed countries can occur through ingestion of infected and undercooked meat. Indeed, swine and human HEV show extremely close genetic relatedness (especially HEV genotype 3) suggesting that these animals may serve as a reservoir for human HEV infection [[10]Feagins A.R. Opriessnig T. Guenette D.K. Halbur P.G. Meng X.J. 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: 912-917Crossref PubMed Scopus (284) Google Scholar].Recently, some concern has arisen about the potential risk of persistent HEV infection with chronic liver disease, occasionally leading to cirrhosis, in some selected clinical situations characterized by reduced immune surveillance, such as those induced by chemotherapy [[11]Tamura A. Shimizu Y.K. Tanaka T. Kuroda K. Arakawa Y. Takahashi K. et al.Persistent infection of hepatitis E virus transmitted by blood transfusion in a patient with T-cell lymphoma.Hepatol Res. 2007; 37: 113-120Crossref PubMed Scopus (161) Google Scholar] or immunosuppression [12Kamar N. Selves J. Mansuy J.M. Ouezzani L. Peron J.M. Guitard J. et al.Hepatitis E virus and chronic hepatitis in organ-transplant recipients.N Engl J Med. 2008; 358: 811-817Crossref PubMed Scopus (1001) Google Scholar, 13Gerolami R. Moal V. Colson P. Chronic hepatitis E with cirrhosis in a kidney-transplant recipient.N Engl J Med. 2008; 358: 859-860Crossref PubMed Scopus (285) Google Scholar, 14Haagsma E.B. van den Berg A.P. Porte R.J. Benne C.A. Vennema H. Reimerink J.H. et al.Chronic hepatitis E virus infection in liver transplant recipients.Liver Transpl. 2008; 14: 547-553Crossref PubMed Scopus (270) Google Scholar]. In particular, Kamar et al. reported 14 cases of HEV infection in solid organ transplant recipients (liver, kidney or kidney and pancreas) [[12]Kamar N. Selves J. Mansuy J.M. Ouezzani L. Peron J.M. Guitard J. et al.Hepatitis E virus and chronic hepatitis in organ-transplant recipients.N Engl J Med. 2008; 358: 811-817Crossref PubMed Scopus (1001) Google Scholar]. Eight of these patients presented with persistent detection of HEV RNA in stools or serum for an average of 15 month after the acute infection. Six of such patients underwent a liver biopsy that showed portal hepatitis with lymphocytic infiltrates, piecemeal necrosis and fibrosis. Four of them had a second liver biopsy that documented the progression of the inflammatory and fibrosis activity scores. Seroconversion was observed in 11 patients (79%). In the same issue of the New England Journal of Medicine, Gérolami et al. reported a single case of a kidney transplant recipient presenting four months after transplantation with elevated liver enzymes, and eighteen months thereafter with a diagnosis of HEV infection [[13]Gerolami R. Moal V. Colson P. Chronic hepatitis E with cirrhosis in a kidney-transplant recipient.N Engl J Med. 2008; 358: 859-860Crossref PubMed Scopus (285) Google Scholar]. At this time point, liver histology had shown the presence of chronic hepatitis with cirrhosis. A third report appeared one month later in Liver Transplantation from a Dutch group, led by Haagsma and colleagues, who described two cases of liver transplant recipients who acquired HEV after liver transplantation [[14]Haagsma E.B. van den Berg A.P. Porte R.J. Benne C.A. Vennema H. Reimerink J.H. et al.Chronic hepatitis E virus infection in liver transplant recipients.Liver Transpl. 2008; 14: 547-553Crossref PubMed Scopus (270) Google Scholar]. Chronic evolution of HEV infection and liver disease occurred in both, leading to retransplantation. The two cases differed slightly, in that the first had been probably infected at the time or shortly after transplant. Six years later, this patient had developed end-stage liver disease with ascites, jaundice and variceal bleeding. A misdiagnosis of autoimmune hepatitis had resulted in increased immunosuppressive therapy, and one year later the patient had worsened to the point of requiring a retransplantation. One year after the second transplant, the liver enzymes were elevated again and once more liver histology showed lobular hepatitis with portal fibrosis. During these years and notably after retransplantation serum HEV RNA levels were persistently