Primaryinfectionwithvaricellazostervirus(VZV)resultsinchickenpox,

characterizedbyviremiawithadiffuserashandseedingofmultiplesensory
ganglia,wherethevirusestablisheslifelonglatency.Herpeszosteriscausedby
reactivationoflatentVZVincranialnerveordorsalrootganglia,withspreadof
thevirusalongthesensorynervetothedermatome.Therearemorethan1million
casesofherpeszosterintheUnitedStateseachyear,withanannualrateof3to4
casesper1000persons.Studiessuggestthattheincidenceofherpeszosteris
increasing.Unvaccinatedpersonswholiveto85yearsofagehavea50%riskof
herpeszoster.Upto3%ofpatientswiththediseaserequirehospitalization.
Themajorriskfactorforherpeszosterisincreasingage.Withincreasingtime
aftervaricellainfection,thereisareductioninthelevelofTcellimmunityto
VZV,which,unlikelevelsofvirusspecificantibodies,correlateswithprotection
againstherpeszoster.Theriskishigherforwomenthanformen,forwhitesthan
forblacks,andforpersonswithafamilyhistoryofherpeszosterthanforthose
withoutsuchabackground.Chickenpoxthatoccursinuteroorearlyininfancy,at
atimewhenthecellularimmunesystemisnotfullymature,isassociatedwith
herpeszosterinchildhood.ImmunocompromisedpersonswithimpairedTcell
immunity,includingrecipientsoforganorhematopoieticstemcelltransplants,
thosereceivingimmunosuppressivetherapy,andthosewithlymphoma,leukemia,
orhumanimmunodeficiencyvirus(HIV)infection,areatincreasedriskforherpes
zosterandforseveredisease.
Postherpeticneuralgia,orpainpersistingaftertherashhasresolved(oftende
finedspecificallyaspainpersistingfor90daysormoreaftertheonsetoftherash),
isafearedcomplicationofherpeszoster.Thepainmaypersistformanymonthsor
evenyears;itmaybesevereandinterferewithsleepandactivitiesofdailyliving,
resultinginanorexia,weightloss,fatigue,depression,withdrawalfromsocial
activitiesandemployment,andlossofindependentliving.Dependingonageand
thedefinitionused,postherpeticneuralgiadevelopsin10to50%ofpersonswith
herpeszoster.Theriskincreaseswithage(particularlyafter50yearsofage)andis
alsoincreasedamongpersonswithseverepainattheonsetofherpeszosterorwith
asevererashandalargenumberoflesions.
Variousneurologiccomplicationshavebeenreportedtooccurwithherpeszoster,
includingBellspalsy,theRamsayHuntsyndrome,transversemyelitis,transient
ischemicattacks,andstroke.Inaddition,ophthalmologiccomplicationsofherpes
zosteroccurringintheV1distributionofthetrigeminalnervecaninclude
keratitis,sclerotic,uveitis,andacuteretinalnecrosis(Table1).
Immunocompromisedpersonscanhaveadditionalcomplications,including
disseminatedskindisease,acuteorprogressiveouterretinalnecrosis,chronic

herpeszosterwithverrucaeskinlesions,anddevelopmentofacyclovirresistant
VZV.Inthesepatients,thediseasecaninvolvemultipleorgans(e.g.,lung,liver,
brain,andgastrointestinaltract),andpatientsmaypresentwithhepatitisor
pancreatitisseveraldaysbeforetherashappears.
Symptoms

