CLINICAL YEAR IN REVIEW - American Thoracic Society · CLINICAL YEAR IN REVIEW ... AstraZeneca LP,...

CLINICAL YEAR IN REVIEW

American Thoracic Society International Conference

Where today’s science meets tomorrow’s careTM

May 19 - May 24Washington, DC

conference.thoracic.org

SECTION1C

YIR

David J. Lederer, MD, MSColumbia University Medical CenterDivision of Pulmonary, Allergy, and Critical Care MedicineNew York, NY

Dee Walker Ford, MD, MSCRMedical University of South CarolinaDepartment of Pulmonary and Critical Care MedicineCharleston, SC

Victor E. Ortega, MD, PhDWake Forest School of MedicineDepartment of Pulmonary, Critical Care, Allergy, and Immunologic MedicineWinston-Salem, NC

A1 SUNDAY, MAY 21•NewToolstoSupportAcuteRespiratoryFailure............................................02•GeneralCriticalCare.......................................................................................06•TheBrainandCriticalCare..............................................................................10•SleepDisorderedBreathing..............................................................................13B1 MONDAY, MAY 22•ILD.....................................................................................................................16•COPD...............................................................................................................20•PulmonaryVascularDiseases...........................................................................24•Asthma..............................................................................................................28

This session and the International Conference are supported by educational grants fromActelion Pharmaceuticals US, Inc., AstraZeneca LP, Teva Pharmaceuticals.

All CME sessions have been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME)

and are free of the control of commercial interest.

C1 TUESDAY, MAY 23•TuberculosisandNontuberculousMycobacteria............................................31•TheHostMicrobiomeinLungDisease...........................................................34•Bronchiectasis.................................................................................................38•LungTransplantation.......................................................................................41This session and the International Conference are supported by an educational grant from

Insmed Incorporated.All CME sessions have been planned and implemented in accordance with the Essential

Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) and are free of the control of commercial interests.

D1 WEDNESDAY, MAY 24•ThoracicOncology............................................................................................45•ThoracicImaging..............................................................................................50•HealthDisparities..............................................................................................53•PalliativeCare...................................................................................................56

TABLE OF CONTENTS

MODERATORS

CLINICAL YEAR IN REVIEW 20172

NEW TOOLS TO SUPPORT ACUTE RESPIRATORY FAILURESUNDAY, MAY 21

Daniel Brodie, MDColumbiaUniversityMedicalCenter/NewYork-PresbyterianHospital

DepartmentofMedicineNewYork,NY

POSTEXTUBATION HIGH-FLOW NASAL CANNULA TO PREVENT REINTUBATIONHernandez G, Vaquero C, Gonzalez P, Subira C, Frutos-VivarF,RialpG,LabordaC,ColinasL,CuenaR,FernandezR.Effect of postextubation high-flow nasal cannula vs conventional oxygen therapy on reintubation in low-risk patients: a randomized clinical trial.JAMA2016;315(13):1354-1361.

SummaryHypoxemia after planned extubation is common andreintubationmayberequiredinsomepatients.Noninvasiveventilation appears to decrease the risk of reintubationin patients who are at high risk for this outcome. High-flow nasal cannula (HFNC) reduced reintubation aftercardiac surgery and in a general critical care population.WhetherHFNC reduces the rateof reintubation ina low-riskpopulation isunknown.Thismulticenter, randomized,controlledtrialinsevenintensivecareunitsinSpain,enrolled527adultswhofulfilledcriteriaforplannedextubationandwere at low risk for reintubation, as predefined by theinvestigators. Low risk criteria included: age below 65years, adequate secretion management, and absenceof heart failure or moderate-to-severe COPD. Patientswho had passed a spontaneous breathing trial afterreceivinginvasivemechanicalventilationformorethan12hourswere randomized toHFNCor conventional oxygentherapy administered immediately after extubation, andfor 24 hours thereafter. Major exclusion criteria includeddo-not-resuscitate orders as well as accidental and self-extubations. The primary outcome, reintubation within72 hours, was less common in the HFNC group [4.9%vs.12.2% in theconventionalgroup;absolutedifference,7.2% (95%CI, 2.5%to 12.2%); P = .004]. The number ofpatients needed to treat to prevent one reintubationwithHFNCwas14(95%CI,8to40).ThesecondaryoutcomeofpostextubationrespiratoryfailurewaslesscommonintheHFNCgroup(8.3%vs14.4%;P=.03).Timetoreintubationwasnotdifferentbetweenthegroups.AllpatientstoleratedtheHFNCandnoadverseeventswerereported.

Comments1.This study demonstrates a clear advantage in usingHFNCascomparedwithconventionaloxygentherapytoreducetheriskofreintubationat72hoursintheselow-riskpatientsafterplannedextubation.

2.Theunusualfocusonlow-riskpatientssuggeststhateventhispopulation,withitsalreadylowrateofreintubation,maybenefitbydrivingthereintubationratedownfurther.

3.Patients with hypercapnia during their spontaneousbreathing trial were excluded because, as the authorsnote,mostoftheirclinicianspreferredtousepreventive

noninvasiveventilationratherthanHFNCorconventionaloxygentherapyatthetimethetrialwasdesigned.

4.Anotablelimitationisthattheclinicianswerenotblindedtothestudygroup,althoughtheriskofbiaswaspartiallymitigated by excluding the investigators from clinicaldecision-makingandpredefiningcriteriaforreintubation

POSTOPERATIVE NONINVASIVE VENTILATION TO PREVENT REINTUBATIONJaber S, Lescot T, Futler E, Paugam-Burtz C, Seguin P,FerrandiereM,LasockiS,MimozO,HengyB,SanniniA,PottecherJ,AbbackP-S,RiuB,BalafiaF,ConstantinJ-M,MasseretE,BeaussierM,VerzilliD,DeJongA,ChanquesG,BrochardL,MolinariN:fortheNIVASStudyGroup.Effect of noninvasive ventilation on tracheal reintubation among patients with hypoxemic respiratory failure following abdominal surgery: a randomized clinical trial.JAMA2016;315(13):1345-1353.

SummaryPost-operative respiratory failure requiring invasivemechanical ventilation (IMV) increases morbidity andmortality. Avoiding IMV may improve outcomes. Thismulticenter, stratified, randomized, parallel-group clinicaltrial comparedstandardoxygen therapywithnoninvasiveventilation (NIV) in 293patients in20 intensivecareunitsin France. The study included patients who experiencedpost-operative acute hypoxemic respiratory failure withinseven days of abdominal surgery. The primary outcomewas tracheal intubation for any cause within seven daysfollowing randomization. Parameters for initially settingNIVwere standardized. Predefined criteria were used forreintubation. The use of high-flow nasal cannula (HFNC)was not permitted in either group.Reintubation occurredin 33.1% in the NIV group as compared with 45.5% inthe standard oxygen therapy group (absolute difference,−12.4%;95%CI,−23.5%to−1.3%;P=.03).NIVwasalsoassociated with more invasive ventilator-free days andfewerhealthcare-associatedinfections(mostprominently:a lower rate of intensive care unit-acquired pneumonia).Therewasatrendtowardimproved90-daymortalityintheNIVgroup.Therewerenosignificantdifferencesinseriousadverseeventsbetweenthegroups.

Comments 1.This well-designed, multicenter, randomized controlledtrial supports theuseofNIVvia facemask, inpatientswithacutehypoxemicrespiratoryfailureafterabdominalsurgery.

2.Thestudygroupswerewellbalancedafterrandomizationwiththeexceptionofalargerpercentageofpatientswithchronic obstructive pulmonary disease (COPD) in the

CLINICAL YEAR IN REVIEW 2017 3

SUNDAY, MAY 21 NEW TOOLS TO SUPPORT ACUTE RESPIRATORY FAILURE

NIV group (19.6% vs. 12.6%),whichmay have biasedtheresultsinfavorofNIVgivenwhatweknowaboutthepotentialbenefitsofNIVinCOPDpatients.

3.Another limitation of this study is the lack of blinding,whichwas addressed by having predefined criteria forreintubation,yetbiascouldstillhavebeenpresent.

4.The main mechanism of benefit in this study is likelythe avoidance of invasive mechanical ventilation andthe consequent decrease in health care-associatedinfections,whichwereledbyadecreaseinintensivecareunit-acquiredpneumoniaintheNIVgroup.

5.The study involved no comparison with HFNC oxygentherapy,andso the relativemeritsofNIVascomparedwithHFNCinthispopulationremainunknown.

POSTEXTUBATION HIGH-FLOW NASAL CANNULA VS NONINVASIVE VENTILATION TO PREVENT REINTUBATIONHernandez G, Vaquero C, Colinas L, Cuena R, GonzalezP, Canabal A, Sanchez S, Rodriguez ML, Villasclaras A,Fernandez R. Effect of postextubation high-flow nasal cannula vs noninvasive ventilation on reintubation and postextubation respiratory failure in high-risk patients: a randomized clinical trial.JAMA2016;316(15):1565-1574.

SummaryEarlier in 2016, this same group from Spain publisheda randomized controlled trial (also in JAMA), whichdemonstrated that the use of high-flow nasal cannula(HFNC) oxygen in postextubation patients at low risk forreintubation reduces the risk of reintubation comparedwith conventional oxygen therapy. The present study ranconcurrently and addressed the issue of postextubationpatientsathighriskofreintubation.Noninvasiveventilation(NIV)hasshownbenefitinthissettingcomparedwithoxygentherapy.Inthismulticenter,randomized,noninferioritystudy,theycomparedHFNCwithNIV,administered immediatelyafter extubation, and for 24hours thereafter. TheauthorshypothesizedthatHFNCisnoninferiortoNIVforpreventingreintubationinhigh-riskpatients.604adultswithatleastonepredefined risk factor suggesting theywouldbehigh riskforreintubation,whohadpassedaspontaneousbreathingtrialafterreceivinginvasivemechanicalventilationformorethan 12 hours,were randomized.Major exclusion criteriaincluded do-not-resuscitate orders as well as accidentalandself-extubations.TitrationofHFNCandNIVwerebothprotocolizedandtheinvestigatorsusedpredefinedcriteriafor reintubation.Theprimaryoutcomeswere reintubation,occurring in 22.8% in the HFNC group compared with19.1% in the NIV group (absolute difference, −3.7%;95%CI,−9.1%to∞);andpostextubationrespiratoryfailureoccurring in 26.9%withHFNC and 39.8%withNIV (riskdifference, 12.9%; 95%CI, 6.6%to ∞), which reachedthe noninferiority threshold. Median post-randomizationintensive care unit length of staywas lower in theHFNCgroup.Importantly,adverseeventsrequiringwithdrawaloftherapywerenotobservedinpatientsintheHFNCgroup,ascomparedwitharateof42.9%intheNIVgroup(P<.001).

Comments1.HFNCwasnotinferiortoNIVinpreventingreintubationandpostextubationrespiratoryfailure inpatientsathighriskofreintubation.

2.ThefindingofnoninferiorityisimportantbecausetheremaybeadvantagestoHFNCcomparedwithNIV,asevidencedby the disparity in adverse events requiringwithdrawal oftherapy; with greater comfort and lower cost, this studycouldprovidetherationaleforpreferentiallyselectingHFNCinmanyofthesepatients.

3.AswithmanyotherstudiesofNIVandHFNC,theclinicianswere not blinded to the study group, although (as withthepriorstudybythisgroup) theriskofbiaswaspartiallymitigated by excluding the investigators from clinicaldecision-makingandpredefiningcriteriaforreintubation.

HELMET NONINVASIVE VENTILATION IN ARDSPatel BK,WolfeKS, PohlmanAS,Hall JB,Kress JP.Effect of noninvasive ventilation delivered by helmet vs face mask on the rate of endotracheal intubation in patients with acute respiratory distress syndrome: a randomized controlled trial.JAMA2016;315(22):2435-2441.

