Transmission routes of respiratory viruses among humans

Transmission

routes

of

respiratory

viruses

among

humans

Jasmin

S

Kutter

,

Monique

I

Spronken

,

Pieter

L

Fraaij

,

Ron

AM

Fouchier

and

Sander

Herfst

Respiratorytractinfectionscanbecausedbyawidevarietyof viruses.Airbornetransmissionviadropletsandaerosols enablessomeofthesevirusestospreadefficientlyamong humans,causingoutbreaksthataredifficulttocontrol.Many outbreakshavebeeninvestigatedretrospectivelytostudythe possibleroutesofinter-humanvirustransmission.Theresults ofthesestudiesareofteninconclusiveandatthesametime datafromcontrolledexperimentsissparse.Therefore, fundamentalknowledgeontransmissionroutesthatcouldbe usedtoimproveinterventionstrategiesisstillmissing.Wehere presentanoverviewoftheavailabledatafromexperimental andobservationalstudiesonthetransmissionroutesof respiratoryvirusesbetweenhumans,identifyknowledgegaps, anddiscusshowtheavailableknowledgeiscurrently implementedinisolationguidelinesinhealthcaresettings.

Addresses

1

DepartmentofViroscience,PostgraduateSchoolofMolecular Medicine,ErasmusMedicalCentre,Rotterdam,TheNetherlands

2_{DepartmentofPediatrics,SubdivisionInfectiousdiseasesand}

Immunology,ErasmusMedicalCentre–Sophia,Rotterdam,The Netherlands

Correspondingauthor:Herfst,Sander(s.herfst@erasmusmc.nl)

3_{Theseauthorscontributedequallytothiswork.}

CurrentOpinioninVirology2018,28:142–151

ThisreviewcomesfromathemedissueonEmergingviruses: intraspeciestransmission

EditedbySanderHerfstandMartinLudlow

ForacompleteoverviewseetheIssueandtheEditorial Availableonline17thJanuary2018

https://doi.org/10.1016/j.coviro.2018.01.001

1879-6257/ã2018TheAuthors.PublishedbyElsevierB.V.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creative-commons.org/licenses/by-nc-nd/4.0/).

Introduction

Viral respiratory tract infections are a leading cause of

morbidityandmortalityworldwide,representingan

enor-mous economic and disease burden [1]. Respiratory

virusesreplicateintherespiratorytractfromwherethey

are subsequently shed and transmitted via respiratory

secretions.Theyareclassifiedindifferentvirusfamilies

anddifferinvirulenceandtargetgroups.Respiratorytract

infections may range from asymptomatic to acute live

threatingdiseasetherebyposingamajorhealththreatto

young children, elderly, and immunocompromised

people. Respiratory viruses spread via three different

transmissionroutes: contact (director indirect),droplet

and aerosol transmission(Table 1)[2,3]. Contact

trans-mission refers to direct virus transfer from an infected

persontoasusceptibleindividual(e.g.viacontaminated

hands)orindirectvirustransferviaintermediateobjects

(fomites).Transmissionofvirusthroughtheaircanoccur

viadropletsoraerosols.Thecommonlyacceptedcut-off

size between the large droplets and small aerosols is

5mm,althoughthisvariesconsiderablybetweenstudies,

ranging up to 12mm [4–8]. Droplets generated during

coughing,sneezingortalkingdonotremainsuspendedin

airandtravellessthan1mbeforesettlingonthemucosa

ofclosecontactsorenvironmentalsurfaces.Aerosolshave

aslow settling velocity,thus theyremain suspended in

theairlongerandcantravelfurther[5,9,10].

Transmissionvia eachof these three routesis complex

and depends on many variables such as environmental

factors (e.g. humidity and temperature), crowding of

people,butalsoonhostfactorssuchasreceptor

distribu-tion throughout the respiratory tract. The fact that all

thesevariablesaffectthedifferenttransmissionroutesof

thedifferentrespiratoryvirusesinadissimilarway,makes

itverydifficulttoinvestigatethemexperimentally[9,11].

