AdjunctiveTreatmentofCommunity-AcquiredPneumonia:

ANewRoleofCorticosteroids?

SarahKlembith,Pharm.D.PGY1PharmacyResident

CentralTexasVeteransHealthCareSystemTheUniversityofTexasatAustinCollegeofPharmacy

January15,2016

LearningObjectives:1. Understandtheepidemiology,pathophysiology,diagnosis,andseverityofpneumonia2. Reviewcurrentguidelinesforthetreatmentofcommunity-acquiredpneumonia3. Reviewcorticosteroidsandtheirroleininflammation4. Analyzeliteratureregardingthebenefitofcorticosteroidsinthetreatmentofcommunity-acquiredpneumonia5. Formulaterecommendationsregardingtheuseofcorticosteroidsincommunity-acquiredpneumonia

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BACKGROUND:PNEUMONIA

I. EpidemiologyA. Overfivemillionadultsareaffectedbycommunity-acquiredpneumonia(CAP)eachyearintheUnitedStates(U.S.)1B. Highmorbidityandmortality

1. Pneumoniaandinfluenzacombined2a. EighthleadingcauseofdeathintheU.S.b. Mostcommoncauseofinfection-relatedmortality

2. Despiteadvancesinantimicrobialtherapy,ratesofmortalityduetopneumoniahavenotdecreasedsignificantly2a. Hospitalinpatientdeaths:3.4%b. MortalityrateforCAPpatientsadmittedtointensivecareunit(ICU)rangesfrom21-58%1

C. Pneumoniaoccursatallages31. Morecommoninelderly

D. EstimatedannualeconomicburdenofCAPintheU.S.exceeds10billiondollars4II. Pneumoniaclassification3

A. Community-acquired:nocontacttoamedicalfacilityB. Hospital-acquired:developing>48hoursafterhospitaladmissionC. Healthcare-associated:non-hospitalizedpatientsatriskofmulti-drugresistant(MDR)pathogens

1. TwoormoreriskfactorsforMDRpathogena. Recenthospitalization≥2dayswithinpast90daysb. Nursinghomeorlong-termcarefacilityresidentc. Recentantibioticuse(past30days),chemotherapy,woundcare,orinfusiontherapyd. Hemodialysise. ContactwithfamilymemberwithinfectioncausedbyMDRpathogen

D. Ventilator-associated:developing>48hoursafterintubationandmechanicalventilationIII. Pathophysiology3

A. Pathogenenterslowerrespiratorytractbythreeroutes1. Inhaled2. Hematogenous3. Aspiration(oropharyngealcontents)

B. Componentsofinnateimmunesystemfailtoclearpathogen1. Normallyexpelledbymucociliaryclearance,cough,antimicrobialpeptides,andlocalinnateimmunedefenses5

C. Systemicinflammationfollows6-81. Increasedpro-inflammatorycytokines2. Highlevelsofinflammationareassociatedwithhigherratesoftreatmentfailure3. PatientswithsevereCAParefoundtohaverelativeadrenalinsufficiency

D. Canprogresstoacuterespiratoryfailure,septicshock,multi-organfailure,anddeathifleftuntreatedE. MostcommonpathogensinCAP3,9

1. Streptococcuspneumoniae-mostcommon2. Atypicalorganisms:Mycoplasmapneumoniae,Legionellaspecies,Chlamydophilapneumoniae3. Haemophilusinfluenzae4. Varietyofviruses

F. Riskfactors31. Chronicobstructivepulmonarydisease(COPD)2. Humanimmunodeficiencyvirus(HIV)infection3. Diabetesmellitus4. Age>65years5. Depressedmucociliarytransport

a. Ethanolandnarcoticuseb. Bronchusobstruction

6. Alteredsensoriumandneuromusculardisease–mayresultinincreasedinoculumsizeIV. Clinicalpresentation

A. Signsandsymptoms3,5,101. Beginsasmildupper-airwayirritation2. Fever,chills,malaise,cough,dyspnea,pleuriticchestpain3. Rust-coloredsputumorhemoptysis

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B. Physicalexam31. Tachypneaandtachycardia2. Dullnesstopercussion3. Diminishedbreathsoundsoveraffectedarea4. Inspiratorycrackles5. Increasedtactilefremitus,whisperedpectoriloquy,andegophony6. Chestwallretractions

C. Oftenmoresubtleinolderpatients101. Oftenpresentswithweaknessanddeclineinfunctionalormentalstatus

V. Diagnosis9,10

A. Lungimagingshowinginfiltraterequiredfordiagnosis1. Chestradiographmostcommon

a. Denselobarorsegmentalinfiltrateb. Patchyconsolidationoccasionallyc. Lobarconsolidation,cavitation,andpleuraleffusionssuggestabacterialetiology

B. Clinicalfeatures1. Cough2. Fever3. Pleuriticchestpain

C. Laboratorytesting91. Investigatedforspecificpathogensthatwouldsignificantlyalterstandardempiricalmanagement

a. Overalllowyieldandinfrequentpositiveimpactonclinicalcarei. Againstroutineuseofcommontests(bloodandsputumcultures)

b. Specificclinicalindicationsformoreextensivediagnostictesting(AppendixA)i. Resultwilllikelychangeindividualantibioticmanagement

2. Sputumandbloodculturesrecommendedforinpatientswithsevereillness10

VI. Severityandsite-of-caredecision9A. Hospitalizationrecommended

1. CURB-65score≥2(moderaterecommendation)a. Confusionb. Bloodureanitrogen(BUN)≥20mg/dLc. Respiratoryrate≥30breaths/mind. Systolicbloodpressure<90mmHgordiastolicbloodpressure≤60mmHge. Age≥65years

2. PneumoniaSeverityIndex(PSI)riskclassIVandVa. Assessespatientdemographics,comorbidities,physicalexaminationfindings,laboratoryandradiographic

findings11(AppendixB)b. Riskstratificationintofiveseverityclasses

3. ObjectivecriteriaofscoresshouldalwaysbesupplementedwithclinicaljudgementB. DirectadmissiontoICU

1. Onemajorcriteriaforseverepneumonia(strongrecommendation)a. Septicshockrequiringvasopressorsb. Acuterespiratoryfailurerequiringintubationandmechanicalventilation

2. Threeormoreminorcriteriaforseverepneumonia(moderaterecommendation)a. Respiratoryrate≥30breaths/minuteb. Arterialoxygenpressure/fractionofinspiredoxygen(PaO2/FiO2)ratio≤250c. Multilobarinfiltratesd. Confusion/disorientatione. BUNlevel≥20mg/dLf. Leukopeniaresultingfrominfection(whitebloodcell[WBC]count<4000cells/mm3)g. Thrombocytopenia(plateletcount<100,000cells/mm3)h. Hypothermia(coretemperature<36°C)i. Hypotensionrequiringaggressivefluidresuscitation

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TREATMENTGUIDELINES:COMMUNITY-ACQUIREDPNEUMONIA

I. InfectiousDiseasesSocietyofAmerica/AmericanThoracicSociety(IDSA/ATS)CAPGuidelines9A. Empiricalantimicrobialtherapydependingonsite-of-caredecision,riskfactorsfordrug-resistantpathogens,and

comorbidities(AppendixC)1. Firstdoseofantibioticshouldbegivenwhilestillintheemergencydepartment(ED)ifadmittedthroughtheED

B. Durationofantibiotics(moderaterecommendation)1. Treatedforaminimumof5days2. Afebrilefor48-72hours3. NomorethanoneCAP-associatedsignofclinicalinstabilitybeforediscontinuationoftherapy

C. Criteriaforclinicalstability1. Temperature≤37.8°C2. Heartrate≤100beats/min3. Respiratoryrate≤24breaths/min4. Systolicbloodpressure≥90mmHg5. Arterialoxygensaturation≥90%orpartialpressureofoxygen(pO2)≥60mmHgonroomair6. Abilitytomaintainoralintake7. Normalmentalstatus

