The typical presentation of an atypical pathogen during an outbreak of Legionnaires’ disease in Vila Franca de Xira, Portugal, 2014

www.revportpneumol.org

ORIGINAL

ARTICLE

The

typical

presentation

of

an

atypical

pathogen

during

an

outbreak

of

Legionnaires’

disease

in

Vila

Franca

de

Xira,

Portugal,

2014

A.

Dias

_,

_A.

_Cysneiros

_,

_F.T.

_Lopes

_,

_B.

_von

_Amann

_,

_C.

_Costa

_,

_P.

_Dionísio

_,

J.

Carvalho

_,

_V.

_Durão

_,

_G.

_Carvalho

_,

_F.

_Paula

_,

_M.

_Serrado

_,

_B.

_Nunes

_,

T.

Marques

_,

_F.

_Froes

_,

_C.

_Bárbara

a_{ChestDepartment,CentroHospitalarLisboaNorte,Lisboa,Portugal}

b_{InternalMedicineDepartment,HospitaldeCascaisDr.JosédeAlmeida,Cascais,Portugal} c_{IntensiveCareUnit,ChestDepartment,CentroHospitalarLisboaNorte,Lisboa,Portugal} d_{EpidemiologyDepartment,InstitutoNacionaldeSaúdeDr.RicardoJorge,Lisboa,Portugal}

e_{CenterforResearchinPublicHealth,EscolaNacionaldeSaúdePública,UniversidadeNOVAdeLisboa,Lisboa,Portugal} f_{ConsultantofDirectorate-GeneralofHealth,Portugal}

g_{InstituteofEnvironmentalHealth(ISAMB),FacultyofMedicine,UniversityofLisbon,Lisboa,Portugal}

Received28November2016;accepted23January2017 Availableonline1March2017

KEYWORDS

Legionnaires’disease; Outbreak;

Clinicalpresentation

Abstract

Background: AnoutbreakofLegionellapneumophilaserogroup1,with403caseswasidentified onthe7thNovember2014inVilaFrancadeXira,Portugal.Outbreaksourcewasthewetcooling systemofalocalfactory.HospitalPulidoValentewasoneofthehospitalsreceivingpatients withLegionnaires’disease(LD).

Methods:Wedescribetheclinicalfindingsanddiagnosticmethodsusedamongthe43confirmed orprobablecasesadmittedtoourdepartment.

Results:60.5%weremale,meanagewas56.1_±13.5yearsandtobaccosmokingwasthemost frequentriskfactor(76.7%).Allpatientshadfever,62.8%≥39.5◦C,72.1%hadchillsand myal-gia/arthralgiaand62.8%haddrycough.Extrapulmonarysymptomswerefrequent:confusion andheadacheoccurredin34.9%andgastrointestinalsymptomsin20.9%.

HighC-ReactiveProtein(55.8%≥30mg/dL)andhyponatremia(62.8%)werethelaboratorial abnormalities mostcommonlyfound. Hypoxemiaoccurred in55.8% andhypocapnia in93%. UrinaryAntigenTest(UAT)waspositivein83.7%ofthecases.

Conclusions: Although notspecific, acombination ofrisk factors, symptomsandlaboratory findings can be highlysuggestiveofLD, evenin anoutbreak. This shouldprompt diagnosis

∗_{Correspondingauthors.}

E-mailaddresses:[email protected](A.Dias),fi[email protected](F.Froes).

http://dx.doi.org/10.1016/j.rppnen.2017.01.007

2173-5115/©2017SociedadePortuguesadePneumologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

confirmation.RoutineuseofUATinlessseverecasesofcommunityacquiredpneumoniamight contributetoearlierdiagnosis.

©2017SociedadePortuguesadePneumologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Legionella species(spp.) is a relatively commonagent of communityandhospitalacquired pneumonia.1 _Itwasfirst

identifiedasthepathogenresponsibleforapneumonia out-breakduringanAmericanLegionConventioninJuly1976in Philadelphia.Hence itsname,Legionnaires’ disease(LD).2

Itoccursinoutbreaksorsporadically.3,4

BacteriaofthegenusLegionella include56speciesand more than 70 serogroups. The most common specie is

Legionellapneumophila,serogroup1whichaccountsfor90%

ofcasesofLDandwastheagentresponsible forthe1976 outbreak.5,6_{Legionellapneumophilaserogroup1isfurther}

dividedintomultiplesubtypes.

