CXCL10; Clade; Hepatitis E virus; Pathogenicity; Risk factor; Severity; Hepatology
Abstract :
[en] ("[en] BACKGROUND & AIMS: HEV genotype (gt) 3 infections are prevalent in high-income countries and display a wide spectrum of clinical presentations. Host - but not viral - factors are reported to be associated with worse clinical outcomes.
METHODS: Demographic, clinical, and biochemical data of laboratory-confirmed HEV infections (by PCR and/or a combination of IgM and IgG serology) at the Belgian National Reference Centre between January 2010 and June 2018 were collected using standardised case report forms. Genotyping was based on HEV open reading frame 2 sequences. Serum CXCL10 levels were measured by a magnetic bead-based assay. H&E staining was performed on liver biopsies.
RESULTS: A total of 274 HEV-infected individuals were included. Subtype assignment was possible for 179/218 viraemic cases, confirming gt3 as dominant with an almost equal representation of clades abchijklm and efg. An increased hospitalisation rate and higher peak serum levels of alanine aminotransferase, bilirubin, and alkaline phosphatase were found in clade efg-infected individuals in univariate analyses. In multivariable analyses, clade efg infections remained more strongly associated with severe disease presentation than any of the previously identified host risk factors, being associated with a 2.1-fold higher risk of hospitalisation (95% CI = 1.1-4.4, p = 0.034) and a 68.2% higher peak of bilirubin levels (95% CI = 13.3-149.9, p = 0.010), independently of other factors included in the model. In addition, acute clade efg infections were characterised by higher serum CXCL10 levels (p = 0.0005) and a more pronounced liver necro-inflammatory activity (p = 0.022).
CONCLUSIONS: In symptomatic HEV gt3 infections, clade efg is associated with a more severe disease presentation, higher serum CXCL10 levels, and liver necro-inflammatory activity, irrespective of known host risk factors.
CLINICAL TRIAL REGISTRATION: The protocol was submitted to clinicaltrials.gov (NCT04670419).
IMPACT AND IMPLICATIONS: HEV genotype (gt) 3 infections display a wide spectrum of clinical presentations currently ascribed to host factors. Here we examined the role of viral factors on liver disease outcomes by combining viral phylogeny with clinical, biochemical, cytokine, and histological data from 274 Belgian adults infected with HEV presenting between 2010 and 2018. HEV gt 3 clade efg infections were associated with a more severe disease presentation, higher serum CXCL10 levels and liver necro-inflammatory activity, irrespective of known host risk factors. HEV gt3 clade-dependent clinical outcomes call for broad HEV gt3 subtyping in clinical practice and research to help identify those at higher risk for worse outcomes and to further unravel underlying virus-host interactions.","[en] ","")
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Peeters, Michael ; Sciensano, Infectious Diseases in Humans, Viral Diseases, National Reference Centre of Hepatitis Viruses, Brussels, Belgium
Schenk, Julie; University of Antwerp, Faculty of Medicine and Health Sciences, Vaccine & Infectious Disease Institute, Centre for Health Economic Research and Modelling Infectious Diseases, Antwerp, Belgium, Hasselt University, Data Science Institute, Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt, Belgium
De Somer, Thomas; University Hospital Antwerp, Gastroenterology & Hepatology, Antwerp, Belgium, Maria Middelares Hospital, Gastroenterology & Hepatology, Ghent, Belgium
Roskams, Tania; KU Leuven, Pathology, Translational Cell and Tissue Research, Leuven, Belgium
Locus, Tatjana ; Sciensano, Infectious Diseases in Humans, Viral Diseases, National Reference Centre of Hepatitis Viruses, Brussels, Belgium
Klamer, Sofieke; Sciensano, Epidemiology of Infectious Diseases, Brussels, Belgium
Subissi, Lorenzo; Sciensano, Infectious Diseases in Humans, Viral Diseases, National Reference Centre of Hepatitis Viruses, Brussels, Belgium, European Public Health Microbiology Training Program (EUPHEM), European Centre for Disease Prevention and Control, Stockholm, Sweden
