Screening of hepatitis E in patients presenting for acute neurological disorders

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Screening of hepatitis E in patients presenting for acute

neurological disorders

Aude Belbézier, Alban Deroux, Françoise Sarrot-Reynauld, Barbara Colombe,

Annick Bosseray, Claire Wintenberger, Perrine Dumanoir, Maxime Lugosi,

Isabelle Boccon-Gibod, Vincent Leroy, et al.

To cite this version:

Aude Belbézier, Alban Deroux, Françoise Sarrot-Reynauld, Barbara Colombe, Annick Bosseray, et al..

Screening of hepatitis E in patients presenting for acute neurological disorders. Journal of Infection

and Public Health, Elsevier, 2020, 13 (7), pp.1047-1050. �10.1016/j.jiph.2019.12.012�. �hal-03222802�

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ContentslistsavailableatScienceDirect

Journal

of

Infection

and

Public

Health

j o u r n al ho me p ag e :h t t p : / / w w w . e l s e v i e r . c o m / l oc a t e / j i p h

Short

Report

Screening

of

hepatitis

E

in

patients

presenting

for

acute

neurological

disorders

Aude

Belbézier

a,∗

_,

_Alban

_Deroux

a

_,

_Franc¸

_oise

_{Sarrot-Reynauld}

a

_,

_Barbara

_Colombe

a

_,

Annick

Bosseray

a

_,

_Claire

_Wintenberger

a

_,

_Perrine

_Dumanoir

a

_,

_Maxime

_Lugosi

a

_,

Isabelle

Boccon-Gibod

a

_,

_Vincent

_Leroy

b

_,

_Maxime

_Maignan

c

_,

_Roselyne

_{Collomb-Muret}

c

_,

Damien

Viglino

c

_,

_Mathieu

_Vaillant

d

_,

_Lorella

_Minotti

d

_,

_Emeline

_Lagrange

d

_,

Olivier

Epaulard

e

_,

_Chantal

_{Dumestre-Perard}

f

_,

_Sébastien

_Lhomme

g,h

_,

_Julien

_Lupo

i

_,

Sylvie

Larrat

i

_,

_Patrice

_Morand

i

_,

_Carole

_Schwebel

j

_,

_Antoine

_Vilotitch

k

_,

_Jean-Luc

_Bosson

k,l

_,

Laurence

Bouillet

a,m

a_Department_of_Internal_Medicine,_Grenoble_University_Hospital,_Grenoble,_France b_Department_of_Hepatology,_Grenoble_University_Hospital,_Grenoble,_France c_Department_of_Emergency,_Grenoble_University_Hospital,_Grenoble,_France d_Department_of_Neurology,_Grenoble_University_Hospital,_Grenoble,_France

e_Univ._Grenoble_Alpes,_Department_of_Infectious_Disease,_Grenoble_University_Hospital,_Grenoble,_France f_Univ._Grenoble_Alpes,_CNRS,_Laboratory_of_Immunology_CHU_Grenoble_Alpes,_TIMC-IMAG,₃₈₀₀₀_Grenoble,_France g_INSERM,_U1043,_Centre_de_{Physiopathologie}_de_Toulouse_Purpan,_Toulouse,_F-31300,_France

h_CHU_Toulouse,_Hôpital_Purpan,_Laboratoire_de_virologie,_F-31300,_France

i_Univ._Grenoble_Alpes,_CEA,_CNRS,_Virology_Laboratory_CHU_Grenoble_Alpes,_IBS,₃₈₀₀₀_Grenoble,_France

j_Univ._Grenoble_Alpes,_Laboratory_of_Bioclinical_Pharmaceutic_CHU_Grenoble_Alpes,_INSERM_U1039,₃₈₀₀₀_Grenoble,_France k_Department_of_Public_Health,_Grenoble_University_Hospital,_Grenoble,_France

l_Univ._Grenoble_Alpes,_CNRS,_Public_Health_Department_CHU_Grenoble_Alpes,_TIMC-IMAG,₃₈₀₀₀_Grenoble,_France m_Univ._Grenoble_Alpes,_Department_of_Internal_Medicine_CHU_Grenoble,_Inserm_(U1036),_CEA,_BIG-BCI,_France