detectable. The second case history started, on the contrary, seven years after liver transplant at the time of a travel-related HEV infection. Within five years of acute HEV infection end-stage liver disease developed requiring retransplantation. In this case HEV RNA was detectable from time of primary infection until retransplantation, but not later on, suggesting viral clearance.These reports may change our view on the natural history of HEV infection. Eleven patients developed chronic infection and three cases progressed to cirrhosis. So far, persistent HEV infection accompanied by chronic, progressive liver damage, occasionally leading to cirrhosis, had never been reported.Some further points are worthy of note. First, except for the one travel-related HEV infection in the report of Haagsma et al. [[14]Haagsma E.B. van den Berg A.P. Porte R.J. Benne C.A. Vennema H. Reimerink J.H. et al.Chronic hepatitis E virus infection in liver transplant recipients.Liver Transpl. 2008; 14: 547-553Crossref PubMed Scopus (270) Google Scholar], all reported patients had acquired HEV in developed countries (France and Netherlands) without any evident known source of contamination. HEV is likely endemic in these countries, probably subclinically with autochthonous strains transmitted through the food chain (zoonotic food-borne transmission) or through blood products (blood-borne transmission). The blood supply is particularly vulnerable to emerging pathogens, especially non-enveloped viruses like HEV because pathogen inactivation methods are insufficient and routine serological tests are not performed [[15]Bihl F. Castelli D. Marincola F. Dodd R.Y. Brander C. Transfusion-transmitted infections.J Transl Med. 2007; 5: 25Crossref PubMed Scopus (135) Google Scholar].Second, chronic HEV might explain many cases of otherwise unexplained post-transplant hepatitis or cryptogenic cirrhosis. However, how should the diagnosis be made? Diagnostic tools to assess HEV infection are available and encompass serological assays to detect anti-HEV antibodies capable of differentiating recent from remote infection (IgG, IgM, IgA). These tests are generally based on detection of antibodies against the highly conserved and immunogenic capsid protein (encoded by the open reading frame 2) and are characterized by broad activity and good reproducibility. Highly specific ELISA for quantifying neutralizing antibodies to HEV genotypes 1–4 are commercially available. Nevertheless, in the reported cases seroconversion occurred on average later than among non-immunosuppressed patients (10 months after acute infection versus 1–3 weeks in immune competent patients). Even more disturbing is the observation that in three of the 11 patients antibodies remained consistently negative. Nucleic acid testing, in contrast, is the most sensitive test for ongoing HEV infection. Nested or real-time PCR may detect viral genomic RNA in serum or stools, especially in acute infection and within the first week after exposure. Therefore, immunosuppressed patients with unexplained elevated liver enzymes most likely should be tested with a combination of serology and nucleic acid assays to ascertain HEV infection.Third, how can we treat or prevent HEV in this setting? Specific treatments and therapeutic recommendations are lacking. However, in transplant recipients with a suspect of chronic HEV infection, the immunosuppressive regimen should probably be lowered to a level sufficient to allow for the humoral and – more importantly – the cellular immunity to curb HEV infection. Since an effective recombinant vaccine against HEV exists [[16]Shrestha M.P. Scott R.M. Joshi D.M. Mammen Jr., M.P. Thapa G.B. Thapa N. et al.Safety and efficacy of a recombinant hepatitis E vaccine.N Engl J Med. 2007; 356: 895-903Crossref PubMed Scopus (422) Google Scholar], its use in patients undergoing immunosuppression for organ transplantation should be considered. Until recently, hepatitis E virus (HEV) infection was believed to be associated with a self-limited acute hepatitis without long-term sequelae. Usually after an incubation period of 3–6 weeks, acute hepatitis E is characterized by a subclinical to severe clinical picture that includes jaundice, dark urine, anorexia, nausea, vomiting and fever, lasting for 1–6 weeks. Typically, young adults and patients with underlying chronic liver disease of diverse etiology are affected with an overall low case fatality rate. However, pregnant women, especially in their third trimester, are at risk of developing more severe disease, which may proceed to liver failure, with a significant mortality rate (up to 20%) [1Purcell R.H. Emerson S.U. Hepatitis E: an emerging awareness of an old disease.J Hepatol. 