Here,wesummarizetheevidencefromexperimentaland

observationalstudiesoninter-humantransmissionroutes

ofimportantrespiratoryviruses(summarizedinTable2).

A literature search was conducted for each respiratory

virus using ‘human transmission experiments’ and

‘transmission (routes)’ of the virusof interest as search

criteria in PubMed and Google Scholar. Subsequently,

the backward snowball method was applied in which

additionalpaperswereidentifiedbasedonthereference

listof apaperofinterest. Asthis review focusesonthe

evidenceoninter-humantransmissionroutes,datafrom

animal studieswereexcluded.Inaddition, intervention

studies,(aircraft)outbreakreportsandhouseholdstudies

wereexcluded ifthetransmissionroutewas not

specifi-callyinvestigated.Thestrengthsandweaknessesofthe

differentmethodsemployedin transmissionstudiesare

summarizedinTable3.Finally,wediscussourfindingsin

thelightofseveralavailable(inter)nationalguidelineson

infectioncontrol.Ourobservationsunderscoretheurgent

needfornewknowledgeonrespiratoryvirustransmission

routes and the implementation of this knowledge in

infectioncontrolguidelinestoadvanceintervention

strat-egiesforcurrentlycirculatingandnewlyemergingviruses

Measles

virus

(MV)

Measles is one of the mostcontagious viral diseases in

humans thathasbeen associated with aerosol

transmis-sionforalongtime[12,13,14,15–17,18].However,it

shouldbenotedthatMValsoreplicatessystemically,and

that there is arole for dead celldebris-associated virus

spreadviafomites.Inthelate1970sandearly1980s,data

fromretrospectiveobservationalstudiesobtainedduring

outbreaksin pediatricpractices, aschool,andasporting

eventsuggestedtransmissionthroughaerosols[14,15–

17,18].Indeed,thosestudiesshowedthatmost

second-ary cases never came in direct contact with the index

patientandsomewereneverevensimultaneously

pres-entinthesameareaastheindexcase[14,18].

Exami-nationofairflowinthepediatricians’officesshowedthat

aerosolswerenotonly dispersed over theentire

exami-nation room but also accumulated in the hallway and

otherareas[14,18].Furthermore,basedonthe

inves-tigationofaircirculationinasportstadium,inwhichaMV

outbreakoccurred,authors suggestedthatMVhadbeen

dispersed through the ventilation system [16]. Thus it

wasconcludedthatMVcanbetransmittedviaaerosols.

Althoughcoughingisacommonsymptomassociatedwith

measlesdisease,indexpatientsweredescribedtocough

Table1

Commonlyacceptedrespiratoryroutesoftransmission

Transmissionroute Particlesinvolvedandparticlecharacteristics Characteristics/definitionoftransmission

Contact Self-inoculationofmucousmembranesbycontaminatedhands. Direct Depositedonpersons. Virustransferfromoneinfectedpersontoanother.

Indirect Depositedonobjects. Virustransferthroughcontaminatedintermediateobjects(fomites).

Airborne

Droplet Droplets(>5mm).

Remainonlyshortlyinair(_<17min)[116]. Dispersedovershortdistances(_<1m).

Shortrangetransmission.

Directinoculationofnaı¨ve personthroughcoughing/sneezing/ breathingofinfectedperson.

Depositionmainlyonmucousmembranesandupperrespiratory tract.

Aerosol Aerosols,dropletnuclei(<5mm),

Remaininairforanalmostinfiniteamountoftime. Dispersedoverlongdistances(_>1m).

Longrangetransmission.

Inhalationofaerosolsinrespirablesizerange.

Depositionalongtherespiratorytract,includingthelowerairways.

Table2

Overviewoftheevidenceontransmissionroutesofrespiratoryvirusesbasedonexperimentaldataandthetransmissionrouteaccording toinfectionpreventionguidelines

Virus Virusfamilya _{Transmissionroute}

Experimentalandobservationaldata Guidelinesb

Measlesvirus Paramyxoviridae Aerosol[75–77,78,79]. Contact[3,110],droplet[3,109–111], aerosol[3,109–111].

