2/19/2017 WelcometoJournaloftheAssociationofPhysiciansofIndia

JournaloftheAssociationofPhysiciansofIndia
Home AboutJAPI BusinessInfo Editor'sPage ArticleSubmission Search ContactJAPI DReAMIndiaProject

PreviousIssues

SpecialIssues
GoverningBody

EditorialBoard

AdvisoryBoard

CurrentIssueJuly2016Vol.64SupplementIssueonRecommendationsforVaccinationAgainstSeasonalInfluenzainAdultHighRiskGroups:SouthAsianRecommendations

ReviewArticle

ExpandedDengue
DBKadam1,SonaliSalvi2,AjayChandanwale3
1Professor&Head,2AssociateProfessor,Dept.ofMedicine,3DeanAllB.J.Govt.MedicalCollege,Pune,Maharashtra
Received:01.12.2015Accepted:23.03.2016

Abstract

The World Health Organization (WHO) has coined the term expanded dengue to describe cases which do not fall into either dengue shock syndrome or dengue
hemorrhagicfever.Thishasincorporatedseveralatypicalfindingsofdengue.Denguevirushasnotbeenenlistedasacommonetiologicalagentinseveralconditionslike
encephalitis,GuillainBarresyndrome.MoreoveritisagreatmimicofcoexistingepidemicslikeMalaria,ChikungunyaandZikavirusdisease,whicharealsomosquito
bornediseases.Theatypicalmanifestationsnotedindenguecanbemutisystemicandmultifacetal.Inclinicalpractice,theoccurrenceofatypicalpresentationshould
promptustoinvestigatefordengue.Knowledgeofexpandeddenguehelpstoclinchthediagnosisofdengueearly,especiallyduringongoingepidemics,avoidingfurther
batteryofinvestigations.

DenguehasprovedtobetheepidemicwiththeabilitytorecurandhasadiversearrayofpresentationasseeninlargeseriesfromIndia,Srilanka,IndonesiaandTaiwan.
WHOhasgiventhecasedefinitionofdenguefeverintheircomprehensiveguidelines.Accordingly,aprobablecaseisdefinedasacutefebrileillnesswithtwoormoreof
anyfindingsviz.headache,retroorbitalpain,myalgia,arthralgia,rash,hemorrhagicmanifestations,leucopeniaandsupportiveserology.

Therehavebeencasesofpatientsadmittedwithfever,alteredmentationwithorwithoutneckstiffnessandpyramidaltractsigns.Somehadseizuresorstatusepilepticus
aspresentation.Whentheyweretestedforserology,denguewaspositive.Afterrulingoutothercauses,dengueremainedtheonlyculprit.Wehavecomeacrossvaried
presentationsofdenguefeverinclinicalpracticeandthepresentarticlethrowslightonatypicalmanifestationsofdengue.

Introduction

ExpandeddengueisaterminologydevelopedintheWHOguidelinesofyear2012(Figure1).1Unusualmanifestationsofpatientswithsevereorganinvolvementsuchas
liver,kidneys,brainorheartassociatedwithdengueinfectionhavebeenincreasinglyreportedindenguehemorrhagicfever(DHF)andalsoindenguepatientswhodo
nothaveevidenceofplasmaleakage.Theseunusualmanifestationsmaybeassociatedwithcoinfections,comorbiditiesorcomplicationsofprolongedshockandcanbe
clubbedundertheexpandeddenguesyndrome(Figure2).Theunusualmanifestationsmaybeunderreportedorunrecognizedornotrelatedtodengue.However,itis
essentialthatproperclinicalassessmentiscarriedoutforappropriatemanagement,andcausalstudiesbedone.

GradesofDenguefever

Fever of 27 days with two or more of following headache, retroorbital pain, myalgia, arthralgia with or without leucopenia, thrombocytopenia and no evidence of
plasmaleakageistheclassicpresentationofdengue.

DHFI:Abovecriteriapluspositivetourniquettestandevidenceofplasmaleakage.Thrombocytopeniawithplateletcountlessthan100,000/cummandhematocritrise
20%overbaseline.

DHFII:Aboveplussomeevidenceofspontaneousbleedinginskinorotherorgans(blacktarrystool,epistaxis,gumbleeds)andabdominalpain.Thrombocytopeniawith
plateletcountlessthan100,000/cummandhematocritrise20%overbaseline.

DHFIII(DSS):Abovepluscirculatoryfailure(weakrapidpulse,narrowpulsepressure<20mmHg.Hypotension,coldclammyskin,restlessness).Thrombocytopeniawith
plateletcountlessthan100,000/cummandhematocritrise20%overbaseline.

