Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian

INFEKZIO BAKTERIANO INBADITZAILEEN IDENTIFIKAZIOA PEDIATRIAN, TXERTO KONBINATUEN GARAIAN IDENTIFICACIÓN DE INFECCIONES BACTERIANAS INVASIVAS EN PEDIATRÍA EN LA ERA DE LAS VACUNAS CONJUGADAS Egilea: Iker Gangoiti Goikoetxea Zuzendariak: Santiago Mintegi eta Francisco Javier Benito (cc)2024 IKER GANGOITI GOIKOETXEA (cc by-sa 4.0) INFEKZIO BAKTERIANO INBADITZAILEEN IDENTIFIKAZIOA PEDIATRIAN, TXERTO KONBINATUEN GARAIAN IDENTIFICACIÓN DE INFECCIONES BACTERIANAS INVASIVAS EN PEDIATRÍA EN LA ERA DE LAS VACUNAS CONJUGADAS Egilea: Iker Gangoiti Goikoetxea Zuzendariak: Santiago Mintegi eta Francisco Javier Benito ATXIKITAKO DERRIGORREZKO DOKUMENTUAK IX HITZAURREA X XI ATARIKOA Tesi honen garapenean bizi momentu ugari igaro ditut, eta tesia berarekiko ere sentimendu kontrajarriak izan. Azken urtean, nire tesiaren ibilbideak urratu asko utzi dizkidan lehengusinaren, AMAIAren bidearekin egin du aurrera. Irakaspenak alde askotatik etorri dira; baina etapa honetan aurrez gorespen handia nion artista baten presentzia jarraiak are bereziago egin du idatzi honen moldaketa. Bertsolari, poeta, idazle, euskal abesti ugariren kantugile, itzultzaile, gidoilari, dokumentalgile, herrigile, historiadore eta istoriogile, eta bere gaixotasunarekin egin duen urte luzeko bidean, Amaiaren ondoan bidaiatu duen laguna; Jon Maiaz ari naiz. Azken proiektuen artean “Kantu bat gara”-k asko markatu ninduen ni eta zuen familia; nola lortu zuen kantuen letren bitartez norberaren eta herriaren bizitza kontatzea; nola eman ziezaiokeen bizia kantatzen jarri zuen herriari…aurretik ere arrailtzen ari zen zerbaitek krak egin zuen nire barruan. Tesia euskeraz egiteko erabakia hartuta, Amaia eta Jon Maia berari zuzendutako keinu gisa eta nik neuk tesiarekin eta bizitako fase honekin adiskidetzeko behar dudan ariketa gisa, nire euskal talde kutunen (nire bizitzako soinu banda izan den Berri Txarrak, batik bat) kantuen zenbait letren hainbat esaldi esanguratsu kapituluz kapituluko sarreretan nahasiak izango dira. XII Heldu herria sustraietatik, tira eta gora jaso. Jarri Kantauri aurrean eta mantendu zutik hari so, ispilu hortan ikus gaitezen herriz-herri, auzoz-auzo. Zauriak gatzez itxi ditzagun, malkoak urez eraso, sano ta libre irla ttiki bat salbatuko gara akaso. Jon Maia Gram tintzioa .......................................................................................................................... 47 Teknika mikrobiologiko berriak .............................................................................................. 47 Polimerasan oinarritutako kate-erreakzioaren teknika (PCR)............................................ 48 Irudi-teknikak .............................................................................................................................. 49 Protokoloak ................................................................................................................................ 50 Aurrez osasuntsuak ez diren pazienteak ................................................................................ 51 Aurrez osasuntsu diren pazienteak ........................................................................................ 51 AZKEN HAMARKADETAKO ALDAKETAK .......................................................................................... 56 Biztanlerian gertatutako gizarte aldaketak ................................................................................ 56 Osasun arloko aldaketak ............................................................................................................ 57 Jaio aurreko ekografia ............................................................................................................ 57 B taldeko estreptokokoaren detekzioa haurdun dauden emakumeengan ........................... 58 Txertaketa egutegia ................................................................................................................ 59 Haemophilus influenzae Bren aurkako txertoa .................................................................. 59 Neisseria meningitidisaren aurkako txertoak .................................................................... 59 Streptococcus pneumoniaeren aurkako txertoak .............................................................. 61 LAN HIPOTESIA ............................................................................................................................... 65 HELBURU NAGUSIAK .................................................................................................................... 66 BIGARREN MAILAKO HELBURUAK .................................................................................................. 66 METODOA ........................................................................................................................................ 69 ARGITARATUTAKO ARTIKULUAK ETA KALITATEZKO INDIZEAK ....................................................... 69 HELBURU BAKOITZAREKIN HARREMANDUTAKO ARTIKULUAK ...................................................... 85 ARTIKULUAK GARATZEKO METODOA ............................................................................................. 95 Erregistro prospektibo unizentriko baten oinarritutako lanak ................................................... 95 Ikerkuntza unizentriko baten oinarritutako artikulua .............................................................. 100 Ikerkuntza zentruanitzetan oinarritutako lanak (SEUPeko Gaixotasun Infekziosoetako Lan Taldearen baitan burututakoak) ............................................................................................... 102 Zentro anitza den behaketa-azterketa prospektiboa ........................................................... 102 Erregistro prospektibo handi batetik eratorritako bigarren mailako analisien emaitza diren artikuluak .............................................................................................................................. 104 ETIKA ............................................................................................................................................. 108 EMAITZAK...................................................................................................................................... 111 HELBURUREN ARABERAKO ARGITARALPENAK ............................................................................. 111 Hamalau urtetik beherako pazienteetan baieztatu diren IBIen aurkezpen klinikoaren karakterizazioa egin eta haien larritasuna deskribatu.............................................................. 111 Hamalau urtetik beherako pazienteen IBIak identifikatzeko egiten diren ohiko odol testen (leukozitoen zenbaketa, neutrofiloen zenbaki absolutua, proteina C erreaktiboa eta prokaltzitonina) balioa analizatu .............................................................................................. 120 Fokurik gabeko sukarra duten eta larrialdi zerbitzura egonkor iristen diren 3-24 hilabete arteko haurrak artatzerakoan odol testik ez erabiltzearen gomendioa ebaluatu ................... 124 E. colik eragindako infekzio inbaditzaileen aurkezpena deskribatu eta balizko profilak eta larritasunarekiko balizko harremana ikertu ............................................................................. 130 B taldeko estreptokokoak eragindako infekzio inbaditzailearen aurkezpena deskribatu eta haren larritasunarekiko balizko harremana ikertu ................................................................... 135 Bigarren mailako helburuaren araberako emaitza. Aurretiaz espero ez zen pandemiak larrialdi zerbitzu baten identifikatu diren IBIen epidemiologian izan duen eragina deskribatu ........... 141 EZTABAIDA.................................................................................................................................... 145 ONDORIOAK .................................................................................................................................. 157 ETORKIZUNA ................................................................................................................................. 163 BIBLIOGRAFIA .............................................................................................................................. 165 LABURDURAK CDC: Gaixotasunen kontrol eta prebentziorako zentroa DNA: azido desoxirribonukleikoa. GIB: giza immunogutxiegitasunaren birusa. IBI: infekzio bakteriano inbaditzailea. KT: konfidantza tartea. LZR: likido zefalorrakideoa. PCR: polimerasan oinarritutako kate erreakzioa. PCV7 eta PVC13: neumokokoaren aurkako txerto konjokatu zazpi eta hamahirubalentea. RNA: azido erribonukleikoa. SEUP: Pediatriako Larrialdietako Medikuntzako Espainiako Elkartea. SIRS: Hantura Erantzun Sindrome Sistemikoa (Systemic Inflammatory Response Syndrome) SAMR: metizilinari erresistentea den S. aureusa. SOFA eskala: Sequential Organ Failure Assessment LABURPENA 1 LABURPENA Zer esan, nola esan, aro eder honetaz? Sormenak, kemenak ezin esan dezakeenik (BTx) Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 2 LABURPENA 3 LABURPENA Sukarra ohiko kontsulta-arrazoia da larrialdi zerbitzu pediatriko batek artatzen dituen pazienteen artean. Kasurik ohikoenetan berez osatzen diren infekzio biralak daude jatorrian, baina batzuetan umeek infekzio bakteriano inbaditzaileak (IBI) pairatu ditzakete. IBIa diagnostikatzeko benetako bakterio patogeno batek izan behar du isolatua odolean edo likido zefalorrakideo, pleural edo artikularrean. Kezka gehien sortzen dituztenak odol eta likido zefalorrakideoan isolatutakoak izan ohi dira. Tesi honen muina 2018 eta 2023 bitartean argitaratutako zortzi artikulu dira. Sarreran, garai pediatrikoan IBIen gehiengoa sorrarazten duten bakterio ohikoenen zerrenda eta bakoitzaren ezaugarriak deskribatzen dira, IBI bakoitzak eragin ditzakeen kuadro kliniko ezberdinak banan-banan azalduz. Larrialdi zerbitzu pediatrikotik abiatu den tesi honetan, bertan lan egiten duen medikuak IBIa duen paziente bat identifikatzeko baliatu ditzakeen tresna multzoa ere deskribatzen da. Izan ere, tresna hauen erabilpenaren errentagarritasuna aldatzen joan da historian zehar, bai osasun munduan eta bai gizarte mailan eman diren aldaketen ondorioz; hauetako batzuen berri ere emango dugu sarreran. Gure ustez, ezinbestekoa da aro pediatrikoan gertatzen diren IBIen egungo epidemiologia, aurkezpen modu eta hauen maneiuan zeresana duten baliabideen errendimendua ezagutzea, IBIen identifikazio eta tratamenduaren giltza izango diren diagnosi eta maneiu estrategia egokienak ezartzeko. Lan hipotesi nagusia ondokoa da: IBIa pairatzen duen pazienteren karakterizazioak eta hauen identifikaziorako ditugun baliabideen errendimenduak aldaketak jasan izan dituela azken urteotan. Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 4 Helburu nagusiak hamalau urtetik beherako pazienteetan baieztatu diren IBIen aurkezpen klinikoaren karakterizazioa egin eta haien larritasuna deskribatzea izan ziren, tartean E. coliak eta B taldeko estreptokokoak eragindakoena. IBIen identifikaziorako erabiltzen diren ohiko odol testen (leukozitoen zenbaketa, neutrofiloen zenbaki absolutua, proteina C erreaktiboa eta prokaltzitonina) balioa analizatzea eta fokurik gabeko sukarra duten eta larrialdi zerbitzura egonkor iristen diren 3-24 hilabete arteko haurrak ebaluatzerakoan odol testik ez erabiltzearen gomendioa analizatzea ere gure helburu nagusietako bat izan da. Tesi honen helburu zuzena ez zen arren, aurretik espero ez genuen pandemia batek larrialdi zerbitzu batean identifikatu diren IBIetan izan duen eragina ere deskribatu nahi izan dugu. Horretarako, arestian esan bezala zortzi artikulu bildu ditugu lan honetan. Lau argitalpen 2008an ireki zen prospektiboki erregistratutako data basean oinarritutako kohorte-ikerketa baten emaitza dira. Hirugarren mailako ospitale bateko larrialdi zerbitzu pediatriko batean, 14 urtetik beherako pazienteetan diagnostikatu diren infekzio bakteriano inbaditzaileak bildu ziren. Gangoiti I, Valle JR, Sota M, Martinez-Indart L, Benito J, Mintegi S. Characteristics of children with microbiologically confirmed invasive bacterial infections in the emergency department. Eur J Emerg Med. 2018 Aug;25(4):274-280 artikuluan, zortzi urte bitarteko denboraldian 223 IBI identifikatu ziren, %83,9 kasutan aurrez osasuntsu ziren pazienteetan. Neumokoko eta meningokoko kasuak ia erdia izan ziren. Hala ere, pazienteen adina, karakterizazioa eta azken diagnosia, eragile izan zen mikroorganismoaren arabera aldatu ziren. Infekzio meningokozikoak izan ziren IBI larrienak. Gehienek ondo eboluzionatu arren, lau kasutan (%1,8) pazientea hil egin zen eta beste zortzik (%3,6) sekuela iraunkorrak pairatu zituen. IBIa larrialdietara egindako LABURPENA 5 bigarren bisita batean diagnostikatu zen 32 pazientetan (%14,3). Bigarren kontsultan IBIa diagnostikatu zitzaien 32 paziente horietatik lauk (%12,5) heriotza edo sekuela iraunkorrak pairatu zituzten. Gaixotasunaren lehenengo 24 orduetan larrialdi zerbitzuetan artatu izana, sukarraz gain beste sintomaren baten presentzia izatea eta larrialdi zerbitzura iristean ebaluazio pediatrikorako triangelu egonkorrik ez izatea larritasun handiagoa izateko arrisku-faktore independente definitu ziren. Gangoiti I, Gorostizaga Z, Aranzamendi M, Gomez B, Benito J, Mintegi S. Repeated Emergency Department Visits Among Children with Invasive Bacterial Infections. Pediatr Infect Dis J. 2021 May 1;40(5) artikuluak, 14 urtetan zehar erregistratutako IBIak bildu zituen, 342. Horietatik aurrez osasuntsu ziren 271 pazientetan burutu genuen analisia. Ehun eta laurogeita hemeretzi pazientek (%73,4) antibiotiko parenterala jaso zuten lehen bisitan. Guztira, hamabost pazientetan larritasun irizpideak objektibatu ziren. Paziente hauetatik, zazpik ez zuten antibiotikorik jaso lehen bisitan. Gangoiti I, Fernandez CL, Gallego M, Gomez B, Benito J, Mintegi S. Markers for invasive bacterial infections in previously healthy children. Am J Emerg Med. 2021 Oct;48:83-86 artikuluan, hamahiru urteko IBIak bildu ziren, 367ri orotara, baina analisia aurrez osasuntsu ziren 286 pazienteekin egin zen. Berrehun pazientek ebaluazio pediatrikorako triangelu egonkorra (%69,9) izan zuten larrialdi zerbitzura iritsitakoan. Azken diagnostikoak sepsia 64 (%22,4) kasutan, meningitisa 38tan (%13,3), bakteriemia ezkutua 63tan (%22,0) eta infekzio fokal inbaditzailea 121tan (%42,3) (arnas aparatuko infekzioa 46tan, gernu-aparatuko infekzioa 33tan, infekzio osteoartikular edo ehun bigunetako infekzioa 33tan eta beste batzuk 9tan) izan ziren. Isolatutako bakterio ohikoenak Streptococcus pneumoniae 89 (%31,1), Neisseria meningitidis 61 (%21,3), Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 6 Escherichia coli 40 (%14) eta Staphylococcus aureus 36 (%12,6) izan ziren (gainontzekoak 60, %21). Oro har, 265ek (%92,7) odol balio anormal bat izan zuten gutxienez. Odol markatzaile bakoitzaren sentikortasuna azken diagnostiko eta bakterio eragilearen arabera aldatu zen. Sepsia eta meningitisaren kasuan prokaltzitonina eta C proteina erreaktiboaren sentikortasuna handiagoa izan zen; infekzio fokal inbaditzaileetan C proteina erreaktiboarena; meningokokoaren kasuan prokaltzitoninarena eta S. aureusaren kasuan C proteina erreaktiboaren sentikortasuna. Bakteriemia ezkutu neumokozikoa diagnostikotzat jaso zuten 3 eta 24 hilabete bitarteko adineko haurren odol-markatzaile bakoitzaren sentikortasuna ondokoa izan zen: prokaltzitonina %43,5 (%95 KT: 25,663,2); C proteina erreaktiboa %48,3 (%95 KT: 31,4-65,6); leukozitoen zenbaketa %75,9 (%95 KT: 57,8-87,8); neutrofiloen zenbaki absolutua %58,6 (%95 KT: 40,7-74,5). Martin-Irazabal G, Gangoiti I, Gomez B, Lizarraga L, Mintegi S. Impact of the COVID19 pandemic on pediatric invasive bacterial infections. An Pediatr (Engl Ed). 2023 Mar;98(3):228-229 artikuluan bi denbora tarte bereizi genituen pandemiaren deklarazioa ebaki-puntu hartuta. Pandemiaren aurreko aldian, 70 IBI diagnostikatu ziren eta 49 pandemian. Pandemia garaian, aurretiaz osasuntsu zen paziente baten IBI diagnostikatzeko probabilitatea nabarmen aldatu zen. Bestetik, pandemia garaiko IBIen erantzuleei dagokienez, aldaketak nabarmenak izan ziren; 2021ean N. meningitidis desagertu egin zen eta 2022an aldiz, S. pneumoniaeren hazkunde (9/22; diagnostikaturiko IBIen %40,9) handia eman zen. Hiru hilabetetik beherako haurrengan, B taldeko estreptokokoa izan zen IBIaren kausa nagusia pandemian ((%33,3) vs. E. coli (%50) pandemia aurreko garaian, p<0,01). SARRERA 13 SARRERA Sukarra ohiko kontsulta-arrazoia da larrialdi zerbitzu pediatriko batek artatzen dituen pazienteen artean1. Egia da kasurik ohikoenetan berez osatzen diren infekzio biralak daudela jatorrian. Dena den, batzuetan umeek infekzio bakteriano inbaditzaileak (IBI) paira ditzakete. IBIa diagnostikatzeko benetako bakterio patogeno batek izan behar du isolatua odol, likido zefalorrakideo, pleural edo artikularrean. Kezka gehien sortzen dituen IBIa odol eta likido zefalorrakideoan isolatutakoa izan ohi da. Horregatik, sepsia eta meningitisa alde batera utzi ezin daitezkeen heriotza arrazoiak dira oraindik ere herrialde garatuetan2, nahiz eta azken hamarkadetako baldintza eta txerto eta antibiotikoen arloan egindako ikerketek aurrerapauso garrantzitsuak ekarri. Honek guztiak, orain ez urte asko infekzio larrien erantzule ziren bakterio ohikoenen isolamenduaren jaitsiera nabarmena eragin du. Bestalde, herrialde garatuetan, agerikoa da pazienteak artatzeko osasun zerbitzuen irisgarritasunak gora egin duela eta haurrak prozesu infekzioso oso goiztiarrekin egiten dutela kontsulta, bai larrialdi zein lehen mailako arreta zerbitzuetan3. Oso ohikoa da, baita ere, paziente hauen adina 2-3 urtetik beherakoa izatea; kuadro klinikoaren adierazkortasunean aldaketak eragin ditzake eta bistara egon ohi ziren ezaugarri, zeinu eta sintomak hain agerikoak ez izatea bultzatu4. Gainera, paziente pediatrikoa artatzen duen profesional medikuaren profilak aldakortasun oso handia du; lehen urteko mediku egoiliar batetik paziente helduak artatu ohi dituen lehen arretako familia mediku batera. Ekuazio honen aldagai guztiek infekzio bakteriano inbaditzailearen identifikazioan eragina dute. Txertaketa kanpainen eragina ez du inork jada zalantzan jartzen. Honela, argi ikusi da mende aldaketarekin etorri zen Haemophilus influenzae bren aurkako txertaketa Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 14 unibertsalak ondorio zuzena izan zuela lehen munduko haurrengan identifikatzen ziren infekzio inbaditzaile larrienetan5; hauen desagertze ia erabatekoa ekarri zuen txertatutako populazioan. Honekin batera Streptococcus pneumoniaeren aurkako txerto konjokatuen merkaturatzeak infekzio inbaditzaile neumokozikoen jaitsiera nabarmena ekarri du3,6,7,8,9. Ohikoa zen txerto hauen komertzializazioa baino lehen, aurrez osasuntsu ziren eta ebaluatzerako orduan itxura ona zeukaten bularreko haurren proportzio txiki batean, sukarra zela eta kontsultatzen zutenen artean, odolean bakterio bat isolatzea (ezkutuko bakteriemia), H. influenzae lehenago eta S. pneumoniae gerora batik bat10. Artikulu klasikoen arabera, populazio baten bakteriemia ezkutuaren prebalentzia esanguratsua zenean, egun baino handiagoa, 39ºCtik gorako fokurik gabeko sukarra duten 3-24 hilabete bitarteko haurretan11 odol kultura bat egitea gomendatzen zen. H. influenzae B eta S. pneumoniaeren kontrako txertoen ezarpena eta gero, prebalentzia honek behera egin du nabarmen12, eta errutinazko bilaketa bat egitea ez legoke guztiz gomendatua, gutxienez neumokokoaren aurkako txertoaren dosi bi jaso dituzten paziente hauetan4,13,14,15,16,17,18. Aitzitik, gaixotasun honen prebalentziak %0,5etik behera egiten duenean, testatzen diren odol frogen errendimenduak, leukozitoen zenbaketak eta neutrofiloen zenbaki absolutuak kasu, behera egiten du nabarmen11,19. Izan ere, Lee-k argitaratu zituen datuen arabera, odol proben errendimendu handiena ezkutuko bakteriemiaren prebalentzia %1,5etik gorakoa denean ematen da. Bakteriemia ezkutuaren prebalentziak gora egiten duela ere deskribatu izan da hauteman den tenperaturaren balioak gora egiten duenean5; sarri erlazionatu dira tenperaturaren gradazioa eta paziente talde honetan identifikatzen zen ezkutuko bakteriemiaren prebalentzia. Talde honek, oso tenperatura altua duten umeen taldeak alegia, berarekin SARRERA 15 dakartzan berezitasunek zalantzak sorrarazten dituzte pazientearen ohe buruan dagoen edozein profesionalengan. Bestetik, azken hamarkada bietan N. meningitidisak sorrarazitako infekzio inbaditzaileen kopuruak nabarmen egin du behera20,21, hein handi batean C serotaldedun N. meningitidisaren aurkako txertoaren unibertsalizazioak ere antzeko eragina izan baitu. N. meningitidisak eragindako infekzio inbaditzaileen kasuan B serotaldea izan da azken urteetan herrialde garatuetan aldaera nagusia. Hala ere azken urteotan beste aldaera batzuek gora egin dute, W eta Y aldaerek batik bat, B serotaldearen joera oro har nahiko egonkor mantendu delarik. Azken urte hauetan, gainera, N. meningitidisaren aldaera ezberdinen aurkako txertoak agertu dira merkatuan. Espainiar Pediatria Elkartearen baitan dagoen Txertoen Aholkularitza Batzordeak jadanik gomendatu ditu22 eta zenbait Autonomia Erkidegok sartu dituzte jada jaio osteko estrategia finantziatuaren barruan (Euskal Autonomia Erkidegoan, 2023 urtean jaiotako haurrak baliatu dira neurri honetaz); honek izango duen eragina, momentuz, ikusteko dago. Aldaketa epidemiologiko guzti hauek infekzio bakteriano inbaditzaileen murrizte garrantzitsua ekartzeaz gain, eragile nagusi diren mikroorganismoen sakabanaketa zabalagoa eragin dute. Egun, garrantzitsuenetakoa E. colia da. Bera da urtebetetik beherako haurrengan bakteriemia gehienen erantzulea, batik bat hiru hilabetetik beherako pazienteetan jakinarazia eta oro har, gernu bideetako infekzioekin erlazionatuta dagoena23. Hala ere, gure inguruan ez zen bakteriemia honen ezaugarri kliniko nahiz ondoriorik aztertzen zuen lagin handidun ikerketarik egin. Pentsatzekoa zen gainera bakteriemia hau pairatzen duten pazienteen profil ezberdinak existituko zirela eta profil bakoitza arrisku maila ezberdin batekin erlazionatuta egotea. Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 16 Horregatik, ez da harritzekoa IBI bat izan dezakeen haurraren identifikazio goiztiarra beti ez lortzea. IBIen azken urteotako gainbeherari, artatzen diren pazienteen ezaugarrien aldaketei (pazientea, kuadro klinikoen zeinu eta sintoma klasikoak agertu aurretik artatu ohi da larrialdi zerbitzu baten) larrialdi zerbitzu batean haurra artatzen duten profesionalen aldakortasun handia gehituz gero, arazo honen azaleratzea baino ez du erakutsi. Ikerketa batek baieztatu zuen meningitis bakteriano edo sepsia pairatu duten paziente pediatrikoen %22a behin baino gehiagotan izan zirela artatuak larrialdi zerbitzu batean24, azken emaitza eta ondorioak lehen kontsultan identifikatutako haurren antzekoak izan zirela nabarmendu zuten arren25. Hala ere, sepsi pediatrikoaren maneiurako gidek zain barneko tratamendu antibiotiko azkarra giltzarria dela azpimarratu izan dute; are gehiago, lehen ordua funtsezkoa da shock egoera bistaratu denean26. Horregatik, paziente talde jakin baten aurrean, odol analisi eta biomarkatzaileek eragiten duen erantzuna IBIa identifikatzeko erabakitze prozesuaren parte den tresna garrantzitsu bihurtzen da. Baina IBIen erantzule izan ohi ziren mikroorganismo sortaren aldaketa eta pazientearen artatze prozesua gero eta goiztiarragoa dela kontutan hartuz gero, test hauen errendimendu eta erantzuna aurretiaz publikatutakotik ezberdina izan daitekeela ondoriozta daiteke. Eskuarki, leukozitosia eta neutrofilia izan dira larrialdi zerbitzu pediatriko baten erabakiak hartzeko parametro analitiko erabilienak, eta berrikiago, C proteina erreaktiboa. Azken urteotan, gainera, prokalzitoninak balio biokimiko erabilgarri gisa jardun du, markatzaile klasikoen aldean abantailak eskaintzen baititu16,17,27,28. Hala ere, biomarkatzaile berriak agertze eta gehitzeak batzuetan zaildu egin dezake IBIa izateko arrisku handiena duten pazienteak identifikatzea19, IBI guztiek ez baitute erantzun bera odol biomarkatzaileetan. SARRERA 17 IBIEN SAILKAPENA Sarreran aipatu bezala, IBIaren diagnostikoa odol, likido zefalorrakideo, likido pleural edo likido artikularrean egindako benetako bakterio patogeno baten isolamenduan oinarritzen da. Dena den, isolamendua garatzen den likidoaren, ostalariarengan duen eraginaren eta ostalariak berak duen erantzunaren arabera, oso egoera kliniko ezberdinak sor daitezke. Bakteriemiaren definizioa odol lagin batean egiten den benetako bakterio patogeno baten isolamenduan datza. Benetako bakterio patogenoak, klasikoki kontaminante gisa definitzen diren mikroorganismoak alde batera uzten ditu, hala nola Staphylococcus epidermidis, Propionibacterium acnes, Streptococcus viridans, Corynebacterium spp., eta bestelako difteroideak. Klasikoki kontaminante deritzen mikroorganismoek ere eragin ditzakete bakteriemiak aurretiaz osasuntsu ez diren pazienteetan: gaixotasun onkologiko bat edo bestelako inmunogutxiegitasuna jasaten duten haurrak, kateter zentral edo deribazio balbula baten garraiatzaile diren pazienteak, teknika diagnostiko edo terapeutiko inbaditzaileak burutu diren pazientea teknika egin eta ondorengo egunetan… Bakteriemien barruan talde handi bi bereiz ditzakegu: infekzio fokal batek sorturikoak (infekzio fokal inbaditzaileak) eta infekzio fokalik gabekoak (bakteriemia ezkutua). Haien garrantzi eta larritasuna, eta ezinbestean atxikitutako hilkortasun eta morbilitate tasak direla eta, meningitisa (infekzio fokal inbaditzailea) eta sepsia (infekzio barreiatua, jatorri infekzio fokal ezagun edo ezezagun bat izan dezakeena) beren-beregi aparteko era baten azalduko ditugu. Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 18 Meningitis bakterianoa Meningitisa meningeen hanturari deritzo, piamadre, araknoide eta gune azpiaraknoideari erasaten diena. Etiologiari dagokionez, aro pediatrikoan jatorri birala izatea da ohikoena; enterobirusa, batik bat, pronostiko oso ona duena. Bakterianoa izatea, likido zefalorrakideoan hazten den bakterio baten isolamenduak mugatuko du. Egoera hau, oro har, mukosen geruzak kolonizatu dituzten organismoek odol-zirkulazioa inbaditu ostean gertatzen da. Azken urteotako txertaketa kanpainek eta B taldeko estreptokokoaren inguruan egiten den profilaxi antibiotikoak meningitis bakterianoaren epidemiolologia erabat aldatu dute. B taldeko estreptokokoa eta bazilo Gram negatiboak izango dira meningitis bakterianoaren eragile hiru hilabetetatik beherako haurretan eta Streptococcus pneumoniae eta Neisseria meningitidis adin honetatik gorako haur osasuntsuetan29,30,31,32,33. Kasu gehienetan, odol hodietan zehar barreiatu eta hesi hematoentzefalikoa zeharkatu ostean araknoide azpiko gunera igaro ohi dira bakterioak. Behin nerbio sisteman ezarria, erreplikazio esponentzial baten eta hantura sortzen duten bitartekari ugari sortu ostean, ehunaren behin betiko lesioa sorraraziko duen prozesua hasiko da. Nahiz eta meningitisaren patogenian mekanismo honek izan indarrik handiena, sudur sinu batetik edo erdiko belarri bidetik hasitako, eta mastoide hezurra eroale delarik gertatzen den hormaz hormako zuzeneko hedapenak ere eragin dezake kuadro kliniko hau. Bestelako zenbait egoerek, likuorrea agertzen den kraneo-haustura batek edo zauri sarkari nahiz neurokirurgiako prozedurek ere erraz dezakete meningitis bat garatzea. Klinika, meningitisa pairatzen duen haurraren adinak, mikroorganismo eragileak, eboluzio denborak eta pazientearen erantzun immunologikoak definituko ditu. Jaioberri SARRERA 19 eta bularreko haur gazteetan, klinika ezohikoa eta espezifikotasun gutxikoa izaten da: suminkortasuna, jan nahi ez izatea, motelago egotea, sukarra ala hipotermia, zianosia, baita apnea bera ere. Bularreko haur nagusiagoen sintomak ere oso inespezifikoak dira, sukarra izan ohi da ia kasu gehienetan, suminkortasuna, letargia, gorakoak, jateari errefusa bestelako zeinu eta sintomez gain. Ume nagusi eta nerabeetan ikusiko lirateke sintoma klasikoenak: sukarra, gorakoak, fotofobia, buruko mina… Meningitisa pairatzen duen pazientearen azterketa fisikoan nabarmendu daitezkeen zeinu klinikoak ere askoz inespezifikoagoak izango dira jaioberri eta bularreko haur txikiengan. Fontanela neurriz handituta edo puztuta egotea garezur barneko hipertentsioaren adierazle da; zeinu berantiarra da eta klasikoki nabarmendu den arren, gaur egunean ez da sarriegi ikusten. Honela, Martinez et alen32 ikerketa baten arabera, hiru hilabete baino gazteago ziren eta meningitisa zuten 11 haurren artean fontanela normala zen hamarretan (bestearen azterketan ez zen adierazi fontanelaren egoera). Ume nagusiagoetan hauteman daitezke meningitisaren zeinu klasikoenak: Kernigena (aldakaren flexioak eragiten duen garondoaren erantzun zurruna) eta Brudzinskirena (garondoak berak, bere flexioaren saiakera egitean eskaintzen duen erantzun zurruna). Garondoaren zurruntasuna bera ere ez da meningitisaren zeinu patognomonikoa, beste prozesu batzuetan ere deskribatu izan direlako, hala nola neumonia, faringoamigdalitisa edo gastroenteritisa bezalako gaixotasunen bilakaeran34,35. Hala ere, zeinu hauen agertze hutsak meningitisaren presentziaren aukera handitu egiten du berau baztertzeko probak burutzea ia ezinbesteko izango delarik30,34,36. Meningitisaren zeinu-sintomek osatzen dituzten ereduen deskripzio klasikoek ere lagun dezakete bere jatorriaren identifikazioan. Meningitis bakterianoek sorturikoen baitan bi eredu nabarmendu izan dira. Bat, hasiera bortitz eta bilakaera jarrai eta azkarra duena eta Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 20 shock, purpura, odol hodietako koagulazio barreiatua, konorte gutxitzea,… eragin dezakeena eta 24 orduren bueltan heriotza; bigarrena, zerbait nahasiagoa, egun batzuetako sukarraren ondotik datorrena, arnas sistema edo liseri aparatuko sintomez lagundua eta progresiboki nerbio sistema zentraleko zeinuak agerian utziko dituena, hala nola suminkortasuna edo letargia. Sepsia Egun pediatrian ez da komunitate zientifiko osoak onartuko duen definizio jakin bat zehaztu; oro har, infekzio baten aurka organismoak ematen duen erantzun immune desegokiak disfuntzio organikoa eragiten duenean sepsiaz arituko gara37. Izan ere, pediatrian onartu zen azken definizio arautua, 2005 urtean egin zen Sepsi Pediatrikoaren Adostasunerako Nazioarteko konferentzian erabakitakoa da38. Honen arabera, organismoak, balizko infekzio edo/eta baieztatutako infekzio baten aurrean ematen duen hantura-erantzun sindrome sistemikoa da sepsia. Hau neurtzeko SIRS (Systemic Inflammatory Response Syndrome/Hantura Erantzun Sindrome Sistemikoa) puntuazio eskala erabiltzen da, infekzioa egon ala ez ager daitekeena eta ondorengo kriterioak dituena: bestela ondorioztatu ezin daitekeen eta adinari atxikitako takikardia (bradikardia urte betetik beherako haurrengan), takipnea adinari atxikia, edo bentilazio mekanikoaren beharra duen arnas prozesu akutua; 38,5ºCtik gorako edo 36ºCtik beherako tenperatura eta leukozitoen zenbaketa anormala (leukozitosia edo leukopenia) edo neutrofilo heldugabeen %10etik gorako zenbaketa; gainera, nahitaezkoak izango dira tenperatura edo odol analisitik eratorritako kriterioak26,38. Egia da SIRS kriterioak oso kritikatuak izan direla sortu zirenetik. Ez dauka sepsia bezalako larritasuna duen kuadroaren diagnostikoa egiteko behar besteko SARRERA 21 baliagarritasunik eta ondorioz, hilkortasun tasa aurreikusteko sentikortasun eta espezifikotasun maila apala da. Horregatik sarri erabilia izan da adostasun dokumentu honetan onartu zen “sepsi larri” kontzeptua38. Honetan, sepsiaren definizioari kriterio hauek gehitu zitzaizkion: disfuntzio kardiobaskularra, arnas zailtasun sindrome akutua edo/eta bestelako bi sistemen disfuntzioa. Shock septikoa, 40ml/kg-rainoko likido isotonikoen administrazioak egonkortzen ez duen sepsi eta disfuntzio organikoa bezala definitu zuten. Guzti honek bultzatuta, 2016an Surviving Sepsis Campaign-ek “Sepsis-3, Nazioarteko hirugarren adostasun dokumentua”39 publikatu zuen, paziente helduari zuzendua. SIRS kriterioak alboratu eta sepsis eta shock septikora sinplifikatu zituzten definizioak, sepsi larria desagerraraziz. Sepsia, hitzarte honen hasieran erakutsi den erara definitzen dute: infekzio baten aurka organismoak ematen duen erantzun immune desegokiak sorrarazi eta bizia arriskuan jartzen duen disfuntzio organikoa. Disfuntzio organiko honen balorazioan SOFA eskala (Sequential Organ Failure Assessment) erabiltzen da, eta 2 edo 2tik gorako puntuazioa izatekotan definituko da sepsia. Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 22 SOFA eskala (Sequential related Organ Failure Assessment) 0 1 2 3 4 Arnas parametroak PaO2/FiO2 (mmhg) o SaO2/FiO2 >400 <400 221-301 <300 142-220 <200 67-141 <100 <67 Koagulazioa Plaketak (103/mm3) >150 <150 <100 <50 <20 Gibel parametroak Bilirrubina (mg/dl) <1,2 1,2-1,9 2,0-5,9 6,0-11,9 >12,0 Kardiobaskularrab Tentsio arteriala Bataz besteko TA>70mmHg Bataz besteko TA<70mmHg Dopamina <5 edo dobutamina edozein dositara Dopamina 515; adrenalina <0,1 edo noradrenalina <0,1 Dopamina>15; adrenalina >0,1 edo noradrenalina >0,1 Nerbio sistema zentrala Glasgow eskala 15 13-14 10-12 6-9 <6 Iraitz sistema Kreatinina mg/dl Gernu fluxua (ml/egun) <1,2 1,2-1,9 2,0-3,4 3,5-4,9 <500 >5 <200 PaO2, oxigenoaren presio partzial arteriala; FiO2, arnastutako oxigenoaren frakzioa; SaO2, oxigeno periferikoaren saturazio arteriala. b, Bataz besteko tentsio arteriala >65mmhgtik gora mantentzeko sendagai basoaktiboen beharra gutxienez ordu betean (unitateak mikrogramo/kg/min) Shock septikoa aldiz, laktatoa > 2mmol/l-tik gora eta droga basoaktiboen beharra duen hipotentsio iraunkorra sortzen duen disfuntzio kardiobaskularra elkartzen direnean definituko da. Azken urteotan saiakera asko egin dira definizio hauek arlo pediatrikora moldatzeko eta p-SOFA deritzon eskala ere planteatu da40. SARRERA 29 (P. aeruginosa, enterobakteriak eta bestelako Gram negatiboak) eta fasziti nekrosantearen kasua (Clostridium eta bestelako anaerobioak)58,59. Aparteko komentarioa merezi dute S. aureus eta S. pyogenesek sorrarazten dituzten toxinek eragiten dituzten sindromeak: azal errearen sindromea eta shock estafilokozikoa S. aureusaren kasuan eta shock estreptokozikoa S. pyogenesaren kasuan. Azal errearen sindromean (Ritter sindromea), S. aureusek azalean sorrarazi duen infekzio lokal batetik abiatuta, epidermisaren lisia eragiteko gaitasuna duten toxinak daude jatorrian. Bat-bateko sukarra, suminkortasuna eta eskarlatina itxura izan dezakeen rash mingarria izango dira sintoma adierazgarrienak. Azal erupzio hau egun bat edo bitara builaz beteko da, handik egun batzutara guztiz deskamatzeko. Shockaren kasuan toxina estafilokozikoek superantigeno modura jardungo dute. Bat-bateko sukarra, gorakoak, beherakoak, mialgiak, eritrodermia eta hipotentsioa izango dira zeinu eta sintoma nabarmenenak. Egonkortze eta mantentze tratamendua eta zain barneko antibioterapia giltzarri izango dira60. Shock estreptokozikoa ume gazteetan eman ohi da eta arrisku faktore nabarmenak erlazionatu dira berarekin: barizela, diabetes mellitusa pairatzea, arnas gaixotasun kronikoa, kardiopatia edo GIBa. Hilkortasun tasa handia duen gaixotasuna da, hipotentsioa, sukarra eritrodermia eta konpromezu organoanitza islatzen duten zeinu eta sintomek definituko dutena. Bere diagnosirako kriterio kliniko, mikrobiologiko eta analitikoak beharrezkoak dira61. Egonkor eta itxuraz ondo dauden pazienteengan burutzen diren odol hazkuntzen errendimendua oso baxua izan ohi da. Odolean isolamendu positiboa gertatzen den kasuan, jatorrian azal eta ehun bigunen infekzioa duen bakteriemiaz mintzatuko gara. Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 30 Bakteriemia ezkutua Sukarraz gain, inolako zeinu eta sintomarik ez duen pazientearen odolean benetako bakteria baten isolamenduari deritzo bakteriemia ezkutua. “Ezkutua” adjektiboak pazientearen egoerari egiten dio erreferentzia. Alde batetik, haurrak itxura ona izan behar du. Hau definitzeko hainbat tresna erabil daitezke. Horietako bat da ebaluazio pediatrikorako triangelua eta honen emaitza “egonkorra” hitzarekin definitzen denean, umeak itxura osasuntsua duela ondorioztatzen da62. Ebaluazio pediatrikorako triangelua tresna azkarra eta oso erabilgarria da paziente pediatrikoaren hasierako ebaluaziorako. Aplikazio erreza du, ez baitu estetoskopiorik, otoskopiorik edo bestelako tresnarik behar, mediku, erizain edo trebatutako teknikariaren ikusmen eta entzumenetik haratago. Tresna hau, laburbilduz, osasun-profesional bakoitzak paziente bat lehen aldiz ikusten duenean egiten duen balorazio subjektiboa egituratzen saiatzen da. Ebaluazio pediatrikorako triangelua erabiltzen den ospitalezentro gehienetan, haren ebaluazioa triagean egiten da, zentroan zeregin horren arduradun diren langileek (mediku nahiz erizainek). Bere izenak dioen bezala, hiru aldek osatzen dute: pazientearen itxura, arnasketa lana eta larruazaleko zirkulazioa. Tresna honek ez digu pazientearen diagnostikorik ematen, baina bai egoera fisiologiko eta homeostasi egokia mantentzeko premiazko beharren berri. Bestetik, pazienteak sukarra bai, baina sukar horren jatorria zein den adieraz dezakeen zeinu edo sintomarik ez du azaldu behar, hala nola eztula, beherakoa, amigdalen hantura, auskultazio patologikoa, polipnea, zeinu meningeoak, eta abar. Susmopean dagoen bakteriaren arabera, bakteriemia bat izatetik meningitis bat izatera dagoen probabilitatea ezberdina da (H. influenzae eta meningokokoaren kasuan handiagoa da neumokokoaren kasuan baino). Behin antibiotiko dosi parenteral bakarra SARRERA 31 jartzeak, probabilitate hori mugatu egiten du, adibidez neumokokoaren kasuan11. Hau da bakteriemia ezkutua bilatzeko egiten diren ahaleginen arrazoi nagusia. Aipatu bezala, kontestu epidemiologikoaren aldaketek, gizarte ohituren aldaketek, eta batik bat arrisku gehien duten pazienteen, gazteenetan oro har, zeinu eta sintomak hain inespezifikoak izateak zaildu egiten du paziente hauen identifikazioa. Saiakera handiak egin dira azken hamarkadetan, bakteriemia ezkutu bat izan dezaketen aurretiaz osasuntsu diren paziente taldeak identifikatzeko. Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 32 HAURTZAROKO IBIETAN GEHIEN INPLIKATUTAKO BAKTERIAK Streptococcus pneumoniae Streptococcus pneumoniae kate laburrak eratzen dituen koko Gram positiboa da. Ehun serotipo ezberdinetik gora ezagutzen dira eta bakoitza polisakarido kapsularraren arabera dago definitua. Azken honen baitan dago serotipo bakoitzaren inmunitate espezifikoa. Bakteria honek bizitzaren lehen hilabeteetan ekiten dio sudur-faringe bidearen kolonizazioari, gorengo kolonizazio maila 3 urtetara lortzen duelarik. Ordurako, haur populazioaren %25 eta %80 bitartean kolonizatuta izango da. Streptococcus pneumoniaek bi eratako infekzioak sor ditzake; IBIak (meningitisa, bakteriemia, sepsia, neumonia bakteriemikoa eta beste batzuk) eta ez inbaditzaileak (neumonia ez bakteriemikoa, otitisa edota sinusitisa). Sudur-faringe bideetako kolonizazioak osatzen du Streptococcus pneumoniaeren gordailu bakarra eta honek errazten du bai familia artean, nahiz komunitatean eman daitekeen barreiadura63. Laurogeita hamarreko hamarkadaren erdian, Streptococcus pneumoniae zen meningitis bakterianoaren erantzule nagusia umeen artean. Azken hamarkadetan, baina, merkaturatu diren txerto konjokatuek epidemiologikoki eragin handia izan dute; erabat behera egin du bere prebalentziak garatu kontsideratzen diren herrialdeetan. Guzti honek, larrialdi zerbitzuetan burutzen ziren diagnosi eta maneiu terapeutikoen aldaketa suposatu du64. Neisseria meningitidis Neisseria meningitidis Gram negatiboa den mikroorganismo diplokokoa da. Gizakia da espezie honen gordailu bakarra eta aho-sudur-faringe bidean isolatu ohi da SARRERA 33 (garraiatzaileen portzentaiak oso aldakorrak dira). N meningitidis, N. gonorrhoeaerekin batera, Neisseria generoko espezie patogeno bakarra da. Antigenikoki gutxienez 13 serotaldetan banatu ohi da eta Neisseria meningitidisaren kapsulako polisakaridoa erabili da bereizgarri. Historikoki B eta C taldeak izan dira mendebaldeko herrialdeetako gaixotasun meningokozikoak sorrarazi dituztenak, nahiz eta Y edo W135 serotaldeek erlatiboki nabarmena izan den igoera izan duten. Bestetik, epidemiak sorrarazten dituena A serotaldea izan ohi da, batik bat garatze bidean dauden herrialdeetan. Gaixotasun meningokoziko inbaditzailearen epidemiologia, oro har, oso aldakorra da. Historian zehar uhin ezberdinak izan ditu eta datuak eskuragarri eta publiko direnetik azken hamarkadaren erdialdera argitaratu zen gaixotasunaren intzidentzia baxuena65,66. Izan ere, 2010eko hamarkadaren azken erdialdean nolabaiteko igoera orokor bat nabarmentzen hasi zen, ez soilik gure inguruan eta batik bat ez C eta ez B serotaldeak izanik erantzule. Aditu batzuen arabera uhin epidemiko baten aurrean egon gintezkeen, baina 2020ko Sars-Cov-2 pandemiak gogor jo eta honen aurrean ezarri ziren neurrien ondorioz (musukoa eta urruntze neurriek batez ere) Covid19 ez zen gaixotasun infekzioso transmitigarrien intzidentzia erabat apaldu zen, tartean gaixotasun meningokoziko inbaditzailearena67,68. Neisseria meningitidisak eragindako infekzio inbaditzailearen formarik ohikoenak meningitisa, sepsia edo bien arteko konbinazioa dira. Inkubazio epea 3-4 egunekoa izan ohi da. Kalkulatzea erreza ez den arren, meningitisak sorrarazten ez duen sepsi meningokozikoak %5-20 bitartekoak dira. Sepsiak hasiera bortitza du; sukarraz gain petekia deritzen orbainak agertzen dira, denbora gutxian areagotu egiten direnak, hipotentsio, shock edo porrot organoanitzari elkartuak sarritan. Gaixotasun honen Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 34 heriotza tasak altua izaten jarraitzen du (publikazio klasikoek %10ean ezartzen dute) diagnosi nahiz tratamendu tekniken aurrerapen handia bizi izan arren; heriotz-tasa handiagoa da sepsiaren kasuan meningitis soilaren kasuan baino30,31,46,63. Intzidentzia gailur nabarmenenak urtebetetik beherako haurrengan, 1-4 urte bitarteko adinean eta 15-19 urte bitarteko nerabeetan eman izan dira hurrenez hurren. Urte osoan zehar gertatzen diren arren, negu eta udaberrian pilatu ohi dira, gripearen birusa agertu eta gero. Lehen ere esan dugu, baina aho-sudur-faringe bidean Neisseria meningitidisaren eramale diren helduak %1-15 bitartean izan daitezke eta aste edo hilabete luzeetan izan gainera. Kolonizazio honek inmunizatu gabeko haur gaztea arrisku handiko egoeretara bultza dezake. Escherichia coli Escherichia coli gehien ikertu den bakterioetakoa da, enterobakterioen familiako bazilo Gram negatiboa, gizakiaren kolon eta ondohesteko bakterio-floraren partaide dena eta gehienetan ez da patogenoa. Hala ere, zenbait anduik birulentzia faktoreak eskuratu dituzte eta ondorioz, gizaki eta animaliengan hainbat infekzio sor ditzakete. Hainbat zeinu eta sintoma eman ditzakete, ondoko sindromeetan bil ditzakegunak: gernubideetako infekzioa, beherakoa/gastroenteritis akutua, bakteriemia eta sepsia/meningitisa. Escherichia Colia, gernubideetako mukosa kolonizatu ondoren, zelula barruan ugaritzen da, ostalariaren defentsak ekidinez. Sindrome klinikoa, batik bat gernu bideetako infekzioa, erraztuko duten hainbat birulentzia faktore izendatu dira: P eta S finbriak, hemolisina69,70. SARRERA 35 Beherakoa/gastroenteritis akutuaren eragile izan daitezke eta bere birulentzia markatuko duen faktore genetiko eta sorrarazitako kuadroaren arabera sailkatuko dira, patotipoak deiturikoak. Hauen artean daude, E. coli enteropatogenoak, enteroinbasiboak, enterotoxigenikoak… Sailkapen hau ez da lan honen helburuetako bat71. Oro har, esan beharrekoa da E. colia 12 hilabetetik beherako haurretan S. pneumoniaerekin batera, odolean isolatzen den bakteria ohikoena dela72, eta 3 hilabetetik beherakoen taldean, burua. Bakteriemia eragiten duten gernu infekzioekin batera, hau izanik diagnostiko ohikoena, bakteriemia ezkutuen eragile ere bada E. colia, baina, baita haur gazteenen sepsi eta meningitisaren eragile ere50. Meningitisaren eragileak geruza mukosoak kolonizatu eta odol bidean inbasioa eragin duten organismoak izango dira. Meningitis bakterianoaren patogenia ostalariaren adinaren araberakoa izango da; jaioberrien kasuan, erditze bidean amaren heste edo jariakin genitalen xurgapen edo kontaktuaren ondorioz barneratu diren patogenoak izango dira hein handi baten eragile. Kasurako E. coliaren K1 antigeno kapsularra, B serotipodun N. meningitidisen kapsulako polisakaridoaren oso antzekoa da eta honek odol bidean zehar barreiatu eta hesi hemato entzefalikoa saihesteko bidea ematen dio73. Staphylococcus aureus Staphylococcus aureus koko Gram positiboa da, anaerobio fakultatiboa, ohiko giza mikrobiotaren parte dena. Selektiboki koloniza ditzake sudur-zuloak, perinea, besapeak eta azal tolesdurak. Egun, aurretiaz osasuntsu diren 5 urtetik gorako paziente pediatrikoen taldean IBI gehien sortzen dituen bakterioa da eta hezur-artikulazio eta azal eta ehun bigunetako infekzioen eragile nagusia74,75. Gainera, shock estafilokoziko nahiz “azal errearen sindrome/Ritter sindromea”ren eragile diren toxinen erantzule ere bada S. aureusa. Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 36 S. aureusak sortzen dituen gaixotasunak bi talde handitan banatzen dira egun: alde batetik ospitale eta osasun-zentroekin erlazionatutako gaixotasunak eta eremu hauetatik kanpo, hau da, gizarte komunitarioan ematen diren gaixotasunak. Izan ere, ospitale eremu eta aurretiaz osasuntsu ez diren pazienteen artean, hala nola gordailu edo deribazio sistemak dituzten pazienteengan, kezka handia sortzen duen bakterioa da. Gainera, ospitalizatutako pazienteengan gertatzen diren bakteriemiak askoz ugariagoak dira fokua duten bakteriemiak baino76. Aurretiaz osasuntsu eta osasun zentroekin zerikusirik izan ez duten pazienteengan gertatzen diren bakteriemiek, jatorrian, hezur eta artikulazio infekzioak, ehun bigun eta larruazalekoak eta proportzio txikiagoan, neumonia izaten dute. Ardura handia sortu duen beste ezaugarri bat, hasieran ospitalera mugatuta zegoen metizilinari erresistentea den S. aureusa (SAMR), handik kanpora eragiteko gaitasuna erakutsi duela da. Ikerketa asko daude abian, SAMRek komunitatean duen intzidentzia jakiteko helburuarekin. Gure inguruan burutu zen ikerketa erretrospektibo baten arabera, intzidentzia %16 inguruan dago77. B taldeko estreptokokoa B taldeko estreptokokoa 3 hilabetetik beherako haurrengan diagnostikatzen diren infekzio bakteriano inbasiboen bigarren erantzule nagusia da E. coliaren ondoren, baina adin honetan gertatzen diren eta etiologia jakina duten sepsi eta meningitisaren eragile nagusia da 43,44,45. Gram positiboa den koko beta-hemolitikoa da eta gaurdaino 10 serotipo identifikatu dira. Liseri hodi eta erditze kanala kolonizatu ohi ditu, behin-behinekoa nahiz iraunkorra izan daitekeelarik. Gizonezko nahiz emakumeen liseri hodia da gordailua78. SARRERA 37 Kolonizatuta dauden emakumeen %40-60ak transmiti diezaioke bakteria hau euren jaioberriari. Transmisio hau haurdun dagoen emakumearen kolonizazio dentsitatearekiko zuzenki proportzionala da eta antigorputz kontzentraziorekiko alderantzizkoa. Haur jaioberri hauen %1-2ak garatuko du hilkortasun eta morbilitate tasa altuak izan ditzakeen infekzioa79,80,81,82. Azken urteetan ezarritako estrategiek, hala nola, haurdunaldiaren azken hiruhilekoan B taldeko estreptokokoaren detekziorako egiten den screening probak eta erditzean ezarritako antibioterapia protokoloek, bakteria honek eragiten dituen infekzio goiztiarren agerpenean eragin zuzena izan du. Hala ere, ez du eragin onuragarri bera izan zazpi egunetik haratago diagnostikatzen diren infekzio inbaditzaileetan 83,84. Honen arrazoiak bi izan daitezke: alde batetik, kolonizazioa iragankorra dela eta baheketan bakteria identifikatu ezin izatea eta bestetik, guztiz argi egon ez arren, jaioberria bera, erditu duen emakumearen liseri eta ugal aparatuko jariakinekin kontaktuan egon izana eta hauek xurgatu izana78. Nahiz eta adin honetan identifikatzen diren bakteriemien erantzule nagusi ez izan, kuadro kliniko larrienak sorrarazten dituen bakterioa da. Bere birulentziaren jatorria kapsulako polisakaridoak ematen dion fagozitazioa ekiditeko ahalmena da86,87. Streptococcus pyogenes S. pyogenes edo A taldeko estreptokoko beta hemolitikoa deritzona, kateetan batzen den koko Gram positiboa da (A antigenoa espresatzen du pareta zelularrean eta beta hemolisia sorrarazten duten S eta O estreptolisinak dauzka). Azal eta ehun bigunen infekzioak sortzen ditu, infekzio otorrinolaringologikoak, neumonia, baina baita larriak izan daitezkeen sakoneko ehun, muskulu eta abarren infekzioak ere (faszitis nekrotizantea kasu)58,59. Odolean isolatzen denean, bakteriemia baten aurrean egongo gara. Paziente Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 38 pediatrikoetan bakteriemia ezkutua eragin dezake aurkezpen ohikoena ez den arren; paziente helduetan garrantzi handiagoa du88. Bada aurkezpen arraroagorik, hilkortasun tasa handia duena ordea, S. pyogenesek sortzen dituen toxinek eragindako shock toxiko estreptokozikoa. Haemophilus influenzae Kokobazilo Gram negatibo hau anaerobio fakultatiboa da. Historikoki bi kategoriatan banatu da bakteria hau: kapsuladunak eta ez kapsuladunak. Kapsula da birulentzia faktore nagusiena eman izan dion ezaugarria eta B tipoko H. influenzae izan da historikoki, infekzio bakteriano larrienen erantzule nagusietakoa honen kontrako txerto konjokatua agertu zen arte. EEBBetan kasurako, urtean 20.000 kasu izatetik 40 kasu baino gutxiagora izatera pasa zen, 2000.urteko lehen hamarkadarako. B tipoaz gain badaude beste 5 serotipo germen kapsulatu honen baitan, goi eta behe arnas bide nahiz infekzio otorrinolaringologikoak eragiten dituztenak, batik bat. Andui hauek gehienetan patogeno oportunisten moduan jarduten dute. Ezaguna da baita ere, S. pneumoniae den era berean, H. influenzaren garraiatzaile diren 5 urtetik beherako haurren kopurua esanguratsua dela. Egia da hala ere, XXI. mendeko bigarren hamarkadan, H. influenzak eragindako infekzio inbasiboek gora egiten dutela, bai serotipagarri diren nahiz serotipagarriak ez diren aldaerak (kapsularik gabekoak) daudelarik euren jatorrian89,90. Beste batzuk Salmonella espeziaren kasuan, egia da S. pneumoniaeren azken hamarkadetako jaitsieraren ondorioz, odol laginetan agertu diren isolamenduen kopuru erlatiboak gora egin duela, batik bat paziente osasuntsuen kasuan. Hala ere, zenbaki absolutuetan ez da aldaketa esanguratsurik nabarmendu64,91. SARRERA 45 teknika batzuk ere badira eskura larrialdi zerbitzu baten: Gram tintzio klasikoa eta azken urteotako teknologiaren garapenak ahalbidetu duten mikroorganismoen identifikazio azkarra burutzeko teknikak, polimerasa kate erreakzioa (PCR) muinean duten testak, esaterako. Kulturak Odol korrontea, gernua (hein handi batetan) eta likido zefalorrakideoa, berez, esterilak dira. Ondorioz, odol lagin batean benetakoa dela kontsideratzen den bakteria isolatzen denean, bakteriemia baten aurrean egongo garela definitzen da. Diagnostiko etiologikoaz gain, antimikrobianoekiko sentsibilitate testak egitea ahalbidetuko du kulturak eta baita hauen tipifikazioa ere. Kulturak, hazkuntza inguru egokiak beharko ditu, bai bakteria aerobio nahiz anaerobioentzat eta diagnosi mikrobiologikoaren urrezko patroia izango da. Hala ere, gutxieneko ugalketa denbora bat pasa beharko du hazkuntzak (24 ordu gutxienez) esanguratsu den isolamendu bat lortzeko. Horrek, larrialdi zerbitzu baten artatzen den paziente pediatrikoaren oheburuan aurrera eramaten den maneiua zaildu egiten du. Likido zefalorrakideoaren kulturari dagokionean, berau, izango da urrezko patroia meningitis bakterianoaren diagnosian eta odol kulturen kasuen moduan, diagnostiko etiologikoaz gain, antimikrobianoekiko sentsibilitate testak eta tipifikazio testak egitea ahalbidetuko du. Likido zefalorrakideoaren prozesamenduak berehalakoa izan behar du, ordu batetik beherakoa112. Hala ere, 24 ordu baino gehiago behar izango du hazkuntzak germenaren ugalketa hauteman ahal izateko. Kultuaren errentagarritasuna gainera, bakterio erantzulearen eta aurretiaz antibiotikorik jaso edo jaso ezaren baitan egongo da. Neumokokoak eragindako %90ean kalkulatzen da kultura positiboa izango dela, baita meningokokoak sortutako %75ean113. Ikertzaile batzuek, zeftriaxonaren dosi bakarrak Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 46 (50mg/kg-ko dosia) meningokokoak eragindako meningitisaren LZRa, ordubete edo bi ordura esteriliza zezakeela ondorioztatu zuten, neumokokoak eragindakoarena 4-10 ordura eta B taldeko estreptokokoak eragindakoa 8 ordura30,114. Gernu infekzioari dagokiolarik, berau baieztatuko duen urrezko froga gernu kultura izango da115. Positibo faltsuak ekidin ahal izateko (batik bat lagina hartzeko prozeduran sortutako akatsak medio), gernu bilketak ahalik eta egokiena izan behar du: neurri higieniko egokiak hartu eta gero, bat-bateko gernua maskuri kontrola duten pazienteengan eta maskuri zundaketa edo ziztada suprapubikoa gainontzekoetan. Isolatzen den bakterio kontzentrazioak ere esanguratsua izan behar du, Ameriketako Akademia Pediatrikoaren arabera edo Espainiako Pediatria Elkarteak ezberdintasun xumeak eskaintzen dituzte116,117. Beste kultura batzuk ere burutuko dira larrialdi zerbitzuetan. Kasuan kasu, eta pazientearen egoeraren arabera, lagin bat edo besteren baten analisia egitea garrantzitsua izan daiteke. Hala nola, nahiz eta azal eta ehun bigunen infekzioa susmatu ezkero, draina daitekeen lesio baten kultura egitea interesgarria izan daiteke, kasu hauei atxikita dauden odol kulturen errentagarritasuna oso txikia delako, batik bat itxura onarekin eta egonkor iristen diren paziente pediatrikoetan. Draina daitezkeen lesio hauez gain, infekzio osteoartikular, isuri pleural edo bestelako jariakinen kulturak ere bere tokia izan dezake paziente baten diagnosi maneiuan (gehienetan prozedura hauek ez dira pazientea larrialdi zerbitzuan dagoela egingo). A taldeko estreptokokoaren bilaketan, aho-faringeko kultura egokia izan daiteke; inbasibitatea eragin dezaketen liseri aparatuko infekzioetan, koprokultiboa. SARRERA 47 Gram tintzioa Likido zefalorrakideoan eginiko Gram tintzioak espezifikotasun handia bai, baina sentsibilitate ertaina ditu ezaugarritzat meningitis bakterianoaren diagnosian118. Hala ere, meningitisiaren prebalentzia baxuaren ondorioz, balio prediktibo positiboa oso eskasa da119. Gainera, LZRan mikroskopio bidez bakteriak ikusteko gaitasuna, bakteria beraren eta bakterioek LZRan duten kontzentrazioaren araberakoa izango da. Meningitis neumokozikoa duten pazienteen %90ak izango du Gram tintzio positiboa, %80ak meningitis meningokozikoaren kasuan, %50ak bazilo Gram negatiboen kasuan eta %33ak Listeria monocitogenesak sortutakoetan30. Gernuaren kasuan, teknika, egin berri den gernuaren tintzio osteko mikroskopio bidezko azterketari deritzo. Espezifikotasun handiko proba da (%99tik gora), baina errekurtso handiagoak behar dituen proba izaki, ez dago beti eskuragarri eta garestia da120. Beraz, paziente berezi edo bereizien maneiuan baliatuko den testa izango da. Teknika mikrobiologiko berriak Azken urteetan teknika mikrobiologiko berriak merkaturatu dira, infekzio bakteriano nahiz biralen diagnosi eta maneiu algoritmoetan leku garrantzitsua hartu dutelarik. Polimerasan oinarritutako kate erreakzioaren teknika eta honetatik eratorritako diagnosi teknikak dira adibide ezagunena. Gainera, eratorri hauek hainbat laginetan erabili dira gaur arte: sudur eta faringe bideetako jariakinak, listuan, gorozkietan,… baina lan honetan oro har, eta bereziki puntu honetan, odol eta likido zefalorrakideoan erabiltzen den teknikaren inguruan arituko gara. Gure inguruan, bakterien identifikaziora mugatzen diren eta odol lagina oinarri duten kit ezberdinak daude eskuragarri, meningokokoa, neumokokoa eta Listeria identifikatzen dituen testa delarik erabiliena infekzio bakterianoen identifikazioari dagokionean. Nerbio Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 48 sistemaren infekzioaren bilaketarako likido zefalorrakideoa helburu duten testak ere merkaturatu dira, infekzio hauen maneiuan aldaketak eragin ditzaketenak. Infekzio biralen identifikazioan ere oso erabilia da polimerasa kate erreakzioan oinarritutako testa: enterobirusak, herpervirusak, arnas sisteman eragiten duten birusak... Test hauen onurarik handiena denbora da, erabakiak hartzeko itxaronaldia askoz laburragoa den denbora tarte batera mugatzen duelako ziurgabetasuna. Hala ere, guztiak ez dira abantailak; ez daude beti eskuragarri, test bakoitzak bakteria multzo bat identifika dezake, beti dira posible positibo faltsuak eta “garestiagoak” dira momentuz. Polimerasan oinarritutako kate-erreakzioaren teknika (PCR) Funtsean DNA zati batetik abiatuta milioika kopia egiteko ahala duen teknika mikrobiologikoa da; genoma bakterianoaren atal jakin batzuen anplifikazioan oinarritzen da. Denbora errealean egiten den PCR bezalako teknika genomikoak praktika klinikorako diagnosi tekniken artean aurrerapen handia ekarri du. Beste teknika batzuekin konparatuta zenbait abantaila eskaintzen ditu. Alde batetik, emaitzak denbora tarte oso laburrean daude eskuragarri. Beti ere, maneiu-algoritmo sendo eta egokien menpean, pazientearen oheburuan erabaki azkarragoak hartzeko bidea zabaltzen dute. Kit eta proba ezberdinek, sentikortasun eta espezifikotasun ezberdinak eskaintzen dituzte; kulturarekin alderatuta ordea, sentikortasuna handiagoa da teknika berri hauekin. Hala ere, momentuz ez da gomendagarria kultura, PCR teknikengatik ordezkatzea IBIen diagnosi algoritmoan121,122. Bestetik, esan beharrekoa da antibiotikoa lagina eskuratu aurretik ezarri izateak ez duela PCR testen identifikazio gaitasunean hain eragin bortitzik, beti ere hazkuntzarekin konparatuz. N. meningitidisaren identifikaziorako, PCR tekniken sentikortasuna %95 ingurukoa da likido zefalorrakideoan eskuratutako laginetarako eta zertxobait baxuagoa SARRERA 49 odol laginetarako. DNA meningokozikoa antibioterapia sistemikoa hasi eta 72 ordura arte antzeman daitekeen arren, kontu handia izan behar da teknika honen bitartez ondorioztatutako emaitza negatiboak interpretatzerako orduan, gaixotasunaren aurkezpen klinikoak, larritasunak, iraupenak eta tratamendu antibiotikoaren hasiera uneak bere eragina izan dezaketelako testaren errendimenduan 3,123,124. Azken aldian teknika honetan oinarritutako beste aukera batzuk merkaturatu dira: mikroorganismo ugari biltzen dituzten panelak, FilmArray panel multipleak kasu, zenbait algoritmotan ohorezko lekua har dezaketenak. Ohiko denbora errealean irakurtzen diren antzeko testekin konparatuta, anplifikazioa eta irakurketa ez dira aldi berean burutzen eta honek agente infekziosoaren material genetikoaren presentziaren edo gabeziaren interpretazio kualitatiboa baino ezin egitea dakar. Abantaila ikaragarriak izan ditzakeen arren (emaitzak ordubetearen buruan izan ditzakegu adibidez FilmArray® Panel meningitis-encefalitis testaren kasuan), test honek ere bere mugak ditu: lortutako emaitzak kualitatiboak dira; panelak eskaintzen dituen mikroorganismo zerrendaren presentzia baino ez du ondorioztatzen; lan-eremu homogeneo batetik kanpoko emaitzek, ondo aztertutako lan-algoritmo hertsietatik kanpora lortutakoek, interpretazio zailak izan ditzakete (herpes birus familiaren presentziaren interpretazioa esaterako, giza-genoman integratzeko duen gaitasuna medio). Irudi-teknikak Zenbait irudi-teknika baliagarri eta osagarri izan daitezke larrialdi zerbitzuan sukarra duen paziente bat artatzen ari garenean. Esaterako, infekzio osteoartikularraren susmopean dagoen pazientearen aurrean, gidek gomendatzen duten lehen irudi-froga erradiografia izaten da75,125. Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 50 Hala ere, gure inguruan kontsultatzen diren infekzio osteoartikularren susmopean dauden kuadro klinikoak larregi eboluzionatu gabeko kuadroak izan ohi dira eta normalena litzateke esanguratsu diren ezaugarri erradiologikoak oraindik ageriko ez izatea eta test honek maneiu terapeutikoan erabakien aldaketarik ez sortaraztea. Ekografia muskuloeskeletikoak, artritisaren susmopean dauden kuadro klinikoetan bere lekua izan dezake, artikulazioan likidorik dagoen edo ez ondorioztatzeko eta drainatze tekniketan lagungarri izateko126. Arnas zailtasuna ageri duten sukardun pazienteengan neumonia izan daiteke diagnostikoetako bat. Gida gehienek ez dute erabat derrigorrezkotzat jotzen irudi erradiologikoaren beharra paziente jakin bati neumonia diagnostikoa ezartzeko, nahiz eta ohiko praktika izan herrialde garatuetan eta batik bat errekurtso hori gau eta egun eskuragarri dagoen zentroetan. Badaude egon, hala ere, erradiografia egitera bultzatuko gaituzten indikazio jakinak55,127. Azken urteetan, halaber, leku handia hartu du pazientearen oheburuan egiten den birika ekografiak, erradiologoa ez den medikuak egiten duena eta emaitza onargarriak izaten ari dena. Hala ere, oraindik ebidentzien babesa ez da erabatekoa; bere mugen artean, profesionalen arteko aldakortasuna da garrantzitsuena eta esperientziak garrantzi handia izango du128. Protokoloak Protokoloak edozein sistemak segurtasunez funtzionatzeko beharrezko dituen tresnak dira. Larrialdi zerbitzu pediatriko bati gagozkiolarik, ebidentzia zientifikoan oinarritutako maneiuak izan behar dute eta tokian tokiko errekurtsoetara moldatuta egotea. Kuadro kliniko ezberdinen aurrean prestatuta ditugun protokoloek, profesional bakoitzak antzeko kuadroaren aurrean egiten duen maneiu terapeutikoan aldakortasuna murriztea SARRERA 51 ekarriko du; sistema eta pazientearen onura klinikoa, ekonomikoa eta segurtasuna, hein handi batean bermatuko du. Hurrengo puntuetan maneiu ezberdinen azalpenaz arduratuko gara. Aurrez osasuntsuak ez diren pazienteak Gero eta ohikoagoa da larrialdi zerbitzu baten aurretik osasuntsu ez diren pazienteak artatzea. Paziente kronikoen bizi kalitate eta esperantzak gora egin du azken hamarkadetan. Ebidentzia zientifikoak aurrera egin ahala, erakunde ezberdinek infekzio bakteriano larri bat izateko arrisku gehiago duten pazienteen diagnosi eta tratamendu algoritmoetan moldaketak egin dituzte. Askotariko dispositiboen garraiatzaile diren pazienteen, hala nola deribazio bentrikulu peritoneal edo antzekoak diren balbula, kateter zentral edo erreserborioa, edo hemodialiasia egiteko beharrezko diren dispositiboak dituztenetan, hurbilketa diagnostikoak ezberdina izan behar du. Azken urteotan paziente onkologiko edo bestelako immunogutxituen prozedurak ere aldatuz joan dira, bestelako paziente kronikoen ikuspuntuak indibidualizatu egin dira, gernu bideetan malformazio garrantzitsuak dituzten paziente pediatrikoen lehentasunak finkatu dira, eta abar luze bat. Tesi honen helburua ez da arrisku-talde bakoitzaren protokoloak banan-banan azaltzea; gainera, tesi honen hasiera markatzen duen artikulutik azkenengora, protokolo ezberdinek aldaerak izan dituzte eta maneiu pertsonalizatuak ere jaso izan dituzte pazienteek kasuan kasu. Aurrez osasuntsu diren pazienteak Gainontzeko pazienteak aurrez osasuntsu diren paziente definituko ditugu. Hauek, oro har, infekzio larriagoak pairatzeko arrisku gutxiago izango dute. Horregatik, paziente Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 52 hauenganako hurbilketak ere garrantzi handia izango du, pazientearen segurtasunean eta sor daitekeen iatrogenian ere eragina izango duelako. Sukarra daukan paziente baten edo infekzio baten susmopean dagoen paziente baten aurrean, medikuak eman behar izaten duen pausurik baliozkoena, paziente horrek tratamenduren bat lehen bait lehen jaso behar duen edo ez erabakitzea da; hau da, larri dagoen edo ez; egonkor dagoen edo ez ebaluatzea. Horretarako hainbat eskala eta erabaki tresna erabiltzen dira, aurrez komentatu den ebaluazio pediatrikorako triangelua deritzona kasurako62. Sukarra dela eta artatzen diren pazienteen gehiengoa egonkor heltzen da larrialdi zerbitzura. Behin egonkortasuna bideratuta, hurrengo erabaki garrantzitsua fokurik gabeko sukar eta fokudun sukarraren arteko ezberdintasuna egitea izango da. Sukar horren jatorria azal dezakeen anamnesi eta azterketa fisikoak, froga osagarriak egitera edo ez egitera eramango dute medikua, batik bat tratamendu antibiotikoa behar duen ala ez erabakitzeko. Goi arnas bideetako infekzio baten kasuan, azterketa fisikoak bentilazio gutxiko birika eremu bat azaleratuz gero, neumonia baten zantzuak hauteman ditzake eta kasuan kasu erabakiko du irudi probaren bat egin behar duen edo ez, tratamenduarekin hasteko. Bestetik, azterketa fisikoak zantzurik eman ezean, gomendio ohikoena tratamendu sintomatikoarekin aurrera jarraitzea izan ohi da55,127, nahiz eta jakin, paziente multzo honen barruan IBI bat paira dezaketenak egon daitezkeela. Gernu-bideekin erlazionatutako sintomak gehitzen bazaizkio sukarrari, gernu-bideetako infekzioa ondorioztatu dezaketen frogak egingo dira; gernu banda erreaktibo eta kultiboa, berau normala izan ezean. Azal eta ehun bigun edo infekzio osteoartikular edo infekzio otorrinolaringologikoen kasuan, azterketa fisikoak informazio handia emango du froga osagarriak egin behar diren edo ez erabakitzeko, eta kasuan kasu, tratamendu antibiotiko anbulatorioa edo zain-barnekoa ezatzeko. SARRERA 53 Meningitisa susmatzen den kasuetan, gerta daiteke pazienteak ebaluazio pediatrikorako triangelu egonkorra izatea, ohikoena izan ez arren. Helburu nagusia, meningitisa pairatzen duen haurraren identifikazioa da eta hurrengoa meningitisaren jatorria birala edo bakterianoa den ondorioztatzea. Meningitis bakteriano baten aurrean antibiotikoaren administrazio goiztiarrak pronostikoaren hobekuntza dakar. Bestetik, birala den meningitisa identifikatzeak, alferrikakoak diren tratamendu eta ospitalizazio egonaldiak ekidingo ditu, sorrarazten duen iatrogeniarekin batera. Hala ere, identifikazio hau ez da batere erraza, zeinu patognomonikorik ez izateak eta pazienteen kontsulta goiztiarrak, zeinu eta sintomen inespezifikotasuna baitarama berarekin. Likido zefalorrakideoaren analisi eta kulturak emango dute diagnostikoa, hau da giltza. Hala ere, kulturaren emaitza ez da berehalakoa eta azken urteetan hainbat saiakera egin dira diagnosi prozesu honen zehaztasuna areagotzeko, hainbat score edo aurreikuspen klinikorako tresna eta gida publikatu baitira ziurgabetasun hau murrizte asmoz129,130. Score hauek datu kliniko eta analitikoak (odol eta likido zefalorrakideoan) uztartzen dituzte. Azkenik, teknika mikrobiologikoen agerpenak eta PCR tekniken agerpenak batik bat, diagnosi algoritmoetan erabaki goiztiarragoak hartzeko aukera erraztu dute. Tesiaren sarreran aipatu bezala, larritasun gehien sorrarazten duten infekzio bakterianoak odol edo LZRan isolatzen diren bakteriek eragindakoak dira. Infekzio bakteriano inbasibo larriena ez den arren, bakteriemia ezkutua, hauen adibidetako bat da. Ebaluazio pediatrikorako triangelu egonkorra duen sukardun paziente baten odolean bakteria bat isolatzen denean definitzen den egoera da, non azterketa fisiko nahiz gaixoaren sintomek sukar honen jatorria zein den azal ezin dezaketenean. Bakteriemia ezkutuaren bilaketa aktiboan ahalegin oso biziak egin diren paziente multzo bat, aurretiaz osasuntsuak diren 0-3 hilabeteko haurren taldea da. Adin honetan, E. coli Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 54 eta B taldeko estreptokokoa dira eragile ohikoenak. Immunitate sistema heldugabeak eta txertaketa programa hasi gabe egoteak ere, beste arrazoi batzuen artean, infekzio bakteriano larri bat izateko hautagai egiten dituzte. Hala ere, haur hauetako asko ingresu eta antibiotikorik gabeko jarraipena izateko hautagaiak dira gaur egun. Asko izan dira saiakerak, Rochesterren irizpideetatik hasi eta gaurdaino (Philadelphia eta Boston irizpideak), baina lortu diren atxikimendu tasak ez dira nabarmenegiak izan131. Azken urteetan agertu diren biomarkatzaile berriek eta urteetan zehar burututako lanaren emaitzek, bularreko haur txikien maneiu berri bat erraztu dute. Gure inguruan, “Step by Step” eta PECARN gida dira paziente hauen maneiuan gehien erabiltzen diren tresnak132,133,134. Hala ere, tresna hauek ez dira finkoak diren estrategiak eta denborarekin eta agertzen ari den ebidentziekin aldaketa nabariak bizi izan dituzte. Nagusiago diren haurretan, batik bat, aurretiaz osasuntsuak diren 3-24 hilabeteko sukarrarekin dauden paziente multzoa da asko ikertu den beste talde bat. Historikoki, talde honetan S. pneumoniae zen gehien isolatzen zen bakteria baina Haemophilus influenzaeren bakteriemia ezkutuak eragiten zituen konplikazioak, meningitisa, ondorio larriak eta heriotza tasa latzak ziren135. Haemophilus influenzaeren kontrako txertoak unibertsalizatu zirenetik, bakteriemia ezkutuaren tasak behera egin zuen nabarmen136. Azken urteetan hedatu diren neumokokoaren aurkako txerto konjokatuek ere infekzio inbasibo neumokozikoen jaitsiera nabarmena ekarri zuten. Txerto zazpibalenteak batik bat bakteriemia ezkutu neumokozikoaren jaitsiera nabarmen bat ekarri zuen berarekin3,7,8. Joera honek 2010 urtean zabaldu zen txerto konjokatu hamahirubalentearekin berdintsu jarraitu zuen eta serie batzuen arabera, neumokokoa ez litzatekeen gehien isolatuko zen bakteria izango 64,137,138. SARRERA 61 gainera, autonomi erkidego batzuren txertaketa kanpainen parte baino ez da oraingoz65,185. Bi mila eta hamabost urtetik aurrera, zifrak zertxobait gora egin zuen, intzidentzia tasa 0,8367 kasutara iritsi zelarik, batik bat W135 serotaldearen areagotzearen ondorioz. Hainbat aditu meningokokoaren uhin epidemiko berri baten aurrean geundela esatera ere iritsi zen. Streptococcus pneumoniaeren aurkako txertoak Hogeitahiru serotiporen babesa eskaintzen zuen txertoa 1977 urteaz geroztik eskuragarri bazegoen ere, ez zen oso eraginkorra 2 urterik beherako haurren artean, sistema immunitarioak adin honetan eskaintzen duen heldutasun falta dela eta. Bi milagarren urtean, S. pneumoniaeren zazpi aldaeren polisakaridoz eratutako (4, 6B, 9V, 14, 18C, 19F y 23F) txerto konjokatu heptabalentea onartu zen (PCV7). Lehendabizi Estatu Batuetan eta gerora, Europar Batasuneko immunizazio programei atxikitu zitzaien. Txerto honek, neumokokoaren eraginez 2000.urtean Estatu Batuetan antzeman ziren infekzio inbaditzaileen %80tik gorako estaldura eskainiko zukeen33,186,187. Txerto honen komertzializaziotik hona, Streptococcus pneumoniaek eragindako infekzio inbaditzaileen intzidentzia orokorrak nabarmen egin du behera adin talde guztietan, baina batik bat urte bitik beherako haurrengan, txertatuta egon edo ez31,183,188. Bestetik, PCV7 bidez eginiko txertaketa ia unibertsala bizi izan zen arren, ikerketa berri eta zenbait zaintza eta begirale-sareren informeek, txertoek eskaintzen zuten estalduraz kanpoko serotipoek eragindako infekzioen gorakada jaso zuten: batik bat, 1, 19A, 7F, 3 eta 6Ak eragindakoak, “serotipoen ordezkapena” bezala deitua. Hemeretzi A serotipoa gainera, multierresistentzia antimikrobianoen %80a bere baitan soilik biltzeko gai izan dena, txerto konjokatu zazpibalentearen sarreraz geroztiko infekzio inbaditzaileen kausa Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 62 garrantzitsu bihurtu zen6,183,188,189. 2010ean, txerto konjokatu hamahirubalenteak zazpibalentea ordezkatu zuen, Estatu Batuetako txertaketa programetan. Txerto honek, aurreko urteetan jazo zen “serotipoen ordezkapena” eragin zuten aldaerak bildu zituen, tartean 19A eta 7F. Gaixotasunen kontrol eta prebentziorako zentroaren (CDC) argitalpen eguneratu baten190 txerto aldaketa honek 5 urtetik beherako umeengan Streptococcus pneumoniaek eragindako infekzio inbaditzaileen %64ko murrizketa eta txerto 13balenteren barnean dauden serotipo berriek eragindako infekzio inbaditzaileen %93ko murrizketa eragin duela publikatu zuen191,192,193,194. Bost eta 15 urte bitarteko pazienteengan txerto 13balentean integratutako serotipoen ondorioz jazotako infekzio inbaditzaileen intzidentziak %75 egin zuen behera. Oro har, adin talde guztietan izan zuen ondorio bera, batik bat 19A eta 7F serotipoen gainbehera zela eta194,195. Guzti honek eragina izan du sukarrarekin datorren bularreko haur baten kudeaketa egiterakoan. Egun, IBI neumokozikoen parte handi baten erantzule diren bi serotipo “berri”, etorkizun hurbilekoko txertaketa egutegietan sartzear daude196. Honek ere azpimarra egiten du IBIen monitorizazioa egiteko beharraren garrantziaz. LAN HIPOTESIA 63 LAN HIPOTESIA Arkatzekin armatuta arriskutsuak gara, hondarrezkoak direnez zuen gaztelu gotorrak ideien olatu honek botako ditu (BTx) Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 64 LAN HIPOTESIA 65 LAN HIPOTESIA Egun, IBIa duen pazientea, oso goiz iritsi ohi da larrialdi zerbitzuetara, sintomak eta azterketa fisikoan ager daitezkeen zeinuak inespezifikoak direnean. Paziente horien gehiengoa oso gaztea da eta horrek infekzio desberdinen karakterizazio klasikoa kasu bakanetan agertzea ondorioztatuko du. Azken urteotan ezarri diren txertaketa kanpaina ezberdinek IBIen ezaugarri epidemiologikoak aldatu dituzte. Honek guztiak medikuaren erabakitzeko gaitasunean bere eragina izan du. Aitzitik, IBI bat izateko arrisku handiagoa duten sukardun pazientea identifikatzeko jardunean, odol analisiaren munduan nahiz bestelako baliabideetan egindako aurrerakuntzek, sukarra dela eta larrialdi zerbitzura datorren pazienteengan egin daitezkeen proben kopurua handitu egin da. Ezaugarri askok izango dute eragina froga hauen errendimenduan; are gehiago, froga hauek egingo diren pazienteak ondo sailkatu ezean. Finean, IBIak arazo larria izaten jarraitzen dute. Azken urteotako aldaketen harira, IBIen zenbaketa globalak behera egin du batetik, eta bestetik, osasun zerbitzuan egiten diren kontsultak askoz goiztiarragoak dira. Medikuaren erronka nagusi bat, egonkor azaldu eta sukarra duen pazienteak IBIa izan dezakeen identifikatzea izango da, anamnesi, azterketa fisiko, eta beharrezko ikusten duenean, beste test eta froga ezberdinez baliatuta. Gure hipotesi nagusia hauxe da: IBIa pairatzen duen pazienteren karakterizazioak eta hauen identifikaziorako ditugun baliabideen errendimenduak aldaketak jasan izan ditzake azken urteotan. Baliabide multzo honetan anamnesia, azterketa fisikoa eta larrialdi zerbitzu batean egin ditzakegun froga osagarriak bilduko ditugu. HELBURU NAGUSIAK 66 HELBURU NAGUSIAK 1. Hamalau urtetik beherako pazienteetan baieztatu diren IBIen aurkezpen klinikoaren karakterizazioa deskribatu. 2. Hamalau urtetik beherako pazienteen IBIen larritasuna deskribatu. 3. Hamalau urtetik beherako pazienteen IBIak identifikatzeko egiten diren ohiko odol testen (leukozitoen zenbaketa, neutrofiloen zenbaki absolutua, proteina C erreaktiboa eta prokaltzitonina) balioa analizatu. 4. Fokurik gabeko sukarra duten eta larrialdi zerbitzura egonkor iristen diren 3-24 hilabete arteko haurrak artatzerakoan odol testik ez erabiltzearen gomendioa ebaluatu. 5. E. colik eragindako infekzio inbaditzaileen aurkezpena deskribatu eta balizko profilak eta larritasunarekiko balizko harremana ikertu. 