Therashofherpeszosterisdermatomeanddoesnotcrossthemidline,afeature
thatisconsistentwithreactivationfromasingledorsalrootorcranialnerve
ganglion.Thethoracic,trigeminal(Fig.1A),lumbar,andcervicaldermatomesare
themostfrequentsitesofrash,althoughanyareaoftheskincanbeinvolved.In
nonimmunocompromisedpersons,afewscatteredlesionsoutsidetheaffected
dermatomearenotunexpected.Therashisoftenprecededbytingling,itching,or
pain(oracombinationofthese)for2to3days,andthesesymptomscanbe
continuousorepisodic.
Dependingonthelocationandseverity,thisprodromalpainmayleadto
misdiagnosisandcostlytesting.Therashbeginsasmaculesandpapules,which
evolveintovesiclesandthenpustules(Fig.1B).Newlesionsappearoveraperiod
of3to5days,oftenwithfillinginofthedermatomedespiteantiviraltreatment.
Therashusuallydrieswithcrustingin7to10days.Somepersonshavepaininthe
absenceofarash,termedzostersineherpete,whichisdifficulttodiagnoseand
mayleadtonumerousunnecessarytestsorprocedures.Immunocompromised
patientsmayhavedisseminatedrasheswithviremiaandnewlesionsoccurring
forupto2weeks.Thecharacteristicsofpainassociatedwithherpeszostervary.
Patientsmayhaveparenthesis(e.g.,burningandtingling),dysesthesia(alteredor
painfulsensitivitytotouch),allodynia(painassociatedwithnopainfulstimuli),or
hyperesthesia(exaggeratedorprolongedresponsetopain).Pruritusisalso
commonlyassociatedwithherpeszoster.
Diagnosis

Mostcasesofherpeszostercanbediagnosedclinically,althoughatypicalrashes
mayrequireadirectimmunofluorescenceassayforVZVantigenorapolymerase
chainreaction(PCR)assayforVZVDNAincellsfromthebaseoflesionsafter
theyareunroofed.InastudycomparingPCRwithotherdiagnosticmethods,the
sensitivityandspecificityofPCRfordetectingVZVDNAwere95%and100%,
respectively,whereasthevaluesforimmunofluorescencetestingforVZVantigen
were82%and76%.Theconditionthatismostcommonlymistakenforherpes
zosterisherpessimplexvirusinfection,whichcanrecurinadermatomal
distribution;accordingly,whenpatientspresentwithrecurrentzosteroratypical
lesionsorareimmunocompromisedwithdisseminatedskinlesions,specific

testingforbothVZVandherpessimplexvirusisoftenuseful.VZVhasbeen
detectedinthesalivaofpersonswithherpeszoster,althoughsuchtestingdoesnot
currentlyhaveademonstratedroleinclinicalpractice.
APCRassayofthecerebrospinalfluid(CSF)hasbeenusedforthediagnosisof
centralnervoussystem(CNS)vasculopathy;evidenceofanincreaseintheratioof
theantiVZVantibodylevelintheCSFtothatinthebloodismoresensitive.A
PCRassayofthebloodmaybehelpfulforthediagnosisofvisceralherpeszoster
inimmunocompromisedpersonswhopresentwithhepatitisorpancreatitisinthe
absenceofarash.APCRassayforVZVinthebloodorCSFhasbeenusedfor
thediagnosisofzostersineherpete.
TreatmentandPrevention
AntiviralTherapy