II. Adjunctivecorticosteroidrecommendations

Table1.Corticosteroidrecommendationsaccordingtovariouspneumoniaguidelines

Guideline RecommendationBTS,2015annotated12

• SteroidsarenotrecommendedintheroutinetreatmentofhighseverityCAP

NICE,201413 • DonotroutinelyofferglucocorticosteroidsinCAPunlesspatienthasotherconditionsforwhichtreatmentisindicated

• BenefitofglucocorticosteroidtreatmentseeninICUsetting;however,cannotmakespecificpositiverecommendationinthissetting

Dutch,201114 • CorticosteroidsarenotrecommendedasadjunctivetherapyIDSA/ATS,20079 • ScreenpatientswithsevereCAPforcorticosteroidinsufficiencyandreplacementis

appropriateifinadequatecortisollevelsaredocumented• Criteriaforsteroidreplacementremainscontroversial• Recommendtightglucosecontrolifcorticosteroidsadministered

BTS–BritishThoracicSociety;NICE–NationalInstituteforHealthandCareExcellence

GLUCOCORTICOIDSANDINFLAMMATION

I. Inflammation15,16,17

A. ReflexiveresponsetodetectionofmicrobialinfectionB. Complementandtoll-likereceptorsactivatedC. SynthesisandreleaseofinflammatorymediatorsD. Effectsonthevasculature

1. Localizedvasodilation2. Increasedvascularpermeability3. Extravasationofplasmaproteins4. Migrationofleukocytes

E. BeneficialroleininhibitionandeliminationofprimaryinfectionF. Excessiveorpersistentinflammationleadstotissuedestructionanddisease

1. Down-regulationofinflammatoryresponsemayimproveclinicalcourseofCAP18a. Glucocorticoidsareoneofthemostprescribedclassesofanti-inflammatorymedicationsworldwide

II. Endogenousglucocorticoids15

A. Hypothalamic-pituitary-adrenalaxis1. Hypothalamussecretescorticotropin-releasinghormone(CRH)2. CRHstimulatesreleaseofcorticotropinfromanteriorpituitary3. Corticotropininducessynthesisandsecretionofcortisolbyadrenalcortex

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B. Glucocorticoidreceptor1. Expressedinvirtuallyallcells2. Steroidhormonereceptorfamily3. Highaffinityforcortisol4. Pleiotropiceffectsofglucocorticoidreceptorsonmultiplesignalingpathways

C. Cortisolanti-inflammatoryactionsbyinhibitingsynthesisofcytokinesandinflammatorymediatorsbyseveralpathways(AppendixD)1. Cortisol-glucocorticoidreceptorcomplexbindsglucocorticoid-responsiveelementsinthenucleusandfacilitates

orinhibitstranscriptiona. InductionandactivationofannexinI

i. AnnexinIinhibitscytosolicphospholipaseA2α(cPLA2α)andblocksreleaseofarachidonicacidandsubsequentconversiontoeicosanoids(prostaglandins,thromboxanes,prostacyclins,andleukotrienes)

b. Inductionofmitogen-activatedproteinkinase(MAPK)phosphatase1i. InactivatesJunN-terminalkinaseandpreventskinasecascade

(i) Inhibitstranscriptionofinflammatoryandimmunegenesii. MayinhibitcPLA2αbyblockingitsphosphorylationbyMAPKs

c. Cortisol-glucocorticoidreceptorcomplexdirectlyinterfereswithc-Jun-mediatedtranscriptionthroughprotein-proteininteractions

2. Interactionbetweencortisol-glucocorticoidreceptorcomplexandothertranscriptionfactorsregulateotherglucocorticoid-responsivegenesa. Inhibitnuclearfactor-κB(NF-κB)transcriptionactivity

i. Blocksproductionofcytokines,chemokines,cell-adhesionmolecules,complementfactorsii. RepressionofNF-κB-inducedtranscriptionofcyclooxygenase-2(COX-2)

b. Occursatlowercortisollevels3. Glucocorticoidsignalingthroughmembrane-associatedreceptorsandsecondmessengers

III. Exogenousglucocorticoids

A. ComparisonofavailableglucocorticoidsTable2.Glucocorticoidrelativepotenciesanddoses19,20

Glucocorticoid EquivalentDose*(mg) RelativeAnti-InflammatoryActivity

RelativeMineralocorticoid(sodium-retaining)Activity

Short-actingHydrocortisone(cortisol)

20 1 1

Cortisoneacetate 25 0.8 0.8Intermediate-actingPrednisone 5 4 0.8Prednisolone 5 4 0.8Methylprednisolone 4 5 0Triamcinolone 4 5 0Long-actingDexamethasone 0.75 30 0Betamethasone 0.75 25 0*Oralorintravenous(IV)administration

B. NumerousindicationsC. Mechanismofaction

1. SameasendogenouscortisolD. Glucocorticoiddosingandpharmacokinetics(AppendixE)E. Discontinuation19

1. Gradualwithdrawalbytaperingdosetopreventadrenalsuppressiona. Long-termtherapyb. Highdoses(>20mg/dayofprednisoneorequivalentfor>3weeks)

F. Drug-druginteractions191. Immunosuppressants2. Non-steroidalanti-inflammatorydrugs(NSAIDs)3. Warfarin

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4. Fluoroquinolones5. Liveandinactivatedvaccines6. Salicylates7. Antidiabeticagents8. Antacids

G. Adverseeffectsfromhigh-doseorprolongedglucocorticoidtherapy15,191. Hyperglycemia2. Osteoporosis3. Hypertension4. Immunosuppression(increasedincidenceofsecondaryinfection,maskacuteinfection,prolongorexacerbate

viralinfections,limitresponsetoinactivatedvaccines)5. Psychiatricdisturbances(severedepression,euphoria,insomnia,moodswings,personalitychanges,psychosis)6. Growthretardationinchildren7. Inhibitionofwoundrepair8. Myopathy9. Increasedintraocularpressure,open-angleglaucoma,andcataracts10. Pepticulcer(withpossibleperforationandhemorrhage)

IV. ClinicalQuestion

A. DoestreatmentwithadjunctivecorticosteroidsimproveclinicaloutcomesinpatientswithCAP?

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LITERATUREREVIEWTable3.SummaryofearlytrialsofadjunctivecorticosteroidtherapyinCAPStudy,Year(Location)

StudyDesign N Sample PrimaryOutcome

CorticosteroidAgentandDuration

Results

Confalonieri,200521(Italy)

Randomized,double-blind,placebo-controlled,multicenter

46 SevereCAPinICUtreatment

PaO2:FiO2

Hydrocortisone200mgIVbolus,then10mg/hourfor7days

• SignificantimprovementinPaO2:FiO2byday8andhospitalmortalitywithhydrocortisone(enrollmentsuspendedatinterimanalysis)

• Significantincreasedsurvivaltohospitaldischargeinhydrocortisonegroup(p=0.009)

Garcia-Vidal,200722(Spain)

Retrospective,observational

308 HospitalizedpatientswithsevereCAP(PSIIVorV)

30-daymortality

Methylprednisolone(mediandose45.7mg/dayorequivalent)

• Mortalitywassimilarinbothgroups(5%nocorticosteroidsand7%corticosteroids)

• Steroidshadaprotectiverole(OR0.287,95%CI0.113-0.732)• Severityofpneumoniaindependentfactorassociatedwith

increasedmortality(OR2.923,95%CI1.262-6.770)Snijders,201023(Netherlands)

Randomized,double-blind,placebo-controlled

213 HospitalizedpatientswithCAP

Clinicalcureatday7

Prednisolone40mgorallyorIVdailyfor7days

• Nodifferenceinclinicalcureatday7• DeclineinCRPlevelsfasterinprednisolonegroupuntilday7;

CRPhigheratday14• Morelatefailuresinnon-severeCAPinprednisolonegroup• Nodifferenceinadverseevents

Meijvis,201124(Netherlands)

