Association of hepatitis E virus infection and myasthenia gravis: A pilot study
2018; Elsevier BV; Volume: 68; Issue: 6 Linguagem: Inglês
10.1016/j.jhep.2018.01.040
ISSN1600-0641
AutoresLin Wang, Feng Gao, Gang Lin, Yun Yuan, Yining Huang, Hong-Jun Hao, Hui Zhuang, Ling Wang,
Tópico(s)Viral gastroenteritis research and epidemiology
ResumoHepatitis E virus infection and acute non-traumatic neurological injury: A prospective multicentre studyJournal of HepatologyVol. 67Issue 5PreviewHepatitis E virus (HEV) is endemic in many developed countries. In such settings, infection is mostly caused by HEV genotypes 3 and 4 (gt3 and 4) and is considered to be largely zoonotic with pigs as the usual source. Locally-acquired HEV infection is mostly (∼95%) asymptomatic but may result in clinically evident hepatitis that mainly affects older males.1,2 Chronic infection has also been documented in immunosuppressed patients including transplant recipients, those undergoing chemotherapy for haematological malignancy, and people living with HIV. Full-Text PDF Reply to: "Association of hepatitis E virus infection and myasthenia gravis: A pilot study"Journal of HepatologyVol. 68Issue 6PreviewHepatitis E virus (HEV) has been associated with several extrahepatic, neurological manifestations.1,2 The associated neurological syndromes are most frequently subacute, post-infectious peripheral nervous system diseases including neuralgic amyotrophy and Guillain-Barre syndrome. In addition, infectious involvement of the central nervous system (HEV encephalitis) has been reported. When the genotype has been determined, neurological injury has almost exclusively been associated with HEV genotype 3 (HEV gt3), but case reports come from both developed and developing countries suggesting that HEV-associated neurological damage is not genotype-specific. Full-Text PDF Recently, a very important prospective multicentre study reported that 2.4% patients with non-traumatic neurological injury had evidence of current/recent hepatitis E virus (HEV) infection, highlighting the role of HEV in inducing neurological diseases.[1]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. 2017; 67: 925-932Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar To date, the full spectrum of HEV-associated neurological injury is still unknown. Myasthenia gravis (MG) has been associated with a number of viral infections, such as Epstein-Barr virus (EBV),[2]Cavalcante P. Serafini B. Rosicarelli B. Maggi L. Barberis M. Antozzi C. et al.Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus.Ann Neurol. 2010; 67: 726-738PubMed Google Scholar poliovirus,[3]Cavalcante P. Barberis M. Cannone M. Baggi F. Antozzi C. Maggi L. et al.Detection of poliovirus-infected macrophages in thymus of patients with myasthenia gravis.Neurology. 2010; 74: 1118-1126Crossref PubMed Scopus (56) Google Scholar and Zika virus.[4]Molko N. Simon O. Guyon D. Biron A. Dupont-Rouzeyrol M. Gourinat A.C. Zika virus infection and myasthenia gravis: report of 2 cases.Neurology. 2017; 88: 1097-1098Crossref PubMed Scopus (28) Google Scholar One study described a woman suffering with MG as a complication of acute HEV infection.[5]Belbezier A. Deroux A. Sarrot-Reynauld F. Larrat S. Bouillet L. Myasthenia gravis associated with acute hepatitis E infection in immunocompetent woman.Emerg Infect Dis. 2014; 20: 908-910Crossref PubMed Scopus (18) Google Scholar In this pilot study, the frequency of current/recent HEV infection in a cohort of Chinese patients with MG was determined in relation to their clinical phenotypes. This study was approved by the ethics committee of the Peking University Health Science Center. All patients or their guardians gave informed consent for the testing of clinical samples. MG patients seen within the Department of Neurology of Peking University First Hospital between January 2014 and December 2016 were enrolled. A total number of 188 newly diagnosed patients fulfilled the study criteria of a definitive MG diagnosis (Supplementary information). Positive anti-HEV IgM was found in 10 patients (5.3%, 10/188). Anti-HEV IgG was detected in 64 patients (34%, 64/188). The 10 anti-HEV IgM-positive patients were all anti-HEV IgG-positive (Table 1). Four of the anti-HEV IgM-positive samples (2.1%, 4/188) were positive for HEV RNA (Table 1). Phylogenetic analysis showed that the four HEV isolates were genotype 4.[6]Wang L. Liu L. Wei Y. Wang Q. Tian Q. Wang L. et al.Clinical and virological profiling of sporadic hepatitis E virus infection in China.J Infection. 