Parainfluenzavirus Paramyxoviridae Limiteddata,contact(byfomite)[83,84]e_{. Contact[3,109–111],droplet[3,109–111],}

aerosol[3,109].

HMPV Pneumoviridae Limiteddata,contact(byfomite)e_{[30] Contact[3,110,111],droplet[3,110,111].}

RSV Pneumoviridae Contact[89,88],droplet[88],aerosol [90,91].

Contact[3,109–111],droplet[3,109,110], aerosol[109,111].

HCoV Coronaviridae Limiteddata,contact(byfomite)[65–67]e_{. Contact[3,110,111],droplet[3,110,111].}

MERS-CoV Coronaviridae Contact[84]e_[89]c_[91_{],droplet[89]}c_,

aerosol[91].

Contact[111],droplet[3,111]

SARS-CoV Coronaviridae Contact[70]e[73,79,101],droplet [73,78,79,117],aerosol[76,118]c[82]c,d.

Contact[3,110,111],droplet[3,110,111], aerosol[3,110,111].

Rhinovirus Picornaviridae Contact[35,36,42],aerosol[37,40,119]. Contact[109–111],droplet[109,111], aerosol[109–111].

Adenovirus Adenoviridae Contact[100]e_{[100,101],droplet[103}_],

aerosol[102,103].

Contact[3,109–111],droplet[3,109,110], aerosol[110,111].

Influenzavirus Orthomyxoviridae Droplet/aerosol[55,56,57,59] Contact[109–111],droplet[3,109–111], aerosol[3,109–111].

a_{Taxonomywasbasedon[62],airbornetransmissionisseeminglylinkedto:}

b _{WIP[108],‘BlueBook’[109],‘RedBook’[110],CDC[3]andUp-To-Date[111].Theconclusionsonexperimentaldataaspresentedinthistable}

reflecttheconclusionsfromtheauthors.

c

Superspreaderevents.

d _{Aerosol-generatingprocedures(inanosocomialsituation).} e_{Conclusionsweredrawnbasedonstabilityexperiments.}

frequently and vigorously in the outbreak reports of

pediatricpractices.Remingtonetal.calculatedthe

infec-tious dose of MV produced by the index casethrough

coughing,usingamathematicalmodelbasedonairborne

transmission.Theyfoundthattheindexcaseproduceda

very highinfectious dosecompared to cases fromother

outbreaks and mentioned a phenomenon called

super-spreading[18].Superspreadersareindividualswhoare

abletoinfectadisproportionallylargenumberof

suscep-tiblecontactswhencomparedtoatypicalindividual[19–

22],whichmaycontributetotheefficienttransmissionof

MV.

Table3

Overviewofthemethodstostudyhuman-to-humantransmissionandtheirrespectivepro’sandcon’s

Studydesign Pro Con Reference

Virusstability Canprovideindirectevidencefor transmissionroute.

Easytoperform.

Notconclusiveastransmissionitselfisnot investigated.

[42,43,65,70]

Outbreak(householdor hospital)reports

Studynaturalinfections. Includesthemostsusceptible patientswhoaredifficulttoinclude inexperimentalstudies.

Retrospective.

Usuallynotconclusiveontransmissionrouteor relativeimportanceoftransmissionroutes.

[120–123]

Outbreakreport— aircraft

Relativelyeasytoperform Outbreakinclosedsetting

Retrospectivewhichcanresultinrecall-biasand hardtotracebackpassengermovements. Inconclusive.

Onlyreportedincaseofsecondaryinfectionsand inthesecasesinfectionsmayalsooccurbeforeor aftertheflight.

[118,124–127]

Non-pharmaceutical Intervention

Canhelptodiscriminatebetween transmissionroutesifperformed properly.

Usuallynocontrolledenvironment. Difficulttodetermineidealtime-pointofthe intervention.

Riskofdrop-outorperseverance.