Randomized,double-blind,placebo-controlled

304 HospitalizedpatientswithconfirmedCAP(excludedifdirectICUadmission)

Lengthofhospitalstay

Dexamethasone5mgIVfor4days

• Statisticallysignificantdifferenceinmedianlengthofhospitalstayby1day

• NodifferenceinsecondaryoutcomesofhospitalmortalityandratesofadmissiontoICU

• GreaterdeclineinCRPandIL-6concentrationsindexamethasonegroupinfirst4days

• HyperglycemiamorecommonindexamethasonegroupNie,201225 Meta-analysis

of9RCTs1001 Hospitalized

patientswithCAP

Mortality Hydrocortisone,prednisolone,dexamethasone,methylprednisoloneDuration1-9days

• Corticosteroidsdidnotsignificantlyreducemortality(PetoOR0.62,95%CI0.37-1.04)

• Subgroupanalysisbyseverity(4trials,N=214):survivalbenefitinsevereCAP(PetoOR0.26,95%CI0.11-0.64)

• Subgroupanalysisdurationofcorticosteroids:significantreductioninmortalityinprolonged(>5days)treatment

• Increasedriskofhyperglycemia• Potentialpublicationbias

Cheng,201418

Meta-analysisof4RCTs

264 HospitalizedpatientswithsevereCAP

Hospitalmortality(oratlongestfollow-uptime)

Hydrocortisone,prednisolone,andmethylprednisolone

• Corticosteroidssignificantlyreducedhospitalmortality(PetoOR0.39,95%CI0.17-0.90)

• Qualityofevidencelowanddowngradedforinconsistencyandimprecision

• Resultsshouldbeinterruptedwithcaution• Moderateheterogeneityamongresults(I2=46%)

OR–oddsratio;CI–confidenceinterval;CRP–C-reactiveprotein;IL–interleukin;RCT–randomizedcontrolledtrial

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TorresA,SibilaO,FerrerM,etal.Effectofcorticosteroidsontreatmentfailureamonghospitalizedpatientswithseverecommunity-acquiredpneumoniaandhighinflammatoryresponse.JAMA.2015;313(7):677-86.26Objective Toassesstheeffectofcorticosteroidsinpatientswithseverecommunity-acquiredpneumoniaandhigh

inflammatoryresponseStudyDesign Multicenter,randomized,double-blind,placebo-controlledtrialPopulation InclusionCriteria:

• Aged18yearsorolder• Clinicalsymptomssuggesting

CAP(cough,fever,pleuriticchestpain,dyspnea)

• Newchestradiographicinfiltrate

• MetsevereCAPcriteria(definedbymodifiedATScriteriaorPSIriskclassV)

• C-reactiveprotein(CRP)level>150mg/Latadmission

ExclusionCriteria:• Priortreatmentwithsystemiccorticosteroids• Nosocomialpneumonia• Severeimmunosuppression(HIVinfection,immunosuppressive

conditionormedications)• Preexistingmedicalconditionwithlifeexpectancy<3months• Uncontrolleddiabetesmellitus• Majorgastrointestinal(GI)bleedingwithin3months• Conditionrequiringacutetreatmentwith>1mg/kg/day

methylprednisoloneorequivalent• H1N1influenzaApneumonia

Outcomes • Primaryoutcome:rateoftreatmentfailure(early,late,oratbothtimes)o Earlytreatmentfailure:clinicaldeteriorationwithin72hoursoftreatment(developmentofshock,

needforinvasivemechanicalventilationnotpresentatbaseline,ordeath)o Latetreatmentfailure:radiographicprogression(increaseof≥50%ofpulmonaryinfiltrates

comparedwithbaseline),persistenceofsevererespiratoryfailure(pO2/FiO2<200mmHg,withrespiratoryrate≥30breaths/mininpatientsnotintubated),developmentofshock,needforinvasivemechanicalventilationnotpresentatbaseline,ordeathbetween72and120hoursaftertreatmentinitiation

• Secondaryoutcomes:timetoclinicalstability,lengthofICUandhospitalstays,in-hospitalmortality• Adverseevents:hyperglycemia,superinfection,GIbleeding,delirium,acutekidneyinjury,acutehepatic

failureMethods • ThreeSpanishteachinghospitals–June2004toFebruary2012

• Randomized1:1toeithermethylprednisolone0.5mg/kgIVbolusevery12hours(N=61)orplacebo(N=59)for5days

• Interventionstartedwithin36hoursofhospitaladmission• AntibiotictreatmentaccordingtoIDSA/ATSCAPguidelines• Laboratoryassessmentatpresentation:renalandliverfunctions,electrolytes,bloodglucose,CRP,

hematology,arterialbloodgases• Biomarkerexamination:interleukin(IL)-6,IL-8,IL-10,procalcitonin,andCRPlevelsobtainedonfirstday

andafter3daysand7daysoftreatmentStatistics • Two-sidedtypeIerrorof0.05and80%powertodetectabsolute20%reductionintreatmentfailureused

todeterminesamplesizeof120• Pre-specifiedinterimanalysisplannedat50%ofpatientaccrual• Efficacydataanalyzedforbothintention-to-treatandper-protocolpopulations• Sensitivityanalysisofprimaryoutcomebylogisticregressionmodels• Primaryandsecondaryoutcomesanalyzedbothwithandwithoutanadjustmentforpotential

confounderso Twopredefinedcovariates:yearofadmissionandthecentero Allvariablesforwhichtherewasimbalancebetweenthegroupsatbaseline(p<0.10)

• Statisticaltests:X2test,Fisherexacttest,ttest,nonparametricMann-Whitneytest,Kaplan-Meiermethod(log-ranktest),Coxproportionalhazardregressionmodels,logisticregressionmodelso Calculated95%confidenceintervalso Alltests2-tailedandsignificancesetat0.05

Results • 120patientsrandomizedand112(93%)completedstudy• Baselinecharacteristicscomparable,except:

o LowerlevelsofprocalcitoninandIL-10atday1inmethylprednisolonegroupo Lowerproportionofpatientswithsepticshockinmethylprednisolonegroup

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PrimaryOutcome(Intention-to-treat)

Methylprednisolone(N=61)No.(%)

Placebo(N=59)No.(%)

DifferenceBetweenGroups,%(95%CI)

PValue

NNT

Treatmentfailure 8(13) 18(31) 18(3to32) 0.02 6Earlytreatmentfailure(0-72h)

6(10) 6(10) 0(-10to11) 0.95

Earlymechanicalventilation

4(7) 5(8) 2(-8to11) 0.74

Earlysepticshock 2(3) 2(5) 2(-5to9) 0.68 Death 2(3) 2(3) 0(-6to7) >0.99

Latetreatmentfailure(72-120h)

2(3) 15(25) 22(10to34) 0.001 5

Radiographicprogression

1(2) 9(15) 14(4to23) 0.007 8

Respiratoryfailure 1(2) 5(8) 7(-1to15) 0.11 Latemechanical

ventilation1(2) 4(7) 5(-2to12) 0.20

Latesepticshock 0 4(7) 7(0to13) 0.06 Death 0 0

Posthocsub-analysis:latetreatmentfailure

excludingradiographicprogression

2(3) 8(14) 10(0to20) 0.04 10

NNT–numberneededtotreatSensitivityanalysisofprimaryoutcomeusinglogisticregressionmodelPrimaryOutcome UnadjustedORorHR

(95%CI)PValue AdjustedORorHR

(95%CI)PValue

Treatmentfailure 0.34(0.14-0.87) 0.02 0.33(0.012-0.90) 0.03Latetreatmentfailure(72-120h)

0.10(0.02-0.46) 0.003 0.09(0.02-0.47) 0.004

Radiographicprogression

0.09(0.01-0.76) 0.03 0.09(0.01-0.78) 0.03

HR–hazardratio• Significantdifferenceintimetotreatmentfailurebetweengroupsinfavorofmethylprednisolone(p=0.03)• Secondaryclinicaloutcomesandadverseevents

o Nostatisticallysignificantdifferencesobserved• Inflammatorymarkers

o Atday3,greaterreductioninlevelsofCRPandIL-10inmethylprednisolonegroupo Atday7,greaterreductioninlevelsofCRPremainedinmethylprednisolonegroupo Patientswithapersistentlyhighinflammatoryresponseatday7hadhigherpercentageoftreatment

failure(p=0.003)andin-hospitalmortality(p=0.042)Authors’Conclusion

TheacuteadministrationofmethylprednisolonecomparedwithplacebodecreasedtreatmentfailureandinflammatoryresponseinpatientswithsevereCAPandhighinitialinflammatoryresponse.HypothesizethathavinglesstreatmentfailurecouldleadtodecreasedmortalityinCAP.

