significance of respiratory virus infections in hsct: not...

SignificanceofrespiratoryvirusinfectionsinHSCT:Notjustacold!

OveimarDeLaCruz,MD.AssistantProfessorofMedicineTransplantInfectiousDiseasesDivisionofInfectiousDiseases

•  Ihavenoconflictofinteresttodiscloserelatedtothispresentation

http://giphy.com/gifs/the-simpsons-brain-sneeze-aohvgsGTzqqYg

Learningobjectives

•  Appreciatetheclinicalsignificanceofrespiratoryvirusinfections(RVI)inHematopoieticStemCellTransplant(HSCT)recipients

•  ReviewmostrelevantrespiratoryvirusesaffectingHSCTpopulation

•  Recognizewhichpatientscanbepotentiallytreated

•  Overviewofavailabletreatmentandpreventionoptions

Advancesindiagnostictechnologyareallowingidentificationofnoveletiologicagentsfor“idiopathic”pneumonia

J.Clin.Microbiol.July2011vol.49no.72449-2453

2-8hours.Sens/Spec+++

MultiplexPCR

https://pt.slideshare.net/zionpattres/lab-diagnosis-of-viruses?ref=

3-10days.Sens/Spec+

https://www.memorangapp.com/flashcards/32795/CMOD+2/

15-30mins.Sens/Spec++

RatesofDiseaseProgression,andmortalityduetoRVIinHSCT

Bowdenetal.Community–AcquiredRespiratoryviruses.Chap27.inTransplantInfections.3rdedition.2010

ImmuneresponsetoRVIandchronicallograftdysfunction

OpenshawEtAl.Fig2.CLINICALMICROBIOLOGYREVIEWS,July2005,P.541–555Gottlieb,Walter.Chronicallograftdysfunction:Amodeldisorderofinnateimmunity.BiomedJ2013;36:209-228

Prolongedviralsheddingandinnateimmunityactivation

Chronicinflammation

(ImageCourtesyofhttp://weknowmemes.com/2013/01/batman-on-flu-season/

Superinfectionafterinfluenzavirusinfection

MurineModel

EpithelialdamageNeuraminidaseactivityenhancestreptococcaladherenceReducedphagocyteactivity

Rynda-Appleetal.InfectionandImmunity.October2015Volume83Number10

IncreasedriskofInvasiveAspergillosis

Marr,KAetAl.Blood,15December2002Volume100,Number13:

–  1682HSCTrecipients–  Patientswithrespiratoryvirus

infectionsatday40postalloHSCThada2.1-foldincreasedriskofsubsequentIA

Martino,Retal.BoneMarrowTransplantationVol44,pages749-756(2009):219AlloHSCT27developedIA(13%)RiskFactors:LRTIbyrespiratoryvirus(HR4.3),GVHD(HR2.9)andCMVinfection(HR2.8)

Complicationsofrespiratoryvirusinfectionsintransplantrecipients

•  LRTI(increasedmortality)•  Acuteandchronicallograftdysfunction•  GVHD•  Coinfection(bacterialandfungal)•  Immunesystemexhaustion?

MOSTRELEVANTRESPIRATORYVIRUSESINHSCTRECIPIENTS

Seasonaldistribution

Ison,MichaelG.Antiviraltherapy.2007

RespiratoryvirusestestingatMCV(Feb2014-May2016)

Adenovirus 5.15%Bordetellapertussis. 0.12%Chlamydophilapneumoniae 0.09%Coronavirus229E 1.07%CoronavirusHKU1 2.35%CoronavirusNL63 2.56%CoronavirusOC43 4.04%HumanMetapneumovirus 6.01%InfluenzaA 0.31%InfluenzaA2009H1 3.80%InfluenzaAH1 0.07%InfluenzaAH3 4.27%InfluenzaB 2.71%Mycoplasmapneumoniae 0.93%Parainfluenza1 1.40%Parainfluenza2 0.59%Parainfluenza3 4.18%Parainfluenza4 1.59%RespiratorySyncytialVir 16.16%Rhinovirus/Enterovirus 42.61%

Inpatientandoutpatient2812patients4213tests

Adenovirus 3 0.44%

Coronavirus229E 19 2.79%

CoronavirusHKU1 26 3.81%

CoronavirusNL63 13 1.91%

CoronavirusOC43 38 5.57%

HumanMetapneumovirus 25 3.67%

InfluenzaA2009H1 15 2.20%

InfluenzaAH3 16 2.35%

InfluenzaB 8 1.17%

Parainfluenza1 16 2.35%




RespiratorySyncytialVir 139 20.38%

Rhinovirus/Enterovirus 302 44.28%

GrandTotal 682 100.00%

BMTinpatientunits,BMT,Daltonandtransplantclinics.