[35,128–131]

Pharmaceutical intervention

Canhelptoidentifyrelative importanceoftransmissionroutes Controlledenvironment

Difficulttoincludeenoughpatientstoobtain statisticallysignificantresults

[132]

Experimentalinfection Controlledenvironment. Donorselectionandcontrol. Real-timedatacollection. Repeatable.

Variousparameterscanbestudied atthesametime.

Possibilitytostudydifferent inoculationroutes.

Ethicalobstacles.

Infectivityanddiseasecandifferfromthatina naturalinfection(attenuatedstrains).

Difficulttocreateidealandcomparable circumstances.

Manyfactorshavetobetakenintoaccount: duration,influenceofsuperspreaders,sampling methods.

Difficulttogetnaı¨ve orriskgroupparticipants whoareinterestingtostudy.

[42,44,102]

Miniaturefieldtrial Candiscriminatebetweencontact andairbornetransmission.

Ethicalobstacles.

Exposuretimemaynotbesufficient. Difficulttocreateidealandcomparable circumstances.

[38,39,40]

Airsampling Noninvasiveforpatients. Quantificationofviablevirusinthe air.

Characterizationofdroplet/ aerosolsize.

Canbeusedinparallelwithhuman studiesoroutbreaks.

Cangaininformationonpossible aerosolspread.

Inanosocomialsettingaerosol-generating procedurescanplayamajorrole.

FrequentlyonlydetectionbyPCR. Directhuman-to-humantransmissionisnot studied(circumstantial).

Technicalissues(proceduremayaffectvirus viability)orfalseinterpretation.

[34,37,57,91,103,133] Airtracerstudies _Monitoringairflowpatterncan

indicatepossibleairborne transmission(ifnotdone retrospectively). Visualizeairstream

Usuallyperformedretrospectivelyandnotduring outbreaks [134,135] Computational Modeling/Simulation Describestransmissionina greatercontext.

Canaccountforheterogeneityof transmissionwithinapopulation. Humanmannequinscanbeused asreplacementforhumans

Theoretical(formathematicalmodeling). Artificialsetting.

Parainfluenza

(PIV)

and

human

metapneumovirus

(HMPV)

Thereisasubstantiallackof(experimental)evidenceon

the transmissionroutes of PIV (types1–4) and HMPV.

For both viruses, contact and droplet transmission are

commonly accepted transmission routes [23–25].

How-ever, only virus stability on various surfaces has been

investigated so farand it hasbeen shown thatPIV and

HMPV are stable on non-absorptive surfaces and can

barely berecovered fromabsorptivesurfaces[26–30].

Respiratory

syncytial

virus

(RSV)

TransmissionofRSVamonghumansisthoughttooccur

viadropletsandfomites[1,7].Inthe1980sthreepotential

transmission routes of RSVwere studied in humansby

dividing infected infants and healthy volunteers into

three groups, representing: Firstly, all transmission

routes, secondly, transmission via fomites and finally,

airbornetransmissionbyallowingthevolunteerstohave

either,firstly, directcontactwithinfants(cuddlers),

sec-ondly, touching potential fomites (touchers) or finally,

sittingnexttotheinfant(sitters).Volunteersinthegroup

of thecuddlersandtouchersbut notthesitters became

infected,suggestingthatdirectcontactanddroplet

trans-missionweretheprobableroutesforefficientinfectionof

thevolunteersandthattransmissionviaaerosolswasless

likely[31].Anotherstudyonthetransmissionviafomites

showedthatRSVcouldberecoveredfromcountertopsfor

severalhours, butonly forseveralminutesfrom

absorp-tivesurfacessuchaspapertissueandskin[32].Lateron,

inthelate1990s,Aintablianetal.detectedRSVRNAin

theairupto7mawayfromapatient’shead[33].Inspite

ofthat,sincevirusinfectivitycouldnotbedemonstrated,

potentialairbornetransmissionof RSVhasbeen

consid-ered negligibleandtransmissionofRSVwas thoughtto

occur mainly throughcontact and droplet transmission.

