A multicentre analysis of Nocardia pneumonia in Spain: 2010-2016

A

multicentre

analysis

of

Nocardia

pneumonia

in

Spain:

2010

–

2016

Maria

Ercibengoa

,

Jordi

Càmara

,

Fe

Tubau

,

Dolores

García-Somoza

,

Alicia

Galar

,

Pablo

Martín-Rabadán

,

Mercedes

Marin

,

Lourdes

Mateu

,

Ignasi

García-Olivé

,

Cristina

Prat

,

Catia

Cilloniz

,

Antonio

Torres

,

Maria-Luisa

Pedro-Botet

,

Carmen

Ardanuy

,

Patricia

Muñoz

,

Jose

María

Marimón

*

a

Biodonostia,InfectiousDiseasesArea,RespiratoryInfectionandAntimicrobialResistanceGroup,OsakidetzaBasqueHealthService,DonostialdeaIntegrated HealthOrganisation,MicrobiologyDepartment,20014SanSebastian,Spain

b_{CIBEREnfermedadesRespiratorias–CIBERES,InstitutodeSaludCarlosIII,Madrid,Spain} c

MicrobiologyDepartment,HospitaldeBellvitge-IDIBELL,L’HospitaletdeLLobregat,Spain

d

ClinicalMicrobiologyandInfectiousDiseases,HospitalGeneralUniversitarioGregorioMarañón–InstitutodeInvestigaciónSanitariaHospitalGregorio Marañón,Madrid,Spain

e

MedicineDepartment,SchoolofMedicine,UniversidadComplutensedeMadrid,Madrid,Spain

f

InfectiousDiseasesUnit–FundacióInstitutd’InvestigacióGermansTriasiPujol,HospitalUniversitariGermansTriasiPujol,Badalona,Spain

g_{UniversitatAutònomadeBarcelona(UAB),Barcelona,Spain}

h_{DepartmentofPneumology,HospitalUniversitariGermansTriasiPujol,Badalona,Spain} i

MicrobiologyDepartment–FundacióInstitutd’InvestigacióGermansTriasiPujol,HospitalUniversitariGermansTriasiPujol,Badalona,Spain

j

DepartmentofPneumology,HospitalClinicofBarcelona–AugustPiiSunyerBiomedicalResearchInstitute(IDIBAPS),UniversityofBarcelona,Barcelona, Spain

k

DepartmentofPathologyandExperimentalTherapeutics,SchoolofMedicine,UniversityofBarcelona,Barcelona,Spain

ARTICLE INFO

Articlehistory:

Received24August2019

Receivedinrevisedform19October2019 Accepted23October2019 Keywords: Nocardia Pneumonia Multicentrestudy Nocardiacyriacigeorgica Spain Respiratoryinfection ABSTRACT

Objective:ToanalyseallcasesofNocardiapneumoniaoccurringbetween2010and2016infiveSpanish hospitals.

Methods:Thiswasaretrospectiveobservationalanalysisofclinicalandmicrobiologicaldatacollected from55casesofNocardiapneumonia.

Results:Therewereoneto20casesperhospitalandsixtoninecasesperyear.Chronicobstructive pulmonarydisease, bronchiectasis,and asthmawerethemainpredisposing underlyingrespiratory conditions.Thirty-fourpatientswerereceivingsystemicand/orinhaledcorticosteroidspriortoinfection, eighthadneoplasia,andsixhadhaematologicalmalignancies.Clinicalandradiologicalfindingswere commontopneumoniaofotherinfectiousaetiologies,exceptforthefrequentpresenceofnodulesand cavitation.Overall,the1-yearmortalitywashigh(38.2%),andmortalitywasdirectlyrelatedtothe pulmonarydiseasein15patients(27.3%).ThemostfrequentlyidentifiedspecieswereN.cyriacigeorgica (n=21),N.abscessus(n=8),andN.farcinica(n=5).AllNocardiaisolatesweresusceptibletolinezolidand allbuttwoweresusceptibletoamikacinandtrimethoprim–sulfamethoxazole.

