Mid-regional proadrenomedullin: An early marker of response in critically ill patients with severe community-acquired pneumonia?

www.revportpneumol.org

ORIGINAL

ARTICLE

Mid-regional

proadrenomedullin:

An

early

marker

of

response

in

critically

ill

patients

with

severe

community-acquired

pneumonia?

J.M.

Pereira

_,

_A.

_Azevedo

_,

_C.

_Basílio

_,

_C.

_Sousa-Dias

_,

_P.

_Mergulhão

_,

J.A.

Paiva

a_{EmergencyandIntensiveCareDepartment,CentroHospitalarSãoJoãoEPE,Porto,Portugal} b_{DepartmentofMedicine,UniversityofPortoMedicalSchool,Porto,Portugal}

c_{HospitalEpidemiologyCentre,CentroHospitalarSãoJoãoEPE,Porto,Portugal}

d_{DepartmentofClinicalEpidemiology,PredictiveMedicineandPublicHealth,UniversityofPortoMedicalSchool,Portugal} e_{EPIUnit---InstituteofPublicHealth,UniversityofPorto,Portugal}

Received7February2016;accepted9March2016 Availableonline6May2016

KEYWORDS Proadrenomedullin; Biomarkers; Severecommunity acquiredpneumonia; Outcome;

Criticallyillpatients

Abstract

Background: Mid-regionalproadrenomedullin(MR-proADM)isanovelbiomarkerwithpotential

prognosticutilityinpatientswithcommunity-acquiredpneumonia(CAP).

Purpose:ToevaluatethevalueofMR-proADMlevelsatICUadmissionforfurtherseverity

strat-ificationandoutcomeprediction,anditskineticsasanearlypredictorofresponseinsevere CAP(SCAP).

Materialsandmethods: Prospective,single-center,cohortstudyof19SCAPpatientsadmitted

totheICUwithin12hafterthefirstantibioticdose.

Results:AtICUadmissionmedianMR-proADMwas3.58nmol/l(IQR:2.83---10.00).Nosignificant

associationwasfoundbetweenitsserumlevelsatadmissionandseverityassessedbySAPSII (Spearman’scorrelation=0.24,p=0.31)orSOFAscore(SOFA<10:<3.45nmol/lvs.SOFA≥10: 3.90nmol/l, p=0.74).Hospital andone-year mortalitywere 26% and 32%,respectively. No significant difference inmedianMR-proADM serum levelswas found between survivorsand non-survivorsanditsaccuracytopredicthospitalmortalitywasbad(aROC0.53).After48h ofantibiotictherapy,MR-proADMdecreasedinallbut5patients(median_−20%;IQR_−56%to +0.1%).Itskineticsmeasuredby thepercent changefrombaseline wasagoodpredictorof clinical response(aROC 0.80).The best discriminationwas achievedby classifying patients

Abbreviations: CAP,community-acquiredpneumonia;ICU,IntensiveCareUnit;COPD,ChronicObstructivePulmonaryDisease;SAPS, SimplifiedAcutePhysiologyScore;PIRO,Predisposition,Insult,Response,Organfailure;SOFA,Sepsis-relatedOrganFailureAssessment;PSI, PneumoniaSeverityIndex;MR-proADM,mid-regionalproadrenomedullin;SD,standarddeviation;IQR,interquartilerange;ROC,receiver operatingcharacteristics;aROC,areaunderthereceiveroperatingcharacteristicscurve.

∗_{Correspondingauthor.}

E-mailaddress:jmcrpereira@yahoo.com(J.M.Pereira).

http://dx.doi.org/10.1016/j.rppnen.2016.03.012

2173-5115/©2016SociedadePortuguesadePneumologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

according to whetherMR-proADM decreased ornot within48h. Nodecrease inMR-proADM serum levels significantlyincreased thechances ofdying independently ofgeneralseverity (SAPSII-adjustedOR174;95%CI2---15,422;p=0.024).

Conclusions: InSCAPpatients,adecreaseinMR-proADMserumlevelsinthefirst48hafterICU

admissionwasagoodpredictorofclinicalresponseandbetteroutcome.

©2016SociedadePortuguesadePneumologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Community-acquired pneumonia (CAP) remains a major cause of morbidity, mortality and healthcare costs.1---3 _In 9---16% of cases, ICU admission is needed, due to severe respiratoryfailure,severesepsisorsepticshock.4---6_Inthese patients,mortalityis high, reaching50% inthosepatients requiringvasopressorsupport.7_{Inadequateinitialantibiotic} therapyisapoorprognosticfactor.8---10

Severityassessmentandoutcomepredictionare funda-mentalinthemanagementofCAPpatients,bothtoallocate the most appropriate site of care and to select empiri-cal antibiotic andadjuvant therapy.Response assessment is also paramount. Early identification of responders and non-responderscouldhelpreduceantibioticconsumptionor allowearlierrescueantibiotictherapy.However,thereisno standarddefinitionforclinicalresponseinsevereCAP.

Efforts have been made to study the usefulness of biomarkers,asacomplement toclinical judgment,in the diagnosis, severity assessment, treatment, prognosis and follow-upofCAP.Inrecentyears,promisingdataregarding theroleofadrenomedullin(ADM)inthemanagementofCAP havebeenpublished.11---13_{Thishormone,apeptidewith52} aminoacids,isapotentvasodilatoragentwithimmune mod-ulatingand metabolic propertiesand bactericidalactivity that increases in sepsis.14 _{It is produced by multiple} tis-suetypesbut,unfortunately,itsserumlevelsaredifficultto measure,sinceitisrapidlyclearedfromthecirculation.15---17 However, the more stable mid-region fragment of proad-renomedullin(MR-proADM)directlyreflectslevelsofADM.18 This biomarker may be as good as validated pneumonia-specific severity scores at detecting patients withsevere CAP and is probably better than other biomarkers, such asprocalcitonin.11,12_{MR-proADMserumlevelcorrelatewell} with mortality(both short andlong term)19 _{and its} addi-tiontoclinicalscoringsystemsimprovestheirdiscriminatory power.11---13

Thepurposeofourstudywastoevaluatethevalueof MR-proADMatICU admissionforfurtherseveritystratification andoutcomepredictionandtoassessitskineticsasanearly markerofresponseinSCAPpatients.

Materials

and

methods

Thiswasasingle-center,observational,prospectivecohort studyof19patientswithsevereCAPadmittedtothe Inten-siveCareDepartmentofatertiarycareuniversityhospital

in Portugal between March 2012 and January 2013. The study wasapproved by the local ethics committee. Writ-teninformedconsentwasobtained fromevery patientor patientrepresentativepriortoinclusioninthestudy.

CAPwasdiagnosedwhen,inadditiontosuggestive clini-calfeatures(e.g.cough,fever,sputumproduction,pleuritic chestpain),ademonstrableinfiltratebychestradiographor CTscanwaspresent.SevereCAPwasdefinedaccordingto theInfectious Diseases Society ofAmerica/American Tho-racicSocietycriteria(IDSA/ATS).20 _{Inordertobeincluded} intothisstudy,patientshadtobeolderthan18 yearsold andhave MR-proADM measured within12h afterthe first antibioticdose.

Datacollection

The following parameters were registered by the investi-gators in a specifically created database at the moment or within the first 24h of ICU admission: age, sex, co-morbidities,corticosteroidsuse,existenceordevelopment ofsepticshockand/oracuterespiratorydistresssyndrome andempiricantibiotictherapy.Thedurationofmechanical ventilation,length of hospital andICU stay andmortality (ICU, hospital and 1-year) were also recorded. Simplified AcutePhysiologyScore(SAPS)II21_{,Sepsis-relatedOrgan} Fail-ure Assessment (SOFA) score22_{, Pneumonia Severity Index} (PSI)6_andPIRO-CAP23_{werecalculated.}

Proadrenomedullindetermination

Within12hofthefirstantibioticdose,abloodsamplewas withdrawnforthedeterminationofMR-proADMandthe pro-cesswasrepeated48hlaterexceptforonepatient.