Antiviraltherapyisrecommendedforherpeszosterincertain
nonimmunocompromisedpatientsandallimmunocompromisedpatients(Table2).
Otherpersonsmightalsobenefitfromantiviraltherapy,althoughtheyhavea
lowerriskofcomplicationsfromherpeszoster.Threeguanosineanalogues
acyclovir,valacyclovir,andfamciclovirhavebeenapprovedbytheFoodand
DrugAdministration(FDA)forthetreatmentofherpeszoster(Table3).Theoral
bioavailabilityandlevelsofantiviraldrugactivityinthebloodarehigherand
moreconsistentinpatientsreceivingthricedailyvalacyclovirorfamciclovirthan
inthosereceivingacyclovirfivetimesdaily.ThisisimportantbecauseVZVis
lesssensitivethanherpessimplexvirustoacyclovir,valacyclovir,and
famciclovir.
Theseantiviralagentshastentheresolutionoflesions,reducetheformationof
newlesions,reduceviralshedding,anddecreasetheseverityofacutepain(Table
3).Forexample,inthelargestrandomized,doubleblindtrialofacyclovirfor
herpeszoster,oralacyclovirgivenwithin47hoursaftertheonsetofrash
shortenedthemeantimetothelastdayofnewlesionformation,thelossof
vesicles,andfullcrustingby0.5days,1.8days,and2.2days,respectively,as
comparedwithplacebo.Inanotherlargetrial,acyclovirreducedthedurationof
viralsheddingby0.8daysascomparedwithplacebo.Inametaanalysisofseveral
randomized,controlledtrials,antiviralagentsdidnotsignificantlyreducethe
incidenceofpostherpeticneuralgia,andtheyarenotapprovedfortheprevention
oftheconditionbytheFDA.Insomestudies,treatmentwitheithervalacycloviror
famciclovirhasbeenshowntobesuperiortotreatmentwithacyclovirforreducing
painassociatedwithherpeszoster.Valacyclovirissimilartofamciclovirinterms

ofefficacyinreducingacutepainandacceleratinghealing.21Ascomparedwith
acyclovir,valacyclovirandfamciclovirrequirefewerdailydosesbutaremore
expensive.
Incontrolledtrials,treatmenthasbeeninitiatedwithin72hoursaftertheonsetof
therash,anditisrecommendedthattreatmentstartasearlyaspossiblewithinthis
interval.However,manyexpertsrecommendthatifnewskinlesionsarestill
appearingorcomplicationsofherpeszosterarepresent,treatmentshouldbe
initiatedeveniftherashbeganmorethan3daysearlier.Treatmentisusually
givenfor7daysintheabsenceofcomplicationsofherpeszoster.Intravenous
acyclovirisrecommendedforimmunocompromisedpersonswhorequire
hospitalizationandforpersonswithsevereneurologiccomplications.Foscarnetis
usedforimmunocompromisedpatientswithacyclovirresistantVZV.
Glucocorticoids

Theuseofglucocorticoidswithantiviraltherapyforuncomplicatedherpeszoster
remainscontroversial.Randomized,controlledtrialshaveshownbenefitsofa
taperingcourseofpredisoneorprednisolone,includingareductioninacutepain,
improvedperformanceofactivitiesofdailyliving,acceleratedearlyhealing,12and
inonestudybutnotanother,areductioninthetimetocompletehealing.The
additionofglucocorticoidstoantiviraltherapyhasnotbeenshowntoreducethe
incidenceofpostherpeticneuralgia.Owingtotheirimmunosuppressive
properties,glucocorticoidsshouldnotbeadministeredforherpeszosterwithout
concomitantantiviraltherapy.Glucocorticoidsshouldbeavoidedinpatientswith
hypertension,diabetesmellitus,pepticulcerdisease,orosteoporosis;particular
cautioniswarrantedinthecaseofelderlypatients,whoareatincreasedriskfor
seriousadverseevents.PrednisoneisusedforthetreatmentofcertainCNS
complicationsofherpeszoster,suchasvasculopathyorBellspalsyinnon
immunocompromisedpatients.
AcutePainAssociatedwithHerpesZoster

Severalmedicationshavebeenusedforthetreatmentofacutepainassociatedwith
herpeszoster(Table4).Nonsteroidalantiinflammatorydrugsoracetaminophen
canbeadministeredinpatientswithmildpain.Opioids,suchasoxycodone,are
usedformoreseverepainassociatedwithherpeszoster.Opioidsweremore
effectivethangabapentinforherpeszosterrelatedpaininarandomized,placebo
controlledtrial.Inonecontrolledtrialbutnotanother,23gabapentinreducedpain
associatedwithherpeszoster.Lidocainepatchesreducedpainassociatedwith
herpeszosterinaplacebocontrolledtrial;theyshouldbeappliedtointactskin
only,nottotheareaoftherash.25Althoughtricyclicantidepressantshavenotbeen

showntobeeffectiveinrandomized,controlledclinicaltrialsforacutepain
associatedwithherpeszoster,theyhavebeenusedwhenopioidswereinsufficient
forpain.
EyeDiseaseAssociatedwithHerpesZoster

