Significance of respiratory virus infections in HSCT: Not just a cold! · 2019-11-06 ·...
Transcript of Significance of respiratory virus infections in HSCT: Not just a cold! · 2019-11-06 ·...
SignificanceofrespiratoryvirusinfectionsinHSCT:Notjustacold!
OveimarDeLaCruz,MD.AssistantProfessorofMedicineTransplantInfectiousDiseasesDivisionofInfectiousDiseases
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
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?
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%
Parainfluenza2 1 0.15%
Parainfluenza3 43 6.30%
Parainfluenza4 17 2.49%
RespiratorySyncytialVir 139 20.38%
Rhinovirus/Enterovirus 302 44.28%
GrandTotal 682 100.00%
BMTinpatientunits,BMT,Daltonandtransplantclinics.
CourtesyofChristopherDoern,PhD.AssociateDirectorofClinicalMicrobiologyatVCUMC
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
Editedfromtable1.Kimetal.SeminRespirCritCareMed.2007Apr;28(2)
BartonandBlumberg.ClinChestMed26(2005)
• 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
Editedfromtable1.Kimetal.SeminRespirCritCareMed.2007Apr;28(2)
BartonandBlumberg.ClinChestMed26(2005)
• 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
Editedfromtable1.Kimetal.SeminRespirCritCareMed.2007Apr;28(2)
BartonandBlumberg.ClinChestMed26(2005)
• 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
Editedfromtable1.Kimetal.SeminRespirCritCareMed.2007Apr;28(2)
Editedfromtable1.Kimetal.SeminRespirCritCareMed.2007Apr;28(2)
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
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.