DHFIV(DSS):profoundshockwithundetectablebloodpressureorpulse.Thrombocytopeniawithplateletcountlessthan100,000/cummandhematocritrise20%over
baseline.2

EndOrganDamage

http://www.japi.org/july_2016/09_ra_expnded_dengue.html 1/5
2/19/2017 WelcometoJournaloftheAssociationofPhysiciansofIndia
Bloodvesselsandplateletsarethetwomainendorgansinvolvedindengue.

BloodVessels

Increased vascular permeability is the hallmark pathophysiology in dengue.3 Intravascular volume gets contracted and leads to shock in severe cases. There is a
selectiveleakageofplasmainthepleuralandperitonealcavitiesoverashortperiod(2448hours).Theunderlyingmechanismisafunctionalchangeinvascularintegrity
mediatedbyvariouscytokines.Thereisrapidrecoveryofshockwithoutsequelaeinthepleuraandperitoneum.

Platelets

ThrombocytopeniaandhemoconcentrationareconstantfindingsinDHF.Adropinplateletcounttobelow100,000cells/mm3isusuallyfoundbetweenthe3rdand10th
daysofillness.DENV2inducesactivation,mitochondrialdysfunctionandapoptosisinplatelets.4

OtherOrganDamage

CentralNervousSystem

Neurologicalinvolvementindenguefeverisheterogeneous.Itoccursacutelywithinfirsttwodaysofacquiringtheinfection.

Intracerebralhemorrhagecanoccurasaresultofdirecttissuelesioncausedbythevirus,capillaryhemorrhage,disseminatedintravascularcoagulationandincasesof
hepaticfailure.Kumaretalhavereported5casesofintracranialhemorrhage,twoofwhich,succumbedtodeath.5Largedataisnotavailableregardingtheoutcomeof
intracerebral bleed however, mortality remains very high. Encephalitis, aseptic meningitis and acute disseminated encephalomyelitis are seen due to neurovirulent
effect of dengue viruses and serotypes 2 and 3 have been isolated from the CSF of these patients. Infiltration of virus laden macrophages seems to be the possible
mechanism.6Cametalhavereportedamortalityof22%.7Outcomeinvariousothercasereports,isfavorable.InJamaica,astudyof401patientswithsuspectedcasesof
viralinfectionoftheCNSshowedthat54(13.5%)werepositivefordengueIschemiccerebralinfarctsareuncommonandariseoutofmeningovasculitis.8Therearetwo
case reports of dengue causing cortical venous sinus thrombosis (CVST). Severe dehydration is the plausible explanation for CVST and requires anticoagulants in
addition to rehydration.9 Hypokalemic periodic paralysis is a rare manifestation and probably relates to redistribution of potassium in the cells. Paralysis responds
promptlytopotassiumsupplementation.10GuillainBarresyndrome(GBS)attributabletodengueisontherise.GBSpresentsintwoformsasaxonalanddemyelinating
and responds to immunoglobulins in a similar fashion as that of nondengue GBS.11,12 Opsoclonusmyoclonus with normal imaging has been noted and needs no
specialtreatment.12Opticneuropathyisthemostcommonposteriorsegmentophthalmicinvolvementandcaneitherrecovercompletelyorprogresstopermanentvisual

http://www.japi.org/july_2016/09_ra_expnded_dengue.html 2/5
2/19/2017 WelcometoJournaloftheAssociationofPhysiciansofIndia
deficit.13Araremuscleinvolvementindenguecantakeformofmyalgiacrurisandispostulatedtobeduetodirectmusclefibreinvasionbydenguevirusorreleaseof
myogenic cytokines. Treatment is symptomatic.14 Dysarthria clumsy hand syndrome is another rare manifestation and is due to a lacunar stroke as a thrombotic
complicationofdengue.15Thus,anyunusualCNSpresentationoccurringamidstadengueepidemic,shouldpromptonetoinvestigateforunderlyingdengueinfection.

Table1enlistsvariousneurologicalmanifestationsofdengue.