Critique Strengths:• Studydesign• Intention-to-treat,per-protocol,

adjustmentforbaselineanalysis• AllsitesusedIDSA/ATS

guidelineforantibiotictherapy• Evaluatedinflammatory

response

Limitations:• Generalizability–limitedtoseverepneumoniawithhigh

inflammatoryresponse• Smallsamplesize• Singledose/durationofmethylprednisolonestudied• Lowertreatmentfailureinplacebogroup(31%)comparedto

studyusedtocalculatesamplesize–lessstatisticalpower• Nolong-termfollow-up

Application CorticosteroidsmaydecreasetreatmentfailureinpatientswithsevereCAPandahighinflammatoryresponse.TodetermineifcorticosteroidsshouldberoutinelyusedinpatientswithCAP,additionalwell-conductedRCTswithlargersamplesizesshouldbeperformed.

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BlumCA,NigroN,BrielM,etal.Adjunctprednisonetherapyforpatientswithcommunity-acquiredpneumonia:amulticentre,double-blind,randomised,placebo-controlledtrial.Lancet.2015;385:1511-8.27Objective Toassesswhethershort-termcorticosteroidtreatmentreducestimetoclinicalstabilityinpatientsadmitted

tothehospitalforcommunity-acquiredpneumoniaStudyDesign Double-blind,multicenter,randomized,placebo-controlledtrialPopulation InclusionCriteria:

• Aged18yearsorolder• HospitaladmissionwithCAP:

o Newinfiltrateonchestradiograph,ando Presenceof≥1ofthefollowingacute

respiratorysignsandsymptoms:cough,sputumproduction,dyspnea,corebodytemperature≥38.0°C,auscultatoryfindingsofabnormalbreathingsoundsorrales,leukocytecount>1000cells/μLor<4000cells/μL

ExclusionCriteria:• ActiveIVdruguse• Acuteburninjury• GIbleedingwithinpast3months• Knownadrenalinsufficiency• Conditionrequiring>0.5mg/kg/dayprednisoneor

equivalent• Pregnancyorbreastfeeding• Severeimmunosuppression(HIVandCD4count<350

cells/μL,immunosuppressivetherapyaftersolidorgantransplantation,neutropenia<500cells/μL,cysticfibrosis,activetuberculosis)

Outcomes • Primaryendpoint:timetoclinicalstability(stablevitalsignsfor≥24hours:temperature≤37.8°C,heartrate≤100beats/minute,systolicbloodpressure≥90mmHg[≥100mmHgifdiagnosedwithhypertension]withoutvasopressorsupport,mentalstatusbacktobaseline,abilityfororalintake,adequateoxygenationonroomair[pO2≥60mmHgorpulseoximetry≥90%)

• Secondaryendpoints:timetoeffectivehospitaldischarge,recurrenceofpneumonia,hospitalre-admission,ICUadmission,all-causemortality,durationoftotalandIVantibiotictherapy,diseaseactivityscoresspecifictoCAP,incidenceofcomplicationsduetoCAP(acuterespiratorydistresssyndrome[ARDS],empyema,persistenceofpneumonia),corticosteroidsideeffects(hyperglycemia,hypertension,delirium,nosocomialinfections,weightgain)

Methods • SeventertiarycarehospitalsinSwitzerland–December1,2009toMay21,2014• Randomized1:1toreceiveeitherprednisone50mgorallydailyorplacebofor7days

o Variableblocksizesoffourtosixandpatientsstratifiedatthetimeofstudyentrybystudycenter• AntibiotictherapyaccordingtoIDSA/ATSCAPguidelines• Patientsassessedforclinicalstabilityevery12hoursduringhospitalstay• Routinelaboratorytestsofinflammatorymarkers(procalcitonin,CRP,WBCcount)weredoneondays1,

3,5,7,andbeforedischarge• Fourbloodglucosemeasurementsperday• Follow-uptelephoneinterviewsforsecondaryoutcomesafterdischargedoneonday30

Statistics • Calculatedneededsamplesizeof800patientsfollowedfor≥14daystoachievestatisticalpowerof85%• UnadjustedHRand95%CIusingCoxproportionalhazardsregressionforprimaryendpoint• Sensitivityanalysis:primaryoutcomeanalysisrepeatedonper-protocolpopulation,multivariableCox

proportionalhazardsmodelfittedwithtreatmentgroupandpre-specifiedpotentialconfounders(patientageandPSIscore)

• Pre-specifiedsubgroupanalysis:patientage,initialCRPconcentration,historyofCOPD,PSIclass,bloodculturepositivity

• Secondaryendpoints:calculatedunadjustedandadjusted(forpatientageandPSIscore)estimateoftheeffectsizeandcorresponding95%CIsusinglinear,logistic,orCoxproportionalhazardsregression

• Two-sided95%CIsandtwo-sided5%significancelevelResults • 802eligiblepatientsinitiallyenrolled:392prednisonegroupand393placebogroup

• Baselinecharacteristicswellbalanced(highburdenofcomorbidities:diabetes,COPD,chronicheartfailure,chronicrenalinsufficiency;approximatelyhalfpatientsinhigh-riskPSIclassesIVandV)

Outcome Prednisone(N=392)

Placebo(N=393)

HR,OR,orDifference(95%CI)

PValue

PrimaryendpointTimetoclinicalstability(days),intention-to-treat

3.0(2.5-3.4) 4.4(4.0-5.0) HR:1.33(1.15to1.50) <0.0001

Timetoclinicalstability(days),per-protocol

3.0(2.5-3.2) 4.4(4.0-5.0) HR:1.35(1.16to1.56) <0.0001

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SecondaryendpointsTimetoeffectivehospitaldischarge(days)

6.0(6.0-7.0) 7.0(7.0-8.0) HR:1.19(1.04to1.38) 0.012

Recurrentpneumonia 23(6%) 18(5%) OR:1.30(0.69to2.44) 0.42Hospitalre-admission 32(9%) 28(8%) OR:1.14(0.67to1.93) 0.64ICUadmission 16(4%) 22(6%) OR:0.72(0.37to1.39) 0.32TimetoICUadmission(days) 1(1-1) 1(1-1) HR:0.73(0.38to1.38) 0.33TimeinICU(days) 3(2-4) 3(1-12) Difference:-0.2

(-8.7to8.2)0.96

All-causemortality 16(4%) 13(3%) OR:1.24(0.59to2.62) 0.57Totaldurationofantibiotictreatment(days)

9.0(7.0-11.0) 9.0(7.0-12.0) Difference:-0.47(-1.21to0.27)

0.22

Intravenousantibiotictreatment(days)

4.0(3.0-6.0) 5.0(3.0-7.0) Difference:-0.89(-1.57to0.20)

0.011

CAPscore*atday5(points) 59(41-78) 58(40-74) Difference1.00(-5.23to7.23)

0.75

CAPscore*atday30(points) 83(67-88) 84(72-89) Difference-1.00(-4.38to2.38)

0.56

Dataaremedian(interquartilerange[IQR])ornumber(%)*Disease-specificscoreforCAPrangesfrom0to100,0markingtheworstscore• Noevidenceofeffectmodificationindifferentpre-specifiedsubgroups• CRPconcentrationssignificantlylowerinprednisonegroupthaninplacebogroupondays3,5,and7Complicationsandadverseeventsuntilday30

Outcome Prednisone(N=392)

Placebo(N=393)

ORorDifference(95%CI)

PValue

ComplicationsduetoCAP 11(3%) 22(6%) 0.49(0.23to1.02) 0.056Weightchange(kg) -1.0

(-3.0to1.0)-1.0(-3.0to0.4)

Difference:0.34(-0.56to1.25)

0.46

Adverseeventscompatiblewithcorticosteroids,any

96(24%) 61(16%) 1.77(1.24to2.52) 0.0020

In-hospitalhyperglycemianeedinginsulintreatment

76(19%) 43(11%) 1.96(1.31to2.93) 0.0010

Otheradverseevent,any 20(5%) 34(9%) 0.57(0.32to1.00) 0.052Dataaremedian(IQR)ornumber(%)• Numberneededtoharm(NNH)foranyadverseeventscompatiblewithcorticosteroidsandNNHforin-

hospitalhyperglycemia:13• Otheradverseeventscompatiblewithcorticosteroidswererareandsimilarbetweengroups

o Ratesofnewneedforinsulintreatmentatday30werelowinbothgroupsAuthors’Conclusion

Findingssupportthehypothesisthatadministrationofcorticosteroidsmodulatestheimmuneresponseandtherebyshortenstimetoclinicalstabilityandlengthofhospitalstay.Resultsconfirmdataofvariousclinicaltrials,systematicreviews,andmeta-analysesshowingabeneficialeffectofcorticosteroidsinCAP.