Summary Noninvasiveventilation (NIV)deliveredvia facemask(FM)hasbeenshowntoimproveoutcomesinselectedpatientswith acute respiratory failure, especially in the setting ofchronic obstructive pulmonary disease and cardiogenicpulmonary edema. However, NIV has produced mixedresultsinacutehypoxemicrespiratoryfailureandtheacuterespiratory distress syndrome (ARDS). Nonetheless, arecent largeobservational study suggests that it is beingusedinasmanyas15%ofARDSpatients.FailureofNIVin this setting could be due, in part, to the FM interfaceitself, especially its inability to reliably or comfortablyprovide high levels of positive end-expiratory pressure(PEEP) due to air leak. The authors hypothesized that ahelmet interface, a transparent hood covering the entireheadandsealedattheneck,couldovercomethislimitationand decrease the need for endotracheal intubation (ETI).This unblinded, single center, randomized, controlled trialof83patientswithARDSaccording to theBerlincriteria,randomized patients after eight hours of NIV via FM, tocontinued FM NIV or switching to the helmet interface.Titration of ventilatory parameters, predefined criteriafor ETI, weaning parameters and prespecified adverseeventswerestandardizedacrossbothgroups.Theprimaryoutcome was the proportion of patients requiring ETI,whichfavoredthehelmet interface,occurring in61.5%inthe FM group and 18.2% in the helmet group (absolutedifference,−43.3%;95%CI,−62.4%to−24.3%;P<.001).The helmet group also had significantly higher ventilator-freedays,lowerintensivecareunitlengthofstayandlowerhospitaland90-daymortality.Nosignificantdifferencesinadverseeventrateswerenoted.

Comments1.This well-performed randomized, controlled trial ofhelmet NIV vs. FM NIV showed a remarkable andstatistically significant difference in the need for ETI


SUNDAY, MAY 21

favoring the helmet interface, and an equally strikingdifferenceinmeaningfulsecondaryendpoints, including90-daymortality.

2.Physiologic differences seen between the groups,including median sustained PEEP and respiratory rateafter transition to the helmet interface, may providebiologicplausibilitytotheresultsofthestudy.

3.Despite all this, the results must be interpreted withconsiderable caution given that this is a single center,unblinded study of an inadequately understoodtechnology,appliedtopatientswithARDSintheabsenceof agreed upon criteria for NIV in this setting, and thestudy was stopped early for both efficacy and safety(likelyresultinginoverestimationoftheeffectsize).

4.Further study to provide external validity andgeneralizability is needed before the helmet interfacecould be considered standard practice; comparisonswithhighflownasalcannulainthissettingmightalsobeinformative.

5.The articlewas controversial at the time of publicationin JAMA given its limitations, accounting for itsdesignationinthejournal(appropriately)asa“PreliminaryCommunication”.

UNDERSTANDING THE TOOLS WE USE FOR ARDSBellaniG,LaffeyJG,PhamT,FanE,BrochardL,EstebanA,GattinoniL,vanHarenF,LarssonA,McAuleyDF,RanieriM, Rubenfeld GD, Thompson BT,Wrigge H, Slutsky AS,Pesenti A; for the LUNG SAFE Investigators and theESICMTrialsGroup.Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.JAMA2016;315(8):788-800.

SummaryLimited information exists about patients with the acuterespiratory distress syndrome (ARDS) within the contextof routine clinical practice around the world. This study,the Large Observational Study to Understand the GlobalImpactofSevereAcuteRespiratoryFailure(LUNGSAFE),isamulticenter,international,prospectivecohortstudy.Thestudywasconductedduringtwoperiods,eachconsistingoffourconsecutiveweeksinthewinterof2014withinthenorthern and southern hemispheres respectively, using alarge convenience sample from 459 intensive care units(ICUs) in 50 countries across 5 continents. All patientsundergoing invasivemechanicalventilationornoninvasiveventilationinthoseICUsduringthefour-weekperiodswereenrolled. The primary outcome was the ICU incidenceof ARDS as defined by the Berlin criteria. SecondaryoutcomesincludedclinicianrecognitionofARDS,ventilatormanagement,useofadjunctiveinterventionsandoutcomesfromARDS.Of29,144patientsadmittedtotheparticipatingICUsduringthestudyperiod,3,022(10.4%)metcriteriaforARDS.Overall clinician recognitionofARDS ranged from51.3%inmildto78.5%insevereARDS.However,clinicianrecognitionofARDSatthetimecriteriaweremetwasonly34.0%, highlighting routine delays in diagnosis. Amongthosereceivinginvasivemechanicalventilation,theperiodprevalence of mild ARDS was 30.0%; moderate ARDS,

46.6%; and severeARDS, 23.4%.Pronepositioningwasusedinonly16.3%ofpatientswithsevereARDS.ClinicianrecognitionofARDSwasassociatedwiththeuseofhigherlevels of positive end-expiratory pressure, more frequentprone positioning and use of neuromuscular blockade.Hospitalmortalitywas 34.9% for thosewithmild, 40.3%forthosewithmoderate,and46.1%forthosewithsevereARDS.

Comments 1.This is the first major epidemiologic study of ARDSpatientsusingtheBerlincriteria,anditappearstounmaskwidespreadunder-recognitionandunder-treatment.

2.The study may have overestimated the incidence ofARDS, most notably because of the gathering of dataonly during winter months, and likewise it may haveoverestimated the degree of under-recognition ofARDSbynotdistinguishingclinicianfailuretodiagnosefrom clinician judgment of an alternate explanation forhypoxemia.

3.The frequent failure of clinicians to recognize ARDSwouldtendtosuppresstheuseofappropriatetherapies;remarkably,fewerthantwothirdsofpatientswithARDSinthisstudyreceivedatidalvolumeof8ml/kgorlessofpredictedbodyweight.

4.Bearinginmindallthecaveatsofaconveniencesample,the LUNG SAFE study is a gold mine of informationaboutARDSandhowitmay(ormaynot)berecognizedandmanagedintherealworld.

5.The sheer size and geographic range of this well-conducted study make it a powerful generatorof hypotheses about the epidemiology, recognition,implementation of evidence-based practices, andoutcomesofpatientswithARDS.

OTHER ARTICLES OF INTERESTNONINVASIVE VENTILATIONCarteaux G, Millan-Guilarte T, De Prost N, Razazi K, Abid S,Thille AW, Schortgen F, Brochard L, Brun-Buisson C, MekontsoDessapA.Failure of noninvasive ventilation for de novo acute hypoxemic respiratory failure: role of tidal volume. Crit Care Med2016;44:282-290.

ThilleAW,BoissierF,Ben-GhezalaH,RazaziK,Mekontso-DessapA,Brun-BuissonC,BrochardL.Easily identified at-risk patients for extubation failure may benefit from noninvasive ventilation: a prospective before-after study.Critical Care2016;20:48.

Bellani G, Laffey JG, Pham T, Madotto F, Fan E, Brochard L,EstebanA,GattinoniL,BumbasirevicV,PiquilloudL,vanHarenF,LarssonA,McAuleyDF,BauerPR,ArabiYM,RanieriM,AntonelliM,RubenfeldGD,ThompsonBT,WriggeH,SlutskyAS,PesentiA;OnbehalfoftheLUNGSAFEInvestigatorsandtheESICMTrialsGroup.Non-invasive ventilation of patients with ARDS: Insights from the LUNG SAFE Study.Am J Respir Crit Care Med2016;inpress

HIGH-FLOW NASAL CANNULA

Mauri T, Turrini C, Eronia N, Grasselli G, Volta CA, Bellani G,Pesenti A.Physiologic effects of high-flow nasal cannula in acute hypoxemic respiratory failure.Am J Respir Crit Care Med2016;inpress.

NEW TOOLS TO SUPPORT ACUTE RESPIRATORY FAILURE


SUNDAY, MAY 21

SemlerMW,JanzDR,LentzRJ,MatthewsDT,NormanBC,AssadTR,KeriwalaRD,FerrellBA,NotoMJ,McKownAC,KocurekEG,WarrenMA,Huerta LE,RiceTW; for theFELLOW Investigatorsand the Pragmatic Critical Care ResearchGroup.Randomized trial of apneic oxygenation during endotracheal intubation of the critically ill.Am J Respir Crit CareMed2016;193;273-280.

HIGH-FREQUENCY OSCILLATORY VENTILATION IN PEDIATRICS

BatemanST,BorasinoS,AsaroLA,CheifetzRM,DianeS,WypijD,CurleyMAQ;fortheRESTOREStudyInvestigators.Early high-frequency oscillatory ventilation in pediatric acute respiratory failure: a propensity score analysis.Am J Respir Crit Care Med2016;193:495-503.

NEW TOOLS FOR TRACHEOSTOMYY

Gobatto ALN, Besen BAMP, Tierno PFGMM, Mendes PV,Cadamuro F, Joelsons D, Melro L, Carmona MJC, SantoriG, Pelosi P, Park M, Malbouisson LMS. Ultrasound-guided percutaneous dilational tracheostomy versus bronchoscopy-guided percutaneous dilational tracheostomy in critically ill patients (TRACHUS): a randomized noninferiority controlled trial.Intensive Care Medicine2016;42:342-351.

NEW TOOLS TO SUPPORT ACUTE RESPIRATORY FAILURE


Dee W. Ford, MD, MSCRMedicalUniversityofSouthCarolina

PulmonaryandCriticalCareMedicineCharleston,SC

RENAL REPLACEMENT THERAPY INITIATIONGaudryS,HajageD,SchortgenF,Martin-LefevreL,PonsB,BouletE,BoyerA,ChevrelG,LerolleN,CarpentierD,deProstN,LautretteA,BretagnolA,MayauxJ,NseirS,MegarbaneB, Thirion M, Forel J-M, Maizel J, Yonis H, Markowicz P,Thiery G, Tubach F, Ricard J-D, Dreyfuss D. AKIKI StudyGroup.Initiation strategies for renal-replacement therapy in the intensive care unit.N Engl J Med2016;375:122-33.DOI:10.1056/NEJMoa16030175

SummaryThe optimal timing of initiation for renal replacementtherapy (RRT) among patients with acute kidney injury(AKI) remains controversialwith conflicting results relatedtomortalityandotherbenefitsassociatedwithearlyversuslaterRRT initiation. This studyprovidesnew insights intothis important clinical question through a multi-center,randomizedtrialconductedin31intensivecareunitsovera 28 month time period. The trial included 620 patientswithKidneyDisease:ImprovingGlobalOutcomes(KDIGO)stage3whorequiredmechanicalventilation,vasopressors,or both but did not have indications for immediate RRT(e.g. hyperkalemia). The early-strategy group began RRTwithin6hoursofKDIGOstage3.The late-strategygroupwasfollowedexpectantlyandRRTinitiatedbasedonpre-specified laboratory derangements, pulmonary edema,or oliguria/anuria > 72 hours after randomization. Therewere no differences between groups with respect to theprimary outcomeof overall survival at day 60whichwas48.5% in the early group and 49.7% in the late-strategygroup.Amongthoseinthelate-strategygroup,49%neverreceivedRRTandamongthosewhodid,thetimebetweenrandomizationandRRT initiationwas50hours.Theearlystrategygrouphadslower recoveryof renal functionandhigherratesofcatheter-relatedbloodstreaminfections.

Comments1.Thisclinicaltrialthatdoesnotsupportroutine,earlyinitiationofRRTamongpatientswithacutekidneyinjurywhodonothaveurgentindicationsforRRTinitiationsuchasmetabolicderangementsorpulmonaryedema.

2.The finding that almost one-half of subjects in the late-strategygroupavoidedRRTandexperiencedearlier renalrecovery has substantial ramifications for patient resourceutilization.

3.The higher incidence of CLBSI among the early-strategygroup has important patient-safety implications given thesignificant impact CLBSI has on patient morbidity andmortality.

4.Amajorityofpatients(85%)inbothgroupswerereceivingvasopressor support at the time of study enrollment, yetthemodeofRRTwas intermittenthemodialysis in50%ofsubjectswhichmay limit generalizability to ICUs inwhich

continuousRRTistheconventionalpracticeamongpatientswithshock.