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received8October2019 Receivedinrevisedform 13December2019 Accepted21December2019 Keywords: HepatitisE Neurologicaldisorder Acutehepatitis Hepatitis

a

b

s

t

r

a

c

t

Introduction:HepatitisEvirus(HEV)infectionhasbeenreportedtobeassociatedwithneurological

disor-ders.However,therealprevalenceofacutehepatitisEinthosediseasesisstillunknown.Wedetermined

theprevalenceofanti-HEVIgMantibodyinapopulationwithacutenon-traumatic,non-metabolic,

non-vascularneurologicalinjury.

Method:AregistrywascreatedinGrenobleHospitalUniversityfrom2014to2018tocollectdataon

patientswithacute(<3months)non-traumatic,non-metabolic,non-vascularneurologicalinjuries.Acute

hepatitisEwasdeﬁnedasanti-HEVIgM-positiveseruminimmunocompetentpatient,andasanti-HEV

IgM-positiveserumorHEVRNA-positiveseruminimmunocompromisedpatients.

Results:Onehundredﬁfty-ninepatientswereincluded.Anti-HEVIgMseroprevalenceinourcohortof

non-traumatic,non-metabolic,non-vascularneurologicalinjurieswas6.9%(elevenpatients,including4

Parsonage-Turnersyndrome(PTS)and2Guillain–Barrésyndrome(GBS)).Elevatedtransaminaseswere

observedinonly64%ofhepatitisEpatientsandcholestasisin64%.

Conclusion:Inthisstudy,6·9%ofpatientswithacutenon-traumatic,non-metabolic,non-vascular

neu-rologicalinjurieshadaprobablerecentHEVinfection.HEVserologyshouldbesystematicallyperformed

inthispopulation,eveninpatientswithnormaltransaminaselevel.

HealthSciences.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.

org/licenses/by-nc-nd/4.0/).

∗ Correspondingauthorat:Cliniqueuniversitairedemédecineinterne,Pôlepluridisciplinairedemédecine,CentrehospitalieruniversitairedeGrenobleAlpes,CS10217, 38043GrenobleCedex09,France.

E-mailaddress:abelbezier1@chu-grenoble.fr(A.Belbézier).

https://doi.org/10.1016/j.jiph.2019.12.012

1876-0341/©2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofKingSaudBinAbdulazizUniversityforHealthSciences.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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1048 A.Belbézieretal./JournalofInfectionandPublicHealth13(2020)1047–1050 Introduction

HEVinfectionhasbeenreportedtobeassociatedwithmany dif-ferentacuteneurologicaldisorders,especiallyinﬂammatoryones [1].Indeed,over100caseshavebeendescribed,includingboth cen-tralnervoussystemdiseases(suchasencephalitisormyelitis)and peripheralneurologicaldiseases(suchasGuillain–Barrésyndrome (GBS),Parsonage–Turnersyndrome(PTS))[1].Kamaretal. recom-mendtotreatthesedisorderswhenthereareassociatedwithHEV withRibavirin,ananti-viralagent[2].However,nonestudyhas alreadyadressedthequestionofHEVprevalenceamong neurolog-icaldisorders.Becauseofthesuspectedimmunologicalunderlying mechanism,weproposedtostudytheprevalenceofacutehepatitis Einacutenon-traumatic,non-vascular,non-metabolic neurologi-calinjuriesamongaFrenchmonocentriccohort.

Materialandmethods

Aregistry wascreatedinGrenoble HospitalUniversity from 2014to2018toprospectivelycollectdataonpatientswithacute (<3months)non-traumatic,non-metabolic,non-vascular neuro-logicalinjuries.AcaseofacutehepatitisEwasdeﬁnedaspositive serum anti-HEV IgM (using Assure HEV IgM Rapid test (MP Biomedicals))inimmunocompetentpatientandaspositiveserum anti-HEVIgMorpositiveserumHEVRNAinimmunocompromised patients[3].