PatientswithherpeszosterintheV1distributionofthetrigeminalnerve
(includinglesionsontheforeheadandtheuppereyelid)andeitherlesionsonthe
tiporsideofthenoseornewvisualsymptomsshouldbeevaluatedbyan
ophthalmologist.Othertreatmentmaybeneededinadditiontoantiviraltherapy,
includingmydriaticeyedropstodilatethepupilandreducetheriskofscarring
(synechiae);topicalglucocorticoidsforkeratitis,episcleritis,oriritis;medications
toreduceintraocularpressureforthetreatmentofglaucoma;andintravitreal
antiviraltherapyforimmunocompromisedpatientswithretinalnecrosis.
PostherpeticNeuralgia

Painassociatedwithpostherpeticneuralgiaisoftenchallengingtotreat.Adetailed
discussionofthemanagementofpostherpeticneuralgiaisbeyondthescopeofthis
article.Inbrief,medicationsshowninrandomizedtrialstoreducepain
associatedwithpostherpeticneuralgiaincludetopicallidocaine,26anticonvulsant
agents(e.g.,gabapentin27andpregabalin28),opioids,29tricyclicantidepressants
(e.g.,nortriptyline30),andcapsaicin.31Combinationtherapy,suchasgabapentin
andnortriptyline32oranopiateandgabapentin,33havebeenmoreeffectivefor
postherpeticneuralgiathansingleagenttherapybutalsoconferagreaterriskof
sideeffects.Evenwithtreatment,manypatientsdonothaveadequatereliefof
pain,andforsuchpatients,referraltoapainspecialistcanbehelpful.
PreventionofHerpesZoster

AliveattenuatedherpeszostervaccineisrecommendedbytheAdvisory
CommitteeonImmunizationPracticesforpersons60yearsofageorolderto
preventherpeszosteranditscomplications,includingpostherpeticneuralgia. On
thebasisoftheresultsofarecentclinicaltrial,thevaccineisnowapprovedbythe
FDAtopreventherpeszosterinpersons50yearsofageorolder. Theefficacyof
thevaccineinpreventingherpeszosteris70%forpersons50to59yearsofage,
64%forpersons60to69yearsofage,and38%forpersons70yearsofageor
older.However,vaccineefficacyinpreventingpostherpeticneuralgiais66%for
persons60to69yearsofageandisundiminishedat67%forpersons70yearsof
ageorolder.Althoughtheeffectivenessofthevaccinetopreventherpeszosteris
reducedinpersons70yearsofageorolder,theincreasedriskofseveredisease
andthepersistingefficacyofthevaccineinpreventingpostherpeticneuralgiain

theseolderpersonsstronglyfavorvaccinatingthem.Afollowupstudyshowed
thatthereductionintheriskofherpeszosterremainedsignificantforatleast5
yearsaftervaccination,thoughtheeffectivenessdeclinedovertime. Invaccinated
(ascomparedwithunvaccinated)personsinwhomherpeszosterdeveloped,pain
wassignificantlyshorterindurationandlesssevere.
Thevaccinecanbegiventopersonswithahistoryofherpeszoster.Inarecent
study,ratesofadverseeventsassociatedwithvaccinationweresimilaramong
personswhohadhadherpeszoster(atameanof3.6yearsbeforevaccination)and
amongthosewithnohistoryofthedisease.
Theoptimaltimingofvaccinationafteranepisodeofherpeszosterisuncertain.
Becausetheriskofrecurrentherpeszosterafterarecentepisodeofthediseaseis
relativelylow39andbecausethecellularimmuneresponsetoVZVduringthefirst
3yearsaftervaccinationissimilartothatafteranepisodeofherpeszoster, one
mightdelayvaccinationfor3yearsinimmunecompetentpersonswitharecent
historyofherpeszoster,providedthatthediagnosisofherpeszosterhasbeenwell
documentedbyahealthcareprovider.Thevaccineiscontraindicatedinpersons
withhematologiccancerswhosediseaseisnotinremissionorwhohavereceived
cytotoxicchemotherapywithin3months,inpersonswithTcell
immunodeficiency(e.g.,HIVinfectionwithaCD4cellcountof200percubic
millimeteror<15%oftotallymphocytes),andinthosereceivinghighdose
immunosuppressivetherapy(e.g.,20mgofprednisonedailyfor2weeksor
antitumornecrosisfactortherapy).
InfectionControl

