Clinical relevance of rhinovirus infections among adult hospitalized patients

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www .e l s e v i e r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Clinical

relevance

of

rhinovirus

infections

among

adult

hospitalized

patients

Alberto

Fica

a,∗

_,

_Jeannette

_Dabanch

a

_,

_Winston

_Andrade

b

_,

_Patricia

_Bustos

a

_,

_Ita

_Carvajal

c

_,

Carolina

Ceroni

c

_,

_Vjera

_Triantaﬁlo

c

_,

_Marcelo

_Castro

d

_,

_Rodrigo

_Fasce

b

a_Servicio_de_{Infectología,}_Hospital_Militar_de_Santiago,_Santiago,_Chile

b_Sección_Virus_{Respiratorios}_y_{Exantemáticos,}_{SubDepartamento}_de_Enfermedades_Virales,_Instituto_de_Salud_Pública_de_Chile,_Santiago,

Chile

c_Departamento_Laboratorio_Clínico,_Hospital_Militar_de_Santiago,_Santiago,_Chile d_Servicio_de_{Imagenología,}_Hospital_Militar_de_Santiago,_Santiago,_Chile

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received10July2014

Accepted3October2014

Availableonline15December2014

Keywords:

Rhinovirus

Respiratorytractinfections

Viralpneumonia

Reversetranscriptasepolymerase

chainreaction

Adult

Hospitalization

a

b

s

t

r

a

c

t

Humanrhinovirus(HRV)isanemergingviralpathogen.

Aim:Tocharacterizeagroupofpatientsadmittedduetoinfectionbythisagentinageneral

hospitalinChile.

Methods:CaseswereidentiﬁedbyRT-PCRfor1yearthroughactivesurveillanceofpatients

admittedwithsevererespiratoryillness.Diagnosiswasnotavailableduring

hospitaliza-tion.Thirty-twocaseswereidentiﬁed,90%were≥60yearsoldorhadco-morbidconditions.

Humanrhinovirus-relatedadmissionsrepresented23.7%ofhospitalizationduetosevere

acuterespiratoryinfectionsamongadultsandrankedsecondtoinﬂuenza(37.8%).Patients

presentedwithpneumonia(68.8%),decompensatedchroniclungconditions(21.9%),heart

failureorinﬂuenza-likeillness(6.3%each).Admissiontointensiveorintermediatecareunits

wasrequiredby31.2%andin-hospitalmortalityreached12.5%.ACURB-65score≥3was

signiﬁcantlyassociatedtoin-hospitalmortality(p<0.05).Mostpatientsreceivedantibiotics

(90%).

Conclusions:Humanrhinovirusinfectionsinelderlypatientswithco-morbidconditionsare

associatedwithhospitalizations,requiringcriticalorsemi-criticalantibioticsuse.Ahigh

CURB-65scorewasassociatedtoin-hospitalmortality.

Introduction

Upper and lower viral respiratory infections represent an

important global health burden for adult patients due to

∗ _{Corresponding}_author_at:_Servicio_de_{Infectología,}_Departamento_de_Medicina,_Hospital_Militar_de_Santiago,_Av._Alcalde_Fernando_Castillo

Velasco9100,LaReina,Santiago,Chile.

E-mailaddresses:albertoﬁca@gmail.com,aﬁca@hms.cl(A.Fica).

theirmorbidity,absenteeism,outpatientmedicalvisits,

hos-pitalizations, mortality, and inappropriate antibioticuse.1–9

Human rhinovirusisoneoftheetiological agentsinvolved

inacuterespiratoryinfectionsandhasbeenassociatedwith

crisisofasthma,exacerbatedchronicbronchitis,bronchiolitis

http://dx.doi.org/10.1016/j.bjid.2014.10.003

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andpneumoniainchildren.10 _Nonetheless,_its_role_in_adult

patientsisless accepteddespiteprogressiveevidenceofits

importanceinoutpatientclinicalsettings4,11,12_or_in

hospital-izedorimmunosuppressedpatients.13,14 _This_unrecognized

roleischangingaftertherecentavailabilityofmolecular

diag-nostictestingthathasenhancedourknowledgeonthisviral

agent.2,3,15,16

Inthisworkwereportseasonality,clinicalfeaturesand

out-comesofadultpatientshospitalizedduring1yearforsevere

respiratory acuteinfection secondary tohumanrhinovirus

infectioninageneralhospital.