However, inarecentstudyauthors wereableto collect

aerosols thatcontained viable virusfromtheair around

RSVinfected children[34].Althoughthedetectionof

viable virusintheairisbyitselfnotenoughto confirm

aerosol transmission,thegeneralpresumption thatRSV

exclusivelytransmitsviadropletsshouldbereconsidered

and exploredfurther.

Rhinovirus

Extensive human rhinovirus transmission experiments

havenotledtoawidely-acceptedviewonthe

transmis-sion route [35–37,38,39,40]. Inhalation of aerosols

(0.2–3mm) resulted in efficient rhinovirus infection

[41],butlittletonoinfectiousrhinoviruscouldbe

dem-onstrated in sneezes and coughs as detected by virus

titration [42]. Rhinoviruscan surviveon stainless steel,

plasticandskinforacoupleofhours[42,43].Additionally,

virus was detected in saliva, occasionally onhands and

could be recovered from the skin of recipients after

rubbing either a contaminated fomite or hand [42,44].

When rubbing of fomites was followed by

auto-inoculation this resulted in infection of the volunteers

[35].In athree-dayrhinovirusexperiment withhealthy

volunteersdifferentexposuremodeswereusedto

inves-tigate the rhinovirustransmission route: Firsrtly,

small-particleexposure(separatingdonorandrecipientsbywire

mesh), secondly, large particle exposure (encouraging

contact, coughing and sneezing while wearing gloves)

and finally, direct contact exposure (hand contact

fol-lowed byself-inoculation).Fromtheresults it was

con-cluded that direct contact was the main transmission

route [36]. Furthermore, rhinovirus RNA was detected

in offices by air sampling studies and subsequent

sequencing resulted in a matched air-mucus pair [37].

Inaminiaturefieldtrail,experimentallyinfecteddonors

with severecolds participated in acardgame with

sus-ceptible recipients for 12hours [38,39,40]. A

restraining device,preventingtouchingof theheadand

face, was used in the aerosol condition and heavily

contaminatedcardsandexaggeratedhand-to-face

move-ments in the fomite condition. In these experiments

aerosoltransmissionwas suggested[40].

In general, transmissionratesand exposure time varied

betweenstudies, which maycontributeto thedifferent

routesoftransmissionthatwereobserved.Therefore,the

donor-hours of exposure was determined using donors

with severerhinovirusinfections. At200hoursof

expo-sure todonors,transmissionhadoccurredto 50%of the

susceptible recipients, though the transmission route

itselfwasnotinvestigated[38].

Influenza

A

virus

Duetotheseverityoftheyearlyinfluenzaepidemicsand

the potential of zoonotic influenza A viruses to cause

severeoutbreaks,therehavebeenmanystudieson

influ-enzaAvirustransmissionamonghumans.Differentkinds

ofstudies,suchasairsamplingandinterventionstudies,

aswellashumanchallengestudieshavebeenconducted.

In addition, transmission events have been described

extensively after outbreaks in aircrafts, households and

hospital settings. However, until today, results on the

relativeimportanceofdropletandaerosoltransmissionof

influenza virusesstayinconclusiveand hence,thereare

manyreviewsintensivelydiscussingthisissue[10,45–50].

Alreadyinthemid-1900shumanchallengemodelswere

used to assess the transmission route of influenza virus

[51,52–54].Itwasshownthatillnessoutcomeis

depen-dentontheinoculationrouteandtendsto bemilderin

intranasally infected volunteersin comparison to

inocu-lation through inhalation [52,53]. Furthermore, illness

seemed to be milderin experimentally infected

volun-teersthaninnaturallyinfectedindividuals[51].

Increas-ing numbers of studies focused on the detection and

quantification of influenzaviruses containedin droplets

and aerosols expelled into the air through breathing,

[9,55–56,57,58–61].InfluenzavirusRNAwasdetectedin

theairupto3.7mawayfrompatientswiththemajorityof

viralRNAcontainedinaerosols(<5mm)[59].The

pres-enceofvirusinaerosolscouldindicatepotentialairborne

transmission,althoughmanystudiesonly quantifiedthe

amountofviralRNA[55,57,61].Afewstudiesquantified

viable virus, although this was only recovered from a

minorityofsamples[9,58,59].

