Onchocerciasis, Loa Loa, Filariasis - Denver, Loa Loa, Filariasis A Case of the Creepy Crawlies Justin Searns, MD Pediatric Infectious Disease Fellow Children’s Hospital

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  • Onchocerciasis,LoaLoa,FilariasisACaseoftheCreepyCrawlies

    JustinSearns,MDPediatricInfectiousDiseaseFellow

    ChildrensHospitalColorado

  • ReviewImportantTissueNematodes Epidemiology ClinicalFindings Diagnosis Treatment

    Onchocerciasis,LoaLoa,Filariasis Past,Present,Future

    GoalsandObjectives

  • NematodeBiology

  • Nematodes=Roundworms

    Microfilariae=babies

    Macrofilariae =adults

  • 53yearoldmanfromSudan 20+yearsofintenselypruritic skin,nodulesonhisribcage,discolorationofsomeareasofskin,nowwithprogressivevisionproblems

    CaseReport

  • Onchocerciasis

    CaseReport

  • RiverBlindness Blackfly livesandbreedsnearfastflowingstreamsand

    rivers Itchy/scalyskinwithblindnesswascalledkru kruor

    crawcraw 1874:Microfilariaseenundermicroscopefromskinsnips

    byIrishnavalsurgeonJohnONeill

    Oncherciasis:Past

  • 123millionpeopleinendemicareas 20 40millionpeopleinfected 500,000withsecondaryvisualimpairment,270,000blind

    HUGEincreaseduringchildhood Hyperendemic area:12%ofkids

  • Onchocerciasis Epidemiology

    WHODistributionofonchocerciasis,worldwide,2013http://www.who.int/mediacentre/factsheets/onchocerciasismap.png?ua=1

  • Blackfly (genusSimulium)=intermediatehost Humans=definitivehost 5stagelifecycle Microfilariae persistinhumanhostfor35years Adultfemaleslivefor1015years

    Onchocerca Volvulus LifeCycle

  • Larvadropfromproboscis humansubcutaneoustissues growtoadults(312months) femalenematodemakesfibrouscapsule,malesmigratefemalesheds100,000smicrofilariea whichmigratemicrofilariae takenupbyblackflyduringmealflys gutmuscles growtolarva proboscis

  • Wolbachia bacteria:BFFtomanyneotropical insects Endosymbiotic rickettsialikebacteriumrequiredforsurvivalofmacrofilariae andforembryogenesis

    O.Volvulus:AFriendIndeed

  • AfricanSavannah Ocularsymptomspredominate Inhyperendemic areas,80100%havesomevision

    symptomsbyage20,blindnessby4050s AfricanForest Skinsymptomspredominate 40%ofpatientsolderthan20withseverepruritus

    TwoPatternsofPresentation

  • SKIN Papular dermatitis,intenselypruritic

    TH1ImmuneResponse Chronicdiseasecandevelopasymptomatic

    depigmentationHypo vs Hyperpigmentation,Leopardskin TH2Immuneresponse

    Lichenification,Lizardskin,ElephantSkin Eosinophilic responsetoonchocerca breakdownproducts Bacterialsuperinfection common

    Onchocerciasis:ClinicalFindings

  • Onchocerciasis SkinFindings

    LeopardSkin Lizard/ElephantSkin

  • SkinNodules:Onchocercomata Subdermal nodulesusuallyoverbony

    prominences,RoblesDiseaseinSouthAmerica

    Raised,round,firm,23cm,containatleast1adult

    May be 1-100 per patient (for each one you see, ~ 5 lie deeper).

    Angiogenic proteinproducedbyadultfemale

    Onchocerciasis:ClinicalFindings

  • Onchocercomata

  • Onchocercomata

  • Lymphatics

    Lymphatic blockage may cause extremity edema, ie equatorial arm

    Lymphadenopathy: Regional or generalized

    Without treatment, lymphadenopathywill become chronic Hanging Groin

    Scarred lymphatic channels can cause Elephantiasis-like syndrome

    Onchocerciasis ClinicalFindings

    HangingGroin

  • Ocularfindings AnteriorDisease:punctate orsclerosing keratitis,uveitis PosteriorDisease:Chorioretinitis,opticatrophy Asmicrofilariae die,theyreleaseWolbachia antigensaswell Immunereactiontoantigens cornealinflammation