Conclusions:Nocardiapneumonia-associatedmortalityremainshigh,probablybecauseofthedebilitated statusofpatientsinwhomthispathogenisabletocausepulmonaryinfection.

©2019TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(

http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Nocardia species are gram-positive aerobic actinomycetes commonlyfoundinsoil.Todate,119Nocardiaspecieshavebeen described (Parte, 2018), and althoughall arepotentially patho-genic(Ercibengoaetal.,2016),onlyasmallproportionhavebeen described asresponsiblefor humaninfections.According tothe

* Correspondingauthor.

E-mailaddress:josemaria.marimonortizdez@osakidetza.eus(J.M.Marimón).

https://doi.org/10.1016/j.ijid.2019.10.032

1201-9712/©2019TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

anatomicallocalization, nocardiosiscanbedivided into pulmo-nary, disseminated (including central nervous system (CNS) involvement), and cutaneous (Minero et al., 2009). Human pulmonaryinfectionsareacquiredmainlythroughtherespiratory routebyinhalationofthebacteria;however,mostinfectionsare limitedtotransientcolonization,andNocardiaactsasapathogen onlyonsomeoccasions(Brown-Elliottet al.,2006).Pulmonary nocardiosisat presentationis subacute(Singhet al., 2016)and usually occurs in immunocompromisedpatients or in patients with chronic underlying pulmonary diseases (Kurahara et al., 2014;Mineroetal.,2009;Muñozetal.,2007; Steinbrinketal., 2018). Clinically, Nocardia pneumonia is indistinguishablefrom pneumonia caused by other infectious agents, making it very difficulttosuspectnocardiosisintheimmunocompetent popula-tion(Fujitaetal.,2016;Kimetal.,2016;Steinbrinketal.,2018). Cell-mediatedimmunity seemstobecrucialfor preventingthe disseminationofNocardiafromtheportalofentryintotherestof thebody. Consequently, patientson corticosteroid therapy and those on other therapies or with diseases causing cellular immunosuppression are at a higher risk of suffering from an invasiveordisseminatedNocardia infection(Kontoyiannisetal., 1998).

Intheirreportpublishedin1997,Menendezetal.established thatthe diagnosis of pulmonary nocardiosis was difficult and usually delayed. Moreover, it was frequently disseminated to other body parts, and a combined, synergistic antimicrobial treatment as initial therapy was proposed (Menéndez et al., 1997). Since then, new Nocardia diagnostic and molecular identification methods, as well as new antibiotics for the treatmentofnocardiosishavebeenintroducedinclinicalpractice (McTaggart et al., 2010;Moylett et al.,2003). In this study, all NocardiapneumoniacasesdiagnosedinSpainovera7-yearperiod werereviewed,thusprovidingalarge,recent,real-lifemulticentre seriesofthisinfrequentinfection.

Methods Patients

ThestudyincludedallcasesofNocardiapneumoniaoccurring between2010and2016infivetertiarySpanishhospitalsinthree different cities (Madrid, Barcelona, and San Sebastian). The inclusion criteria for a case of Nocardia pneumonia were the presenceofaradiologicalimagecompatiblewithpneumoniaanda Nocardiasppculturedfromarespiratorysecretionandidentified asthepathogenresponsiblefortheinfection.

Clinicalandmicrobiologicaldatawerereviewedretrospectively andrecordedaccordingtoapreviouslydesigned questionnaire; these included the patients’ conditions and risk factors, as describedinTable1.

Ethics

Theworkwasdoneaccordingtotheregulatoryrequirementsof theSpanishlegislation inforce (LeyOrganica3/2018)and data were processed and analysed anonymously. Publication of the resultsofthisstudywasapprovedbytheClinicalResearchEthics CommitteeoftheBasqueCountry(reference2017161).