6. B taldeko estreptokokoak eragindako infekzio inbaditzailearen aurkezpena deskribatu eta haren larritasunarekiko balizko harremana ikertu. BIGARREN MAILAKO HELBURUAK Tesi honen helburu ez zen arren, aurretik espero ez genuen pandemia batek larrialdi zerbitzu baten identifikatu diren IBIen epidemiologian izan duen eragina deskribatu. METODOA 67 METODOA Nola azalera irten? (BTx ) Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 68 METODOA 69 METODOA ARGITARATUTAKO ARTIKULUAK ETA KALITATEZKO INDIZEAK 1. Gangoiti I, Valle JR, Sota M, Martinez-Indart L, Benito J, Mintegi S. Characteristics of children with microbiologically confirmed invasive bacterial infections in the emergency department. Eur J Emerg Med. 2018 Aug;25(4):274-280. doi: 10.1097/MEJ.0000000000000453. PMID: 28118320 • ISSN: 0969-9546 • JCR: Science Edition, 2018 • Impact factor: 1.383 • Category: Emergency Medicine. Posición: 18/29 • Quartil: Q3 Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 70 In conclusion, paediatric IBIs currently present more frequently in previously healthy young children, with a clinical and epidemiological pattern that is highly dependent on the age of the patient and the bacterium isolated. The evolution of children with an invasive infection was generally good, although those patients who consulted with a shorter time to progression, symptoms other than fever or who did not present a good general condition upon arrival at the ED were associated with more severe processes. Pneumococcus spp. was responsible for more than half of the cases that resulted in death or the appearance of sequelae in these children. Acknowledgements Conflicts of interest There are no conflicts of interest. 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Repeated emergency department visits among children admitted with meningitis or septicemia: a population-based study. Ann Emerg Med 2015; 65:625–632. 20 Green SM, Nigrovic LE, Krauss BS. Sick kids look sick. Ann Emerg Med 2015; 65:633–635. Table 6 Univariate and multivariate analyses to identify the risk factors for severity in children diagnosed with an invasive bacterial infection Univariate Multivariate POR (95% CI) POR (95% CI) Age (>24 months) 0.691 1.123 (0.633–1.994) Sex (female) 0.257 1.395 (0.785–2.481) Previous visit to the emergency department 0.162 1.736 (0.802–3.759) Duration of fever (<24 h) 0.080 1.740 (0.937–3.233) <0.001 4.082 (1.859–8.964) Symptoms other than fever <0.001 4.935 (2.114–11.523) 0.005 3.869 (1.507–9.938) Physical examination (altered) <0.001 4.825 (2.398–9.705) Temperature recorded upon arrival at the emergency department (≥39) 0.025 2.199 (1.104–4.382) Maximum temperature at home (<39) 0.552 1.206 (0.651–2.234) Well-appearing (no) <0.001 8.910 (4.543–17.478) <0.001 8.286 (3.737–18.370) Patient previously healthy (no) 0.062 2.421 (0.957–6.125) CI, confidence interval; OR, odds ratio. Characteristics of paediatric IBI Gangoiti et al.7 Copyright r2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. METODOA 71 2. Gangoiti I, Rodriguez E, Zubizarreta A, Benito J, Mintegi S. Prevalence of Occult Bacteremia in Infants With Very High Fever Without a Source. Pediatr Infect Dis J. 2018 Nov;37(11):e271-e273. doi: 10.1097/INF.0000000000001955. PMID: 29462106. • ISSN: 0891-3668 • JCR: Science Edition, 2018 • Impact factor: 2,317 • Category: Pediatrics. Posición: 39/125 • Quartil: 2 Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 72 Downloaded from http://journals.lww.com/pidj by VA2NP/EQXy5eAF3OZjUWq1xwD37/nWyagW5BHJqgwOhSu001FdfUrgaICuRdtVc1lY841S/5eJyFYfhbyXZE3ysfQMuwLtjpQx1lgvT6Z6tccJNU/qnYxpfYoLto/vx+OizeI0klFa0enzj2w4wdwQ== on 10/12/2018 Downloaded from http://journals.lww.com/pidj by VA2NP/EQXy5eAF3OZjUWq1xwD37/nWyagW5BHJqgwOhSu001FdfUrgaICuRdtVc1lY841S/5eJyFYfhbyXZE3ysfQMuwLtjpQx1lgvT6Z6tccJNU/qnYxpfYoLto/vx+OizeI0klFa0enzj2w4wdwQ== on 10/12/2018 Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. © 2018 Wolters Kluwer Health, Inc. All rights reserved. www.pidj.com | e271 The Pediatric Infectious Disease Journal • Volume 37, Number 11, November 2018 Occult Bacteremia in Infants with Very High Fever PREVALENCE OF OCCULT BACTEREMIA IN INFANTS WITH VERY HIGH FEVER WITHOUT A SOURCE Iker Gangoiti, MD, Elva Rodriguez, MD, Ane Zubizarreta, MD, Javier Benito MD, PhD, and Santiago Mintegi, MD, PhD Abstract: We carried out a prospective registry-based cohort study at the emergency department of 363 previously healthy well-appearing infants 3–24 months of age with fever without a source ≥40.5°C based on local protocol. Four were diagnosed with occult bacteremia (1.1%; 95% confidence interval: 0–2.2). Recommendations for nontesting for occult bacteremia screening in these children may have to be reconsidered when fever ≥40.5°C. Larger studies are needed to confirm these results. Key Words: occult bacteremia, very high fever, fever without source, infants Accepted for publication February 13, 2018. From the Paediatric Emergency Department, Cruces University Hospital, University of the Basque Country, Bilbao, Basque Country, Spain. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Santiago Mintegi, MD, PhD, Paediatric Emergency Department, Cruces University Hospital, Plaza de Cruces s/n, E-48903 Barakaldo, Bizkaia, Spain. E-mail: [email protected]. After the introduction of the pneumococcal conjugate vaccines (PCVs), pneumococcal invasive infections in febrile infants, including occult bacteremia (OB), declined dramatically.1–3 In a cost-effectiveness study, it was stated that when the rate of OB in febrile infants falls below 0.5% strategies that use empiric testing and treatment should be eliminated.4 On the other hand, if bacteremia rate is over 1.5%, it is cost-effective to obtain blood tests.4 Currently, in vaccinated populations, the rate of OB in febrile infants is less than 0.5%. Nevertheless, these studies included infants with temperature greater than 39°C, and it is known that the prevalence of bacteremia increases at higher temperatures.5 To our knowledge, no study has addressed the rate of OB in well-appearing, highly febrile infants in the era of PCV. The objective of this study is to analyze the prevalence of OB in previously healthy well-appearing infants 3–24 months of age with fever without a source (FWS) equal or higher than 40.5°C in the era of PCV. PATIENTS AND METHODS We carried out a registry-based cohort study at the pediatric emergency department (ED) of a tertiary level teaching hospital attending 55,000 visits annually. We included all previously healthy well-appearing infants 3–24 months of age with FWS ≥40.5°C brought to the ED between 2013 and 2016. Each month, all the febrile infants with a blood culture obtained were identified using the electronic databases of the Microbiology Service and the ED. After that, the main investigator selected for inclusion all infants 3–24 months of age with FWS ≥40.5°C with a blood culture obtained when evaluated in the ED. To check that all infants 3–24 months of age with FWS ≥40.5°C were included, we also reviewed a randomized sample of the patients coming to the ED during the period of the study. In this way, we revised all the episodes of children admitted to the ED 1 week per month during the period of the study. We collected the following data from the electronic clinical records of our ED: age, gender, personal history, PCV status, duration of fever, associated symptoms, temperature, previous consultation in the ED, appearance on arrival, physical examination, different blood tests (white blood cell count, absolute neutrophil Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/INF.0000000000001955 despite the highly variable baseline microbiota of patients with a tracheostomy.7 The traditional reductionist approach of categorizing ARIs as either viral or bacterial may be too simplistic a clinical framework for ARIs in individuals with a tracheostomy, and possibly all people with ARIs.7 On D1 of ARI, the majority of the current prospective cohort had a virus detected and a “bloom” of already present genera (ie, Haemophilus and Moraxella). The tracheal finding of Haemophilus and Moraxella blooming are consistent with findings from previous studies utilizing nasopharyngeal samples to examine acute respiratory illness outcomes.9 And although viral–bacterial interactions during ARIs have been described,10 the present results extend previous research by suggesting that these ARIs were not infections due to acquisition of a new bacterial pathogen as Koch’s postulates suggest, but rather a bloom of colonizing genera in the context of a viral infection. Conceptualizing ARIs as “blooms” may be more complex to operationalize clinically than the current reductionist approach, but may eventually provide opportunities for novel, targeted treatment methods. Although beyond the scope of these data, ARIs may be best understood as an emergent phenomenon7 that (1) is driven by a complex interplay among the infecting virus, microbiome and host response9 and (2) results in a continuum of ARI severity anchored by pneumonia. The next step is to better understand the pathobiology of ARI in this high-risk population with variable underlying microbiota to develop novel targets for ARI treatment and to provide guidance about when to use antimicrobials and which bacteria to treat. Until this time of improved ARI understanding and clinical guidance, many clinicians will continue to overuse and misuse antimicrobials for ARIs in children with a tracheostomy. ACKNOWLEDGMENTS We thank the GWU Colonial One High-Performance Computing Cluster for computational time. REFERENCES 1. Mortality GBD, Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117–171. 2. Dosa NP, Boeing NM, Ms N, et al. Excess risk of severe acute illness in children with chronic health conditions. Pediatrics. 2001;107:499–504. 3. Zhu H, Das P, Roberson DW, et al. Hospitalizations in children with preexisting tracheostomy: a national perspective. Laryngoscope. 2015;125:462– 468. 4. Sterni LM, Collaco JM, Baker CD, et al.; ATS Pediatric Chronic Home Ventilation Workgroup. An Official American Thoracic Society Clinical Practice Guideline: pediatric chronic home invasive ventilation. Am J Respir Crit Care Med. 2016;193:e16–e35. 5. Rusakow LS, Guarín M, Wegner CB, et al. Suspected respiratory tract infection in the tracheostomized child: the pediatric pulmonologist’s approach. Chest. 1998;113:1549–1554. 6. Pérez-Losada M, Graham RJ, Coquillette M, et al. The temporal dynamics of the tracheal microbiome in tracheostomised patients with and without lower respiratory infections. PLoS One. 2017;12:e0182520. 7. Dickson RP, Erb-Downward JR, Huffnagle GB. Towards an ecology of the lung: new conceptual models of pulmonary microbiology and pneumonia pathogenesis. Lancet Respir Med. 2014;2:238–246. 8. Yang C, Wang Q, Simon PN, et al. Distinct Network Interactions in ParticleAssociated and Free-Living Bacterial Communities during a Microcystis aeruginosa Bloom in a Plateau Lake. Front Microbiol. 2017;8:1202. 9. Hasegawa K, Mansbach JM, Ajami NJ, et al.; the MARC-35 Investigators. Association of nasopharyngeal microbiota profiles with bronchiolitis severity in infants hospitalised for bronchiolitis. Eur Respir J. 2016;48:1329– 1339. 10. Mansbach JM, Hasegawa K, Henke DM, et al. Respiratory syncytial virus and rhinovirus severe bronchiolitis are associated with distinct nasopharyngeal microbiota. J Allergy Clin Immunol. 2016;137:1909–1913.e4. Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Gangoiti et al The Pediatric Infectious Disease Journal • Volume 37, Number 11, November 2018 e272 | www.pidj.com © 2018 Wolters Kluwer Health, Inc. All rights reserved. cell count, C-reactive protein and procalcitonin), microorganism isolated, final diagnosis and disposition of the patient. In our ED, we recommend blood culture, white blood cell, absolute neutrophil cell, serum C-reactive protein, procalcitonin, urine dipstick and polymerase chain reaction for pneumococcus and meningococcus in all febrile infants 3–24 months old with FWS ≥40.5°C, regardless their vaccination status. Other tests (urine culture, chest radiograph, cerebrospinal fluid examination) were obtained at the discretion of the physician in charge. Definitions •Previously healthy patients: patients without any of the following risk factors: immunosuppression (oncologic illness, chronic renal failure, transplant patient, sickle cell disease), the presence of a mechanical device (indwelling catheter, ventricle-peritoneal shunt, auditory prostheses) and an invasive diagnostic or therapeutic procedure in the previous 10 days. •Well-appearing patients: patients with a stable pediatric assessment triangle upon arrival at the ED. Pediatric assessment triangle is a rapid tool recommended by the American Academy of Pediatrics to assess the first general impression of any child. The appearance, the work of breathing and the circulation to the skin are evaluated using specific predefined physical, visual or auditory findings. If any of these 3 components is abnormal, the patient is considered unstable. •FWS: axillary or rectal temperature higher than 38°C registered at home or in the ED, without associated respiratory symptoms, diarrhea process and findings on physical examination that allows identifying the source of the fever. •OB: isolation of pathogenic bacterium in the blood of a wellappearing child with FWS. PCV13 was included in the public immunization program in January 2013. Currently, PCV vaccination coverage in the Basque Country is around 95%. We carried out the statistical analysis using the statistical program SPSS 23, Chicago, IL. The qualitative variables were described using absolute frequencies and percentages and the continuous variables were described using both the mean and standard deviation or median and interquartile range. The χ2 test was used to study the association between qualitative variables. The Clinical Research Ethics Committee of the hospital approved the study. To maintain patient confidentiality, the database did not include any data that would have allowed the identification of patients. As identities remained anonymous and no intervention was performed on patients, informed consent was not required. RESULTS During the study period, blood cultures were obtained on 543 infants 3–24 months of age with fever ≥40.5°C, including all the 363 previously healthy well-appearing infants with FWS ≥40.5°C (Fig. 1). Mean age of the 363 previously healthy well-appearing infants with FWS ≥40.5°C was 13.9 ± 4.9 months and 189 (52.1%) were female. PCV dosing was unknown in 23 (6.3%), and 51 (14%) had not received any dose. Fever duration was shorter or equal than 48 hours in 297 (81.8%). Most common final diagnoses were FWS 282 (77.7%); urinary tract infection 36 (9.9%); fever and rash 16 (4.4%); pneumonia 13 (3.6%) and bacteremia 4 (1.1%). All patients did well. Four previously healthy well-appearing infants with FWS ≥40.5°C were diagnosed with OB (OB prevalence: 1.1%; 95% confidence interval [CI]: 0–2.2): 3 pneumococcal OB (one 16-month-old non-PCV vaccinated girl, and two 16-month and 19-month-old fully vaccinated girls; pneumococcal OB prevalence: 0.82%; 95% CI: 0%–1.8%) and a 12-month-old boy with a nontype b Haemophilus influenza bacteremia. All were managed as outpatients (3 of them after receiving 1 dose of IM ceftriaxone as a result of alterations of the blood biomarkers) and all did well. Among those 289 infants who have received at least 1 dose of PCV, 2 were diagnosed with pneumococcal OB (0.69%; 95% CI: 0–1.6). During the study period, blood cultures were also obtained in 140 previously healthy well-appearing infants with fever with a source ≥40.5°C (mainly respiratory symptoms). Blood culture was positive for Streptococcus pneumoniae in one 19-month-old boy fully vaccinated infant diagnosed with mastoiditis. DISCUSSION Although being lower than the reported in the pre-PCV studies,4 the rate of OB in previously healthy well-appearing infants 3–24 months of age with FWS equal or higher than 40.5°C does not support the recommendation for not testing these infants to identify those at higher risk for OB. Even though the rate of bacteremia in fully PCV-immunized infants is 0.5% or greater. Nowadays, most guidelines recommend not testing fully immunized (including PCV) febrile infants and do not give any specific recommendation for those with very high fever.6 In fact, laboratory evaluation and empiric antibiotic therapy do not significantly Fever with a source, 140 (25.8%) Bacteremia 1, 0.71% 0.12-3.9 Fever without a source, 363(66.8%) Occult bacteremia 4, 1.11%, CI 95%0.4-2.8 Non previously healthy, 10 (1.9%) Bacteremia 0 Previously healthy, 503 (92.6%) Bacteremia 5, 0.99%, CI 95% 0.42-2.3 Non well-appearing, 30 (5.5%) Bacteremia 0 Infants with fever equal or higher than 40.5ºC: 543 Bacteremia 5, 0.92%, CI 95% 0.39-2.1 Well-appearing 513 (94.5%) Bacteremia 5, 0.97%, CI 95%0.41-2.25 FIGURE 1. Patients’ flow chart. Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. © 2018 Wolters Kluwer Health, Inc. All rights reserved. www.pidj.com | e273 The Pediatric Infectious Disease Journal • Volume 37, Number 11, November 2018 Occult Bacteremia in Infants with Very High Fever CARDIAC AND PULMONARY CYSTIC ECHINOCOCCOSIS WITH MASSIVE OBSTRUCTION OF THE PULMONARY VESSEL SYSTEM IN A 16-YEAR-OLD GIRL Benno Kohlmaier, MD,* Andreas Trobisch, MD,* Klaus Pfurtscheller, MD,* Igor Knez, MD,† Walter Klepetko, MD,‡ Alexander Pilhatsch, MD,§ Sabrina Schweintzger, MD,¶ and Werner Zenz, MD* Abstract: We describe herein the management of a 16-year-old girl with cystic echinococcosis of the right ventricle and massive obstruction of the pulmonary vessel system by parasitic metastatic dissemination. After resection of the cardiac cyst, pulmonary thromboendarterectomy was performed to remove parts of the obstructive parasitic material. The treatment reduced the elevated pulmonary arterial pressure, improving the patient’s overall condition. Key Words: cystic echinococcosis, thromboendarteriectomy, pulmonary intravascular cyst, cardiac cyst, albendazole, praziquantel Accepted for publication December 23, 2017. From the *Department of General Pediatrics, and †Department of Cardiac Surgery, Medical University of Graz, Graz, Austria; ‡Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria; and §Department of Pediatric Radiology, and ¶Department of Pediatric Cardiology, Medical University of Graz, Graz, Austria. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Werner Zenz, MD, Department of General Pediatrics, Medical University of Graz, Graz, Austria. E-mail: werner.zenz@ medunigraz.at. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.pidj.com). Cystic echinococcosis (CE), caused by Echinococcus granulosus, is a common parasitic disease with high incidence rates in rural areas in Southern Europe, Middle East, Asia and Africa.1,2 In rare cases, it primarily affects the heart. Ruptures of the cyst membranes can lead to cardiac tamponade, anaphylactic shock or embolization and obstruction of pulmonary vessels, resulting in severe cardiopulmonary symptoms.3,4 Here, we present a complex case with cardiac and pulmonary involvement and massive obstruction of the pulmonary arteries. CASE REPORT A 16-year-old previously healthy female was admitted to our hospital with a 2-month history of increasing dyspnea and coughing. She grew up in a CE endemic area in Romania and moved to Austria 2 years ago. She lived together with her family and was working as a waitress. Physical examination showed normal weight and height, normal heart rate, no cardiac murmur, normal blood pressure, normal breathing, no dyspnea at rest and no edema. Oxygen saturation was 93%–96% at normal respiratory rate. Chest radiograph showed multiple intrapulmonary nodules in both lungs and widening of the upper mediastinum. Echocardiography revealed a cystic lesion in the apex of the right ventricle (Fig. 1A). Thoracic computed tomographic scan displayed a cystic Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/INF.0000000000002066 alter the likelihood of progression to focal bacterial infection and are no longer recommended in an otherwise healthy child with FWS who is completely immunized.7 In addition, since the routine immunization of children with PCV7 or PCV13 vaccine, pathogens other than S. pneumoniae have being reported to be the cause of the majority of cases of unsuspected bacteremia.8 In our study, 4 previously healthy well-appearing infants 3–24 months of age with FWS equal or higher than 40.5°C were diagnosed with OB, 3 of them caused by Streptococcus pneumoniae. Two were fully immunized. These results emphasize the importance to rule out serious bacterial infection in young high feverish children, including OB, and highlight the relevance of pneumococcal infection in this selected population in the era of the PCV. Our study shows certain limitations. The main limitation is the sample size. The CIs of the obtained bacteremia rate do not allow giving a strong recommendation for this population. Nevertheless, the results obtained emphasize the importance to carry out a larger study, preferably multicenter, to establish if nontesting strategy is adequate when fever is over 40.5°C. On the other hand, this is a unicenter study. Nevertheless, results should be similar in populations with similar vaccination status. Finally, to include all the patients in a prospective way, collecting the data when the infants are in the ED would have been more adequate to include all patients. Nevertheless, with the random revision of the episodes registered in the ED, we think that only very few patients were missed, if any. We conclude that, despite recommendations for nontesting for pneumococcal OB screening in well-appearing febrile infants, these recommendations may have to be reconsidered in infants with FWS ≥40.5°C, including those fully vaccinated. Larger and preferably multicenter studies are needed to confirm these results. Accordingly, a prospective multicenter study will begin on 2018 under the scope of the Research network of the Spanish Society of Pediatric Emergency Medicine (Red de Investigación de la Sociedad Española de Urgencias de Pediatría-Spanish Pediatric Emergency Research Group RISEUP-SPERG). ACKNOWLEDGMENTS I.K. conceptualized and designed the study, supervised data collection, analyzed the data, wrote the initial draft of the manuscript and approved the final manuscript as submitted. E.R. collaborated in the design of the study, collected data, critically revised the manuscript and approved the final manuscript as submitted. A.Z. collected data, critically revised the manuscript and approved the final manuscript as submitted. J.B. collaborated in the design of the study, critically revised the final manuscript and approved the final manuscript as submitted. S.M. conceptualized and designed the study, analyzed the data, revised multiple versions of the initial manuscript and approved the final manuscript as submitted. REFERENCES 1. Herz AM, Greenhow TL, Alcantara J, et al. Changing epidemiology of outpatient bacteremia in 3to 36-month-old children after the introduction of the heptavalent-conjugated pneumococcal vaccine. Pediatr Infect Dis J. 2006;25:293–300. 2. Joffe MD, Alpern ER. Occult pneumococcal bacteremia: a review. Pediatr Emerg Care. 2010;26:448–454; quiz 455. 3. Kaplan SL, Mason EO Jr, Wald ER, et al. Decrease of invasive pneumococcal infections in children among 8 children’s hospitals in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine. Pediatrics. 2004;113(3 pt 1):443–449. 4. Lee GM, Fleisher GR, Harper MB. Management of febrile children in the age of the conjugate pneumococcal vaccine: a cost-effectiveness analysis. Pediatrics. 2001;108:835–844. 5. Lee GM, Harper MB. Risk of bacteremia for febrile young children in the post-Haemophilus influenzae type B era. Arch Pediatr Adolesc Med. 1998;152:624–628. 6. NICE Guidance. Fever in under 5s: assessment and initial management. Accessed August 2017. 7. Avner JR, Baker MD. Occult bacteremia in the post-pneumococcal conjugate vaccine era: does the blood culture stop here? Acad Emerg Med. 2009;16:258–260. 8. Greenhow TL, Hung YY, Herz A. Bacteremia in children 3 to 36 months old after introduction of conjugated Pneumococcal vaccines. Pediatrics. 2017;139:e20162098. doi: 10.1542/peds.2016–2098. METODOA 73 3. Gangoiti I, Zubizarreta A, Elgoibar B, Mintegi S; Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies (SEUP). Occult Bacteremia in Young Children with Very High Fever Without a Source: A Multicenter Study. Pediatr Infect Dis J. 2020 Dec;39(12):e462-e464. doi: 10.1097/INF.0000000000002891. PMID: 32898089 • ISSN: 0891-3668 • JCR: Science Edition, 2020 • Impact factor: 2,129 • Category: Pediatrics. Posición: 69/129 • Quartil: Q3 Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 74 Acta Paediatrica. 2020;00:1–6. | 1wileyonlinelibrary.com/journal/apa 1 | BACKGROUND Fever is a very common reason for consultation among children attending the emergency department (ED). In most cases, the cause is a self-limiting viral infection. Despite advances in vaccinations and antibiotics, invasive bacterial infections remain significant causes of death of children in developed countries. General infant immunization programmes against the most common pathogens (Haemophilus influenzae type b, Streptococcus pneumoniae and Neisseria meningitides) have led to a significant decrease of childhood invasive Received: 8 May 2020 | Revised: 29 July 2020 | Accepted: 18 August 2020 DOI: 10.1111/apa.15549 REGULAR ARTICLE Paediatric Escherichia coli bacteraemia presentations and high-risk factors in the emergency department Borja Elgoibar1 | Iker Gangoiti1 | Juan José Garcia-Garcia2 | Susanna Hernandez-Bou3 | Borja Gomez1 | Lorea Martinez Indart4 | Santiago Mintegi1 | Bacteremia Study Working Group from the Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies (SEUP) ©2020 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd Abbreviations: E. coli, Escherichia coli; ED, emergency department; ICU, intensive care unit; UTI, urinary tract infection. 1Paediatric Emergency Department, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, University of the Basque Country, UPV/EHU, Bilbao, Basque Country, Spain 2Paediatrics Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain 3Paediatric Emergency Department, Hospital Sant Joan de Déu, Barcelona, Spain 4BioCruces Bizkaia Health Research Institute, Bilbao, Spain Correspondence Santiago Mintegi, Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain. Email: [email protected] Abstract Aim: Escherichia coli (E coli) is a known cause of paediatric bacteraemia. The main objective was to characterise the emergency department (ED) presentations of paediatric E coli bacteraemia and secondarily to identify those related to greater severity. Methods: This was a sub-study of a multicentre cross-sectional prospective registry including all with E coli bacteraemia episodes between 2011 and 2016. We used multiple correspondence and cluster analysis to identify different patterns. Results: We included 291 patients and 43 met criteria for severe disease (14.3%, 95% confidence interval 11.2-19.3). We identified four types of paediatric E coli bacteraemia presentations. Two (178 patients, 61.2%) were related to well-appearing previously healthy infants with associated urinary tract infection (UTI). Well-appearing children older than 12 months old with underlying disease (n = 60, 20.6%) and nonwell-appearing children of different ages (n = 53, 18.2%) corresponded to the other two types; these had associated UTI infrequently and higher severity rate (15% and 50.9%, respectively, higher when compared with the two previous types, P < .01), including the two patients who died. Conclusion: There were four different types of ED paediatric E coli bacteraemia presentations with different severity. Febrile young children with associated UTI showed the best outcome. KEYWORDS bacteraemia, Escherichia coli, outcome, risk factor, urinary tract infection 2 | ELGOIBAR Et AL. bacterial infections1,2 and changes in the distribution of most frequently isolated pathogens. Escherichia coli is a known cause of bacteraemia in febrile infants under 12 months of age3 and has been widely reported mainly in febrile infants <3 months of age, many of them associated with a urinary tract infection (UTI).4,5 In a previous study under the scope of the Spanish Society of Emergency Medicine, E coli accounted for 20% of the bacteraemia episodes registered in previously healthy children in Spanish EDs.6 To our knowledge, no large series have analysed the clinical presentation and outcome of children with E coli bacteraemia. Our study may help to better identify these children in the ED, especially those at higher risk for severe disease. The main objective was to characterise the ED presentations of paediatric E coli bacteraemia. The secondary objective was to identify presentations related to higher severity. Our hypothesis was that there are different profiles of paediatric E coli bacteraemia presentations with different risk for severe illness. 2 | PATIENTS AND METHODS We performed a secondary analysis of a large, multicentre, crosssectional prospective registry of childhood bacteraemia presentations to 23 Spanish EDs. In 2010, the Spanish Society of Paediatric Emergency Medicine proposed the establishment of a prospective multicentre registry of positive blood culture obtained at Spanish paediatric EDs. Patients between 0 months and 20 years were prospectively enrolled between 2011 and 2016. During 2011, 15 paediatric EDs participated in the recruitment, 22 during 2012, 21 during 2013, 19 during 2014, 17 during 2015 and 13 during 2016. Blood culture technique was explained in the study published in 2014.6 For the purpose of this study, we included those children with E coli isolated in the blood culture. We used the Paediatric Assessment Triangle (PAT) to assess the first general impression of the child. The PAT is a rapid tool recommended by the American Academy of Pediatrics to assess the first general impression of any child. The appearance, the work of breathing and the circulation to the skin are evaluated using specific predefined physical, visual or auditory findings. If any of these three components are abnormal, the patient is considered as non-well appearing.7 Certain factors were considered as increasing the risk of having a bacteraemia. These factors included immunosuppression such as oncological illness, chronic renal failure, transplant patient and sickle cell disease; the presence of a mechanical device, such as an indwelling catheter or a ventriculo-peritoneal shunt; an invasive diagnostic or therapeutic procedure in the previous 10 days; a serious kidney or urinary tract malformations such as double renal system, severe bilateral vesicoureteral reflux and presence of ureterostomy or vesicostomy; and patients with multiorgan syndromes or systemic illness. For the purpose of this study, patients without any of these risk factors were considered previously healthy. We defined occult bacteraemia as isolation of E coli in the blood in the absence of an identifiable focus of infection. A new positive blood culture after adequate antibiotic treatment (sensitive antibiogram and adequate dose and duration of the antibiotic) was considered as a new episode of bacteraemia. For the purpose of this study, we adapted the sepsis criteria published by Goldstein et al8 A patient with a positive blood culture was diagnosed with sepsis if presenting with any of the following signs: tachycardia >180 bpm not due to external or painful stimuli or long-term medication; bradycardia <100 bpm not due to external vagal stimulus, β-blocker drugs or congenital heart disease (only applicable in infants younger than 1 year old); tachypnoea >50 rpm; and signs of organ dysfunction as listed in the aforementioned publication.8 Septic shock was considered in those patients with persisting hypotension requiring vasopressors despite adequate resuscitation. Higher severity was considered when children met one or more of the following criteria: death, sequelae, admission to the intensive care unit (ICU), sepsis, meningitis and/or acute complications including renal or hepatic failure, stroke, acute respiratory distress syndrome or catheter replacement. We created two forms to be completed online using Google Drive application (Google LLC). Questionnaires were initially distributed to all participating EDs seeking to ensure the clarity of the methods and to enhance the quality of the data collected and were fulfilled by the site investigators. The first questionnaire was a patient registration form for each positive blood culture collected, with epidemiological and clinical data, the results of tests performed, final diagnosis and outcome. A second form was used to provide the following additional, monthly data: total number of patients attended, of blood cultures taken and of positive blood cultures obtained. Only the research coordinator had access to the two resulting online databases, being responsible for downloading regular backups of both databases and reviewing them for possible errors in data Key notes • We characterised the emergency department presentations of paediatric E coli bacteraemia and identified those related to greater severity in 291 patients <18 years of age. • We identified four types of presentations related to previous illnesses, age, sex, appearance upon the arrival and association with urinary tract infection. • Association with urinary tract infection in febrile wellappearing previously healthy young children showed the best outcome. | 3 ELGOIBAR Et AL. entry. The participating researcher in each centre was responsible for reviewing the episodes with potential errors. To identify types of E coli bacteraemia presentations, we used multiple correspondence analysis and cluster analysis. In order to perform multiple correspondence analyses,9 we used the following categorical variables: sex, age, PAT, previously healthy, fever, other symptoms and physical examination. Age was categorised into <3 months, 3-12 months and >12 months; PAT into normal, altered appearance, altered circulation to the skin and altered work of breathing. We then performed the cluster analysis, which organises information from apparently heterogeneous episodes into relatively homogenous groups. We used the factors obtained in the multiple correspondence analyses as variables to perform the cluster analysis and to obtain the appropriate grouping of E coli bacteraemia presentations.10 To create clusters, we used the squared euclidean distance and Ward method.11 This method combined correspondence analysis and cluster analysis to categorise E coli bacteraemia cases into groups. These groups were suggested by the data and not defined a priori. The groups were made in a way such that cases in a given group of E coli bacteraemia were similar to each other and those in different groups were dissimilar. Finally, chi-square test was used to study the association between severity and different types of E coli bacteraemia presentations. Outcome measure was the presence of, at least one of the severity criteria described previously. We performed all statistical analyses using SPSS vs. 23.0 statistical software and R project, version 3.6.2 ‘Dark and Stormy Night’ (IBM). This study was approved by the Ethical Committee of the Basque Country (registration number PI2011040). Approval for the study and for data sharing with the coordinating institution and with the centralised data centre was granted by the institutional review board at each participating institution. To maintain patient confidentiality, the forms did not include any data that would have allowed the identification of any patient. 3 | RESULTS During the time of the study, we registered a total of 3 936 827 ED episodes, of which a positive blood culture was isolated in 1696 (0.04%, CI 95% 0.04-0.05). In 291 (17.6%, 95% CI 15.4-19.0), blood culture was positive for E coli. Table 1 reports descriptive statistics for the main epidemiological variables, management and outcome of the children with E coli bacteraemia. Final diagnosis were UTI with associated bacteraemia 206 (70.8%); occult bacteraemia 27 (9.3%); sepsis/shock 32 (11%, three of them with associated meningitis); meningitis 5 (1.7%); catheter-associated bloodstream infection 6 (2.1%); and others 15 (5.1%). Of the 291 patients, 43 (14.8%, 95% CI 11.2-19.3) were considered to have severe illness (Table 2). Two patients died. The multiple correspondence analyses rand cluster analysis identified four main types of paediatric E coli bacteraemia presentations (Table 3). Two types of E coli bacteraemia presentations (groups A and B) were mainly related to well-appearing previously healthy infants <12 months old with associated UTI (85.0% and 98.5%, Age (in months)a 3 (1-11) Sex (female) 131 (45%) Nonpreviously healthy patients 67 (23%) Immunosuppression 27 (9.3%) Patients with multiorgan syndromes or systemic illness 16 (5.4%) Serious kidney or urinary malformationsb 13 (4.5%) Presence of a mechanical device 7 (2.4%) Invasive diagnostic or therapeutic procedure in the previous 10 d 4 (1.4%) Duration of the fever (in hours)a 12 (3-24) Temperature upon arrival to the emergency department (°C)c 37.9 ± 1.0 Well appearing upon arrival to the emergency department 244 (83.8%) No findings in the physical examination 226 (77.7%) Urine culture performed 263 (90.4%) Lumbar puncture performed 71 (24.4%) Chest X-ray performed 33 (11.3%) Administered antibiotic 284 (97.6%) Admission to ward/Intensive care unit 255 (87.6%) Note: Data are expressed as n and percentage. aAge and evolution time are expressed as median and interquartile range. bSerious kidney or urinary malformations: double renal system, severe bilateral vesicoureteral reflux and presence of ureterostomy or vesicostomy. cTemperature is expressed as mean ± standard deviation. TABLE 1 Epidemiological and clinical characteristics, complementary tests, management and disposition of the patients with E coli bacteraemia 4 | ELGOIBAR Et AL. respectively, compared with 50% and 30.2% of groups C and D). The main differences between groups A and B were the age and the sex, but, overall, they did well. Group A included mostly males younger than 3 months of age (81.4%) and group B mainly females (87.7%) 3-12 months old. Rate of severity was 5.3% and 3.1%, respectively. Well-appearing children older than 12 months with underlying diseases accounted for the majority of the third group of patients (group C). The last group (group D) included non-well-appearing children of different ages, one-third of them non-previously healthy. Associated UTI was significantly lower in these two groups (group C = 50.0%, group D = 30.2%), and the rate of severity was 15% and 50.9%, respectively (significantly higher than in groups A and B, P < .01). The two patients who died were included in group D. Eight children were diagnosed with bacterial meningitis (three of them with associated sepsis). All of them were younger than 5 months. The rate of associated meningitis in febrile infants with E coli bacteraemia is shown in Table 4. 