2016; 73: 271-279Abstract Full Text Full Text PDF PubMed Scopus (28) Google ScholarTable 1Clinical and laboratory features of myasthenia gravis patients with hepatitis E virus infection.Patient12345678910Age/Sex22F63F49M79M43M78M45F46M76M53MYear of inclusion2016201620162016201620152015201420142014JaundiceNoNoNoNoNoNoNoNoNoNoImmunocompetentYesYesYesYesYesYesYesYesYesYesHEV testing IgM++++++++++ IgG++++++++++ PCR−++−+−−+−− Genotypen.a.4a4dn.a.4 hn.a.n.a.4dn.a.n.a.Liver functionaPatient No. 3 and 6 had previous medical records of liver function tests. Other patients were tested using stored serum samples during the present study. ALT, U/LbALT normal range 9–50 U/L.12.017.189.013.015.413.430.022.4100.110.7 AST, U/LcAST normal range 9–50 U/L.10.014.2n.t.11.615.916.111.227.148.815.2 T-Bil, μmol/LdT-Bil normal range 5–22 μmol/L.n.t.n.t.11.7n.t.n.t.n.t.n.t.n.t.n.t.n.t.Thymic conditionNormalNormalThymomaNormalThymomaNormalThymomaNormalHyperplasiaThymomaMG antibodiesAchR +AchR +AchR +AchR +AchR +AchR +dSNMGdSNMGdSNMGdSNMGMaximum MGFA gradeIIIIbIIVbIIIIbIIaIIIbTreatmentNeostigmineNeostigmineNeostigmineNilIntravenous immune globulin + cyclosporine ANeostigmine + prednisone + mycophenolate mofetilNeostigmine + prednisoneNeostigmineTacrolimusPrednisoloneOutcomeeFisher's Exact Test.RecoveryRecoveryRecoveryRecoveryRecoveryRecoveryRecoveryRecoveryRecoveryRecoveryDisease course19 months18 months22 months23 months25 months31 months73 months42 months41 months39 monthsAchR, acetylcholine receptor; ALT, alanine aminotransferase; AST, aspartate aminotransferase; dSNMG, double sero-negative myasthenia gravis; HEV, hepatitis E virus; MG, myasthenia gravis; MGFA, Myasthenia Gravis Foundation of America; MuSK, muscle-specific kinase; NA, not applicable; NT, not tested; T-Bil, total bilirubin.a Patient No. 3 and 6 had previous medical records of liver function tests. Other patients were tested using stored serum samples during the present study.b ALT normal range 9–50 U/L.c AST normal range 9–50 U/L.d T-Bil normal range 5–22 μmol/L.e Fisher's Exact Test. Open table in a new tab AchR, acetylcholine receptor; ALT, alanine aminotransferase; AST, aspartate aminotransferase; dSNMG, double sero-negative myasthenia gravis; HEV, hepatitis E virus; MG, myasthenia gravis; MGFA, Myasthenia Gravis Foundation of America; MuSK, muscle-specific kinase; NA, not applicable; NT, not tested; T-Bil, total bilirubin. Of the 10 patients who had a current/recent HEV infection (HEV+), seven were male and three female. They had a median age of 51, and ranged from 22 to 79. At diagnosis, six of these ten HEV+ MG patients were anti-acetylcholine receptor (AchR) positive MG and the other four patients were double sero-negative MG. Their maximum Myasthenia Gravis Foundation of America Grade was obtained and compared to HEV- MG patients but this revealed no statistically significant difference (Table S1). There was also no statistical difference between HEV+ and HEV- patients regarding age at onset, sex, MG antibodies and preceding thymic hyperplasia (Table S1). However, HEV+ MG patients did have a significantly higher rate of preceding thymoma than HEV− MG patients (40.0% vs. 9.6%, p = 0.02). Additional analysis of the ten HEV+ patients was carried out as shown (Table 1). Jaundice was not observed in any of these patients at diagnosis; serology for HBV, HCV and HIV were all negative. Anti-cytomegalovirus IgG was detected in all patients. Anti-EBV IgG was detected in nine patients (except Patient No. 6). Patient No. 1 was found to be anti-EBV IgM-positive, however no EBV DNA was detected. In standard clinical practice in China, liver function tests were rarely performed in patients with MG. Only two patients (Patient No. 3 and 6) had recorded results of liver function tests and other patients were tested using stored serum samples. Patient No. 3 and 9 had a mildly elevated alanine aminotransferase level of 89.0 U/L and 100.1 U/L, respectively. All patients were immunocompetent before onset. All patients presented with ptosis and 50% (5/10) of them subsequently developed ocular MG. Patients 2, 7, 8 and 10 all developed dysphagia. Patient No. 5 had more severe presentation, including ptosis, dysphagia, dyspnea and four-limb weakness. Five patients in this group were treated with immunosuppressants for their MG until their neurological symptoms were relieved. The disease outcome of all patients in the group was monitored at six months after initial diagnosis and all reported significant symptomatic improvement. At the end, complete neurological resolution was achieved in all patients (Table 1). The current study, conducted on a cohort of Chinese patients with MG, indicates that approximately 5% of the patients have acute HEV infection. HEV viraemia was detected in 4/188 MG patients (2.1%, 1:47), a prevalence that is at least 20 times greater than that reported for Chinese blood donors (0.07%, 1:1,493).