Microbiologicalstudies

AllisolateswerepresumptivelyidentifiedasNocardiaaccording to their phenotypic growth characteristics. Definitive species identificationwasperformedbymatrix-assistedlaserdesorption/ ionization time-of-flight mass spectrometry (MALDI-TOF MS; Bruker Daltonics, Germany) after direct transfer–formic acid

preparation and a species cut-off score value of >1.7, or by sequencingafragmentofthe16SrRNA(Steingrubeetal.,1997), hsp65(Telentietal.,1993),andsecA1(Convilleetal.,2006)genes. A99% similarity with the corresponding sequences of the reference species available in GenBank (http://www.ncbi.nlm. nih.gov)wasrequiredforspeciesidenti_fication(CLSI(Clinicaland LaboratoryStandardsInstitute),2018).

Susceptibility testing was performed at each of the participating hospitalsby broth microdilution methodusing Sensititremicrotitre trays(ThermoFisher, Inc.,West Sussex, UK) or by Etest (AB Biodisk, Solna, Sweden). Staphylococcus aureusATCC29213wasusedascontrol.Antibioticstestedineach hospitalvaried,buttrimethoprim–sulfamethoxazole(TMP–SMZ), imipenem,amikacin,linezolid,andciprofloxacinweretestedinall participating hospitals. Minimum inhibitory concentrations (MICs)were recordedand interpreted accordingtotheClinical and Laboratory StandardsInstitute (CLSI)interpretative criteria for Nocardia (CLSI (Clinicaland LaboratoryStandards Institute), 2011).

Statisticalanalysis

Frequenciesofcategoricalvariableswerecomparedusingthe Chi-squaretestorFisher’sexacttest,asappropriate.Aunivariate logistic regression analysis was performed to calculate the relationshipbetweeneachoftheconditionsincludedinTable1

and pneumonia mortality. In this analysis, patients who died becauseofothercauseswereexcluded.Thevariablesthatresulted inap-valueof<0.20levelofsignificancewereanalysedusinga multivariate logistic regression model. The final selection of variablesassociatedwithmortalitywasmadewiththebackward stepwise selection method. The statistical analyses were per-formedusingIBMSPSSStatisticsversion25.0(IBMCorp.,Armonk, NY,USA).

Table1

Mainpredisposingconditionsstudiedin55patientswithNocardiapneumonia. Number % Respiratoryconditions COPD 20 36.4 Bronchiectasis 16 29.1 Asthma 7 12.7 Lungcarcinoma 2 3.6 Previouspneumonia 2 3.6 Otherconditions Cardiovasculardisease 18 32.7 Diabetes 10 18.2

Chronicrenalfailure 9 16.4 Neoplasiaa 7 12.7 Haematologicalmalignancies 6 10.9 Liverdisease 5 9.1 HCVinfection 2 3.6 Chronicgastritis 1 1.8 Immunosuppression Systemiccorticosteroids 29 52.7 Inhaledcorticosteroids 22 40.0 HIVinfection 5 9.1

Haematopoieticstemcelltherapy 4 7.3 Riskhabits

Alcoholicorex 6 10.9

Smokerorex 21 38.2

IVDUorex 3 5.5

Delaytotreatmentinitiation

Symptomstotreatment(days)meanSDb

11.4514.01 RXdiagnosistotreatment(days)meanSDc _6.2911.97

COPD, chronic obstructive pulmonary disease; HCV, hepatitis C virus; IVDU, intravenous drug user; SD,standard deviation; RX,radiological; CNS, central nervoussystem.

a

CNS(n=2),kidney,prostate,rectal,anal,colon.

b

Datacorrespondingto44patients.

Results

Overall,55patientsfulfilledthecriteriaforNocardia pneumo-nia.Theaverageageatthetimeofinfectionwas67.5years(range 23–90years)and35(63.6%)weremale.