    Eventualscarringfromyearsofrepeatedinfections Impairedvisionstartsbyseconddecade

    Onchocerciasis:ClinicalFindings

  • Skinsnip Smallsnipofskin(onlydermis),place

    onslidewithsaline,microfilariaecrawloutovernightintosaline

    6snipsprovidethemostsensitivity,iliaccrest,scapula,thigh,buttocks

    Takes1.5yearsformaturewormtomakeenoughmicrofilariaetomakethemdetectablebythismeans

    Lowsensitivityofthistesting(1950%)

    Onchocerciasis:Diagnosis

  • Onchocerciasis SkinBiopsy

  • Slitlampoftheanterioreyecanshowmicrofilariae orpunctatekeratitis Patientsshouldsitwithheadsbetweenlegsfor510minutesfirst

    Newstrategies:ELISAPCRtissue,Rapidserumantibody,Rapidurineantigen,fingerprickwholebloodO.Volvulus IgG4 Underdevelopment

    Mazzotti reaction,nolongerperformed Give0.51mg/kgofDiethylcarbamazine Killsmicrofilariaewithinseveralhoursdevelopsmaculopapular rash,

    fever,edema,pruritus,andHA Cancauseanaphylaxisanddeath

    Onchocerciasis Diagnosis

  • Ivermectin (150ug/kgevery312months) Killsmicrofilariae,butnotmacrofilariae Skindensitiesdrop8595%by2months,backupto20%by1year Repeattreatmentsforthelifespanoftheadultworm

    Remember,femaleslivefor1015years!

    Posttreatmentreactions(edema,pruritus,backpain)decreasesovertime

    NOTE:PatientcoinfectedwithLoaLoa candevelopencephalopathyafterIvermectin RuleoutLoaLoa First!

    Oncho:Treatment

  • Suramin Onlyapprovedmedicineeffectiveagainstadultworms,

    olderdrug InjectionsBIDforseveralweeks Toxicthough,sonolongerused

    Moxidectin Showngoodeffectagainstadultwormsinanimal

    studies,bettersafetyprofileinhumans PhaseIITrials

    Onchocerciasis Treatment

  • Blackfliesbiteduringtheday,bestpreventionistopreventgettingbitten!

    DEET,longpantsandlongshirts APOC:GoaltoeradicateOnchocerciasis from23nationsby2015withIvermectin for90millionpeople

    Havealreadytreated68millionpeople,limitedbyconflictareas

    Oncho Prevention

  • Doxycycline(100mgqday x6weeks)effectivelykillstheWolbachia endosymbionts

    PretreatmentwithDoxy,followedbyIvermectinresultedin19monthsofamicrofilaridermia,aswellas100%eliminationofWolbachia speciesfromwormsthatwereisolated

    Unclearsafetyoftreatmentatthesametime,needstoberesearchedfurtherforinteractions

    CDCsaysTreatmentwithDoxycyclineoneweekafterIvermectin wouldbereasonable

    Onchocerciasis:Doxycycline

  • Onchcerca lupi,anemergingNorthAmericanpathogen CanineandFelineparasiticinfection,nodulesineyelid,sclera,conjunctiva 6casesofhumanO.lupi infectionreportedfromUS,alltraveledthroughSW Simulium blackfliesfromSouthernCA Skinnodulesaswellas3withnodulesnearcervicalspinalcanal

    Onchocerciasis:Future

    Otrantoetal. Parasit Vectors(2015)8:89 Dudleyetal. Lancet(2015) Eberhard etal. AmJTropMedHyg(2013)88:601

  • 35yearoldman,complainingofperiodicswellinginhisarmsandlegs

    Willlastforseveraldays,pruritic,edema,oftenwithpaininnearbyjoints

    Thenresolves Nowwithsomethingwigglinginhisfieldofview

    CaseReport

  • LoaLoa

  • 1778: SurgeonFranoisGuyot notedwormsintheeyesofWestAfricanslavesonaFrenchshiptoAmerica;hesuccessfullyremovedawormfromoneman'seye

    1890:OphthalmologistStephenMcKenziediscoveredmicrofilaria

    1895:ScottishOphthalmologist,DouglassArgyllRobertson,CoastalNigeriantownofCalabar,localizededemaofextremitiesnoted