Critique Strengths:• Studydesign• Largestandmostconclusiverandomized

placebo-controlledtrialtodate• AllseverityclassesofCAPincluded• Sensitivityanalysis• 30-dayfollow-up• Oralprednisone–easeofadministration

Limitations:• Limitedgeneralizabilitytoonlyhospitalizedpatients• Notpoweredformortality• Slightlysmallersamplesizethanpredicted• Limitationsofprimaryendpointoftimetoclinical

stability(combinedendpointincludingseveralparameters)

• Corticosteroid-inducedhyperglycemiamayhaveledtoun-blinding

Application CorticosteroidsappeartoreducethetimetoclinicalstabilityandmayimprovetheclinicalcourseofdiseaseinpatientshospitalizedwithCAP.Hyperglycemiaisthemostcommonadverseeventassociatedwithshort-termcorticosteroidtreatment.

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SiemieniukR,MeadeOM,Alonso-CoelloP,etal.Corticosteroidtherapyforpatientshospitalizedwithcommunity-acquiredpneumonia:asystematicreviewandmeta-analysis.AnnInternMed.2015;163(7):519-28.28Objective Toexaminetheeffectofadjunctivecorticosteroidtherapyonmortality,morbidity,anddurationof

hospitalizationinpatientswithcommunity-acquiredpneumoniaStudyDesign Systematicreviewandmeta-analysisofrandomizedcontrolledtrialsPopulation InclusionCriteria:

• AdultswithCAPassignedtooralorIVcorticosteroidtherapyversusplaceboornotreatment

• Studiesreportedon≥1outcomeofinterest

ExclusionCriteria:• Ventilator-associatedpneumonia,aspiration

pneumonia,orPneumocystisjiroveciipneumonia

• StudieslimitedtopatientswithCOPDOutcomes All-causemortality,needformechanicalventilation,ICUadmission,developmentofARDS,durationof

hospitalization,timetoclinicalstabilityMethods • PreviousCochranereviewwithsimilarinclusioncriteriaidentifiedstudiesuptoDecember201029

• MEDLINE,EMBASE,andtheCochraneCentralRegisterofControlledTrialssearchedfromJanuary1,2010toMay24,2015usingtheMedicalSubjectHeadingterms“pneumonia”and“corticosteroids”

• Ifstudyreportedoutcomesatmorethanonetimepoint,datawasabstractedclosestto30daysfromrandomization

• GradingofRecommendationsAssessment,Development,andEvaluation(GRADE)systemusedtoassesscertaintyofevidenceforeachoutcomeandforentirebodyofevidence

Statistics • Random-effectsmodels(Mantel-Haenszelriskratiosandmeandifferences)• Nonparametricdataconvertedtomeansandstandarddeviations• Sensitivityanalysis:omittingstudiesinwhichmeanswereestimatedfrommediansandomittingone

studythatwasstoppedearlyforalargeeffect• HeterogeneityassessedusingvisualinspectionoftheresultsandtheI2statistic• 95%confidenceintervalscalculated

Results • ThirteenRCTsidentified(ninestudiesnotincludedinthepreviousreview)• Samplesizesrangedfrom30-784hospitalizedpatients• Corticosteroids:dexamethasone,prednisone,prednisolone,methylprednisolone,orhydrocortisone• Durationoftreatmentrangedfromonedoseto10days• Follow-uprangedfromin-hospitalto60daysfromenrollment• Studiesoftenexcludedpatientsathighriskforadverseeffectsfromcorticosteroids(GIhemorrhagewithin

3months,immunosuppression,pregnantwomen)

Outcome Corticosteroids(n/N)

Control(n/N)

RR(95%CI)

I2(%)

CertaintyofEvidence

NNT

All-causemortality(12studies,N=1974)

7.9%(79/997) 5.3%(52/977)

0.67(0.45-1.01)

6 Moderate

Mechanicalventilation(5studies,N=1060)

3.1%(17/550) 5.7%(29/510)

0.45(0.26-0.79)

0 Moderate 39

ICUadmission(3studies,N=950)

5.3%(25/476) 7.6%(36/474)

0.69(0.46-1.03)

0 Moderate

ARDS(4studies,N=945)

0.42%(2/473) 3.0%(14/472)

0.24(0.10-0.56)

0 Moderate 39

RR–riskratio

Outcome Corticosteroids

Control

MeanDifference,days(95%CI)

I2(%)

CertaintyofEvidence

Durationofhospitalization(9studies,N=1644)

-2.96(-5.18to-0.75)

94

Durationofhospitalization(3studiesatlowriskofbias,N=1288)

7.9days 9.1days

-1.00(-1.79to-0.21)

0 High

TimetoClinicalStability(5studies,N=1180)

3.5days

4.7days -1.22(-2.08to-0.35)

38 High

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SubgroupanalysisbypneumoniaseverityOutcome Corticosteroids

(n/N)Control(n/N)

RR(95%CI)

I2(%)

NNT

All-causemortality Severepneumonia(6studies,N=388)

7.4%(16/215) 22%(38/173) 0.39(0.20-0.77) 0 7

Notseverepneumonia

(6studies,N=1586)

4.7%(36/762) 5.0%(41/824) 1.00(0.79-1.26) 0

Mechanicalventilation Severepneumonia(3studies,N=230)

11.1%(15/135) 18.9%(18/95) 0.54(0.50-0.58) 0 13

Notseverepneumonia

(2studies,N=830)

0.48%(2/415) 2.7%(11/415) 0.18(0.08-0.43) 0 45

Adverseevents

Outcome Corticosteroids(n/N)

Control(n/N)

RR(95%CI)

I2(%)

Hyperglycemiarequiringtreatmenta(6studies,N=1534)

15.2%(119/784) 8.7%(65/750) 1.49(1.01-2.19) 6

Gastrointestinalhemorrhage(7studies,N=1223)

1.1%(7/628) 1.7%(10/595) 0.82(0.33-1.62) 0

Severeneuropsychiatriccomplications(4studies,N=1217)

1.8%(11/602) 1.3%(8/615) 1.65(0.88-3.08) 0

Rehospitalization(2studies,N=1089)

7.2%(39/543) 6.3%(35/546) 1.12(0.59-2.13) 0

aHighcertaintyofevidence• NNHforhyperglycemiarequiringtreatment:16• Subgroupanalyses:riskofbias,yearofpublication,severityofpneumoniaatenrollment,durationof

corticosteroidtherapydidnotshowaconsistentinteractionacrossoutcomes• Sensitivityanalyses:omissionofonestudythatwasstoppedearlyforbenefithadnoappreciableeffecton

theresults;omissionofstudiesinwhichmeanswereestimatedfrommedianvaluesforcontinuousoutcomehadnegligibleeffectontheresults

Authors’Conclusion

Resultsprovidehigh-qualityevidenceforthebenefitsofadjunctivecorticosteroidsinCAPanddecisionmakersshouldstronglyconsidertheuseofcorticosteroidsinpatientshospitalizedwithCAP,particularlyinthosewhoaremoreseverelyaffected.Overallcertaintyofavailableevidenceratedashighforthebenefitofadjunctivecorticosteroids.