Thenumberofpatientsvariedgreatlyamonghospitals,from oneto20.However,theoverallnumberofcasesperyearwasvery homogeneous,rangingfromsixcasesin2014toninecasesin2011 and2012(Table2).Mostpatients(52/55,94.5%)hadpredisposing respiratory factors for developing pneumonia and many were immunocompromisedasa resultof diseaseor pharmacological treatment(Table1).

Clinicalmanifestations

Theaveragedurationofinfectionfromtheonsetofsymptoms todiagnosis,registeredin24patients,was12.9days(range2–34 days).Coughandpurulentexpectorationwerethemostfrequent clinicalmanifestations(Table3).

TheinfectionwasdisseminatedtotheCNSintwopatients.The time-to-diagnosisinthesetwopatientswasslightlylongerthan theaverageoftherestofthepatients(28and34days).Thefirst caseofCNSinvolvementwasaN.cyriacigeorgicainfectionina 23-year-oldwomanwho eventuallydiedbecauseofacute megalo-blasticleukaemia.ThesecondcasewascausedbyaNocardiaspp (not identified to the species level) in a 25-year-old man, ex-intravenousdruguser(IVDU),whowasinfectedwithhepatitisC virus(HCV)andHIVandwasnotonantiretroviraltherapy(1109

leukocytes/l,1%CD4count,91710HIVcopies/ml).HisinitialTMP– SMZ treatment was changed to oral linezolid 600mg/12h and meropenem2g/8hintravenously (IV) dueto a cutaneousrash. Meropenemwasreplacedafter30dayswithceftriaxoneIV1g/24h andthepatientrecovered.

Pulmonaryradiologicalfindings

The most common radiological finding was consolidation (n=33),followedbynodules(n=27),cavitation(n=14), bronchi-ectasis(n=6),andinfiltrates(n=4).Fibrotictractswereobserved in two patients, aninterstitiallung pattern in onepatient, and groundglassopacitiesinonepatient.

Consolidationwastheonlyradiologicalfindingin10patients; consolidation was observed together with nodules in eight patients,withnodulespluscavitationinfivepatients,withpleural effusioninthreepatients,andwithcavitationandpleuraleffusion intwopatients.Intotal,fourpatientspresentedpleuraleffusion, threeofwhomwereinfectedwithN.abscessus.

Thepresenceofconsolidationwithnodulesand/orcavitation wasnotassociatedwithanyspecificNocardiaspecies.Still,seven outofnine(77.8%)patientswithN.farcinicaorN.otitidiscaviarum pneumoniahadconsolidationwithnodules(threeandoneofthem with cavitation, respectively). However the high presence of nodulesinpneumoniacausedbyN.farcinicaandN.otitidiscaviarum comparedtotherestofthespecies(18/46,39.1%)didnotreach statisticalsignificance(p=0.063).Cavitationwasfoundin13of41 immunocompromisedpatientsandinoneof13 immunocompe-tent patients(p= 0.146).Thetwo patientswithlungcarcinoma showedcavitation;itwasnotpossibletodeterminewhetherthe cavitationwasduetothecarcinomaortotheNocardiainfection. Treatmentsandoutcomes

The1-yearmortalityassociatedwithNocardiapneumoniawas high:38.2%(21/55).The30-dayall-causemortalityafteraNocardia pulmonarydiagnosiswas18.2%(10/55).Overall,sixdeathswere not directly related to the Nocardia pneumonia but to the underlyingdisease:HIV,massivebleedingina cirrhoticpatient, cardiacinsufficiency,leukaemia,analneoplasia,andastrocytoma. Intheother15cases,mortalitywasrelatedtothelungdiseasethat occurredin thepatients,allofwhomwerereceiving corticoste-roidsatthetimeofinfection(oneinhaled,fivesystemic,andnine both). Furthermore, seven had chronic obstructive pulmonary disease(COPD)(onewithbronchiectasisand asthma),twoonly bronchiectasis, threewereonhaematopoieticstem celltherapy (oneofwhomalsohadCOPD),twohadneoplasia (glioblastoma andpulmonaryadenocarcinoma),onehadcryptogenicorganized pneumonia, and the last one was an85-year-old manwithno pulmonaryunderlyingdiseasebutwithcardiovasculardiseaseand hepatomegaly.