4 | DISCUSSION Our data suggest four different types of paediatric E coli bacteraemia presentations to the ED with different degree of severity. Association with UTI in children less than a year was most common, whereas older age was associated with greater severity, mainly when the child was unwell upon presentation to the ED. Many children did not have high fever and abnormal findings in the physical examination were uncommon. In addition, the majority of these children appeared well when evaluated in the ED. This underlines the importance of having a high index of suspicion in selected patients. E coli is the most common pathogen involved in invasive bacterial infections in young febrile infants.3,5 Many of these are associated with UTI, which is the most common serious bacterial infection in young febrile infants.12 Young febrile infants with UTI are more prone to have associated bacteraemia.12 Around 5% of febrile infants <3 months of age with UTI have an associated bacteraemia, with the highest risk in infants <28 days.13 Traditionally, it has been recommended to hospitalise young febrile infants with suspected UTI due to the concern of acute adverse events and for missing concomitant bacteraemia. During the last years, efforts have been made to identify young febrile infants <3 months with suspected UTI at low risk for bacteraemia and suitable for outpatient management.14,15 Several studies have assessed the course of febrile infants with UTIs and suggest that otherwise well-appearing infants with or without concomitant bacteraemia have benign clinical outcomes when treated with appropriate antibiotics.16-18 Our study may support a less conservative management. In fact, in our study, only around 5% of febrile infants with E coli bacteraemia had a severe disease, including those <3 months of age. Nevertheless, all except one of the children with bacterial meningitis were younger than two months of age. Nearly 10% of TABLE 2 Number of patients with each severity criteria Severity criteria N (%) Sepsis 32 (11.0) Admission to the intensive care unita 22 (7.6) Acute complications 8 (2.7) Meningitis 8 (2.7) Sequelae 7 (2.4) Death 2 (0.7) Note: Data are expressed as n and percentage. Twenty patients (6.9%) presented a single severity criteria. Sixteen patients (5.5%) presented two severity criteria. Seven patients (2.4%) presented three or more severity criteria. aThere is no patient with this severity criteria exclusively. TABLE 3 Main types of paediatric E coli bacteraemia presentations Variable A (n = 113, 38.8%) B (n = 65, 22.3%) C (n = 60, 20.6%) D (n = 53, 18.2%) P value Sex Female 21 (18.6%) 57 (87.7%) 36 (60%) 17 (32.1%) <.001 Age <3 mo 95 (84.1%) 10 (15.4%) 3 (5%) 24 (45.3%) <.001 3-12 mo 18 (15.9%) 55 (84.6%) 6 (10%) 15 (28.3%) >12 mo 0 0 51 (85%) 14 (26.4%) Previously healthy No 3 (2.7%) 047 (78.3%) 17 (32.1%) <.001 Fevera Yes 88 (77.9%) 65 (100%) 58 (96.7%) 41 (77.4%) <.001 Other symptoms Yes 24 (21.2%) 40 (61.5%) 30 (50%) 45 (84.9%) <.001 Paediatric assessment Triangle Altered appearance 1 (0.9%) 1 (1.5%) 2 (3.3%) 35 (66%) <.001 Altered circulation 1 (0.9%) 01 (1.7%) 18 (34%) Altered breathing 0 0 0 6 (11.3%) Physical examination Altered 7 (6.2%) 5 (7.7%) 8 (13.3%) 45 (84.9%) <.001 Associated UTI Yes 96 (85%) 64 (98.5%) 30 (50%) 16 (30.2%) <.001 Note: Data are expressed as n and %. The P values demonstrate the differences between groups among the analysed variables. aTemperature higher than 38ºC at home and/or at the emergency department. | 5 ELGOIBAR Et AL. febrile infants younger than 1 month old with E coli bacteraemia had associated bacterial meningitis. Higher risk of meningitis associated UTI has been previously published in febrile neonates.16 Our study supports the decision of making a cerebrospinal fluid examination in febrile neonates with confirmed or suspected E coli bacteraemia.15 Although the diagnosis of bacterial meningitis is very rare in older children with E coli bacteraemia, severe illness is more common in these patients. In our series, around 50% of non-well-appearing children with E coli bacteraemia had a severe disease, including two children who finally died. This emphasises the importance to consider UTI in those non-well-appearing febrile children and, if possible, to collect a urine culture before initiating the antibiotics. This also confirms that PAT is a reliable tool to identify children with severe illness upon the arrival to the ED.7 Finally, the group of older febrile children with underlying diseases had a 15% rate of severe disease. This underscores the importance of a more cautious management of children with underlying diseases because of the high risk of invasive infections when these children present to the ED.19,20 Our study shows certain limitations. Our registry was not designed to characterise the ED presentations of paediatric E coli bacteraemia. Nevertheless, we think that collected data allow us to define the different types of these presentations and to relate them with severity. This study was conducted to identify risk factors in children with E coli bacteraemia and not UTI. In addition, E coli is not the single pathogen responsible for UTI especially in children with underlying diseases. Thus, our results cannot be extrapolated to febrile UTI. Finally, we think that defining the indications for cerebrospinal fluid examination would require a specific larger study. Nevertheless, our data support to strongly consider cerebrospinal fluid examination in infants <2 months old with E coli bacteraemia. 5 | CONCLUSION We conclude that there are four different types of paediatric E coli bacteraemia presentations to the ED with different rate of severity. UTI-associated bacteraemia in infants <12 months were most common but those involving older children account for large amount of patients and are related to higher risk, mainly when the child is unwell upon the arrival to the ED. Associated bacterial meningitis is rare in children older than two months of age. ACKNOWLEDGEMENTS Collaborators: We are grateful to our collaborators from paediatric emergency departments across Spain: Laura Herrero (Gipuzkoa), Mª Ángeles García (Madrid), Juana Barja (Madrid),Sara Garcia (Las Palmas), Zulema Lobato (Barcelona), Berta Brussosa (Barcelona), Carla Pascual (Barcelona), Maria Landa (Bizkaia), Usune Gonzalez (Bizkaia), Sofia Mesa (Madrid), Ramón Fernández-Alvárez (Asturias),Begoña Fernández (Asturias), Carmen Pérez (Islas Baleares), Goizalde López (Gipuzkoa), José Rodríguez (Murcia), Mercedes de la Torre (Madrid), Clara Garcia-Bermejo (Madrid), Francisca Aguilar (Córdoba), Esther Oliva (Barcelona), Mª Nathalie Campo (Valladolid), Juncal Mena (Valladolid) and Claudia Coderch (Barcelona). Our thanks also go to Nieves De Lucas from Samur, Madrid. CONFLICT OF INTEREST The authors have no conflicts of interest to declare. ORCID Iker Gangoiti https://orcid.org/0000-0001-5391-2423 Santiago Mintegi https://orcid.org/0000-0002-2342-8881 REFERENCES 1. Fitzwater SP, Chandran A, Santosham M, Johnson HL. The worldwide impact of the seven-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2012;31:501-508. 2. Whittaker R, Dias JG, Ramliden M, et al. The epidemiology of invasive meningococcal disease in EU/EEA countries, 2004–2014. Vaccine. 2017;35:2034-2041. 3. Cruz AT, Mahajan P, Bonsu BK, et al. Accuracy of complete blood cell counts to identify febrile infants 60 days or younger with invasive bacterial infections. JAMA Pediatr. 2017;171(11):e172927. 4. De la Torre M, de Lucas N, Velasco R, Gómez B, Mintegi S, Group for the study of febrile infant of the RISeuP-SPERG Network (RISeuPSPERG). A etiology and outcomes of potentially serious infections in febrile infants less than 3 months old. Anales de Pediatría. 2017;87(1):42-49. 5. Gomez B, Mintegi S, Benito J, Egireun A, Garcia D, Astobiza E. Blood culture and bacteremia predictors in infants under three months of age with fever without source. Pediatr Infect Dis J. 2010;29(1):43-47. 6. Gomez B, Hernandez-Bou S, Garcia-Garcia JJ, Mintegi S. Bacteraemia Study Working Group from the Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies (SEUP). Bacteremia in previously healthy children in Emergency Departments: clinical and microbiological characteristics and outcome. Eur J Clin Microbiol Infect Dis. 2015;34(3):453-460. 7. Dieckmann R, Brownstein D, Gausche-Hill M. The pediatric assessment triangle. Pediatr Emerg Care. 2010;26(4):312-315. 8. Goldstein B, Giroir B, Randolph A;International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005; 6(1):2-8. 9. Greenacre MJ (Eds) Theory and Applications of Correspondence Analysis. London, UK: Academic Press; 1984. 10. Lebart L, Morineau A, Piron M. (Eds.) Statistique exploratoire multidimensionnelle. Paris, France: Dunod; 1995. TABLE 4 Rate of associated meningitis in febrile infants with E coli bacteraemia related to the age Group of age Rate of bacterial meningitis <1 mo old 6/64, 9.4%, 95% CI 4.4-19 1 mo old 1/38, 2.6%, 95% CI 0.5-13.5 2 mo old 0/30, 0, 95% CI 0-11.3 3-24 mo old 1/107, 0.9%, 95% CI 0.2-5.1 Note: Data are expressed as n, percentage and confidence interval. Abbreviation: CI, confidence interval. 6 | ELGOIBAR Et AL. 11. Ward JH. Hierarchical grouping to optimize an objective function. J Am Stat Assoc. 1963;58:236-244. 12. Dorney K, Bachur RG. Febrile infant update. Curr Opin Pediatr. 2017;29(3):280-285. 13. Bonilla L, Gomez B, Pintos C, Benito J, Mintegi S. Prevalence of bacterial infection in febrile infant 61–90 days old compared with younger Infants. Pediatr Infect Dis J. 2019;38(12):1163-1167. 14. Schnadower D, Kuppermann N, Macias CG, et al. American Academy of Pediatrics Pediatric Emergency Medicine Collaborative Research Committee. Febrile infants with urinary tract infections at very low risk for adverse events and bacteremia. Pediatrics. 2010;126(6):1074-1083. 15. Velasco R, Gómez B, Hernández-Bou S, et al. Validation of a predictive model for identifying febrile young infants with altered urinalysis at low risk of invasive bacterial infection. Eur J Clin Microbiol Infect Dis. 2017;36(2):281-284. 16. Bachur R, Caputo GL. Bacteremia and meningitis among infants with urinary tract infections. Pediatr Emerg Care. 1995;11(5):280-284. 17. Dayan PS, Hanson E, Bennett JE, Langsam D, Miller SZ. Clinical course of urinary tract infections in infants younger than 60 days of age. Pediatr Emerg Care. 2004;20:85-88. 18. Hoberman A, Wald ER, Hickey RW, et al. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics. 1999;104(1 PT 1):79-86. 19. Castagnola E, Fontana V, Caviglia I, et al. A prospective study on the epidemiology of febrile episodes during chemotherapy-induced neutropenia in children with cancer or after hematopoietic stem cell transplantation. Clin Infect Dis. 2007;45(10):1296-1304. 20. McGirt M, Zaas A, Fuchs H, George TM, Kaye K, Sexton DJ. Risk factors for pediatric ventriculoperitoneal shunt infection and predictors of infectious pathogens. Clin Infect Dis. 2003;36(7):858-862. How to cite this article: Elgoibar B, Gangoiti I, Garcia-Garcia JJ, et al; Bacteremia Study Working Group from the Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies (SEUP). Paediatric Escherichia coli bacteraemia presentations and high-risk factors in the emergency department. Acta Paediatr. 2020;00:1–6. https://doi. org/10.1111/apa.15549 METODOA 77 5. Gangoiti I, Fernandez CL, Gallego M, Gomez B, Benito J, Mintegi S. Markers for invasive bacterial infections in previously healthy children. Am J Emerg Med. 2021 Oct;48:83-86. doi: 10.1016/j.ajem.2021.04.018. Epub 2021 Apr 13. Erratum in: Am J Emerg Med. 2021 Apr 22; PMID: 33862390. • ISSN: 0735-6757 • JCR: Science Edition, 2021 • Impact factor: 5,928 • Category: Emergency Medicine. Posición: 98/826 • Quartil: Q1. Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 78 Markers for invasive bacterial infections in previously healthy children Iker Gangoiti a , Catarina-Livana Fernandez a ,MikelGallego b , Borja Gomez a , Javier Benito a , Santiago Mintegi a, ⁎ a Pediatric Emergency Department, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, University of the Basque Country, UPV/EHU, Bilbao, Basque Country, Spain b Microbiology Department, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, University of the Basque Country, UPV/EHU, Bilbao, Basque Country, Spain 1. Introduction Most previously healthy febrile children have self-limited viral infections. However, sometimes, fever is due to an invasive bacterial infection (IBI). Prompt identification of these children is essential to initiate an early and appropriate treatment. Nevertheless, this identification may be difficult. In a recent study, 22% of children with bacterial meningitis or sepsis had repeated emergency department (ED) visits before admission [1]. Currently, these children are often brought very early to the ED, and signs and symptoms of children with an IBI can be difficult to distinguish from self-limited febrile illnesses [2]. Furthermore, most of these patients are younger than 2–3 years-old, being the clinical expression of different infections more unspecific. Therefore, physicians may not be confident enough in the physical exam and seek for blood tests like white blood cell count (WBC) or the absolute neutrophil count (ANC) to guide initial clinical decisionmaking in certain febrile children. In the last decades, C-reactive protein (CRP) and procalcitonin (PCT) have emerged as valuable riskstratification tests to identify high-risk infants [3]. To analyze the response of blood biomarkers commonly used in the ED in children with microbiologically confirmed IBIs seems important. Our hypothesis is that the response of the blood tests to IBI varies related to the causative pathogens and the final diagnosis. The objective of the study is to analyze the markers' profile in previously healthy children when evaluated in the ED and finally diagnosed with an IBI: WBC, ANC, CRP and PCT. 2. Patients and method This was a retrospective, descriptive study based on a registry of a cohort of children under 14-years-old microbiologically diagnosed with an IBI in a pediatric ED of a tertiary teaching hospital in Spain between January 2008 and May 2020. We identified patients with IBI from the hospital's electronic records as we have previously described [4]. We obtained the information of the patients from the electronic clinical records of the pediatric ED and Basque Public Health System, including socio-demographic data, personal history, month and year of consultation, pneumococcal and meningococcal vaccination status, duration of fever, associated symptoms, maximum temperature, previous consultation in the ED, appearance upon arrival, physical exam, performed tests, microorganism isolated, final diagnosis, disposition and evolution of the patient. We included these data in the registry of IBI in the month after the visit to the ED. For the purpose of this subanalysis, we included those children classified as previously healthy patients and excluded those non-previously healthy: immunosuppression (oncological illness, chronic renal failure, transplant patient, sickle cell disease); presence of a mechanical device (indwelling catheter, ventriculoperitoneal shunt, auditory prostheses); and chronic diseases/severe malformative syndromes. 2.1. Definitions Invasive bacterial infection (IBI): isolation in blood or cerebrospinal fluid (CSF) of a bacterial pathogen, using bacterial culture or real time polymerase chain reaction (PCR) technique to detect S. pneumoniae and N. meningitidis. Fever without a source (FWS): axillary or rectal temperature higher than 38 °C registered at home or in the ED, without associated respiratory symptoms, diarrhea process and findings on physical examination that allows identifying the source of the fever. Occult bacteremia (OB): presence of a pathogenic bacterium in the blood of a well-appearing febrile child in the absence of an identifiable focus of infection. Sepsis: based on the criteria published by Goldstein et al., with the following adjustment: well-appearing patients with fever and leukocytosis were not diagnosed with sepsis unless they had another added criterion (tachycardia, bradycardia, tachypnea or signs of organ dysfunction). [5] Normal blood tests values: in accordance with the most accepted limits, we considered the following normal values: WBC between 5000 and 15,000/mm 3 , ANC between 1500 and 10,000/mm 3 , CRP less than 20 mg/L, PCT less than 0.5 ng/mL. Well-appearing patients: patients with a stable pediatric assessment triangle [6] upon arrival at the ED. 2.2. Statistical analysis We performed the statistical analysis using the IBM SPSS Statistics for Windows, version 23.0 (IBM, Armonk, New York, USA). American Journal of Emergency Medicine 48 (2021) 83–86 ⁎Corresponding author at: Pediatric Emergency Department, Hospital Universitario Cruces, Plaza de Cruces s/n, E-48903 Barakaldo, Bizkaia, Spain. E-mail address: [email protected] (S. Mintegi). https://doi.org/10.1016/j.ajem.2021.04.018 0735-6757/© 2021 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem Fig. 1. Profile of white blood cell count, absolute neutrophil count, C-reactive protein and procalcitonin in invasive bacterial infections. I. Gangoiti, C.-L. Fernandez, M. Gallego et al. American Journal of Emergency Medicine 48 (2021) 83–86 84 Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. © 2021 Wolters Kluwer Health, Inc. All rights reserved. www.pidj.com | e207 The Pediatric Infectious Disease Journal • Volume 40, Number 5, May 2021 Delayed Diagnoses of Invasive Infections DISCUSSION A significant percentage of previously healthy children with an IBI are not identified on their first visit to the ED. Failure to identify IBI and not initiating antibiotic on first visit is associated with higher mortality and sequelae rate. Nearly half of the patients with severe outcome had previously visited the ED and were managed as outpatients without antibiotics. In our study, around a quarter of children with an IBI had previous ED visit before admission, similar to previously published in children with more severe IBIs, such as sepsis and/or meningitis.3 In that previous study,3 children with bacterial meningitis or sepsis with repeated ED visits before admission had health outcomes similar to those of children admitted on initial visit. It was argued that both sepsis and meningitis were probably not present at the first visit, not being possible to be diagnosed.7 This is quite controversial. Recommendations on the management of children with IBIs, and specifically with sepsis, underline the importance of early recognition and considering sepsis in all children with signs or symptoms that indicate possible infection and that delays in the administration of antibiotics worsen outcomes of sepsis and meningitis.8 In addition, currently, children are brought very promptly to the ED. In a recent study, the median of the duration of the fever in infants younger than 3 months was 2 hours.9 Such an early consultation may alter the performance of the physical examination to identify patients to be tested for IBI. In our series, no tests were performed on around twothirds of children not diagnosed on first visit. A sepsis screening tool should be included in a recognition bundle to aid clinicians evaluating children with possible sepsis. For these tools to be effective, all children presenting to the ED should be screened for sepsis and most tools emphasize the use of clinical parameters rather than laboratory tests.10 However, many febrile children have warning signs of sepsis, but the large majority have nonlife-threatening infections. The main limitation of our study is that it is a unicenter study, so the conclusions must be cautiously extrapolated to other settings. Although, we consider that results are similar in other pediatric ED of developed countries. This was also a retrospective study being challenging to assess whether clear overall clinical signs were present at the first visit. Nevertheless, all the episodes of our ED are registered electronically making easier to obtain the data in the following month after the visit, although some important items as vital signs were not recorded in all the patients, and it was not possible to analyze them. This reflects a common problem of the pediatric EDs. Finally, sample size limits the ability to do a specific analysis of the sepsis and meningitis. Although, the percentage of children with sepsis and/or meningitis not diagnosed on first visit was similar to that of all IBIs. Not identifying children with an IBI and not administering antibiotics on the first visit to the ED is associated with a severe outcome. Best practices need to be identified for the early identification and prompt antibiotic administration in children with IBI. REFERENCES 1. Watson RS, Carcillo JA, Linde-Zwirble WT, et al. The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med. 2003;167:695–701. 2. Brook I. Unexplained fever in young children: how to manage severe bacterial infection. BMJ. 2003;327:1094–1097. 3. Vaillancourt S, Guttmann A, Li Q, et al. Repeated emergency department visits among children admitted with meningitis or septicemia: a populationbased study. Ann Emerg Med. 2015;65:625–632.e3. 4. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45:486–552. 5. Gangoiti I, Valle JR, Sota M, et al. Characteristics of children with microbiologically confirmed invasive bacterial infections in the emergency department. Eur J Emerg Med. 2018;25:274–280. 6. Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6:2–8. 7. Green SM, Nigrovic LE, Krauss BS. Sick kids look sick. Ann Emerg Med. 2015;65:633–635. 8. Weiss SL, Peters MJ, Alhazzani W, et al. Surviving Sepsis Campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med. 2020;21:e52–e106. 9. Bonilla L, Gomez B, Pintos C, et al. Prevalence of bacterial infection in febrile infant 61-90 days old compared with younger infants. Pediatr Infect Dis J. 2019;38:1163–1167. 10. Hilarius KWE, Skippen PW, Kissoon N. Early recognition and emergency treatment of sepsis and septic shock in children. Pediatr Emerg Care. 2020;36:101–106.Gangoiti et alDelayed Diagnoses of Invasive Infections TABLE 1. Characteristics of Previously Healthy Patients With an Invasive Bacterial Infection in Relation to the Administration or Nonadministration of Parenteral Antibiotic on the First Visit to the Emergency Department Characteristics Parenteral Antibiotic Administered in the First ED Visit PYes (n = 199) No (n = 72) Age (mo) 15 (5–43) 14 (4–42) NS Sex (female) 87 (43.7%) 31 (43.1%) NS Season <0.01 Spring 33 (16.6%) 21 (29.2%) Summer 31 (15.6%) 16 (22.2%) Autumn 68 (34.2%) 19 (26.4%) Winter 67 (34.2%) 16 (22.2%) Fever: yes 195 (98%) 59 (81.9%) <0.01 Duration of fever (h) 12 (5–32) 12 (8–48) NS Not well-appearing upon the arrival to the ED 56 (28.1%) 2 (2.8%) <0.01 No other symptom except fever 58 (29.1%) 33 (45.9%) 0.01 Digestive 44 (22.1%) 11 (15.3%) Respiratory tract and ORL 37 (18.6%) 18 (25%) Neurological 37 (18.6%) 3 (4.2%) Exanthema 22 (11.1%) 2 (2.8%) Joint/soft tissue 17 (8.5%) 7 (9.7%) Normal physical examination 72 (36.2%) 51 (70.8%) <0.01 Other signs Exanthema 50 (25.1%) 6 (8.3%) Neurological 38 (19.1%) 2 (2.8%) Respiratory tract and ORL 28 (14.1%) 11 (15.3%) Joint/soft tissue 17 (8.5%) 2 (2.8%) Isolated microorganism NS Streptococcus pneumoniae 60 (30.2%) 24 (33.3%) Neisseria meningitidis 47 (23.6%) 10 (13.9%) Staphylococcus aureus 20 (10.1%) 14 (19.4%) Escherichia coli 31 (15.5%) 7 (9.7%) S. agalactiae 11 (5.5%) 1 (1.4%) Others 30 (15.1%) 17 (22.3%) Final diagnosis NS Sepsis 47 (23.6%) 14 (19.4%) Meningitis 28 (14.1%) 8 (11.1%) Occult bacteremia 36 (18.1%) 19 (26.4%) Focal infection with bacteremia 88 (44.2%) 31 (43.1%) Urinary tract infection 28 (14.1%) 4 (5.6%) Pneumonia 24 (12.1%) 8 (11.1%) Osteoarticular or soft tissue infection 19 (9.5%) 12 (16.7% Others 17 (8.5%) 7 (9.7%) Severe outcome 8 (4%) 7 (9.7%) 0.07 NS indicates not significant; ORL, otorhinolaryngological. Data expressed as n (%) except for age and duration of fever (median and interquartile range). METODOA 81 7. Ecclesia FG, Alonso Cadenas JA, Gómez B, Gangoiti I, Hernández-Bou S, de la Torre Espí M; Bacteremia Study Working Group from the Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies. Late-onset Group B Streptococcus Bacteremia Evaluated in the Pediatric Emergency Department and Risk Factors for Severe Infection. Pediatr Infect Dis J. 2022 Jun 1;41(6):455-459. doi: 10.1097/INF.0000000000003520. Epub 2022 May 6. PMID: 35446825 • ISSN: 0891-3668 • JCR: Science Edition, 2022 • Impact factor: 3,6 • Category: Pediatrics. Posición: 23/130 • Quartil: Q1 Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 82 Copyright © 2022 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The Pediatric Infectious Disease Journal • Volume 41, Number 6, June 2022 www.pidj.com | 455 ISSN: 0891-3668/22/4106-0455 DOI: 10.1097/INF.0000000000003520 Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. Original Studies Accepted for publication March 4, 2022 *Pediatric Emergency Department, Hospital Infantil Universitario Niño Jesús, Madrid, Spain, †Pediatric Emergency Department, Hospital Cruces (Barakaldo), Vizcaya, Spain, and ‡Pediatric Emergency Department, Hospital Sant Joan de Déu (Esplugues de Llobregat), Barcelona, Spain Bacteremia Study Working Group from the Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies (SEUP) The authors have no funding or conflicts of interest to disclose. Address for correspondence: Francesco Giuseppe Ecclesia, MD, Pediatric Emergency Department, Hospital Infantil Universitario Niño Jesús, Avenida de Menedez Pelayo 65, 28009, Madrid, Spain. E-mail: francesco.ecclesia@ gmail.com Late-onset Group B Streptococcus Bacteremia Evaluated in the Pediatric Emergency Department and Risk Factors for Severe Infection Francesco Giuseppe Ecclesia, MD,* José Antonio Alonso Cadenas, MD,* Borja Gómez, PhD,† Iker Gangoiti, MD,† Susanna Hernández-Bou, MD,‡ and Mercedes de la Torre Espí, MD* on behalf of the Bacteremia Study Working Group from the Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies Background: To describe the infants presenting to pediatric emergency departments (PEDs) and diagnosed with group B Streptococcus (GBS) lateonset disease (LOD) bacteremia and identify risk factors for severe infection and pediatric intensive care unit (PICU) admission. Methods: Observational study and subanalysis of a multicenter prospective registry. Setting: pediatric emergency department. Inclusion criteria: infants between 7 and 89 days of age with positive blood culture for GBS seen between 2011 and 2016 at any of 22 Spanish PEDs. Main outcome: risk factors (clinical and laboratory variables) for severe infection (sepsis/ septic shock or meningitis) and PICU admission. Second, the prevalence of poor outcomes (acute complications, sequelae or death). Results: Among 118 patients with LOD, 74 (62.7%) presented a severe infection: 66 sepsis/septic shock (11 with associated meningitis) and 8 meningitis. Thirty-five patients (29.7%) were admitted to a PICU. An altered Pediatric Assessment Triangle (PAT) upon arrival and leukopenia were the only independent risk factors for severe infection [odds ratio (OR): 43.6; 95% confidence interval (CI): 8.1–235.7, P < 0.01] and PICU admission (OR: 11.6; 95% CI: 1.5–91.4; P < 0.019), respectively. Six patients (5.1%) developed a poor outcome, including 2 deaths (1.7%); all had an altered PAT, elevated procalcitonin (range 4.7–100 ng/ml), and were diagnosed with sepsis/septic shock and admitted to a PICU. Four developed leukopenia. Conclusions: Infants with GBS LOD frequently develop sepsis/septic shock and bacterial meningitis, associated with non-negligible morbidity and mortality. Clinical appearance was the only risk factor for severe infection, whereas leukopenia was related to PICU admission. Key Words: bacteremia, children, Streptococcus agalactiae, emergency department, sepsis (Pediatr Infect Dis J 2022;41:455–459) INTRODUCTION Group B Streptococcus (GBS) is the second most frequent cause of invasive bacterial infection (IBI) among febrile infants younger than 3 months of age, behind Escherichia coli, and it is the leading cause of sepsis and bacterial meningitis in this population.1–3 GBS infection in these infants is classified into early-onset disease (EOD: neonates 1–6 days old) and late-onset disease (LOD: infants 7–89 days old). The incidence of EOD has declined with the introduction of universal screening of pregnant women for GBS colonization and with the widespread use of intrapartum antibiotic prophylaxis (IAP).4,5 However, IAP has not been shown to be effective in decreasing LOD;4,6 in fact, in developed countries where IAP is used for prevention, the relative proportion of EOD and LOD is changing4 in favor of LOD-GBS disease. Although GBS is a known cause of bacteremia in febrile infants between the ages of 7 and 89 days, to our knowledge no large series have analyzed GBS infections in pediatric emergency departments (PEDs) for this age group. The main objective of this study was to describe the epidemiologic and clinical features and laboratory results of infants presenting to participating PEDs and diagnosed with LOD-GBS bacteremia. As a secondary objective, we sought to identify risk factors for severe infection and pediatric intensive care unit (PICU) admission in these patients. MATERIALS AND METHODS Database We performed a secondary analysis of a large, multicenter, cross-sectional prospective registry created in 2010 by the Spanish Society of Pediatric Emergency Medicine and comprising positive blood cultures (BC) obtained in 22 PEDs between 2011 and 2016. The methodology applied and the BC technique were explained in the parental study.7 To perform the current secondary analysis, we included infants from the registry between the ages of 7 and 89 days with GBS-related bacteremia. Data Collection Data were collected through a standardized online form, which included age, sex, risk factors for EOD GBS, Pediatric Assessment Triangle (PAT) on arrival at the PED, duration and degree of fever, other associated symptoms, physical examination (PE) findings, results of laboratory tests, diagnosis, management and outcome. Medical records were reviewed for all patients, and the parents or caregivers of the infants received a follow-up telephone call within 1 month after the initial visit to the PED to collect further data on the course of the episode. Definitions LOD: GBS infection in infants 7–89 days old. Risk factors for EOD GBS infection included maternal GBS colonization or unknown status and delivery at <37 weeks of gestation. The PAT was used to assess the overall initial impression of the child. The PAT is a tool used to evaluate appearance, work of breathing, and circulation to skin by using specific and predefined Copyright © 2022 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The Pediatric Infectious Disease Journal • Volume 41, Number 6, June 2022 456 | www.pidj.com © 2022 Wolters Kluwer Health, Inc. All rights reserved. Ecclesia et al physical, visual and auditory findings. If any of these 3 components was abnormal, the patient was considered unstable. PE was considered to be altered if any findings related to the infectious process were in evidence. GBS occult bacteremia (OB): isolation of GBS in the blood of a well-appearing febrile infant in the absence of an identifiable focus of infection. Sepsis: based on the criteria published by Goldstein et al.8 If a patient presented persistent hypotension and needed vasopressors despite adequate fluid resuscitation, they were diagnosed with septic shock. Meningitis: isolation of a bacterial pathogen from a cerebrospinal fluid (CSF) culture, detection of a bacterial pathogen in the CSF by molecular methods or isolation of bacteria from BC in a patient with CSF pleocytosis. Severe LOD-GBS: sepsis/septic shock, meningitis and sepsis/septic shock with associated meningitis. Poor outcome: acute complications, sequelae or death. Blood test values considered normal were as follows: white blood cell count (WBC) 5000–15,000/mm3, absolute neutrophil count (ANC) 1500–10,000/mm3, C-reactive protein (CRP) <20 mg/L and procalcitonin (PCT) <0.5 ng/ml. Analysis Data normality was determined by calculating skewness in relation to standard error values. Normally distributed data were expressed as mean ± standard deviation (SD) and non-normally distributed data as the median and interquartile range (IQR). Twotailed t-tests were used to compare mean values between groups for normally distributed data, and the Mann-Whitney U test was used for non-normally distributed data. Categorical variables are expressed as percentages and were compared using the chi-square test (or Fisher’s exact test where expected values were <5 for >25% of cells or <1 for any cell). A P-value <0.05 was deemed statistically significant. The sensitivity of each blood test in identifying GBS bacteremia overall and in distinguishing severe from nonsevere disease was calculated. Baseline risk factors for severe infection and PICU admission were age, maximum temperature, EOD GBS infection risk factors, altered PAT upon arrival, altered PE upon arrival, WBC (categorized into 3 groups: <5000/mm3, 5000–15,000/mm3 and >15,000/mm3), ANC (categorized into 3 groups: <1500/mm3, 1500–10,000/mm3 and >10,000/mm3); CRP and PCT and were analyzed by means of binary logistic regression. As an exploratory test, backward stepwise regression (likelihood ratio) was performed for those binary variables with a P-value <0.2 on univariate analysis. Statistical analyses were performed using STATA v.15. This study was approved by the Ethics Committee of the Basque Country (approval number PI2011040). Approval for the study and for the sharing of data with the coordinating institution and with the centralized data center was granted by the institutional review board of each participating institution. RESULTS Between 2011 and 2016, we recorded 3,936,827 PED episodes and obtained 1696 bacterial isolates in BC [0.04%; 95% confidence interval (CI): 0.04–0.05]. GBS grew in 134 (7.9%, CI: 6.6–9.2) of these cultures, 118 from infants (88.1 %) with LOD (Fig.1). Table1 contains the epidemiological and clinical data of these 118 infants. Seventeen (14.4%) patients with LOD had at least one EOD GBS risk factor: 10 infants with maternal GBS colonization or unknown colonization status, 5 preterm infants and 2 infants with FIGURE 1. Flow-chart indicating included and excluded patients. EOD, early-onset disease; GBS, group B Streptococcus; LOD, late-onset disease; PED, pediatric emergency department; VLOD, very late-onset disease. Table 1. Epidemiologic and clinical features, management, and outcomes of infants with late-onset disease Group B Streptococcus Late-onset disease (N = 118) Sex (males), n (%) 68 (57.6) Age–days, median (IQR) 28 (16–43) Normal PAT upon arrival, n (%) 56 (47.5) Reported symptoms, n (%) Fever 86 (72.9) Fever without a source 29 (24,6) Fever with other symptoms 57 (48.3) Irritability 38 (32.2) Somnolence, lethargy 20 (16.9) Respiratory symptoms 13 (11.0) Others* 16 (13.6) Fever, timesince onset–hours, median,(IQR) 2 (0-4) Normal PE, n (%) 56 (47.5) Discharge to home, n (%) 3 (2.5) Admission, n (%) Ward 80 (67.8) PICU 35 (29.7) Outcomes, n (%) Acute complications 6 (5.1) Sequelae 2 (1.7) Death 2 (1.7) *Digestive, local pain. CI indicates confidence interval; IQR, interquartile range; PAT, Pediatric Assessment Triangle; PE, physical examination; PICU, pediatric intensive care unit. Copyright © 2022 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The Pediatric Infectious Disease Journal • Volume 41, Number 6, June 2022 © 2022 Wolters Kluwer Health, Inc. All rights