CourtesyofChristopherDoern,PhD.AssociateDirectorofClinicalMicrobiologyatVCUMC

Influenza

http://www.who.int/mediacentre/factsheets/fs211/en/

InfluenzaAandB•  Incidence:9.4to47%(among

patientswithrespiratoryinfections).1.3%overall

•  Mortality:4.5upto47.8%•  Clinicalcourse:LRTI,secondary

superinfectionwithfungalorbacterialpathogens.EmergenceofM2inhresistance

•  Dx:DirectantigenDetection(DAD),PCR.

•  Rx:FluAorB-neuraminidaseinhibitors(oseltamivirPO,PeramivirIVorzanamivirInh),M2inhibitor(amantadineandrimantadine-FluA.RBVmaybeincombination

Editedfromtable1.Kimetal.SeminRespirCritCareMed.2007Apr;28(2)

BartonandBlumberg.ClinChestMed26(2005)

1918pandemicfluinfected500million,killedaround100millions

ARDSsecondarytoH1N1infection

RSV



•  Incidence:23.9-31%(amongpatientswithrespiratoryinfection).Overall8.7%

•  Mortality:6.5-26%(~80%ifuntreatedfromolderreports)

•  ClinicalcourseURTI,LRTI,graftfailure,airflowdecline

•  Yearroundtransmission,peakinthecoldseasons.Nosocomialoutbreaks

•  Dx:Viralculture,DAD,PCR.•  Rx:RBV,IVIG,Palivizumab

JournalofMedicalCaseReports2017.11:353

Adenovirus



•  Severalserotypes•  Incidence2.7-47%.Mortality

18-52.8%•  Clinicalcourse:URTI,LRTI,extra-

pulmonarymanifestations(Enteritis,hemorrhagiccystitis,renalfailure,hepatitis,CNSinvolvement),graftfailureordelayedengraftment,dissemination

•  Communityacquiredorreactivation.Peakatsummermonths

•  DX:PCR•  Rx:Cidofovir.Gancyclovirand

Acyclovirhavepooractivity.Reductionofimmunosuppression

www.medscape.com

JThoracDis2016;8(5):848-854

Parainfluenza



•  Incidence:PIV-3>PIV1>PIV2>PIV4.9.6-28%Amongpatientswithrespiratoryinfection.Overall7.1-13.8%

•  Mortality:4-75%•  Clinicalcourse:URTI,LRTI,encephalitis.Commoncoinfection

withA.fumigatus,CMV,RSVandotherbacterialpathogens.Airflowdecline

•  Highrateofasymptomaticshedding.Nosocomialtransmissioniscommon

•  DX:ViralCulture,DAD,PCR•  Rx:+/-RBV,IVIG.DAS-181?

HMPV•  Incidence:3-4%•  Mortality:dataobscured

duetoco-infection.~12.5%

•  Clinicalcourse:URI,LRTI,respiratoryfailure,pulmonaryhemorrhage

•  Dx:ViralCulture,DAD,PCR

•  Rx:?Ribavirin,?IVIG

Coronavirus•  Yearroundcirculation,

slightpredominanceinwinter

•  LRTI<10%inHSCT•  Mortalityestimated<10%•  Deadlycoronaviruses:

SARSandMERS•  Rx:Lackofantiviral

agentsandclinicaltrials



Rhinovirus/Enterovirus•  Rhinoviruses:

–  Incidence:7.8%– Mortality:Fatalcasesreported–  Clinicalcourse:URI,LRTI(rare).Prolongedshedding–  Supportivetherapy

•  Enteroviruses:–  Incidence:0.7%inBALspecimens.6%inpatientswithrespiratoryinfections

– Mortality:Fatalcasesreported–  Clinicalcourse:LRTI,ARDS,Meningitis-Encephalitis–  Supportivetherapy

HighlightsofclinicalpresentationinHSCTrecipients

•  Widerangeofdisease:URI-trachea-bronchitis–bronchiolitis– pneumonia

•  Oftenpresentwithmildoratypicalsymptomsandfevermaybeabsent

•  Viralsheddingisusuallyprolonged•  Lookforsubsequentdevelopmentofbacterialandfungalpneumonia

WHONEEDSTOBETREATED?