AlthoughL.pneumophilaserogroup1accountsfor90%of casesinEuropeandAmerica,thisincidencecouldbelower insomecountries,suchasAustraliaandNewZealand,where

Legionellalongbeacheaeaccountsfor30%ofcases.7

Theincubationperiodisusuallybetween2and10days.4,8

Inabout 10%ofcasestheincubation periodcanbelonger, lastingmorethan10daysandupto19days.9,10

Diagnosis is based on clinical suspicion together with laboratory confirmation. Legionella culture of a respira-tory specimen and urinary antigen testing are the most widely used.4,8 _{Although the clinical manifestations are}

non-specific,a combinationof risk factors,symptomsand laboratorialfindingscanbesuggestiveofLD.11---13_Itusually

presentsasseverepneumoniawithaparticularpatternof multisystemdysfunction.Aswithotherpneumoniascaused by ‘‘atypical pathogens’’, respiratory symptoms may not be the most prominent. Neurological and gastrointesti-nalinvolvement,myalgiaandarthralgia,hepaticcytolysis, hyponatremia,hypophosphatemiaandrenalfailureare fre-quentlypresent.4,11---15

An outbreak of L. pneumophila serogroup 1 with 403 cases,377confirmedand26probablecases,wasidentified onthe7thNovember2014inVilaFrancadeXira,located30 KmnorthofLisbon,Portugal.16_{Theoutbreakstartedonthe}

12th October, with peakincidence on the 6th November. Control of outbreak was achieved onthe 21st November, withitsend declaredonthe 2ndDecember(dateof start of symptomsof the lastcase). Of the total of 403cases, therewere 14 reporteddeaths, leading toa 3.5% overall case fatalityrate. Epidemiological investigationidentified themostprobableoutbreaksourceasthewetcooling sys-temof alocalfactory.These facilitieswereshut downon the9thNovember.17_{Interestinglyitwasduringthisoutbreak}

thattheveryfirstprobablepersontopersontransmissionof LDhasbeendescribed.18

During the outbreak several hospitals were appointed toreceive patientsfromVilaFrancadeXira,andHospital PulidoValente---CentroHospitalarLisboaNortewasoneof

them. Theauthors describetheclinical findingsand diag-nostic methodsused amongthe43 confirmed or probable casesofLDadmittedinourtrust.

Materials

and

methods

Forty-three patients withconfirmed or probable LD were admittedtotheChestDepartmentatHospitalPulidoValente betweenthe7thand15thNovember2014.Casedefinition wasbasedonestablishedcriteriabytheLegionnaires’ Dis-easeSurveillanceEuropean Union(EU)whichwasadopted by the Portuguese Directorate General of Health (DGH) (Table1).8,19

Aquestionnaire wasappliedtoallpatients transferred fromtheat riskareaswithaclinicalsuspicionofLD.Data regardingdemographics,riskfactors,clinicalpresentation, laboratorial and radiological features and microbiological testingwascollectedandanalyzed.

Asmokerwasdefinedasapersonwho,atthetimeofthe survey,hadsmokedatleast100cigarettesinhis/herlifetime andcurrentlysmokescigarettes everydayoroccasionally. Anex-smokerwasapersonwhousedtobeasmokerbuthad notsmokedat allforatleast6monthsatthetimeofthe survey.20

Statisticalanalysiswasperformedaimedatadescriptive analysis of the LD cases.More specificallyfor categorical variablesabsoluteandrelativefrequencieswerecalculated, fornumericalvariablesmeans,mediansandstandard devi-ations(sd)wereusedtocharacterizetheirdistribution.All dataanalysiswasperformedusingMicrosoftExcel(2007).

Results

Ofthe43patients,38(88.4%)wereconfirmedcasesand5 (11.6%)were probablecases.The totalof 43cases repre-sentsaround10.7%ofthetotal403casesidentifiedduring theoutbreak.

Allpatientsreceivedlevofloxacinandinourseriesthere werenodeaths.Sevenpatientswereadmittedtothe Inten-sive CareUnit (ICU) and11totheIntermediateCareUnit (ITCU). Invasive Mechanical Ventilation(IMV) wasneeded intwopatientsandNonInvasiveVentilation(NIV)ineight patients.Allpatientswereadmittedaftertheoutbreakhad beendeclared.ThemajoritywasfirstseenintheEmergency Room(ER)closesttotheoutbreaksource(HospitaldeVila FrancadeXira).

