TheEffectofCRPandProcalcitonin LevelsontheEstimationofInfectionin. RespiratoryFailure ORİJİNAL ARAŞTIRMA. Ferah ECE, MD, a Levent KILIÇKAN, MD, b

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1 ORİJİNAL ARAŞTIRMA TheEffectofCRPandProcalcitonin LevelsontheEstimationofInfectionin thecopdpatientsadmittedtoicuwith RespiratoryFailure Ferah ECE, MD, a Levent KILIÇKAN, MD, b Jale AYTAÇ, MD, c Halim İŞSEVER, MD, d Osman BAYINDIR, MD b Departments of a Chest Diseases, b Anesthesiology and Reanimation, İstanbul Bilim University, Medical School, c Department of Microbiology, Çağlayan Florence Nightingale Hospital, d Department of Public Health, İstanbul University, Medical School, İstanbul Ge liş Ta ri hi/received: Ka bul Ta ri hi/accepted: Ya zış ma Ad re si/correspondence: Ferah ECE, MD İstanbul Bilim University, Medical School, Department of Chest Diseases, İstanbul, TÜRKİYE/TURKEY fkorap@hotmail.com ABSTRACTObjective:AcuterespiratoryfailureisoneofthemostfrequentreasonforICUadmittanceofpatientswithCOPDexacerbation.ThosepatientsalmostalwaysreceiveantimicrobialtreatmentinICU.Unnecessaryantibioticusagecausesincreaseinantibioticresistance,excesshospital chargeandundesirablesideeffects.inthisstudyweaimedtoinvestigatetheeffectofcrpandprocalcitoninlevelsondecisionofantimicrobialtherapyinpatientswithcopdexacerbation.materialandmethods:twentyfourpatientswhowereadmittedtoicuwithacuterespiratoryfailure aftercopdexacerbationwereexamined.c-reactiveprotein,procalcitonin,cpisandcurb-65 scoreswereassessedforeachpatientatthetimeofadmittancetoicu.microbialcultureoftrachealsecretions,urine,andbloodsamplesweredoneroutinelyaswell.accordingtotheresultsof antibiogramtests,patientsreceivedantimicrobialtreatment.howeveriftherewasasuspicionof theinfectivediseasesuchasfever(>40 o C,<35 o C),leukocytosis(>30000),leukopenia(<4000),new radiologicalinfiltration,etc.,empiricantibiotictreatmentwasgiventothepatients.results:patientswithmicrobialculturepositiveresultsshowedsignificantlyhigherlevelsofcrpandprocalcitoninthanpatientswithmicrobialculturenegativeresults.cpisandcurb-65scoreswere comparablewiththecrpandprocalcitoninlevels.afterantimicrobialtreatment,crpandprocalcitoninlevelsweredecreasedinpatientsbothtreatedaccordingtoantibiogramandtreatedempirically,howeveritwasstatisticallysignificantonlyinthecasestreatedaccordingtoantibiogram. Conclusion:Accordingtothisstudy,theinitiationofantimicrobialtherapymaybemanipulatedby thelevelsofcrpandprocalcitonin.antibiotherapymightbeconsideredinpatientswithmicrobialculturepositiveresultsinsteadofgivingittoeverypatientadmittedtoicu. KeyWords:Procalcitonin;C-reactiveprotein;pulmonarydisease,chronicobstructive ÖZETAmaç: KOAHalevlenmesiilehastaneyebaşvuranhastalarınönemlibirbölümüakutsolunumyetmezliğiileyoğunbakımünitesine(YBÜ)sevkedilmektedir.Buhastalarınhementamamı YBÜ deantimikrobiyaltedavialmaktadır.uygunolmayanantibiyotikkullanımıhastaneyatışmaliyetini,antibiyotikleredirenciveyanetkigörülmeolasılığınıartırmaktadır.buçalışmadac-reactiveprotein(crp)veprokalsitoninseviyelerininkoahalevlenmesihastalarındauygulanacak antimikrobialtedavikararıüzerindekietkisiniaraştırmayıamaçladık.gereçveyöntemler:koah alevlenmesisonrasıakutsolunumyetmezliğiileybü'neyatırılan24hastaincelendi.ybü'egelen herhastanıncrpveprokalsitoninseviyeleri,cpisvecurb-65skorlarıölçüldü.rutinolarakher