ECIL-4 Guideline for Respiratory Viruses • CID 2013:56

RespiratoryvirusinfectionsandAlloimmunelungsyndrome(IPS,BOS,

COP)

BiolBloodMarrowTransplant16:782-791(2010)

•  110PedalloHSCT•  27%developedallo-LSstrongly

associatedtoRVI•  18IdiopathicPulmonary

syndrome•  12Bronchiolitisobliterans

•  OverallsurvivalisdecreasedassociatedAlloimmune–LungSyndromes

PreventiveMeasuresRespiratory Virus. Incubation

Period (days)Mode of transmission Infection Prevention

Principles

RSV 4.4 Direct or indirect contact; droplet Standard. Contact and Droplet precautions.

ADV 5-9 Direct contact; aerosols; fecal-oral Standard. Contact and Droplet precautions.

Influenza 1-4 Contact; droplet; aerosol Standard. Droplet precautions. Airborne with invasive ventilation;Seasonal vaccination;Post exposure prophylaxis with Oseltamivir

PIV 2.6 Direct contact; droplet; large particle aerosol

Standard. Airborne and Droplet precautions.

hMPV 4-6 Direct contact; droplet; large particle aerosols

Standard. Contact precautions.

Rhinovirus/Enterovirus 1-9 Direct or indirect contact; large or small particle aerosol

Standard. Droplet precautions.

DeLaCruzetal.IntJournalofInfDiseases.2017

TherapiesunderdevelopmentforHSCTandHMRVIs

Waghmareetal.BLOOD,JUNE2016

�BiolBloodMarrowTransplant.2016May;22(5):965-70.Epub2016Feb22.(56%completeclinicalresponsetoDAS181)

�PB1inhibitor(ofviralpolymerasecomplex)approvedforuseagainstpandemicfluinJapan.

DiLilloetal.NatMed.2014Feb;20(2):143-51.doi:10.1038/nm.3443.Epub2014Jan12.Broadlyneutralizinghemagglutininstalk-specificantibodiesrequireFcγRinteractionsforprotectionagainstinfluenzavirusinvivo.

Rossignol,J.AntiviralResearch110(2014)94–103Rossignol�Antiparasiticdrug,withbroadspectrumantiviralactivity(Flu,RSV,PIV,Coronavirus,Norovirus,.BlocksmaturationofHematugglutinin.NoavailabledatapublishedyetfromNCT01610245(OseltvsNTZvsOselt/NTZvsplacebo).

ALS-8176:NucleosideanalogtargetingRSVpolymerase,demonstratedreductiononVLAnddiseaseseverity.ALN-RSV01.SmallinterferingRNAwithrobustVLdecreaseinvitroandmice.

�AvailablethroughFDAEIND.UsefulforOseltamevirresistancestrains

Summary•  RVIareincreasinglyrecognizedassignificantthreattoHematopoieticStemCelltransplantrecipients–  Highfrequencyofnosocomialacquisition,frequencyofprogressiontopneumonia,secondaryAlloimmuneLungsyndromesandhighmortalityrate

•  Influenza,RSV,PIV,HMPVandadenovirusescausemostseriousdiseaseinimmunocompromisedhosts

•  Therapeuticoptionsarecurrentlylimited,withfewantiviralagentsapprovedforclinicaluse

•  Infectioncontrolmeasuresandimmunizationagainstpathogensforwhichvaccinesareavailableisimportant

Acknowledgements

•  InfectiousDiseasesDivisionatVirginiaCommonwealthUniversity.Richmond,VA.USA.

•  BoneMarrowTransplantTeamatMasseyCancerCenter.VCUHS.

Questions?

significance of respiratory virus infections in hsct: not...

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