To investigate the influence of the different risk factors on mortality,thesixpatientswhodiedofcausesnotdirectlyrelatedto thepneumoniaandonesurvivorforwhommostclinicaldatawere notavailablewereexcludedfromtheanalysis.Ofallriskfactors described inTable1,onlyfourshoweda p-valueof<0.2inthe univariate analysis (Table 4).The multivariate analysis demon-strated that having systemic corticosteroids(p=0.002)was the onlyindividualriskfactorassociatedwithmortality.Thesystemic corticosteroids administeredvariedgreatly betweenpatients in termsofthetype,dosage,andcombinations.Twelvepatientswere receivingmethylprednisolone, 11prednisone,fivedexamethasone, and onedeflazacort atthetimeofinfection.Beinga smokeror former smoker, having inhaled corticosteroids, and being on haematopoietic stemcell therapy,although having a p-valueof <0.2intheunivariateanalysis,didnotshowanassociationwith mortality in the multivariate analysis (p=0.376, p= 0.383, p=0.106, respectively). A delay in initiating the antibiotic treatment, from symptom onsetor from radiologicaldiagnosis, was not associated with mortality in the univariate analysis (p=0.459andp=0.535,respectively).

Table2

AnnualdistributionofthecasesofNocardiapneumoniarecordedinfiveSpanish hospitals,2010–2016. Total 2010 2011 2012 2013 2014 2015 2016 Total N.abscessus 1 1 2 2 0 0 2 8 N.arthritidis 0 0 0 0 0 1 0 1 N.beijingensis 0 0 0 0 0 0 1 1 N.cyriacigeorgica 3 2 2 4 4 3 3 21 N.farcinica 0 0 1 1 1 1 1 5 N.otitidiscaviarum 2 0 1 0 1 0 0 4 N.pseudobrasiliensis 0 0 1 0 0 0 0 1 N.wallacei 0 1 0 0 0 0 0 1 Nocardiaspp 1 3 1 1 0 2 0 8 N.transvalensis 0 2 1 0 0 0 1 4 N.veterana 1 0 0 0 0 0 0 1 Total 8 9 9 8 6 7 8 55 Table3

Clinicalmanifestationsin55patientswithNocardiapneumonia.

Clinicalmanifestations Number %

Cough 39 71 Purulentexpectoration 39 71 Fever 25 45.5 Dyspnoea 19 34.5 Fatigue 14 25.5 Pleuriticpain 11 20 Confusion 5 9.1 Sweating 3 5.5 Weightloss 1 1.8

Excluding the patients who died, the average length of treatmentwas6.3months(range3–13months,median6months). Forty-threepatientsweretreatedwithTMP–SMZ,eitheralone(23 patients)orincombination(20patients)withotherantibiotics. ThemostfrequentcombinationwasTMP–SMZ withimipenem/ meropenem (11 patients), in five of them also with amikacin. Linezolidwasusedinthreepatients(aloneintwopatientsandin combinationwithmeropenemin onepatient)duetosecondary effectstoTMP–SMZ(rashandrenaltubularacidosis)orinvitro suspected Nocardia TMP–SMZ resistance. In the two patients treated with linezolid alone, the duration of treatment was 5monthsand7months,respectively.Thefirstpatienthadtostop his treatment because of polyneuropathy, but was considered cured.

Excluding thesixdeaths notdirectlyrelatedtotheNocardia pneumonia,therewasnodifferenceinthesurvivalofpatientswith pulmonarynocardiosistreatedwithonlyTMP–SMZcomparedto

otherantibiotictreatments:5/15(33.3%)patientsdiedand15/34 (44.1%)survived(p= 0.54).