hastanıntrakealsekresyon,idrarvekanörneklerininkültürleriyapıldı.antibiyogramtestsonuçlarınagörehastalaraantibiyotiktedavisiverildi.ancakateş(>40 o C,<35 o C),lökositoz(>30000),lökopeni(<4000),vb.gibiinfeksiyonşüphesiolduğundaampirikolarakantibiyoterapibaşlandı. Bulgular:KültürpozitifolanhastalardaCRPveprokalsitoninseviyelerikültürnegatifhastalaragöreanlamlıolarakdahayüksekti.CPISveCURB-65skorlarıCRPveprokalsitoninseviyeleriile uyumluidi.antibiyotiktedavisindensonra,crpveprokalsitoninseviyelerihemampiriktedavi grubundahemdekültürpozitifgrubundaazaldı,ancaksadecekültürpozitifgrubundaistatistiksel olarakanlamlıidi.sonuç:buçalışmayagörecrpveprokalsitoninseviyeleriantimikrobiyaltedavikararınıvermedeyönlendiriciolabilir.antibiyoterapininybü'eyatanherhastayerinesadece kültürpozitifhastalaraverilmesiuygunolacaktır. AnahtarKelimeler: Prokalsitonin;C-reaktifprotein;kronikobstrüktifakciğerhastalığı Cop yright 2009 by Tür ki ye Kli nik le ri TurkiyeKlinikleriArchLung2009;10(1):13-7 TurkiyeKlinikleriArchLung2009;10(1) 13

2 FerahECEetal THEEFFECTOFCRPANDPROCALCITONINLEVELSONTHEESTIMATIONOFINFECTIONINTHECOPDPATIENTS... hronic obstructive pulmonary disease (COPD)isseenfrequentlythroughoutthe world.exacerbationsarethemajorcauseof morbidity and mortality in patients with COPD andassociatedwithimpairedqualityoflife,declineinlungfunctionandpooreroutcome. 1 Mostof thesecopdcaseswithacuteexacerbationsarereferredtointensivecareunit(icu)and26-74%patientsareintubated. 2 Viralinfectionsaremainly responsiblefortheexacerbation,synergistic effect ofviralandbacterialinfectionsisalsoimportant. However,almostallpatientsinICUreceiveantibiotictherapyempiricallyduetodifficultyindefinitive determination of an infectious cause of COPDexacerbation.Infactadequateantibiotictreatmentwasdefinedascoverageofallpathogens isolated,anddeterminedbythesensitivitypattern intheantibiogram. 3 Besides,conditionsotherthan respiratoryinfections,includingindustrialpollutants,allergens,sedatives,congestiveheartfailure, andpulmonaryembolism,havebeenidentifiedas well. 4,5 DiscriminationofthecausesofacuteexacerbationofCOPDisimportantinordertomanagethetreatment.Ithasbeendemonstratedthat bacterialexacerbationwasassociatedwithsignificantly greater neutrophilic inflammation than nonbacterial exacerbation, with higher levels of inflammatorymarkers. 6 C-reactiveprotein(CRP) isanacute-phasereactantwithwell-documented sensitivitythatiscommonlyusedtodiagnoseinfectiousandinflammatoryconditions,including COPDexacerbation. 7,8 Circulatinglevelsofprocalcitonin(PCT) are markedly elevated in patients withbacterialinfectionscomparedtothosewith viralinfectionsorotherinflammatoryconditions. 9 Ithasbeenindicatedthatguidancewiththemeasurementofprocalcitoninlevelsreducestheexposureofpatientstoantibioticsafterpresentationto the emergency department for exacerbations of COPD. 10 Unnecessaryantibioticusagecausesincreaseinantibioticresistance,excesshospitalcharge andundesirablesideeffects.inthisstudy,weaimedtoinvestigatetheeffectofcrpandprocalcitoninlevelsondecisionofantimicrobialtherapy, the correlation of CRP and procalcitonin levels with the clinical pulmonary infection score (CPIS) 11 andcurb-65(confusion,urea>7 mmol/l, respiratoryrate30/min,lowbloodpressure, and age65 yrs) 12 scoreinthosedefinedpatients. 