reserved. www.pidj.com | 457 Late-onset Group B Streptococcus Bacteremia both risk factors. Two preterm infants with unknown maternal GBS status did not receive IAP; both were diagnosed with sepsis and required PICU admission. Regarding laboratory findings, WBC and ANC were performed in all patients, CRP was measured in 117 (99.2%) and PCT in 93 (78.8%). Overall, 91 (77.1%) had at least one altered test. The sensitivity of each test was as follows: PCT 80.6% (95% CI: 71.1– 88.1), WBC 44.1% (95% CI: 34.9–53.5), ANC 34.7% (95% CI: 26.2–44.1) and CRP 27.4% (95% CI: 19.5–36.4). The sensitivity of the blood tests for diagnosing severe infections is shown in Table2. The final diagnosis was sepsis/septic shock in 66 patients (55.9%, 11 with associated meningitis), OB in 40 (33.9%), meningitis in 8 (6.8%) and focal infection in 4 infants [3.4%, 2 osteoarticular and 2 urinary tract infection (UTI)]. Overall, 74 (62.7%) had a severe infection. Among the patients with severe infection, 15 (20.3%) had normal PAT upon arrival: 7 were neonates younger than 21 days of age and 7 had abnormal values on blood tests. The remaining patient was a 26-day-old neonate diagnosed with cellulitis-adenitis and associated meningitis with normal values on blood tests and no findings of note on arrival to the PED. From the multivariate model, the baseline risk factors associated with severe infection are shown in Table3. GBS was isolated in another location in 20 patients (16.9%): in CSF in 17 patients and in urine in 3 patients. Seven patients had a concomitant UTI caused by another bacterium and one patient had concomitant bacterial meningitis due to E. coli. Admission was required in 115 patients, that is, 80 (67.8%) to the ward and 35 (29.7%) to the PICU. Three patients (2.5%) were discharged home (Table1): a 35-day-old infant, another 39-day-old patient and another who was 52 days old; all had a normal PAT, normal blood values and were diagnosed with OB. None of the 3 developed a poor outcome. Table4 shows the baseline risk factors associated with PICU admission from the multivariate model. Six (5.1%) patients presented a poor outcome, all of whom were neonates (range 9–26 days of life) with altered PAT, elevated PCT (range 4.7–100 ng/ml), diagnosed with sepsis/septic shock (2 with associated meningitis) and admitted to the PICU. Four had leukopenia (range 2300–9200 WBC/mm3). All of them presented acute complications: seizures (2), cerebral candidiasis (1), disseminated intravascular coagulopathy (1), endocarditis (1) and pneumonia with pleural effusion (1). Two (1.7%) developed sequelae: one presented a pulmonary valve residual wart and another developed central diabetes insipidus and epileptic encephalopathy. Two patients died (1.7%), including a 12-day-old neonate whose mother was colonized by GBS and received IAP, and another, a 26-day-old infant with a premature (35 weeks) birth with an unknown state of mother’s vaginal swab in whom IAP was not administered. DISCUSSION Almost two-thirds of the infants with GBS LOD bacteremia studied here presented a severe infection, and around 5% developed acute complications or sequelae, including a mortality rate of nearly 2%. Presenting an altered PAT on arrival to the PED was the only risk factor identified for a severe infection, and this factor also seems to be related to a poor outcome. Our registry study is one of the largest prospective series analyzing GBS bloodstream infections in infants between the ages of 7 and 89 days. Preliminary data from the original study demonstrated that GBS was the second most common cause of bacteremia among febrile infants younger than 3 months behind E. coli,7 as found in recent multicenter studies.4,9,10 Compared with data published on E. coli bacteremia11, GBS bloodstream infections are more severe and more frequently lead to sepsis/septic shock and meningitis.12 Acute complications and deaths are also more frequent with GBS. In our study, risk factors for EOD GBS infection were present in less than 20% of the infants with GBS LOD. Most of the infants 7–89 days old with a GBS bacteremia were previously healthy and presented no risk factors, thus contrasting with data from studies on EOD4. Our results support previous studies finding that IAP does not prevent GBS LOD4,13 and that other strategies, such as the administration of multivalent vaccines in pregnant women should be considered.14–16 PAT alterations are the only independent risk factor for severe infection. An altered PAT should always be considered a risk factor for a poor outcome in pediatric patients. Even so, in our study, only one infant diagnosed with a severe GBS LOD Table 2. Epidemiologic features, clinical characteristics, laboratory test results, and management with severe and nonsevere infections Nonsevere infection* (n = 44) Severe infection† (n = 74) P-value Sex (males), n (%, 95% CI) 28 (63.6, 47.8–77.6) 40 (54.1, 42.1–65.7) n.s. Risk factors for GBS, n (%, 95% CI) 3 (6.8, 1.4–18.7) 14 (18.9, 10.7–29.7) n.s. Age – median days (IQR) 28.5 (16–42.5) 28 (15–43) n.s. Normal PAT upon arrival, n (%, 95% CI) 41 (93.2, 81.3–98.6) 15 (20.3, 11.8–31.2) <0.001 Normal PE upon arrival, n (%, 95% CI) 31 (70.5, 54.8–83.2) 25 (33.8, 23.2–45.7) <0.001 Admission <0.001 Ward 37 (84.1, 69.9–93.4) 43 (58.1, 46.1–69.5) PICU 4 (9.1, 2.5–21.7) 31 (41.9, 30.5–53.9) WBC (median/mm3, IQR) Sensitivity (WBC <5000 or >15,000/mcL) 11,840 (8300–16,455) 38.6% (95% CI:24.4–54.5%) 7,300 (4100–11,200) 35.1% (95% CI: 24.4–47.1%) <0.001 ANC (median/mm3,IQR) Sensitivity (ANC <1500 or >10,000/mcL) 6,310 (4500–10,598) 34.1% (95% CI: 20.5–49.9%) 4,530 (1975–8,300) 35.1% (95% CI: 24.2–47.1%) 0.01 CRP (median mg/L, IQR) Sensitivity (CRP ≥20 mg/L) 5.5 (2.1–18.0) 23.3% (95% CI: 11.8–38.6%) 7.7 (3.6–24.0) 29.7% (95% CI: 19.7–41.5%) n.s. PCT (median ng/ml, IQR) Sensitivity (PCT ≥0.5 ng/ml) 1.7 (0.4–6.5) 71.8% (95% CI: 55.1–85.0%) 3.5 (0.7–21.8) 87.0% (95% CI: 75.1–94.6%) n.s. *Included: occult bacteremia and focal infection (osteoarticular and urinary tract infection). †Included: sepsis/septic shock, meningitis, and sepsis/septic shock with associated meningitis. ANC indicates absolute neutrophil count; CI, confidence interval; CRP, C-reactive protein; GBS, Group B Streptococcus; n.s., not significant; PAT, Pediatric Assessment Triangle; PCT, procalcitonin; PE, physical examination; PICU, pediatric intensive care unit; WBC, white blood cell count. Copyright © 2022 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The Pediatric Infectious Disease Journal • Volume 41, Number 6, June 2022 458 | www.pidj.com © 2022 Wolters Kluwer Health, Inc. All rights reserved. Ecclesia et al had a normal PAT upon arrival to the PED, including 7 of the 10 patients with meningitis. This could be partially explained by the short history of symptoms at the time of PED assessment and by the young age of these infants, which makes it more difficult to properly implement the PAT. In fact, most infants in our sample were brought to the PED after only a few hours of fever (median 2 hours), and 11 of the 15 infants with a severe infection and normal PAT were neonates. Clinical decisions regarding these infants should be supported by laboratory tests (blood, urine and CSF) in addition to PAT and PE to identify infants at high risk of IBI, as recommended by a majority of the validated approaches for febrile infants ≤90 days old.17,18 PCT was the blood biomarker with the highest sensitivity (80.6% vs. 27.4% for CRP); indeed, PCT sensitivity was even higher for identifying a severe infection, while CRP sensitivity remained poor.19,20 The short time between the symptom onset and presentation to the PED could explain this finding, since CRP is generally not detectable in serum until 12 hours after the onset of inflammation,21 whereas PCT has a faster kinetic. With the exception of one 26-day-old neonate, all infants in our series with severe infections and normal PAT fulfilled the high-risk criteria for IBI, such as age under 21 days or abnormal analytical values,18 and antibiotic therapy was administered in all cases. The aforementioned neonate did not develop a poor outcome. Leukopenia was the only independent risk factor for PICU admission. Curiously, leukopenia in well-appearing infants was not found to be a risk factor for a poor outcome, thus contrasting with previous reports.22,23 On the one hand, a significant number of GBS colonizations were isolated in locations other than the blood (20, 16.9%), mainly CSF (17, 14.4%). This reaffirms the current recommendation to perform a lumbar puncture, if it has not been done before, when GBS bacteremia is identified in infants under 3 months of age.24 GBS was also isolated concomitantly in urine, but much less frequently (2.5%), as reported in previous studies.9 On the other hand, 8 (6.8%) other infants had a positive culture for other microorganisms, 7 in urine (3 UTI) and 1 CSF culture. All were Gram-negative microorganisms, which are the most common in these infants.9 Our study has certain limitations. First, it was not specifically designed to investigate GBS in patients with positive bloodstream culture. Not all known GBS risk factors have been considered in our registry, as only maternal GBS colonization or unknown status and delivery at <37 weeks of gestation have been reported. Second, although the same criteria were established to detect sepsis/septic shock, some infants may have been misclassified. Third, PICU admission did not follow the same criteria and may have varied from one hospital to another. Additionally, the indication for respiratory and hemodynamic support was also unknown. Nevertheless, we believe that the data collected allow us to characterize GBS LOD and may help to better identify these children in the PED, especially those with severe infection. We conclude that infants with LOD due to GBS frequently develop sepsis/septic shock and bacterial meningitis with nonnegligible morbimortality, especially those infants with an altered PAT and leukopenia. Different prevention strategies are necessary for these infants. ACKNOWLEDGMENTS We are grateful to our collaborators from paediatric emergency departments across Spain and to the members of the Bacteraemia Study Working Group from the Infectious Diseases Working Group of the Spanish Society of Pediatric Emergencies. The 22 participating centers and their researchers were: Hospital Sant Joan de Déu Barcelona, Universitat de Barcelona (Joaquín Astete), Hospital Universitari Vall D’Hebrón (Nuria Worner, Susana Melendo), Niño Jesús Children’s University Hospital (Mercedes de la Torre), Cruces University Hospital (Edurne López, Jorge Barrón), Canaries University Hospital Maternity Ward (Sara García), Son Espases University Hospital (Carmen Pérez, José Gil), Hospital Universitario 12 de Octubre (Olga Ordóñez, Francisca Sanz), Príncipe de Asturias University Hospital (María Ángeles García, Peña Gómez), Corporació sanitaria Parc Tauli, Hospital de Sabadell, Institut universitari Parc Tauli - UAB (Laura Marzo, Dionisia Fontanals), Basurto University Hospital (María Landa, José Luis Díaz de Tuesta), Cabueñes Hospital (Ramón Fernández, Elisa García), Althaia. Xarxa Assistencial Universitaria de Manresa (Zulema Lobato, Montse Morta), Mendaro Hospital (Jesús Alustiza, Jose María Manterota), Hospital Moncloa (Alfonso González, Luis Moises Ruíz), Alto Deba General Hospital, (Itziar Iturralde, Goizalde López, Ainara Rodríguez), Hospital Universitario Virgen de la Arrixaca (José Rodríguez, Table 3. Multivariate analysis to identify independent risk factors for severe infection Risk factors for severe infection OR 95% CI P-value Age (days) 0.9 0.95–1.02 n.s. Maximum temperature (ºC) 0.7 0.4–1.2 n.s. Altered PAT upon arrival (%) 43.6 8.1–235.7 <0.001 Altered PE upon arrival (%) 1.5 0.3–6.9 n.s. WBC (/mm3) Group 1: <5000 1.5 0.05–45.3 n.s. Group 2: 5000–15,000 Reference Reference Group 3: >15,000 5.1 0.6–45.4 n.s. ANC (/mm3) Group 1: <1500 1.2 0.02–86.1 n.s. Group 2: 1500–10,000 Reference Reference Group 3: >10,000 0.2 0.02–2.3 n.s. CRP (mg/L) 1.0 0.9–1.0 n.s. PCT (ng/ml) 1.0 0.9–1.1 n.s. ANC indicates absolute neutrophil count; CI confidence interval; CRP, C-reactive protein; n.s., not significant; OR, odds ratio; PAT, Pediatric Assessment Triangle; PCT, procalcitonin; PE, physical examination; WBC, white blood cell count. Table 4. Multivariate analysis to identify independent risk factors for pediatric intensive care unit admission Risk factors for PICU admission OR 95% CI P-value Age (days) 0.9 0.9–1.0 n.s. Maximum temperature (ºC) 1.0 0.3–3.9 n.s. GBS infection risk factors (%) 1.4 0.3–6.7 n.s. Altered PAT upon arrival (%) 7.1 0.9-56-5 n.s. Altered PE upon arrival (%) 3.2 0.5–21.3 n.s. WBC (/mm3) Group 1: <5000 11.6 1.5–91.4 0.019 Group 2: 5000–15,000 Reference Reference Group 3: >15,000 0.08 0.01–2.2 n.s. ANC (/mm3) Group 1: <1500 0.8 0.1–8.1 n.s. Group 2: 1500–10,000 Reference Reference Group 3: >10,000 7.0 0.3–156.7 n.s. CRP (mg/L) 1.1 0.999–1.14 n.s. PCT (ng/ml) 1.0 0.968–1.04 n.s. ANC indicates absolute neutrophil count; CRP, C-reactive protein; CI, confidence interval; GBS, Group B Streptococcus; n.s., not significant; OR, odds ratio; PAT, Pediatric Assessment Triangle; PCT, procalcitonin; PE, physical examination; PICU, pediatric intensive care unit; WBC, white blood cell count. Copyright © 2022 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The Pediatric Infectious Disease Journal • Volume 41, Number 6, June 2022 © 2022 Wolters Kluwer Health, Inc. All rights reserved. www.pidj.com | 459 Late-onset Group B Streptococcus Bacteremia Ana Blázquez), Hospital Universitario Infanta Sofía (Alfredo Tagarro, Esteban Aznar), Hospital Universitari Sant Joan de Reus (Neus Rius, Clara Calbet), Hospital General de Catalunya (Esther Oliva), Hospital Universitario Reina Sofía (Francisca Aguilar, Angela Bello), Hospital Universitario Río Hortega (María Nathalie Campo Fernández, Garazi Fraile), Hospital del Tajo (Clara García-Bermejo), S.A.M.U.R. - Municipal Emergency and Rescue Assistance Service (Nieves de Lucas). REFERENCES 1. Greenhow TL, Hung YY, Herz AM. Changing epidemiology of bacteremia in infants aged 1 week to 3 months. Pediatrics. 2012;129:e590–e596. 2. Greenhow TL, Hung YY, Herz AM, et al. The changing epidemiology of serious bacterial infections in young infants. Pediatr Infect Dis J. 2014;33:595–599. 3. Biondi E, Evans R, Mischler M, et al. Epidemiology of bacteremia in febrile infants in the United States. Pediatrics. 2013;132:990–996. 4. Nanduri SA, Petit S, Smelser C, et al. Epidemiology of invasive early-onset and late-onset Group B Streptococcal Disease in the United States, 2006 to 2015: multistate laboratory and population-based surveillance. JAMA Pediatr. 2019;173:224–233. 5. Schrag SJ, Zywicki S, Farley MM, et al. Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis. N Engl J Med. 2000;342:15–20. 6. Jordan HT, Farley MM, Craig A, et al; Active Bacterial Core Surveillance (ABCs)/Emerging Infections Program Network, CDC. Revisiting the need for vaccine prevention of late-onset neonatal group B streptococcal disease: a multistate, population-based analysis. Pediatr Infect Dis J. 2008;27:1057–1064. 7. Gomez B, Hernandez-Bou S, Garcia-Garcia JJ, et al; Bacteraemia Study Working Group from the Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies (SEUP). Bacteremia in previously healthy children in emergency departments: clinical and microbiological characteristics and outcome. Eur J Clin Microbiol Infect Dis. 2015;34:453–460. 8. Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6:2–8. 9. de la Torre M, de Lucas N, Velasco R, et al; [Aetiology and outcomes of potentially serious infections in febrile infants less than 3 months old]. An Pediatr (Barc). 2017;87:42‐49. 10. Powell EC, Mahajan PV, Roosevelt G, et al; Febrile Infant Working Group of the Pediatric Emergency Care Applied Research Network (PECARN). Epidemiology of bacteremia in febrile infants aged 60 days and younger. Ann Emerg Med. 2018;71:211–216. 11. Elgoibar B, Gangoiti I, Garcia-Garcia JJ, et al; Bacteremia Study Working Group from the Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies (SEUP). Paediatric Escherichia coli bacteraemia presentations and high-risk factors in the emergency department. Acta Paediatr. 2021;110:1032–1037. 12. Berardi A, Rossi C, Lugli L, et al; GBS Prevention Working Group, EmiliaRomagna. Group B streptococcus late-onset disease: 2003-2010. Pediatrics. 2013;131:e361–e368. 13. Puopolo KM, Lynfield R, Cummings JJ; Committee On Fetus And Newborn; Committee On Infectious Diseases. Management of infants at risk for group B streptococcal disease. Pediatrics. 2019;144:e20191881. 14. Madhi SA, Cutland CL, Jose L, et al. Safety and immunogenicity of an investigational maternal trivalent group B streptococcus vaccine in healthy women and their infants: a randomised phase 1b/2 trial. Lancet Infect Dis. 2016;16:923–934. 15. Dzanibe S, Madhi SA. Systematic review of the clinical development of group B streptococcus serotype-specific capsular polysaccharide-based vaccines. Expert Rev Vaccines. 2018;17:635–651. 16. Hillier SL, Ferrieri P, Edwards MS, et al. A Phase 2, Randomized, Control Trial of Group B Streptococcus (GBS) Type III Capsular Polysaccharidetetanus Toxoid (GBS III-TT) vaccine to prevent vaginal colonization with GBS III. Clin Infect Dis. 2019;68:2079–2086. 17. Kuppermann N, Dayan PS, Levine DA, et al; Febrile Infant Working Group of the Pediatric Emergency Care Applied Research Network (PECARN). A clinical prediction rule to identify febrile infants 60 days and younger at low risk for serious bacterial infections. JAMA Pediatr. 2019;173:342–351. 18. Gomez B, Mintegi S, Bressan S, et al; European Group for Validation of the Step-by-Step Approach. Validation of the “Step-by-Step” approach in the management of young febrile infants. Pediatrics. 2016;138:e20154381. 19. Gomez B, Bressan S, Mintegi S, et al. Diagnostic value of procalcitonin in well-appearing young febrile infants. Pediatrics. 2012;130:815–822. 20. Hatherill M, Tibby SM, Sykes K, et al. Diagnostic markers of infection: comparison of procalcitonin with C reactive protein and leucocyte count. Arch Dis Child. 1999;81:417–421. 21. Deis JN, Creech CB, Estrada CM, et al. Procalcitonin as a marker of severe bacterial infection in children in the emergency department. Pediatr Emerg Care. 2010;26:51–60; quiz 61. 22. Gomez B, Mintegi S, Lopez E, et al. Diagnostic value of leukopenia in young febrile infants. Pediatr Infect Dis J. 2012;31:92–95. 23. Gomez B, Mintegi S, Benito J; Group for the Study of Febrile Infant of the RiSeuP-SPERG Network. A prospective multicenter study of leukopenia in infants younger than ninety days with fever without source. Pediatr Infect Dis J. 2016;35:25–29. 24. Hernández-Bou S, Álvarez Álvarez C, Campo Fernández MN, et al. [Blood cultures in the paediatric emergency department. Guidelines and recommendations on their indications, collection, processing and interpretation]. An Pediatr (Barc). 2016;84:294.e1–e9. METODOA 85 HELBURU BAKOITZAREKIN HARREMANDUTAKO ARTIKULUAK 1. Hamalau urtetik beherako pazienteetan baieztatu diren IBIen aurkezpen klinikoaren karakterizazioa egin. • Characteristics of children with microbiologically confirmed invasive bacterial infections in the emergency department. EJEM 2018. • Repeated Emergency Department Visits Among Children with Invasive Bacterial Infections. PIDJ 2021. 2. Hamalau urtetik beherako pazienteen IBIen larritasuna deskribatu. • Characteristics of children with microbiologically confirmed invasive bacterial infections in the emergency department. EJEM 2018. • Repeated Emergency Department Visits Among Children with Invasive Bacterial Infections. PIDJ 2021. 3. Hamalau urtetik beherako pazienteen IBIak identifikatzeko egiten diren ohiko odol testen (leukozitoen zenbaketa, neutrofiloen zenbaki absolutua, proteina C erreaktiboa eta prokaltzitonina) balioa analizatu. • Markers for invasive bacterial infections in previously healthy children. Am J Emerg Med. 2021. 4. Fokurik gabeko sukarra duten eta larrialdi zerbitzura egonkor iristen diren 3-24 hilabete arteko haurrak artatzerakoan odol testik ez erabiltzearen gomendioa ebaluatu. • Prevalence of Occult Bacteremia in Infants With Very High Fever Without a Source. PIDJ 2018. Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 86 • Occult Bacteremia in Young Children with Very High Fever Without a Source: A Multicenter Study. PIDJ 2020. 5. E. colik eragindako infekzio inbaditzaileen aurkezpena deskribatu eta balizko profilak eta larritasunarekiko balizko harremana ikertu. • Paediatric Escherichia coli bacteraemia presentations and high-risk factors in the emergency department. Acta Paediatr 2021. 6. B taldeko estreptokokoak eragindako infekzio inbaditzailearen aurkezpena deskribatu eta haren larritasunarekiko balizko harremana ikertu. • Late-onset Group B Streptococcus Bacteremia Evaluated in the Pediatric Emergency Department and Risk Factors for Severe Infection. PIDJ 2022. 7. Bigarren mailako helburua. Aurretik espero ez genuen pandemia batek larrialdi zerbitzu baten identifikatu diren IBIen epidemiologian izan duen eragina deskribatu. • Impact of the COVID-19 pandemic on pediatric invasive bacterial infections. An Pediatr (Engl Ed) 2023. Tesiarekin harreman zuzenik izan ez arren larrialdi zerbitzu pediatrikoan gaixotasun infekziosoen inguruan egindako ikerketen argitalpenak puntu honetan gehituko ditugu. o van Houten CB, Naaktgeboren CA, Ashkenazi-Hoffnung L, Ashkenazi S, Avis W, Gangoiti I, Bont LJ et al; IMPRIND consortium. Expert panel diagnosis demonstrated high reproducibility as reference standard in infectious diseases. J Clin Epidemiol. 2019 Aug;112:20-27. doi: 10.1016/j.jclinepi.2019.03.010. Epub 2019 Mar 28. PMID: 30930247. • ISSN: 0895-4356 METODOA 87 • JCR: Science edition, 2019 • Impact factor: 2,702 • Quartil: Q1 • Abstract: Objective: If a gold standard is lacking in a diagnostic test accuracy study, expert diagnosis is frequently used as reference standard. However, interobserver and intraobserver agreements are imperfect. The aim of this study was to quantify the reproducibility of a panel diagnosis for pediatric infectious diseases. Study design and setting: Pediatricians from six countries adjudicated a diagnosis (i.e., bacterial infection, viral infection, or indeterminate) for febrile children. Diagnosis was reached when the majority of panel members came to the same diagnosis, leaving others inconclusive. We evaluated intraobserver and intrapanel agreement with 6 weeks and 3 years' time intervals. We calculated the proportion of inconclusive diagnosis for a three-, five-, and seven-expert panel. Results: For both time intervals (i.e., 6 weeks and 3 years), intrapanel agreement was higher (kappa 0.88, 95%CI: 0.81-0.94 and 0.80, 95%CI: NA) compared to intraobserver agreement (kappa 0.77, 95%CI: 0.71-0.83 and 0.65, 95%CI: 0.52-0.78). After expanding the three-expert panel to five or seven experts, the proportion of inconclusive diagnoses (11%) remained the same. Conclusion: A panel consisting of three experts provides more reproducible diagnoses than an individual expert in children with lower respiratory tract infection or fever without source. Increasing the size of a Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 88 panel beyond three experts has no major advantage for diagnosis reproducibility. Keywords: Diagnosis; Expert panel; Gold standard; Infectious diseases; Reference standard; Reproducibility. o Gangoiti I, Martinez-Fernandez E, Garmendia O, Diez A, Mintegi S. Impacto de la vacunación en embarazadas sobre la reemergencia de la tosferina y su forma de presentación en urgencias [Impact of whooping cough vaccine during pregnancy on the resurgence of the disease and its form of presentation in paediatric emergency departments]. An Pediatr (Engl Ed). 2020 Aug;93(2):129-131. Spanish. doi: 10.1016/j.anpedi.2019.11.002. Epub 2019 Dec 27. PMID: 31889662. • ISSN: 2341-2879 • JCR: Science edition, 2020 • Impact factor: 1,5 • Quartil: Q3 • Abstract: Introduction: The resurgence of pertussis led to immunize pregnant women in 2015. The objective is to analyse the impact of immunizing pregnant women on the resurgence and way of presentation of pertussis in a paediatric emergency department (ED). Methods: Retrospective cohort analysis between 2008 and 2017. We compared the episodes with a diagnosis of pertussis before and after immunizing pregnant women. METODOA 89 Results: During the study period, 196 children were diagnosed with pertussis. In the pre-vaccine period, we diagnosed initially 1 episode of pertussis/8903 episodes in the ED vs 1/1178 in 2015, decreasing to 1/3203 episodes after vaccination. The median age of patients diagnosed with pertussis increased after vaccination (9 vs. 38 months, p = 0,02) and the admission rate dropped from 36.9% to 8.8% (p < 0.01). Conclusion: Vaccination has reversed the trend of rising pertussis cases in the paediatric ED, decreasing the number of more severe episodes. o Funk AL, Florin TA, Kuppermann N, Tancredi DJ, Xie J, Gangoiti I, Freedman SB et al; Pediatric Emergency Research Network-COVID-19 Study Team. Outcomes of SARS-CoV-2-Positive Youths Tested in Emergency Departments: The Global PERN-COVID-19 Study. JAMA Netw Open. 2022 Jan 4;5(1):e2142322. doi: 10.1001/jamanetworkopen.2021.42322. PMID: 35015063; PMCID: PMC8753506. • ISSN: 2574-3805 • JCR: Science edition, 2022 • Impact factor: 4,108 • Quartil: Q1 • Abstract: Importance: Severe outcomes among youths with SARS-CoV-2 infections are poorly characterized. Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 90 Objective: To estimate the proportion of children with severe outcomes within 14 days of testing positive for SARS-CoV-2 in an emergency department (ED). Design, setting, and participants: This prospective cohort study with 14day follow-up enrolled participants between March 2020 and June 2021. Participants were youths aged younger than 18 years who were tested for SARS-CoV-2 infection at one of 41 Eds across 10 countries including Argentina, Australia, Canada, Costa Rica, Italy, New Zealand, Paraguay, Singapore, Spain, and the United States. Statistical analysis was performed from September to October 2021. Exposures: Acute SARS-CoV-2 infection was determined by nucleic acid (eg, polymerase chain reaction) testing. Main outcomes and measures: Severe outcomes, a composite measure defined as intensive interventions during hospitalization (eg, inotropic support, positive pressure ventilation), diagnoses indicating severe organ impairment, or death. Results: Among 3222 enrolled youths who tested positive for SARS-CoV2 infection, 3221 (>99.9%) had index visit outcome data available, 2007 (62.3%) were from the United States, 1694 (52.6%) were male, and 484 (15.0%) had a self-reported chronic illness; the median (IQR) age was 3 (0-10) years. After 14 days of follow-up, 735 children (22.8% [95% CI, 21.4%-24.3%]) were hospitalized, 107 (3.3% [95% CI, 2.7%-4.0%]) had severe outcomes, and 4 children (0.12% [95% CI, 0.03%-0.32%]) died. Characteristics associated with severe outcomes included being aged 5 to 18 years (age 5 to <10 years vs <1 year: odds ratio [OR], 1.60 [95% CI, METODOA 91 1.09-2.34]; age 10 to <18 years vs <1 year: OR, 2.39 [95% CI 1.38-4.14]), having a self-reported chronic illness (OR, 2.34 [95% CI, 1.59-3.44]), prior episode of pneumonia (OR, 3.15 [95% CI, 1.83-5.42]), symptoms starting 4 to 7 days prior to seeking ED care (vs starting 0-3 days before seeking care: OR, 2.22 [95% CI, 1.29-3.82]), and country (eg, Canada vs US: OR, 0.11 [95% CI, 0.05-0.23]; Costa Rica vs US: OR, 1.76 [95% CI, 1.05-2.96]; Spain vs US: OR, 0.51 [95% CI, 0.27-0.98]). Among a subgroup of 2510 participants discharged home from the ED after initial testing and who had complete follow-up, 50 (2.0%; 95% CI, 1.5%-2.6%) were eventually hospitalized and 12 (0.5%; 95% CI, 0.3%-0.8%) had severe outcomes. Compared with hospitalized SARS-CoV-2-negative youths, the risk of severe outcomes was higher among hospitalized SARSCoV-2-positive youths (risk difference, 3.9%; 95% CI, 1.1%-6.9%). Conclusions and relevance: In this study, approximately 3% of SARSCoV-2-positive youths tested in Eds experienced severe outcomes within 2 weeks of their ED visit. Among children discharged home from the ED, the risk was much lower. Risk factors such as age, underlying chronic illness, and symptom duration may be useful to consider when making clinical care decisions. o Funk AL, Kuppermann N, Florin TA, Tancredi DJ, Xie J, Gangoiti I, Freedman SB et al; Pediatric Emergency Research Network–COVID-19 Study Team. PostCOVID-19 Conditions Among Children 90 Days After SARS-CoV-2 Infection. JAMA Netw Open. 2022 Jul 1;5(7):e2223253. Doi: Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 92 10.1001/jamanetworkopen.2022.23253. Erratum in: JAMA Netw Open. 2022 Aug 1;5(8):e2231131. PMID: 35867061; PMCID: PMC9308058. • ISSN: 2574-3805 • JCR: Science edition, 2022 • Impact factor: 4,108 • Quartil: Q1 • Abstract: Importance: Little is known about the risk factors for, and the risk of, developing post-COVID-19 conditions (PCCs) among children. Objectives: To estimate the proportion of SARS-CoV-2-positive children with PCCs 90 days after a positive test result, to compare this proportion with SARS-CoV-2-negative children, and to assess factors associated with PCCs. Design, setting, and participants: This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2-positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2-negative controls. Exposure: SARS-CoV-2 detected via nucleic acid testing. Main outcomes and measures: Post-COVID-19 conditions, defined as any persistent, new, or recurrent health problems reported in the 90-day follow-up survey. Results: Of 8642 enrolled children, 2368 (27.4%) were SARS-CoV-2 positive, among whom 2365 (99.9%) had index ED visit disposition data METODOA 93 available; among the 1884 children (79.7%) who completed follow-up, the median age was 3 years (IQR, 0-10 years) and 994 (52.8%) were boys. A total of 110 SARS-CoV-2-positive children (5.8%; 95% CI, 4.8%-7.0%) reported PCCs, including 44 of 447 children (9.8%; 95% CI, 7.4%-13.0%) hospitalized during the acute illness and 66 of 1437 children (4.6%; 95% CI, 3.6%-5.8%) not hospitalized during the acute illness (difference, 5.3%; 95% CI, 2.5%-8.5%). Among SARS-CoV-2-positive children, the most common symptom was fatigue or weakness (21 [1.1%]). Characteristics associated with reporting at least 1 PCC at 90 days included being hospitalized 48 hours or more compared with no hospitalization (adjusted odds ratio [aOR], 2.67 [95% CI, 1.63-4.38]); having 4 or more symptoms reported at the index ED visit compared with 1 to 3 symptoms (4-6 symptoms: aOR, 2.35 [95% CI, 1.28-4.31]; ≥7 symptoms: aOR, 4.59 [95% CI, 2.50-8.44]); and being 14 years of age or older compared with younger than 1 year (aOR, 2.67 [95% CI, 1.43-4.99]). SARS-CoV-2-positive children were more likely to report PCCs at 90 days compared with those who tested negative, both among those who were not hospitalized (55 of 1295 [4.2%; 95% CI, 3.2%-5.5%] vs 35 of 1321 [2.7%; 95% CI, 1.9%- 3.7%]; difference, 1.6% [95% CI, 0.2%-3.0%]) and those who were hospitalized (40 of 391 [10.2%; 95% CI, 7.4%-13.7%] vs 19 of 380 [5.0%; 95% CI, 3.0%-7.7%]; difference, 5.2% [95% CI, 1.5%-9.1%]). In addition, SARS-CoV-2 positivity was associated with reporting PCCs 90 days after the index ED visit (aOR, 1.63 [95% CI, 1.14-2.35]), specifically systemic health problems (eg, fatigue, weakness, fever; aOR, 2.44 [95% CI, 1.19-5.00]). Infekzio bakteriano inbaditzaileen identifikazioa pediatrian, txerto konbinatuen garaian 94 Conclusions and relevance: In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older. RESUMEN 197 Los artículos escritos con el objetivo de investigar la caracterización del estreptococo del grupo B y del E. coli y su posible relación con la gravedad, son el resultado del análisis secundario de un gran registro prospectivo que tenía como objetivo realizar la caracterización de las bacteriemias que se detectan en la edad pediátrica. En 2010, la Sociedad Española de Urgencias de Pediatría (SEUP), liderada por el Grupo de Trabajo de Enfermedades Infecciosas, propuso establecer un registro multicéntrico prospectivo de los cultivos sanguíneos positivos aislados en los servicios de urgencias de pediatría en España. El reclutamiento prospectivo de pacientes con edades comprendidas entre los niños recién nacidos y los 20 años se llevó a cabo entre 2011 y 2016. En 1.696 pacientes se aisló una bacteria patógena real en sangre. Para alcanzar los objetivos de estos estudios, se analizaron los pacientes en los que en su muestra de sangre se aislaron estreptococo del grupo B y E. Coli. En el artículo de Elgoibar B, Gangoiti I, García-García JJ, Hernández-Bou S, Gómez B, Martínez Indart L, Mintegi S; Bacteremia Study Working Group from the Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies (SEUP). Paediatric Escherichia coli bacteraemia presentations and high-risk factors in the emergency department. Acta Paediatr. 2021 Mar; 110 (3);1032-1037 se identificaron 291 pacientes diagnosticados de IBI por E. coli. Los diagnósticos más frecuentes recogidos fueron la infección invasiva urinaria en 206 casos (70,8%), la sepsis 32 (11%) y la bacteriemia oculta 27 (9,3%). Cuarenta y tres casos cumplieron criterios de gravedad (14,8%, IC 95%: 11,2-19,3) y de ellos, dos fallecieron. Los análisis de Correspondencia Múltiple y en análisis Clúster identificaron cuatro tipos principales de presentaciones de la bacteriemia pediátrica por E. coli. Los dos primeros grupos fueron formados por niños previamente sanos menores de un año y con buen aspecto general, diagnosticados de IBI secundaria a infección urinaria y con una buena evolución en general. El tercer grupo estaba formado Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 198 en gran parte por pacientes previamente no sanos, de más de 12 meses de edad; en el último grupo había niños de diferentes edades, un tercio no era previamente sano y la proporción de niños inestables según el TEP era mayor que en el resto de grupos. Estos dos últimos grupos tenían menor relación infección urinaria y las tasas de gravedad fueron significativamente superiores, 15% y 50,9% respectivamente (p < 0,01). Los dos pacientes fallecidos pertenecían al último grupo. Ocho niños fueron diagnosticados de meningitis bacteriana, todos ellos menores de 5 meses. La tasa de meningitis detectada en las bacteriemias causadas por E. coli en lactantes menores de un mes de edad fue del 9,4% y en los niños de uno y dos meses 2,6%. Únicamente se diagnosticó un caso de meningitis en niños mayores de dos meses. En el artículo de Ecclesia FG, Alonso Cadenas JA, Gómez B, Gangoiti I, Hernández-Bou S, de la Torre Espí M; Bacteremia Study Working Group from the Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies. Late-onset Group B Streptococcus Bacteremia Evaluated in the Pediatric Emergency Department and Risk Factors for Severe Infection. Pediatr Infect Dis J. 2022 Jun 1; 41 (6) 455-459 se estudiaron 134 pacientes diagnosticados de IBI por estreptococo grupo B. Sólo se encontró algún factor de riesgo en el 14,4% de los pacientes. En cuanto a la sensibilidad de los análisis de los diferentes marcadores sanguíneos para el diagnóstico de la infección grave, no se encontraron diferencias estadísticamente significativas, aunque se detectaron valores de procalcitonina superiores a 0,5 ng/ml en las infecciones más graves. De los 74 pacientes con infecciones graves (sepsis y/o meningitis) sólo 15 presentaron un TEP estable cuando fueron atendidos en el servicio de urgencias. El análisis multivariante identificó como único factor de riesgo independiente relacionado con la infección grave la situación de inestabilidad a la llegada a urgencias identificada mediante el TEP. En seis pacientes (5,1%) la evolución no fue buena, todos tuvieron complicaciones agudas graves RESUMEN 199 (5,1%), dos sufrieron secuelas persistentes y otros dos fallecieron. Los seis pacientes eran menores de 26 días, no estaban estables según el TEP y presentaron valores altos de procalcitonina y cuatro de ellos presentaron además leucopenia. Los artículos que han analizado la recomendación de no utilizar de manera sistemática test sanguíneos a la hora de evaluar a los niños de 3 a 24 meses de edad, previamente sanos y con fiebre sin foco y buen estado general, son fruto de los resultados de dos trabajos que se desarrollaron con una metodología diferente. El artículo de Gangoiti I, Rodriguez E, Zubizarreta A, Benito J, Mintegi S. Prevalence of Occult Bacteremia in Infants With Very High Fever Without a Source. Pediatr Infect Dis J. 2018 Nov; 37 (11): e271-e273 es el resultado de un estudio retrospectivo, descriptivo y analítico realizado en un servicio de urgencias de Pediatría (SUP) de un hospital terciario que forma parte del Sistema Público de Salud. La población investigada fueron los lactantes previamente sanos de 3 a 24 meses de edad, estables y con una temperatura igual o superior a 40,5 ºC en su domicilio o en el hospital, atendidos en el servicio pediátrico de urgencias entre enero de 2013 y diciembre de 2016. La variable resultado fue la identificación de una bacteria patógena real. En total se recogieron 543 cultivos y posteriormente se realizó un análisis según el origen conocido o desconocido de la fiebre. La prevalencia de bacteriemia oculta entre 363 niños con fiebre sin focalidad se estimó en un 1,1% (IC 95%: 0-2,2). La evolución de todos ellos fue buena. El artículo de Gangoiti I, Zubizarreta A, Elgoibar B, Mintegi S; Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies (SEUP). Occult bacteremia in young children with very high fever without a source: a multicenter study. Pediatr Infect Dis J. 2020 Dec; 39 (12):e462-e464 trata de una investigación prospectiva y multicéntrica (niños atendidos en 6 servicios de urgencias de pediatría españoles) y se basó en una Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 200 cohorte de pacientes previamente sanos y con temperatura igual o superior a 40,5 ºC, sin foco aparente. Los pacientes fueron reclutados prospectivamente desde el 1 de enero de 2018 hasta el 31 de diciembre de 2019. Los criterios de inclusión, el manejo terapéutico, las definiciones y la variable resultado que se plantearon en este estudio son los mismos empleados en la investigación unicéntrica comentada previamente. En total se reclutaron 203 pacientes y en 31 pacientes se diagnosticó una infección bacteriana potencialmente grave: infección urinaria 14 (6,9%), neumonía 11 (5,4%) y bacteriemia 6 (3%). En 3 de los 6 niños diagnosticados de bacteriemia oculta se aisló un neumococo bien por cultivo o por técnicas de PCR; la prevalencia de bacteriemia oculta neumocócica se estimó en un 1,48% (IC 95%: 0,5-4,3). La evolución de todos los pacientes fue buena. Todos los artículos recogidos en esta tesis inciden en que la investigación y vigilancia continuada de las IBI debería ser una actividad imprescindible para ofrecer la atención de mayor calidad al niño, niña y adolescente que pueda sufrir una enfermedad de este tipo. Aunque no fuera motivo esencial de esta tesis, el impacto de la pandemia COVID sobre la epidemiología de las IBI diagnosticadas en nuestro entorno confirma lo anterior. INTRODUCCIÓN 201 INTRODUCCIÓN La fiebre es un motivo habitual de consulta en pacientes atendidos en un SUP1. Aunque es cierto que lo más frecuente es que el origen de la fiebre sea una infección viral autolimitada, en ocasiones puede ser un síntoma inicial de una infección bacteriana invasiva (IBI). Para diagnosticar una IBI, una bacteria patógena debe ser identificada en sangre, líquido cefalorraquídeo, pleural o articular. La IBI que más preocupa es aquélla en la que se aísla el germen en sangre o líquido cefalorraquídeo, ya que la sepsis y la meningitis continúan siendo una causa de muerte no despreciable en los países desarrollados2, a pesar de que las condiciones de vida y los estudios realizados en el campo de las vacunas y antibióticos en las últimas décadas, hayan supuesto importantes avances. Esto último ha provocado un notable descenso del aislamiento de las bacterias más comunes responsables de infecciones graves en los últimos años. Por otro lado, en los países desarrollados, es evidente el aumento de la accesibilidad de los servicios sanitarios de atención a pacientes y que los niños y niñas consultan con procesos infecciosos muy precoces, tanto en los servicios de urgencias hospitalarios como en atención primaria3, siendo también muy frecuente que la edad de estos pacientes sea inferior a 2-3 años. Todo ello puede provocar cambios en la expresividad del cuadro clínico y favorecer que las características, signos y síntomas clásicos de presentación de las IBI décadas atrás, sean ahora menos visibles4. Además, el perfil del profesional médico que atiende al paciente pediátrico presenta una variabilidad muy elevada; desde un médico residente de primer año a un médico de familia de atención primaria que suele atender a pacientes adultos. Todas las variables de esta ecuación han influido en la identificación precoz de la IBI. Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 202 El impacto de las campañas de vacunación es incuestionable. Así, se ha visto claramente que la vacunación universal contra la Haemophilus influenzae b, que vino con el cambio de siglo, tuvo una consecuencia directa en una de las infecciones invasivas más graves que se identificaban en los niños del primer mundo5, suponiendo su erradicación casi total en la población vacunada. Junto a esto, la comercialización de vacunas conjugadas frente a Streptococcus pneumoniae ha supuesto un descenso significativo de infecciones invasivas neumocócicas3,6,7,8,9. Era frecuente que, antes de la llegada de estas vacunas, en una pequeña proporción de lactantes previamente sanos con fiebre y buen estado general se aislara una bacteria en sangre (bacteriemia oculta), tanto H. influenzae como S. pneumoniae10. Según artículos clásicos, cuando la prevalencia de la bacteriemia oculta de una población era superior a la actual, se recomendaba la realización de hemocultivo a los niños de 3 a 24 meses con fiebre sin foco y temperatura superior a 39ºC11. Tras la implantación de las vacunas frente al H. influenzae B y S. pneumoniae, esta prevalencia ha disminuido drásticamente y la búsqueda sistemática de bacteriemia oculta no está recomendada en los niños que hubieran recibido al menos dos dosis de vacuna frente al neumococo4,13,14,15,16,17,18. De hecho, cuando la prevalencia de bacteriemia oculta baja del 0,5%, el rendimiento de las pruebas que se testan en sangre, como el recuento leucocitario y el número absoluto de neutrófilos, disminuye notablemente11,19. Y es que, según los datos que publicó Lee, el mayor rendimiento de estas pruebas de sangre se produce cuando la prevalencia de bacteriemia oculta supera el 1,5%. También se sabe que la prevalencia de bacteriemia oculta aumenta cuando aumenta el valor de la temperatura objetivada5 y se ha relacionado frecuentemente la gradación de la temperatura con la prevalencia de bacteriemia oculta. Las peculiaridades que ofrece el INTRODUCCIÓN 203 grupo de niños con una temperatura muy elevada, generan dudas en cualquier profesional que esté a la cabecera del paciente. Por otro lado, en las dos últimas décadas el número de infecciones invasivas causadas por N. meningitidis ha disminuido considerablemente20,21, debido en parte al efecto que ha tenido la universalización de la vacuna frente a N. meningitidis del serogrupo C. La N. meningitidis del serogrupo B ha sido el principal causante de IBI en los países desarrollados en los últimos años. Sin embargo, recientemente otras variantes, especialmente W e Y, han ido ganando terreno, manteniéndose en general relativamente estable la tendencia del serogrupo B. En los últimos años, además, han aparecido en el mercado vacunas contra los diferentes serogrupos de N. meningitidis. El Consejo Asesor de Vacunas de la Asociación Española de Pediatría las ha recomendado22 y algunas Comunidades Autónomas ya las han incluido en su estrategia postnatal financiada (en en el País Vasco se han beneficiado de esta medida niños nacidos en 2023), y su impacto está por ver. Estos cambios no sólo han supuesto una importante reducción de las IBI, sino que indirectamente han provocado una mayor dispersión de los principales microorganismos causantes. Hoy en día, uno de los más importantes es la E. coli. Es el responsable de la mayor parte de las bacteriemias en niños menores de un año, especialmente en pacientes menores de tres meses y generalmente relacionadas con las infecciones de las vías urinarias23. Sin embargo, en nuestro entorno, no se ha llevado a cabo ningún estudio con una muestra amplia que analizara las características clínicas y las consecuencias de esta bacteriemia. Por lo tanto, está por dilucidar si existen diferentes perfiles de pacientes que sufren bacteriemia por E. coli y si estos diferentes perfiles están relacionados con un nivel de gravedad diferente. Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 204 Por todo lo expresado anteriormente, no es de extrañar que en ocasiones sea difícil la identificación precoz del niño que puede tener una IBI. El declive de las IBI en los últimos años, los cambios en las características de los pacientes atendidos (el paciente suele ser atendido en un servicio de urgencias antes de la aparición de los signos y síntomas más clásicos de los cuadros clínicos), y la gran variabilidad de los profesionales que atienden al niño en un servicio de urgencias, inciden en una mayor dificultad para identificar estas enfermedades. Un estudio afirmó que el 22% de los pacientes pediátricos que han sufrido meningitis bacteriana o sepsis consultaron en varias ocasiones un servicio de urgencias24, aunque destacaron que los resultados y evolución finales fueron similares a los de los niños identificados en la primera consulta25. Sin embargo, las guías de manejo de la sepsis pediátrica han insistido en que el tratamiento antibiótico intravenoso rápido, cuando se ha visualizado el estado de shock y se ha implantado dentro de la primera hora, es clave26. Por ello, la respuesta a los análisis y biomarcadores de sangre de un determinado grupo de pacientes se convierte en una importante herramienta que forma parte del proceso de decisión para identificar la IBI. Si se tiene en cuenta que el cambio de microorganismos que habitualmente eran responsables de las IBI y que el proceso de atención al paciente es cada vez más precoz, el rendimiento y la respuesta de estos test será probablemente diferente a lo publicado clásicamente. En general, la leucocitosis y la neutrofilia han sido los parámetros analíticos más utilizados en la toma de decisiones en un servicio pediátrico de urgencias y más recientemente, la proteína C reactiva. En los últimos años, además, la procalcitonina ha actuado como un marcador bioquímico útil, ya que ofrece ventajas frente a los marcadores clásicos16,17,27,28. Sin embargo, la aparición y adición de nuevos biomarcadores puede dificultar en ocasiones la identificación de los pacientes con mayor riesgo de IBI19, ya que no todas las infecciones influyen de la misma manera en los biomarcadores en sangre. INTRODUCCIÓN 205 CLASIFICACIÓN DE LAS IBI Como se ha mencionado en la introducción, el diagnóstico de IBI se basa en el aislamiento de una bacteria patógena en sangre, líquido cefalorraquídeo, líquido pleural o líquido articular. Sin embargo, dependiendo del líquido en el que se desarrolle el aislamiento, de su influencia en el huésped y de la respuesta que éste proporcione, pueden surgir situaciones clínicas muy diferentes. La definición de bacteriemia consiste en el aislamiento de una bacteria patógena que se realiza en una muestra de sangre en pacientes previamente sanos. Se excluyen de esta manera los microorganismos que se definen clásicamente como contaminantes, como Staphylococcus epidermidis, Propionibacterium acnes, Streptococcus viridans, Corynebacterium spp., y otros difteroides. Los microorganismos denominados clásicamente contaminantes también pueden provocar bacteriemias en pacientes no previamente sanos: niños que sufren una enfermedad oncológica u otra inmunodeficiencia, pacientes portadores de catéter central o válvula de derivación, pacientes con técnicas diagnósticas o terapéuticas invasivas en los días posteriores a la realización de la extracción, ... Dentro de la bacteriemia podemos distinguir dos grandes grupos: los producidos por una infección focal (infecciones focales invasivas) y los que carecen de infección focal (bacteriemia oculta). Dada su importancia y gravedad, así como las tasas de mortalidad y morbilidad inexorablemente asociadas a las mismas, la meningitis (infección focal invasora) y la sepsis (infección diseminada que puede tener un origen focal conocido o desconocido) se exponen de forma específica. Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 206 Meningitis bacteriana Se denomina meningitis a la inflamación de las meninges, que afecta a la piamadre, aracnoide y zona subaracnoidea. Respecto a su etiología, lo más frecuente en la edad pediátrica es el origen viral, sobre todo el enterovirus, cuyo pronóstico es muy bueno de forma general. La denominación bacteriana estará limitado al aislamiento de una bacteria que crece en el líquido cefalorraquídeo. Esta situación se produce, generalmente, después de que los organismos que han colonizado las capas mucosas, hayan invadido la circulación sanguínea. Las campañas de vacunación de los últimos años y la profilaxis antibiótica que se realiza en torno al estreptococo del grupo B han cambiado radicalmente la epidemiología de la meningitis bacteriana. El estreptococo del grupo B o los Gram negativos serán causantes de la meningitis bacteriana en niños menores de tres meses y el Streptococcus pneumoniae y Neisseria meningitidis en niños sanos mayores de esta edad29,30,31,32,33. En la mayoría de los casos, las bacterias se extienden por los vasos sanguíneos y tras atravesar la barrera hematoencefálica pasan a la zona interior de la aracnoides. Una vez alcanzado el sistema nervioso, tras una replicación exponencial y la creación de numerosos intermediarios generadores de inflamación, se iniciará el proceso que dará lugar a la lesión definitiva del tejido. Aunque en la patogenia de la meningitis este mecanismo sea el más importante, también podrían provocar este cuadro clínico la trasmisión a partir de un seno nasal, del ojo o a través del hueso mastoides. Otras situaciones, como la fractura de cráneo con presencia de licuorrea o los procedimientos de neurocirugía o los causados por herida penetrante, también pueden facilitar el desarrollo de una meningitis. INTRODUCCIÓN 213 El resto de síntomas pueden ser variados, irritabilidad, vómitos, estancamiento de la ganancia de peso, rechazo a la comida, ... Entre los recién nacidos, la infección urinaria también puede ser la causa de la ictericia que dura más de una semana48. Entre los pacientes de mayor edad, el cuadro clínico puede ser más preciso. Son frecuentes la disuria, la polaquiuria y en ocasiones puede aparecer hematuria. De hecho, la infección urinaria es la principal causa de hematuria en la infancia. Cuando la infección afecta al riñón, además de la fiebre alta, puede aparecer dolor abdominal o lumbar y escalofríos. Durante el examen físico, la puño percusión renal suele ser dolorosa, indicativa de la inflamación de la capsula renal. Escherichia coli es la bacteria que más se aísla en las infecciones de las vías urinarias; otras enterobacterias, especialmente las Gram negativas (Klebsiella y otras), suelen ser frecuentes en los aislamientos del cultivo urinario. En los lactantes pequeños la presencia de cocos gram positivos como Enterococcus spp puede ser habitual. En pacientes no previamente sanos, también podemos encontrar otras bacterias causantes, clásicamente relacionados con enfermedad más grave, aunque esto se haya puesto en duda en estos últimos años49. Cuando la bacteria responsable de la infección en las vías urinarias pasa a la corriente sanguínea, estaremos ante una bacteriemia. E. coli es la bacteria que más se aísla en la sangre en niños menores del año con fiebre, y más aún por debajo de los tres meses, en los que el origen de la bacteriemia es, en muchas ocasiones, la infección de las vías urinarias50. Sin embargo, y en general, la tasa de bacteriemia objetivada en lactantes con infección urinaria febril es baja. La excepción en nuestro entorno son los lactantes más pequeños, Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 214 observándose una tasa de bacteriemia del 11,3% en los niños menores de un mes, del 5,9% entre uno y dos meses y del 2,3% entre los que han cumplido dos meses51. Neumonía Según la organización sanitaria mundial, la neumonía es la principal responsable de las muertes de niños menores de 5 años; la quinta parte de las muertes de niños de esta edad en países en desarrollo se deben a esta enfermedad. En los países desarrollados la situación es totalmente diferente; se trata de un diagnóstico relativamente frecuente pero que rara vez produce efectos graves y las tasas de hospitalización no son excesivamente altas, debido al éxito general del tratamiento antibiótico ambulatorio52,53,54. El diagnóstico debe estar basado en un proceso infeccioso que incluya síntomas respiratorios. El examen físico puede poner de manifiesto signos como áreas pulmonares de hipoventilación, estertores, crepitantes o soplo tubárico. No es obligatorio para el diagnóstico la imagen radiológica, pero en los países desarrollados es casi universal que la imagen radiológica confirme la sospecha diagnóstica. Lo más habitual es que el paciente pueda presentar una dificultad respiratoria leve. Sin embargo, en determinados casos, ciertos aspectos fisiológicos básicos (el equilibrio hemodinámico, el nivel de consciencia, ...) estarán comprometidos. En estos casos, la gravedad será significativamente mayor, pudiendo llegar a cumplir los criterios de sepsis siendo imprescindibles las medidas de estabilización. Si el hemocultivo o la identificación del patógeno por técnicas de biología molecular es positivo, estaríamos ante una bacteriemia con una infección respiratoria en origen. Aun así, la mayoría de las neumonías son causadas por virus, especialmente en niños menores de 5 años. Entre las bacterias, la principal responsable es S. pneumoniae a cualquier edad. Entre los niños mayores, la identificación de Mycoplasma pneumoniae INTRODUCCIÓN 215 también es común. Otras bacterias que pueden ser responsables en niños previamente sanos son S. aureus, S. pyogenes, C. pneumoniae y H. influenzae no tipo b. Entre los niños no previamente sanos, pueden ser responsables la Legionella, hongos oportunistas (Candida, Aspergillus…), P. jiroveci, otras bacterias anaerobias, … en pacientes con VIH, fibrosis quística u otro tipo de inmunosupresión54,55. Infección osteoarticular Nos centraremos en la artritis séptica y la osteomielitis. La artritis séptica es una emergencia ortopédica que requiere de una acción inmediata para evitar posibles complicaciones o secuelas persistentes. Se denomina artritis a la infección bacteriana de una o varias articulaciones, que puede aparecer a cualquier edad, con una mayor incidencia alrededor de los dos años. Normalmente se produce en una sola articulación, pero en los casos producidos por N. meningitidis o N. gonorrhoeae son más frecuentes las poliartritis. Fiebre, irritabilidad, limitación para la movilización de la articulación, … son síntomas y signos habituales. Staphylococcus aureus suele ser el principal responsable cuando el cuadro sistémico es llamativo. Salmonella (en pacientes con anemia drepanocítica), S. pneumoniae, Streptococcus pyogenes (en personas que han pasado la varicela recientemente), o los mencionados previamente también son agentes que pueden producir artritis. Entre los niños recién nacidos y más pequeños la infección puede ser causada por estreptococo del grupo B y enterobacterias56. Kingella Kingae aparece en primer plano en el origen de las infecciones osteoarticulares en los últimos años. El cuadro clínico suele ser menos florido, la fiebre es menos frecuente, el estado general de los pacientes no es malo y la limitación para el movimiento es más sutil. Las nuevas técnicas de laboratorio han permitido detectar la presencia de Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 216 esta bacteria57. Hoy en día, es la principal causa de artritis séptica entre los 4 meses y los 4 años de edad. La osteomielitis, por su parte, suele ser una infección que se localiza en el lado metafisario del hueso y que puede pasar a la médula ósea, invadiéndola. La lista de agentes causantes es muy similar56,57. La propagación de estas infecciones al torrente sanguíneo puede producirse tanto por efecto de pared a pared como por paso directo. Cuando el aislamiento de esta bacteria causante de la infección osteoarticular se realiza también en sangre, nos referiremos a la bacteriemia que tiene origen en una infección osteoarticular. Infección de piel y tejidos blandos Como su nombre indica, en este grupo recogeremos las infecciones bacterianas de las diferentes capas que componen la piel y también de otros tejidos como tendones, músculos, etc. Entre ellas, podemos encontrar al impétigo, la celulitis, la foliculitis, la linfangitis, … que son muy comunes y habitualmente de poca gravedad. Por otro lado, podemos tener erisipela, forunculosis o abscesos que pueden conllevar mayor gravedad. Por último, la piomiositis y la fascitis necrosante van a requerir un tratamiento más agresivo y en los casos más graves será imprescindible el tratamiento quirúrgico. En general, el origen de la infección se debe a una herida o lesión que se ha originado en la piel; pocas veces se deberá a una infección que se ha extendido desde otro sistema del organismo. Los principales responsables serán las bacterias que conviven habitualmente en la piel, principalmente S. aureus y S. pyogenes. Se considerarán situaciones especiales los casos de heridas en agua (P. aeruginosa, A. hydrophila y V. Vulnificus), mordeduras (P. multocida y anaerobios), neonatales (estreptococo del grupo B y Gram negativos), INTRODUCCIÓN 217 pacientes inmunosuprimidos (P. aeruginosa, enterobacterias y otros Gram negativos) y casos como la fascitis necrosante (Clostridium y otros anaerobios)58,59. Mención aparte merecen síndromes producidos por las toxinas de S. aureus y S. pyogenes: síndrome de piel escaldada y shock estafilocócico en el caso de S. aureus y shock estreptocócico en el caso de S. pyogenes. El síndrome de la piel escaldada (síndrome de Ritter) ocurre a partir de una infección local que S. aureus ha originado en la piel. La fiebre brusca, la irritabilidad y un rash doloroso que puede ser inicialmente escarlatiniforme serán los síntomas más llamativos. Esta erupción cutánea asociará el desarrollo de bullas uno o dos días después para ser totalmente denudadas posteriormente. En el caso del shock las toxinas estafilocócicas actuarán como superantígenos. Fiebre brusca, vómitos, diarrea, mialgias, eritrodermia e hipotensión serán los signos y síntomas más destacados. El tratamiento de estabilización y sostén junto a la antibioterapia intravenosa serán claves60. El shock estreptocócico se produce en pacientes jóvenes y se han relacionado factores de riesgo significativos como varicela, diabetes mellitus, enfermedad respiratoria crónica, cardiopatía o VIH. Se trata de una enfermedad con una alta tasa de mortalidad, definida por signos y síntomas como la hipotensión, fiebre, eritrodermia y el compromiso multiorgánico. Para su diagnóstico son necesarios criterios clínicos, microbiológicos y analíticos61. Globalmente, en las infecciones de piel y tejidos blandos, el rendimiento de los cultivos sanguíneos en pacientes estables y previamente sanos suele ser muy bajo. En el caso de aislamiento positivo en sangre, hablamos de bacteriemia cuyo origen es una infección de piel y tejidos blandos. Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 218 Bacteriemia oculta La bacteriemia oculta es el aislamiento de una bacteria real en la sangre del paciente que tiene buen estado general y no presenta ningún signo ni síntoma además de la fiebre. El adjetivo “oculta” hace referencia al estado del paciente, es decir, el niño debe tener un buen estado general. Para definirlo se pueden utilizar varias herramientas, uno de ellos es el Triángulo de Evaluación Pediátrica, TEP, cuyo resultado cuando se interpreta como "estable" se entiende que el niño tiene un aspecto saludable62. El TEP es una herramienta rápida y muy útil para la evaluación inicial del paciente pediátrico. Su aplicación es sencilla, ya que no requiere estetoscopio, otoscopio u otros instrumentos más allá de la visión y audición del médico, enfermero o técnico formado. Esta herramienta trata de estructurar la valoración subjetiva que hace cada profesional sanitario cuando ve por primera vez a un paciente. En la mayoría de los centros hospitalarios donde se utiliza el triángulo de evaluación pediátrica, su evaluación se realiza en el triaje por el personal responsable de esta tarea en el centro (médicos y enfermeras). Como su nombre indica, se compone de tres lados: aspecto del paciente, trabajo respiratorio y circulación cutánea. El triángulo de evaluación pediátrica no nos da un diagnóstico del paciente, pero sí nos informa de las necesidades urgentes que tiene el paciente para mantener un estado fisiológico y homeostasis adecuados. Por otro lado, el paciente no debe presentar signos o síntomas que puedan indicar el origen de la fiebre, tales como tos, diarrea, inflamación de amígdalas, auscultación patológica, polipnea, signos meníngeos, etc. Según la bacteria sospechosa, la probabilidad de que una bacteriemia progrese a una meningitis es diferente (en el caso de H. influenzae y meningococo es mayor que con el neumococo). Una vez administrada una única dosis de antibiótico parenteral, la INTRODUCCIÓN 219 probabilidad de que avance la bacteriemia producida por el neumococo es limitada11. Esta es la principal razón de los esfuerzos que se hacen para buscar la bacteriemia oculta. Como ya se ha mencionado, los cambios en el contexto epidemiológico, en los hábitos sociales, y sobre todo el hecho de que los pacientes con mayor riesgo de bacteriemia oculta sean en general los más pequeños, hace que su identificación sea dificultosa. En las últimas décadas se han realizado grandes intentos para identificar grupos de pacientes previamente sanos susceptibles de padecer una bacteriemia oculta. Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 220 BACTERIAS MÁS IMPLICADAS EN LAS IBI DE LA INFANCIA Streptococcus pneumoniae Streptococcus pneumoniae es un coco Gram positivo que forma cadenas cortas. Se conocen más de cien serotipos diferentes y cada uno de ellos está definido por la cápsula polisacárida. De esta última depende la inmunidad específica de cada serotipo. Esta bacteria inicia la colonización de la vía nasofaríngea en los primeros meses de vida, alcanzando su máximo nivel de colonización a los 3 años. Para entonces, entre el 25% y el 80% de la población infantil estará colonizada. Streptococcus pneumoniae puede producir dos tipos de infecciones: IBI (meningitis, bacteriemia, sepsis, neumonía bacteriémica y otras) y no invasivas (neumonía no bacteriémica, otitis o sinusitis por ejemplo). La colonización de las vías nasofaríngeas constituye el único reservorio de Streptococcus pneumoniae, lo que facilita la dispersión tanto familiar como comunitaria63. A finales de los años 90, Streptococcus pneumoniae era el principal responsable de la meningitis bacteriana entre los niños. Sin embargo, en las últimas décadas, las vacunas conjugadas comercializadas han tenido un gran impacto epidemiológico; su prevalencia ha descendido drásticamente en los países que se consideran desarrollados. Todo ello ha supuesto un cambio en la aproximación diagnóstico-terapéutica ante los niños febriles en los servicios de urgencias pediátricos64. Neisseria meningitidis Neisseria meningitidis es un microorganismo diplococo Gram negativo. El humano es el único reservorio de esta especie y suele aislarse en la vía buconasofaringea (los INTRODUCCIÓN 221 porcentajes de portadores son muy variables). N. meningitidis, junto con N. gonorrhoeae, son las únicas especies patógenas del género Neisseria. Antigénicamente se divide en al menos 13 serogrupos, caracterizados por el polisacárido de la cápsula de la Neisseria meningitidis. Históricamente han sido los grupos B y C los que han originado las enfermedades meningocócicas de los países occidentales, aunque los serogrupos Y o W135 han experimentado un aumento relativamente notable durante los últimos años. Por otro lado, el serogrupo causante de epidemias es el A, especialmente en los países en vías de desarrollo. La epidemiología de la enfermedad meningocócica invasora es generalmente muy variable. A lo largo de la historia ha vivido diferentes olas y desde que los datos son accesibles y públicos, la incidencia más baja de la enfermedad se ha situado a mediados de la última década65,66. Sin embargo, en la última mitad de la década de 2010 comenzó a detectarse un cierto aumento generalizado, no sólo en nuestro entorno; además los responsables no eran especialmente los serogrupos B y C. Según algunos expertos, podríamos encontramos ante una onda epidémica, pero debido a las medidas que se impusieron ante la pandemia de Sars-Cov-2 de 2020 (sobre todo la mascarilla y las medidas de distanciamiento), la incidencia de ciertas enfermedades infecciosas transmisibles se redujo de manera sustancial, y entre ellas la de la enfermedad meningocócica invasiva67,68. Las formas más frecuentes de infección invasiva por Neisseria meningitidis son la meningitis, la sepsis o la combinación de ambas. El plazo de incubación suele ser de 3-4 días. Aunque no es fácil de calcular, las sepsis meningocócicas que no producen meningitis oscilan entre el 5 y el 20%. La sepsis tiene un comienzo brusco, además de la fiebre aparecen lesiones llamadas petequias, que aumentan en poco tiempo, asociadas a Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 222 menudo a hipotensión, shock o fracaso multiorgánico. La mortalidad de esta enfermedad sigue siendo alta (establecida en un 10% por las publicaciones clásicas) a pesar del gran avance de las técnicas diagnósticas y de tratamiento; la tasa de mortalidad es mayor en el caso de sepsis que en el de la meningitis30,31,46,63. Los picos de incidencia más significativos se dan en niños y niñas menores de 1 año, en edades de 1 a 4 años y en adolescentes de 15 a 19 años. Aunque pueden producirse a lo largo de todo el año, suelen acumularse en invierno y primavera tras la aparición del virus de la gripe. Ya lo hemos dicho anteriormente, pero los adultos portadores de Neisseria meningitidis en la vía buconasofaríngea pueden ser entre un 1% y un 15% y serlo además durante semanas o meses. Esta colonización puede conducir al paciente pediátrico no inmunizado a situaciones de alto riesgo. Escherichia coli Escherichia coli es una de las bacterias más investigadas históricamente. Es un bacilo Gram negativo de la familia de las enterobacterias, que forma parte de la flora bacteriana colorrectal y que en la mayoría de los casos no es patógena. Sin embargo, algunas cepas han adquirido factores de virulencia, por lo que pueden producir infecciones en humanos y animales. Pueden ocasionar diferentes signos y síntomas; los podemos agrupar en los siguientes cuadros clínicos: infección de vías urinarias, diarrea/gastroenteritis aguda, bacteriemia y sepsis/meningitis. Tras la colonización de la mucosa de las vías urinarias por Escherichia Coli, prolifera en su interior, evitando las defensas del huésped. Se han designado varios factores de virulencia que favorecerán el síndrome clínico, especialmente la infección en las vías urinarias, las fimbrias P y S, la hemolisina, ...69,70 INTRODUCCIÓN 229 Los leucocitos y neutrófilos no cumplen con la definición exacta de biomarcador, pero en la práctica pueden asumir una función similar y por eso los incluiremos en este grupo de test y a partir de este momento hablaremos de biomarcadores. Recuento leucocitario y número absoluto de neutrófilos La infección bacteriana se ha asociado tradicionalmente con un aumento del recuento leucocitario y, específicamente, al número absoluto de neutrófilos. Se ha investigado mucho sobre estos reactantes; los puntos de corte más utilizados para la identificación del paciente con mayor riesgo de bacteriemia oculta, sobre todo neumocócica, han sido 15.000 leucocitos y 10.000 neutrófilos, respectivamente, por microlitro11. Sin embargo, debido a su bajo valor predictivo, basar la decisión de aplicar tratamiento antibiótico con estos resultados implicaría un sobretratamiento excesivo18,93,94. Mientras que algunos autores han llegado a la conclusión de que el número absoluto de neutrófilos es un test más exacto, en general se cree que tiene un perfil similar95. Proteína C reactiva Es un biomarcador que sintetiza el hígado como respuesta al aumento de citoquinas por inflamación. El hígado comienza a sintetizarlo entre 4 y 6 horas después de la aparición de la inflamación y alcanzará su valor máximo en 36 horas. Los puntos de corte asociados al diagnóstico de una infección bacteriana difieren según la edad. La literatura científica admite valores de 10 a 15 mg/l en niños recién nacidos y de 20 a 40 mg/l en niños más mayores. Sin embargo, también se ha demostrado que la inflamación por infecciones virales aumenta los valores de la Proteína C reactiva. Varios estudios describían una sensibilidad similar a la procalcitonina a la hora de identificar la infección bacteriana. Sin embargo, su especificidad es mucho más baja96. Por otro lado, según diversos estudios, comparándolo con el recuento leucocitario y el Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 230 número absoluto de neutrófilos, se ha llegado a la conclusión de que tiene un valor predictivo más alto. Sin embargo, a la hora de decidir podría ser preferible combinarlo con otros biomarcadores, ya que este biomarcador por sí solo ha mostrado importantes limitaciones94,95. Procalcitonina La procalcitonina es la precursora de la calcitonina, molécula sintetizada en pequeñas cantidades por las células C de la tiroides y las células neuroendoteliales pulmonares en situaciones normales. Ante una infección, su concentración sanguínea aumentará, ya que otros tejidos se encargarán de su síntesis, como el bazo, los testículos, el tejido graso y el cerebro. En comparación con la proteína C reactiva, el aumento de la concentración de procalcitonina en el torrente sanguíneo es mucho más rápido. La procalcitonina es el biomarcador que mayor rendimiento ofrece para la identificación de infecciones bacterianas invasivas según diversos estudios realizados a lo largo de los años27,98,99,100. A pesar de la controversia persistente sobre los puntos de corte y de que la concentración de 2 ng/ml es la más descrita en pediatría, los últimos estudios abogan por concentraciones de 0,5 ng/ml98. Análisis de orina La infección urinaria es una infección bacteriana con alta prevalencia, especialmente en niños menores de dos años101. La presencia de leucocituria o nitrituria o una tinción de Gram positiva sustentarán la sospecha diagnóstica. Una vez confirmada la sospecha, el cultivo de orina recogido de manera estéril deberá demostrar el aislamiento de una bacteria102,103. INTRODUCCIÓN 231 Tira reactiva de orina Se trata de una prueba complementaria, sencilla y barata, que permite realizarla a la cabecera del paciente, dar un resultado inmediato y realizar una interpretación rápida, por lo que será un test que encontraremos a menudo en los algoritmos de diagnóstico y manejo. Existen numerosos estudios que comparan la tira reactiva (tanto leucocituria como nitrituria) con un urocultivo positivo102. Este test en sí mismo no indica explícitamente la presencia de leucocitos; es decir, es capaz de identificar la esterasa que desprenden los leucocitos en la orina debido a la inflamación104. La sensibilidad que ofrece este test para que el urocultivo sea positivo es del 83%, con una específicidad del 79% y un valor predictivo positivo del 89%. La nitrituria, en cambio, tiene un valor predictivo muy alto (95%), pero hay bacterias que no son capaces de producir nitritos y que pueden ser habituales en los análisis de orina (enterococos, Staphylococcus o Pseudomona). El sedimento y la tira reactiva han sido comparados por numerosos estudios. Esta última se considera un test adecuado para el screening en pacientes con riesgo de infección urinaria, ya que ofrece buen rendimiento, es rápido, muy barato y es un recurso disponible en la cabecera del paciente105,106. Además, se ha publicado que la presencia de nitrituria en los niños más pequeños es un factor de riesgo independiente de una infección invasiva107. Análisis citoquímico del líquido cefalorraquídeo El análisis del líquido cefalorraquídeo (LCR) es un estudio imprescindible para el diagnóstico de la meningitis. Se trata de un análisis a realizar en todos los pacientes con sospecha de meningitis, siempre que el estado del paciente lo permita. El LCR normal se caracteriza por ser incoloro, sin olor, con forma de agua destilada, pero con varios componentes que conforman la sangre. Si se presta atención a su análisis Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 232 bioquímico, se deduce que contiene proteínas; sí, pero, en una proporción 200 veces inferior al plasma; la glucosa, por su parte, oscilará entre el 50% y el 75% de la concentración presente en suero sanguíneo. El recuento de leucocitos de LCR también varía en función de la edad del paciente. Aunque es un tema controvertido, lo más aceptado es que en niños menores de un mes el punto de corte de la pleocitosis sea de 20 a 25 células/mm3 y a partir de esta edad sea 10 o 5 células/mm3. Además, la mayoría de los leucocitos serán linfocitos o monocitos108. Por tanto, será imprescindible analizar las características bioquímicas del LCR en el manejo terapéutico del paciente bajo sospecha de meningitis. Las variaciones en las características habituales serán indicativas de inflamación. En términos clásicos, la sospecha de meningitis viral o bacteriana solía establecerse conscientes de estas características. El LCR no claro, la pleocitosis con predominio de neutrófilos, la glucorraquia baja, así como la alta concentración de proteínas incrementa el riesgo de una meningitis bacteriana. Sin embargo, en la práctica cotidiana, no se ha observado que estas características muestren limitaciones109,110. Además, el LCR del paciente sospechoso de meningitis que haya recibido previamente antibiótico podría sufrir alteraciones como un cierto aumento de glucosa o una reducción de proteínas, aunque es frecuente que el número de leucocitos o neutrófilos no sufra variación111. Herramientas para la identificación de microorganismos Clásicamente, el test más útil para evidenciar la presencia de infección bacteriana era el crecimiento de microorganismo en el cultivo de la muestra tomada en diferentes medios (sangre, líquido cefalorraquídeo, orina u otro). Pero el crecimiento de la bacteria necesita su tiempo. Existen otras técnicas más rápidas y con un rendimiento no inferior, disponibles en un servicio de urgencias que podrían influir en la capacidad de decisión INTRODUCCIÓN 233 como son la tinción de Gram y los test que se basan en la técnica de reacción en cadena de la polimerasa. Cultivos El torrente sanguíneo, la orina (en general) y el LCR son, en sí mismos, estériles. En consecuencia, cuando se aísla una bacteria patógena en una muestra de sangre, se define que estaremos ante una bacteriemia. Además del diagnóstico etiológico, el cultivo permitirá realizar test de sensibilidad a los antimicrobianos y su tipificación. El cultivo necesitará entornos de cultivo adecuados, tanto para bacterias aerobias como anaerobias y será el “gold standard” para el diagnóstico microbiológico. Sin embargo, deberá pasar un tiempo mínimo de reproducción para que el aislamiento (mínimo 24 horas) logre un crecimiento significativo. Esto dificulta el manejo que se lleva a cabo en la cabecera del paciente pediátrico que es atendido en un servicio de urgencias. En cuanto al cultivo del LCR, éste sigue siendo el patrón oro en el diagnóstico de la meningitis bacteriana y al igual que los casos de los hemocultivos, además del diagnóstico etiológico, permitirá la realización de test de sensibilidad de los antimicrobianos y la tipificación del germen. El procesamiento del LCR debe ser inmediato, inferior a una hora112. Posteriormente, el crecimiento tardará más de 24 horas en poder detectar la reproducción del germen. La rentabilidad del cultivo dependerá, además, de la bacteria responsable y de la no recepción de antibioterapia previa. En el 90% de las meningitis por neumococo se estima que el crecimiento será positivo al igual que en el 75% de las meningitis meningocócicas113. Algunos investigadores concluyeron que una sola dosis de ceftriaxona (dosis de 50 mg/kg) podría esterilizar el LCR de la meningitis meningocócica en una media de dos horas, la neumocócica en 4-10 horas y la del estreptococo del grupo B en 8 horas30,114. Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 234 En cuanto a la infección urinaria, la prueba de oro que la confirmará será el urocultivo115. Para evitar falsos positivos (sobre todo por errores en el procedimiento de toma de muestra), la recogida de orina debe ser lo más adecuada posible: orina espontanea e instantánea (en pacientes con control vesical) una vez tomadas las medidas higiénicas adecuadas y sondaje vesical o punción suprapúbica en el resto. La concentración de bacterias que se aísla también debe ser significativa, si bien la Academia Pediátrica Americana o la Asociación Española de Pediatría difieren en pequeños detalles116,117. También podrán realizarse otros cultivos en los servicios de urgencias. En cada caso, y dependiendo del estado del paciente, el análisis de una u otra muestra puede ser importante. Por ejemplo, si se sospechara una infección de piel y tejidos blandos, podría ser interesante realizar un cultivo de una lesión susceptible de drenaje, ya que la rentabilidad de los hemocultivos en estos casos es muy baja, sobre todo en pacientes pediátricos previamente sanos y estables. Además de estas lesiones susceptibles de drenaje, el cultivo de líquido sinovial, derrames pleurales u otros fluidos también puede tener su lugar en el manejo diagnóstico de un paciente (muchos de estos procedimientos no se realizarán estando el paciente en el servicio de urgencias). Para el diagnóstico de una infección causada por el estreptococo del grupo A, el cultivo faringoamigdalar puede ser adecuado; y en las infecciones del aparato digestivo que pudieran provocar invasividad, el coprocultivo. Tinción de Gram La tinción de Gram en LCR se caracteriza por una gran especificidad, pero una sensibilidad media para el diagnóstico de meningitis bacteriana118. Sin embargo, la baja prevalencia de meningitis hace que el valor predictivo positivo sea muy escaso119. INTRODUCCIÓN 235 Además, la capacidad de visualizar bacterias por microscopio en el LCR dependerá de la propia bacteria y de la concentración de la misma. El 90% de los pacientes con meningitis neumocócica tendrá una tinción positiva, el 80% en meningitis meningocócica, el 50% en las causadas por bacilos Gram negativos y el 33% en las causadas por Listeria monocitogenes30. En el caso de la tinción de Gram en orina, la técnica se realizará inmediatamente después de recoger la muestra de orina recién realizada. Se trata de una prueba de alta especificidad (por encima del 99%), pero al ser una prueba que requiere mayores recursos no siempre está disponible120. Será, por tanto, un test que se utilizará en el manejo de pacientes individualizados. Nuevas técnicas microbiológicas En los últimos años se han comercializado nuevas técnicas microbiológicas que han ocupado un lugar destacado en los algoritmos de diagnosis y manejo de infecciones bacterianas y virales. Las técnicas diagnósticas basadas en la reacción en cadena de polimerasa son el ejemplo más conocido. Además, estas nuevas técnicas se han utilizado hasta la fecha con diferentes muestras: secreciones nasales y faríngeas, saliva, heces, ... pero en este trabajo en general, y en este punto en particular, nos centraremos en la técnica utilizada en sangre y LCR. En nuestro entorno existen diferentes opciones para la identificación bacteriana en muestra sanguínea, siendo el test que identifica el meningococo, el neumococo y la Listeria el más utilizado. También se han comercializado test que tienen como objetivo la identificación bacteriana en LCR y que han provocado cambios en el manejo de estas infecciones. También es muy utilizado en la identificación de infecciones virales: enterovirus, herpesvirus, virus que afectan al sistema respiratorio, ... El mayor beneficio Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 236 de estos test es el ahorro de tiempo. Sin embargo, no todo son ventajas; no siempre están disponibles, cada test puede identificar un conjunto limitado de bacterias, son posibles los falsos positivos y por el momento tienen un coste importante. Técnica basada en la reacción en cadena de la polimerasa (PCR) Se trata de una técnica microbiológica que básicamente tiene el poder de hacer millones de copias a partir de un fragmento de ADN y se basa en la amplificación de determinadas partes del genoma bacteriano. La PCR ha supuesto un gran avance entre las técnicas de diagnóstico en la práctica clínica. Ofrece algunas ventajas respecto a otras técnicas. Por un lado, los resultados están disponibles en un periodo muy corto de tiempo. Siempre bajo algoritmos de manejo sólidos y adecuados, abren el camino a decisiones más rápidas a pie de la cabecera del paciente. Las diferentes pruebas ofrecen diferentes sensibilidades y especificidades; sin embargo, en comparación con el cultivo, la sensibilidad, de manera general, es mayor con estas nuevas técnicas. Aún así, por el momento, no se ha recomendado sustituir el cultivo por la PCR en el algoritmo diagnóstico de las IBI121,122. Por otro lado, el hecho de que el antibiótico se haya administrado antes de la toma de la muestra, tiene un impacto menor en la capacidad de identificación bacteriana, en comparación con el cultivo. Para la identificación de N. meningitidis, la sensibilidad de las técnicas PCR ronda el 95% para las muestras obtenidas en el LCR y algo más baja para las muestras de sangre. Aunque el ADN meningocócico puede detectarse hasta 72 horas después del inicio de la antibioterapia sistémica, es recomendable ser prudente al interpretar los resultados negativos deducidos mediante esta técnica, ya que la presentación clínica, la gravedad, la duración y el momento de inicio del tratamiento antibiótico de la enfermedad podrían afectar al rendimiento3,123,124. INTRODUCCIÓN 237 En los últimos años se han lanzado al mercado otras opciones basadas en esta técnica, paneles que recogen una gran variedad de microorganismos, paneles múltiples FilmArray, que pueden ocupar un lugar preferente en algunos algoritmos. En comparación con los test habituales similares que son leídos a tiempo real, la amplificación y la lectura no se llevan a cabo simultáneamente, lo que supone que el test realiza una interpretación cualitativa de la presencia o ausencia de material genético del agente infeccioso. A pesar de las enormes ventajas que estos paneles ofrecen (los resultados los podemos tener en una hora por ejemplo en el caso del test FilmArray ® Panel meningitis-encefalitis), también tienen sus limitaciones: los resultados obtenidos son cualitativos; el panel sólo deduce la presencia de la lista de los microorganismos que ofrece; los resultados fuera de algoritmos de trabajo estrictos bien estudiados pueden tener interpretaciones difíciles (interpretación por ejemplo de la presencia positiva de los virus de la familia herpes virus, por su capacidad de integración en el genoma humano). Técnicas de imagen Algunas técnicas de imagen pueden ser útiles cuando estamos atendiendo a un paciente con fiebre en el servicio de urgencias. Por ejemplo, ante el paciente sospechoso de infección osteoarticular, la primera prueba de imagen recomendada por las guías suele ser la radiografía75,125. Sin embargo, los cuadros clínicos bajo sospecha de infección osteoarticular que se consultan en nuestro entorno suelen ser cuadros poco evolucionados y lo normal es que las características radiológicas significativas aún no fueran visibles y que este test no provocara cambios de decisión en el manejo terapéutico. La ecografía musculoesquelética puede ocupar su lugar en los cuadros clínicos con sospecha de artritis séptica para deducir la presencia o no de líquido en la articulación y ayudar en las técnicas de drenaje126. Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 238 En pacientes febriles con dificultad respiratoria la neumonía puede ser uno de las causas. La mayoría de las guías no consideran del todo obligatoria la necesidad de imagen radiológica para aplicar el diagnóstico de neumonía a un determinado paciente, a pesar de ser una práctica habitual en los países desarrollados y sobre todo en los centros donde este recurso está disponible día y noche. Existen, sin embargo, determinadas indicaciones que sugieren realizar una radiografía55,127. En los últimos años también ha ocupado un lugar importante la ecografía pulmonar que se realiza a la cabecera del paciente, realizada por el médico no radiólogo, y que está teniendo resultados aceptables. Sin embargo, la evidencia científica todavía no es completa; entre sus limitaciones, la variabilidad entre los profesionales es la más importante, en relación con la experiencia del explorador128. Protocolos Son las herramientas necesarias que facilitan que cualquier sistema funcione con seguridad. En el caso de un servicio de urgencias pediátrico, debe tratarse de estrategias diagnóstico-terapéuticas basadas en la evidencia científica y adaptadas a los recursos locales. Los protocolos diseñados para diferentes cuadros clínicos van dirigidos a disminuir la variabilidad en la práctica clínica de los profesionales, garantizando en gran medida el beneficio clínico, económico y la seguridad del paciente. En los siguientes puntos nos ocuparemos de la explicación de los diferentes protocolos clínicos. Pacientes previamente no sanos Cada vez es más frecuente atender a pacientes con patología crónica en un servicio de urgencias. La calidad de vida y la esperanza de los pacientes crónicos ha aumentado en INTRODUCCIÓN 245 fue de dos horas146 en una serie de pacientes reclutados en los últimos cinco años. Esto dificulta la identificación de pacientes con IBI. Cambios en sanidad En las últimas décadas se han producido importantes avances en el ámbito de la salud como en cualquier otro ámbito, sobre todo a partir de los avances de la tecnología. Todos estos cambios afectarán a la gestión que desde el servicio de urgencias realizamos en colaboración con la familia de los niños que consultan por un proceso febril. Ecografía prenatal La universalización de la ecografía prenatal ha facilitado el diagnóstico prenatal de muchas de las importantes malformaciones que puede sufrir un recién nacido. Las anomalías más frecuentes son las relacionadas con el riñón y el aparato urinario147,148. Entre ellas, la anomalía más frecuente es la hidronefrosis, con una incidencia del 0,51%149,150. Aunque no todos los niños en los que se detecta hidronefrosis prenatal sufrirán posteriormente patologías relacionadas con las vías urinarias, un porcentaje significativo de este grupo de pacientes puede presentar una lesión que le provoque alteraciones pieloureterales importantes151 y, según otros autores, el 35% de este grupo de pacientes puede presentar reflujo vesicoureteral152. Clásicamente, las malformaciones más evidentes se podían sospechar en la primera exploración física rutinaria del recién nacido, sobre todo ayudado por la palpación renal o a raíz de signos y síntomas derivados de la insuficiencia renal. No obstante, en la mayoría de los casos, el diagnóstico se sospechaba al diagnosticar una infección urinaria en un lactante que consultaba con fiebre sin focalidad y realizar el subsiguiente estudio. Actualmente, gracias a la ecografía prenatal, el pediatra tiene la capacidad de conocer gran parte del grupo de niños con riesgo de sufrir una infección urinaria. Por ello, el proceso de estudio de estos pacientes será diferente. Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 246 Detección del estreptococo del grupo B en mujeres embarazadas El estreptococo del grupo B o Streptococcus agalactiae fue declarada la principal causa de sepsis neonatal y meningitis en la década de 1970153. Otros autores lo han relacionado posteriormente con tasas muy destacadas de meningitis (39%), otras infecciones focales (10%) y sepsis (7%)154. En los últimos años, el uso de profilaxis antibiótica intraparto ha reducido la incidencia de infecciones por este germen155,156,157. Esta profilaxis ha reducido sobre todo las infecciones precoces, aunque no se ha descrito una reducción paralela de infecciones tardías por el estreptococo del grupo B158,159,160. Según algunos estudios, la incidencia de la enfermedad por estreptococo del grupo B de Estados Unidos ha disminuido de 1,8 casos por 1.000 nacimientos en 1990 a 0,32 por 1.000 en 2003161,162. La mortalidad global de la enfermedad precoz causada por Streptococcus de grupo B, ha pasado del 50% registrado en la década de los 70 al 5-6% detectado entre 1993 y 2003, gracias principalmente a los mecanismos de atención y cuidados que se prestan al recién nacido160,163. La búsqueda sistemática de la bacteria que se realiza en el tercer trimestre del embarazo de las mujeres y las decisiones que se toman en función de este resultado (tratamiento antibiótico que se administra en el trabajo de parto) ha reducido la incidencia de recién nacidos infectados por el estreptococo del grupo B164,165. En los últimos años podemos afirmar que esta bacteria no es la bacteria más común que se aísla en infecciones invasivas en pacientes menores de 3 meses con fiebre sin foco en nuestro entorno23,166. De cara al futuro, la instauración y el impacto que puedan tener las vacunas frente al estreptococo del grupo B son esperanzadoras. INTRODUCCIÓN 247 Calendario vacunal A nivel mundial y tras el procedimiento de potabilización del agua, el avance que más ha disminuido históricamente el riesgo de infección ha sido la implantación del calendario vacunal. La vacunación sistemática rebaja mucho la probabilidad de sufrir infecciones graves. Las campañas de vacunación de los últimos años han supuesto una reducción de las sepsis y meningitis, con la consiguiente reducción de daños colaterales y secuelas de larga duración y muerte. En este capítulo de esta tesis nos centraremos en la vacunación conjugada contra Haemophilus influenzae, meningococo y neumococo, que son las vacunas que más han influido en los IBI de nuestro entorno. Vacuna frente a Haemophilus influenzae B La vacunación universal frente a H. influenzae de tipo B ha eliminado casi por completo las enfermedades invasivas causadas por esta bacteria167. De hecho, hoy en día es excepcional que un niño correctamente vacunado sufra una infección invasiva por H. influenzae de tipo B168. En la era prevacunal, la gran mayoría de los casos de infecciones invasivas por H. influenzae de tipo B (más del 80%) se detectaban en niños menores de cinco años y sobre todo en menores de dos años167. Esta bacteria fue una de las principales responsables de bacteriemias ocultas, pero también causante de la mayoría de las complicaciones. De hecho, alrededor de un 10-20% de estas bacteriemias provocaban posteriormente una meningitis169. Debido a la suma de la protección directa e indirecta provocada por la universalización de esta vacuna, el manejo del niño atendido con fiebre sin foco en urgencias varió ya que acarreó una disminución casi total de la enfermedad170,171,172,173,174,175. Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 248 Vacunas frente a Neisseria meningitidis El meningococo es una bacteria que produce ondas epidémicas. En la década de 1980 a 1990 se produjo un notable aumento de las enfermedades meningocócicas. Es cierto que este aumento puede explicarse en parte por la mejora de las técnicas diagnósticas basadas en la PCR176,177. En cualquier caso, en aquellos años los casos de enfermedad meningocócica por serogrupo C aumentaron de forma importante en varios países europeos, como Inglaterra y Gales178,179, Grecia180 o España181). Este aumento también fue notificado en Canadá182. El incremento fue más importante entre estos dos grupos de edad, los menores de 2 años y los de 15 a 19 años. El descenso de las enfermedades invasivas causadas por H. influenzae B también es aplicable al meningococo C gracias a la incorporación de una vacuna específica183. De hecho, esta disminución se puede explicar por la campaña de vacunación iniciada en el año 2000. Su efectividad se ha comprobado año tras año. Así, la incidencia de infecciones invasivas por serogrupo C disminuyó drásticamente, con 0,04 casos/100.000 habitantes en la temporada 2014-2015184,185. No obstante, en nuestro entorno, el serogrupo B ha sido el más prevalente de todos, exceptuando esta importante onda provocada por el serogrupo C de la década de los 90. La incidencia global de infecciones por Neisseria meningitidis ha tenido además una tendencia a la baja en España desde el año 2000. La tasa de incidencia más baja de casos confirmados se situó en el periodo 2013-2014 en torno a 0,5 casos por 100.000 habitantes. Sin embargo, más de la mitad de los casos siguieron siendo provocados por el serogrupo B. Este descenso comenzó hace dos décadas y puede estar en parte explicado por el patrón periódico que ofrece la propia enfermedad, ya que la vacuna conjugada frente al serogrupo B no parece que haya podido tener un impacto tan significativo por el INTRODUCCIÓN 249 momento; la comercialización comenzó en octubre de 2015 y además, no forma parte de las campañas de vacunación de todas las comunidades autónomas65,185. A partir del año 2015, la cifra aumentó ligeramente, alcanzando una tasa de incidencia de 0,83 casos67 por 100000 habitantes, debido principalmente al aumento del serogrupo W135. Varios expertos llegaron a afirmar que estábamos ante una nueva onda epidémica del meningococo. Vacuna frente a Streptococcus pneumoniae Aunque la vacuna que ofrecía la protección frente a 23 serotipos ya estuviera disponible desde 1977, no era efectiva en niños menores de 2 años debido a la falta de madurez que ofrece el sistema inmunitario a esta edad. En el año 2000 se aprobó la vacuna conjugada heptavalente (PCV7) formada por polisacáridos de siete variantes de S. pneumoniae (4, 6B, 9V, 14, 18C, 19F y 23F). Primero en Estados Unidos y posteriormente, progresivamente, se adhirió a los programas de inmunización de la Unión Europea. Esta vacuna habría ofrecido una cobertura superior al 80% de las infecciones invasivas neumocócicas detectadas en Estados Unidos en el año 200033,186,187. Desde la comercialización de esta vacuna, la incidencia global de infecciones invasivas por Streptococcus pneumoniae ha descendido considerablemente en todos los grupos de edad, pero especialmente en niños menores de dos años, incluso en no vacunados31,183,188. Por otro lado, aunque se vivió una vacunación casi universal con la PCV7v, nuevos estudios e informes de diferentes redes de vigilancia y monitorización describieron un aumento de las infecciones por serotipos fuera de la cobertura que ofrecían las vacunas: principalmente las causadas por el serotipo 1, 19A, 7F, 3 y 6A; es la denominada "sustitución de serotipos". Además, el serotipo 19A, capaz de copar el 80% de las Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 250 multiresistencias antimicrobianas, se convirtió en una importante causa de infecciones invasivas desde la introducción de la vacuna conjugada heptavalente6,183,188,189. En 2010, la vacuna conjugada 13valente sustituyó a la PCV7v en los programas de vacunación de Estados Unidos. Esta vacuna recogió serotipos que provocaban la "sustitución de serotipos" que se produjo en años anteriores, entre ellos el 19A y el 7F. Una publicación actualizada del Centro de Control y Prevención de Enfermedades (CDC)190, concluyó que este cambio de vacuna habría provocado una reducción del 64% de las infecciones invasivas por Streptococcus pneumoniae en niños menores de 5 años y una reducción del 93% de las IBI por nuevos serotipos incluidos en la vacuna 13valente 191,192,193,194. La incidencia de IBI por serotipos integrados en la vacuna 13valente en pacientes de entre cinco y 15 años disminuyó un 75%. En general, tuvo el mismo efecto en todos los grupos de edad, debido principalmente al declive de los serotipos 19A y 7F194,195. Todo esto ha cambiado el manejo de un lactante con fiebre. Próximamente, dos "nuevos" serotipos responsables de gran parte de las IBI neumocócicas actuales podrían estar a punto de entrar en los calendarios de vacunación196. Esto también incide en la importancia de mantener una estrecha monitorización de las IBI. HIPÓTESIS DE TRABAJO 251 HIPÓTESIS DE TRABAJO En la actualidad, el paciente con IBI suele acudir en estadios muy precoces a los servicios de urgencias, cuando los síntomas y los signos que presentan en la anamnesis y en el examen físico pueden ser inespecíficos. La mayoría de estos pacientes son pequeños, lo que facilita que los signos y síntomas clásicos de las diferentes infecciones aparezcan en casos aislados. Las diferentes campañas de vacunación implantadas en los últimos años han cambiado las características epidemiológicas de los IBI. Todo esto ha podido dificultar la aproximación del médico a los pacientes con fiebre. Por otra parte, los avances en la identificación del paciente febril con mayor riesgo de sufrir una IBI, debido al avance tecnológico y la disponibilidad de análisis más avanzados, han incrementado el número de pruebas que se pueden realizar en estos pacientes. Son muchas las características que influirán en el rendimiento de estas pruebas, máxime si los pacientes a los que se van a realizar no han sido previamente seleccionados. En definitiva, las IBI siguen constituyendo un grave problema y un reto para el pediatra de urgencias. Uno de los principales retos será identificar la posibilidad de que el paciente febril que está estable pueda padecer una IBI, combinando la anamnesis, la exploración física y utilizando los diferentes test y pruebas complementarias cuando lo considere necesario. Nuestra principal hipótesis es que la caracterización del paciente que sufre IBI y el rendimiento de los recursos disponibles para su identificación han podido sufrir variaciones en los últimos años. Este conjunto de recursos incluye anamnesis, exploración física y pruebas complementarias que podemos realizar en un servicio de urgencias. OBJETIVOS PRINCIPALES 252 OBJETIVOS PRINCIPALES 1. Caracterizar la presentación clínica de las IBI confirmadas en pacientes menores de catorce años. 2. Describir la gravedad de las IBI en pacientes menores de catorce años. 3. Analizar el valor de los test sanguíneos habituales (recuento leucocitario, número absoluto de neutrófilos, proteína C reactiva y procalcitonina) que se realizan para la identificación de IBI en pacientes menores de catorce años. 4. Evaluar la indicación de los test en sangre, en el manejo de niños de 3 a 24 meses de edad con fiebre sin focalidad y estabilidad clínica. 5. Describir la presentación clínica de las infecciones invasivas por E. Coli y analizar posibles perfiles y su posible relación con la gravedad. 6. Describir la presentación clínica de la infección invasiva por estreptococo del grupo B y analizar su posible relación con su gravedad. OBJETIVOS SECUNDARIOS Aunque no era objetivo de esta tesis, describir el impacto de una pandemia no esperada en la epidemiología de las IBI identificadas en un servicio de urgencias pediátrico. MÉTODO 253 MÉTODO ARTÍCULOS PUBLICADOS E ÍNDICES DE CALIDAD 1. Gangoiti I, Valle JR, Sota M, Martinez-Indart L, Benito J, Mintegi S. Characteristics of children with microbiologically confirmed invasive bacterial infections in the emergency department. Eur J Emerg Med. 2018 Aug;25(4):274280. doi: 10.1097/MEJ.0000000000000453. PMID: 28118320 • ISSN: 0969-9546 • JCR: Science Edition, 2018 • Impact factor: 1.383 • Category: Emergency Medicine. Posición: 18/29 • Quartil: Q3 Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 254 In conclusion, paediatric IBIs currently present more frequently in previously healthy young children, with a clinical and epidemiological pattern that is highly dependent on the age of the patient and the bacterium isolated. The evolution of children with an invasive infection was generally good, although those patients who consulted with a shorter time to progression, symptoms other than fever or who did not present a good general condition upon arrival at the ED were associated with more severe processes. Pneumococcus spp. was responsible for more than half of the cases that resulted in death or the appearance of sequelae in these children. Acknowledgements Conflicts of interest There are no conflicts of interest. References 1 Armon K, Stephenson T, Gabriel V, MacFaul R, Eccleston P, Werneke U, Smith S. Determining the common medical presenting problems to an accident and emergency department. Arch Dis Child 2001; 84:390–392. 2 Herrero M, Alcalde M, Gómez B, Hernández JL, Sota M, Benito J, Mintegi S. Invasive bacterial infections in a paediatric emergency department in the era of the heptavalent pneumococcal conjugate vaccine. Eur J Emerg Med 2012; 19:89–94. 3 Brook I. Unexplained fever in young children: how to manage severe bacterial infection. BMJ 2003; 327:1094–1097. 4 Lee GM, Harper MB. Risk of bacteriemia for febrile young children in the post-Haemophilus influenza type b era. Arch Pediatr Adolesc Med 1998; 152:624–628. 5 Kaplan SL, Mason EO, Wald ER, Schutze GE, Bradley JS, Tan TQ, et al. Decrease of invasive pneumococcal infections in children among 8 children’s hospitals in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine. Pediatrics 2004; 113:443–449. 6 Trotter CL, Chandra M, Cano R, Larrauri A, Ramsay ME, Brehony C, et al.A surveillance network for meningococcal disease in Europe. FEMS Microbiol Rev 2007; 31:27–36. 7 Gausche-Hill M, Fuchs S, Yamamoto L. Advanced pediatric life support: the pediatric emergency medicine resource. Sudbury, MA: American College of Emergency Physicians and Jones & Bartlett Publishers; 2003. 8 Singer M, Deutschman CS, Seymou CW, Shankar-Hari M, Annane D, Bauer M, et al. the third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315:801–810. 9 Moore MR, Link-Gelles R, Schaffner W, Lynfield R, Holtzman C, Harrison LH, et al. Effectiveness of 13-valent pneumococcal conjugate vaccine for prevention of invasive pneumococcal disease in children in the USA: a matched case–control study. Lancet Respir Med 2016; 4:399–406. 10 Del Amo E, Esteva C, Hernandez-Bou S, Galles C, Hernandez-Bou S, Hernandez-Bou S, et al. Serotypes and clonal diversity of Streptococcus pneumoniae causing invasive disease in the era of PCV13 in Catalonia, Spain. PLoS One 2016; 11:e0151125. 11 Kaplan SL, Barson WJ, Lin PL, Romero JR, Bradley JS, Tan TQ, et al. Early trends for invasive pneumococcal infections in children after the introduction of the 13-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J 2013; 32:203–207. 12 Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. Vaccine 2009; 27 (Suppl 2):B51–B63. 13 Morales D, Moreno L, Herranz M, Bernaola E, Martínez-Baz I, Castilla J. Invasive meningococcal disease in Navarra in the era of a meningococcal C vaccine. An Pediatr (Barc) 2016. [Epub ahead of print]. 14 Javid MH, Ahmed SH. Meningococcemia clinical presentation. Available at: http://emedicine.medscape.com/article/221473-clinical#b3. [Accessed date 18 August 2016]. 15 Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, Whistley RJ. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39:1267–1284. 16 Carrol ED, Newland P, Thomson AP, Hart CA. Prognostic value of procalcitonin in children with meningococcal sepsis. Crit Care Med 2005; 33:224–225. 17 Gomez B, Hernandez-Bou S, Garcia-Garcia JJ, Mintegi S. Bacteraemia Study Working Group from the Infectious Diseases Working Group; Spanish Society of Pediatric Emergencies (SEUP). Bacteremia in previously healthy children in Emergency Departments: clinical and microbiological characteristics and outcome. Eur J Clin Microbiol Infect Dis 2015; 34:453–460. 18 Arnold SR, Elias D, Buckingham SC, Thomas ED, Novais E, Arkader A, Howard C. Changing patterns of acute hematogenous osteomyelitis and septic arthritis: emergence of community-associated methicillin-resistant Staphylococcus aureus.J Pediatr Orthop 2006; 26:703–708. 19 Vaillancourt S, Guttmann A, Li Q, Chan IY, Vermeulen MJ, Schull MJ. Repeated emergency department visits among children admitted with meningitis or septicemia: a population-based study. Ann Emerg Med 2015; 65:625–632. 20 Green SM, Nigrovic LE, Krauss BS. Sick kids look sick. Ann Emerg Med 2015; 65:633–635. Table 6 Univariate and multivariate analyses to identify the risk factors for severity in children diagnosed with an invasive bacterial infection Univariate Multivariate POR (95% CI) POR (95% CI) Age (>24 months) 0.691 1.123 (0.633–1.994) Sex (female) 0.257 1.395 (0.785–2.481) Previous visit to the emergency department 0.162 1.736 (0.802–3.759) Duration of fever (<24 h) 0.080 1.740 (0.937–3.233) <0.001 4.082 (1.859–8.964) Symptoms other than fever <0.001 4.935 (2.114–11.523) 0.005 3.869 (1.507–9.938) Physical examination (altered) <0.001 4.825 (2.398–9.705) Temperature recorded upon arrival at the emergency department (≥39) 0.025 2.199 (1.104–4.382) Maximum temperature at home (<39) 0.552 1.206 (0.651–2.234) Well-appearing (no) <0.001 8.910 (4.543–17.478) <0.001 8.286 (3.737–18.370) Patient previously healthy (no) 0.062 2.421 (0.957–6.125) CI, confidence interval; OR, odds ratio. Characteristics of paediatric IBI Gangoiti et al.7 Copyright r2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. MÉTODO 255 2. Gangoiti I, Rodriguez E, Zubizarreta A, Benito J, Mintegi S. Prevalence of Occult Bacteremia in Infants With Very High Fever Without a Source. Pediatr Infect Dis J. 2018 Nov;37(11):e271-e273. doi: 10.1097/INF.0000000000001955. PMID: 29462106. • ISSN: 0891-3668 • JCR: Science Edition, 2018 • Impact factor: 2,317 • Category: Pediatrics. Posición: 39/125 • Quartil: 2 Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 256 Downloaded from http://journals.lww.com/pidj by VA2NP/EQXy5eAF3OZjUWq1xwD37/nWyagW5BHJqgwOhSu001FdfUrgaICuRdtVc1lY841S/5eJyFYfhbyXZE3ysfQMuwLtjpQx1lgvT6Z6tccJNU/qnYxpfYoLto/vx+OizeI0klFa0enzj2w4wdwQ== on 10/12/2018 Downloaded from http://journals.lww.com/pidj by VA2NP/EQXy5eAF3OZjUWq1xwD37/nWyagW5BHJqgwOhSu001FdfUrgaICuRdtVc1lY841S/5eJyFYfhbyXZE3ysfQMuwLtjpQx1lgvT6Z6tccJNU/qnYxpfYoLto/vx+OizeI0klFa0enzj2w4wdwQ== on 10/12/2018 Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. © 2018 Wolters Kluwer Health, Inc. All rights reserved. www.pidj.com | e271 The Pediatric Infectious Disease Journal • Volume 37, Number 11, November 2018 Occult Bacteremia in Infants with Very High Fever PREVALENCE OF OCCULT BACTEREMIA IN INFANTS WITH VERY HIGH FEVER WITHOUT A SOURCE Iker Gangoiti, MD, Elva Rodriguez, MD, Ane Zubizarreta, MD, Javier Benito MD, PhD, and Santiago Mintegi, MD, PhD Abstract: We carried out a prospective registry-based cohort study at the emergency department of 363 previously healthy well-appearing infants 3–24 months of age with fever without a source ≥40.5°C based on local protocol. Four were diagnosed with occult bacteremia (1.1%; 95% confidence interval: 0–2.2). Recommendations for nontesting for occult bacteremia screening in these children may have to be reconsidered when fever ≥40.5°C. Larger studies are needed to confirm these results. Key Words: occult bacteremia, very high fever, fever without source, infants Accepted for publication February 13, 2018. From the Paediatric Emergency Department, Cruces University Hospital, University of the Basque Country, Bilbao, Basque Country, Spain. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Santiago Mintegi, MD, PhD, Paediatric Emergency Department, Cruces University Hospital, Plaza de Cruces s/n, E-48903 Barakaldo, Bizkaia, Spain. E-mail: [email protected]. After the introduction of the pneumococcal conjugate vaccines (PCVs), pneumococcal invasive infections in febrile infants, including occult bacteremia (OB), declined dramatically.1–3 In a cost-effectiveness study, it was stated that when the rate of OB in febrile infants falls below 0.5% strategies that use empiric testing and treatment should be eliminated.4 On the other hand, if bacteremia rate is over 1.5%, it is cost-effective to obtain blood tests.4 Currently, in vaccinated populations, the rate of OB in febrile infants is less than 0.5%. Nevertheless, these studies included infants with temperature greater than 39°C, and it is known that the prevalence of bacteremia increases at higher temperatures.5 To our knowledge, no study has addressed the rate of OB in well-appearing, highly febrile infants in the era of PCV. The objective of this study is to analyze the prevalence of OB in previously healthy well-appearing infants 3–24 months of age with fever without a source (FWS) equal or higher than 40.5°C in the era of PCV. PATIENTS AND METHODS We carried out a registry-based cohort study at the pediatric emergency department (ED) of a tertiary level teaching hospital attending 55,000 visits annually. We included all previously healthy well-appearing infants 3–24 months of age with FWS ≥40.5°C brought to the ED between 2013 and 2016. Each month, all the febrile infants with a blood culture obtained were identified using the electronic databases of the Microbiology Service and the ED. After that, the main investigator selected for inclusion all infants 3–24 months of age with FWS ≥40.5°C with a blood culture obtained when evaluated in the ED. To check that all infants 3–24 months of age with FWS ≥40.5°C were included, we also reviewed a randomized sample of the patients coming to the ED during the period of the study. In this way, we revised all the episodes of children admitted to the ED 1 week per month during the period of the study. We collected the following data from the electronic clinical records of our ED: age, gender, personal history, PCV status, duration of fever, associated symptoms, temperature, previous consultation in the ED, appearance on arrival, physical examination, different blood tests (white blood cell count, absolute neutrophil Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/INF.0000000000001955 despite the highly variable baseline microbiota of patients with a tracheostomy.7 The traditional reductionist approach of categorizing ARIs as either viral or bacterial may be too simplistic a clinical framework for ARIs in individuals with a tracheostomy, and possibly all people with ARIs.7 On D1 of ARI, the majority of the current prospective cohort had a virus detected and a “bloom” of already present genera (ie, Haemophilus and Moraxella). The tracheal finding of Haemophilus and Moraxella blooming are consistent with findings from previous studies utilizing nasopharyngeal samples to examine acute respiratory illness outcomes.9 And although viral–bacterial interactions during ARIs have been described,10 the present results extend previous research by suggesting that these ARIs were not infections due to acquisition of a new bacterial pathogen as Koch’s postulates suggest, but rather a bloom of colonizing genera in the context of a viral infection. Conceptualizing ARIs as “blooms” may be more complex to operationalize clinically than the current reductionist approach, but may eventually provide opportunities for novel, targeted treatment methods. Although beyond the scope of these data, ARIs may be best understood as an emergent phenomenon7 that (1) is driven by a complex interplay among the infecting virus, microbiome and host response9 and (2) results in a continuum of ARI severity anchored by pneumonia. The next step is to better understand the pathobiology of ARI in this high-risk population with variable underlying microbiota to develop novel targets for ARI treatment and to provide guidance about when to use antimicrobials and which bacteria to treat. Until this time of improved ARI understanding and clinical guidance, many clinicians will continue to overuse and misuse antimicrobials for ARIs in children with a tracheostomy. ACKNOWLEDGMENTS We thank the GWU Colonial One High-Performance Computing Cluster for computational time. REFERENCES 1. Mortality GBD, Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117–171. 