Antimicrobialsusceptibility

TheNocardiawasisolatedfromthesputumof42patients,from thebronchoalveolarlavageoraspirate(BAL/BAS)of 10patients, andfromthetrachealaspirate,transthoracicbiopsy,andpleural fluidofonepatienteach.

Antimicrobial susceptibility results were available for 49 isolates,withallbeing susceptibletolinezolidand allbuttwo, oneN.farcinicaandoneN.otitidiscaviarum,beingsusceptibleto amikacin(Table5).ThereweretwoTMP–SMZ-resistantisolates: oneN.otitidiscaviarumandoneNocardiaspp(notidentifiedtothe specieslevel).HalfoftheN.abscessusandN.otitidiscaviarumwere imipenem-resistant,whilenearlyallisolatesofotherspecieswere susceptibletocarbapenems.Fluoroquinolonesweretheantibiotics

Table4

Significantriskfactorsformortalityinthelogisticregressionanalyses(n=48). Univariatea

Multivariable

Variable OR 95%CI p-Value OR 95%CI p-Value

Inhaledcorticosteroids 4.00 1.10to14.60 0.036 - -

-Systemiccorticosteroids 28.00 3.25to241.34 0.002 28.00 3.25to241.34 0.002 Haematopoieticstemcelltherapy 8.00 0.76to84.59 0.084 - -

-Currentsmokerorex-smoker 2.63 0.75to9.24 0.132 - -

-OR,oddsratio;CI,confidenceinterval.DataareshownastheestimatedOR(95%CI)oftheexplanatoryvariablesinthemortalitygroup.ORisdefinedastheprobabilityofbeing inthemortalitygroupdividedbytheprobabilityofbeinginthenon-mortalitygroup.Thep-valuesarebasedonthenullhypothesisthatallORsrelatingtoanexplanatory variableequalunity(noeffect).

a

ThevariablesanalysedintheunivariateanalysiswerethosedescribedinTable1.

Table5

Susceptibilitycriteriaandrange,MIC50andMIC90,andnumberofsusceptibleisolatesoftheNocardiaspeciesmostfrequentlyfoundincasesofpneumoniainSpain,2010–

2016.

Species Number Amikacin Ciprofloxacin Imipenem Linezolid TMP–SMZ

Susceptiblecriteria 8 1 4 8 2/38 N.cyriacigeorgica 21 Range 1–1.5 1–>4 2–64 1–2 0.25–1 MIC50 1 >4 2 1 0.25 MIC90 1 >4 4 1 1 Sa 21/21 2/20 19/21 21/21 21/21 N.abscessus 8 Range 1 0.12–>4 2–>64 1 0.25–0.5 MIC50 1 4 4 1 0.25 MIC90 1 >4 >64 1 0.5 Sa _{8/8 1/7 4/8 7/7 8/8} N.farcinica 5 Range 1–16 1–4 2–>64 1–4 0.5–2 MIC50 1 4 2 1 0.5 MIC90 16 >4 12 4 2 Sa 4/5 1/4 2/4 5/5 5/5 N.otitidiscaviarum 4 Range 1–16 1–>4 2–32 0.5–2 0.25–4 MIC50 1 1 2 0.5 0.5 MIC90 16 >4 32 2 4 Sa 3/4 2/4 2/4 4/4 3/4 N.transvalensis 4 Range 1–4 0.25–>4 2 1 0.25–0.5 MIC50 1 0.25 2 1 0.25 MIC90 4 >4 2 1 0.5 Sa 4/4 3/4 4/4 4/4 4/4 Nocardia(all)b 49 Range 0.06–16 2–64 2–>64 1–4 0.25–32 MIC50 1 >4 2 1 0.25 MIC90 2 >4 64 1 2 Sa _{47/49 11/45 31/41 47/47 47/49}

MIC,minimuminhibitoryconcentration;TMP–SMZ,trimethoprim–sulfamethoxazole.

a

Numberofsusceptibleisolatesofalltested.

b

Including21N.cyriacigeorgica,8N.abscessus,5N.farcinica,4N.otitidiscaviarum,4N.transvalensis,4Nocardiaspp,andoneeachN.arthritidis,N.beijingensis,andN. veterana.

withthehighestratesofresistance(75%resistantisolates),mainly due tothepredominance ofN. cyriacigeorgica infections in the populationofthisstudy.