Coronavirus

In humans, alpha (229E and NL63) and beta

corona-viruses(OC43,HKU1,SARSandMERS)areassociated

withrespiratorydisease[62,63].Alphacoronaviruseshave

ahighattack rateearlyin lifeandspread rapidlyduring

outbreaks,indicatingefficienthumantohuman

transmis-sion[63].Furthermore,samplesobtainedfromstaffand

patientsof aneonatal and pediatricintensive careunit

showedahighincidenceofhumancoronaviruses

HCoV-229E and HCoV-OC43, suggesting staff-to-patient and

patient-to-stafftransmission[64].Unfortunately,thereis

verylittledatatocorroborateontheHCoV-229E,

HCoV-NL63 and HCoV-OC43 transmission routes.

HCoV-OC43,HCoV-229EandHCoV-NL63infectivitywaslost

between 0 and 72hours on non-absorptive surfaces,

althoughit cansurviveseveral days in medium orPBS

[65–67]. Aerosolized HCoV-229E had a half-life of

67hours in a rotating steel drum (at 20C and 50%

relative humidity) [68]. SARS-CoV and MERS-CoV

appearedto have anunusualcapacityto surviveondry

surfacesas comparedto HCoV-229E,HCoV-OC43,and

HCoV-NL63[69,70].

The SARS outbreak was primarilylinkedto healthcare

settings,with49%ofthecaseslinkedtohospitals[71],

mostprobably caused byaerosol-generating procedures

on severely ill patients[72,73]. Aerosol-generating

pro-cedureslike intubation, theuse of continuous

positive-pressureventilationanddrugdeliveryvianebulizersare

likelyto produce‘fine infectiousdroplets’, whichtravel

further than droplets from coughs [74]. Additionally,

superspreading events contributed to the dispersion of

theSARS outbreak[73,75–77],particularlyin theHotel

Metropole and the Prince of Wales Hospital in Hong

Kong[76].Moreover,alinkwithtransmissionto

health-care workers was observed when they were in close

proximity(<1m)to an indexpatient,suggestingdirect

contactordroplettransmission[73,78,79].Airsamples

and swabs from frequently touched surfaces in a room

occupied by a SARS patient tested positive by PCR,

althoughnoviruscouldbecultured fromthesesamples

[80].IntheAmoy gardensoutbreak fecaldroplet

trans-missionwassuggested[81,82].

To date, there is little data on the human-to-human

MERS-CoV transmission route [83]. MERS-CoV

remainedstable on non-absorptivefor 8 up to 48hours

and for 10min at 20C and 40% relative humidity in

aerosols[84].MERS-CoVoutbreaksinhumansare,like

those with SARS-CoV, primarily linked to healthcare

settings, with a link to hospitals in 31% of the cases

[71,85,86] and healthcare associated human-to-human

transmissionwasobserved[87,88].Superspreaderevents

were shown to play an important role in nosocomial

outbreaks[71,89].Viruswasisolatedfromenvironmental

samples in hospital rooms, suggesting direct contact or

fomitetransmission.Moreover, theairbornepotentialof

MERSwasinvestigatedbyairsampleanalysis[90,91].

Viral RNA was detected on the inlet of air ventilation

equipment[90]and viruswasisolated fromairsamples

and surfaces from inaccessible areas like the ventilator

exit,implicatingpotential aerosoltransmission[91].

Adenovirus

Human adenoviruses can cause respiratory disease

(mainly type 1–5, 7, 14 and 21) [92,93], conjunctivitis

orinfantilegastroenteritis(type40and41)[94].Theyare

acommoncauseofrespiratoryillnessandpneumonia in

children[95,96],whereasinfectionsaregenerally

asymp-tomatic in adults [92]. Adenoviruses cause nosocomial

outbreaks, especially in pediatric care facilities, where

theyspreadrapidly[95,97,98].Moreover,adenovirustype

4 and 7 are responsible for large outbreaks of acute

respiratory disease, especially in crowded conditions.