13,14 MA TE RI ALS AND MET HODS Thestudywasconductedintheintensivecareunit ofbilimuniversitymedicalschoolavrupaflorencenightingalehospital.twentyfourpatients(15 female,9male)whowereadmittedtoicuwitha diagnosisofacuterespiratoryfailureaftercopd exacerbationwereexaminedretrospectivelyafter theapprovalbytheethicalcommitteeofthelocal medicalfaculty.exacerbationofcopdwasdefinedas asustainedworseningofthepatient scondition,fromthestablestateandbeyondnormal day-to-dayvariations,thatisacuteinonsetandnecessitatesachangeinregularmedicationinapatientwithunderlyingcopd. 15 Allpatientsneeded mechanicalventilationandtheyintubatedorotracheally.indicationsforinvasivemechanicalventilationwereseveredyspneawithuseofaccesory musclesandparadoxicalabdominalmotion;respiratoryfrequency>35breaths/minute,severeacidosis (ph <7.25) and/or hypercapnia (PaCO2 >60 mmhg);lifethreateninghypoxemia;andunableto toleratenivaccordingtogoldcriteria. 16 ExclusioncriteriawerecoexistenceofTBinfectionor lungcancer,anduseofchronicoralorparenteral steroids.cpisvecurb-65scoreswerecalculated atthetimeofadmittancetoicuandchestx-ray, arterialbloodgases,completebloodcount,bun, creatinine,totalbilirubin,albumin,sodium,potassium,chloride,crp,pctwereobtainedandrepeatedonthefourthandfourteenthday.crpwas measured by BPC BIOSED Prime-photometer, Italy.Procalcitoninwasmeasuredusing20to50µL ofplasmaorserumbyatime-resolvedamplified cryptateemissiontechnologyassay(pctkryptor; BRAHMS).Microbiologiccultureoftrachealaspiration,blood,nasalsmearandurineweredoneroutinely. Pathogen isolation achieved patients (culturepositivegroup)receivedantibiotictreatmentaccordingtoantibiogram,andpatientswith noisolatedpathogens(culturenegativegroup)receivedempiricaltreatmentdependingonsuspicion ofinfectionsuchashyperorhypothermia(<35 o C 14 TurkiyeKlinikleriArchLung2009;10(1)

3 THEEFFECTOFCRPANDPROCALCITONINLEVELSONTHEESTIMATIONOFINFECTIONINTHECOPDPATIENTS... FerahECEetal or >38 o C), leukocytosis (>30.000) or leukopenia (<2.000),andinfiltrationonchestX-ray.Others havenottakenanyantibiotictherapy. StatıStıcalanalySıS Analyseswereperformedusingastatisticalsoftwarepackage.Discretevariablesareexpressedascounts (percentages) and continuous variables as mean±sdormedian(range).mann-whitneyu andwilcoxonwtestswereusedforthecomparisonofcrpandpctlevelsbetweenthegroups,beforeandaftertreatment.alltestsweretwo-tailed; p<0.05wasdefinedasbeingsignificant. RE SULTS Themeanageofthepatientswas79.08± Theoverallventilationrangedfrom2to11days (median5days).noneofthepatientswascurrent smoker.patientswereclassifiedintothreegroups: Group 1 included patients receiving appropriate antibiotictreatmentaccordingtotheresultsofantibiogram;group2patientshadempiricantibiotic treatmentinspiteofnegativemicrobiologicexamination;andgroup3patientswerenottreated withantibioticbecauseofnegativeresults.patient characteristicsarepresentedintable1. Themicrobialagentsisolatedfromthevariousspecimensobtainedfromgroup1patientsare listedintable2. MeanscoreofCPISinallpatientswas2.71 (1.37)andCURB-65was1.92(0.78).Group1showed significantly higher levels of CURB-65 and CPISscoresthanpatientswithnopathogenisola- TABLE 1: Patient characteristics according to the groups. Parameter Group 1 (n= 12) Group 2 (n= 3) Group 3 (n= 9) p Age (years)* (11.94) 80 (15.71) (10.46) NS Gender (male) % NS Smoking (>50 pack/year) % NS CPIS score* 1 st day 3.38 (1.32) 2.51 (0.57) 1.6 (0.91) < th day 2.72 (1.02) 1.99 (1.12) 1.0 (0.85) < th day 1.2 (0.96) 1.21 (1.03) 0.66 (0.51) NS CURB-65 score* 1 st day 2.23 (0.59) 1.66 (0.57) 1.37 (0.51) < th day 1.17 (0.98) 1.2 (0.4) 1.01 (0.56) NS 14 th day 0.5 (0.12) 0.46 (0.21) 0.35 (0.11) NS *Re sults are gi ven as me an ± SD. Gro up 1vs Gro ups 2-3. CPIS; cli ni cal pul mo nary in fec ti on sco re, 6 = low-in ter me di a te pro ba bi lity, >6 = high pro ba bi lity. CURB-65; se ve rity sco - re for com mu nity ac qu i red pne u mo ni a, Con fu si on, Ure a nit ro gen, Res pi ra tory ra te, Blo od pres su re, 65 ye ars of age and ol der, 0= very low risk of de ath, 1-2= in cre a sed risk of de ath, 3-4= high risk of de ath. TABLE 2: Microbial etiology of the patients. Microorganism* Tracheal secretion (+) No.(%) Blood (+) No.(%) Nasal smear (+) No.(%) Urine (+) No.(%) Streptococcus pneumonia 2 (8.3) 5 (20.8) MSSA 8 (33.3) 6 (25) MRSA 3 (12.5) 1 (4.1) Pseudomonas aeruginosa 13 (54.1) 5 (20.8) 6 (25) Klebsiella pneumonia 8 (33.3) 4 (16.6) *In so me cul tu res mo re than one or ga nism was iso la ted from sa me and/or dif fe rent spe ci mens. MSSA: Met hi cil lin sen si ti ve Staph ylo coc cus Au re us, MRSA: Met hi cil lin re sis tant Staph - ylo coc cus Au re us. TurkiyeKlinikleriArchLung2009;10(1) 15

4 FerahECEetal THEEFFECTOFCRPANDPROCALCITONINLEVELSONTHEESTIMATIONOFINFECTIONINTHECOPDPATIENTS... FIGURE 3: CRP levels according to antibiotic treatment. DIS CUS SI ON tion(table1).crpandpctlevelsalsoweresignificantlyhigheringroup1patientsthanotherpatients(figure1,2).afterantimicrobialtreatment, CRP and procalcitonin levels were decreased in bothgroup1andgroup2.butingroup2,differenceinpctlevelswasnotstatisticallysignificant (Figure3,4).CPISandCURB-65scoresweredecreasedinallpatientsmedian8daysafterICUadmittance. C-reactiveproteinandprocalcitoninareusedasparameterstosupportthediagnosisofinfection. 17,18 IthasbeenwrittenthatCRPlevelswerehighestin bacterialinfection. 19 Therefore,someofthepatientsshownormallevelsofCRPduringCOPDexacerbations because of lack of infection, and exacerbationsmightbecausedbyvirusesorconcomitant heart failure requiring different treatment.inagreementtothisreport,crplevelswere higherinpathogenisolationachievedcasesthan patientswithoutpathogenisolationinourstudy. Inastudy,itwasdemonstratedthatantibioticad- FIGURE 1: CRP levels according to microbiological examination. culture (+): Group 1, culture (-): Group 2-3. FIGURE 2: PCT levels according to microbiological examination. culture (+): Group 1, culture (-): Group 2-3. FIGURE 4: PCT levels according to antibiotic treatment. ministrationwithin4hofhospitaladmissionresultedinamarkedincreaseinmisdiagnosisandinappropriateantibioticutilization. 20 Similarlyinour practice,mostofthepatientswithcopdexacerbationwerestartedempiricantibotherapyimmediately after ICU admittance. We hypothesized thatifwemeasureinflammatorymarkersbefore the begining of antibiotic treatment it might be helpfulforthedecisionofinitiationofthistherapy. BrieletalreportedthatPCTguidanceinantibiotic usageavoidedunnecessaryantibioticuse. 