HepatobiliarySystem

Liverinvolvementindenguecanrangefromasymptomaticelevationofliverenzymestofulminanthepaticfailure(Table2).Transaminitisisseeninupto30%ofpatientsin
present epidemic.16 In DHF and DSS, acute liver failure occurs rapidly and jaundice can be evident on first day of illness. Laboratorywise, AST elevation is
proportionatelygreaterpossiblyattributedtomonocytedamage.Thelevelsofaminotransferases(usuallynotmorethan100U)generallyreachmaximumvaluesaround
theninthdayafterthefirstepisodeoffeverandgraduallytaperofftowardnormalitywithintwoweeks.DSSisassociatedwithhighermortalitythanDHF.Fataldengue
hemorrhagic fever is associated with acute, severe liver damage due primarily to massive direct infection of hepatocytes and Kupffer cells with minimal cytokine
response.17

Acalculouscholecystitishasbeendocumentedinmanycasereports.Asymptomaticgallbladderedemaasanultrasoundexaminationfindingcanbeasurrogatemarker
ofdenguebeforearrivaloflaboratoryinvestigationsreport.Abnormallevelsofalkalinephosphatase,thickenedgallbladderwall,apositiveMurphyssign,pericholecystic
fluidcollection,andnostone(s)inthegallbladderarethefeatures.Cholecystectomyisnotadvised,however,aclosewatchforimpendinggangrenousgallbladderisa
must.18

Acute pancreatitis with raised amylase and pancreatic edema is also reported and usually runs a benign course.19 A very rare and lifethreatening complication of
dengueissplenicruptureandisfatal.20

Anacutebilateralparotitismimickingmumpshasalsobeendescribedindengue.21

CardiovascularSystem

Myocarditisisthemostcommoncardiacinvolvementseenindengue.Myocardialendotheliumandcardiomyocytesareinflamed.Themyotubesareinfectedbydengue
virusandhaveincreasedexpressionoftheinflammatorygenesandproteinIP10andariseinintracellularCa2+concentration.22Incidenceofasymptomaticmyocarditis
canbeashighas24%.Significantmortality(23%)hasbeenreportedinpatientswithclinicalevidenceofmyocarditis.Myocarditiscanbeasymptomatictostartwithand
progresstowardspalpitations,syncope.RestingtachycardiaandECGshowingTinversionsaresuggestiveofmyocarditis.

2D echocardiographic evaluation shows chamber dilatation, an irregular jerky movement of the ventricular wall, and a minor degree of atrioventricular valvular
regurgitation.Rightventricle(RV)dilationwithassociatedtricuspidregurgitationismorecommonthanleftventriculardilatation.Isolatedtricuspidregurgitationcanalsobe
seen(Table3).

Ejectionfractionispreserved.ThefindingssimulatethoseinTakotsubocardiomyopathy.Theseabnormalitiesaretransientwithnoresidualdeficitattheendofthree
months.23

CPKMBcanbeavaluabletooltocorrelate,ifECGfindingsandclinicalpicturesuggestiveofmyocarditisarepresent.Corticosteroidshavenoroleinthemanagementof
denguemyocarditis.

Tachycardiaandvolumelossindicatepoorprognosis.Suchpatientsshouldbehydratedtilltheydeveloparelativebradycardia.Continuouscentralvenouspressure
monitoringduringfluidresuscitationishelpful.

Kidneys

http://www.japi.org/july_2016/09_ra_expnded_dengue.html 3/5
2/19/2017 WelcometoJournaloftheAssociationofPhysiciansofIndia
Renalinvolvementindengueisuncommon(Table4)ascomparedtootherorganinvolvement.Thecommonestrenalpresentationisthatofaprerenalacutekidneyinjury
(AKI)relatedtothirdspacefluidlossanddehydration.LeeetalfromTaiwanhavereportedanincidenceof3.3%(10/304).PatientswithrenalfailureassociatedwithDHF
had high mortality than those without renal failure. Amongst the fatal DHF cases, an incidence rate of 33.3% was reported. Preexisting renal disease (diabetic
nephropathyandhypertensivenephrosclerosis)adverselyaffectsthesurvival.24

AKIcanoccurwithorwithoutrhabdomyolysis.DHFandDSSareassociatedwithacutetubularnecrosis.Rhabdomyolysisleadstopigmentdepositionandacutetubular
necrosis.IgAnephropathyandhemolyticuremicsyndromehavealsobeendescribedindengue.25,26

AKIindenguenecessitatesappropriatefluidmanagement.Hemodialysishasbeenrequiredinvariablenumberofpatientsindifferentseriesreported.Hyperkalemiathat
is unresponsive to conventional treatment, progressively declining urine output despite intravenous hydration and uremia are the common indications for dialysis in
denguerelatedAKI.Lowplateletcountcanoccurduetouremiaortheuseofheparin,whichfurthercomplicatestheclinicalpictureofdengue.