    1910:Dr.PatrickMansonmadeconnectionfromLoaLoatoCalabar Swellings

    1912:BritishParasitologist RobertLeiperdiscoveredChyrsops specieswerethevector

    LoaLoa:Past

  • LimitedtoWestandCentralAfrica Typicallyforestregions,alsosavannahs Fliesbreedinthecanopiesofrainforests,morecommoninrainyseason

    14millionpeopleliveinareasofhighendemicity 2040%ofpeoplehavehadapastinfection

    LoaLoa:Epidemiology

  • TransmittedbyTabanid fly GenusChrysops Deerfly/Mangofly/Mangrovefly PrimarilyChrysops silacea andChrysops dimidiata

    LoaLoa:LifeCycle

  • LoaLoa:LifeCycle

    Looksfamiliar

  • Microfilariae climbintodermisthroughholecutinskinbyfly Moveontolymphatics Adultwormssetupshopinthetissuebetweenthefascial

    layersofmuscleandtheskin Adultlifespanupto17years Oncefertilized,femalesstartreleasing1020Kmicrofilariae

    perday Microfilariae passintothelymphaticsmove tolungblood Somepercentagecontinueontoperipheralblood

    17monthsfrompenetrationintoskintofoundblood

    LoaLoa:LifeCycle

  • Microfilariae livefor~612mos Diurnalperiodicity:Densitiesof

    microfilariae peakbynoon,anddecreasetolowlevelsatnight

    Chrysops fliesactiveindaytime

    LoaLoaLifeCycle

    Peripheral bloodUrine SalivaAscitic fluidHydrocele fluid CSF(rare)

  • Asymptomatic Lifethreateningcomplications Firstsigns5monthsupto13yearspostinfection Calabar Swellngs:Subcutaneous,nonpitting,nontender

    edemas Limbsandforearms Itching,decreasedROMatnearestjoint,resolveafterseveral

    days Reappearatirregularintervals

    Hematuria,proteinuria,MPGN,Renalfailure Cardiomyopathy Pulmonaryinfiltratesandpleuraleffusions Arthralgia (kneesandwrists)andarthritis

    LoaLoa:Clinicalpresentation

  • Mostspecificsignispassageofadultwormunderconjunctiva

    Canlastfor3060minutestomorethan24hours Itching,photophobia,congestionofeye Seenin50%ofpeoplewholiveinhyperendemic areas

    LoaLoa:ClinicalFindings

  • LoaLoa:EyeWorm

  • LoaLoa:Eye

  • Eyeworm=pathognomonic Oftensevereeosinophilia Bloodsmear,oftencanseemicrofilariaelashingabout Collectduringdaygivendiurnalpattern

    IgG4ELISAcanhelpwithoccultinfections PCRthatdetectsspeciesspecificprotein 100%Specific,95%sensitive

    LoaLoa:Diagnosis

  • Diethycarbamazine:Treatmentofchoice Microandmacrofilariae ,onlyoptionwithboth 810mg/kg/daydividedTIDx21days Typicallytakes23roundsforadefinitivecure

    BUTSevereadverseeventsforpatientswithhighmicrofilariaeloads Itching,rash,edema,Headaches,feverin50%ofpatients Encephalopathymostseverereaction,oftenfatal,unknownmechanism

    Ivermectin:Bigmicrofilaricidal effect,butnomacro Canalsocauseencephalopathyinpatientswithhighloads,dontuse

    Albendazole:Onlymicro,nomacro Dailyfor3weeks,dropinmicrofilariaecounts MaybeusefulaspretreatmentbeforeDEC

    LoaLoa:Treatment

    USUALLYHARMLESS,TREATMENTOFTENNOTNECESSARY

  • Proposedprotocol1. GiveAlbendazole orPlasmapharesis todropto

  • 35yearoldmanwhohashadprogressiveswellingofhisleftlegforseveralyears,nowitisgettingevenbiggerandmorechallengingtowalk

    CaseReport

  • Canbefoundasearlyas2000BC Pharoah Mentuhotep II

    JanHuygen Linschoten 1588inGoa Inhabitantswereallbornwithoneof

    theirlegsandonefootfromthekneedownwardsasthickasanelephantsleg.