Whenavailable,serum HEVRNA wasdonetoconﬁrmacute HEVinfection(usingCeeramtools®_Real-time_reverse_{transcription}

polymerasechainreaction(PCR)kits,CeeramSAS). Statisticalanalysis

Continuousvariableswerecomparedusingthenon-parametric Wilcoxontest.CategoricalvariableswerecomparedusingtheChi squaretest(ifnumberofpatientswas>5patients)orusingthe Studenttest.Alltestsweretwo-sided.p<0.05wasconsideredto besigniﬁcant.

Casereports

From2014 to2018,we prospectively included159patients (medianage57[19–92],66females).Writtenconsentsfromall patientswerecollected.

Resultsof anti-HEV IgM assaywerepositive for11 patients (6.9%) and equivocal for three patients. Among them, ﬁve had positive HEV RNA identiﬁed in serum (BankIt2288249Gre-143251634.MN747090, BankIt2288249Gre-170663087. MN747091, BankIt2288249Gre-172652224.MN747092, BankIt2288249Gre-172652258.MN747093, BankIt2288249Gre-181722177.MN747094).

Anti-HEVIgMwerestatisticallymorefrequentamongpatients withincreasedtransaminaselevel(AST>37IU/LforandALT>78 IU/L)(7/47inpatientswithtransaminaselevelincrementversus 4/107inpatientswithnormaltransaminaselevel,oddsratio(OR): 4.46,95% CI 1.07–21.9;p=0.035).Likewise,anti-HEV IgMwere morefrequentinpatientswithcholestasis(bilirubin>17␮mol/l, ALP>117IU/L,GGT>85IU/L)thaninpatientswithout cholesta-sis(7/11inHEV-,33/136 innon-HEVpatients, OR:5.38, 95%CI 1.28–26.7,p=0.01).QuantitativevalueofAST,ALTandALPdidnot differ(p=0.64,0.37and0.83respectively).

Neurological injuries associated with possible acute HEV infectionweremiscellaneous:PTS(n=4);GBS(n=2), meningoen-cephalitis(n=2),meningoradiculitis(n=1),paresthesia(n=1)and a facial paralysis associated with paresthesia (n=1) (Table 1). Amongthem,threecaseshadotherinfections(onewith

varicella-Table1

Typeofacuteneurologicalevent.

Typeofacuteneurologicalevent(No) Allpatients (159) HEVpatients (11) Central 71 2 Encephalitis 43 2a Infectious 22 HSV 5 VZV 2 Inﬂuenzae 2 HHV6 1

EBV+Mycoplasmapneumonia 1

Bartonellahenselae 2 Neisseriameningitis 2 Listeriamonocytogenes 1 Streptoccuspneumoniae 2 Streptococcusdysgalactiae 1 Staphylococcusaureus 1 Cysticerci 1 Plasmodiumfalciparum 1 Dysimmune 6 GAD-65Ab 1 GABA-RAb 1 AtypicalAb 1 Hashimotoencephalitis 1 NoAb 2 Unknown 15 Myelitisb ₈ Multiplesclerosis 13 NMO 1 Lymemyeloradiculitis 1 Pachymeningitis 3 Unknown 2 Peripheral 79 9 TypicalGBS 45 2 MFS 5 Bickerstaffsyndrome 1 Meningoradiculitis 4 1 Multiplemononeuropathy 3

Atypicalfacialpalsyc ₆ ₁

PTS 7 4

CIDP 2

Axonalsensoryneuropathy 1

Smallﬁberneuropathy 1

Ataxicneuropathy 1

Painlesssensorydisorders 3 1

Myasthenia 9

HSV: herpes simplex virus; VZV: varicella zoster virus; HHV6: human her-pesvirustype6;EBV:EpsteinBarrvirus;GAD-65:glutamicaciddecarboxylase65; Ab:antibodies;GABA-R:␥-aminobutyricacid;NMO:neuromyelitisoptica;GBS: Guillain–Barrésyndrome;MFS:Miller-Fishersyndrome;PTS:Parsonage–Turner syndrome;CIDP:Chronicinﬂammatorydemyelinatingpolyneuropathy.

a_Two_cases_of_presence_of_positive_HEV_and_another_infection.

b_Myelitis_secondary_to_Multiple_Sclerosis_were_not_included_in_this_section. c ₂_patients_with_bilateral_facial_palsy,₁_with_unilateral_facial_palsy_associated_with

vestibularsyndromeand3withunilateralfacialpalsyassociatedwithparesthesia.

zoster virus, one with Listeria monocytogenes and one with cytomegalovirus(CMV)infection).Inthesecases,serumHEVRNA werenegative(Table2).