Critique Strengths:• Assessedeligibilityandrisk

ofbiasinduplicate• Rigorousliteraturesearch• AppliedGRADEsystemto

evaluatecertaintyofevidence

• Subgroupandsensitivityanalyses

Limitations:• Useofvariouscorticosteroids,routesofadministration,doses,and

treatmentduration• Generalizability• Someoutcomeswithsmallnumberofevents(needformechanical

ventilation,admissiontoICU,ARDS)• Publicationbiascouldnotberuledout• Highdegreeinheterogeneityinprimaryanalysisofdurationof

hospitalization• “Rapidmeta-analysis”methodnewandnotyetvalidated

Application CorticosteroidsmaybenefitseveraloutcomesinCAP,withthemajoradverseeventinshort-termtreatmentbeinghyperglycemia.LargerRCTscouldimprovecertaintyofthebenefitofadjunctivecorticosteroidsinCAP.Additionaltrialsareneededtodetermineoptimalcorticosteroid,dose,durationoftreatment,andtheidealpatientpopulation.

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FUTURESTUDIESI. ExtendedSteroidinCAP(e)(ESCAPe)30

A. Objective:todetermineifprovidingearlytreatmentwithmethylprednisolonewillimprovesurvivalincriticallyillpatientswithsevereCAP

B. Primaryoutcome:all-causemortalityat60daysC. Intervention:methylprednisolone40mg/dayfor7days,then20mg/dayfor7days,then6daysoftaperingdose(12

mg/dayand4mg/day)D. Currentlyrecruitingparticipants

1. Estimatedcompletiondate:January2018

II. Santeon-CAP;DexamethasoneinCommunity-acquiredPneumonia31A. Objective:toinvestigatethebeneficialeffectsofadjunctivedexamethasoneinpatientshospitalizedforCAPwithan

aimtoassesswhichpatientsbenefitthemostfromtreatmentB. Primaryoutcome:lengthofhospitalstayC. Intervention:dexamethasone6mgdailyfor4daysD. Currentlyrecruitingparticipants

1. Estimatedcompletiondate:December2015

III. CorticosteroidTherapyforSevereCommunity-AcquiredPneumonia32A. Objective:toassesstheefficacyofadjunctivemethylprednisoloneinpatientswithCAPB. Primaryoutcome:all-causemortalityat30daysC. Intervention:methylprednisolone80mg/dayfor3days,then40mg/dayfor3daysD. Currentlyrecruitingparticipants

1. Estimatedcompletiondate:May2017

IV. Community-AcquiredPneumonia:EvaluationofCorticosteroids(CAPE_COD)33A. Objective:todetermineifcorticosteroidsimprovesurvivalincritically-illpatientswithsevereCAPB. Primaryoutcome:all-causemortalityat28daysC. Intervention:hydrocortisone200mg/daybycontinuousIVinfusionfor4or7days,then100mg/dayfor2or4days,

andthen50mg/dayfor2or3days(durationchosenuponpatientinitialimprovement)D. Notyetopenforrecruitment

1. Estimatedcompletiondate:December2018

V. CorticosteroidsinCommunity-acquiredPneumonia34A. Objective:todeterminetheefficacyoftheadditionofcorticosteroidtherapytoantibioticsinchildrenhospitalized

withCAPB. Primaryoutcome:lengthofhospitalstayC. Intervention:dexamethasone0.6mg/kg/dayormethylprednisolone1mg/kg/dayD. Notyetopenforrecruitment

1. Estimatedcompletiondate:March2017

CONCLUSIONANDRECOMMENDATIONSI. Shouldadjunctivecorticosteroidsbeusedinthetreatmentofcommunity-acquiredpneumonia?

A. NumerousstudiesinvestigatingthepotentialbenefitofadjunctivecorticosteroidtherapyinthetreatmentofCAP1. Mostaresmall,singlesitestudies2. Variousoutcomesstudied3. Variousanti-inflammatoryagents,doses,anddurationoftreatment4. Manystudiesshowedabenefitwithcorticosteroids

a. Limitedstudiespoweredtoshowmortalitybenefit5. Hyperglycemiamostcommonadverseeffectobserved6. Limitationswithearliermeta-analyses

a. MortalitybenefitonlyinsubgroupanalysisofsevereCAP(N=214)25i. Possiblepublicationbias

b. Reductioninmortalityinmeta-analysisofonlyfourtrialsandqualityofevidencedown-gradedduetomoderateheterogeneity18i. Resultsshouldbeinterruptedwithcaution

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B. RecentRCTsandmeta-analysisconfirmbeneficialeffectsofcorticosteroidsasadjunctivetreatmentinCAPwithlimitedadverseevents1. Positiveoutcomes

a. Decreaseintreatmentfailureb. Decreasetimetoclinicalstabilityby1day

i. Maytranslatetodecreasedlengthofhospitalstay(i) Economicbenefit(ii) Patientatdecreasedriskofnosocomialinfectionsanddeepveinthrombosis

2. Mortalitybenefitobservedinmeta-analysissubgroupanalysisofpatientswithsevereCAP

II. AdditionalareasofresearchA. Specificpopulationwithpotentialforthemostbenefitfromcorticosteroidtherapy

1. Pneumoniaseverity2. Outpatient3. Elderly

B. Optimalcorticosteroidagent,dose,anddurationoftreatment

III. ClinicalrecommendationsA. FurtherstudiesareneededbeforecorticosteroidsshouldbebroadlyrecommendedasadjunctivetreatmentofCAPB. AdjunctivecorticosteroidsshouldbeconsideredinpatientshospitalizedwithsevereCAP

1. PSIriskclassIVandVorCURB-65score≥22. Prednisone50mgorallydailyormethylprednisolone0.5mg/kgIVevery12hours3. Treatmentdurationof5-7days

C. Evaluatepatient-specificrisksversusbenefitsofcorticosteroidtherapy

REFERENCES

1. RestrepoMI,MortensenEM,VelezJA.Acomparativestudyofcommunity-acquiredpneumoniainpatientsadmittedtothewardandtheICU.Chest.2008;133:610-7.

2. CentersforDiseaseControlandPrevention.FastStats.Deathsandmorality.http://www.cdc.gov/nchs/faststats/pneumonia.htm.AccessedDecember12,2015.

3. BlackfordMG,GloverML,ReedMD.Chapter85.LowerRespiratoryTractInfections.In:DiPiroJT,TalbertRL,YeeGC,MatzkeGR,WellsBG,PoseyL.eds.Pharmacotherapy:APathophysiologicalApproach,9e.NewYork,NY:McGraw-Hill;2014.Availableat:http://accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu/content.aspx?bookid=689&sectionid=45310531.AccessedDecember12,2015.

4. ThomasCP,RyanM,ChapmanJD,etal.IncidenceandcostofpneumoniainMedicarebeneficiaries.Chest.2012;142:973-81.5. VanderPollT,OpalSM.Pathogenesis,treatment,andpreventionofpneumococcalpneumonia.Lancet.2009;374:1543-56.6. EndemanH,MeijvisSC,RijkersGT,etal.Systemiccytokineresponseinpatientswithcommunity-acquiredpneumonia.EurRespirJ.

2011;37(6):1431-8.7. MenendezR,CavalcantiM,ReyesS,etal.Markersoftreatmentfailureinhospitalizedcommunity-acquiredpneumonia.Thorax.

2008;63(5):447-52.8. SalluhJ,PovoaP,SoaresM,etal.Theroleofcorticosteroidsinseverecommunity-acquiredpneumonia:asystematicreview.CritCare.

2008;12(3):R76.Availableat:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2481473/.AccessedDecember12,2015.9. MandellLA,WunderinkRG,AnzuetoA,etal.InfectiousDiseasesSocietyofAmerica/AmericanThoracicSocietyconsensusguidelineson

themanagementofcommunity-acquiredpneumoniainadults.CID.2007;44:S27-72.10. WatkinsRR,LemonovichTL.Diagnosisandmanagementofcommunity-acquiredpneumoniainadults.AmFamPhysician.