This is illustrated by, for example, outbreaks among

militaryrecruitsforwhichairbornespreadwassuggested

[92,94,99]. It is difficult to eliminate adenovirus from

skin,fomites andenvironmental surfaces[100].An

out-breakinamentalcarefacilitywasprobablyenhancedby

spendingthedaymainlyinacrowdedroomwhilesharing

cigarettes and soda cans, suggesting indirect fomite

spread[101].Inastudypublishedin1966,experimental

infectionswithadenovirusadministeredasaerosols(0.3–

2.5mm) or droplets (15mm) to healthy, male inmates,

resultedininfectionofallvolunteers,althoughthe

result-ing illness resembled a natural infection only in the

aerosol group [102]. During a military training period,

increasednumbersofadenovirusinfectionsoccurredover

time, which correlated with an increased detection of

PCR-positive air filters. Additionally, a correlation

between disease and the extent of ventilation was

observed,withmoreventilationresultinginfewerdisease

cases[103].Inamorerecentstudyin militaryrecruits,

positiveviralDNAsamplesweremainly obtainedfrom

pillows,lockersandrifles,althoughadenovirusDNAwas

also detected in air samples. No consistent correlation

betweenincreased positive environmental samples and

diseasewas observed[104].

Discussion

Studiesonthetransmissionroutesof respiratoryviruses

have been performed since the beginning of the 20th

century [105]. Despite this, the relative importance of

transmissionroutesofrespiratoryvirusesisstill unclear,

environment (e.g.temperatureandhumidity),pathogen

and host [5,19].Differences in virusshedding between

individuals can contribute to the transmissibility rate,

especially in the case of superspreaders [75,106]. In

addition,theSARS-CoVoutbreakhighlightedtheimpact

ofaerosol-generatingproceduresontheincreasedriskof

human-to-human transmission [74,107], demonstrating

that for these procedures additional containment

mea-sures arenecessary.

Inter-human transmissionhasbeenstudiedundermany

different (experimental) conditions. A summary of the

advantages and disadvantages of the different study

designs (Table 3) highlights the difficulty of human

transmissionexperiments.Asaconsequence,contrasting

resultshavebeenobtainedformanyviruses.Thisisalso

reflectedinTable2,summarizingtheexperimentaldata

on inter-human transmission. Besides the difficulty of

performing studies under well-controlled conditions,

another key issue is that often (attenuated) laboratory

strains are studied in healthy adults, which does not

reflect the natural circumstances and target group and

henceinfluencetheoutcomeofthestudies.

Respiratoryvirusesareanimportantcauseofnosocomial

infections, especially in children. Therefore, we

con-sulted the guidelines on infection prevention from

National [108], European [109], American [3,110] and

International[111])organizationsfortheirinformationon

transmission routes (Table 2) and associated isolation

guidelines (Figure 1). Unfortunately, terms and

defini-tions of respiratory transmission routes and isolation

guidelinesarenotalwaysusedinauniformway,leaving

room for personal interpretation.But more importantly,

information on the transmission route does not always

reflecttheisolationguidelines(e.g.forPIVand

rhinovi-rus, Figure 1). As a proxy for transmission route, virus

stabilityis oftenreferredto in theguidelines, however,

thiscanonlyimplyaroleforindirectcontacttransmission

butisbynomeansconclusiveonthetransmissionroute.