5.Thisstudysupports theuseofcarefulclinicalobservationandexpectantmanagementregardingRRTinitiationamongICUpatientssufferingfromacutekidneyinjury

Zarbock A, Kellum JA, Schmidt C, Van Aken H, WempeC,PavenstädtH,BoantaA,GerßJ,MeerschM.Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized clinical trial. JAMA 2016;315(20):2190-2199.DOI:10.1001/jama.2016.5828

SummaryThis second study on timing of initiation of RRT amongICUpatientswithAKIisarandomized,single-centerstudyconducted over a 23 month period. The trial included231 adult patients with KDIGO stage 2 despite optimalresuscitationwhoalsohadaplasmaneutrophilgelatinase-associated lipocalin > 150ng/mlwith one ormore of thefollowing: severe sepsis, use of vasopressors, refractoryfluid overload, or progression of non-renal organ systemfailures.EarlyRRTwas initiatedwithin8hoursofstage2AKI.DelayedRRTwasinitiatedwithin12hoursofstage3AKI or if ametabolic indication forRRTdeveloped.Bothgroupswere treatedwith identical RRT protocols and allpatients received continuous RRT. The primary outcomeof overall 90 day mortality was significantly improved inthe early initiation group at 39.3% versus in the delayedgroup at 54.7%. Several secondary outcomes were alsoimproved in the early initiation group versus the delayedgroupincluding:renalfunctionrecoverybyday90(53.6%versus 38.7%); less duration of RRT (9 days versus 25days);andshorterhospital lengthofstay (51daysversus82 days). Among those in the delayed group, 90.7%ultimatelyreceivedRRT.

Comments1.Thissinglecenterrandomizedtrialsupportsearly initiationofRRTamongICUpatientswithAKIonthebasisof90dayoverallmortality andseveral clinically importantoutcomesincludingrenalrecovery.

2.Animportantfactorlimitinggeneralizabilityistheenrollmentcriteria of a plasma neutrophil gelatinase-associatedlipocalin>150ng/ml(anindicatorofseverityofAKI)whichisnotusedinroutineclinicalpractice.

3.AllpatientsreceivedthesameRRTprotocolwithcontinuousRRTandthuswhethersimilaroutcomeswouldbereplicatedwithintermittentRRTisunknown.

4.The actual therapeutic differences between the early andlate initiation groups were small with 90.7% of patientsin the delayed group ultimately receivingRRT on averagewithin24hoursoftheearlyinitiationgroup.

SUNDAY, MAY 21 GENERAL CRITICAL CARE



5.Despitemodest therapeutic differences between the earlyand delayed groups, substantial improvements in primaryand secondary outcomes were observed that should beinterpreted with caution given the risk of overestimatingeffectsizesinsinglecenterstudies.

TREATMENT OF AGITATED ICU DELIRIUMReadeMC, EastwoodGM, BellomoR, BaileyM, BerstenA,CheungB,DaviesA,DelaneyA,GhoshA,vanHarenF,HarleyN,KnightD,McGuinessS,Mulder J,O’DonoghueS, Simpson N, Young P; DahLIA Investigators and theAustralianandNewZealandIntensiveCareSocietyClinicalTrials Group. Effect of dexmedetomidine added to standard care on ventilator-free time in patients with agitated delirium: A randomized clinical trial. JAMA2016;315(14):1460-1468.DOI:10.1001/jama.2016.2707

SummaryAgitateddelirium isasignificantproblemfor ICUpatientsreceivingmechanicalventilationandmayimpedeventilatorliberation.TheDahLIAInvestigatorsenrolled74intubated,mechanicallyventilatedpatients inaprospective,double-blind, placebo-controlled, parallel-group randomized,multi-centerclinical trial.Patient’s treatingphysicianshadto perceive the degree of agitation as being sufficientlysevere so as tomake lessening sedation and extubationunsafe. Additional requirements included physical and/or pharmacologic sedation and quantification of agitateddelirium via CAM-ICU andMAAS scores. Patients in thedexmedetomidine groupwere started at dose of 0.5 μg/kg/handtitrationwasbasedonphysicianorderedsedationgoals. After 48 hours of study drug, treating physicianscould prescribe open-label dexmedetomidine. Thedexmedetomidine group showed significant improvementin the primary outcome of reduced ventilator-free hoursin the 7 days post-randomization (median, 144.8 hoursvs 127.5 hours). Several secondary outcomes were alsoimproved including: reduced time to extubation (median,21.9 hours vs 44.3 hours) and accelerated resolution ofdelirium(median,23.3hoursvs40.0hours).Therewerenosignificantdifferencesinadverseeventsbetweentreatmentandplacebogroups.Comments1.This study supports the use of dexmedetomidine,a sedative α2-agonist, as a treatment for agitateddelirium in the specific and clinically important subsetof patients who are perceived to fail liberation frommechanicalventilationduetotheirdelirium.2.This studycontrastswithotherstudiesofdexmedetomidineinwhichit has been evaluated as a sedative for mechanicallyventilatedpatientsandbuildsonsecondaryfindingsfromthese studies which suggested dexmedetomidine mayhaveefficacyintreatingdelirium.

3.Themechanism(s)bywhichdexmedetomidineachievesimprovement in delirium may include both primarytherapeuticeffectand/orasasparingagentforalternativesedativesandanalgesics.

4.The study screened 21,500 ICU admissions ofintubated patients in order to randomize 74 subjects

so generalizability is a concern and the very specificclinicalscenariostudied(i.e.agitateddeliriumprecludingextubation) should be consideredwhen applying thesefindingstoclinicalpractice.

5.Duetoslowerthanexpectedenrollment,thestudywasstoppedpriortotheplannedtargetof96patientsraisinga concern for an exaggerated effect size. Simulationswere conducted to ascertain the risk of false positiveresultswhichwasfoundtobe<7%.

ICU QUALITY IMPROVEMENTWriting Group for the CHECKLIST-ICU Investigators andtheBrazilianResearchinIntensiveCareNetwork(BRICNet).Effect of a quality improvement intervention with daily round checklists, goal setting, and clinician prompting on mortality of critically ill patients: A randomized clinical trial.JAMA.2016;315(14):1480-1490.DOI:10.1001/jama.2016.3463

SummaryICU quality improvement (QI) is an important issue anda variety of approaches have demonstrated improvedoutcomes,oftentiedtoaspecificinitiative.Inthisstudy,theBRICNetinvestigatorsundertookthegoalofimplementingand evaluating a multi-faceted ICU QI interventionthroughoutBrazil.Thestudyenrolled118ICUsintoatwophasestudy.Phase1wasanobservationalperiodduringwhich clinical outcomes, care process measures, andperceivedICUworkclimateweremeasured.Phase2wasacluster randomizedtrial inwhichhalf the ICUsreceivedthe multi-faceted intervention (daily checklist review bytheICUteam,goalsettingduringmultidisciplinaryrounds,and follow-upclinicianprompting for11careprocesses).During each phase, participating ICUs enrolled 40-60consecutive patients with an ICU stay > 48 hours. Inphase2,3327patientswereenrolled in intervention ICUsand 3434 in usual care ICUs. The study did not meetthe primary outcome of reduced in-hospitalmortality nordid it improve secondary clinical outcomes of reducedICUmortality,CLBSI,VAP,orUTI.However, anumberofcare process measures did improve in the interventionICUs versus control ICUs including adherence to tidalvolumes ≤ 8cc/kg predicted body weight (67.5% versus58.9%);moderate sedation levels (40.5% versus 35.0%);and reduced urinary catheter use (62.8% versus 74.8%).Perceptionsof teamworkclimateandsafetyclimatealsoimprovedininterventionICUs.

Comments1.AlthoughtheQIinterventiondidnotimprovein-hospitalmortality or secondary clinical outcomes, severalprocessesofcaremeasuresdidimproveasdidindicatorsof ICU safety environmentwhich have been previouslyassociatedinotherinvestigationswithimprovedpatientoutcomes.

2.ManyQIreportsapplymulti-facetedstrategiestargetingtheareaofinterestandutilizingbefore/afterdesignsandanotablestrengthofthisstudyistheclusterrandomizeddesignwithanobservationalrun-inperiod.


3.The importance of organizational culture, includingsafety climate and multidisciplinary care, are believedto be important determinants to patient outcomes yetchallenging to empirically alter. It is notable that theinterventionwas able tomodify two domains of safetyclimate.

4.The clinical domains included in the QI checklistwere broad, touching on numerous ICU patient safetyinitiatives currently at the forefront and ranging fromventilator and sedationmanagement, DVT prophylaxis,andnutrition toallmajordevice related infections.Thismayhave represented toomanyseparate initiatives forparticipatingICUstoaddressconcurrently.

5.Another potential explanation for lack of clinicalimprovement may be the relatively short duration ofthe intervention which was less than five months andfuture research should extend intervention activitiesover a longer period of time to ascertain if process ofcareimprovementswilltranslateintosubstantiveclinicalimprovements.

ICU PHYSICAL THERAPYMoss M, Nordon-Craft A, Malone D, Van Pelt D, FrankelSK, Warner ML, Kriekels W, McNulty M, Fairclough DL,SchenkmanM.A randomized trial of an intensive physical therapy program for patients with acute respiratory failure.Am J Respir Crit Care Med.2016;193(10):1101-1110.DOI:10.1164/rccm.201505-1039OC

SummaryMultiplestudieshavedemonstratedICU-acquiredweaknessiscommonandimposessubstantialmorbidityandmortalityamong ICU survivors which has inspired various ICUphysical therapy (PT) programs. This study sought todeterminewhetheranintensivePTprogramforpatientswithacute respiratory failure could improve long-term physicalfunctionalperformancecomparedtostandardPTcare.Thisrandomized trial enrolled 120patients from five ICUsoverapproximately five years. Patients had to have receivedmechanicalventilationfor≥fourdaysandwererandomizedat the time of awakening. Each site had a dedicated PTteamfortheinterventionversusstandardcaregroups.Theintensive PT group received active treatment for 28 daysfrom enrollment including in-home/outpatient treatment.Thestandardcaregroupdidnot receiveoutpatientPTbutreceived attention control with telephone follow-up. Theprimaryoutcomewasavalidatedandstructuredassessmentof functional status one month after study enrollment.SecondaryoutcomesincludedICU-andhospital-freedays,dischargetohome,andall-causemortality.TheintensivePTgroupreceivedasubstantiallyhigherdosethanthestandardgroupbyall implementationmeasures;however,therewasno difference in either primary or secondary outcomesbetweengroups.Comments1.This study utilized a novel, patient-centered outcomevia the short form of the Continuous Scale PhysicalFunctionalPerformanceTest(CS-PFP-10)whichreflectsthe ability to conduct typical activities of living such

as sweeping or carrying groceries. The CS-PFP-10quantifies physical performancebasedon time,weight,anddistanceandthusreflectsacombinationofstrength,balance,andendurancethatispredictiveoftheabilitytoliveindependently.

2.This was a rigorous study that achieved early andmeaningfuldifferentiationregardingPTdosebetweentheintensive and standardPTgroupsbut unfortunatelydidnotachievesignificantdifferenceswithregardstopatientoutcomesuptosixmonthsafterstudyenrollment.

3.PatientsreceivedtheirfirstPTsessionsonaverageeightdays after initiation of mechanical ventilation at whichpointmostpatientswillhaveexperiencedsubstantiallossinmusclemass. Additional research is needed to learnwhether earlier PT might mitigate loss of strength andportendimprovedpatientoutcomes.

4.Patientswithventilatordependentrespiratoryfailureareaheterogeneousgroupwhomayderivedifferentialbenefitsfrom various doses of PT, thus, in addition to timing,furtherresearchintoup-titratingthedoseofPTbasedonpatientresponsemayaddimportantnewinsights.