Discussion

Our studydemonstratesa highprevalence(6.9%)of positive anti-HEVIgMinourcohortofacutenon-traumatic,non-vascular neurologicalinjurycomparedtoanti-HEVIgMseroprevalencein Isere’sblood-donor(0.4%95%CI0.01–2.3)atthesameperiodof time[4].

InourpopulationwithpossibleacutehepatitisE,threedifferent syndromeswerepredominant:PTS,GBSandencephalitis.

MorethanhalfofthePTSpatients(57%)hadpositiveanti-HEV IgM.UnliketypicalPTS,patientwithHEVoftenpresentedbilateral neuralgia(p<0.0001),asitwasdescribedbefore[5].Wereported

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Table 2 Clinical and laboratory features of possible acute HEV patients. Patient No. Sex/ Age at onset y Neurological disorder Season at the onset Warning signs Liver enzymes a Co-diagnosis HEV Treatment Sequelae Follow up times (week) Cytolysis Cholestasis Serum PCR CSF PCR Stool PCR GT 1 M/50 PTS spring No 1.5 N3 NN o – – – NA No PTS 8 2 F/43 PTS summer flu like 2N 3 NN o + NA + 3f No PTS 3 3 F/34 Atypical FP spring flu like No No No – – – NA No FP 2 4 F/83 GBS summer diarrhea 1.5 N 1.5 NN o + NA NA 3h IV Ig GBS 7 5 F/49 Painless sensory disorders summer No No 1.5 NN o – NA NA NA No Paresthesia 18 6 M/75 ME automn No No No Listeria – NA NA NA No No 3 7 M/58 PTS automn myalgia 5 N4 NN o – NA NA 3c IV Ig PTS 17 8 F/20 GBS winter flu like 2 NN o CMV NA NA NA NA IV Ig + ACV No 16 9 M/34 MR summer diarrhea 9 N 1.5 NN o + NA + 3f No No 1 10 M/80 ME automn No No No VZV – NA NA NA ACV No 1 11 M/38 PTS summer flu like 28 N8 NN o + NA NA 3f CT PTS 2 HEV: hepatitis E virus; M : male; F : female; y : year; bilirubin normal range 3− 17 ␮ mol/l; AST (aspartate aminotransferase) normal range <37 IU/L; ALT (alanine aminotransferase) normal range <78 IU/L, ALP (alkaline phosphatase) normal range 45–117 IU/L; GGT (gamma glutamyl transferase) normal range 15–85 IU/L,WBC: white blood count; CSF: cerebrospinal fluid; y: year, CMV: cytomegalovirus, VZV: varicella-zona virus, PTS: Parsonage–Turner syndrome, GBS: Guillain–Barré syndrome, ME: meningoencephalitis, FP: nerve facial paralysis, MR: meningoradiculitis, PCR: polymerase chain reaction, GT: genotype, IV Ig: intravenous immunoglobulin, ACV: acyclovir, NA: not available. N: normal value. a Results were expressed in times greater than normal if elevated liver enzyme was present.

twocaseswithphrenicdamageorlimbmanifestation.These fea-tureshadalsobeendescribedbefore[5].

Amongthe45patientswithGBS,two hadpositiveanti-HEV IgMserology(4.4%).GBSisknowntobetriggeredbysome infec-tionsuchasCMV[6].HEVcouldbeanothertrigger.Thus,inthe literature,morethan50casesofGBSweredescribedassociated withHEV[6].Inourstudy,oneofthetwopatientswithGBShad, concomitantlywithpositiveHEVIgMserology,anacuteCMV infec-tion:this raisesthequestionoftherealunderlyingrole ofHEV inthiscase.Fewcasesofcross-occurrenceofCMVandHEVhave beendescribedbefore[7].Becauseoftheknowncross-reactivity withEBV(whichisdescribedinthemanufacturer’sinstructionsfor MikrogenrecomLineHEVIgG/IgMtest),cross-reactivitybetween CMVandHEVshouldbeconsidered.

