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GasGangrene:Background,Pathophysiology,Epidemiology
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References

Background
Gasgangreneandclostridialmyonecrosisareinterchangeabletermsusedtodescribeaninfectionofmuscletissue
bytoxinproducingclostridia.In1861,LouisPasteuridentifiedthefirstclostridialspecies,Clostridiumbutyricum.In
1892andlater,Welch,Nuttall,andotherscientistsisolatedagrampositiveanaerobicbacillusfromgangrenous
wounds.Thisorganism,originallyknownasBacillusaerogenescapsulatus,waslaterrenamedBacillusperfringens,
andthenClostridiumwelchii.TheorganismisnownamedClostridiumperfringens.
Gasgangrenegainedrecognitionforitswartimeincidence,duringwhichonlyapaucityofciviliancasesoccurred.
DuringWorldWarI,gasgangrenecomplicated6%ofopenfracturesand1%ofallopenwounds.Thesefigures
steadilydecreasedto0.7%duringWorldWarII,0.2%duringtheKoreanWar,and0.002%duringtheVietnamWar.
NocasesofgasgangrenewerereportedduringthebattleintheFalklandIslandsin1982. [1]
Despitenumerouscasualtiescausedbyenormousfirepowerandimprovisedexplosivedevices(IEDs),nocasesof
gasgangrenehavebeenreportedamongUSsoldiersduringtheongoingoperationIraqiFreedom.Thelethalityof
warwoundshasdecreasedfrom24%duringoperationDesertStorm(1991)toanunprecedented10%during
operationIraqiFreedom.TheUSmilitarymedicinehascreditedthistothemobilityoftheforwardsurgicalteams
(FSTs)inkeepingupwiththefastmovingmilitaryunits. [2,3,4]
Theincidenceofgasgangrenewas0.96%inastudyof1970survivorsadmittedtoSichuanProvincialPeoples
Hospitalafterthe2008Wenchuanearthquake. [5]Anotherstudyof226patientsduringthesameearthquakeshowed
theimportanceofrapidandaccuratescreening,aswellasisolation,inthesuccessfultreatmentofgasgangrene
andinhelpingtopreventnosocomialdiffusion.Debridement,amputation,andsupportivetreatmentyielded
acceptabletherapeuticresults. [6]
NextSection:Epidemiology

Pathophysiology
Gasgangreneiscausedbyananaerobic,grampositive,sporeformingbacillusofthegenusClostridium.C
perfringensisthemostcommonetiologicagentthatcausesgasgangrene.Othercommonclostridialspeciesthat
causegasgangreneincludeClostridiumbifermentans,Clostridiumsepticum,Clostridiumsporogenes,Clostridium
novyi,Clostridiumfallax,Clostridiumhistolyticum,andClostridiumtertium. [7]
Theseorganismsaretruesaprophytesandareubiquitousinsoilanddust.Clostridiahavebeenisolatedfromthe
mucousmembranesofhumans,includingtheGItractandthefemalegenitaltract.Clostridiamayalsocolonizethe
skin,especiallyaroundtheperineum.Clostridiaareobligateanaerobes,butsomespeciesarerelatively
aerotolerant.Bacterialmultiplicationandtheproductionofsolubleproteinscalledexotoxinsrequirealowoxygen
tension.
Otherbacteriaarealsocapableofproducinggas,andnonclostridialorganismshavebeenisolatedin6085%cases
ofgasgangrene.Arecentclinicalseriesongasgangrenedemonstratedapredominance(83.3%)ofaerobicgram
negativebacilliinwoundculturescomparedwithanaerobicgrampositivebacilli,withClostridiumspeciesaccounting
for4.5%oftheisolates.ThemostfrequentlyidentifiedaerobicgramnegativebacteriawereEscherichiacoli,Proteus
species,Pseudomonasaeruginosa,andKlebsiellapneumoniae. [7,8,9]
Cperfringensproducesatleast20exotoxins.Themostimportantexotoxinsandtheirbiologiceffectsareasfollows:
AlphatoxinLethal,*lecithinase,necrotizing,hemolytic,cardiotoxic
BetatoxinLethal,*necrotizing
EpsilontoxinLethal,*permease
IotatoxinLethal,*necrotizing