Inhospitalsettings,preventionofcontacttransmissionis

generally implementedinstandardinfectionprevention

Fig.1 PIV MV MERS-CoV Lim.exp.data No guideline Aerosol Droplet Contact Lim.exp.data No guideline Aerosol Droplet Contact WIP Blue boo k CDC Red book_Up-to-d ate Experimental WIP Blue book CDC Red b ook Up-to-da te Experimenta l WIP Blu e book CDC Red book Up-to-date

Experimental WIP Blue book

CDC Red book Up-to-date

Experimental WIP Blue book

CDC Red book Up-to-date

Exper imental

SARS-CoV Rhinovirus Adenovirus Influenza virus

HMPV RSV HCoV

Current Opinion in Virology

Isolationguidelinesforrespiratoryvirusinfectionsincomparisontoexperimentalevidenceontransmissionroutes.Isolationguidelinesforall respiratoryvirusesdiscussedinthisreviewfromNational(WorkingGroupInfectionPrevention(WIP)[108],fromtheNetherlandsNationalInstitute forPublicHealthandtheEnvironment(RIVM)),European(‘TheBlueBook’[109]),American(‘TheRedBook’[110]andtheCentersforDisease Control(CDC)[3])andInternational(UpToDate[111])organizationsareshownontheX-axis,togetherwiththeexperimentalevidenceon transmissionroutes(Table2).ThecategoriesontheY-axisarethedifferenttransmissionroutes(contact,dropletoraerosol),theabsenceof guidelinesforinfectionprevention(‘Noguideline’),orthelimitedavailabilityofexperimentaldata(‘Lim.exp.data’).Theinformationshownfor influenzavirusreflectstheguidelinesonseasonalinfluenzavirus.Closedsquares(_&):isolationguidelinesfortherespectiverespiratoryvirus. Opensquares(&):guidelinesareonlyforchildren6yearsold.Opencircles():datafromstabilityexperimentsonly.Opentriangles(~):specific CDCguidelinesforHealthcareProfessionals[115](nottheisolationguideline[3]usedinthisreview).

precautions such as stricthand hygiene and cough

eti-quette. It is important to note differences in isolation

guidelinesbetweendifferentorganizations andthelack

ofcorrelationtoscientificdata.Thevariationindescribed

transmission routes and associated isolation guidelines

amongthedifferentorganizationsunderscoresthelackof

convincingdata.

Well-designed human infection studies could be

employed to investigate therole of transmission routes

of respiratory viruses among humans [112].However,

sincehumantransmissionexperimentsarevery

challeng-ing,animaltransmissionmodelscanprovideanattractive

alternativeandshouldbeexploredanddevelopedforall

respiratoryviruses.Insuchexperiments,theinfluenceof

environmentalfactorsontransmissionroutescanalsobe

investigated[113].However,beforeextrapolating

exper-imentally generated data to humans, it is important to

understandthelimitationsofthesemodels,and

appreci-atetheheterogeneityofexperimentalsetupsemployedin

laboratories[114].Furthermore,quantitativedatasuchas

viral load in the air can be obtained by air sampling

methods in various environments, such as hospital

set-tings. Air sampling of viruses is an increasingly used

technologyinanimalandhumanexperiments.However,

whereas most studies rely on the detection of viral

genomecopies,viabilityassayssuch asplaqueassays or

virustitrationshouldbeincludedtogaininformationon

virusinfectivity.

Ultimately,theknowledgegaponinter-human

transmis-sionshouldbefilledbydevelopingandperforming

state-of-the art experiments in a natural setting. Combined

with animal transmission models and air sampling in

different(health care and experimental) settings,these

datashouldresultinathoroughscientificunderstanding

of the inter-human transmission routes of respiratory

viruses. Eventually, this knowledge will help with an

evidence-basedriskassessmentofthedifferent

transmis-sion routes to improve existing infection prevention

strategies.

Acknowledgements

WethankDr.RikdeSwart,Dr.BartHaagmans,Dr.ArnoAndeweg,and Dr.SabrinaSchreinerforhelpfuldiscussions.JKandSHaresupportedby anNWOVIDIgrant(contractnumber91715372),andMS,RFandSHby NIAID/NIHcontractHHSN272201400008C.PFreceivesfundingfromthe EUFP7projectPREPARE(grantnumber602525).Thesponsorshadno roleinthecollection,analysisandinterpretationofdata,inthewritingof thereport,andinthedecisiontosubmitthearticleforpublication.

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