MR-proADM concentrations (normal<0.52nmol/l) were measuredattheClinicalBiochemistryLaboratoryofHospital UniversitarioCentraldeAsturias(Oviedo,Spain)inan auto-matedKryptoranalyzer,usingTRACEtechnology(Kryptor; BRAHMS,Hennigsdorf,Germany),withoutanypre-analytical treatments (i.e., extraction or derivatization). Analytical characteristics of the assay and reference values for the healthyadultpopulationhavealreadybeendescribed.24 Microbiologicevaluation

Atthepointofinclusionintothestudy,twopairsofblood cultures were collected. Blood cultures were processed usinganautomatedmicrobiologygrowthanddetection sys-tem(BACTEC).Iftherewasbacterialgrowth,sampleswere Gramstainedand subcultured.A bacteremic episode was

definedasgrowthofatypicalorganismforCAPinatleast oneoffourcollectedbloodcultures.

Trachealaspiratewastakenfromeverypatientwhenever possibleto test for bacteriaaccording tostandard proce-dures. Representative sputum originating from the lower respiratorytractwasvalidatedby thecriteriaof >25 gra-nulocytesand<10epithelialcellsperlowpowerfield(total magnification×100).

Urine samples were collected and tested whenever possible for Legionella pneumophila and Streptococcus

pneumoniae with an antigen test. Real-time polymerase

chainreactionwasusedtoevaluatethepresenceof respi-ratory virus in nasopharyngeal swab and bronchoalveolar lavage when clinically and epidemiologically indicated. Pleuralfluidwhenavailablewasalsocollected.

Identificationofmicroorganismsandsusceptibility test-ingwasperformedaccordingtostandardmethods.

Statisticalanalysis

Categorical variables are described as counts and per-centages and continuous variables as the median and interquartile range (IQR). MR-proADM kinetics was quan-tified as the percent change from baseline accord-ingto:(100*(MR-proADM[48h]− MR-proADM[baseline])/MR-proADM[baseline]. Spearman’s correlations were used to quantify the association between MR-proADM and sever-ityscores.MedianMD-proADMlevelswerecomparedacross subgroups using the Kruskal---Wallis test. The area under the receiver operating characteristics (ROC) curves was estimated to quantify the discrimination of MR-proADM in predicting death at different times. The association betweenthechangeinMR-proADManddeathwasassessed byoddsratios(OR)estimatedbylogisticregression, adjus-tingforseverityscores.

Statistical analysis was performed using the statistical packageStataversion11.1forWindows(StataCorpLP, Col-legeStation,TX).

Results

Demographicandclinicalcharacteristicsofpatients The median age of the overall cohort was 68 years (IQR=64---82),58%weremaleand89.5%ofthecaseswere in high-risk PSIclasses IV andV. MedianSAPS II andSOFA scorewere55(IQR=41---61)and9(IQR=8---12),respectively.

Table 1 shows global baseline characteristics at hospital admission.

SCAPwasmicrobiologicallydocumentedin58%casesand

S. pneumoniae (n=6) was the leading pathogen followed

byL. pneumophila (n=3). Allpatients receivedantibiotic

therapyconcordantwithIDSA/ATSguidelines.20

ProadrenomedullinatICUadmissionandseverity scores

Median MR-proADM at ICU admission was 3.58nmol/l (IQR=2.83---10.00). In this cohort, no significant associ-ation was found between MR-proADM serum levels at

Table1 Maindemographicandclinicalcharacteristicsof thestudysample(n=19).

n(%)a Age(years)b _68(64---82) Malesex 11(58) SAPSIIscoreb _51(41---61) PSIb _5(4---5) PIRO-CAP Mild-risk 6(32) High-risk 10(52) Veryhigh-risk 3(16) SOFAscoreb _9(8---12) Co-morbidities 14(74) Diabetesmellitus 7(37) COPD 6(32)

Chronicrenalfailure 2(11)