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DeltatoxinLethal,*hemolysin
PhitoxinHemolysin,cytolysin
KappatoxinLethal,*collagenase,gelatinase,necrotizing
LambdatoxinProtease
MutoxinHyaluronidase
NutoxinLethal,*deoxyribonuclease,hemolytic,necrotizing
*Lethalastestedbyinjectioninmice
Significantvarianceexistsamongclostridialspeciesastothemechanismofactionofthealphatoxin.InC
septicum,thealphatoxinformsporesandinducesnecrosisbycausingtherapidlossofintracellularpotassiumand
depletionofadenosinetriphosphate(ATP).Strainsthatdonotproducealphatoxinarelessvirulent,underscoringits
importance. [10]Inmicemodels,alphatoxininducedlethalitywasinhibitedbythepreadministrationoferythromycin.
Erythromycinresultedinareductionofthereleaseofcytokinestumornecrosisfactoralpha(TNFalpha),interleukin
1,andinterleukin6.Additionally,TNFalphadeficientmicewereresistanttoCperfringensalphatoxin,suggesting
thatTNFalphaisanimportantcontributortothetoxiceffectsofclostridialproteins. [11]
Geneticregulationofclostridialcytotoxicexotoxinproductionisunderthecontrolofseveraldifferentregulatory
systems,includingtheglobalVirR/VirS2componentsignaltransductionsystem,andtheRevR.TheVirR,a
membraneboundexternalsensor,andtheVirS,ageneresponseregulator,togethertransmitandreceivesignals
fromtheenvironmenttotheinsideofthecell.TheVirR/VirSsystemusesRNAintermediatestocontrol147distinct
genesandtheirassociatedoperons. [12]
Thephitoxinisahemolysin.Althoughitdoesnotdirectlysuppressmyocardialfunctioninvitro,itcontributesto
myocardialsuppressioninvivo,possiblybyincreasingthesynthesisofsecondarymediatorsthatdosuppress
myocardialfunctioninvitro.Athigherconcentrations,thephitoxincancauseextensivecellulardegenerationand
directvascularinjury.
ThekappatoxinproducedbyCperfringensisacollagenaseresponsiblefordestructionofbloodvesselsand
connectivetissue.Othertoxinsincludeadeoxyribonucleaseandhyaluronidase.
Contaminationwithclostridialsporesinposttraumaticorpostoperativelesionsestablishestheinitialstageof
infection.Localwoundconditionsaremoreimportantthanthedegreeofclostridialcontaminationinthe
developmentofgasgangrene.Disruptedornecrotictissueprovidesthenecessaryenzymesandalow
oxidation/reductionpotential,allowingforsporegermination.Foreignbodies,prematurewoundclosure,and
devitalizedmusclereducethesporeinoculumnecessarytocauseinfectioninlaboratoryanimals.
Thetypicalincubationperiodforgasgangreneisfrequentlyshort(ie,<24h),butincubationperiodsof1hourto6
weekshavebeenreported.Selfperpetuatingdestructionoftissueoccursviaarapidlymultiplyingmicrobial
populationandtheproductionoflocallyandsystemicallyactingexotoxins.Localeffectsincludenecrosisofmuscle
andsubcutaneousfatandthrombosisofbloodvessels.Markededemamayfurthercompromisebloodsupplytothe
region.Fermentationofglucoseisprobablythemainmechanismofgasproductioningasgangrene.InCsepticum
spontaneousgasgangrene,nitrogenisthepredominantgascomponent(74.5%),followedbyoxygen(16.1%),
hydrogen(5.9%),andcarbondioxide(3.4%).Productionofhydrogensulfideandcarbondioxidegasbeginslateand
dissectsalongmusclebelliesandfascialplanes.Theselocaleffectscreateanenvironmentthatfacilitatesrapid
spreadoftheinfection. [13]
Systemically,exotoxinsmaycauseseverehemolysis.Hemoglobinlevelsmaydroptoverylowlevelsand,when
occurringwithhypotension,maycauseacutetubularnecrosisandrenalfailure.Arapidlyprogressiveinfectioncan
quicklyresultinshock.Themechanismofshockispoorlyunderstood.UnconcentratedfiltratefromCperfringens,
purifiedalphatoxin,andpurifiedphitoxinscausehypotension,bradycardia,anddecreasedcardiacoutputwhen
injectedintolaboratoryanimals.Becausealphatoxinsandphitoxinsarelipophilicandmayremainlocallyboundto
tissueplasmamembranes,thetoxinsmaystimulatesynthesisofsecondarymediatorsthatcausecardiovascular
abnormalities.
Previous
NextSection:Epidemiology