2. Dosa NP, Boeing NM, Ms N, et al. Excess risk of severe acute illness in children with chronic health conditions. Pediatrics. 2001;107:499–504. 3. Zhu H, Das P, Roberson DW, et al. Hospitalizations in children with preexisting tracheostomy: a national perspective. Laryngoscope. 2015;125:462– 468. 4. Sterni LM, Collaco JM, Baker CD, et al.; ATS Pediatric Chronic Home Ventilation Workgroup. An Official American Thoracic Society Clinical Practice Guideline: pediatric chronic home invasive ventilation. Am J Respir Crit Care Med. 2016;193:e16–e35. 5. Rusakow LS, Guarín M, Wegner CB, et al. Suspected respiratory tract infection in the tracheostomized child: the pediatric pulmonologist’s approach. Chest. 1998;113:1549–1554. 6. Pérez-Losada M, Graham RJ, Coquillette M, et al. The temporal dynamics of the tracheal microbiome in tracheostomised patients with and without lower respiratory infections. PLoS One. 2017;12:e0182520. 7. Dickson RP, Erb-Downward JR, Huffnagle GB. Towards an ecology of the lung: new conceptual models of pulmonary microbiology and pneumonia pathogenesis. Lancet Respir Med. 2014;2:238–246. 8. Yang C, Wang Q, Simon PN, et al. Distinct Network Interactions in ParticleAssociated and Free-Living Bacterial Communities during a Microcystis aeruginosa Bloom in a Plateau Lake. Front Microbiol. 2017;8:1202. 9. Hasegawa K, Mansbach JM, Ajami NJ, et al.; the MARC-35 Investigators. Association of nasopharyngeal microbiota profiles with bronchiolitis severity in infants hospitalised for bronchiolitis. Eur Respir J. 2016;48:1329– 1339. 10. Mansbach JM, Hasegawa K, Henke DM, et al. Respiratory syncytial virus and rhinovirus severe bronchiolitis are associated with distinct nasopharyngeal microbiota. J Allergy Clin Immunol. 2016;137:1909–1913.e4. Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Gangoiti et al The Pediatric Infectious Disease Journal • Volume 37, Number 11, November 2018 e272 | www.pidj.com © 2018 Wolters Kluwer Health, Inc. All rights reserved. cell count, C-reactive protein and procalcitonin), microorganism isolated, final diagnosis and disposition of the patient. In our ED, we recommend blood culture, white blood cell, absolute neutrophil cell, serum C-reactive protein, procalcitonin, urine dipstick and polymerase chain reaction for pneumococcus and meningococcus in all febrile infants 3–24 months old with FWS ≥40.5°C, regardless their vaccination status. Other tests (urine culture, chest radiograph, cerebrospinal fluid examination) were obtained at the discretion of the physician in charge. Definitions •Previously healthy patients: patients without any of the following risk factors: immunosuppression (oncologic illness, chronic renal failure, transplant patient, sickle cell disease), the presence of a mechanical device (indwelling catheter, ventricle-peritoneal shunt, auditory prostheses) and an invasive diagnostic or therapeutic procedure in the previous 10 days. •Well-appearing patients: patients with a stable pediatric assessment triangle upon arrival at the ED. Pediatric assessment triangle is a rapid tool recommended by the American Academy of Pediatrics to assess the first general impression of any child. The appearance, the work of breathing and the circulation to the skin are evaluated using specific predefined physical, visual or auditory findings. If any of these 3 components is abnormal, the patient is considered unstable. •FWS: axillary or rectal temperature higher than 38°C registered at home or in the ED, without associated respiratory symptoms, diarrhea process and findings on physical examination that allows identifying the source of the fever. •OB: isolation of pathogenic bacterium in the blood of a wellappearing child with FWS. PCV13 was included in the public immunization program in January 2013. Currently, PCV vaccination coverage in the Basque Country is around 95%. We carried out the statistical analysis using the statistical program SPSS 23, Chicago, IL. The qualitative variables were described using absolute frequencies and percentages and the continuous variables were described using both the mean and standard deviation or median and interquartile range. The χ2 test was used to study the association between qualitative variables. The Clinical Research Ethics Committee of the hospital approved the study. To maintain patient confidentiality, the database did not include any data that would have allowed the identification of patients. As identities remained anonymous and no intervention was performed on patients, informed consent was not required. RESULTS During the study period, blood cultures were obtained on 543 infants 3–24 months of age with fever ≥40.5°C, including all the 363 previously healthy well-appearing infants with FWS ≥40.5°C (Fig. 1). Mean age of the 363 previously healthy well-appearing infants with FWS ≥40.5°C was 13.9 ± 4.9 months and 189 (52.1%) were female. PCV dosing was unknown in 23 (6.3%), and 51 (14%) had not received any dose. Fever duration was shorter or equal than 48 hours in 297 (81.8%). Most common final diagnoses were FWS 282 (77.7%); urinary tract infection 36 (9.9%); fever and rash 16 (4.4%); pneumonia 13 (3.6%) and bacteremia 4 (1.1%). All patients did well. Four previously healthy well-appearing infants with FWS ≥40.5°C were diagnosed with OB (OB prevalence: 1.1%; 95% confidence interval [CI]: 0–2.2): 3 pneumococcal OB (one 16-month-old non-PCV vaccinated girl, and two 16-month and 19-month-old fully vaccinated girls; pneumococcal OB prevalence: 0.82%; 95% CI: 0%–1.8%) and a 12-month-old boy with a nontype b Haemophilus influenza bacteremia. All were managed as outpatients (3 of them after receiving 1 dose of IM ceftriaxone as a result of alterations of the blood biomarkers) and all did well. Among those 289 infants who have received at least 1 dose of PCV, 2 were diagnosed with pneumococcal OB (0.69%; 95% CI: 0–1.6). During the study period, blood cultures were also obtained in 140 previously healthy well-appearing infants with fever with a source ≥40.5°C (mainly respiratory symptoms). Blood culture was positive for Streptococcus pneumoniae in one 19-month-old boy fully vaccinated infant diagnosed with mastoiditis. DISCUSSION Although being lower than the reported in the pre-PCV studies,4 the rate of OB in previously healthy well-appearing infants 3–24 months of age with FWS equal or higher than 40.5°C does not support the recommendation for not testing these infants to identify those at higher risk for OB. Even though the rate of bacteremia in fully PCV-immunized infants is 0.5% or greater. Nowadays, most guidelines recommend not testing fully immunized (including PCV) febrile infants and do not give any specific recommendation for those with very high fever.6 In fact, laboratory evaluation and empiric antibiotic therapy do not significantly Fever with a source, 140 (25.8%) Bacteremia 1, 0.71% 0.12-3.9 Fever without a source, 363(66.8%) Occult bacteremia 4, 1.11%, CI 95%0.4-2.8 Non previously healthy, 10 (1.9%) Bacteremia 0 Previously healthy, 503 (92.6%) Bacteremia 5, 0.99%, CI 95% 0.42-2.3 Non well-appearing, 30 (5.5%) Bacteremia 0 Infants with fever equal or higher than 40.5ºC: 543 Bacteremia 5, 0.92%, CI 95% 0.39-2.1 Well-appearing 513 (94.5%) Bacteremia 5, 0.97%, CI 95%0.41-2.25 FIGURE 1. Patients’ flow chart. Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. © 2018 Wolters Kluwer Health, Inc. All rights reserved. www.pidj.com | e273 The Pediatric Infectious Disease Journal • Volume 37, Number 11, November 2018 Occult Bacteremia in Infants with Very High Fever CARDIAC AND PULMONARY CYSTIC ECHINOCOCCOSIS WITH MASSIVE OBSTRUCTION OF THE PULMONARY VESSEL SYSTEM IN A 16-YEAR-OLD GIRL Benno Kohlmaier, MD,* Andreas Trobisch, MD,* Klaus Pfurtscheller, MD,* Igor Knez, MD,† Walter Klepetko, MD,‡ Alexander Pilhatsch, MD,§ Sabrina Schweintzger, MD,¶ and Werner Zenz, MD* Abstract: We describe herein the management of a 16-year-old girl with cystic echinococcosis of the right ventricle and massive obstruction of the pulmonary vessel system by parasitic metastatic dissemination. After resection of the cardiac cyst, pulmonary thromboendarterectomy was performed to remove parts of the obstructive parasitic material. The treatment reduced the elevated pulmonary arterial pressure, improving the patient’s overall condition. Key Words: cystic echinococcosis, thromboendarteriectomy, pulmonary intravascular cyst, cardiac cyst, albendazole, praziquantel Accepted for publication December 23, 2017. From the *Department of General Pediatrics, and †Department of Cardiac Surgery, Medical University of Graz, Graz, Austria; ‡Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria; and §Department of Pediatric Radiology, and ¶Department of Pediatric Cardiology, Medical University of Graz, Graz, Austria. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Werner Zenz, MD, Department of General Pediatrics, Medical University of Graz, Graz, Austria. E-mail: werner.zenz@ medunigraz.at. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.pidj.com). Cystic echinococcosis (CE), caused by Echinococcus granulosus, is a common parasitic disease with high incidence rates in rural areas in Southern Europe, Middle East, Asia and Africa.1,2 In rare cases, it primarily affects the heart. Ruptures of the cyst membranes can lead to cardiac tamponade, anaphylactic shock or embolization and obstruction of pulmonary vessels, resulting in severe cardiopulmonary symptoms.3,4 Here, we present a complex case with cardiac and pulmonary involvement and massive obstruction of the pulmonary arteries. CASE REPORT A 16-year-old previously healthy female was admitted to our hospital with a 2-month history of increasing dyspnea and coughing. She grew up in a CE endemic area in Romania and moved to Austria 2 years ago. She lived together with her family and was working as a waitress. Physical examination showed normal weight and height, normal heart rate, no cardiac murmur, normal blood pressure, normal breathing, no dyspnea at rest and no edema. Oxygen saturation was 93%–96% at normal respiratory rate. Chest radiograph showed multiple intrapulmonary nodules in both lungs and widening of the upper mediastinum. Echocardiography revealed a cystic lesion in the apex of the right ventricle (Fig. 1A). Thoracic computed tomographic scan displayed a cystic Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/INF.0000000000002066 alter the likelihood of progression to focal bacterial infection and are no longer recommended in an otherwise healthy child with FWS who is completely immunized.7 In addition, since the routine immunization of children with PCV7 or PCV13 vaccine, pathogens other than S. pneumoniae have being reported to be the cause of the majority of cases of unsuspected bacteremia.8 In our study, 4 previously healthy well-appearing infants 3–24 months of age with FWS equal or higher than 40.5°C were diagnosed with OB, 3 of them caused by Streptococcus pneumoniae. Two were fully immunized. These results emphasize the importance to rule out serious bacterial infection in young high feverish children, including OB, and highlight the relevance of pneumococcal infection in this selected population in the era of the PCV. Our study shows certain limitations. The main limitation is the sample size. The CIs of the obtained bacteremia rate do not allow giving a strong recommendation for this population. Nevertheless, the results obtained emphasize the importance to carry out a larger study, preferably multicenter, to establish if nontesting strategy is adequate when fever is over 40.5°C. On the other hand, this is a unicenter study. Nevertheless, results should be similar in populations with similar vaccination status. Finally, to include all the patients in a prospective way, collecting the data when the infants are in the ED would have been more adequate to include all patients. Nevertheless, with the random revision of the episodes registered in the ED, we think that only very few patients were missed, if any. We conclude that, despite recommendations for nontesting for pneumococcal OB screening in well-appearing febrile infants, these recommendations may have to be reconsidered in infants with FWS ≥40.5°C, including those fully vaccinated. Larger and preferably multicenter studies are needed to confirm these results. Accordingly, a prospective multicenter study will begin on 2018 under the scope of the Research network of the Spanish Society of Pediatric Emergency Medicine (Red de Investigación de la Sociedad Española de Urgencias de Pediatría-Spanish Pediatric Emergency Research Group RISEUP-SPERG). ACKNOWLEDGMENTS I.K. conceptualized and designed the study, supervised data collection, analyzed the data, wrote the initial draft of the manuscript and approved the final manuscript as submitted. E.R. collaborated in the design of the study, collected data, critically revised the manuscript and approved the final manuscript as submitted. A.Z. collected data, critically revised the manuscript and approved the final manuscript as submitted. J.B. collaborated in the design of the study, critically revised the final manuscript and approved the final manuscript as submitted. S.M. conceptualized and designed the study, analyzed the data, revised multiple versions of the initial manuscript and approved the final manuscript as submitted. REFERENCES 1. Herz AM, Greenhow TL, Alcantara J, et al. Changing epidemiology of outpatient bacteremia in 3to 36-month-old children after the introduction of the heptavalent-conjugated pneumococcal vaccine. Pediatr Infect Dis J. 2006;25:293–300. 2. Joffe MD, Alpern ER. Occult pneumococcal bacteremia: a review. Pediatr Emerg Care. 2010;26:448–454; quiz 455. 3. Kaplan SL, Mason EO Jr, Wald ER, et al. Decrease of invasive pneumococcal infections in children among 8 children’s hospitals in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine. Pediatrics. 2004;113(3 pt 1):443–449. 4. Lee GM, Fleisher GR, Harper MB. Management of febrile children in the age of the conjugate pneumococcal vaccine: a cost-effectiveness analysis. Pediatrics. 2001;108:835–844. 5. Lee GM, Harper MB. Risk of bacteremia for febrile young children in the post-Haemophilus influenzae type B era. Arch Pediatr Adolesc Med. 1998;152:624–628. 6. NICE Guidance. Fever in under 5s: assessment and initial management. Accessed August 2017. 7. Avner JR, Baker MD. Occult bacteremia in the post-pneumococcal conjugate vaccine era: does the blood culture stop here? Acad Emerg Med. 2009;16:258–260. 8. Greenhow TL, Hung YY, Herz A. Bacteremia in children 3 to 36 months old after introduction of conjugated Pneumococcal vaccines. Pediatrics. 2017;139:e20162098. doi: 10.1542/peds.2016–2098. MÉTODO 257 3. Gangoiti I, Zubizarreta A, Elgoibar B, Mintegi S; Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies (SEUP). Occult Bacteremia in Young Children with Very High Fever Without a Source: A Multicenter Study. Pediatr Infect Dis J. 2020 Dec;39(12):e462-e464. doi: 10.1097/INF.0000000000002891. PMID: 32898089 • ISSN: 0891-3668 • JCR: Science Edition, 2020 • Impact factor: 2,129 • Category: Pediatrics. Posición: 69/129 • Quartil: Q3 Identificación de infecciones bacterianas invasivas en pediatría en la era de las vacunas conjugadas 258 Acta Paediatrica. 2020;00:1–6. | 1wileyonlinelibrary.com/journal/apa 1 | BACKGROUND Fever is a very common reason for consultation among children attending the emergency department (ED). In most cases, the cause is a self-limiting viral infection. Despite advances in vaccinations and antibiotics, invasive bacterial infections remain significant causes of death of children in developed countries. General infant immunization programmes against the most common pathogens (Haemophilus influenzae type b, Streptococcus pneumoniae and Neisseria meningitides) have led to a significant decrease of childhood invasive Received: 8 May 2020 | Revised: 29 July 2020 | Accepted: 18 August 2020 DOI: 10.1111/apa.15549 REGULAR ARTICLE Paediatric Escherichia coli bacteraemia presentations and high-risk factors in the emergency department Borja Elgoibar1 | Iker Gangoiti1 | Juan José Garcia-Garcia2 | Susanna Hernandez-Bou3 | Borja Gomez1 | Lorea Martinez Indart4 | Santiago Mintegi1 | Bacteremia Study Working Group from the Infectious Diseases Working Group, Spanish Society of Pediatric Emergencies (SEUP) ©2020 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd Abbreviations: E. coli, Escherichia coli; ED, emergency department; ICU, intensive care unit; UTI, urinary tract infection. 1Paediatric Emergency Department, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, University of the Basque Country, UPV/EHU, Bilbao, Basque Country, Spain 2Paediatrics Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain 3Paediatric Emergency Department, Hospital Sant Joan de Déu, Barcelona, Spain 4BioCruces Bizkaia Health Research Institute, Bilbao, Spain Correspondence Santiago Mintegi, Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain. Email: [email protected] Abstract Aim: Escherichia coli (E coli) is a known cause of paediatric bacteraemia. The main objective was to characterise the emergency department (ED) presentations of paediatric E coli bacteraemia and secondarily to identify those related to greater severity. Methods: This was a sub-study of a multicentre cross-sectional prospective registry including all with E coli bacteraemia episodes between 2011 and 2016. We used multiple correspondence and cluster analysis to identify different patterns. Results: We included 291 patients and 43 met criteria for severe disease (14.3%, 95% confidence interval 11.2-19.3). We identified four types of paediatric E coli bacteraemia presentations. Two (178 patients, 61.2%) were related to well-appearing previously healthy infants with associated urinary tract infection (UTI). Well-appearing children older than 12 months old with underlying disease (n = 60, 20.6%) and nonwell-appearing children of different ages (n = 53, 18.2%) corresponded to the other two types; these had associated UTI infrequently and higher severity rate (15% and 50.9%, respectively, higher when compared with the two previous types, P < .01), including the two patients who died. Conclusion: There were four different types of ED paediatric E coli bacteraemia presentations with different severity. Febrile young children with associated UTI showed the best outcome. KEYWORDS bacteraemia, Escherichia coli, outcome, risk factor, urinary tract infection 2 | ELGOIBAR Et AL. bacterial infections1,2 and changes in the distribution of most frequently isolated pathogens. Escherichia coli is a known cause of bacteraemia in febrile infants under 12 months of age3 and has been widely reported mainly in febrile infants <3 months of age, many of them associated with a urinary tract infection (UTI).4,5 In a previous study under the scope of the Spanish Society of Emergency Medicine, E coli accounted for 20% of the bacteraemia episodes registered in previously healthy children in Spanish EDs.6 To our knowledge, no large series have analysed the clinical presentation and outcome of children with E coli bacteraemia. Our study may help to better identify these children in the ED, especially those at higher risk for severe disease. The main objective was to characterise the ED presentations of paediatric E coli bacteraemia. The secondary objective was to identify presentations related to higher severity. Our hypothesis was that there are different profiles of paediatric E coli bacteraemia presentations with different risk for severe illness. 2 | PATIENTS AND METHODS We performed a secondary analysis of a large, multicentre, crosssectional prospective registry of childhood bacteraemia presentations to 23 Spanish EDs. In 2010, the Spanish Society of Paediatric Emergency Medicine proposed the establishment of a prospective multicentre registry of positive blood culture obtained at Spanish paediatric EDs. Patients between 0 months and 20 years were prospectively enrolled between 2011 and 2016. During 2011, 15 paediatric EDs participated in the recruitment, 22 during 2012, 21 during 2013, 19 during 2014, 17 during 2015 and 13 during 2016. Blood culture technique was explained in the study published in 2014.6 For the purpose of this study, we included those children with E coli isolated in the blood culture. We used the Paediatric Assessment Triangle (PAT) to assess the first general impression of the child. The PAT is a rapid tool recommended by the American Academy of Pediatrics to assess the first general impression of any child. The appearance, the work of breathing and the circulation to the skin are evaluated using specific predefined physical, visual or auditory findings. If any of these three components are abnormal, the patient is considered as non-well appearing.7 Certain factors were considered as increasing the risk of having a bacteraemia. These factors included immunosuppression such as oncological illness, chronic renal failure, transplant patient and sickle cell disease; the presence of a mechanical device, such as an indwelling catheter or a ventriculo-peritoneal shunt; an invasive diagnostic or therapeutic procedure in the previous 10 days; a serious kidney or urinary tract malformations such as double renal system, severe bilateral vesicoureteral reflux and presence of ureterostomy or vesicostomy; and patients with multiorgan syndromes or systemic illness. For the purpose of this study, patients without any of these risk factors were considered previously healthy. We defined occult bacteraemia as isolation of E coli in the blood in the absence of an identifiable focus of infection. A new positive blood culture after adequate antibiotic treatment (sensitive antibiogram and adequate dose and duration of the antibiotic) was considered as a new episode of bacteraemia. For the purpose of this study, we adapted the sepsis criteria published by Goldstein et al8 A patient with a positive blood culture was diagnosed with sepsis if presenting with any of the following signs: tachycardia >180 bpm not due to external or painful stimuli or long-term medication; bradycardia <100 bpm not due to external vagal stimulus, β-blocker drugs or congenital heart disease (only applicable in infants younger than 1 year old); tachypnoea >50 rpm; and signs of organ dysfunction as listed in the aforementioned publication.8 Septic shock was considered in those patients with persisting hypotension requiring vasopressors despite adequate resuscitation. Higher severity was considered when children met one or more of the following criteria: death, sequelae, admission to the intensive care unit (ICU), sepsis, meningitis and/or acute complications including renal or hepatic failure, stroke, acute respiratory distress syndrome or catheter replacement. We created two forms to be completed online using Google Drive application (Google LLC). Questionnaires were initially distributed to all participating EDs seeking to ensure the clarity of the methods and to enhance the quality of the data collected and were fulfilled by the site investigators. The first questionnaire was a patient registration form for each positive blood culture collected, with epidemiological and clinical data, the results of tests performed, final diagnosis and outcome. A second form was used to provide the following additional, monthly data: total number of patients attended, of blood cultures taken and of positive blood cultures obtained. Only the research coordinator had access to the two resulting online databases, being responsible for downloading regular backups of both databases and reviewing them for possible errors in data Key notes • We characterised the emergency department presentations of paediatric E coli bacteraemia and identified those related to greater severity in 291 patients <18 years of age. • We identified four types of presentations related to previous illnesses, age, sex, appearance upon the arrival and association with urinary tract infection. • Association with urinary tract infection in febrile wellappearing previously healthy young children showed the best outcome. | 3 ELGOIBAR Et AL. entry. The participating researcher in each centre was responsible for reviewing the episodes with potential errors. To identify types of E coli bacteraemia presentations, we used multiple correspondence analysis and cluster analysis. In order to perform multiple correspondence analyses,9 we used the following categorical variables: sex, age, PAT, previously healthy, fever, other symptoms and physical examination. Age was categorised into <3 months, 3-12 months and >12 months; PAT into normal, altered appearance, altered circulation to the skin and altered work of breathing. We then performed the cluster analysis, which organises information from apparently heterogeneous episodes into relatively homogenous groups. We used the factors obtained in the multiple correspondence analyses as variables to perform the cluster analysis and to obtain the appropriate grouping of E coli bacteraemia presentations.10 To create clusters, we used the squared euclidean distance and Ward method.11 This method combined correspondence analysis and cluster analysis to categorise E coli bacteraemia cases into groups. These groups were suggested by the data and not defined a priori. The groups were made in a way such that cases in a given group of E coli bacteraemia were similar to each other and those in different groups were dissimilar. Finally, chi-square test was used to study the association between severity and different types of E coli bacteraemia presentations. Outcome measure was the presence of, at least one of the severity criteria described previously. We performed all statistical analyses using SPSS vs. 23.0 statistical software and R project, version 3.6.2 ‘Dark and Stormy Night’ (IBM). This study was approved by the Ethical Committee of the Basque Country (registration number PI2011040). Approval for the study and for data sharing with the coordinating institution and with the centralised data centre was granted by the institutional review board at each participating institution. To maintain patient confidentiality, the forms did not include any data that would have allowed the identification of any patient. 3 | RESULTS During the time of the study, we registered a total of 3 936 827 ED episodes, of which a positive blood culture was isolated in 1696 (0.04%, CI 95% 0.04-0.05). In 291 (17.6%, 95% CI 15.4-19.0), blood culture was positive for E coli. Table 1 reports descriptive statistics for the main epidemiological variables, management and outcome of the children with E coli bacteraemia. Final diagnosis were UTI with associated bacteraemia 206 (70.8%); occult bacteraemia 27 (9.3%); sepsis/shock 32 (11%, three of them with associated meningitis); meningitis 5 (1.7%); catheter-associated bloodstream infection 6 (2.1%); and others 15 (5.1%). Of the 291 patients, 43 (14.8%, 95% CI 11.2-19.3) were considered to have severe illness (Table 2). Two patients died. The multiple correspondence analyses rand cluster analysis identified four main types of paediatric E coli bacteraemia presentations (Table 3). Two types of E coli bacteraemia presentations (groups A and B) were mainly related to well-appearing previously healthy infants <12 months old with associated UTI (85.0% and 98.5%, Age (in months)a 3 (1-11) Sex (female) 131 (45%) Nonpreviously healthy patients 67 (23%) Immunosuppression 27 (9.3%) Patients with multiorgan syndromes or systemic illness 16 (5.4%) Serious kidney or urinary malformationsb 13 (4.5%) Presence of a mechanical device 7 (2.4%) Invasive diagnostic or therapeutic procedure in the previous 10 d 4 (1.4%) Duration of the fever (in hours)a 12 (3-24) Temperature upon arrival to the emergency department (°C)c 37.9 ± 1.0 Well appearing upon arrival to the emergency department 244 (83.8%) No findings in the physical examination 226 (77.7%) Urine culture performed 263 (90.4%) Lumbar puncture performed 71 (24.4%) Chest X-ray performed 33 (11.3%) Administered antibiotic 284 (97.6%) Admission to ward/Intensive care unit 255 (87.6%) Note: Data are expressed as n and percentage. aAge and evolution time are expressed as median and interquartile range. bSerious kidney or urinary malformations: double renal system, severe bilateral vesicoureteral reflux and presence of ureterostomy or vesicostomy. cTemperature is expressed as mean ± standard deviation. TABLE 1 Epidemiological and clinical characteristics, complementary tests, management and disposition of the patients with E coli bacteraemia 4 | ELGOIBAR Et AL. respectively, compared with 50% and 30.2% of groups C and D). The main differences between groups A and B were the age and the sex, but, overall, they did well. Group A included mostly males younger than 3 months of age (81.4%) and group B mainly females (87.7%) 3-12 months old. Rate of severity was 5.3% and 3.1%, respectively. Well-appearing children older than 12 months with underlying diseases accounted for the majority of the third group of patients (group C). The last group (group D) included non-well-appearing children of different ages, one-third of them non-previously healthy. Associated UTI was significantly lower in these two groups (group C = 50.0%, group D = 30.2%), and the rate of severity was 15% and 50.9%, respectively (significantly higher than in groups A and B, P < .01). The two patients who died were included in group D. Eight children were diagnosed with bacterial meningitis (three of them with associated sepsis). All of them were younger than 5 months. The rate of associated meningitis in febrile infants with E coli bacteraemia is shown in Table 4. 4 | DISCUSSION Our data suggest four different types of paediatric E coli bacteraemia presentations to the ED with different degree of severity. Association with UTI in children less than a year was most common, whereas older age was associated with greater severity, mainly when the child was unwell upon presentation to the ED. Many children did not have high fever and abnormal findings in the physical examination were uncommon. In addition, the majority of these children appeared well when evaluated in the ED. This underlines the importance of having a high index of suspicion in selected patients. E coli is the most common pathogen involved in invasive bacterial infections in young febrile infants.3,5 Many of these are associated with UTI, which is the most common serious bacterial infection in young febrile infants.12 Young febrile infants with UTI are more prone to have associated bacteraemia.12 Around 5% of febrile infants <3 months of age with UTI have an associated bacteraemia, with the highest risk in infants <28 days.13 Traditionally, it has been recommended to hospitalise young febrile infants with suspected UTI due to the concern of acute adverse events and for missing concomitant bacteraemia. During the last years, efforts have been made to identify young febrile infants <3 months with suspected UTI at low risk for bacteraemia and suitable for outpatient management.14,15 Several studies have assessed the course of febrile infants with UTIs and suggest that otherwise well-appearing infants with or without concomitant bacteraemia have benign clinical outcomes when treated with appropriate antibiotics.16-18 Our study may support a less conservative management. In fact, in our study, only around 5% of febrile infants with E coli bacteraemia had a severe disease, including those <3 months of age. Nevertheless, all except one of the children with bacterial meningitis were younger than two months of age. Nearly 10% of TABLE 2 Number of patients with each severity criteria Severity criteria N (%) Sepsis 32 (11.0) Admission to the intensive care unita 22 (7.6) Acute complications 8 (2.7) Meningitis 8 (2.7) Sequelae 7 (2.4) Death 2 (0.7) Note: Data are expressed as n and percentage. Twenty patients (6.9%) presented a single severity criteria. Sixteen patients (5.5%) presented two severity criteria. Seven patients (2.4%) presented three or more severity criteria. aThere is no patient with this severity criteria exclusively. TABLE 3 Main types of paediatric E coli bacteraemia presentations Variable A (n = 113, 38.8%) B (n = 65, 22.3%) C (n = 60, 20.6%) D (n = 53, 18.2%) P value Sex Female 21 (18.6%) 57 (87.7%) 36 (60%) 17 (32.1%) <.001 Age <3 mo 95 (84.1%) 10 (15.4%) 3 (5%) 24 (45.3%) <.001 3-12 mo 18 (15.9%) 55 (84.6%) 6 (10%) 15 (28.3%) >12 mo 0 0 51 (85%) 14 (26.4%) Previously healthy No 3 (2.7%) 047 (78.3%) 17 (32.1%) <.001 Fevera Yes 88 (77.9%) 65 (100%) 58 (96.7%) 41 (77.4%) <.001 Other symptoms Yes 24 (21.2%) 40 (61.5%) 30 (50%) 45 (84.9%) <.001 Paediatric assessment Triangle Altered appearance 1 (0.9%) 1 (1.5%) 2 (3.3%) 35 (66%) <.001 Altered circulation 1 (0.9%) 01 (1.7%) 18 (34%) Altered breathing 0 0 0 6 (11.3%) Physical examination Altered 7 (6.2%) 5 (7.7%) 8 (13.3%) 45 (84.9%) <.001 Associated UTI Yes 96 (85%) 64 (98.5%) 30 (50%) 16 (30.2%) <.001 Note: Data are expressed as n and %. The P values demonstrate the differences between groups among the analysed variables. aTemperature higher than 38ºC at home and/or at the emergency department. | 5 ELGOIBAR Et AL. febrile infants younger than 1 month old with E coli bacteraemia had associated bacterial meningitis. Higher risk of meningitis associated UTI has been previously published in febrile neonates.16 Our study supports the decision of making a cerebrospinal fluid examination in febrile neonates with confirmed or suspected E coli bacteraemia.15 Although the diagnosis of bacterial meningitis is very rare in older children with E coli bacteraemia, severe illness is more common in these patients. In our series, around 50% of non-well-appearing children with E coli bacteraemia had a severe disease, including two children who finally died. This emphasises the importance to consider UTI in those non-well-appearing febrile children and, if possible, to collect a urine culture before initiating the antibiotics. This also confirms that PAT is a reliable tool to identify children with severe illness upon the arrival to the ED.7 Finally, the group of older febrile children with underlying diseases had a 15% rate of severe disease. This underscores the importance of a more cautious management of children with underlying diseases because of the high risk of invasive infections when these children present to the ED.19,20 Our study shows certain limitations. Our registry was not designed to characterise the ED presentations of paediatric E coli bacteraemia. Nevertheless, we think that collected data allow us to define the different types of these presentations and to relate them with severity. This study was conducted to identify risk factors in children with E coli bacteraemia and not UTI. In addition, E coli is not the single pathogen responsible for UTI especially in children with underlying diseases. Thus, our results cannot be extrapolated to febrile UTI. Finally, we think that defining the indications for cerebrospinal fluid examination would require a specific larger study. Nevertheless, our data support to strongly consider cerebrospinal fluid examination in infants <2 months old with E coli bacteraemia. 5 | CONCLUSION We conclude that there are four different types of paediatric E coli bacteraemia presentations to the ED with different rate of severity. UTI-associated bacteraemia in infants <12 months were most common but those involving older children account for large amount of patients and are related to higher risk, mainly when the child is unwell upon the arrival to the ED. Associated bacterial meningitis is rare in children older than two months of age. ACKNOWLEDGEMENTS Collaborators: We are grateful to our collaborators from paediatric emergency departments across Spain: Laura Herrero (Gipuzkoa), Mª Ángeles García (Madrid), Juana Barja (Madrid),Sara Garcia (Las Palmas), Zulema Lobato (Barcelona), Berta Brussosa (Barcelona), Carla Pascual (Barcelona), Maria Landa (Bizkaia), Usune Gonzalez (Bizkaia), Sofia Mesa (Madrid), Ramón Fernández-Alvárez (Asturias),Begoña Fernández (Asturias), Carmen Pérez (Islas Baleares), Goizalde López (Gipuzkoa), José Rodríguez (Murcia), Mercedes de la Torre (Madrid), Clara Garcia-Bermejo (Madrid), Francisca Aguilar (Córdoba), Esther Oliva (Barcelona), Mª Nathalie Campo (Valladolid), Juncal Mena (Valladolid) and Claudia Coderch (Barcelona). Our thanks also go to Nieves De Lucas from Samur, Madrid. CONFLICT OF INTEREST The authors have no conflicts of interest to declare. ORCID Iker Gangoiti https://orcid.org/0000-0001-5391-2423 Santiago Mintegi https://orcid.org/0000-0002-2342-8881 REFERENCES 1. 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