5.WhileearlierstudiesofICUPThavefoundpositiveimpacton patient and resource use measures, recent clinicaltrials are calling these benefits into question althoughgiventhefavorablepatientsafetyprofileriskappearslow

INTUBATION DURING CARDIOPULMONARY RESUSCITATIONAndersen LW, Granfeldt A, Callaway CW, Bradley SM,Soar J, Nolan JP, Kurth T, Donnino MW; American HeartAssociation’s Get With The Guidelines-ResuscitationInvestigators. Association between tracheal intubation during adult in-hospital cardiac arrest and survival.JAMA. 2017. DOI: 10.1001/jama2016.20165. [Epub aheadofprint]

SummaryThisretrospective,observationalstudyutilizeddatafromtheGetWiththeGuidelines-Resuscitation(GWTG-R)repositorytoexaminetheimpactoftimingofendotrachealintubationduring cardiopulmonary resuscitation on patient survivaland neurologic outcomes. Data were collected between2000through2014from108,079patientsat668hospitals.Mostpatients(66.3%)wereintubatedwithin15minutesofcardiac arrest. Due to the large sample size and detailedmeasuresavailableintheGWTG-Rdatabase,sophisticatedanalytic techniques could be applied to create a case-controlstudybasedontheminuteof intubationrelativetotheonsetofcardiacarrestinwhichintubatedpatientswerematchedtocontrolpatientsthathadn’tyetbeenintubatedby that same specificminute. For eachoutcome studied,intubatedpatientsdidworseincludinglowersurvival(16.3%vs19.4%),lowerlikelihoodofROSC(57.8%vs59.3%),andlowerrateofgoodneurologicaloutcome(10.6%vs13.6%).Multiple sub-groups were examined including shockableversus non-shockable rhythms and primary respiratoryetiology as cause for cardiac arrest and among no sub-groupdidendotracheal intubation improveoutcomes.Formostsub-groupsalloutcomeswereworseamongpatientsintubatedwithin15minutes.




Comments1.Thisstudyiscongruentwithotherobservationalreportsof both in-hospital and out-of-hospital cardiac arrestdemonstratingthatendotrachealintubationisassociatedwithworsepatientoutcomesalthoughaunique featureof this report is the highly specific time of intubationrelativetothecardiacarrestthatenabledamoredetailedassessment.

2.Whileaggregatedpatientoutcomeswereworse,thesub-groupswithshockablerhythmsandthoseinthe“medicalcardiac” illness group demonstrated especially pooroutcomesassociatedwith intubationwithin 15minutesofcardiacarrest.

3.Despite theavailabilityof robustdata, thepossibilityofresidualconfoundingduetounmeasuredvariablessuchasillnessseverityorclinicianexpertiseremainsariskandsothesefindingsshouldnotbeinterpretedascausal.

4.The lack of randomized trials regarding the role ofendotracheal intubation in the context of in-hospitalcardiacarrestmeansthatcurrentresuscitationpracticesare derived from clinical tradition as opposed to highquality evidence and thus large observational datasources represent important tools to provide empiricinsight.

5.In 2010 the mantra in cardiopulmonary resuscitation(CPR) was changed from ‘ABC’ (Airway, Breathing,Circulation)to‘CAB’(Circulation,Airway,Breathing)withthegoalofminimizingpotential interruptions toCPR,aparadigmshiftthesedatawouldappeartosupport.

OTHER ARTICLES OF INTERESTRCT’S OF PREVENTIVE INTERVENTIONSKor DJ, Carter RE, Park PK, Festic E, Banner-Goodspeed VM,HindsR,TalmorD,GajicO,WareLB,GongMN.Effect of Aspirin on Development of ARDS in At-Risk Patients Presenting to the Emergency Department: The LIPS-A Randomized Clinical Trial. JAMA.2016;315(22):2406-14.DOI:10.1001/jama.2016.6330;

TimsitJF,AzoulayE,SchwebelC,CharlesPE,CornetM,SouweineB,KloucheK,JaberS,et.al.Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU-Acquired Sepsis, Candida Colonization, and Multiple Organ Failure: The EMPIRICUS Randomized Clinical Trial. JAMA.2016;316(15):1555-64.DOI:10.1001/jama.2016.14655;

Gordon AC, Perkins GD, Singer M, McAuley DF, Orme RM,Santhakumaran S, Mason AJ, Cross M, Al-Beidh F, Best-LaneJ,BrealeyD,NuttCL,McNameeJJ,ReschreiterH,BreenA,LiuKD,AshbyD.Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis. N Engl J Med.2016;375(17):1638-48.DOI:10.1056/NEJMoa1609409;

Keh D, Trips E, Marx G, Wirtz SP, Abduljawwad E, BerckerS, Bogatsch H, Briegel J, et.al. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA. 2016;316(17):1775-85.DOI:10.1001/jama.2016.14799;

GordonAC,MasonAJ,ThirunavukkarasuN,PerkinsGD,CecconiM, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ,SanthakumaranS,AshbyD,BrettSJ.Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic

Shock: The VANISH Randomized Clinical Trial. JAMA.2016;316(5):509-18.DOI:10.1001/jama.2016.10485

PATIENT-FAMILY CENTERED CARE

SchmidtK,WorrackS, VonKorffM,DavydowD,Brunkhorst F,EhlertU,PauschC,MehlhornJ,SchneiderN,ScheragA,FreytagA,ReinhartK,WensingM,GensichenJ.Effect of a Primary Care Management Intervention on Mental Health-Related Quality of Life Among Survivors of Sepsis: A Randomized Clinical Trial.JAMA.2016;315(24):2703-11.DOI:10.1001/jama.2016.7207;

CameronJI,ChuLM,MatteA,TomlinsonG,ChanL,ThomasC,FriedrichJO,MehtaS,et.al.One-Year Outcomes in Caregivers of Critically Ill Patients.N Engl J Med. 2016;374(19):1831-41.DOI:10.1056/NEJMoa1511160.

RESUSCITATION

PrandoniP,LensingAW,PrinsMH,CiammaichellaM,PerlatiM,MumoliN,BucheriniE,VisonaA,BovaC,ImbertiD,CampostriniS,BarbarS.Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope.N Engl J Med.2016;375(16):1524-31.DOI:10.1056/NEJMoa1602172;

ChanPS,BergRA,TangY,CurtisLH,SpertusJA.Association Between Therapeutic Hypothermia and Survival After In-Hospital Cardiac Arrest.JAMA. 2016;316(13):1375-82.DOI:10.1001/jama.2016.14380

VENTILATOR MANAGEMENTPanwarR,HardieM,BellomoR,BarrotL,EastwoodGM,YoungPJ, Capellier G, Harrigan PW, Bailey M. Conservative versus Liberal Oxygenation Targets for Mechanically Ventilated Patients. A Pilot Multicenter Randomized Controlled Trial.Am J Respir Crit Care Med. 2016;193(1):43-51. DOI: 10.1164/rccm.201505-1019OC;

Girardis M, Busani S, Damiani E, Donati A, Rinaldi R, MarudiA, Morelli A, Antonelli M, Singer M.Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: The oxygen-icu randomized clinical trial.JAMA.2016;316(15):1583-9.DOI:10.1001/jama.2016.11993.

PEDIATRIC CRITICAL CARE

Fivez T, Kerklaan D, Mesotten D, Verbruggen S, Wouters PJ,VanhorebeekI,DebaveyeY,VlasselaersD,DesmetL,CasaerMP,GarciaGuerraG,HanotJ,JoffeA,TibboelD,JoostenK,VandenBergheG.Early versus Late Parenteral Nutrition in Critically Ill Children.N Engl J Med.2016;374(12):1111-22.DOI:10.1056/NEJMoa1514762.

Gupta P, Rettiganti M, Rice TB, Wetzel RC. Impact of 24/7 In-Hospital Intensivist Coverage on Outcomes in Pediatric Intensive Care. A Multicenter Study.Am J Respir Crit Care Med.2016;194(12):1506-13.DOI:10.1164/rccm.201512-2456OC.

ICU CLINICIAN BURNOUTMossM,GoodVS,GozalD,KleinpellR,SesslerCN.An Official Critical Care Societies Collaborative Statement: Burnout Syndrome in Critical Care Health Care Professionals: A Call for Action.Am J Respir Crit Care Med 2016; 194(1): 106–113.DOI:10.1164/rccm.201604-0708ST


SUNDAY, MAY 21 THE BRAIN AND CRITICAL CARE

Thomas P. Bleck, MCCM RushMedicalCollege

NeurologicalSciences,Neurosurgery,Anesthesiology,andMedicineChicago,IL

CRANIECTOMY FOR HEAD TRAUMA Hutchinson PJ, Kolias AG, Timofeev IS, et al. Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension.N Engl J Med2016;375:1119-1130.

Summary408 patients with traumatic brain injury and refractoryintracranialhypertensionwererandomizedtoreceiveeithera decompressive craniectomy or medical management.TheprimaryoutcomemeasurewastheGlasgowOutcomeScale–Extended.Atsixmonths,27%ofthedecompressedgrouphaddied,comparedwith40%ofthemedicalgroup.Patients in the surgical arm had less time with elevatedICPbutmorecomplications.Moderatedisabilityandgoodrecovery rates in thesurgicalarmwerenotdifferent fromthoseinthemedicalarm

Comments1.The majority of the craniotomies were bifrontalprocedures, already shown to be deleterious in theDECRA trial (CooperDJ,RosenfeldJV,MurrayL,etal.Decompressive craniectomy in diffuse traumatic braininjury.NEnglJMed2011;364:1493-502).

2.The outcomes of the patients undergoing lateralhemicraniectomy, the preferred procedure in NorthAmerica,havenotbeenreportedseparately.

3.Since patients undergoing the bifrontal proceduremayhaveworseoutcomes,weawaitdataabouttheselateralsurgerypatients.

4.ICUlengthofstaywas15daysinthesurgicalgroupand21daysinthemedicalgroup.

5.19% of the surgical arm received barbiturates for ICPcontrol,comparedto87%ofthemedicalarm.

WITH INTRAVENOUS RT-PA TREATMENT FOR ACUTE STROKE, FASTER YIELDS BETTER OUTCOMES BUT MAY NOT BE SAFER Whiteley WN, Emberson J, Lees KR, et al. Risk of intracerebral haemorrhage with alteplase after acute ischaemic stroke: a secondary analysis of an individual patient data meta-analysis. Lancet Neurol 2016;15:925-933.

SummaryData from 6756 participants in nine randomized trials ofrt-PAforacuteischemicstrokevsplacebowereanalyzedonaper-patientbasis.Symptomatic intracranial hemorrhageoccurred in 6.8%of active treatment patients, compared

with1.3%ofcontrols(OR5.55);fatalhemorrhageoccurredin2.7%vs0.4%(OR7.14).Symptomatichemorrhagewasdefinedintwodifferentways(parenchymalhemorrhage2,asintheNINDStrials,andusingtheSITS-MOSTdefinition,which is more commonly employed in European trials).Thehigherriskwasindependentoftreatmentdelay(upto4.5hours)orpatientage,butdidincreasewithincreasingstrokeseverity.Despitethis,therewasbenefitbasedonthemodifiedRankinscaleoffunctionaloutcomeinallgroups.

Comments1.Prioranalyseslackedthepowertoexaminethisnumberof variables to estimate the effects of each on patientoutcomes.

2.Althoughtheefficacyofrt-PAdecreaseswithtimeupto4.5hours,thebenefitoftreatmentisstillmeasureableouttothistimepoint.

3.Agelessthanorgreaterthan80yearsdidnotaffecttheriskofhemorrhageafterrt-PA.

4.Eveninpatientswiththemostseverestrokes(NIHSS>22),thebenefitofrt-PAexceededtherisk.

5.These trials preceded the advent of endovascularthrombectomy;whetherintravenousrt-PAshouldprecedeattemptstoremove largevessel thrombiremainsunderinvestigation.

ENDOVASCULAR THROMBECTOMY IN STROKE DUE TO LARGE VESSEL OCCLUSION HAS A PROFOUNDLY BENEFICIAL EFFECTGoyalM,MenonBK,vanZwamWH,etal.Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet2016;387:1723-1731.