Epidemiology
Frequency
UnitedStates
Clostridiaspeciesareubiquitousandwidelydistributedinthesoil,especiallyincultivatedland.Thedensityof
clostridiainthesoilisacontributingfactorinthedevelopmentoftraumarelatedgasgangrene.Civiliancasesofgas
gangrenearemorecommon,withapproximately3000casesperyear.Gasgangrenecanbeclassifiedas
posttraumatic,postoperative,orspontaneous.Posttraumaticgasgangreneaccountsfor60%oftheoverall
incidencemostcasesinvolveautomobilecollisions. [14]
From19982002,Csepticumwasimplicatedincausingseriousinfectionsinrecipientsofcontaminated
musculoskeletaltissueallografts.Inaddition,5pediatricpatientswhohadhemolyticuremicsyndrome(HUS)
secondarytoinfectionbyEscherichiacoliO157werelaterinfectedbyCsepticumwithfatalcomplications. [15]
Recently,Clostridiumsordellii,anuncommonhumanpathogen,causedfataltoxicshocksyndrome,bacteremia,and
extensiveendometritisin4youngwomenwhounderwentmedicalabortionwithoralmifepristoneandvaginal
misoprostol. [16]
International
FromApril2000toJune2000,severalusersofinjectiondrugsinScotland,Ireland,andEnglanddevelopedserious
clostridialinfections(CnovyiandCperfringens)complicatedbyahighmortalityrate(97%).Mostofthesepatients
reportedinjectingheroinintramuscularlywithintheprevioustwoweeks. [17]
Withmorethan200,000liposuctionsperformedinGermanyin2003,severalseriouscomplicationshadbeen
reported.Necrotizingfasciitisandgasgangrenewerethemostfrequent,majorandlethalcomplicationsobservedin
areviewof72casesofcomplicationscausedbyliposuctionperformedinGermanybetween1998and2002. [18]
AtsunamiravagedIndonesiainDecember2004andkilledmorethan200,000Indonesians.Soakingin
contaminatedwater,severalinjuredpersonslaterdiedoftetanusorgasgangrene.
InMay2008,theSichuanearthquakeinChinacausedmorethan70,000deathsandapproximately400,000
injuriesseveralinjuredpersonsdevelopedgasgangreneandlaterunderwentamputations.Among2131survivors
admittedtoapublichospitalintheSichuanarea,atleast19patients(0.9%)developedgasgangrene. [5]

Mortality/Morbidity
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Gasgangreneisundoubtedlyaninfectionthatcarriesaveryhighmortalityrate.Thereportedmortalityratesvary
widely,witharateof25%inmostrecentstudies.Themortalityrateapproaches100%inindividualswith
spontaneousgasgangreneandinthoseinwhomtreatmentisdelayed. [19,20]

Sex
Gasgangrenehasnoreportedsexualpredilection,andthesexoftheindividualdoesnotaffecttheoutcome.