Althoughherpeszosterislesscontagiousthanvaricella,patientswithherpes
zostercantransmitVZVtosusceptiblepersons,inwhomvaricellamaydevelop.
Fornonimmunocompromisedpersonswithdermatomalherpeszoster,contact
precautionsshouldbeused,andlesionsshouldbecoveredifpossible. Despite
thesemeasures,viraltransmissionhasoccasionallybeenreportedinsuchpatients.
Forpersonswithdisseminatedlesionsandforimmunocompromisedpersonswith
herpeszoster,airborneandcontactprecautionsarerequireduntilalllesionshave
crusted.
AreasofUncertainty
Improvedtherapiesareneededforpainassociatedwithherpeszosterandpost
herpeticneuralgiaandtopreventthedevelopmentofpostherpeticneuralgia.In
addition,studiesareneededtodeterminewhichpatientsareathighestriskfor
postherpeticneuralgiasothatmoreaggressivetherapycanbegiven.Thereis

uncertaintyregardingthesafetyandeffectivenessofthevaccineinpersonswith
immunocompromisingconditionsthatarecurrentlyconsideredcontraindications
tovaccination,thedurationofimmunityinducedbythevaccine,andtheneedfor
boosterdoses.
Guidelines
Recommendationshavebeendevelopedforthemanagementofherpeszosterbya
groupofexpertsandforthepreventionofherpeszosterbytheAdvisory
CommitteeonImmunizationPractices.Thepresentreviewisgenerallyconcordant
withtheserecommendations.
ConclusionsandRecommendations
Whereasherpeszosterisoftenmildinhealthyyoungpersons,olderpersonsareat
increasedriskforpainandcomplications,includingpostherpeticneuralgia,ocular
disease,motorneuropathy,andCNSdisease.Inthevastmajorityofcases,the
diagnosiscanbemadeclinically.Antiviraltherapyismostbeneficialforpersons
whohavecomplicationsofherpeszosterorwhoareatincreasedriskfor
complications,suchasolderpersonsandimmunocompromisedpersons,and
shouldbeinitiatedassoonaspossible,generallywithin72hoursaftertheonsetof
the
rash.Valacyclovirorfamciclovirispreferredoveracyclovirowingtothereduced
frequencyofdosingandhigherlevelsofantiviraldrugactivity.Thepatient
describedinthevignetteshouldreceiveoralantiviraltherapy,medicationforpain
(e.g.,anopioid,withtheadditionofgabapentinifneeded),andpromptreferralto
anophthalmologist.Heshouldalsobeadvisedtoavoidcontactwithpersonswho
havenothadvaricellaorhavenotreceivedthevaricellavaccineuntilhislesions
havecompletelycrusted.Iwouldrecommendherpeszostervaccinationtoreduce
theriskofrecurrence,butinanimmunecompetentpatientsuchasthisone,I
woulddefervaccinationforapproximately3years,sincethecurrentepisodeof
herpeszostershouldboosthiscellularimmuneresponsetoVZVforthatperiodof
time.