Feverwaspresentforameanof4.0daysbeforepatients soughtmedicalassistance.EverypatientwithsuspectedLD andepidemiologicallinkwasmedicatedwithhighdose levo-floxacin(750mg)beforebeingtransferredtoourhospital.

Table1 OutbreakcasedefinitionadoptedbyPortugueseDirectorate-GeneralofHealthbasedontheLegionnaires’Disease SurveillanceEuropeanUnion(EU)casedefinitioncriteria.

Casedefinition Probablecase:Anypersonmeetingtheclinicalandepidemiologicalcriteriaandat leastonelaboratorycriterionforaprobablecase

Confirmedcase:Anypersonmeetingtheclinicalandepidemiologicalcriteriaand atleastonelaboratorycriterionforaconfirmedcase

Clinicalcriteria Anypersonwithpneumonia

Epidemiologicalcriteria Symptomonsetoccurringbetween12/10/2014and02/12/2014andhistoryof living,workingorvisitingatriskareas7_{duringtheperiodof2to19daysbefore} symptomonset.

Laboratorycriteriaforconfirmedcase Atleastoneofthethreefollowinglaboratoryfindings:a)isolationofLegionella

spp.fromrespiratorysecretionsoranynormallysterilesite;b)detectionof

Legionellapneumophilaantigeninurine;c)significantriseinspecificantibody leveltoLegionellapneumophilaserogroup1inpairedserumsamples.

Laboratorycriteriaforprobablecase Atleastoneofthefollowingfourlaboratoryfindings:a)detectionofLegionella pneumophilaantigeninrespiratorysecretionsorlungtissuee.g.byDFAstaining usingmonoclonal-antibodyderivedreagents;b)detectionofLegionellaspp. nucleicacidinrespiratorysecretions,lungtissueoranynormallysterilesite;c) significantriseinspecificantibodyleveltoLegionellapneumophilaotherthan serogroup1orotherLegionellaspp.inpairedserumsamples;d)singlehighlevel ofspecificantibodytoLegionellapneumophilaserogroup1inserum.

Table2 Demographicsandhostriskfactorsofthe43 con-firmed/probablepatients. Characteristics Confirmed/probable cases N(%) Gender Male 26(60.5) Female 17(39.5) Age(mean±SD) 56.1±13.5 Agemedian 59

Activesmokerorex-smoker 33(76.7)

Chronicrespiratorydisease 9(20.9)

COPD 6(14.0)

Asthma 2(4.7)

OSAS 2(4.7)

Diabetesmellitus 7(16.3)

Activecancer/Malignancy 1(2.3)

Chronictherapywithsystemic steroidsorother

immunosuppressivetreatment

0

≥1riskfactor 10(23.3)

SD:standarddeviation;COPD:ChronicObstructivePulmonary Disease;OSAS:ObstructiveSleepApneaSyndrome.

Patientswere maintainedonmonotherapy withhigh dose levofloxacinforameanperiodof8.9days.

Demographiccharacteristicsandhostriskfactors

Demographic characteristicsandhost risk factorsare pre-sented in Table 2. Twenty-six patients were maleand 17 were female.Mean age was56.1 and medianage was 59 yearsold.Theyoungestandoldestpatientswere22and85 yearsold,respectively.Aroundthreequarterswereofactive age:74.4%werewithin35---65years.

The main risk factors identifiedwere tobacco smoking (active smokers or ex-smokers) accounting for 76.7% of patients,chronic respiratorydisease (20.9%)and diabetes mellitus(16.3%).Morethan1riskfactorwaspresentin23.3% ofpatients.Onepatienthadgastriccancerandnonewere understeroidsorotherimmunosuppressivetreatment.HIV serologywasperformed in35patients(81.4%).HIV-2 sero-logywaspositiveinonepatientwithaCD4+lymphocytecell countof454cells/␮L.Althoughnotestablishedasarisk fac-tor,56.8%hadcardiovasculardisease,mainlyhypertension. Clinical,laboratorialandradiologicalpresentation Clinicalfeatures,radiologicalandlaboratoryresultsare pre-sentedinTable3.Allpatientshadfever(T≥38◦C),in79.1% ofpatients≥39◦_{C,in62.8%≥39.5}◦_Candmaximum temper-aturewas40.5◦C.

