Sir, Hepatitis E virus (HEV) is a well-known cause of acute hepatitis worldwide and a member of the genus Hepevirus in the Hepeviridae family.1 In Western European countries, hepatitis E infection is an emerging disease, where an increasing number of autochthonous hepatitis E cases have been reported.1 In these countries HEV infection is typically caused by genotype 3, mainly affects middle-aged or elderly males and is zoonotic with a porcine primary host.1–3 HEV infection usually leads to acute hepatitis but it may evolve to a chronic state, especially in immunosuppressed individuals.2 Like other viral hepatitis, several extra-hepatic manifestations have been described in association with hepatitis E, including neurological disorders such as Guillain–Barré Syndrome, neuralgic amyotrophy and encephalitis.4–6 Herein, to our knowledge, we report for the first time in Spain a case where simultaneous acute hepatitis and meningitis occurred in a patient infected by HEV, and in whom HEV RNA was detected and characterized in serum and CSF. A middle-aged patient, working as a chef in Galicia (in the northwest of Spain), was hospitalized due to a 3-day history of fever, arthralgia, myalgia and intense headache. He did not complain about earache, cough, expectoration, abdominal pain, nausea, vomiting, change in bowel habit or lower urinary tract symptoms. He denied recent trips abroad. Upon arrival he presented with a temperature of 37.4°C. General physical examination revealed the presence of hepatomegaly. The patient was fully conscious and oriented. Nuchal rigidity and Kernig’s or Brudziński’s signs were absent. The rest of the neurological examination was also normal. At admission, blood tests detected slight neutrophilia without leucocytosis and elevation of AST (277 IU/L; reference 8–34 IU/L), ALT (441 IU/L; reference 9–38 IU/L) and GGT (344 IU/L; reference 9–38 IU/L). Coagulation tests were normal. Urinalysis showed no evidence of infection. Chest X-ray and brain computed tomography revealed no alterations. CSF examination showed a mild lymphocytic pleocytosis (34 cells/mm3; 95% lymphocytes; no red blood cells) with a slight hyperproteinorrachia (0.49 g/L, reference 0.15–0.45 g/L) and no glucose consumption. After 5 days of hospitalization significant worsening in blood tests was detected: AST 880 IU/L, ALT 2725 IU/L, GGT 607 IU/L and total bilirubin 1.3 mg/dL (reference 0.2–1.2 mg/dL). Abdominal ultrasound study showed severe hepatic steatosis and fibrosis, probably related to previous chronic and excessive alcohol consumption. Standard cultures of CSF remained negative and several infectious diseases responsible for neurological symptoms (Lyme disease, syphilis, mycoplasma, Brucella, Coxiella, Leptospira, HIV, herpesviruses, measles, mumps, parvovirus B19, enteroviruses) and acute hepatitides (hepatitis A, B, C) were excluded by nucleic acid and serology assays performed on serum and CSF. In contrast, HEV infection was diagnosed by detection of anti-HEV IgM [index >1.2; threshold value 1.0 in ELISA test (DIA.PRO, Milan, Italy)] in serum and HEV RNA in serum and CSF. HEV RNA was recovered from CSF and serum by using in-house protocols of reverse transcription and nested PCR with a set of universal HEV PCR primers capable of detecting all four known genotypes.7 The obtained products were confirmed by sequencing and these sequences (GenBank accession numbers KY203906 and KY203907 from CSF and serum, respectively) showed 100% nucleotide identity with each other and phylogenetic analysis identified genotype 3 subgenotype f (Figure 1), which is commonly found in autochthonous cases in western Spain.8 The patient did not receive specific treatment and experienced a complete recovery without sequelae. Within 8 weeks, liver enzyme levels returned to their normal ranges and HEV RNA became undetectable both in serum and CSF. Figure 1 View largeDownload slide Phylogenetic analysis of hepatitis E virus based on partial ORF2 sequence region (193 nt). The phylogenetic tree was constructed by the maximum-likelihood method, using the general time-reversible