2008; 48: 494-503Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar, 2Mushahwar I.K. Hepatitis E virus: molecular virology, clinical features, diagnosis, transmission, epidemiology, and prevention.J Med Virol. 2008; 80: 646-658Crossref PubMed Scopus (210) Google Scholar]. HEV, the causative agent of hepatitis E, is a non-enveloped, single-stranded RNA virus of the Hepevirus genus. HEV is mainly transmitted enterically through contaminated water. Nevertheless, parenteral transmission (blood-borne) or vertical transmission (mother-to-child) have been reported [[2]Mushahwar I.K. Hepatitis E virus: molecular virology, clinical features, diagnosis, transmission, epidemiology, and prevention.J Med Virol. 2008; 80: 646-658Crossref PubMed Scopus (210) Google Scholar]. The epidemiology of HEV is mostly unknown; the disease is worldwide endemic with a predominance in developing countries with tropical or subtropical climate. Thus, HEV accounts for the majority of acute hepatitis cases among adults in some areas of the Middle East, North Africa, and Central and Southeast Asia [[1]Purcell R.H. Emerson S.U. Hepatitis E: an emerging awareness of an old disease.J Hepatol. 2008; 48: 494-503Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar]. In industrialized countries, hepatitis E is considered an emerging disease, formerly associated with travel to highly endemic regions. However, a worrying observation is the accumulating evidence of sporadic cases of HEV infection in developed countries due to spread of autochthonous viral strains [3Borgen K. Herremans T. Duizer E. Vennema H. Rutjes S. Bosman A. et al.Non-travel related Hepatitis E virus genotype 3 infections in the Netherlands; a case series 2004–2006.BMC Infect Dis. 2008; 8: 61Crossref PubMed Scopus (103) Google Scholar, 4Dalton H.R. Stableforth W. Hazeldine S. Thurairajah P. Ramnarace R. Warshow U. et al.Autochthonous hepatitis E in Southwest England: a comparison with hepatitis A.Eur J Clin Microbiol Infect Dis. 2008; 27: 579-585Crossref PubMed Scopus (56) Google Scholar]. Indeed, epidemiologic studies conducted among blood donors showed a 1–9.3% prevalence of anti-HEV antibodies in Europe (1–3% Spain; 3.2% France; 9.3% Sweden) [5Clemente-Casares P. Pina S. Buti M. Jardi R. Martin M. Bofill-Mas S. et al.Hepatitis E virus epidemiology in industrialized countries.Emerg Infect Dis. 2003; 9: 448-454Crossref PubMed Scopus (250) Google Scholar, 6Boutrouille A. Bakkali-Kassimi L. Cruciere C. Pavio N. Prevalence of anti-hepatitis E virus antibodies in French blood donors.J Clin Microbiol. 2007; 45: 2009-2010Crossref PubMed Scopus (120) Google Scholar, 7Olsen B. Axelsson-Olsson D. Thelin A. Weiland O. Unexpected high prevalence of IgG-antibodies to hepatitis E virus in Swedish pig farmers and controls.Scand J Infect Dis. 2006; 38: 55-58Crossref PubMed Scopus (111) Google Scholar] and 3.7–7.9% in Japan and a not negligible number of blood donors with detectable HEV RNA (0.05–0.13% in Japan) [8Fukuda S. Sunaga J. Saito N. Fujimura K. Itoh Y. Sasaki M. et al.Prevalence of antibodies to hepatitis E virus among Japanese blood donors: identification of three blood donors infected with a genotype 3 hepatitis E virus.J Med Virol. 2004; 73: 554-561Crossref PubMed Scopus (60) Google Scholar, 9Gotanda Y. Iwata A. Ohnuma H. Yoshikawa A. Mizoguchi H. Endo K. et al.Ongoing subclinical infection of hepatitis E virus among blood donors with an elevated alanine aminotransferase level in Japan.J Med Virol. 