Chills,myalgia andarthralgiawerepresent in72.1% of the patients. Dry cough was the most frequent respira-torysymptom (62.8%)andproductivecough wastheleast (16.3%).Bothdyspneaandchestpainwerepresent inless than40%ofthecases.Extrapulmonarysymptomswere fre-quent, with 34.9% of patients presenting with confusion and/orheadache.Gastrointestinalsymptoms,suchas nau-sea,vomitingand diarrheawerereportedin 20.9%of the patients.

Fifty-sixpercentofthepatientshadC-ReactiveProtein (CRP)above30mg/dL (meanvalueof 33.8,minimum14.3 andmaximum66.9mg/dL).Leukocytosiswasfoundin48.8% ofthepatients(meanvalueof12210×109_{cells/L).Normal} plateletcount (150---450×109_{/L) wasfound in the} major-ityofpatients(n=36,83.7%)and22.5%hadplateletcount below171×109_{/L.Themostcommonlaboratory} abnormal-itieswere:hyponatremia(Na<135mmol/L)in 62.8%,with Na<130in20.9%,hepaticcytolysis(AST>34U/L)in54.8%, raisedcreatininein51.2%,andhypophosphatemiain42.9% ofthecases.

Table3 Clinicalandlaboratoryfeatures.

Characteristics Confirmed/probable cases

N(%)

Clinicalfeatures(allitemswerecollectedseparately)

Generalsymptomsandsigns

FeverT≥38◦C 43(100.0) FeverT_≥39◦C 34(79.1) FeverT≥39.5◦C 27(62.8) Chills 31(72.1) Myalgia/arthralgia 31(72.1) Lethargy/tiredness 19(44.2) Respiratorysymptoms Drycough 27(62.8) Productivecough 7(16.3) Dyspnea 17(39.5) Chestpain 14(32.6) Neurologicalsymptoms Headache 15(34.9) Mentalconfusion 15(34.9) Gastrointestinalsymptoms Nausea 9(20.9) Vomiting 9(20.9) Diarrhea 9(20.9) Laboratoryresults CRP≥18mg/dL 39(90.7) CRP≥25mg/dL 31(72.1) CRP≥30mg/dL 24(55.8) Leukocytosis(>12×109_{cells/L) 21(48.8)} Platelets<171×109_{cells/L 11(25.5)} Na<135mEq/L 27(62.8) P<2.4mEq/L 9(42.9) performed inn=21 AST>34U/L 23(54.8) performed inn=42 Creatinine>1.3mg/dL 22(51.2) CK>294U/L 10(28.6) performed inn=35

ArterialBloodGasresultsa

PO2<60mmHg 13(30.2)

PO2<70mmHg 24(55.8)

PCO2<45mmHg 43(100.0)

PCO2<35mmHg 40(93)

a_{ABGperformedatadmissionwithFIO} 221%.

Allpatientshadarterialbloodgassamplesdrawnonroom air(FiO221%)onadmission.Hypoxemia(PO2<70mmHg)was foundin55.8%ofthepatientsand93%hadhypocapnia(PCO2 <35mmHg).

Allpatients had achest X-ray onadmission document-ingevidenceofpneumonia.X-raywasrepeatedwithin72h, despiteclinicalevolution.Fourteenpercent(n=6)had bilat-eralinvolvement at admission and half of these patients were treated in the intermediate/intensive Care Units. Twenty-three percent (n=10) had worsening radiological

featureswithinthefirst72hof hospitalizationandhalf of themwereadmittedtotheICU.

Microbiologicaltesting

AllpatientshadUrinaryAntigenTestingforL.pneumophila

serogroup 1 (Alere BinaxNOW® Legionella Urinary Antigen Card).Thiswaspositiveinn=36(83.7%).Inthe36confirmed casesby UAT,serologywasnot performedand respiratory secretions werecollected in 15patients, and culturewas positive in 6. Among the 7 patients with negative UAT, there weretwo additionalconfirmed cases:one by

isola-tionofLegionellaspp.fromrespiratorysecretionsandone

byanalysisofsignificantserologicaltiterelevationinpaired samples.The5remainingcaseswereprobablecases,with a singlehigh level ofspecific antibody toL.pneumophila

serogroup1inserum.

Bloodcultureswereperformed inallpatientsand neg-ativeinallforanypathogen,specificallyforStreptococcus pneumoniae.