plus rate variation among sites model and 1000 replicates of bootstrap resampling as implemented in the PhyML software (version 3.0). Bootstrap values of >50% are indicated at the respective branches. Reference sequences available from GenBank with previously identified genotypes are labelled. The virus from the case described in this study is indicated in bold. Figure 1 View largeDownload slide Phylogenetic analysis of hepatitis E virus based on partial ORF2 sequence region (193 nt). The phylogenetic tree was constructed by the maximum-likelihood method, using the general time-reversible plus rate variation among sites model and 1000 replicates of bootstrap resampling as implemented in the PhyML software (version 3.0). Bootstrap values of >50% are indicated at the respective branches. Reference sequences available from GenBank with previously identified genotypes are labelled. The virus from the case described in this study is indicated in bold. In this case report, to our knowledge, we present the first case in Spain of an immunocompetent patient with simultaneous acute meningitis and hepatitis secondary to autochthonous HEV infection. Although the causality of HEV infection in non-hepatic manifestations might be a subject for discussion,9 the exclusion of other possible aetiologies, the temporal association between meningitis and hepatitis and the HEV RNA detection in both serum and CSF, together support the causal relationship to HEV infection in our patient. There are several reported cases of neurological disorders secondary to HEV infection, concomitant with both acute and chronic hepatitis, and both in immunocompromised and immunocompetent patients.4–6 The spectrum of manifestations is broad. Among them, peripheral nervous system disorders such as Guillain–Barré Syndrome and neuralgic amyotrophy are the most common. However, HEV infection as a cause of meningitis is rare in immunocompetent patients according to published literature.4,5 Finally, these findings highlight the importance of performing HEV diagnostic tests in patients who have concurrent hepatitis and neurological manifestations. As HEV infection is an emerging issue in the developed world, clinicians in these countries should be aware of this possibility. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. References 1 Kamar N , Dalton HR , Abravanel F et al. Hepatitis E virus infection . Clin Microbiol Rev 2014 ; 27 : 116 – 38 . Google Scholar CrossRef Search ADS PubMed 2 Hartl J , Wehmeyer MH , Pischke S. Acute hepatitis E: two sides of the same coin . Viruses 2016 ; 8 : 299. Google Scholar CrossRef Search ADS 3 Bilh F , Negro F. Hepatitis E virus: a zoonosis adapting to humans . J Antimicrob Chemother 2010 ; 65 : 817 – 21 . Google Scholar CrossRef Search ADS PubMed 4 Bazerbachi F , Haffar S , Garg SK et al. Extra-hepatic manifestations associated with hepatitis E virus infection: a comprehensive review of the literature . Gastroenterol Rep 2015 ; 4 : 1 – 15 . 5 Kamar N , Marion O , Abravanel F et al. Extrahepatic manifestations of hepatitis E virus . Liver Int 2016 ; 36 : 467 – 72 . Google Scholar CrossRef Search ADS PubMed 6 Dalton HR , Kamar N , van Eijk JJ et al. Hepatitis E virus and neurological injury . Nat Rev Neurol 2016 ; 12 : 77 – 85 . Google Scholar CrossRef Search ADS PubMed 7 Meng J , Dai X , Chang JC et al. Identification and characterization of the neutralization epitope(s) of the hepatitis E virus . Virology 2001 ; 288 : 203 – 11 . Google Scholar CrossRef Search ADS PubMed 8 Echevarría JM , Fogeda M , Avellón A. Epidemiology of hepatitis E virus infection in Spain . Enferm Infecc Microbiol Clin 2015 ; 33 : 281 – 6 . Google Scholar CrossRef Search ADS PubMed 9 Pischke S , Hartl J , Pas SD et al. Hepatitis E virus: infection beyond the liver? J Hepatol 2017 ; 66 : 1082 – 95 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: firstname.lastname@example.org. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Journal of Antimicrobial Chemotherapy – Oxford University Press
Published: Feb 21, 2018
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