Patients

and

methods

Studydesignandsetting

TheHospitalMilitarofSantiagoisoneofthesixactive

surveil-lancecentersforacutesevererespiratoryinfectionsrequiring

admission,asystemlaunchedinJuly2011bythePan

Ameri-canHealthOrganization(PAHO)andtheChileanMinistryof

Healthafterthe inﬂuenzaA(H1N1)pandemic torecognize

newrespiratoryviralthreats.Itattendsactiveandretired

mili-tarypersonnelandtheirrelatives.Theaverageageofadmitted

patientsis76years.

Thiswasaprospectivedescriptivestudythatincludedall

adultpatients≥18yearsadmittedduetosevereacute

respi-ratoryinfection (SARI) associatedwithaconﬁrmed human

rhinovirusdetectionobtainedfromrespiratorysamples

dur-ingtheyear2012(seebelow).SARIwasdeﬁnedbythepresence

of fever and respiratory symptoms associated either with

tachypnea(≥30min–1₎_or_a_low_digital_pulse_oxymetry_(<90%)

atroomair.17Allpatientsfulﬁllingthesecriteriawerereported

on-line to acentralized surveillance system and

nasopha-ryngeal swab samples are assessed, at local level, for the

presenceofinﬂuenzaA-B,respiratorysyncytialvirus,

parain-ﬂuenza1,2,and3,adenovirusandhumanmetapneumovirus

byindirectimmunoﬂuorescenceusingcommercialreagents.

InﬂuenzaAorBpositivesamplesaswellasallnegative

sam-pleswerereferredtoareferencelaboratory(InstitutodeSalud

Pública:ISP)forfurtheranalysesusingmoleculartechniques.

Inﬂuenza virus was tested and subtyped with the

molec-ular kit FluRUO-01, and non-inﬂuenza respiratory viruses

using kit KK0812, provided by the CDC. The latter allows

detectionbyPCRofadenovirus,respiratory syncytialvirus,

humanmetapneumovirus,parainﬂuenza1,2,and3,aswell

asrhinovirus(HRV),notincludedinthe initial

immunoﬂu-orescence panel.18 _For _nucleic _acid _extraction_we _used_the

automatedEasyMagsystemfromBiomerieux.Ampliﬁcation

wasperformed usingAgPath –ID kitsfrom Ambion and a

realtimethermocycler(AppliedBiosystems).Theresultsof

apositiveHRVdetectionwerenotavailableduring

hospital-ization.

Cases were analyzed according to demographic

infor-mation, seasonality, comorbidities, clinical presentation

includingchestX-ray,PaFiO2,andoutcomeatthemomentof

discharge.Sometopicswere collectedprospectively

(demo-graphics, comorbidities, vaccine history, tobacco smoking,

place of hospitalization) and other retrospectively (clinical

presentationandsymptoms,laboratory data,management,

severityscoreandoutcome).Respiratoryfailurewasdeﬁned

asaPaFiO2<300andgraded.19,20

Statisticalanalysis

Resultsare shown isa descriptive manner.Factors

associ-atedtomortalitywereidentiﬁedcalculatingoddsratios(OR)

withtheirrespectiveconﬁdenceintervals.Twoseverityscores

(CURB-65andCAP-PIRO)werecalculatedandcomparedto

pre-dictin-hospitalmortality.21,22

Results

Thirty-two conﬁrmed patients, each with a single severe

episodeofHRVinfectionwere admittedduring2012.Cases

presentedaseasonalpatternalongtheyearbutweredetected

continuouslyduring8monthsfromMarchtoOctober

(sum-mertospringinsouthernhemisphere)(Fig.1).Of135adult

patientsadmittedwithSARIduringyear2012withaconﬁrmed

viraletiology,HRVrankedsecondonlytoinﬂuenzainfections

(23.7%versus37.8%forinﬂuenza).