Discussion

TherespiratorytractisthemainportalofentryforNocardia, andasaconsequence,around50%to70%ofnocardiosispatients havepulmonaryinvolvement(Ambrosionietal.,2010; Hashemi-Shahraki et al., 2015; Minero et al., 2009; Uhde et al., 2010). Pulmonarynocardiosishasalowincidence,andtheincidencein Spainhasbeenmaintainedataregularleveloverthepastdecade (Mineroetal.,2009).Inthisstudy,performedbetween2010and 2016,theincidenceofpulmonarynocardiosisvariedgreatlyamong hospitals,from one to20 cases.However, the total number of annual cases was quite uniform, without the presence of any outbreak.N.cyriacigeorgicawasthemostprevalentspeciescausing pneumonia, followedby N.abscessus andN.farcinica, a species distributionsimilartootherSpanishstudies(Mineroetal.,2009; Portoláet al.,2009;Valdezateet al.,2017).Theabsenceof any pulmonary infection caused by N. nova was surprising, as this speciesiscommonin Spainandothercountries(Lebeauxetal., 2019;Uhdeetal.,2010;Valdezateetal.,2017).

Pulmonarynocardiosis commonly affects debilitatedpatients withpredisposingconditions,especiallythosewhoare immuno-compromiseddueto organtransplantationand/orcorticosteroid treatmentandCOPDpatients(Ambrosionietal.2010;Singhetal., 2016;Steinbrinketal.,2018;Takiguchietal.,2017;Ottetal.,2019).In thepresentstudy,all55patientswithNocardiapneumoniahadan immunologicalorrespiratorypredisposingfactor.Overallmortality (38.2%) and mortality directly related to Nocardia pneumonia (27.3%)wasbetweenthe18.9%and56.7%mortalitydescribedin similarseries(Muñozetal.,2007;Singhetal.,2016;Steinbrinketal., 2018;Takiguchietal.,2017;Ottetal.,2019).Systemiccorticosteroid therapywastheonlyindividualriskfactor associated withmortality intheunivariateandmultivariateanalysis.Someauthorshavenot foundanydifferencesinthetreatmentoutcomebetween immu-nocompetentandimmunocompromisedpatients(Kimetal.,2016), althoughinotherworksanincreaseintherateofdisseminated infectionsandhighermortalityhavebeenobservedin immuno-compromisedpatients(Steinbrinketal.,2018).

Radiologicalfindingsin patientswithpulmonarynocardiosisdid not differ from those of patients with pneumonia caused by other respiratorypathogens,except for thepresenceofnodulesin26 of the55patients,acommonradiologicalpicturedescribedpreviously (Singh et al., 2016; Steinbrink et al., 2018; Yang et al., 2014). Nodules were notsignificantlymorefrequentinpneumoniacausedbyanyparticular Nocardia species, although N. farcinica and N. otitidiscaviarum showed a tendency towards causing nodules more commonly. Otherstudieshavefoundanincreasedproportionofcavitationin immunocompromisedhosts (Kim etal., 2016; Steinbrink etal., 2018).Inthepresentstudy,althoughallbutoneofthe14patients withcavitationwereimmunocompromised,thisdifferencewasnot signi_ficantcomparedtoimmunocompetentpatients.

Clinicalmanifestationswereverysimilartothoseobservedin pneumoniaofotheraetiologies,exceptforthelackoffeverinmore thanhalfofthepatients,whichcouldbesuggestiveofpulmonary nocardiosis (Steinbrink et al., 2018). Despite the high rate of immunocompromised patients, disseminated infections were identifiedinonlytwopatients,bothintheCNS,aratesimilarto thatdescribedbyKuraharaetal.(2014),butmuchlowerthanis commonlyobserved(Ottetal.,2019;Singhetal.,2016;Steinbrink etal.,2018).Inthesetwoseverelyimmunocompromisedpatients, thetime-to-diagnosiswasaround1month,adelaythatcouldhave favoureddisseminationoftheinfectiontothebrain.