2007; 79: 734-742Crossref PubMed Scopus (61) Google Scholar]. In addition, increasing evidence suggests that HEV might be a zoonosis and viral spread in humans involves consumption of edible wild animals, like wild boar and deer, or domestic pigs. The meat of the latter constitutes a substantial part in the human food chain and viral spread in developed countries can occur through ingestion of infected and undercooked meat. Indeed, swine and human HEV show extremely close genetic relatedness (especially HEV genotype 3) suggesting that these animals may serve as a reservoir for human HEV infection [[10]Feagins A.R. Opriessnig T. Guenette D.K. Halbur P.G. Meng X.J. 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: 912-917Crossref PubMed Scopus (284) Google Scholar]. Recently, some concern has arisen about the potential risk of persistent HEV infection with chronic liver disease, occasionally leading to cirrhosis, in some selected clinical situations characterized by reduced immune surveillance, such as those induced by chemotherapy [[11]Tamura A. Shimizu Y.K. Tanaka T. Kuroda K. Arakawa Y. Takahashi K. et al.Persistent infection of hepatitis E virus transmitted by blood transfusion in a patient with T-cell lymphoma.Hepatol Res. 2007; 37: 113-120Crossref PubMed Scopus (161) Google Scholar] or immunosuppression [12Kamar N. Selves J. Mansuy J.M. Ouezzani L. Peron J.M. Guitard J. et al.Hepatitis E virus and chronic hepatitis in organ-transplant recipients.N Engl J Med. 2008; 358: 811-817Crossref PubMed Scopus (1001) Google Scholar, 13Gerolami R. Moal V. Colson P. Chronic hepatitis E with cirrhosis in a kidney-transplant recipient.N Engl J Med. 2008; 358: 859-860Crossref PubMed Scopus (285) Google Scholar, 14Haagsma E.B. van den Berg A.P. Porte R.J. Benne C.A. Vennema H. Reimerink J.H. et al.Chronic hepatitis E virus infection in liver transplant recipients.Liver Transpl. 2008; 14: 547-553Crossref PubMed Scopus (270) Google Scholar]. In particular, Kamar et al. reported 14 cases of HEV infection in solid organ transplant recipients (liver, kidney or kidney and pancreas) [[12]Kamar N. Selves J. Mansuy J.M. Ouezzani L. Peron J.M. Guitard J. et al.Hepatitis E virus and chronic hepatitis in organ-transplant recipients.N Engl J Med. 2008; 358: 811-817Crossref PubMed Scopus (1001) Google Scholar]. Eight of these patients presented with persistent detection of HEV RNA in stools or serum for an average of 15 month after the acute infection. Six of such patients underwent a liver biopsy that showed portal hepatitis with lymphocytic infiltrates, piecemeal necrosis and fibrosis. Four of them had a second liver biopsy that documented the progression of the inflammatory and fibrosis activity scores. Seroconversion was observed in 11 patients (79%). In the same issue of the New England Journal of Medicine, Gérolami et al. reported a single case of a kidney transplant recipient presenting four months after transplantation with elevated liver enzymes, and eighteen months thereafter with a diagnosis of HEV infection [[13]Gerolami R. Moal V. Colson P. Chronic hepatitis E with cirrhosis in a kidney-transplant recipient.N Engl J Med. 2008; 358: 859-860Crossref PubMed Scopus (285) Google Scholar]. At this time point, liver histology had shown the presence of chronic hepatitis with cirrhosis. A third report appeared one month later in Liver Transplantation from a Dutch group, led by Haagsma and colleagues, who described two cases of liver transplant recipients who acquired HEV after liver transplantation [[14]Haagsma E.B. van den Berg A.P. Porte R.J. Benne C.A. Vennema H. Reimerink J.H. et al.Chronic hepatitis E virus infection in liver transplant recipients.Liver Transpl. 2008; 14: 547-553Crossref PubMed Scopus (270) Google Scholar]. Chronic evolution of HEV infection and liver disease occurred in both, leading to retransplantation. The two cases differed slightly, in that the first had been probably infected at the time or shortly after transplant. Six years later, this patient had developed end-stage liver disease with ascites, jaundice and variceal bleeding. A misdiagnosis of autoimmune hepatitis had resulted in increased immunosuppressive therapy, and one year later the patient had worsened to the point of requiring a retransplantation. One year after the second transplant, the liver enzymes