Meanage was elevated(79.5 years)and 90% were older

than 60 years (Table 1). Onlytwo patientslived in a

long-termcarefacility,butnear20%werebedridden.Over50%of

thepatientshadtwoormorecomorbidities,mainlychronic

pulmonary conditions, heart disease,diabetes mellitus, or

neurologic diseases.Cancer, morbidobesity, or kidney

dis-easewerenotcommon.Nocasewasassociatedwithchronic

liverdiseaseand onlyonepatientwasimmunosuppressed.

Previoustobaccosmokingaffectednearathirdofthis

popu-lationandcurrentsmokingwasstilladmittedbytwooutof

32 patients.Almostone-third ofpatientswithchroniclung

diseaseweredomiciliaryoxygenusers(Table1).

Clinicalmanifestations

Most patients were admitted under the diagnosis of

community-acquired pneumonia, followed by chronic

8 6 Frequency 4 2 0 1 2 3 4 5 6 7 Month 8 9 10 11 12

Fig.1–Monthlydistributionof32patientsadmittedwith humanrhinovirus-associatedsevereacuterespiratory infectionduringoneyearatageneralhospitalinChile.

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Table1–Featuresof32patientsadmittedwithSARI associatedwithhumanrhinovirus.

Variable Results

Ageinyears,mean(range) 79.5(49–95) Age≥60years,n(%) 31(90%) Female,n(%) 17(53.1%) Bedridden,n(%) 6(18.8%) Long-termcarefacility,n(%) 2(6.3%) Previoustobaccosmoking,n(%) 9(28.1%) Currenttobaccosmoking,n(%) 2(6.3%) Asthma/COPD/lungﬁbrosis,n(%) 17(53.1%) Domiciliaryoxygenuser,n(%) 5(15.6%) Cerebrovasculardisease/dementian(%) 10(31.3%) Diabetesmellitusn(%) 10(31.3%) Heartdiseasen(%) 11(34.4%) Kidneydiseasen(%) 3(9.4%) Morbidobesityn(%) 2(6.3%) Malignancies,n(%) 3(9.4%) Immunosuppresion,n(%) 1(3.1%) Anycomorbidity,n(%) 30(93.8%) Onecomorbidityn(%) 12(37.5%) ≥2comorbidities,n(%) 18(56.3%)

obstructive pulmonary disease (COPD) exacerbations or

other conditions (Table 2). Symptoms in descending order

offrequency were coughand sputum, fever in nearlyhalf

ofcases, and confusion/disorientation(Table 2). The latter

manifestationwasstronglyassociatedwithprevious

neuro-logicaldisease.Sevenoutof10patientswithaneurological

condition presented disorientation or confusion compared

withtwo out of22 withoutthis comorbidity (OR23.2;95%

CI 3.2–169, p<0.01). Classic upper respiratory symptoms

such as headache,rhinorrhea, and odynophagia were less

frequent(<25%).Nopatientspresenteddiarrhea,andonlytwo

developednauseasorabdominalpain.Bronchialobstructive

signswerecommon(∼60%),aﬁndingassociatedwithchronic

Table2–Clinicalmanifestationsamong32patients admittedwithhumanrhinovirus-associatedsevere respiratoryinfectionduringyear2012.

Variable,n(%) Results

Clinicalpresentation

Community-acquiredpneumonia 22(68.8%) COPDexacerbation 5(15.6%) Decompensatedlungﬁbrosis 2(6.3%) Decompensatedchronicheartfailure 2(6.3%) Inﬂuenza-likeillness 1(3.1%) CURB-65score <2 14(43.8) ≥2 18(56.3%) Cough 32(100%) Sputum 26(81.3%) Fever 14(43.8%) Confusion/disorientation 9(28.1%) Rhinorrhea 7(21.9%) Myalgia 4(12.5%) Odynophagia 2(6.3%) Headache 2(6.3%) Nausea/abdominalpain 2(6.3%) Hypotension 7(21.9%)

Bronchialobstructivesigns 19(59.4%)

Table3–Medicalconsultationsandphysicaland laboratoryparametersatadmissionamong32patients withhumanrhinovirus-associatedrespiratoryinfection duringyear2012.

