04/09/2015

Epidemiologyandpathogenesisofacuterheumaticfever

OfficialreprintfromUpToDate
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Epidemiologyandpathogenesisofacuterheumaticfever
Author
AllanGibofsky,MD,JD,
FACP,FCLM

SectionEditors
RobertSundel,MD
DanielJSexton,MD
SheldonLKaplan,MD

DeputyEditor
ElizabethTePas,MD,MS

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Aug2015.|Thistopiclastupdated:Oct04,2013.
INTRODUCTIONAcuterheumaticfever(ARF)isadelayed,nonsuppurativesequelaofapharyngeal
infectionwiththegroupAstreptococcus(GAS).Followingtheinitialpharyngitis,alatentperiodoftwotothree
weeksoccursbeforethefirstsignsorsymptomsofARFappear[1].Thediseasepresentswithvarious
manifestationsthatmayincludearthritis,carditis,chorea,subcutaneousnodules,anderythemamarginatum.
TheepidemiologyandpathogenesisofARFarereviewedhere.Theclinicalmanifestations,diagnosis,
treatment,andpreventionofthisdisorderarediscussedseparately.(See"Clinicalmanifestationsand
diagnosisofacuterheumaticfever"and"Treatmentandpreventionofacuterheumaticfever".)
EPIDEMIOLOGYIndevelopingareasoftheworld,acuterheumaticfever(ARF)andrheumaticheart
diseaseareestimatedtoaffectnearly20millionpeopleandaretheleadingcausesofcardiovasculardeath
duringthefirstfivedecadesoflife[2].Rheumaticfevercanoccuratanyage,althoughmostcasesoccurin
children5to15yearsofage[35].Worldwide,thereare470,000newcasesofrheumaticfeverand233,000
deathsattributabletorheumaticfeverorrheumaticheartdiseaseeachyearmostoccurindevelopingcountries
andamongindigenousgroups[2,6].ThemeanincidenceofARFis19per100,000[7].
IntheUnitedStatesandotherdevelopedcountries,theincidenceofARFismuchlowerat2to14casesper
100,000thisisprobablyduetoimprovedhygienicstandardsandroutineuseofantibioticsforacutepharyngitis
[8,9].Manycasesthatdooccurarepartoflocalizedoutbreaks[1015].(See"Evaluationofacutepharyngitisin
adults"and"Approachtodiagnosisofacuteinfectiouspharyngitisinchildrenandadolescents".)
Duringepidemicsinthemid1900s,asmanyas3percentofuntreatedacutestreptococcalsorethroatswere
followedbyrheumaticfeverinendemicinfections,theincidenceofrheumaticfeverissubstantiallyless[16].
RheumatogenicstrainsTheobservationinsomestudiesthatonlyafewMserotypes(types3,5,6,14,
18,19,24,and29)wereimplicatedinoutbreaksofrheumaticfeverintheUnitedStatessuggestedaparticular
"rheumatogenic"potentialofcertainstrainsofgroupAstreptococcus(GAS)[10,1719].
Toaddressthe"rheumatogenic"potentialofGAS,aserologicsurveillancestudycomparedtheMtypesof
GASrecoveredfromchildreninChicagowithacutepharyngitisduringthetimeperiod1961to1968totheGAS
strainsrecoveredfromChicagochildrenandchildrenfromacrosstheUnitedStatesinthetimeperiod2000to
2004[18].Rheumatogenicstrains(eg,types3,5,6,14,18,19,and29)werelessprevalentamongthelatter
isolates(10.6versus49.7percentintheearliertimeperiod)[18].
TheauthorshypothesizedthatthemarkeddecreaseintheincidenceofARFintheUnitedStatescorrelates
withthereplacementofrheumatogenictypesbynonrheumatogenictypes.However,anaccompanyingeditorial
notedthatalthoughtheprevalenceofrheumatogenicstrainsdecreasedtwotofivefold,thereductioninthe
incidenceofARFoverthesameperiodwas20fold[20].Thus,ashiftintheprevalenceofrheumatogenicM
typeGASstrainsdoesnotappeartofullyexplainthedecreaseinARF.
Ourownseries,gatheredovera20yearperiod,hasproduceddifferentresults.Weisolatedalargenumberof
differentMserotypes,includingsixstrainsthatwerenontypable.Inaddition,severaldifferentMtypeswere
isolatedfromthepatientsseenduringamid1980soutbreakofARFinUtahthesestrainswerebothmucoid
andnonmucoidincharacter[21].Inaddition,MserotypesdifferentfromthoseintheUnitedStateshavebeen
associatedwithARFinTrinidadandHawaii[2224].