Coinfections

Malaria

Malariaisbyfarthecommonestcoinfectionseeninmalaria.Coinfectionratehasbeendocumentedintherangeof8.3%inaBrazilianseriesto26%inanIndianseries.
Pl.falciparumismostcommonlyassociatedasperIndianstudieshowever,Pl.vivaxhasbeenreportedinforeignliterature.27,28

Typicalfeverparoxysmsareabsent.Jaundiceandbleedingmanifestationsarecommonpresentationalongwithheadache,myalgiasandbackache.Hypotensionand
hepatosplenomegalyarenoted.Laboratorywise,anemia,leucopeniaandthrombocytopeniaaremoresevereincoinfection.Hematocritmaynotbeausefulguideto
treatmentinthepresenceofmalaria.Malariaparasiteindexisreportedlylowinthepresenceofdengue.

Chikungunya

AedesaegyptiisthecommonvectorforbothDengueandChikungunya.About12%ofDenguepatientsexperiencearthralgias.SodiagnosingChikungunyainthesetting
of dengue fever is a challenging task. Evidence of serositis, shock and thrombocytopenia point towards dengue.29 Arthralgia in dengue is selflimiting, whereas
Chikungunyaleadstodisablingarthritiswhichmaylastformonths.

Leptospirosis

Leptospirosisanddengueoftenconcurrentlyinfectindividualsasbothoccurduringrainyseason.Coinfectionratevariesfrom1.3%toashighas17.8%.Mostofthe
patientspresentedwithhepatorenaldysfunctionandthrombocytopenia.Thus,incaseswherehepatorenalimpairmentisevidentatpresentation,concurrentleptospirosis
mustbesuspectedandantibiotictherapyneedstobeinitiated.Mortalityisduetomultiorgansystemfailureanddisseminatedintravascularcoagulation.30

ZikaVirusDisease

ThenewemergentZikaviruscausesasyndromeoffeverthatisoftenindistinguishablefromdenguevirus.Theoccurrenceofarthralgiaiscommontobothinfections.Zika
virusdiagnosisismadeonlyaftertheexclusionofdengueinfectionwithappropriateserologicaltests.

Table5describesfewfeaturesthatcanbehelpfulindifferentiatingbetweenthetwo.

DengueinHighRiskGroups

DiabetesMellitus

Diabetesmellitusisthemostsignificantriskfactorfordengue.Apoptosisofmicrovascularendothelialcellsleadstoincreasedvascularpermeabilityandprogressionto
DHFandDSS.Also,indiabetesmellitus,riseincytokinespotentiatesvascularleakage.31

Hypertension

HypertensionisproposedtohaveeffectmodificationontheriskofDHFoutcomeindenguepatientswithdiabetes.Chinesewhohaddiabeteswithhypertensionhad2.1
(95%CI:1.074.12)timeshigherriskofDHFcomparedwithChinesewhohadnodiabetesandnohypertension.31

ChronicKidneyDisease

http://www.japi.org/july_2016/09_ra_expnded_dengue.html 4/5
2/19/2017 WelcometoJournaloftheAssociationofPhysiciansofIndia
CKDpredisposestoacutekidneyinjuryindengueasdiscussedearlier.24

References

1.WorldHealthorganizationComprehensiveguidelinesforpreventionandtreatmentofdengueanddenguehemorrhagicfever.NewDelhi:WHO,SEAROrevised
andexpandededition.

2.Nationalguidelinesforclinicalmanagementofdenguefever.Ministryofhealth.NationalVectorbornediseasecontrolprogramme.

3.Cardier JE, Marino E, Romano E. et al. Proinflammatory factors present in sera from patients with acute dengue infection induce activation and apoptosis of
humanmicrovascularendothelialcells:possibleroleofTNFalphainendothelialcelldamageindengue.Cytokine200530:35965.

4.HottzED,OliveiraMF,NunesPCG,etal.Dengueinducesplateletactivation,mitochondrialdysfunctionandcelldeaththroughmechanismsthatinvolveDCSIGN
andcaspases.JThrombHaemost201311:95162.

5.KumarR,PrakashO,SharmaBS.Intracranialhemorrhageindenguefever:managementandoutcome:Aseriesof5casesandreviewofliterature.SurgNeurol
200972:429433.

6.LumLC,LamSK,ChoyYS,etal.DengueEncephalitis:aTrueEntity?AmJTropMedHygiene199654:256259.

7.CamBV,FonsmarkL,HueNB,etal.Prospectivecasecontrolstudyofencephalopathyinchildrenwithdenguehemorrhagicfever.AmJTropMedHygiene2001
65:848851.