Variable Results

Consultationsbeforeadmission

0–1 29(90.6%)

>1 3(9.4%)

Dayswithsymptomsbefore hospitalizationmean(range)

3(1–21) Temperature◦C,mean(range) 37.2(36.0–40.0) Temperature<37◦C,n(%) 16(50%) Respiratoryrate/min,mean(range) 27.1(18–40) Respiratoryrate≥30/min,n(%) 13(40.6%) Heartrate/min,mean(range) 98.3(55–131)

O2pulsedigitaloxymetry%,mean(range) 85.1(67–95)

O2Saturation<90%,n(%) 25(78.1%)

PaO2atadmissionmmHg,mean(range) 58.8(39.5–78.3)

PaO2<60mmHg,n(%) 16(50.0%)

PaFiO2,mean(range) 239.4(78–367)

PaFiO2<300,n(%) 22(78.6%)*

PaFiO2200–299,n(%) 15(53.6%)*

PaFiO2100–199,n(%) 6(21.4%)*

PaFiO2<100,n(%) 1(3.6%)*

Bloodleukocytecount/␮L,mean(range) 12012(4800–27200)

Leucocytosis>12,000/␮L 13(40.6%)

Leucocytosis>15,000/␮L 8(25.0%)

Bloodpolymorphonuclearcount/␮L,mean

(range)

9984(3860–25910)

Neutrophilia>8000/␮L 19(59.4%)

Neutrophilia>12,000/␮L 12(37.5%)

Lymphocytecount/␮L,mean(range) 1225.8(180–7750)

Lymphocytecount<1000/␮L,n(%) 19(59.4%)

Erythrocytesedimentationratemm/h,

mean(range)

42.6(2–106)

PlasmasodiumconcentrationmEq/L,

mean(range)

138.4(120–150)

Hyponatremia(plasmasodium<135mEq/L) 4(12.5%)

LDHinplasmaU/Lmean(range) 232.1(117–468)

Bloodureanitrogenmg/dLmean(range) 25(7–77)

C-reactiveproteinmg/L,mean(range) 122.8(7.2–494)

C-reactiveprotein≥100mg/L,n(%) 15(46.9%)

∗ _of₂₈_patients_with_available_information.

lung disease (OR20.7;95% CI 3.2–133,p<0.01), or previous

or current tobacco consumption (OR 24.4; 95% CI 1.3–469,

p<0.01).Hypotensionwaspresentinoneﬁfthofpatientsat

admission.

Symptomsevolvedbetweenoneand21daysbefore

admis-sion (average ﬁve, mean three days) and 90% presented

symptoms for less than seven days before hospitalization.

Nearlytwo-thirdsofthesepatientswerehospitalizedatﬁrst

consultation(Table2).

SomephysicalandlaboratoryﬁndingsareshowninTable3.

As part of the severe respiratory infection deﬁnition used

in thiswork, mostpatientspresentedwithtachypnea, low

O2 saturation,or respiratory failure(PaFiO2<300;25% with

a PaFiO2<200) but only half had fever. Leukocytosis,

neu-trophilia,elevatederythrocytesedimentationrate,plasmatic

LDHorBUNwerenotremarkableandhyponatremiawas

anec-dotal(Table3).OfinterestisthatlymphopeniaandC-reactive

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Table4–Managementandoutcomesamong32patients withhumanrhinovirus-associatedrespiratoryinfection duringyear2012. Variable Results Placeofhospitalization,n(%) Generalward 22(68.8%) Intermediatecare 9(28.1%) Intensivecare 1(3.1%) Ventilatorysupport

Non-invasivemechanicalventilation,n(%) 6(18.8%)

Treatment,n(%) Systemiccorticoids 19(59.4%) Inhaledcorticoids 11(34.4%) Antibiotics 29(90.6%) Antivirals(oseltamivir) 21(65.6%) Hospitallength

Mean(range)indays 11.8(2–49) ≥7days,n(%) 20(62.5%) Deceased,n(%) 4(12.5%)

Nootherviralagentwasdetectedinanyofthesepatients byRT-PCR.Bloodculturesweretakeninninepatients(28.1%)

withoutdemonstratingpathogenicmicroorganismsandtwo

cases presented urinary pneumococcal antigen detection

(6.2%),oneofthemwithhypotensionand aCURB-65score

of4.