Age
Althoughageisnotaprognosticfactoringasgangrene,advancedageandcomorbidconditionsareassociatedwith
ahigherlikelihoodofmortality.
Previous
ClinicalPresentation
ContributorInformationandDisclosures
Author
HoiHo,MDAssociateDeanforFacultyAffairsandDevelopment,Professor,DepartmentofInternalMedicine,
Director,CenterforAdvancedTeachingandAssessmentinClinicalSimulation(ATACS),PaulLFosterSchool
ofMedicine,TexasTechUniversityHealthSciencesCenterConsultingPhysician,UniversityMedicalCenter
HoiHo,MDisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha,AmericanAssociationforthe
AdvancementofScience,AmericanCollegeofForensicExaminersInstitute,AmericanCollegeofPhysicians,
AmericanSocietyforMicrobiology,InfectiousDiseasesSocietyofAmerica
Disclosure:Nothingtodisclose.
Coauthor(s)
EnesKanlic,MDProfessor,DepartmentofOrthopedicSurgery,TexasTechUniversityHealthScienceCenter
Disclosure:Nothingtodisclose.
LorenzoBAragon,MDAssociateProfessor,DepartmentofFamilyMedicine,PaulLFosterTexasTech
UniversityHealthSciencesCenterMedicalDirector,AmbrosioGuillenTexasStateVeteransHome
LorenzoBAragon,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofFamily
Physicians,AMDATheSocietyforPostAcuteandLongTermCareMedicine,SocietyofTeachersofFamily
Medicine,TexasMedicalAssociation
Disclosure:Nothingtodisclose.
JuanBFigueroaCasas,MDAssociateProfessor,DivisionofPulmonaryandCriticalCareMedicine,Texas
TechUniversityHealthSciencesCenter,PaulLFosterSchoolofMedicine
Disclosure:Nothingtodisclose.
DavidGMaxfieldTexasTechUniversityHealthSciencesCenter,PaulLFosterSchoolofMedicine
DavidGMaxfieldisamemberofthefollowingmedicalsocieties:AmericanCollegeofPhysicians,Texas
MedicalAssociation,CongressofNeurologicalSurgeons
Disclosure:Nothingtodisclose.
SpecialtyEditorBoard
FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedicalCenter
CollegeofPharmacyEditorinChief,MedscapeDrugReference
Disclosure:ReceivedsalaryfromMedscapeforemployment.for:Medscape.
CharlesVSanders,MDEdgarHullProfessorandChairman,DepartmentofInternalMedicine,Professorof
Microbiology,ImmunologyandParasitology,LouisianaStateUniversitySchoolofMedicineatNewOrleans
MedicalDirector,MedicineHospitalCenter,CharityHospitalandMedicalCenterofLouisianaatNewOrleans
ConsultingStaff,OchsnerMedicalCenter
CharlesVSanders,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofPhysicians,
AllianceforthePrudentUseofAntibiotics,TheFoundationforAIDSResearch,SouthernSocietyforClinical
Investigation,SouthwesternAssociationofClinicalMicrobiology,AssociationofProfessorsofMedicine,
AssociationforProfessionalsinInfectionControlandEpidemiology,AmericanClinicalandClimatological
Association,InfectiousDiseaseSocietyforObstetricsandGynecology,OrleansParishMedicalSociety,
SoutheasternClinicalClub,AmericanAssociationfortheAdvancementofScience,AlphaOmegaAlpha,
AmericanAssociationofUniversityProfessors,AmericanAssociationforPhysicianLeadership,American
FederationforMedicalResearch,AmericanGeriatricsSociety,AmericanLungAssociation,AmericanMedical
Association,AmericanSocietyforMicrobiology,AmericanThoracicSociety,AmericanVenerealDisease
Association,AssociationofAmericanMedicalColleges,AssociationofAmericanPhysicians,InfectiousDiseases
SocietyofAmerica,LouisianaStateMedicalSociety,RoyalSocietyofMedicine,SigmaXi,SocietyofGeneral
InternalMedicine,SouthernMedicalAssociation
Disclosure:ReceivedroyaltyfromBaxterInternationalforother.
ChiefEditor
BurkeACunha,MDProfessorofMedicine,StateUniversityofNewYorkSchoolofMedicineatStonyBrook
Chief,InfectiousDiseaseDivision,WinthropUniversityHospital
BurkeACunha,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofChestPhysicians,
AmericanCollegeofPhysicians,InfectiousDiseasesSocietyofAmerica
Disclosure:Nothingtodisclose.
AdditionalContributors
PranatharthiHaranChandrasekar,MBBS,MDProfessor,ChiefofInfectiousDisease,ProgramDirectorof
InfectiousDiseaseFellowship,DepartmentofInternalMedicine,WayneStateUniversitySchoolofMedicine
PranatharthiHaranChandrasekar,MBBS,MDisamemberofthefollowingmedicalsocieties:AmericanCollege
ofPhysicians,AmericanSocietyforMicrobiology,InternationalImmunocompromisedHostSociety,Infectious
DiseasesSocietyofAmerica