2011;83(11):1299-1306.11. FineMJ,AubleTE,YealyDM,etal.Apredictionruletoidentifylow-riskpatientswithcommunity-acquiredpneumonia.NEnglJMed.

1997;336:243-50.12. LimWS,BaudouinSV,GerogeRC,etal.BritishThoracicSocietyguidelinesforthemanagementofcommunityacquiredpneumoniain

adults:update2009.Thorax.2009;64(SupplIII):iii1-55.13. NationalInstituteforHealthandClinicalExcellence(NICE).Pneumonia:diagnosisandmanagementofcommunity-andhospital-

acquiredpneumoniainadults.2014.NationalClinicalGuidelineCentre.Availableat:https://www.nice.org.uk/guidance/cg191.AccessedDecember26,2015.

14. TheDutchWorkingPartyonAntibioticPolicy(SWAB)/DutchAssociationofChestPhysicians(NVALT).Dutchguidelinesonthemanagementofcommunity-acquiredpneumoniainadults.SecretariatSWAB;2011.Availableat:http://www.nvalt.nl/uploads/tu/wM/tuwMzyy_4f79AWZcyuYvPQ/SWAB-richtlijn-Community-Acquired-Pneumonia-in-Adults-Nov-2011-def.pdf.AccessedDecember26,2015.

15. RhenT,CidlowskiJA.Antiinflammatoryactionofglucocorticoids–newmechanismsforolddrugs.NEnglJMed.2005;353(16):1711-23.16. BusilloJM,Cidlowski.ThefiveRsofglucocorticoidactionduringinflammation:ready,reinforce,repress,resolve,andrestore.Trends

EndocrinolMetab.2013;24(3):109-19.17. RittirschD,FlierlMA,WardPA.Harmfulmolecularmechanismsinsepsis.NatRevImmunol.2008;8:776-87.

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18. ChengM,PanZ,YangJ,etal.Corticosteroidtherapyforseverecommunity-acquiredpneumonia:ameta-analysis.RespirCare.2014;59(4):557-63.

19. Lexi-DrugsTM.Lexi-CompOnlineTM[databaseonline].Hudson,OH:Lexi-Comp,Inc.;2014.Availableathttp://online.lexi.com.ezproxy.lib.utexas.edu.AccessedDecember26,2015.

20. DietrichE,SmithSM,GumsJG.Chapter59.LowerAdrenalGlandDisorders.In:DiPiroJT,TalbertRL,YeeGC,MatzkeGR,WellsBG,PoseyL.eds.Pharmacotherapy:APathophysiologicalApproach,9e.NewYork,NY:McGraw-Hill;2014.Availableat:http://accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu/content.aspx?bookid=689&sectionid=45310511.AccessedDecember19,2015.

21. ConfalonieriM,UrbinoR,PotenaA,etal.Hydrocortisoneinfusionforseverecommunity-acquiredpneumonia:apreliminaryrandomizedstudy.AmJRespirCritCareMed.2005;171:242-8.

22. Garcia-VidalC,CalboE,PascualV,etal.Effectsofsystemicsteroidsinpatientswithseverecommunity-acquiredpneumonia.EurRespirJ.2007;30:951-6.

23. SnijdersD,DanielsJ,GraaffCS,etal.Efficacyofcorticosteroidsincommunity-acquiredpneumonia.AmJRespirCritCareMed.2010;181:975-82.

24. MeijvisS,HardemanH,RemmeltsH,etal.Dexamethasoneandlengthofhospitalstayinpatientswithcommunity-acquiredpneumonia:arandomised,double-blind,placebo-controlledtrial.Lancet.2011;377:2023-30.

25. NieW,ZhangY,ChengJ,etal.Corticosteroidsinthetreatmentofcommunity-acquiredpneumoniainadults:ameta-analysis.PLoSOne.2012;7(10):e47926.

26. TorresA,SibilaO,FerrerM,etal.Effectofcorticosteroidsontreatmentfailureamonghospitalizedpatientswithseverecommunity-acquiredpneumoniaandhighinflammatoryresponse.JAMA.2015;313(7):677-86.

27. BlumCA,NigroN,BrielM,etal.Adjunctprednisonetherapyforpatientswithcommunity-acquiredpneumonia:amulticentre,double-blind,randomised,placebo-controlledtrial.Lancet.2015;385:1511-8.

28. SiemieniukR,MeadeOM,Alonso-CoelloP,etal.Corticosteroidtherapyforpatientshospitalizedwithcommunity-acquiredpneumonia:asystematicreviewandmeta-analysis.AnnInternMed.2015;163(7):519-28.

29. ChenY,LiK,PuH,etal.Corticosteroidsforpneumonia(review).CochraneDatabaseSystRev.2011:CD007720.Availableat:http://onlinelibrary.wiley.com.ezproxy.lib.utexas.edu/doi/10.1002/14651858.CD007720.pub2/abstract.AccessedNovember29,2015.

30. Evaluatethesafetyandefficacyofmethylprednisoloneinhospitalizedveteranswithseverecommunity-acquiredpneumonia(ESCAPe).Availableat:https://clinicaltrials.gov/ct2/show/NCT01283009.AccessedDecember26,2015.

31. Santeon-CAP;DexamethasoneinCommunity-acquiredPneumonia.Availableat:https://clinicaltrials.gov/ct2/show/NCT01743755?term=community+acquired+pneumonia&rank=7.AccessedDecember26,2015.

32. Efficacyofmethylprednisoloneinseverecommunity-acquiredpneumonia,amulti-centerrandomizedcontrolledtrial.Availableat:https://clinicaltrials.gov/ct2/show/NCT02552342?term=pneumonia+and+corticosteroids&rank=16.AccessedDecember26,2015.

33. Effectsoflow-dosecorticosteroidsonsurvivalofseverecommunity-acquiredpneumonia(CAPE_COD).Availableat:https://clinicaltrials.gov/ct2/show/NCT02517489?term=community+acquired+pneumonia&rank=2.AccessedDecember26,2015.

34. Corticosteroidsincommunity-acquiredpneumonia.Availableat:https://clinicaltrials.gov/ct2/show/NCT01631916?term=community+acquired+pneumonia&rank=6.AccessedDecember26,2015.

Table4.AbbreviationsARDS AcuterespiratorydistresssyndromeBTS BritishThoracicSocietyBUN BloodureanitrogenCAP Community-acquiredpneumoniaCI ConfidenceintervalCOPD ChronicobstructivepulmonarydiseaseCOX-2 Cyclooxygenase-2cPLA2α CytosolicphospholipaseA2αCRH Corticotropin-releasinghormoneCRP C-reactiveproteinED EmergencydepartmentERS/ESCMID EuropeanRespiratorySociety/EuropeanSocietyofClinicalMicrobiologyandInfectiousDiseasesGI GastrointestinalGRADE GradingofRecommendationsAssessment,Development,andEvaluationHIV HumanimmunodeficiencyvirusHR HazardratioICU IntensivecareunitIDSA/ATS InfectiousDiseasesSocietyofAmerica/AmericanThoracicSocietyIL InterleukinIQR InterquartilerangeIV IntravenousMAPK Mitogen-activatedproteinkinase

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MDR Multi-drugresistantNF-κB Nuclearfactor-κBNICE NationalInstituteforHealthandCareExcellenceNNH NumberneededtoharmNNT NumberneededtotreatNSAID Non-steroidalanti-inflammatorydrugOR OddsratioPaO2/FiO2 Arterialoxygenpressure/fractionofexpiredoxygenpO2 PartialpressureofoxygenPSI PneumoniaSeverityIndexRCT RandomizedcontrolledtrialRR RiskratioUS UnitedSatesWBC Whitebloodcell

APPENDICESAppendixA:ClinicalIndicationsforExtensiveDiagnosticTesting9

Indication Bloodculture

Sputumculture

LegionellaUAT

PneumococcalUAT

Other

ICUadmission X X X X XFailureofoutpatientantibiotictherapy X X X Cavitaryinfiltrates X X XLeukopenia X X Activealcoholabuse X X X X Chronicsevereliverdisease X X Severeobstructive/structurallungdisease