Imagingstudies

Interstitial(n=8;25%),consolidated(n=6;18.8%),andmixed (n=8;25%)patternswere observedinchest X-rayand one-thirdhadnormalimaging(n=10;31.3%).Pleuraleffusionwas alsorecorded(n=8;25%).

Managementandoutcome

Ten patients (31.2%) were transferred to an intermediate

careunit(n=9)orcoronaryunit(n=1)(Table4).Sixpatients

requirednon-invasivemechanicalsupport.Inaddition, one

patientevolved withacutelung edemasecondary toheart

failure.Antibioticandoseltamivirusewerefrequent(Table4).

Fourpatientsdied(in-hospitalmortality12.5%).Meanlength

ofstay(LOS)was8.3days(range1to24)andover60%remained

inthehospitalmorethanaweek(Table4).

Severityscoresandriskfactorsformortality

ACURB-65score<2pointswaspresentin43.7%ofthe

pop-ulation(n=14), avalueconsidered ascutoffforambulatory

management.Forthewholegroup,theonlyfactorassociated

tomortalitywasaCURB65score≥3(OR23.4;95%CI1.11–489,

p<0.05bybilateralFisher’stest)butwasnotsigniﬁcantamong

the22patients withpneumonia.Thearea underthecurve

(AUC)obtainedbytheReceiverOperatorCurve(ROC)to

pre-dictin-hospitalmortalitybytheCURB-65scorewas0.799(95%

CI0.650–0.948)(Fig.2A)and0.813(95%CI0.626–0.999)forthe

subgroupwithpneumonia,avaluethatwasnotsigniﬁcantly

different(Fig.2B).Using acutoffscore≥3pointstopredict

mortality,sensitivitywas100%andspeciﬁcity71.4%.Acutoff

scoreforthesubgroupwithpneumoniawasnotpossibleto

determinate duetothesmall numberofpatientsdeceased

withthis condition(n=2).TheAUCforthe CAP-PIROscore

was0.509demonstratingfutilitytopredictmortality(Fig.2A).

Deceasedpatients were notassociatedwith pneumococcal

infection andtwoofthemdidnothavepneumoniaon the

chestX-ray.

Discussion

HRVhasbeenprogressivelyrecognizedasoneoftheleading

causesofacuterespiratoryinfectionsamongadultspatientsin

ambulatory11,12,23,24_or_in-patient_settings.3,25–27_Its_frequency

may surpass other viral agents as a cause of respiratory

infections.12_Admissions_by_HRV_infection_are_associated_with

asthmaticcrisis,chronicmedicalconditions,malignancies,or

immunosuppression,11,28–32_and_occurs_during_the_inﬂuenza

season as beyond this timeframe.16 _In _addition, _HRV _has

beenassociatedtooutbreakswithanincreasedcase-fatality

ratio.33,34_The_spectrum_of_clinical_illness_in_adults_includes

asthma, exacerbations of chronic pulmonary obstructive,

heartfailureandpneumonia.29

DetaileddescriptionsofadultpatientsaffectedbyHRVare

scarceas theexpansion ofmoleculartechniquesis recent,

besides case-mixing with other etiologies or bias toward

severelyillpatients.3,13,16,23,25,27,35 _In_this _work_we_aimed_to

characterizeseasonalityandclinicalfeaturesofadultpatients

admittedbyHRVinfectionduringoneyearofactive

surveil-lance.Severalﬁndingsinthiscaseseriesdeservecomments.