Thus,theissueofpotential"rheumatogenic"strainsremainsunresolved.Astreptococcalstraincapableof
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causingawelldocumentedpharyngitisalmostalwaysispotentiallycapableofcausingrheumaticfever,
althoughsomeexceptionshavebeenrecorded[25].Thelackofspecificrheumatogenicstrainsalsomay
explaintherelativelyhighriskofrecurrentdiseasewithnewstreptococcalinfections,incontrastto
poststreptococcalglomerulonephritis,inwhichonlyafew"nephritogenic"strainsappeartobecapableof
inducingthedisease(eg,type12withpharyngitisandtype49withimpetigo),andrecurrentdiseaseis
uncommon[26,27].
PATHOGENESISThepathogenicmechanismsthatleadtothedevelopmentofacuterheumaticfever
(ARF)remainincompletelyunderstood.Clearlystreptococcalpharyngealinfectionisrequired,andgenetic
susceptibilitymaybepresent.Ontheotherhand,evidenceissparsethattoxinsproducedbythe
streptococcusareimportant.
Withinthisframework,molecularmimicryisthoughttoplayanimportantroleintheinitiationofthetissueinjury
(see'Molecularmimicry'below).However,thefactorsresponsibleforperpetuationoftheprocessremain
unclear.
RoleofthestreptococcusDespitethelackofevidenceforthedirectinvolvementofgroupA
streptococcus(GAS)intheaffectedtissuesofpatientswithARF,significantepidemiologicandimmunologic
evidenceindirectlyimplicatestheGASintheinitiationofdisease.
Outbreaksofrheumaticfevercloselyfollowepidemicsofstreptococcalpharyngitisorscarletfeverwith
associatedpharyngitis[25,28].
Adequatetreatmentofadocumentedstreptococcalpharyngitismarkedlyreducestheincidenceof
subsequentrheumaticfever[29].
AppropriateantimicrobialprophylaxispreventstherecurrenceofdiseaseinpatientswhohavehadARF
[17,30].
MostpatientswithARFhaveelevatedantibodytiterstoatleastoneofthreeantistreptococcalantibodies
(streptolysin"O",hyaluronidase,andstreptokinase),whetherornottheyrecallanantecedentsorethroat
[31].
Incontrasttothehighsensitivityofantistreptococcalantibodiesforthedocumentationofstreptococcal
infection,therateofisolationofGASfromtheoropharynxofpatientswithARFisextremelylow,evenin
populationsthatgenerallydonothaveaccesstomicrobialantibiotics.Theclinicaldocumentationofan
antecedentpharyngitisalsoappearstohaveanagerelatedvariability.Onestudy,forexample,notedthatthe
recollectionofpharyngitisapproached70percentinolderchildrenandyoungadultsversusonly20percentin
youngerchildren[11].Thus,ahighindexofsuspicionofARFisimportant,particularlyinchildrenoryoung
adultspresentingwithsignsofarthritisand/orcarditis,evenintheabsenceofadocumentedepisodeof
pharyngitis.
ImportanceofpharyngitisStreptococcalpharyngitisistheonlystreptococcalinfectionthathasbeen
associatedwithARF.Asanexample,therehavebeenmanydocumentedoutbreaksofimpetigothatcan
causeglomerulonephritisbutalmostneverARF[27,32].Inaddition,astudyofpatientsinTrinidadwithARFor
acuteglomerulonephritis(AGN)diagnosedduringanoutbreakofscabiesandsecondaryimpetigofoundthatthe
streptococcalstrainscolonizingtheskininpatientswithimpetigoweredifferentfromthoseassociatedwith
rheumaticfever[32].ThepresenceofimpetigowasassociatedwithAGN,butdidnotinfluencetheincidence
ofARF.
IncommunitiesofaboriginalAustralians,pharyngealcarriageofGASisuncommonalthoughratesofARFare
high[33].SuchfindingshaveledtothehypothesisthatARFmayarisefromGASpyodermaorfrom
pharyngitisduetonongroupAstreptococcalstrainsthatinheritedcertaingroupAstreptococcalantigensor
enzymesthatareimportantforinitiatingARF[33].Theseissuesarediscussedseparately.(See"Clinical
manifestationsanddiagnosisofacuterheumaticfever",sectionon'Predisposingfactors'.)
BacterialgeneticfactorsmaybeanimportantdeterminantofthesiteofGASinfection.Fivechromosome
patternsofemmgenes,whichcodeforMandMlikesurfaceproteins,havebeenrecognizedandlabeledAE.