Noassociation betweenmortalityandadelay ininitiating the antibiotic treatment was observed, which has been suggested in other works as a risk factor for developing Nocardiapneumonia(Singhetal.,2016;Yangetal.,2014).TMP– SMZ resistancehasalsobeenidentified asanindependent and significantrisk factor foroverallmortalityin pulmonary nocar-diosis (Kurahara et al., 2014). In our study, TMP–SMZ was the treatmentusedformostpatients,eitheraloneorincombination withcarbapenemsoramikacin,despitewhichthemortalityrate was high. As in other studies (Muñoz et al., 2007), patient outcomes were not related tothe antibiotic prescribed, which suggests that in the prognosis of Nocardia pneumonia, other factorssuchasunderlyingdiseasesorclinicalandimmunological status at the time of infection have more influence than the antibioticsusedinthetreatment.

Most Nocardia isolates causing pneumonia showed in vitro susceptibilitytothemajorityofantimicrobialsusedfortreatment, suchaslinezolidorTMP–SMZ.Imipenemresistancewasstrongly related to N.abscessus and N. otitidiscaviarum,while nearly all isolatesofotherspeciesweresusceptible,ashasbeendescribed previously(Larruskainetal.,2011;Muñozetal.,2007;Uhdeetal., 2010). Most Nocardia isolates – 75.6% – were cipro floxacin-resistant, apercentageofresistancehigherthanreportedinthe UnitedStates(Uhdeetal.,2010),butsimilartoreportsfromSpain (Larruskainetal.,2011).Incontrast,theprevalenceofTMP–SMZ resistance,at4.1%,waslowerthanthe10.8–42%describedinsome studies(Mineroet al.,2009;Uhde etal.,2010;Valdezate etal., 2017).AlthoughN.farcinicaisamongthespeciesmorefrequently resistanttoTMP–SMZ(Mineroetal.,2009;Kuraharaetal.,2014; Valdezate etal., 2017), in thepresent studyallfive N.farcinica isolatesweresusceptible.

The mainlimitationof this studyis itsretrospectivedesign, whichmeantthatsomecasescouldhavebeenlost,andsomedata, likethespeciesidentificationortheantimicrobialsusceptibilityof some of the isolates, could not be determined. Also, the retrospectivedesignmadeitimpossibletoevaluatetheseverity of COPD in patients with this disease and consequently the influenceofNocardiapulmonaryinfectionsintheiroutcomes.The stringent conditions used for patient recruitment (presence of radiologicallyconfirmedpneumoniaandtheisolationofaNocardia ingoodqualityrespiratorysamples)couldhavebiasedthestudy towards more ill patients, excluding milder cases of Nocardia pneumoniain thepopulationwithfewerunderlying conditions. Finally, thelow numberofcasesforthestatisticalanalyses,the widerangeoftheconfidenceintervals,andthelownumbersof variables included in the multivariate analysis imply that the resultsshouldbeinterpretedwithcaution.

Inconclusion,thisstudygatheredoneofthelargestseriesof Nocardia pneumonia, which usually occurs in patients with underlying pulmonary conditions or immunosuppression. The progression of disease was not associated with the antibiotic therapyused.InSpain,N.cyriacigeorgicawasthemostprevalent speciescausingpneumoniaandwassusceptibletomostantibiotics usedinNocardiatreatment.

Conflictofinterest None.

Acknowledgements

To Albert Gabarrús Barri, MSc, from the Department of Pneumology, Respiratory Institute, Hospital Clínic of Barcelona (IDIBAPS) for hisassistance in performingand interpreting the statisticalanalysis.

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