    JosephBancfort discoveredadultworm 1877:PatrickMansonfoundmosquitoes

    wereintermediatehost Firsttimeanarthropodwasdiscoveredto

    beavectorofdisease

    Filiariasis:Past

  • Filiariasis:Present

    W.Bancrofti (90%)Foundthroughout

    tropics

    Brugia malayiOnlySE/EastAsia

    Brugia timoriOnlyTimorislands

  • 120millionpeopleinfected 1billionatrisk

    80countries:but70%ofcasesfoundinIndia,Nigeria,Bangladesh,andIndonesia

    Africa,SouthAsia,WestPacificIslands,South/CentralAmerica,Caribbean(HaitiandDominicanRepublic)

    Mentowomenis10:1,thoughtduetoclothing

    Filiariasis:Epidemiology

  • Filariasis:Global

  • Filariasis:LifeCycle

    Ohnonotagain

  • Adultwormsliveinlymphaticvesselsfor510years Microfilariae canliveforupto1.5years Mosquitoes:Aedes,anopheles,culex,ormansonia

    Filariasis LifeCycle

  • Asymptomatic(atleast50%) Lymphaticdilatationandabnormallymphflowwithout

    symptoms Microscopichematuria andproteinuria StudywithU/Sshowedofadultmenwith

    asymptomaticmicrofilaraemia hadnestsofmotileadultwormsintheirscrotalsacs

    Acuteattacks Episodic Lymphadenitis,lymphangitis,feverandmalaise

    Lymphadenopathy/Lymphedema Adultwormsblockingthelymphatics,inflammation

    veryimportanttoprocess Inguinal,crural,axillary,intrascrotal lymphaticvessels Canbeseeninchildren Legs,scrotum,penis,andarms

    Filariasis:ClinicalManifestations

  • Elephantiasis Clinicalfeature,notsynonymous Recurrentinfections,inflammationand

    fibrosis Chronicskininfectionsfrom

    streptococcalspeciesandfungalinfections

    Travelers Acutefilariallymphangitis 26monthsafterexposure Acuteinflammation(usuallyleg,

    scrotum,orarm),progressesdistally Indurated,tender,erythematous,

    resolvesin37days

    Filariasis:Clinical

  • TropicalPulmonaryEosinophilia (TPE) Asthmalikesymptoms

    1/3ofchildrenwithcoughandwheezehadfilarialinfection,symptomsimprovedaftertreatmentwithDEC

    Peripheraleosinophilia,elevatedIgE,lowgradefever,lymphadenopathy

    Typicallyfoundinmen2040yearsold

    Chyluria Passageoflymphintheurinesothatit

    appearsmilky

    Filariasis:ClinicalManifestations

  • W.bancrofti inLymphatics

  • Microfilariae onathickbloodsmear Filtrationof15mlofbloodwithfilterismoresensitive Highestbloodspecimenconcentrationsatnight Distinguishthethreespeciesmorphologically Childrenoftennegative AssaystodetectW.bancrofti antigenareavailable

    Filariasis:Diagnosis

  • Diethylcarbamazine (DEC)isthedrugofchoice,usedsince1947 Microfilaricidal +Macrofilaricidal Singledoseof6mg/kg/dayaseffectiveas12daytherapyperCDC CookingsaltmedicatedwithDEChasbeenusedformasstreatment

    programs Severityofreactiontotreatmentisdependentonmicrofilarial

    density Usuallyselflimited DECnotusedinareasthathavecoendemicity withonchocerciasis or

    loa loa forriskofseverereactions,insteaduse400mgofAlbendazole+150ug/kgofivermectin

    DECnotrecommendedduringpregnancy TreatchildrenwithTPEwithDECtopreventchronicILD

    Filariasis:Treatment

  • Properhygiene

    SkincareTreatingskinlesions

    Exercise

    Filariasis Treatment

    ArrestLymphedemaPotentiallyReverse

  • FilarialDanceSign

  • ICTFilarialantigentest Rapid Simpleenoughtouseinthefield Nearlyimmediateresults 100%sensitivity,96%specificity

    Somevaccineworkunderwayusingclonedfilarialantigens Promisingworkwithtreatingthewolbachia bacteria

    Tetracyclineanddoxycycline havebeenshowntoinhibitmotility,viability,andreleaseofmicrofilariae

    ConsiderpretreatingwithDoxy100mgPOBIDx 4weeksthen1doseofDEC

    Filariasis:Future

  • Questions?

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