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Disclosure:Nothingtodisclose.
Acknowledgements
TheauthorsandeditorsofMedscapeReferencegratefullyacknowledgethecontributionsofpreviouscoauthors
JeffreyPNelson,MDMiguelAngelPenaRuiz,MDandKarlCBentley,MS,tothedevelopmentandwritingof
thisarticle.
References
1. ChapnickEK,AbterEI.Necrotizingsofttissueinfections.InfectDisClinNorthAm.1996Dec.
10(4):83555.[Medline].
2. GawandeA.CasualtiesofwarmilitarycareforthewoundedfromIraqandAfghanistan.NEnglJMed.
2004Dec9.351(24):24715.[Medline].
3. MurrayCK,HsuJR,SolomkinJS,KeelingJJ,AndersenRC,FickeJR.Preventionandmanagementof
infectionsassociatedwithcombatrelatedextremityinjuries.JTrauma.2008Mar.64(3Suppl):S23951.
[Medline].
4. U.S.casualtystatus.DepartmentofDefense,2004.Availableat
http://www.defenselink.mil/news/casualty.pdf.
5. WangY,HaoP,LuB,YuH,HuangW,HouH,etal.Causesofinfectionafterearthquake,China,
2008.EmergInfectDis.2010Jun.16(6):9745.[Medline].[FullText].
6. WangY,LuB,HaoP,YanMN,DaiKR.Comprehensivetreatmentforgasgangreneofthelimbsin
earthquakes.ChinMedJ(Engl).2013Oct.126(20):38339.[Medline].
7. DeA,VaraiyaA,MathurM,BhesaniaA.Bacteriologicalstudiesofgasgangreneandrelatedinfections.
IndianJMedMicrobiol.2003JulSep.21(3):2024.[Medline].[FullText].
8. HartGB,LambRC,StraussMB.Gasgangrene.JTrauma.1983Nov.23(11):9911000.[Medline].
9. NicholsRL,SmithJW.Anaerobesfromasurgicalperspective.ClinInfectDis.1994May.18Suppl
4:S2806.[Medline].

10. KnappO,MaierE,MkaddemSB,BenzR,BensM,ChenalA,etal.Clostridiumsepticumalphatoxin
formsporesandinducesrapidcellnecrosis.Toxicon.2010Jan.55(1):6172.[Medline].

Apatientdevelopedgasgangreneafterinjectingcocaine.Clostridiumsepticumwasisolatedinbothbloodand
woundcultures.
Gasfeatheringinthearmsofttissueofapatientwithgasgangrene.
Extensionofgasgangrenetothechestwalldespiteinitialdebridement.

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RelatedReferenceTopics
ClostridialGasGangrene
EmergentTreatmentofGasGangrene
EmergentManagementofNecrotizing
SoftTissueSkinInfections

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