SummaryApatient-levelmeta-analysisofdatafromfiverandomizedtrials of endovascular thrombectomy for acute ischemicstrokeduetolargevesselocclusionstudied1287patients.The primary outcome was reduction in disability on themodifiedRankinscale.Inadditiontothewholepopulation,the authors studied subgroups including the site ofocclusion (internal carotid, first or second branch of themiddlecerebral),age,sex,baselinestrokeseverity,useofrt-PA,baselineASPECTscore(ameasureoftissuedamageintheCTscanonpresentation),andtimefromstrokeonsettorandomization.Overall,thrombectomyledtoasignificantreductionindisability(OR2.49);thenumberneededtotreatorreducedisabilitybyatleastonemRSpointwas2.6.


THE BRAIN AND CRITICAL CARESUNDAY, MAY 21

Comments1.Patients older than 80 years had at least as great abenefitasyoungerpatients(OR3.68).

2.Patientstreatedmorethan300minutesfromstrokeonsetstill benefitted (OR2.43);most stopped enrolling at sixhours.

3.Patientsnoteligiblefor intravenousrt-PAstillbenefitted(OR2.43).

4.Intracranial bleeding was not significantly differentbetweenthetreatedpatientsandthecontrols.

5.Mortalitywas slightly better, but not significantly so, inthethrombectomygroup(15.3%vs18.9%).

REMOVAL OF INTRAVENTRICULAR CLOT IN ICH PATIENTS WITH VENTRICULAR BLEEDING DID NOT IMPROVE OUTCOMES … YETHanleyDF,LaneK,McBeeNetal.Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet2017;389:603-611.

Summary500 acute intracerebral hemorrhage patients (withhemorrhagevolume<30mL)inwhomanexternalventriculardrainhadbeenplacedforclinicalreasonswererandomizedto receive either repeated doses of rt-PA (1mg/dose) orsaline,afterrepeatedCTscansshowedthatthehemorrhagesizewasstable.Allpersonnelweremaskedregardingthedrug being administered. The primary outcome measurewasthemRSat180days,performedbyevaluatorsmaskedto the treatment assignment. There was no significantdifferenceinoutcomebetweenthegroups.Therewaslowermortalityat180daysinthetreatedgroup(hazardratio0.6),butatthecostofmorepatientswithseveredisability (RR1.99). Therewas nodifference in bleeding rates betweenthetwogroups.

Comments1.Getting into thisstudywasdifficult;10,538 ICUpatientswereevaluatedtorandomize500.

2.ThereisasignalsuggestingthatIVHvolume(calculatedbycomputer)of20mLorgreatermightbenefit…staytuned.

3.However,ingeneral,thereisnoapparentbenefitintryingto clear blood from the ventricular system with rt-PA,despitegreatenthusiasmfordoingso.

4.Investigators often guessed wrong regarding whetheran individualpatientwas receiving rt-PAorsaline;salinemighthavebeeneffective,althoughtherateofclearanceissimilartootherobservationalstudieswithoutintervention.

5.Therearenewdevicesthatcanremoveclot,buttheyareunprovenatthispoint.

AUTOIMMUNE ENCEPHALITIS IS THE MOST COMMONLY PROVEN ETIOLOGY OF REFRACTORY AND SUPER-REFRACTORY STATUS EPILEPTICUS Gaspard N, Foreman BP, Alvarez V, et al. New-onset refractory status epilepticus: Etiology, clinical features, and outcome.Neurology2015;85:1604-1613..

SummaryThis is a retrospective review of 130 cases of new-onset refractory status epilepticus (NORSE). 19% of thepatientshadanautoimmuneencephalitis,and18%hadaparaneoplasticdisorder.22%ofpatientsdied,12%hadagood outcome (mRS 0-1), 26% fair (mRS 2-3), and 39%poor (mRS4-5).UncontrolledSEwas thecauseofdeathin27%ofthepatientsinwhomanetiologywasfound,but59% of the cases in which no etiology was determined.Withdrawal of supportwas theproximatecauseofdeathin12patients..

Comments1.Of theautoimmuneencephalitides,anti-NMDAreceptorencephalitiswasthemostcommon.

2.Only8%ofpatientswereeventually shown tohaveaninfectiouscauseoftheirsyndrome.

3.In52%ofpatients,noetiologywasdetermined.4.38%ofpatientshadnoabnormalitiesonMRI.5.CSF was abnormal in 73%; 52% had a pleocytosis,but rarely above 15WBCs; protein was onlymodestlyelevated.

BRAIN-INJURED PATIENTS WHO CAN COUGH CAN BE EXTUBATED DESPITE A LOW GLASGOW COMA SCALE SCOREMcCredie VA, Ferguson ND, Pinto RL et al. Airway Management Strategies for Brain-injured Patients Meeting Standard Criteria to Consider Extubation. A Prospective Cohort Study. Ann Am Thorac Soc2017;14:85-93

SummaryThe authors prospectively identified 192 adult brain-injuredpatientsreceivingmechanicalventilation.79%wereextubated, and 21% underwent tracheostomy directly.Extubation failurewas nomore common in patientswhowere extubatedmore than 24 hours after intubation thanthoseextubatedearlier.LowerGCSoften lead toadelayin extubation when it was otherwise being considered,but higher GCS scores were not associated with moresuccessfulextubations..

Comments1.Diminishedconsciousnessisfrequentlycitedasareasonto delay extubation in patients who have adequateoxygenationandventilation.


SUNDAY, MAY 21 THE BRAIN AND CRITICAL CARE

2.Earlierstudieshavesuggestedthat,inthepresenceofanadequatecough,suchpatientscanbesafelyextubatedratherthanrequiringatracheostomy.

3.Inthisstudy,thepresenceofacoughwasthestrongestpredictorofextubationsuccess.

4.Although the presence of a gag reflex increased thelikelihood of successful extubation, the cough was amuchstrongerpredictor.

5.Increasingageandmorepositivefluidbalancedecreasedthelikelihoodofsuccess..

OTHER ARTICLES OF INTERESTBaharogluMI,CordonnierC,Al-ShahiSalmanR, et al.Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial.Lancet.2016;387(10038):2605-13.

DaSilva IR,GomesJA,WachsmanA,deFreitasGR,ProvencioJJ. Hematologic counts as predictors of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. J Crit Care.2017Feb;37:126-129.

deOliveiraManoelAL,GoffiA,MarottaTR,etal.The critical care management of poor-grade subarachnoid haemorrhage.Crit Care.2016Jan23;20:21.

Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al.Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: Executive Summary. A Statement for Healthcare Professionals From the Neurocritical Care Society and the Society of Critical Care Medicine.Crit Care Med.2016Dec;44(12):2251-2257.

Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD,CecconiM,CepkovaM,PogsonDG,AyaHD,AnjumA,FrazierGJ, Santhakumaran S, Ashby D, Brett SJ. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial.JAMA.2016;316(5):509-18.DOI:10.1001/jama.2016.10485

HanleyDF,ThompsonRE,MuschelliJ,etal.Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, open-label, phase 2 trial.Lancet Neurol.2016Nov;15(12):1228-1237.HockerSE,WijdicksEF.Neurologic complications of sepsis.Continuum (Minneap Minn).2014Jun;20(3NeurologyofSystemicDisease):598-613.LorussoR,BariliF,MauroMD,etal.In-Hospital Neurologic Complications in Adult Patients Undergoing Venoarterial Extracorporeal Membrane Oxygenation: Results From the Extracorporeal Life Support Organization Registry.Crit Care Med.2016Oct;44(10):e964-72.McGillF,HeydermanRS,PanagiotouS,TunkelAR,SolomonT.Acute bacterial meningitis in adults.Lancet.2016Dec17;388(10063):3036-3047.NeedhamDM,ColantuoniE,DinglasVD,etal.Rosuvastatin versus placebo for delirium in intensive care and subsequent

cognitive impairment in patients with sepsis-associated acute respiratory distress syndrome: an ancillary study to a randomised controlled trial. Lancet Respir Med.2016Mar;4(3):203-12.PurruckerJC,HaasK,RizosT,etal.Early Clinical and Radiological Course, Management, and Outcome of Intracerebral Hemorrhage Related to New Oral Anticoagulants.JAMA Neurol.2016Feb;73(2):169-77RamanJ,BallalA,HotaB,etal.Reconstructive valve surgery within 10 days of stroke in endocarditis.Asian Cardiovasc Thorac Ann.2016Jul;24(6):523-9OudeLansink-HartgringA,HesselsL,WeigelJ,etal.Long-term changes in dysnatremia incidence in the ICU: a shift from hyponatremia to hypernatremia. Ann Intensive Care.2016Dec;6(1):22.ShethKN,ElmJJ,MolyneauxBJ,etal.Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial.Lancet Neurol.2016Oct;15(11):1160-9.UdyAA,VladicC,SaxbyER,etal.Subarachnoid Hemorrhage Patients Admitted to Intensive Care in Australia and New Zealand: A Multicenter Cohort Analysis of In-Hospital Mortality Over 15 Years.Crit Care Med.2017Feb;45(2):e138-e145.WalterspacherS,KirchbergerA,LambeckJ,etal. Respiratory Muscle Assessment in Acute Guillain-Barré Syndrome.Lung.2016Oct;194(5):821-8


SUNDAY, MAY 21

Susan S. Redline, MD, MPHBrighamandWomen’sHospital

DepartmentofMedicineBoston,MA

COMORBIDITY OF SDB AND ASTHMAWangY,LiuK,HuK,YangJ,LiZ,NieM,DongY,HuangH,ChenJ.Impact of obstructive sleep apnea on severe asthma exacerbations.Sleep Med.2016;26:1-5

SummaryAsthma and obstructive sleep apnea (OSA) commonlyco-aggregate. There are several explanations for this,includingtheoccurrenceofcommonriskfactors(obesity)for each condition, as well as causal associations. Thisprospective study evaluated the incidence of asthmaexacerbations among 146 patients with asthma followedforoneyear.ItalsocomparedtheprevalenceofOSAintheasthmagroupwith157matchedcontrolswithoutasthma.OSAwasfoundin19.2%oftheasthmapatientsand9.6%of the controls (RR: 2.25; 1.15-4.40; p=0.016). A 14-foldincrease in asthma exacerbations was reported in thosewithOSAcompared to thosewithoutOSA.Frequencyofasthma exacerbations was correlated with level of AHIandovernighthypoxemia.Thesefindingswereinterpretedas evidence for OSA as a risk factor for asthma andasthma exacerbations.Mechanismsmay relate to a pro-inflammatorystatesecondarytoOSA-relatedhypoxiaandoxidative stress, elevations in leptin levels with immune-modulation,orOSA-relatedalterationsinparasympathetic-sympatheticbalance.

Comments1. The criteria (threshold) for diagnosing OSA were not

clear, although most appeared to have mild to moderate sleep apnea.

2. Although a high 14-fold increase in risk of asthma exacerbations was observed, the confidence intervals surrounding this estimate was large.

3. BMI was higher among the OSA group and its role in asthma exacerbation unclear.

4. The overall higher prevalence of OSA among asthmatics vs controls, and increased asthma exacerbations suggests value in considering each alternative condition when caring for asthmatic or OSA patients

TREATMENT OF SLEEP APNEA ON CARDIOVASCULAR OUTCOMESMcEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, ZhangX,MedianoO,ChenR,Drager LF, LiuZ,ChenG,DuB,McArdleN,MukherjeeS,TripathiM,BillotL,LiQ,Lorenzi-Filho G, Barbe F, Redline S, Wang J, Arima H, Neal B,White DP, Grunstein RR, Zhong N, Anderson CS.CPAP

for prevention of cardiovascular events in obstructive sleep apnea.N Engl J Med.2016;375:919-931

SummaryTheSAVEtrial–TheSleepApneaCardiovascularEndpointstrial is a large international randomized controlled trialevaluating the role of CPAP for secondary preventionof cardiovascular disease. The study randomized2,717 patients with moderate to severe OSA (oxygendesaturation>12)andexistingCVD,ages45 to75yearsold, toCPAP or usual care. The primary endpointwas acompositeofmyocardial infarction,stroke,hospitalizationfor unstable angina, heart failure, or transient ischemicattack. Participants were following for a mean of 3.7years. Despite support, patients used CPAP for anaverage of only 3.3 hours per night during the durationoftheintervention.NosignificantdifferencesbetweentheCPAPandcontrolgroupwereobserved in thecompositeendpoint or individual cardiovascular endpoint in primaryanalyses.However,secondaryanalysesshoweddecreasedsleepiness, anxiety, depression scores, reduced missedworkdays,andimprovedqualityoflife.Asubanalysisthatfocusedonpatientsadherent toCPAP (withapropensitymatched control group) showed a lower risk of stroke(hazardratio:0.56;95%CI0.32,1.0).Comments1.Patients with severe sleepiness (Epworth SleepinessScale >15) were excluded from the trial; thus, resultscannotbegeneralizedtothishighriskgroup.