Alchoolabuse 1(5)

Congestiveheartfailure 1(5)

Cancer 1(5) Microbiologicaldocumentation 11(58) Microorganisms Streptococcuspneumoniae 6(32) Legionellapneumophila 3(16) Haemophilusinfluenza 1(5) Klebsiellapneumoniae 1(5) Streptococcusmitis 1(5) Secondarybacteremia 5(26)

Appropriateantibiotictherapy 11(100) Mediantimetofirstantibioticdose(min)b _{129(78---160)} Durationofmechanicalventilation(days)b _8(6---10)

Vasopressorsuse 13(68%)

ICULOS(days)b _11(9---14)

HospitalLOS(days)b _17(13---24) Mortality

ICU 3(16)

Hospital 5(26)

28-day 5(26)

One-year 6(32)

SAPS:SimplifiedAcutePhysiologyScore;PSI:Pneumonia Sever-ityIndex;PIRO-CAP:Predisposition,Infection,Response,Organ dysfunction-Community-acquired pneumonia; SOFA; Sepsis-relatedOrganFailure Assessment;COPD:ChronicObstructive Pulmonary Disease; IDSA/ATS: Infectious Diseases Society of America/AmericanThoracicSociety;ICU:Intensive CareUnit; LOS:Lengthofstay.

a _{Unlessotherwisespecified.} b _{Datapresentedasmedian(IQR).}

admission and severity assessed by SAPS II (Spearman’s correlation=0.24;p=0.31)(Fig.1).MR-proADMserum lev-els were higher in patients with SOFA score ≥10, but this differencedidnotreachstatistical significance (SOFA score≥10: 3.90nmol/l vs. SOFA score<10: 3.45nmol/l;

p=0.74)(Fig.2).

As for SOFA score, patients with higher pneumonia-specific severity scores, such as PSI (class III and IV:

0 10 20 30

Proadrenomedullin, nmol/L (day 1)

20 40 60 80 100

SAPS II

Figure 1 Serum mid-regional proadrenomedullin levels accordingtoSAPSIIscore.

0 10 20 30

Proadrenomedullin, nmol/L (day 1)

SOFA≥10 SOFA<10

Figure 2 Serum mid-regional proadrenomedullin levels accordingtoSOFAscore.

2.78nmol/lvs.classV:3.74nmol/l;p=0.29)andPIROCAP (mildrisk:2.53nmol/lvs.highrisk:4.93nmol/lvs.veryhigh risk:3.89;p=0.23),hadhigherMR-proADMserumlevelsbut thedifferenceswerenotstatisticallysignificant.

0.00 0.25 0.50 0.75 1.00 S en s itivity 0.00 0.25 0.50 0.75 1.00 1-specificity In-hospital death

Figure4 Discrimination ofmid-regionalproadrenomedullin kineticsinthefirst 48hafterantibiotictherapy,asmeasured bythepercentdecreasefrombaseline,topredicthospital mor-tality(aROC0.80;95%CI0.47---1.00).

ProadrenomedullinatICUadmissionandoutcome ICU,hospitalandone-yearmortalitywere16%,26%and32%, respectively.MedianMR-proADMserumlevelsweresimilar, insurvivorsandnon-survivorsregarding hospital[survivors 3.51nmol/l(IQR=2.60---13.00)vs.non-survivors3.89nmol/l (IQR=3.10---8.10);p=0.89] and1-year mortality[survivors 3.58nmol/l(IQR=2.40---13.00)vs.non-survivors3.67nmol/l (IQR=3.30---7.20);p=1.0]. Receiveroperating characteris-tic(ROC)curveanalysisshowedthatthisbiomarkeratICU admissionhadabaddiscriminatorypowertopredict hospi-tal[aROC0.53;95%confidenceinterval(CI)0.26---0.79]and 1-yearmortality(aROC0.51;95%CI0.25---0.78)(Fig.3).