8.JacksonST,MullingsA,BennettF,etal.Dengueinfectioninpatientspresentingwithneurologicalmanifestationsinadengueendemicpopulation.WestIndian
MedJ200857:3736.

9.VasanthiN,VairamonPM,GowthamT,DasAK.UnusualPresentationofDengueFeverCerebralVenousThrombosis.JClinDiagRes20159:OD09OD10.

10.JhaS,AnsariMK.Dengueinfectioncausingacutehypokalemicquadriparesis.NeurolIndia201058:4.

11.SoaresCN,FariaLC,PeraltaJMetal.(2006)Dengueinfection:neurologicalmanifestationsandcerebrospinalfluid(CSF)analysis.JNeurolSci2006249:1924.

12.VermaR,SharmaP,GargRK,etal.Neurologicalcomplicationsofdenguefever:ExperiencefromatertiarycenterofnorthIndia.AnnIndianAcadNeurol2011
14:272278.

13.SanjayS,WagleAM,AuEongKG.Opticneuropathyassociatedwithdenguefever.Eye(Lond)200822:7224.

14.AhmadR,LatiffAKA,RazakSA.Myalgiacrurisepidemica:anunusualpresentationofdenguefever.SoutheastAsianJTropMedPublicHealth200738.

15.SeetRC,LimEC.Dysarthriaclumsyhandsyndromeassociatedwithdenguetype2infection.JNeurol2007254:11291130.

16.LeeLK,GanVC,LeeVJ,etal.Clinicalrelevanceanddiscriminatoryvalueofelevatedliveraminotransferaselevelsfordengueseverity.PLoSNeglTropDis2012
6:e1676.

17.Macedo C. Histologic, Viral, and Molecular Correlates of Dengue Fever Infection of the Liver Using Highly Sensitive Immunohistochemistry. Diagn Molecular
Pathol200615:223228.

18.SharmaN,MahiS,BhallaAetal.DenguefeverrelatedacalculouscholecystitisinaNorthIndiantertiarycarehospital.JGastroenterolHepatol200621:664667.

19.SimadibrataM.AcutePancreatitisinDengueHemorrhagicFever.IndonesianJInternMed201244:1.

20.RedondoMC.HemorrhagicDenguewithSpontaneousSplenicRupture:CaseReportandReview.ClinInfectDis199725:12623.

21.TorresJR,LiprandiF,GoncalvezAP.AcuteParotitisDuetoDengueVirus.ClinInfectDis200031:e289.

22.Salgado.HeartandSkeletalMuscleAreTargetsofDengueVirusInfection.PediatrInfectDisJ201029:238242.

23.Satarasinghe RL, Arultnithy K, Amerasena NL, et al. Asymptomatic myocardial involvement in acute dengue virus infection in a cohort of adult Sri Lankans
admittedtoatertiaryreferralcentre.BrJCardiol200714:1713.

24.Kuoetal.ImpactofRenalFailureontheOutcomeofDengueViralInfection.ClinJAmSocNephrol20083:13501356.

25.UpadhayaBK,SharmaA,KhairaA,etal.TransientIgANephropathywithAcuteKidneyInjuryinaPatientwithDengueFever.SaudiJKidneyDisTranspl2010
21:521525.

26.PatelJB.DengueFeverInducedHemolyticUremicSyndrome.ClinInfectDis200643:799800.

27.MagalhaES.ClinicalProfileofConcurrentDengueFeverandPlasmodiumvivaxMalariaintheBrazilianAmazon:CaseSeriesof11HospitalizedPatients.AmJ
TropMedHyg201287:11191124.

28.MohapatraMK,PatraP,AgrawalR.Manifestationandoutcomeofconcurrentmalariaanddengueinfection.JVectorBorneDis201249:262265.

29.ChaharHS,BharajP,DarL,etal.CoinfectionswithChikungunyaVirusandDengueVirusinDelhi,India.EmergingInfectiousDiseases200915:7.

30.KarandeS,GandhiD,KulkarniMetal.ConcurrentoutbreakofleptospirosisanddengueinMumbai,India2002.JournalofTropicalPediatrics200551:174181.

31.PangJ,SalimA,LeeVJ,etal.Diabeteswithhypertensionasriskfactorsforadultdenguehemorrhagicfeverinapredominantlydengueserotype2epidemic:a
casecontrolstudy.PLoSNeglTropDis20126:e1641.

JournaloftheAssociationofPhysiciansofIndia2011
SiteDesigned@URVICOMPUGRAPHICS

http://www.japi.org/july_2016/09_ra_expnded_dengue.html 5/5