2.Modest CPAP adherence result in a suboptimalintervention.

3.Despite lowCPAPadherence,significant improvementswereseeninmultiplepatientreportedoutcomes.

4.The results suggest that with adequate CPAP,cerebrovasculardisease, inparticular,maybenefit fromCPAP.

TREATMENT OF CENTRAL SLEEP APNEA: NEUROSTIMULATIONCostanzo MR, Ponikowski P, Javaheri S, Augostini R,GoldbergL,HolcombR,KaoA,KhayatRN,OldenburgO,StellbrinkC,AbrahamWT.Transvenous neurostimulation for central sleep apnoea: A randomised controlled trial. Lancet.2016;388:974-982

SummaryThe results from the SERVE-HF trial, which found thatadaptive servo-ventilation used in patients with centralsleepapneaandheartfailurewithreducedejectionfraction

SLEEP DISORDERED BREATHING


SUNDAY, MAY 21 SLEEP DISORDERED BREATHING

(EF<45%) was associated with increased cardiovascularmortality, left a void in treatment options for this patientpopulation.Phrenicnervestimulationisapromisingtherapybut long termdataare lacking.Aprospectivemulticenterrandomized trial evaluated the impact of a transvenousphrenic nerve stimulator (leading to diaphragmaticsimulation) on change in the AHI after 6 months oftreatment. 151 patients with predominant central sleepapnea(AHI>20;>50%centralevents)wererandomizedtotheneurostimulatorortonotreatment(deviceimplantationwithnostimulation).Thesamplewasheterogeneous,withheart failure present in 64%, diabetes in 30% and priorstrokein8%.At6months,theAHIwasreducedto>50%ofbaselinevaluein51%ofthetreatedgroupand11%ofthecontrolgroup(p<0.0001).However,meanfollowupAHIremained elevated evenwith treatment (25.4). Sleepinessand global quality of life improvedmore in the treatmentgroupcomparedtothecontrolgroup.At12months,8%ofthetreatmentgrouphasaseriousadverseeventassociatedwiththeprocedure/treatment.

Comments1.The study showed that transvenous neurostimulationof the phrenic nerve results in significant reductions intheAHI,particularlycentral events, inaheterogeneouspopulationwithpredominantcentralsleepapnea.

2.Although the AHI did not “normalize,” the interventionresulted in improved oxygen saturation, sleepiness,arousalindex,andglobalhealthscore.

3.The magnitude of improvement in AHI was similar towhathasbeenreportedforCPAPintheCANPAPtrial.

4.Additional research is needed to determine if clinicalendpointsareimpactedbythistreatment

TREATMENT OF OBSTRUCTIVE SLEEP APNEA IN PATIENTS WITH CORONARY ARTERY DISEASE: CPAPPeker Y, Glantz H, Eulenburg C, Wegscheider K, HerlitzJ, Thunstrom E. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with non-sleepy obstructive sleep apnea: The RICCADSA randomized controlled trial.Am J Respir Crit Care Med.2016;194(5):613-20.

SummaryThe RICCADSA (Randomized Intervention with CPAP inCAD and OSA) is a single site, prospective randomizedcontrolled trial that examined the impact ofCPAP (vs noCPAP)inpatientswithmoderateOSA(AHI>15)andwithoutsleepiness (Epworth Sleepiness Scale score < 10) whohada recent coronary artery revascularizationprocedure.The primary endpoint was a composite cardiovascularendpoint (repeat revascularization, myocardial infarction,or cardiovascularmortality). A total of 244 patients wererandomizedtooneofthetreatmentarms,andfollowedforamedian of 57months. The incidence of the composite

endpointwas18.1%intheCPAPgroupand22.1%inthecontrolgroup,resultinginanon-significanthazardratioof0.80; 0.10-0.86). Almost 50% of those prescribed CPAPreturneditafter2yearsuse.ThosewhocontinuedtouseCPAP for more than 4 hours per night had a significantreductionincardiovasculareventscomparedtothosewhowerenotadherenttoCPAP.

Comments1.CPAPadherenceislowamongnon-sleepypatientswithcoronaryarterydisease.

2.The study suggested a high rate of moderate sleepapneainpatientswithcoronaryarterydisease.

PREGNANCY AND SLEEP APNEAFacco FL, Parker CB, Reddy UM, Silver RM, Koch MA,Louis JM, Basner RC, Chung JH, Nhan-Chang CL, PienGW,RedlineS,GrobmanWA,WingDA,SimhanHN,HaasDM, Mercer BM, Parry S, Mobley D, Hunter S, SaadeGR, Schubert FP, Zee PC.Association between sleep-disordered breathing and hypertensive disorders of pregnancy and gestational diabetes mellitus.Obstetrics and gynecology.2017;129:31-41

SummaryThe nuMoM2b (Nulliparous Pregnancy Outcomes Study:Monitoring Mothers To Be) is a multicenter prospectivecohortstudyofnulliparouswomenstudiedinearlyandlatepregnancy with in-home sleep apnea testing. This studyaimed todeterminewhethersleepapneawasassociatedwith an increase incidence of hypertensive disorders orpregnancyandgestationaldiabetes.Intotal,3,705womenwerestudied.Sleepdisorderedbreathing(SDB),definedasanAHI>5,waspresentin3.6%ofwomeninearlypregnancyandin8.3%ofwomeninlatepregnancy.Afteradjustingforage,BMIandchronichypertension,SDBwasassociatedwithanalmost2-foldincreasedprevalenceofpreeclampsiaand 3.5-fold increased prevalence of diabetes. Higherlevels of AHI categories were associated with increasedodds for gestational diabetes and hypertensive disordersofpregnancy.

Comments1.The prevalence of SDB increases from early to latepregnancy.

2.IndependentofageandBMI,SDBisassociatedwithanincreased risk of hypertensive disorders of pregnancyandgestationaldiabetes.

3.The extent to which results could be confounded byvisceralobesity,sedentaryactivity,insufficientsleepandracewasnotfullyevaluated.

4.Prevalence of hypertensive disorders and gestationaldiabetesincreaseswithincreasingseverityofSDB.


SLEEP DISORDERED BREATHINGSUNDAY, MAY 21

HEART FAILURE AND SLEEP APNEAJavaheriS,BlackwellT,Ancoli-IsraelS,EnsrudKE,StoneKL,RedlineS.Sleep-disordered breathing and incident heart failure in older men.Am J Respir Crit Care Med. 2016;193:561-5681

SummaryA prospective cohort study of 2,865 men (mean age 76years) followed for a mean of 7.3 years was conductedto determine whether sleep disordered breathing (SDB)at baseline was associated with an increased risk ofdeveloping incidentordecompensatedheart failure.SDBwasmeasuredusingfullin-homepolysomnography(Type2device).Heartfailurewasadjudicated.Analysesseparatedthe influences from predominant central from obstructivesleepapnea.11%of thesamplehadanelevatedcentralapneaindex(>5)orCheyneStokesRespiration(CAI/CSR).45% had an obstructive apnea index > 15, consistentwithmoderate SDB. After adjusting formultiple potentialconfounders, including baseline heart failure, CSA andCSRwere each associatedwith a significantly increasedincidence of incident heart failure (Odds ratios: 1.55 to2.29).Theseresultsremainedsignificantafteradjustingforsleep fragmentation, hypoxemia and obstructive apnea.TheObstructiveApneaHypopneaIndexwasnotassociatedwithincidentheartfailureafteradjustingforconfounders..

Comments1.BothCheyneStokesRespiration (definedaspresentorabsent:>10minutes)andCentralApneaIndex(>5)weresignificantlyassociatedwith incidentheart failure, evenafteradjustingforconfounders.

2.CheynesStokesRespirationwasmorestronglyassociatedwithincidentheartfailurethantheCentralApneaIndex,and this association persisted after adjusting for sleepfragmentationandhypoxemia.

3.The relationship between incident heart failure andObstructive Sleep Apneawas confounded by age andobesity.

4.Itispossiblethatincreasedsympatheticnervousactivity,associatedwithCSR/CSA,contributestoadversecardiacfunction.

5.Astudyweaknesswasthelackofcardiacimagingdataandinabilitytofullyteaseapartthecausalassociations..

OTHER ARTICLES OF INTERESTLiu L, Cao Q, Guo Z, Dai Q. Continuous positive airway pressure in patients with obstructive sleep apnea and resistant hypertension: A meta-analysis of randomized controlled trials.J Clin Hypertens (Greenwich).2016;18:153-15.

Campos-Rodriguez F, Queipo-Corona C, Carmona-Bernal C,Jurado-GamezB,Cordero-GuevaraJ,Reyes-NunezN,Troncoso-Acevedo F, Abad-Fernandez A, Teran-Santos J, Caballero-RodriguezJ,Martin-RomeroM,Encabo-MotinoA,Sacristan-BouL, Navarro-Esteva J, Somoza-Gonzalez M, Masa JF, Sanchez-

Quiroga MA, Jara-Chinarro B, Orosa-Bertol B, Martinez-GarciaMA. Continuous positive airway pressure improves quality of life in women with obstructive sleep apnea. A randomized controlled trial.Am J Respir Crit Care Med.2016;194:1286-1294.

Bakker JP, Wang R, Weng J, Aloia MS, Toth C, MorricalMG, Gleason KJ, Rueschman M, Dorsey C, Patel SR, WareJH, Mittleman MA, Redline S. Motivational enhancement for increasing adherence to cpap: A randomized controlled trial. Chest.2016;150:337-345.


MONDAY, MAY 22

Tamera J. Corte, MBBS, BSc(Med), PhDRoyalPrinceAlfredHospitalandUniversityofSydney

DepartmentofRespiratoryMedicineSydney,NSW,Australia

EARLY DIAGNOSIS OF INTERSTITIAL LUNG DISEASEArakiT,PutmanRK,HatabuH,GaoW,DupuisJ,LatourelleJC,NishinoM,ZazuetaOE,KurugolS,RossJC,SanJoseEsteparR,SchwartzDA,RosasIO,WashkoGR,O’ConnorGT,HunninghakeGM.Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study. Am J Respir Crit CareMed.2016;194:1514-1522.

SummaryIn this pivotal study from the Framingham Heart Studypopulation, the prevalence, progression and prognosticutility of subclinical interstitial lung abnormalities (ILA)is evaluated. ILA have been associated with decreasedpulmonaryfunctiontestsandreducedexercisecapacity,butthenaturalhistoryoftheirprogressioniswellunderstood.Inthisstudy,1867subjectswith2sequentialchestcomputedtomography (CT) scans (mean difference 6.4yrs), wereindependently scored by three blinded reviewers for thepresenceof ILA, the radiologicalpattern,and thechangebetween the two CT scans. This study demonstratesthat 8% of the participants had ILA, with the majority(83%) having a subpleural reticular pattern. In addition,6% had developed or had progressive ILA during thefollow up period. Subjects with progression were morelikely to be older, have a greater smoking exposure, andmore likely to have increasing copies of the MUC5Bpromoter polymorphism. Thosewith ILAprogression hadgreaterphysiologicaldeclineandincreasedmortalitythanthose without ILA. This increased mortality has beenconfirmed separately by the same investigators in fourseparate cohorts. These findings suggest that theremaybe important clinical implications for early, subclinicalinterstitiallungabnormalities.