21 Inour resultsbothcrpandpctlevelswerefoundhigh whichwascomparablewiththemicrobiologiccultureresults.alsowecombinedassessmentofcpis andcurb-65scoresinordertosupporttheaccuracyofinfection.inastudycombinationofpct andcpisscoreworkedtoexcludemisdiagnosisof ventilatorassociatedpneumonia. 22 Anotherrecent studyshowedprocalcitoninmightaidinidentifyingpneumoniaseverityindex/curb65high-risk patients. 23 Wedeterminedthatpatientswithbacterialinfectionshowedhighseverityscores.Nevertheless,itwassuggestedinareviewthatantibiotic therapysignificantlydecreasedmortalityandlack 16 TurkiyeKlinikleriArchLung2009;10(1)

5 THEEFFECTOFCRPANDPROCALCITONINLEVELSONTHEESTIMATIONOFINFECTIONINTHECOPDPATIENTS... FerahECEetal ofresponsetotreatmentinpatientswithcopdexacerbation. 24 Eleventrialswith917patientswere includedinthisreview.tentrialshaduseddiagnosticcriteriaofincreasedcough,sputumvolume andpurulenceforcopdexacerbationasindicators ofbacterialinfection.inthisreviewantimicrobial therapywassupportedaccordingtotheresultsof decreaseinmortality. Adequateantibiotictreatment,whichmeans coverageofallpathogensisolated,anddetermined bythesensitivitypatternintheantibiogram,shoulddefinitelybeconsideredininfectedcopdca- ses.accordingtoourresults,managementofpati- ents with negative microbiologic examination mightneedtheaidofinflammatorymarkerlevels inordertogivecorrectdecision. Asaconclusion,appropriateantibiotherapyis essential in the patients admitted to ICU with COPD exacerbation. Initiation of antimicrobial therapymaybemanipulatedbythelevelsofcrp andprocalcitonin.thisstudygivesaminorbutencouragingresult.furtherstudieswithlargernumberofcasesarenecessarytoconfirmthedataand toestablishtheuseofthesedatainpractice. 1. So ler-ca ta luña JJ, Martínez-García MA, Román Sánchez P, Sal ce do E, Na var ro M, Oc - han do R. Se ve re acu te exa cer ba ti ons and mor ta lity in pa ti ents with chro nic obs truc ti ve pulmo nary di se a se. Tho rax 2005;60(11): Mo ran JL, Gre en JV, Ho man SD, Le e son RJ, Lep pard PI Acu te exa cer ba ti ons of chro nic obs truc ti ve pul mo nary di se a se and mec ha ni cal ven ti la ti on: a re e va lu a ti on. Crit Ca re Med 1998;26(1): Lu na CM, Blan za co D, Ni e der man MS, Ma ta - ruc co W, Ba re des NC, Des mery P, et al. Re - so lu ti on of ven ti la tor-as so ci a ted pne u mo ni a: pros pec ti ve eva lu a ti on of the cli ni cal pul mo - nary in fec ti on sco re as an early cli ni cal pre dictor of out co me. Crit Ca re Med 2003;31(3): Cel li BR, Mac Ne e W; ATS/ERS Task For ce. Stan dards for the di ag no sis and tre at ment of pa ti ents with COPD: a sum mary of the ATS/ERS po si ti on pa per. Eur Res pir J 2004; 23(6): Rutsc hmann OT, Cor nuz J, Po let ti PA, Bri de - va ux PO, Hug li OW, Qa nad li SD, Sho uld pulmo nary em bo lism be sus pec ted in exa cer ba ti on of chro nic obs truc ti ve pul mo nary di se a se? Tho rax. 2007;62(2): Set hi S, Mus ca rel la K, Evans N, Kling man KL, Grant BJ, Murphy TF. Air way inf lam ma ti on and eti o logy of acu te exa cer ba ti ons of chro - nic bronc hi tis. Chest 2000;118(6): Hurst JR, Do nald son GC, Pe re ra WR, Wil kin - son TM, Bi lel lo JA, Ha gan GW, Use of plas - ma bi o mar kers at exa cer ba ti on of chro nic obs truc ti ve pul mo nary di se a se. Am J Res pir Crit Ca re Med 2006;174(8): Mül ler B, Tamm M. 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