PharyngealstrainstypicallyhavepatternsAC,whereasalmostallimpetigostrainsshowDandEpatterns
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[34].(See'Rheumatogenicstrains'above.)
AnotherfactoraffectinglocalizationtothepharynxmaybeCD44,ahyaluronicacidbindingproteinthat
appearstoactasapharyngealreceptorforGAS.Afterintranasalinoculation,GAScolonizetheoropharynxin
wildtypemicebutnottransgenicmicethatdonotexpressCD44[35].
AfewtheorieshavetriedtoexplainwhyARFisonlyassociatedwithstreptococcalpharyngitis,buttheexact
explanationremainsobscure.GASfallintotwomainclassesbasedupondifferencesintheCrepeatregionsof
theMprotein[36].Oneclassisassociatedwithstreptococcalpharyngealinfectiontheother(withsome
exceptions)belongstostrainscommonlyassociatedwithimpetigo.Thus,theparticularstrainofstreptococcus
maybecrucialininitiatingthediseaseprocess.Thepharyngealsiteofinfection,withitslargerepositoryof
lymphoidtissue,alsomaybeimportantintheinitiationoftheabnormalhostresponsetothoseantigenscross
reactivewithtargetorgans.
Impetigostrainsdocolonizethepharynx.However,theydonotappeartoelicitasstronganimmunologic
responsetotheMproteinmoietyasthepharyngealstrains[37,38].Thisobservationmayprovetobean
importantfactor,especiallyinlightoftheknowncrossreactionbetweenvariousstreptococcalstructuresand
mammalianproteins.
MolecularmimicryAsaresultofmolecularmimicry,antibodiesdirectedagainstGASantigenscrossreact
withhostantigens[3943].Inadditiontotheroleofantibody,observationssuggestaroleforcellularimmunity
inmolecularmimicryinARF.AstudyofhumanheartintralesionalTcellclonesfoundthat63percentof
patientsreactedwithmeromyosin[44].Furthermoremanyoftheseclonescrossreactedwithmyosin,valve
derivedproteins,aswellasstreptococcalM5peptides.
CarditisStreptococcalMproteinandNacetylbetaDglucosamine(NABG,theimmunodominant
carbohydrateantigenofGAS)shareepitopeswithmyosin[40,41,43].Rodentsimmunizedwithrecombinant
streptococcalMproteintype6developbothvalvulitisandfocalcardiacmyositis[45].
Thepotentialclinicalsignificanceoftheseobservationswasillustratedinastudyinwhichmonoclonal
antibodiesweregeneratedfromtonsillarorperipheralbloodlymphocytesofpatientsinfectedwithGAS[42].
Someoftheseantibodiescrossreactedwithmyosinandcertainotherproteins.Inaddition,antimyosin
antibodiespurifiedfrompatientswithARFcrossreactedwithGASandMprotein.Similarantibodieswere
presentinmuchlowerconcentrationsinsomenormalsubjects.
Inalaterreport,amonoclonalantibodyisolatedfromapatientwithrheumaticcarditiswasdirectedagainst
myosinandNABG[43].Theantibodywascytotoxicforhumanendothelialcelllinesandreactedwithhuman
valvularendotheliumthisreactivitywasinhibitedbymyosin>laminin>NABG.Thereactivitywiththe
extracellularmatrixproteinlamininmayexplainthereactivityagainstthevalvesurface.
ChoreaMolecularmimicrymayalsobeinvolvedinthedevelopmentofSydenhamchorea.Inananimal
model,monoclonalantibodiesthatcausedchoreaboundtobothNABGandmammalianlysoganglioside[46].
Exposureofculturedhumanneuronalcellstoeithermonoclonalantibodiesorserumfrompatientswithchorea
ledtoinductionofcalcium/calmodulinproteinkinase.Exposuretoserumfrompatientsfollowingstreptococcal
infectionthatwasnotcomplicatedbychoreadidnothavethiseffectonneuronalcells.(See"Sydenham
chorea".)
GeneticsusceptibilityTheconceptthatrheumaticfevermightbetheresultofahostgeneticpredisposition
hasintriguedinvestigatorsformorethan100years[47].Duringthattime,suggestionshaveincludedthetheory
thatthediseaseistransmittedinanautosomaldominantfashion[48],inanautosomalrecessivefashionwith
limitedpenetrance[49],orviagenesrelatedtodeterminantsofbloodgroupsecretorstatus[50].
Renewedinterestinthegeneticsofrheumaticfeveroccurredwiththerecognitionthatgeneproductsofthe
humanMHCwereassociatedwithcertainclinicaldiseases.Severalstudieshavereportedgenetic
associationswithARFsomeappeartobeMHCrelated,othersarenonMHCrelated.