Suin, Vanessa; Sciensano, Infectious Diseases in Humans, Viral Diseases, National Reference Centre of Hepatitis Viruses, Brussels, Belgium
Delwaide, Jean ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gastroentérologie, hépatologie, onco. digestive
Colle, Isabelle; A.S.Z. Aalst, Gastroenterology & Hepatology, Aalst, Belgium, Ghent University Hospital, Department of Hepatology and Gastroenterology, Ghent, Belgium
Van Hoof, Marc; Clinique Saint-Luc, Gastroenterology & Hepatology, Bouge, Belgium
Van Acker, Jos ; AZ Sint-Lucas, Clinical Microbiology, Ghent, Belgium
Van Steenkiste, Christophe; University Hospital Antwerp, Gastroenterology & Hepatology, Antwerp, Belgium, Maria Middelares Hospital, Gastroenterology & Hepatology, Ghent, Belgium
Moreno, Christophe; CUB Hôpital Erasme, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Université Libre de Bruxelles, Brussels, Belgium
Janssens, Filip ; Jessa Hospital, Gastroenterology & Hepatology, Hasselt, Belgium
Reynders, Marijke ; AZ Sint-Jan Brugge-Oostende AV, Medical Microbiology, Laboratory Medicine, Brugge, Belgium
Steverlynck, Matthias; CHM Mouscron, Department of Gastroenterology, Mouscron, Belgium
Verlinden, Wim; University Hospital Antwerp, Gastroenterology & Hepatology, Antwerp, Belgium, Vitaz, Gastroenterology & Hepatology, Sint-Niklaas, Belgium, University of Antwerp, Laboratory of Experimental Medicine and Pediatrics, Viral Hepatitis Research Group, Antwerp, Belgium
Dastis, Sergio Negrín; Grand Hôpital de Charleroi, Gastroenterology & Hepatology, Charleroi, Belgium
Boes, Juul; AZ Turnhout, Turnhout, Belgium
Nijs, Jochen ; Sint-Trudo Ziekenhuis, Department of Gastroenterology, Sint-Truiden, Belgium
Beyls, Jan; Sint-Andriesziekenhuis, Department of Gastroenterology, Tielt, Belgium
Hens, Niel ; University of Antwerp, Faculty of Medicine and Health Sciences, Vaccine & Infectious Disease Institute, Centre for Health Economic Research and Modelling Infectious Diseases, Antwerp, Belgium, Hasselt University, Data Science Institute, Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt, Belgium
Nevens, Frederik ; University Hospitals KU Leuven, Gastroenterology & Hepatology, Leuven, Belgium
Van Gucht, Steven; Sciensano, Infectious Diseases in Humans, Viral Diseases, National Reference Centre of Hepatitis Viruses, Brussels, Belgium. Electronic address: Steven.VanGucht@sciensano.be
Vanwolleghem, Thomas ; University Hospital Antwerp, Gastroenterology & Hepatology, Antwerp, Belgium, University of Antwerp, Laboratory of Experimental Medicine and Pediatrics, Viral Hepatitis Research Group, Antwerp, Belgium. Electronic address: Thomas.Vanwolleghem@uza.be
This study is a retrospective analysis of routinely collected data, within the Belgian National Reference Centre (NRC) programme funded by the National Institute for Health and Disability Insurance (RIZIV-INAMI, Belgium). TV is supported by a senior clinical investigator grant of the Research Foundation Flanders (FWO) (number 18B2821N , Belgium). JS and NH acknowledge funding from the European Research Council (ERC) Horizon 2020 research and innovation program (grant agreement 682540 — TransMID , European Union). The funding sources did not have any role in study design, in the collection, analysis, and interpretation of data, in the manuscript writing, or in the decision to submit the paper for publication.
Nicot, F., Dimeglio, C., Migueres, M., Jeanne, N., Latour, J., Abravanel, F., et al. Classification of the zoonotic hepatitis E virus genotype 3 into distinct subgenotypes. Front Microbiol, 11, 2021, 3631.
Smith, D.B., Izopet, J., Nicot, F., Simmonds, P., Jameel, S., Meng, X.-J., et al. Update: proposed reference sequences for subtypes of hepatitis E virus (species Orthohepevirus A). J Gen Virol 101 (2020), 692–698.
European Association for the Study of the Liver. EASL clinical practice guidelines on hepatitis E virus infection. J Hepatol 68 (2018), 1256–1271.