Proadrenomedullinkineticsandoutcome

After 48h of antibiotic therapy, MR-proADM serum levels decreasedinallbut5patients(median−20%;IQR=−56%to +0.1%).MR-proADMkineticsmeasuredbythepercentchange frombaseline wasa good predictor of hospital mortality (aROC0.80;95%CI:0.47---1.00)(Fig.4).

0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00 Sensitivity 0.00 0.25 0.50 0.75 1.00 1-specificity In-hospital death Sensitivity 0.00 0.25 0.50 0.75 1.00 1-specificity 1-year mortality

Figure3 Discriminationofserummid-regionalproadrenomedullinlevelsatday1topredicthospital(aROC0.53;95%CI0.26---0.79) andone-yearmortality(aROC0.51;95%CI0.25---0.78).

The best discrimination was achieved by classifying patients according toMR-proADM decreasing (one patient diedoutof13)ornot(4outof5died)within48hof antibi-otic therapy. The absence of reduction in this biomarker significantly increased the chances of dying in the hospi-talindependentlyofgeneralseverity[SAPSII-adjustedodds ratio(OR)174;95%CI:2---15,422;p=0.024].

Discussion

In ourstudy MR-proADM at ICU admissionand within 12h of first antibiotic dose did not further stratify severity in patients withSCAP. Furthermore,serum MR-proADM at this stage did not perform well as a predictor of both short- (ICU and hospital) and long-term (one-year) mor-tality. Nevertheless, MR-proADM kinetics in the first 48h afterantibiotictherapywasagoodtooltopredicthospital mortality.

Consideringthemorbidityandmortalityassociatedwith CAP,earlyidentificationofhighriskpatientsisofparamount importance. Several papers demonstrate an association betweenthisbiomarker’sserumlevelsandseverityassessed bypneumoniaspecificscoressuchasPSI.Christ-Cainetal. andHuang DT et al.,11,12 _{reported that MR-proADM levels} consistently rise as PSI class increases (p<0.001). In 49 patientswithseveresepsis/septicshockduetoCAP admit-tedtotheICU,MR-proADMconsistentlyroseasPSIadvanced fromIItoV(p=0.02).25_{Yet,ourresults,likethoseofAkpinar} etal.,26_{,donot supportthisfinding. Althoughpatients in} PSIclassV presented higherMR-proADM serumlevels,we didnotobserveanysignificant differenceacrossdifferent risk classes of thisscore. Besides the sample size, differ-ences in study cohort, namely the fact that only severe CAP patients were included, may explain these different results.

Wealsodidnotfindasignificantassociationwith sever-ityassessed by SAPS II or SOFA score. In contrast,Marino etal.,27_{, in a prospective observational study in patients} withsuspectedsepsispresentingtotheEmergency Depart-ment,observedamoderateassociationofMR-proADMwith severityofdiseaseevaluatedby APACHEII score(r=0.46;

p<0.001).ThiscorrelationwasalsodescribedbyTravaglino et al.28 _{In a Swiss study with 101 critically ill patients,} MR-proADM levels on ICU admission exhibited correlation withAPACHEII score(r=0.42; p<0.001)andSAPS IIscore (r=0.5; p<0.001).29 _{These differences may be explained} by the differenttypes of population studied. Indeed,our study was the first to include only critically ill patients with severe sepsis or septic shock, a significant propor-tionof them(68%)needingvasopressors atICUadmission. Thefactthat MR-proADMserumlevelsarehigherinthese groups of patients27,29 _{may explain the lack of} relation-ship between this biomarker and severity scores in our study.

Intheemergencydepartment,MR-proADMseemstobe a very good prognostic tool to predict both short and long-termoutcomeinpatientswithlowerrespiratorytract infections.19_{However,whentheanalysisisrestrictedtothe} most severe patients, conflicting results have been pub-lished. According to Christ-Crain study,29 _{the prognostic} accuracyforICUmortalityofthisbiomarkeronadmission,

in septic critically ill patients, is good (AUC 0.81), simi-lar toseverity scores suchasAPACHE II and SAPS II score and significantly better than other biomarkerssuch as C-reactive protein. Huang’s study12 _{showed that, withinPSI} classesIV/V(n=546),subjectswithMR-proADMhigherthan 1.45nmol/lhadahigher30-daymortalityrate(23%vs.9%;