X

Asplenia(anatomicorfunctional) X X Recenttravel(withinpast2weeks) X XPositiveLegionellaUATresult X - PositivepneumococcalUATresult X X - Pleuraleffusion X X X X XUAT–urinaryantigentestAppendixB:PneumoniaSeverityIndexforCommunity-AcquiredPneumonia11

RiskFactor PointsDemographicsMen Age(years)Women Age(years)–10Nursinghomeresident +10ComorbiditiesNeoplasm +30Liverdisease +20HeartFailure +10Stroke +10Renalfailure +10PhysicalexamAlteredmentalstatus +20Respiratoryrate≥30breaths/min +20Systolicbloodpressure<90mmHg +20Temperature<35°Cor≥40°C +15Pulse≥125beats/min +10

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LaboratoryandradiographicfindingsArterialpH<7.35 +30Bloodureanitrogen>30mg/dL +20Sodium<130mmol/L +20Glucose≥250mg/dL +10Hematocrit<30% +10Partialpressureofarterialoxygen<60mmHg +10Pleuraleffusion +10AppendixC:EmpiricalAntimicrobialTreatmentforCAP9

PatientCharacteristics RecommendationsOutpatientandpreviouslyhealthyandnouseofantibioticsinlast3months

• Macrolide• Alternative:doxycycline

Outpatientwithpresenceofcomorbidities(chronicheart,lung,liver,orrenaldisease;diabetes;alcoholism;malignancies;asplenia;immunosuppressingconditions;useofantibioticswithinpast3months)

• Respiratoryfluoroquinolone(levofloxacin,moxifloxacin)• Beta-lactamplusmacrolide

Outpatientinregionswith>25%ofinfectionswithhigh-level(MIC≥16µL/mL)macrolide-resistantS.pneumoniae

Considerrespiratoryfluoroquinoloneorbeta-lactamplusmacrolide

Inpatient,non-ICU • Respiratoryfluoroquinolone• Beta-lactamplusmacrolide

Inpatient,ICU Betalactam(cefotaxime,ceftriaxone,orampicillin-sulbactam)pluseitherazithromycinorrespiratoryfluoroquinolone

AppendixD:GlucocorticoidAnti-InflammatoryMechanismsofAction15

n engl j med 353;16 www.nejm.org october 20, 2005

The new england journal of medicine

1718

(eNOS).17 Glucocorticoids stimulate the activity ofphosphatidylinositol-3-hydroxykinase (PI3K) in aglucocorticoid receptor–dependent, but transcrip-tion-independent, manner in human endothelial

cells. Activation of PI3K leads to phosphorylationof Akt. Phosphorylated Akt then phosphorylatesand activates eNOS, resulting in the production ofnitric oxide. In mice, glucocorticoid-induced acti-

Figure 4. Partial Molecular Architecture Underlying the Glucocorticoid-Induced Antagonism of Inflammation.

Inflammatory pathways are characterized by positive feedback loops (i.e., cytokines activate NF-kB, which in turn stimulates the synthesis of more cytokines) and by redundancy (i.e., cytokines also activate c-Jun–Fos). The glucocorticoid receptor inhibits these pathways at multiple points by directly blocking the transcription of inflammatory proteins by NF-kB and activator protein 1 and by inducing the expression of antiinflammatory proteins such as IkB, annexin I, and MAPK phosphatase I. 5-LOX denotes 5-lipoxygenase, and COX-2 cyclooxygenase 2. Red lines denote in-hibition, and black arrows activation. An interactive version of this figure is available with the full text of the article at www.nejm.org.

Glucocorticoidreceptor

Annexin I

cPLA2a

COX-2

NF-kB

c-Jun Fos

Jun N-terminalkinase

MAPKphosphatase I

MAPK-interactingkinase

IkB kinase

IkB

MAPKs

Calcium kinase II5-LOX

Cortisol

Arachidonic acid

Prostaglandins

Inflammation

Leukotrienes

Phospholipids

Protein kinase Inflammatorytranscription factor

EnzymeMinor pathways

Core pathways

Inhibitory proteinProteinphosphatase

CytokinesBacteriaViruses

Free radicalsUltraviolet radiation

CytokinesCytokine receptors

Chemotactic proteinsAdhesion molecules

CytokinesHormonesMitogensEndotoxinAntigen

CytokinesGrowth factors

MitogensBacteriaViruses

Ultraviolet radiation

CytokinesCytokine receptors

Chemotactic proteinsAdhesion molecules

CollagenasesMatrix metalloproteinases

Repression by means of negative glucocorticoid-responsive elements

Corticotropin-releasing hormonePro-opiomelanocortin

OsteocalcinProliferinKeratins

Interleukin-1b

Calcium/calmodulin–dependent kinase II

Calcium

HOC

CH2OH

OOH

O

The New England Journal of Medicine Downloaded from nejm.org at UT AUSTIN on December 24, 2015. For personal use only. No other uses without permission.

Copyright © 2005 Massachusetts Medical Society. All rights reserved.

PointTotal RiskClass<51 I51-70 II71-90 III91-130 IV>130 V

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AppendixE:GlucocorticoidPharmacology19

Glucocorticoid Dosing Routesofadministration

Pharmacokinetics Comments

Hydrocortisone 15-240mgQ12h(Nodosageadjustments)

PO,IM,IV • Absorption:rapid• Metabolism:hepatic(minorsubstrateCYP3A4,P-

glycoproteinsubstrate)• Half-life:8-12hours• Excretion:urine

Off-labelsepticshockindication

Cortisoneacetate 25-300mg/day(PO)(Nodoseadjustments,usewithcautioninrenalandhepaticimpairment)

PO,IM • Absorption:readily• Distribution:muscles,liver,skin,intestines,kidneys• Metabolism:hepatictoactivemetabolite

hydrocortisone(cortisol)• Bioavailability:interindividualvariability:43.7%• Half-lifeelimination:0.5hours• Excretion:urineandfeces

Prednisone 5-60mgdaily(Nodoseadjustments)

PO • Absorption:50-90%• Metabolism:hepatictoprednisolone(minorCYP3A4

substrate,weak/moderateCYP2C19inducer)• Half-life:2-3hours• Excretion:urine

Off-labelCOPDexacerbationindication

Prednisolone 5-60mgdaily(Nodosageadjustments,usewithcautioninrenalimpairment)

PO,IM,IV,intra-articular,intradermal,softtissueinjection

• Metabolism:primaryhepatic(minorCYP3A4substrate),alsometabolizedinmosttissues

• Half-lifeelimination:3.6hours• Excretion:primarilyurine

Off-labelCOPDexacerbationindication

Methylprednisolone • Oral:2-60mg/day• IM(sodiumsuccinate):10-80mg/day• IM(acetate):10-80mgQ1-2weeks• IV(sodiumsuccinate):10-40mgover

severalminutesandrepeatedIVorIMatintervalsdependingonclinicalresponse

(Nodosageadjustments,usecautioninrenalfailure)

PO,IM,IV • Distribution:0.7-1.5L/kg• Metabolism:minorCYP3A4substrate,weakCYP2C8

inhibitor• Half-lifeelimination:3-2.5hours(reducedinobese)• Excretion:reducedinobese

Off-labelCOPDexacerbationindication

Dexamethasone • Oral,IM,IV:0.75-9mg/dayQ6-12h(individeddoses)

• Intra-articular,intralesional,softtissue:0.4-6mg/day

(Nodosageadjustments,usewithcautioninrenalimpairment)

PO,IM,IV,intra-articular,intradermal,softtissueinjection

• Absorption:oral61-86%• Metabolism:hepatic(majorCYP3A4substrate,P-

glycoproteinsubstrateandinhibitor,weak/moderateCYP2A6,CYP2B6,CYP2C9inducer,weakCYP3A4inducer,P-glycoproteinandUGT1A1inducer

• Half-lifeelimination:oral~4hours;IV1-5hours• Excretion:urine