were elevated again and once more liver histology showed lobular hepatitis with portal fibrosis. During these years and notably after retransplantation serum HEV RNA levels were persistently detectable. The second case history started, on the contrary, seven years after liver transplant at the time of a travel-related HEV infection. Within five years of acute HEV infection end-stage liver disease developed requiring retransplantation. In this case HEV RNA was detectable from time of primary infection until retransplantation, but not later on, suggesting viral clearance. These reports may change our view on the natural history of HEV infection. Eleven patients developed chronic infection and three cases progressed to cirrhosis. So far, persistent HEV infection accompanied by chronic, progressive liver damage, occasionally leading to cirrhosis, had never been reported. Some further points are worthy of note. First, except for the one travel-related HEV infection in the report of Haagsma et al. [[14]Haagsma E.B. van den Berg A.P. Porte R.J. Benne C.A. Vennema H. Reimerink J.H. et al.Chronic hepatitis E virus infection in liver transplant recipients.Liver Transpl. 2008; 14: 547-553Crossref PubMed Scopus (270) Google Scholar], all reported patients had acquired HEV in developed countries (France and Netherlands) without any evident known source of contamination. HEV is likely endemic in these countries, probably subclinically with autochthonous strains transmitted through the food chain (zoonotic food-borne transmission) or through blood products (blood-borne transmission). The blood supply is particularly vulnerable to emerging pathogens, especially non-enveloped viruses like HEV because pathogen inactivation methods are insufficient and routine serological tests are not performed [[15]Bihl F. Castelli D. Marincola F. Dodd R.Y. Brander C. Transfusion-transmitted infections.J Transl Med. 2007; 5: 25Crossref PubMed Scopus (135) Google Scholar]. Second, chronic HEV might explain many cases of otherwise unexplained post-transplant hepatitis or cryptogenic cirrhosis. However, how should the diagnosis be made? Diagnostic tools to assess HEV infection are available and encompass serological assays to detect anti-HEV antibodies capable of differentiating recent from remote infection (IgG, IgM, IgA). These tests are generally based on detection of antibodies against the highly conserved and immunogenic capsid protein (encoded by the open reading frame 2) and are characterized by broad activity and good reproducibility. Highly specific ELISA for quantifying neutralizing antibodies to HEV genotypes 1–4 are commercially available. Nevertheless, in the reported cases seroconversion occurred on average later than among non-immunosuppressed patients (10 months after acute infection versus 1–3 weeks in immune competent patients). Even more disturbing is the observation that in three of the 11 patients antibodies remained consistently negative. Nucleic acid testing, in contrast, is the most sensitive test for ongoing HEV infection. Nested or real-time PCR may detect viral genomic RNA in serum or stools, especially in acute infection and within the first week after exposure. Therefore, immunosuppressed patients with unexplained elevated liver enzymes most likely should be tested with a combination of serology and nucleic acid assays to ascertain HEV infection. Third, how can we treat or prevent HEV in this setting? Specific treatments and therapeutic recommendations are lacking. However, in transplant recipients with a suspect of chronic HEV infection, the immunosuppressive regimen should probably be lowered to a level sufficient to allow for the humoral and – more importantly – the cellular immunity to curb HEV infection. Since an effective recombinant vaccine against HEV exists [[16]Shrestha M.P. Scott R.M. Joshi D.M. Mammen Jr., M.P. Thapa G.B. Thapa N. et al.Safety and efficacy of a recombinant hepatitis E vaccine.N Engl J Med. 2007; 356: 895-903Crossref PubMed Scopus (422) Google Scholar], its use in patients undergoing immunosuppression for organ transplantation should be considered.
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