p<0.001).Inasubgroupofpatients(n=61)withhighriskPSI scores(classesIVandV),Courtaisetal.,30 _{showedthat,in} univariatelogisticregressionanalysis,MR-proADMlevels sig-nificantlypredicted30-daymortalityrisk(OR4.68;95%CI: 1.66---20.22)withanaROCcurveof0.81(95%CI:0.65---0.96). Nevertheless,only24ofthesepatientswereadmittedtothe ICU.

Like other studies, we observed a low discriminatory powerofMR-proADMtopredicthospitalandone-year mor-tality. Apkinar26 _{reported that this biomarker had a bad} discriminatorypowertopredict4-(AUC0.505)and8-week mortality(AUC0.513)andMarinoetal.27_showedapoor per-formance topredict 28 day-mortality(AUC0.60). Despite beingslightly better thanpreviously reported,in Subervi-ola’sstudythediscriminatorypowerofthispro-hormoneto predicthospitalmortalitywasonlymoderate(AUC0.72).25

Untilnow,therehavebeennopublisheddataregarding thevalueofMR-proADMkineticsinthemanagementofSCAP patients.Inourcohort,wefoundthatafter48hofantibiotic therapy,thepercentchangefrombaselinewasagood pre-dictorofhospitalmortality.Indeed,theabsenceofdecrease inserumlevelswasanindependentriskfactorforhospital mortality. Similarfindings were described in other groups ofpatients.Forinstance,in febrilepatientswith hemato-logic malignancies,31 _{serum MR-proADM levels dropped in} patientswhorespondedtotherapywhereasinpatientswho did not respondtherewas nosignificant change between initial(atfeveronset)andfollow-uplevels(4---7dayslater). Furthermore, septic patients admitted to the emergency departmentwithhighplasmaADM(>70pg/ml)thatpresent a decrease in serum levelsin the first 4 days of therapy haveahighersurvivalratethanthosepatientswhoselevels remainabovethatthreshold(100%vs.36%).27

The factthat this biomarker wascollected within12h afterthefirstantibioticdoseinpatientswithoutprior antibi-oticuseandthatallpatientswereprospectivelyenrolledare twoofthestrengthsofthisstudy.However,somelimitations alsomeritconsideration,namelythefactthatitwasasingle centerstudyandthatthegeneralizabilityofourfindingsis limitedbythesmallsamplesize(only19patients). There-fore,theseresultsshouldbevalidatedinalargemulticenter study.

Conclusions

We concluded that, in SCAP patients, MR-proADM on ICU admission is not useful for further severity stratification and to predict both short-and long-term outcome. How-ever,itskineticsinthefirst48hafterantibiotictherapymay beahelpfultooltoassistcliniciansinidentifyingpatients withabetterclinicaloutcome.Moreover,althoughfurther studiesareneeded,decreasinglevelsofthisbiomarker,as a sign of early response to therapy, may lead to shorter durationofantibiotictherapyandplayaroleinantibiotic stewardship.

Authors’

contributions

All authors have made substantial contribution to the conceptionanddesignofthestudyaswellasinthedrafting, revising andfinalapprovalof theversiontobepublished. JMPandAAperformedstatisticalanalysis.

Ethical

disclosures

Protection of human and animal subjects.The authors declarethatnoexperimentswereperformedonhumansor animalsforthisstudy.

Confidentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcenteronthe publica-tionofpatientdata.

Right to privacy and informed consent.The authors declare thatthe procedures followedwere in accordance withtheregulationsoftherelevantclinicalresearchethics committeeandwiththoseoftheCodeofEthicsoftheWorld Medical Association (Declaration ofHelsinki). The authors haveobtainedthewritteninformedconsentofthepatients included inthisstudy.Thecorrespondingauthorisin pos-sessionofthisdocument.

Conflict

of

interest

Theauthorsdeclarethattheyhavenocompetinginterests.

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