Usinganalloserumfromamultiparousdonor,anincreasedfrequencyofaBcellalloantigenthatwasnot
MHCrelatedwasreportedinseveralgeneticallydistinctandethnicallydiversepopulationsofindividuals
withARF[51].
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Inanotherreport,monoclonalantibodiesweregeneratedbyimmunizingmicewithBcellsfrompatients
withrheumaticfever.Oneoftheseantibodies,D8/17,wasfoundtoidentifyamarkerexpressedon
increasednumbers(>20percent)ofBcellsin100percentofpatientswithARFofdiverseethnicorigins
[52].ThepercentageofD8/17+Bcellsrangedfrom4to6percentinapproximately90to95percentof
nonaffectednormalsubjects.Incontrast,thenumberofD8/17+Bcellswasonestandarddeviation
abovenormal(10to12percent)in4to7percentofsubjects.Thus,thismarkermightidentifya
populationofrheumaticfeversusceptibleindividuals.Theantigendefinedbythismonoclonalantibody
showednoassociationwithorlinkagetoanyknownMHCallele,nordiditappeartoberelatedtoBcell
activationantigens.
AnincreasedfrequencyoftheclassicMHCclassIIalleles,HLADR4andDR2,hasbeennotedin
Caucasianandblackpatientswithrheumaticheartdisease[53].OtherstudieshaveimplicatedDR1and
DRW6assusceptibilityfactorsinSouthAfricanblackpatientswithrheumaticheartdisease[54]anda
closeassociationwithHLADR7andDW53hasbeennotedinARFpatientsinBrazil[55].
TheseapparentlydifferingresultsconcerningHLAantigensandARFsusceptibilityhaveledtospeculationthat
thereportedassociationsmightbeofgenescloseto,butnotidenticalto,theARFsusceptibilitygene.
Alternatively,andmorelikely,susceptibilitytoARFispolygenic,andtheD8/17antigenmightbeassociated
withonlyoneofthegenesconferringsusceptibilitywhereasanothermightbetheMHCcomplexencodingfor
DRantigens.Althoughtheexactexplanationremainstobedetermined,thepresenceofanincreased
percentageofD8/17+BcellsappearstoidentifyapopulationatspecialriskofcontractingARF.
SUMMARY
Acuterheumaticfever(ARF)isadelayed,nonsuppurativesequelaofapharyngealinfectionwiththe
groupAstreptococcus(GAS).(See'Introduction'above.)
MostcasesofARFoccurinchildren5to15yearsofage.ARFismorecommonindevelopingthan
developedcountries.CertainstrainsofGASmayhavegreaterrheumatogenicpotential.(See
'Epidemiology'above.)
ThepathogenicmechanismsthatleadtothedevelopmentofARFremainincompletelyunderstood.
Streptococcalpharyngealinfectionisrequired,althoughevidenceissparsethattoxinsproducedbythe
streptococcusareimportant.Molecularmimicry,duetoactivationofautoreactiveBandTcellsbyGAS
antigens,isthoughttoplayanimportantroleintheinitiationofthetissueinjury.Geneticsusceptibility
mayalsobeafactor.(See'Pathogenesis'above.)
ACKNOWLEDGMENTTheeditorialstaffatUpToDatewouldliketoacknowledgeJohnBZabriskie,MD,
whocontributedtoearlierversionsofthistopicreview.
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic3151Version9.0

Disclosures
Disclosures:AllanGibofsky,MD,JD,FACP,FCLMNothingtodisclose.RobertSundel,MD
Nothingtodisclose.DanielJSexton,MDGrant/Research/ClinicalTrailSupport:Cubist[C.difficile
infection(Fidaxomycin)].Consultant/AdvisoryBoards:Johnson&Johnson[Pelvicmeshrelated
infection]Sterilis[Medicalwastedisposalsystems]MagnoliaMedicalTechnologies[Intravenous
devices].OtherFinancialInterest:NationalFootballLeague[Infectioncontrolprogram].Equity
Ownership/StockOptions:MagnoliaMedicalTechnologies[Intravenousdevices].SheldonLKaplan,
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MDGrant/Research/ClinicalTrialSupport:Pfizer[vaccine(PCV13)]ForestLab[antibiotic
(Ceftaroline)]Optimer[antibiotic(fidaxomicin)].Consultant/AdvisoryBoards:Pfizer[vaccine(PCV13)].
ElizabethTePas,MD,MSNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,these
areaddressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsfor
referencestobeprovidedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofall
authorsandmustconformtoUpToDatestandardsofevidence.
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