Comments1.Overasixyear followupperiod, thedevelopmentandprogressionofILAarecommonlyobserved(in6%)inthegeneralpopulation.

2. There are demographic and genetic risk factors forprogressionofILAincludingolderage,increasedtobaccosmokeexposure,andtheMUC5Bpromotergenotype

3. ILA progression is associatedwith accelerated clinicaldeclineandincreasedriskofdeathduringfollowup.

4. There may be important clinical consequences forsubjectswithsubclinicalILA.

5.Considerationastotherisksandbenefitsforscreeningfor early diagnosis of interstitial lung disease must beevaluatedinfurtherstudies.

DIAGNOSIS OF INTERSTITIAL LUNG DISEASE (MULTIDISCIPLINARY TEAM MEETING)Walsh SL, Wells AU, Desai SR, Poletti V, Piciucchi S,DubiniA,NunesH,ValeyreD,BrilletPY,KambouchnerM,et.al. Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study. Lancet Respir Med 2016;4:557-565.

SummaryIn this multicenter evaluation of 70 patients presentingto the interstitial lung disease (ILD) unit at the RoyalBrompton Hospital, London, the agreement betweenmultidisciplinaryteammeetings(MDTM)insevencountriesfor the diagnosis of ILD was assessed. Clinicians,radiologists and pathologists (if biopsy was performed)at each site independently assessed each case, andselected up to five differential diagnoses each with itsdiagnostic confidence (%). This process was repeatedby each site at their MDTM. The overall agreementfor first-choice ILD diagnosis between MDTM was onlymoderate(Kappa0.50),althoughtheagreementforafirst-choicediagnosis of idiopathicpulmonary fibrosis (IPF) orconnectivetissuedisease-relatedILDwasgood(weightedKappa0.71;0.73respectively).ThedistinctionbetweenIPFand other ILD diagnoses at eachMDTMwas supportedby a non-significant difference inmortality during follow-up.These findingshavehighclinical relevance,given therecommendationforILDdiagnosisatMDTMinthecurrentguidelines. While it is reassuring that the inter-MDTMagreementforthediagnosisof IPFandCTD-ILDisgood,it is somewhat disconcerting that the gold-standard forotherILDdiagnosesisvariableacrosscenters.ThisstudyhighlightstheimportanceofstandardizingMDTMandILDdiagnosisglobally.

Comments1.Thereisonlymoderatediagnosticagreementoverallforthefirst-choiceILDdiagnosisbetweenMTDM.

2.Diagnostic agreement betweenMDTM is good for IPFandCTD-ILD.

3.Thediagnosticagreementforhypersensitivitypneumonitiswaslow.

4.ThispivotalstudyhighlightstheneedforstandardizationoftheapproachtoILDdiagnosisatMDTMglobally.

5.In particular, this study lends support for the need formore specific diagnostic criteria for the diagnosis ofhypersensitivitypneumonitis.

ILD


MONDAY, MAY 22 ILD

TRIGGERS OF PROGRESSION OF INTERSTITIAL LUNG DISEASEKreuter M, Wuyts W, Renzoni E, Koschel D, Maher TM,KolbM,WeyckerD,SpagnoloP,KirchgaesslerKU,HerthFJ,CostabelU.Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis.Lancet RespirMed2016;4:381-389.

SummaryIn this large post-hoc analysis of patients from theplacebogroupfromthethreephaseIIIpirfenidonestudies(CAPACITY004,CAPACITY006,andASCEND),theeffectof antacid therapy at baselinewas evaluated against IPFdisease progression. Gastro-oesophageal reflux diseasehas a relatively high prevalence in patientswith IPF, andto date, its relationship with the pathogenesis of thedisease remains unclear. Several retrospective studieshavesuggestedasurvivalbenefitforpatientstreatedwithantacid therapy, or indeed surgical fundoplication. In thisstudy, the effect of antacid therapy use (either histamineH2-receptorantagonistsorproton-pumpinhibitors;n=291,47%) vsnoantacid therapy (n=333,53%)wasevaluatedagainst theprimaryendpoint,diseaseprogressionatoneyear. Interestingly, there was no significant differencedemonstrated in disease progression between the twogroups(p=0.484),norforall-causeorIPFrelatedmortality.Adverseeventswerealsosimilarbetweenthetwogroups,except for infection andpulmonary infectionwhichwere,infact,higherinpatientswithadvancedIPFusingantacidtherapy versus those not using antacid therapy. Thesefindings are particularly pertinent to consider in view ofthe conditional 2015ATS/ERSguideline recommendationin favor of antacid therapy for asymptomatic gastro-oesophagealrefluxinIPFpatients.

Comments1.In contrastwith the findings of previous studies, thesefindingsdonotsupportanybeneficialeffectofantacidtherapyinpatientswithIPF.

2.PatientswithadvancedIPFwhoreceivedantacidtherapyhad a significantly higher incidence of overall andpulmonary infections than those not receiving antacidtherapy.

3.Long-term controlled studies are urgently needed tofurtherevaluatetheeffectofantacidtherapyinpatientswithIPF,particularlyadvanceddisease.

IPF BIOMARKERSWhiteES,XiaM,MurrayS,DyalR,FlahertyCM,FlahertyKR, Moore BB, Cheng L, Doyle TJ, Villalba J, DellaripaPF,Rosas IO,KurtisJD,MartinezFJ.Plasma Surfactant Protein-D, Matrix Metalloproteinase-7, and Osteopontin Index Distinguishes Idiopathic Pulmonary Fibrosis from Other Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med2016;194:1242-1251.

SummaryInthislandmark,biomarkerstudy,apanelof35extracellularmatrix (ECM)-related and lung specific proteins wereevaluatedfortheirutilitytodistinguishIPFfromalternativeinterstitiallungdiseases(a-ILD).Aderivationcohortof86IPFpatientswasanalyzedtodeterminetheoptimalbiomarkerpanel, before this was applied to a separate validationcohort. The pre-specified panel of biomarker analyteswas analyzed via five multiplexed assays simultaneously(FibroPlexversion2).Thethreebestperformingcandidatebiomarkerswereconsistentlymetalloproteinase7(MMP-7),surfactantproteinD(SPD)andosteopontin.Amultivariablemodel incorporatingthesebiomarkerswasconstructedtobestdistinguishIPFfroma-ILD.ThecombinationofthesebiomarkersledtoanadjustedareaunderthecurveforIPFdiagnosis of 0.766 with 82.6% of IPF patients having atleastonebiomarkerabovethethresholdlevel.Aone-pointelevationinthebiomarkerindexscoreledtoa1.9xhigherlikelihood of an IPF diagnosis (p=0.005). These findingswere confirmed in the validation cohort. Interestingly, thebiomarkerprofiledidnotdistinguishIPFfromRheumatoidArthritisassociatedILD.

Comments1.PlasmalevelsofSP-D,MMP-7,andosteopontinmaybeuseful(aloneandincombination)todistinguishIPFfromalternativeILD.

2.Therewasnoutility for thisplasmabiomarkerpanel todistinguishIPFfromRheumatoidArthritisassociatedILD.

3.ThesefindingshavepotentialclinicalimplicationforILDpatientswithanuncertaindiagnosis,whoareunableorunwillingtoundergosurgicallungbiopsy.

4.Furtherstudies, includingthisbiomarkerpanel togetherwith traditional clinical markers predictive of an IPFdiagnosisarenecessary.

ACUTE EXACERBATION OF IDIOPATHIC PULMONARY FIBROSISCollardHR,RyersonCJ,Corte TJ, JenkinsG,KondohY,LedererDJ,LeeJS,MaherTM,WellsAU,AntoniouKM,et,al.Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report.Am J Respir Crit Care Med 2016;194:265-275.

SummaryThisinternationalworkinggroupprovidesacomprehensiveupdate on acute exacerbation of idiopathic pulmonaryfibrosis (AE-IPF). Key changes proposed by this workinggroup included the removal of the term “idiopathic”from the definition of AE-IPF in recognition that there islittle clinical or biological data supporting the distinctionbetween idiopathic and non-idiopathic exacerbations.The revised definition of AE-IPF proposed is “an acute,clinicallysignificant respiratorydeteriorationcharacterizedby evidence of new,widespread alveolar abnormality.” Asecondimportantchangeinthediagnosticcriteriawasthe


MONDAY, MAY 22 ILD

changefromthemorespecific timeperiodof30days, to“typicallylessthanonemonth”toallowmoreflexibilityinthediagnosisofAE-IPF.Athirdchangeincludedtheexclusionof cardiac failure or fluid overload as the cause of therespiratorydeterioration.Whiletherearemanyunansweredquestions with regard to the etiology, pathobiology andmanagement of AE-IPF, this working group provides aconceptual framework for respiratory deterioration in IPF,allowingthesequestionstobesystematicallyapproachedinfutureresearchstudies.

Comments1.The revised definition of AE-IPF is “an acute, clinicallysignificant respiratory deterioration characterized byevidenceofnewwidespreadalveolarabnormality.”

2.Thetime-frameforAE-IPFhasbeenredefinedasacuteworseningordevelopmentofdyspneatypicallylessthanonemonthduration.

3.ThetermidiopathichasbeenremovedfromtheAE-IPFdefinition, inrecognitionthatthere is littletodistinguishidiopathicfromnon-idiopathicexacerbations.

4.ThedeteriorationofAE-IPFmustnotbe fullyexplainedbycardiacfailureorfluidoverload.

5.WhilethisworkinggroupprovidesaclearframeworktoconsiderAE-IPF, therearemanyunansweredquestionswhichurgentlyneedassessmentinfutureclinicaltrials.

TREATMENT OF INTERSTITIAL LUNG DISEASETashkin DP, Roth MD, Clements PJ, Furst DE, KhannaD, Kleerup EC, Goldin J, Arriola E, Volkmann ER, KafajaS, et.al, Scleroderma Lung Study III. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med2016;4:708-719.

SummaryThis multicenter double-blind parallel group randomizedcontrolledtrialfrom14centersacrosstheU.S.Aevaluatedthe use of mycophenolate mofetil compared to oralcyclophosphamide in patients with scleroderma-relatedinterstitial lung disease ofmoderate severity (forced vitalcapacity,FVC45-80%).142patientswere randomized toreceivemycophenolatemofetil(n=69;targetdose1500mgtwice daily) for 24 months, or oral cyclophosphamide(n=72;targetdose2mg/kg/day)for12monthsfollowedbyplacebo for 12months. The primary endpoint, change inFVCasapercentageofthepredictedvalue(FVC%)overthecourseof24months,wasassessedinamodifiedintention-to-treatanalysis.Of the126patients included in the finalanalysis,theadjustedFVC%improvedfrombaselineto24monthsby2.19%inthemycophenolatemofetilgroupand2.88%inthecyclophosphamidegroup,withnodifferencein the course of the FVC% between the two treatmentgroups. Fewer patients receiving mycophenolate mofetilhad significant side effects, withdrew from the study

drug, or died (7% vs 15%) compared to those receivingcyclophosphamide. Improvements in skin scores anddyspnea scores with both therapies suggest an overallsystemicbenefitforbothmedications.

Comments1.Treatment of scleroderma-related interstitial lungdisease with either mycophenolate mofetil for 2 yearsor cyclophosphamide for 1 year leads to small butsignificantimprovementsinFVC%.

2. There was no additional efficacy of mycophenolatemofetiloveroralcyclophosphamideforthetreatmentofscleroderma-relatedinterstitiallungdisease.

3.Mycophenolatemofetilwasassociatedwithlesstoxicityand was better tolerated, with fewer withdrawals thanoralcyclophosphamide

4.Thesefindingssupporttheincreasingclinicaluseofbothmycophenolate mofetil and oral cyclophosphamide forpatientswithscleroderma-relatedinterstitiallungdisease.