First, HRV infections had a prolonged seasonality that

encompassed three quarters of the year, and represented

nearlyaquarterofadulthospitalizationsbySARIofaknown

viral cause, underscoring its medical and pathogenic

rel-evance. Only inﬂuenza remained more important in our

prospective study,as described previously.36 _Some _authors

have shown that HRV infections have the most prolonged

seasonality among viral causes of pneumonia in adults,

surpassing inﬂuenza, adenovirus, coronavirus, respiratory

syncytial virus, or parainﬂuenza.3 _Second, _as _indicated _by

others, HRV-associated hospitalization affected elderly and

frailpatientswithchroniccomorbiditiesandwithapastor

currenthistoryofsmoking.12,33,35_Third,_admissions_were

rel-evantbecausetheywereprolonged,requiredintermediateor

intensivecareresourcesinnearly30%ofcases,andhadacase

fatalityrateover10%.Thisproﬁlehasbeendescribedinthe

lit-eratureandunderscorestherelevanceofthisviralagent.3,33,34

Asawayofcomparison,mortalitybyseasonalorpandemic

inﬂuenza A is similar.3,5 _The _proportion _of _HRV _infected

patients thatrequires hospitalization (∼2–10%) dependson

the populationstudiedandintensity ofsearch.3,13,25,27,35 _In

addition,HRVismorefrequentlyencounteredinsymptomatic

adultpatientsthanincontrolsdemonstratingitspathogenic

relevance.1,2,26_All_of_these_facts_indicate_that_HRV_infections

cannolongerbeconsideredaminornuisanceandits

diag-nosticsearchisjustiﬁed.

Fourth, clinical manifestations were variable and

mod-ulated by underlying conditions such as cardiac,

neuro-logic, or pulmonary diseases, and tobacco smoking. Some

(5)

1.0 0.8 0.6 CURB 65 CAP PIRO CURB-65 pneumonia subgroup Sensitivity 0.4 0.2 0.0 0.0 0.2 0.4 0.6 1 - Specificity 0.8 1.0 1.0 0.8 0.6 Sensitivity 0.4 0.2 0.0 0.0 0.2 0.4 0.6 1 - Specificity 0.8 1.0

A

B

Fig.2–(A)ROCanalysisforCURB-65andCAP-PIROscoretopredictin-hospitalmortality.Allpatientswereincluded.(B)ROC analysisforthesubgroupwithpneumonia.

decompensated chroniccondition. Fever was notuniversal

and,if present,wasoflow grade;upperrespiratory illness

wasnotahallmark.Fifth,tothebestofourknowledge,

mor-talityriskfactorshavenotbeendescribedforHRVinfection

inadults,3,28,30,33,34 _although_a_high _severity_score_has_been

linkedtopneumococcalco-infection.3 _The_higher_mortality

registeredforthosewithaCURB65≥3isinlinewiththe

orig-inalreportofthisscoringsystem22_and_provides_evidence_that

itisasuitableapproachforHRVinfectionsevenwhenpatients

donothavepneumonia.Infact,theAUCoftheCURB-65ROC

analysisforthewholegroupandthepneumoniasubgroupdid

notrevealdifferences,suggestingthatthedistinctionbetween

patientswithand withoutrespiratory inﬁltratesisperhaps

notnecessaryinpatientsaffectedbyHRVinfections.Onthe

otherside,despitetheirseverityatadmission,nearly40%of

patientshadalowscore(<2)ofCURB-65,andthespeciﬁcityof

ahigherscorewaslowtopredictmortality(∼70%)indicating

alimitedutilityasasurrogatemarkerofrisk.CAP-PIROscore

demonstratedtobeuselessnessandnocutoffcalculationwas

attempted.ThelimitationsobservedwithCURB-65to

recog-nizepatientsinneedofadmissionwereprobablyrelatedtothe

infrequentpresenceofhypotensioninmostviralrespiratory

illnessandtothefactthatalowdigitalpulseoxymetryisnot

consideredforriskevaluation.Inthissense,thecurrent

crite-riaadoptedbytheChileanMinistryofHealthtogetherwith

thePanAmericanHealthOrganizationappearstobebetter

adaptedtorecognizeseverelyillpatientsaffectedby

respira-toryviraldiseases.17

HRVinfectionappearsassociatedtoawidespectrumof

dis-easeandisabletorapidlydecompensatevulnerablepatients

asreﬂectedbytherelativelyshortsymptomaticperiodbefore

admissionandthehighrateofhospitalizationattheﬁrst

med-icalvisit.