Fig.1showsthestandarddemographicandclinical find-ingsofLDinourstudiedpopulation(our‘‘typical’’patient).

Discussion

To date, the largest outbreak of LD happened in Murcia, Spainin2001with449confirmedcases.TheVilaFrancade Xiraoutbreak,with403cases,wasthesecondlargest.16,17,21

Theoutbreakstartedonthe12thOctober2014butwas only declared, 26 days later, on the 7th November.8 _Our

study was not able to identify the reason for the delay in declaring the outbreak, but we hypothesize that this could be related to the high population density of the areaaffectedbytheoutbreakandthenumberofdifferent health care facilities involved. Other reasons include the factthattherearenonationalrecommendationsin Portu-galforrequestingUATinpatientswithCommunityAcquired Pneumonia.As for this,UATisperformed insevere cases, those admitted to ICU or during an outbreak, as recom-mended by the Portuguese Respiratory Society guidelines forthemanagementofcommunity---acquiredpneumoniain immunocompetentadults.22

As the outbreak had already been declared when the patientswereadmittedtoourhospital,UATwasperformed onallofthem,regardlessofdiseaseseverity.

Althoughourpopulationofpatientsamountedto43cases (10.7%ofthetotalnumberofcases)webelieveitis repre-sentativeoftheclinicalmanifestationsofLD,whicharein linewiththeliterature.Thedistributionofgenderandage reflect the demographic characteristics of the population exposedtocontamination.Thisismainlyaworking popula-tioninanindustrialarea,manyofwhomcommutetowork inthecapital.

All series report a greater incidence in males11,14,23,24

althoughtheagedistributioninourserieswasyoungerwith 74.4%ofcasesbeingbetween35and65yearsofagewith ameanageof56.1years.TheMurciaoutbreakshowedan olderpopulationwith70%ofpatientsbeingolderthan5021

andinthereviewbySopena52.2%whereolderthan60.3_In

theanalysisofCAPNETZbyvonBaumetal.,themeanage was63.25

Patient ID: male, 56 years old Findings in % patients T ≥ 38ºC CRP ≥ 18mg/dL PaCO2< 35 mmHg Cigarrete smoking T _{≥ 39º} C Chills Myalgia/arthralgya CRP ≥ 25 mg/dL Positive UAT Male gender T _{≥ 39.5ºC} Dry cough Na _{< 135 mEq/L} ≥ 60% ≥ ≥ 90% 70% Mental confusion (34.9%) Headache (34.9%) Fever ≥ 39.5ºC (62.8%) Dry cough (62.8%) Chills (72.1%) Myalgia/arthralgia (72.1%) CRP ≥ 25 mg/dL (72.1%) Na < 135 mEQ/L (62.8%) P < 2.4 mEQ/L (42.9%) PCO2 < 35 mmHg (93%) UAT + (83.7%) Nausea, vomiting, diarrhea (20.9%)

Figure1 Our‘‘typical’’patient.

Our series showed that the most prevalent risk factor wassmokinghistory(currentorpast)whichwaspresentin 76.7%ofpatients.Againthiswasinaccordancewithprevious series.3,25---27_{Chronicrespiratorydiseases,frequentlyquoted}

asariskfactor, 9.7%intheSopenaseries3_and36%invon

Baum’s,25 _{wasidentifiedin 20.9%of ourpopulationIn our}

series,diabetesmellituswasfoundin16.3%ofpatients. Sim-ilarvalueswerealsofoundinotherstudies.3,13,26_However,

diabetesmellitus prevalencein thePortuguesepopulation aged20---79yearsoldwas13.1%in2014.28_Also,inan

out-breakofLDin2000inMelbourne,Australia,acase---control study did not find significant difference in risk factors between patients and the general population, with the exceptionofsmoking.26

Thelowincidenceofimmunosuppressivetherapyand/or active cancer as well as a high incidence of high blood pressure in the population reflect the demographic char-acteristicsandis likelytohave noother significance.Itis unknown what the HIV prevalence wasin the population exposed to LD outbreak, however the patient diagnosed withHIV-2hadaCD4lymphocytecellcount≥350cells/␮L. Thus, in this patient HIV infection probably did not con-tributesignificantlyasarisk factor forLD, whichremains inaccordancetootherpublisheddata.29