[7]Kamar N. Izopet J. Pavio N. Aggarwal R. Labrique A. Wedemeyer H. et al.Hepatitis E virus infection.Nat Rev Dis Primers. 2017; 3: 17086Crossref PubMed Scopus (289) Google Scholar Six patients with recent HEV infection were HEV RNA-negative and this is not uncommon.1Dalton 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. 2017; 67: 925-932Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 6Wang L. Liu L. Wei Y. Wang Q. Tian Q. Wang L. et al.Clinical and virological profiling of sporadic hepatitis E virus infection in China.J Infection. 2016; 73: 271-279Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar During acute HEV infection, the duration of HEV viraemia is relatively short (about four weeks). HEV RNA will quickly become undetectable after clinical symptoms occur. Anti-HEV IgM level will persist for about 6–9 months, which is much longer than the duration of HEV viraemia.[7]Kamar N. Izopet J. Pavio N. Aggarwal R. Labrique A. Wedemeyer H. et al.Hepatitis E virus infection.Nat Rev Dis Primers. 2017; 3: 17086Crossref PubMed Scopus (289) Google Scholar Previous studies reported that EBV[2]Cavalcante P. Serafini B. Rosicarelli B. Maggi L. Barberis M. Antozzi C. et al.Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus.Ann Neurol. 2010; 67: 726-738PubMed Google Scholar and poliovirus[3]Cavalcante P. Barberis M. Cannone M. Baggi F. Antozzi C. Maggi L. et al.Detection of poliovirus-infected macrophages in thymus of patients with myasthenia gravis.Neurology. 2010; 74: 1118-1126Crossref PubMed Scopus (56) Google Scholar can be detected in the thymus of patients with MG and a viral contribution to the intrathymic alterations may lead to the disease. HEV has now been discovered having a broad tissue tropism and can directly induce associated injury on-site. Recently, a case report found that HEV can infect endothelial cells, recruit immune cells and subsequently induce cutaneous lymphoproliferation.[8]Mallet V. Bruneau J. Zuber J. Alanio C. Leclerc-Mercier S Roque-Afonso A.M. et al.Hepatitis E virus-induced primary cutaneous CD30(+) T cell lymphoproliferative disorder.J Hepatol. 2017; 67: 1334-1339Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar However no evidence to date shows that HEV can replicate in human thymus. An animal study has reported detecting negative-stranded HEV RNA and viral proteins in the thymus of rabbits, indicating that the thymus is a potential replication site for HEV.[9]Wu Q. An J. She R. Shi R. Hao W. Soomro M. et al.Detection of genotype 4 swine hepatitis E virus in systemic tissues in cross-species infected rabbits.PLoS One. 2017; 12: e171277Google Scholar Therefore, it is possible that HEV contributes to MG by replicating in thymus, inducing the bystander effect or antigen-specific T cell stimulation. This warrants future studies.[10]Cavalcante P. Cufi P. Mantegazza R. Berrih-Aknin S. Bernasconi P. Le Panse R. et al.Etiology of myasthenia gravis: innate immunity signature in pathological thymus.Autoimmun Rev. 2013; 12: 863-874Crossref PubMed Scopus (72) Google Scholar Alternatively, it is quite possible that patients already have latent MG and the subsequent HEV infection contributes to the condition, becoming a final trigger of clinical disease. In general, the results of the present study suggest that, at least in China, 5.3% of patients with MG have an acute HEV infection. Conclusions cannot be drawn on casuality and future prospective studies should investigate whether HEV-associated MG could occur in other geographical locations. This study was funded by the National Science Foundation of China (grant number 81772175) and the Beijing Natural Science Foundation (grant no. 7162103). The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. LinW, LingW, HZ and HH designed the study. FG, GL, YY, YH and HH collected the clinical data. LinW performed the study and analyzed the data. LinW, LingW and HH wrote the manuscript. LingW and HH conceived and supervised the study. We thank Professor Malcolm A. McCrae from University of Warwick, UK, for proofreading the manuscript. 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