There are probably few distinctive clinical differences

between viral and bacterial pneumonia in adults. Lobar

condensation,leukocytosisandhyponatremiaaremore

fre-quently described in patients with bacterial disease, but

overlappingiscommon.25,37_In_accordance_with_these_reports,

ourpatientswere characterizedbyminorchanges inthese

parameters and witha lowfrequencyofconsolidation. On

the other hand, neutrophilia, lymphopenia and elevated

C-reactive protein (≥100mg/L) were frequent ﬁndings in

this work.Neutrophiliahasbeencommonlyfoundinadult

patientshospitalizedwithdifferentagentsofviralpneumonia

butlessfrequentlyininﬂuenzacases3_;_lymphopenia_has_been

describedinpatientswithpandemicA(H1N1)inﬂuenza,SARS

andmetapneumovirusinfection,5,38–40_and_CRP_is_increased_in

afractionofpatientsadmittedwithinﬂuenza.5

Unfortunately,theresultsofviraldiagnoseswerenot

avail-able at the time of the study and could notbe useful for

de-escalation of antibiotic therapy or to suspend antiviral

inﬂuenza therapy. Knowing of a speciﬁcviral etiology has

been on one hand associated to a reduction in antibiotic

consumption inpatients with respiratory viral illness, but

on theotherhand,the presenceofabnormallung ﬁndings

has prompted antibioticcontinuation despitea recognized

viral infection.9 _Moreover, _the _probability _of _{viral-bacterial}

co-infectionisanothermodulatingfactorthatcaninﬂuence

antibiotic therapeutic decisions. Bacterial-viral co-infection

ratesarevariableamongpatientswithrespiratoryinfections

(range4–17%)3,25,27_and_before_a_full_array_of_rapid

diagnos-tictechniquesforetiologicalagentsareavailable,15_it_would

bedifﬁculttocurtailorde-escalateantibioticconsumption.

Animperativeeffortonmedicaleducationwillbenecessary

becauseaviraldiagnosis,evenwithnormalchestX-ray,isnot

consideredbyclinicianstobesufﬁcienttostopantibiotics.7

EmergenceofantibioticresistanceandClostridiumdifﬁcileare

onthevergeofthisdiagnosticshortcoming.

Our work has somelimitations that require comments.

HRV can be detected some weeks after infection and can

beampliﬁedfromrespiratorysamplesgeneratinga

subopti-malspeciﬁcity.18,41 _However,_these_are _universal_limitations

present acrossall studies,and donotinvalidatethe

scien-tiﬁcevidenceshowingsimilarresultsindifferentscenarios.

In addition, a systematic search for respiratory bacterial

pathogens was notcarriedout inourstudy,making

possi-ble thatpartoftheresultsbeexplainedbyco-infectionsas

(6)

factorisrathersecondarybecausesomepatientshadnegative

bloodculturesandthereportedfrequencyofviral-bacterial

co-infectionisnothighintheliterature(<20%).36_On_the_other

hand,noviral-viralco-infectioncouldbedemonstratedinour

patientsmaking our ﬁndings unbiasedbythe contribution

ofotherviralrespiratoryagents.Thefrequencyofviral-viral

co-infectionappearstobelowinadultswithrespiratory

infec-tions(<10%).36_Finally,_the_results_of_this_work_were_derived

fromstringentcriteriaforseverityandtheydonotnecessarily

representcaseswithmilddisease.

Conclusions

ThisworkprovidesfurtherevidencethatHRVisanimportant

respiratorypathogenamongpatientsadmittedwithSARInot

onlyduetoitsrelativelyhighfrequencybutalsobecauseHRV

infectionsareabletotumblevulnerableadultpatients

asso-ciatedtoawidespectrumofillness,usingupintermediate

orcriticalcareresources,andsometimesassociatedwith

pro-longedhospitalizationordeath.Inaddition,theabsenceofa

timelydiagnosisforHRVandotherviralrespiratorypathogens

iscontributingtoaninappropriateantibioticuse.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

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