Allpatientshadfever,≥39◦Cinnearly80%ofpatients. Accordingtosomeauthorsthisaloneshouldraisethe sus-picionofLD.15_{Asexpected,respiratorysymptomswerenot}

predominant,withthemostcommonbeingadrycoughin two thirds of patients.15,30 _{Chills, myalgia and arthralgia}

werepredominantinourseries(72.1%ofcases)andis doc-umented intheliterature,15 _{howeverthelatter wasmore}

prevalentwhencomparedwithotherstudiesthatquoteda prevalencearound40%.15,30,31

Aroundonethirdofpatientshadneurologicalcomplaints (headacheand/orconfusion)and20.9%hadgastrointestinal symptoms,mainlydiarrhea,nauseaandvomit.Thesevalues aresimilartovaluesfromotherstudies.15,23,30,32

Regarding laboratory findings our series confirms very high CRP (mean value: 33.8mg/dL) which is in line with otherseries.13,33,34_{Other findingsalreadydescribed inthe}

literatureincludehyponatraemia,13,30,35_{hypophosphatemia,}

raised liver enzymes and decreased renal function.15

AlthoughCRPwasmarkedlyhigh,51%ofthepatientsdidnot haveraised whitecellcountorneutrophilia, whichagain, wasfoundbySopena,3_Viasus30_andBenito.32

In25.5% of patients,therewasa plateletcountbelow 171×109_{/L, which is one of the independent} predic-tor variables in the LD score proposed by Fiumefreddo etal.13

Themajorityofpatientshadhypoxemia(PO2<70mmHg), with30.2%havingPO2<60mmHg,findingsthataresimilarto thosefoundbyBenitoetal.,32_{with33%andSopenaetal.}3

with31%.Itisunusualtofindanyreferencesintheliterature toPCO2valuesbutourseriesshowedthatPCO2wasbelow 35mmHgin93%ofpatientsandthishypocapniacouldbean indirectmarkeroftachypnea.

Twenty-three percent of cases showed worsening of radiologicalfindingsduringthefirst72hofadmission.This hasbeendescribedinotherstudies36_{suggestingthatitcould}

beamoreparticular featureofLD thanofother pneumo-nias.HalfofthesepatientsneededadmissiontotheICUand tworequiredIMV.

Despitebeinghighlysensitive,asensitivitycloseto100% according to Rihs et al.,37 _{the UAT for L. pneumophila}

serogroup 1(Alere BinaxNOW® Legionella Urinary Antigen Card),which wasappliedtoallourpatients,waspositive

in83.7%.AnevensmallernumberwasfoundintheMurcia outbreak,withonly47.7%ofthecaseshavingpositiveUAT. Thevariabilityofsensitivitycouldreflectdiseaseseverity; withhigherpositiveratesinmoreseveredisease.38_Ourdata

alsoquestions theindication for blood culturesduring LD outbreaks.

Finally,inourseriesallpatientsweretreatedwithhigh doselevofloxacininmonotherapyandtherewerenodeaths. However, alertness was high because the outbreak had already been declared when our patients were admitted (after7thNovember2014).Toevaluatecasefatalityrate, theDGHincludeddeathsoccurringsince1stOctober2014 andafewpatientsdiedwithinthisperiod.8

Inourseriesearlydiagnosis,prompttreatmentand opti-mizationofprocessofcaremayhavecontributedtothese results.

Conclusions

Although clinical presentation is not specific, our study shows that even during an outbreak, the combination of riskfactors,symptomsandlaboratoryfindingscanbehighly suggestiveofLD.Thiscanandshouldpromptfurther inves-tigations in order to confirm LD, particularly in patients withless severe presentation or withnegative UAT. Also, widespreaduseof UAT,notlimitedtothesevere casesof communityacquired pneumonia withICU admission crite-ria,mightcontributetoearlierdiagnosis,both insporadic casesandinoutbreaksofLD.

Ethical

responsibilities

Protection of human and animal subjects.The authors

declarethatnoexperimentswereperformedonhumansor animalsforthisstudy.

Confidentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcenteronthe publica-tionofpatientdata.

Righttoprivacyandinformedconsent.Theauthorshave

obtainedthe written informed consentof the patients or subjectsmentionedinthearticle.Thecorrespondingauthor isinpossessionofthisdocument.

Conflict

of

interest

Theauthorsdeclarethattheyhavenoconflictofinterest.

Acknowledgments

The authors would like to thank Dr. Francisco George, Director-GeneralofthePortuguese DirectorateGeneralof Health.

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