Kamar, N., Garrouste, C., Haagsma, E.B., Garrigue, V., Pischke, S., Chauvet, C., et al. Factors associated with chronic hepatitis in individuals with hepatitis E virus infection who have received solid organ transplants. Gastroenterology 140 (2011), 1481–1489.
Dalton, H.R., Bendall, R.P., Rashid, M., Ellis, V., Ali, R., Ramnarace, R., et al. Host risk factors and autochthonous hepatitis E infection. Eur J Gastroenterol Hepatol 23 (2011), 1200–1205.
Wallace, S.J., Swann, R., Donnelly, M., Kemp, L., Guaci, J., Murray, A., et al. Mortality and morbidity of locally acquired hepatitis E in the national Scottish cohort: a multicentre retrospective study. Aliment Pharmacol Ther 51 (2020), 974–986.
Lenggenhager, D., Pawel, S., Honcharova-Biletska, H., Evert, K., Wenzel, J.J., Montani, M., et al. The histologic presentation of hepatitis E reflects patients’ immune status and pre-existing liver condition. Mod Pathol 34 (2021), 233–248.
Smith, D.B., Ijaz, S., Tedder, R.S., Hogema, B., Zaaijer, H.L., Izopet, J., et al. Variability and pathogenicity of hepatitis E virus genotype 3 variants. J Gen Virol 96 (2015), 3255–3264.
Tedder, R.S., Tettmar, K.I., Brailsford, S.R., Said, B., Ushiro-Lumb, I., Kitchen, A., et al. Virology, serology, and demography of hepatitis E viremic blood donors in South East England. Transfusion 56 (2016), 1529–1536.
Subissi, L., Peeters, M., Lamoral, S., Klamer, S., Suin, V., Van Gucht, S., Subtype-specific differences in the risk of hospitalisation among patients infected with hepatitis E virus genotype 3 in Belgium, 2010–2018. Epidemiol Infect, 147, 2019, e224.
Abravanel, F., Dimeglio, C., Castanier, M., Péron, J.-M., Kamar, N., Lhomme, S., et al. Does HEV-3 subtype play a role in the severity of acute hepatitis E? Liver. Int 40 (2020), 333–337.
European Association for the Study of the Liver. Asociación Latinoamericana para el Estudio del Hígado. EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol 63 (2015), 237–264.
UK Health Security Agency. Public health England. Chapter 6: contraindications and special considerations. Immunisation against infectious disease: the green Book, 2017 https://www.gov.uk/government/publications/contraindications-and-special-considerations-the-green-book-chapter-6. (Accessed 31 January 2022)
Suin, V., Klamer, S.E., Hutse, V., Wautier, M., Jacques, M., Abady, M., et al. Epidemiology and genotype 3 subtype dynamics of hepatitis E virus in Belgium, 2010 to 2017. Eurosurveillance, 24, 2019, 1800141.
Huang, F.F., Haqshenas, G., Guenette, D.K., Halbur, P.G., Schommer, S.K., Pierson, F.W., et al. Detection by reverse transcription-PCR and genetic characterization of field isolates of swine hepatitis E virus from pigs in different geographic regions of the United States. J Clin Microbiol, 40, 2002, 1326.
Boxman, I.L.A., Jansen, C.C.C., Hägele, G., Zwartkruis-Nahuis, A., Cremer, J., Vennema, H., et al. Porcine blood used as ingredient in meat productions may serve as a vehicle for hepatitis E virus transmission. Int J Food Microbiol 257 (2017), 225–231.
Madeira, F., Park, Y.M., Lee, J., Buso, N., Gur, T., Madhusoodanan, N., et al. The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res 47 (2019), W636–W641.
Kumar, S., Stecher, G., Li, M., Knyaz, C., Tamura, K., MEGA X: molecular evolutionary genetics analysis across computing platforms. Mol Biol Evol 35 (2018), 1547–1549.
Benjamini, Y., Hochberg, Y., Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Stat Methodol 57 (1995), 289–300.
Yu, C., Boon, D., McDonald, S.L., Myers, T.G., Tomioka, K., Nguyen, H., et al. Pathogenesis of hepatitis E virus and hepatitis C virus in chimpanzees: similarities and differences. J Virol 84 (2010), 11264–11278.