Thequestionofcross-reactivityis raisedin2described HEV patientswithmeningoencephalitis.Indeed,thesetwocaseshad otherinfections(onevaricella-zostervirus(VZV)andoneListeria monocytogenes).DiagnosisofHEV,accordingtotheFrench recom-mendations[3],wasdoneinthisstudybypositiveHEVIgMserology withtheuseofIgMrapidtest.Variouscommerciallyavailable sero-logicalanti-HEVdiagnostictestscurrentlyexist. Allofthemare verysensitive(from85%to94%)[8].Insteadofa high sensitiv-ityofallthesemethods,importantdifferencesintheperformance betweenthemhavebeenobserved[8,9].Recently,Vollmeretal. [8] have foundthat MP-Bioassay hasa highersensitivity than WantaiorMikrogenassay,buta smallerpositive post-infection period. Neurologicalmanifestations afteracute hepatitis E may appearafewmonthsafterinfection[2].Forthatreasonandbecause ofpossiblecross-reactivity[7,10],interpretationofHEVserology assayshouldbeconsideredwithcaution.BloodPCRseemstobe more speciﬁc however its period of positive testing is shorter [2,9].

Inourstudy,otherneurologicalpatternshavebeenfound,like atypicalfacialnervepalsy(1)ormeningoradiculitis(1)orpainful sensorydisorder(1).Thoseentitieswerealsopreviouslydescribed inassociationwithhepatitisE[11,12].

Aliverenzymeincrementwasfoundmorefrequentlyinpatients withpositiveanti-HEVIgM.Thisunderlinesthefactthattheacute HEVinfectionisoftenbutnotsystematicallyassociatedwithliver enzymemodiﬁcation.

Thiscurrent study hasseverallimitations, among them, the smallsamplesizeandtheabsenceofcontrolgroup.

Conclusion

Thisprospectivemonocentricstudyhighlightedahigh prob-ability (6.9%) of HEV acute infection. in acute non-traumatic, non-metabolic,non-vascularneurologicalinjuries(especiallyGBS, PTSandencephalitis);acausalrelationshipbetweenHEVandsuch neurologicaldisordersispossible.Thisstudycontributesto iden-tifyofsubpopulationinwhichribavirintherapeutictrialcouldbe investigated.

Authorcontributions

Wrotetheﬁrstdraftofthemanuscript:AB.Contributedtothe writingofthemanuscript:AB,AV,AD,FSR,BC,AB,IBG,CW,ML, MD,ML,VL,MM,RCM,DVDV,MV,EL,OE,CDP,JL,SL,PM,CS,JLB, LB.ICMJEcriteriaforauthorshipreadandmet:AB,AV,AD,FSR,BC, AB,IBG,JL,CW,ML,VL,MM,RCM,DVDV,PD,ML,MV,EL,OE,CDP,JL, SL,PM,CS,JLB,LB.Agreewithmanuscriptresultsandconclusions: AB,AV,AD,FSR,BC,AB,IBG,CW,ML,PD,ML,VL,MM,RCM,DVDV, MV,EL,OE,CDP,JL,SL,PM,CS,JLB,LB.

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1050 A.Belbézieretal./JournalofInfectionandPublicHealth13(2020)1047–1050

LaurenceBouillethadfullaccesstoallthedatainthestudyand takesresponsibilityfortheintegrityofthedataandtheaccuracyof thedataanalysis.

Collaborators

The authors thank Jérémie Papassin, Clémentine Uginet, Anne-SophieJob,Olivier Casez,MartialMallaret,GérardBesson, MylèneMaillet,CharlotteDentan,FannyAndry,PatriciaPavèse, AurélieMadelon toparticipateatthis study.Theauthorsthank Mélanie Arnaud and Pierre Audoin, the clinical research asso-ciates. Funding Nofundingsources. Competinginterests Nonedeclared. Ethicalapproval Notrequired. References

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