Choi, Y.H., Zhang, X., Tran, C., Skinner, B., Expression profiles of host immune response-related genes against HEV genotype 3 and genotype 1 infections in rhesus macaques. J Viral Hepat 25 (2018), 986–995.
You, C.R., Park, S.H., Jeong, S.W., Woo, H.Y., Bae, S.I., Choi, J.Y., et al. Serum IP-10 levels correlate with the severity of liver histopathology in patients infected with genotype-1 HCV. Gut Liver 5 (2011), 506–512.
Ho, E., Schenk, J., Hutse, V., Suin, V., Litzroth, A., Blaizot, S., et al. Stable HEV IgG seroprevalence in Belgium between 2006 and 2014. J Viral Hepat 11 (2020), 1253–1260.
Yin, X., Ying, D., Lhomme, S., Tang, Z., Walker, C.M., Xia, N., et al. Origin, antigenicity, and function of a secreted form of ORF2 in hepatitis E virus infection. Proc Natl Acad Sci U S A 115 (2018), 4773–4778.
Montpellier, C., Wychowski, C., Sayed, I.M., Meunier, J.C., Saliou, J.-M., Ankavay, M., et al. Hepatitis E virus lifecycle and identification of 3 forms of the ORF2 capsid protein. Gastroenterology 154 (2018), 211–223.e8.
Brown, A., Halliday, J.S., Swadling, L., Madden, R.G., Bendall, R., Hunter, J.G., et al. Characterization of the specificity, functionality, and durability of host T-cell responses against the full-length hepatitis E virus. Hepatology 64 (2016), 1934–1950.
El Costa, H., Gouilly, J., Abravanel, F., Bahraoui, E., Peron, J.-M., Kamar, N., et al. Effector memory CD8 T cell response elicits hepatitis E virus genotype 3 pathogenesis in the elderly. Plos Pathog, 17, 2021, e1009367.
Sen, E.S., Ramanan, A.V., Cytokine storm syndrome associated with hemorrhagic fever and other viruses. Cron, R.Q., Behrens, E.M., (eds.) Cytokine storm syndrome, 2019, Springer International, Cham, 27797.
van de Garde, M., Pas, S.D., van Oord, G.W., Gama, L., Choi, Y., de Man, R.A., et al. Interferon-alpha treatment rapidly clears Hepatitis E virus infection in humanized mice. Sci Rep, 7, 2017, 8267.
Tarantino, G., Ortolani, A., Marinelli, K., Benedetti, A., Marconi, G., Calzolari, M., et al. Locally acquired hepatitis E virus in Marche Italy: clinical/laboratory features and outcome. Dig Liver Dis 52 (2020), 434–439.
Fukae, J., Tsugawa, J., Ouma, S., Umezu, T., Kusunoki, S., Tsuboi, Y., Guillain–Barré and Miller Fisher syndromes in individuals with anti-hepatitis E virus antibody: a hospital-based survey in Japan. Neurol Sci 37 (2016), 1849–1851.
Dalton, H.R., van Eijk, J.J.J, Cintas, P., Madden, R.G., Jones, C., Webb, G.W., et al. Hepatitis E virus infection and acute non-traumatic neurological injury: a prospective multicentre study. J Hepatol 67 (2017), 925–932.
Mendoza-Lopez, C., Lopez-Lopez, P., Atienza-Ayala, S., Rivero-Juarez, A., Benito, R., Parsonage-Turner syndrome associated with hepatitis E infection in immunocompetent patients. Virus Res, 290, 2020, 198165.
Ripellino, P., Pasi, E., Melli, G., Staedler, C., Fraga, M., Moradpour, D., et al. Neurologic complications of acute hepatitis E virus infection. Neurol Neuroimmunol Neuroinflamm, 7, 2019, e643.
Woolson, K.L., Forbes, A., Vine, L., Beynon, L., McElhinney, L., Panayi, V., et al. Extra-hepatic manifestations of autochthonous hepatitis E infection. Aliment Pharmacol Ther 40 (2014), 1282–1291.
Wang, B., Harms, D., Papp, C.P., Niendorf, S., Jacobsen, S., Lütgehetmann, M., et al. Comprehensive molecular approach for characterization of hepatitis E virus genotype 3 variants. J Clin Microbiol 56 (2018), e01686–e01717.