OTHER ARTICLES OF INTERESTDIAGNOSING INTERSTITIAL LUNG DISEASEJacobJ,BartholmaiBJ,RajagopalanS,KokosiM,NairA,KarwoskiR, Walsh SL, Wells AU, Hansell DM. Mortality prediction in idiopathic pulmonary fibrosis: evaluation of computer-based CT analysis with conventional severity measures.Eur Respir J 2017;49.

TomassettiS,WellsAU,CostabelU,CavazzaA,ColbyTV,RossiG, Sverzellati N, Carloni A, Carretta E, BuccioliM, TantaloccoP,RavagliaC,GurioliC,DubiniA,PiciucchiS,RyuJH,PolettiV. Bronchoscopic Lung Cryobiopsy Increases Diagnostic Confidence in the Multidisciplinary Diagnosis of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2016; 193:745-752.

PROGRESSION OF INTERSITITAL LUNG DISEASELeyB,BradfordWZ,VittinghoffE,WeyckerD,duBoisRM,CollardHR.Predictors of Mortality Poorly Predict Common Measures of Disease Progression in Idiopathic Pulmonary Fibrosis.Am J Respir Crit Care Med 2016;194:711-718.

RussellAM,AdamaliH,MolyneauxPL,LukeyPT,MarshallRP,Renzoni EA, Wells AU, Maher TM. Daily Home Spirometry: An Effective Tool for Detecting Progression in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2016; 194:989-997.

PATHOBIOLOGY AND GENETICS OF INTERSTITIAL LUNG DISEASEMolyneauxPL,WillisOwenSA,CoxMJ, JamesP,CowmanS,LoebingerM, Blanchard A, Edwards LM, Stock C, Daccord C,Renzoni EA, Wells AU, Moffatt MF, Cookson WO, Maher TM.Host-Microbial Interactions in Idiopathic Pulmonary Fibrosis.Am J Respir Crit CareMed2017.

Fingerlin TE, Zhang W, Yang IV, Ainsworth HC, Russell PH,Blumhagen RZ, Schwarz MI, Brown KK, Steele MP, Loyd JE,et.al. Genome-wide imputation study identifies novel HLA


MONDAY, MAY 22

locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genet2016;17:74.

NewtonCA,BatraK,TorrealbaJ,KozlitinaJ,GlazerCS,AravenaC,MeyerK,RaghuG,CollardHR,GarciaCK.Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive.Eur Respir J2016;48:1710-1720.

PetrovskiS,ToddJL,DurheimMT,WangQ,ChienJW,KellyFL,FrankelC,MebaneCM,RenZ,BridgersJ,UrbanTJ,MaloneCD,FinlenCopelandA,BrinkleyC,AllenAS,O’RiordanT,McHutchisonJG, Palmer SM, Goldstein DB. An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis. Am J Respir Crit Care Med2017.

TREATMENT OF INTERSTITIAL LUNG DISEASEKhannaD,AlberaC,FischerA,KhalidiN,RaghuG,ChungL,ChenD,SchiopuE,TagliaferriM,SeiboldJR,GorinaE.An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial.J Rheumatol2016;43:1672-1679.

Kreuter M, Wijsenbeek MS, Vasakova M, Spagnolo P, KolbM, Costabel U, Weycker D, Kirchgaessler KU, Maher TM.Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis: methodological concerns.Eur Respir J 2016;48:1524-1526.

BehrJ,BendstrupE,CrestaniB,GuntherA,OlschewskiH,SkoldCM, Wells A, Wuyts W, Koschel D, Kreuter M, Wallaert B, LinCY,BeckJ,AlberaC.Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial.Lancet Respir Med2016;4:445-453.

Nathan SD, Albera C, Bradford WZ, Costabel U, GlaspoleI, Glassberg MK, Kardatzke DR, Daigl M, Kirchgaessler KU,Lancaster LH, Lederer DJ, Pereira CA, Swigris JJ, Valeyre D,NoblePW.Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis. Lancet Respir Med 2017;5:33-41.

RaghuG,Wells AU, Nicholson AG, Richeldi L, Flaherty KR, LeMaulfF,StowasserS,Schlenker-HercegR,HansellDM.Effect of Nintedanib in Subgroups of Idiopathic Pulmonary Fibrosis by Diagnostic Criteria.Am J Respir Crit Care Med2017;195:78-85.

INTERSTITIAL LUNG DISEASE SYMPTOMSSwigris JJ, Esser D, Wilson H, Conoscenti CS, Schmidt H,StansenW, LeidyNK, BrownKK. Psychometric properties of the St George’s Respiratory Questionnaire in patients with idiopathic pulmonary fibrosis.Eur Respir J2017;49.

MilneKM,KwanJM,GulerS,WinstoneTA,LeA,KhalilN,CampPG,Wilcox PG, Ryerson CJ. Frailty is common and strongly associated with dyspnoea severity in fibrotic interstitial lung disease.Respirology2016Nov9.doi:10.1111/resp.12944

ILD


MONDAY, MAY 22

MeiLan K. Han, MD, MSUniversityofMichigan

DivisionofPulmonaryandCriticalCareAnnArbor,MI

SCREENING FOR COPDSiu AL, Bibbins-Domingo K, Grossman DC, DavidsonKW, Epling JW, Garcia FA, GillmanM, Kemper AR, KristAH,KurthAE, LandefeldCS,MangioneCM,HarperDM,Phillips WR, Phipps MG, Pignone MP. Screening for Chronic Obstructive Pulmonary Disease: US Preventive Services Task Force Recommendation Statement.JAMA2016;315:1372-7.

SummaryEstimates suggest a significant number of individualswithCOPDareundiagnosed,but thebestway to identifytheseindividualshasnotbeencompletelyclear.Inits2016update,theU.S.PreventiveServicesTaskForce(USPSTF)maintained its 2008 recommendation against screeningasymptomatic adults for COPD including the use ofprescreeningquestionnairesandspirometry.Thetaskforcebasedtheirrecommendationonlackofadequateevidencethat screening asymptomatic persons alters the courseof disease or improves health outcomes. Asymptomaticindividualsaredefinedasindividualswhodonotrecognizeor report respiratory symptoms,but the report states thisdoesnotapplytoat-riskpersonswhopresenttoclinicianswithsymptomssuchaschroniccough,sputumproduction,dyspneaorwheezeortoindividualswithafamilyhistoryofalpha-1antitrypsindeficiency.Thereportalsoemphasizesthatalladultswhousetobaccoshouldbecounseledtoquit.Thereportalsonotesthatfuturetrialsareneededtobetterassess the effects of screening and treatment of at-riskindividualsinprimarycareonlong-termhealthoutcomes.

Comments1.Whilethisrecommendationisbasedonthebestavailableevidence,itisworthnotingthekeyword“asymptomatic.”ManyindividualsatincreasedriskforCOPDself-restrictactivitytominimizesymptoms.

2.Therecommendation isbasedon lackofevidence,notnegative evidence. USPSTF actually found no studiesthatdirectlyassessedtheeffectsofscreeningforCOPDinasymptomaticadultsonmorbidity,mortality,orhealth-relatedqualityoflife.TheUSPSTFalsofoundnostudiesthatexaminedtheeffectivenessofscreeningonrelevantimmunizationrates.

3.The recommendation assumes thatmedical treatmentsforCOPD reduce symptomsandexacerbationsbutdonotalternaturalhistoryorreducemortality.

4.TheUSPSTFalsofoundnostudiestoprovideevidenceto estimate the short- or long-term harms of thesescreeningtests.

5.TheGlobalInitiativeforChronicObstructiveLungDiseaserecommends case-finding in symptomatic patientsbut does not recommend screening in asymptomaticpopulations.

SYMPTOMATIC SMOKERS WITH PRESERVED SPIROMETRYWoodruffPG,BarrRG,BleeckerE,ChristensonSA,CouperD,CurtisJL,GouskovaNA,HanselNN,HoffmanEA,annerRE,KleerupE,LazarusSC,MartinezFJ,PaineR,RennardS, Tashkin DP, Han MK for the SPIROMICS ResearchGroup.Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function. N Engl J Med 2016;374:1811-21.

SummaryAdiagnosisofCOPD iscurrentlybasedon thepresenceofairflowobstructionasdefinedbyapost-bronchodilatorforced expiratory volume in 1 second (FEV1) to forcedvital capacity (FVC) ratioof less than0.70assessedwithspirometry.However, it is recognized that some smokerswhodonotmeetthisdefinitionforairflowobstructionstillexperience significant respiratory symptoms. Woodruffandcolleaguesperformedananalysisof theSPIROMICScohort and demonstrated that among current or formersmokers with preserved pulmonary function, those whowere symptomatic, as defined by a COPD AssessmentTest (CAT) score ≥ 10, had a higher rate of respiratoryexacerbations (0.27 vs. 0.08 events per year, p<0.001),a shorter 6-minutewalkdistance andgreater airwaywallthickening on chest CT as compared to unobstructedsmokers who were asymptomatic. In fact, exacerbationfrequency and airway wall thickening approached thelevel of abnormality seen in symptomatic GOLD 1 and2 individuals. However, the “symptomatic smokers withpreserved spirometry” had a paucity of emphysema ascompared to GOLD 1 and 2 individuals. Many of thesesymptomaticsmokerswerealreadybeingtreatedbytheirown physicians with bronchodilators (42%) and inhaledcorticosteroids(23%).

Comments1.Thisstudyhighlightstheneedtothinkaboutthebroadereffects of smoking related morbidity beyond COPDalone.

2.Itremainsuncertainatthispointwhetherthesepatientsrepresent a transitional pre-COPDphaseor a separateclinicalentity.

COPD


MONDAY, MAY 22 COPD

3.Additionalanalyseswereperformedtoadjustforhistoryofasthmaandcurrentsmokingandtheresultsremainedessentiallythesame.

4.The authors also demonstrated that CAT score wasa better predictor for future exacerbations than post-bronchodilatorFEV1.

5.The fact that a significant proportion of individualsstudiedwerealreadybeingtreatedwithbronchodilatorsunderscorestheneedtoestablishatherapeuticevidencebasisforthispatientpopulation.

SUPPLEMENTAL OXYGEN IN COPDLong-Term Oxygen Treatment Trial Research Group.A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation. N Engl J Med.2016;375(17):1617-1627.

SummaryTheuseofsupplementaloxygenforpatientswithmild-to-moderatehypoxemia inCOPDiswidespread,butupuntilrecentlytheevidencebasisforthiswasprovidedprimarilyby two trials conducted in patients with severe restinghypoxemia. The Long-Term Oxygen Treatment Trial wasoriginally designed to determine whether supplementaloxygeninCOPDpatientswithmoderaterestingdesaturation(oxyhemoglobin saturation of 89-93%) delays time todeath, after sevenmonths and the randomization of only34patients,thetrialwasredesignedtoalsoincludepatientswithmoderate exercise-induceddesaturation (SpO280%for≥5minutesand<90%for≥10minutesduring6-minutewalktest)andtoincorporatetimetofirsthospitalizationforany cause into a composite primary outcome. Ultimately738 patients were randomized to receive long-termsupplementaloxygen(24-houroxygenforthosewithrestingdesaturationandduringexerciseandsleepfor thosewithexercise desaturation) versus no long-term supplementaloxygen. In time-to-event analysis, no difference betweensupplementalandno-supplementaloxygengroupsintimeto death or first hospitalization was found (hazard ratio0.94;95%CI0.79-1.12;p=0.52).Nodifferenceinratesofhospitalization, COPD exacerbations, quality of life, lungfunctionor6-minutewalkdistancewasdetected.Comments1.Patients in the supplemental-oxygen groupwho had aCOPDexacerbation1-2monthsbeforeenrollment,thosegreaterthan71yearsatenrollmentandthosewithlowerquality of life at enrollment did experience longer timeto death or first hospitalization although these effectsdid not remain significant when adjusted for multiplecomparisons.

2.Lack of evidence for benefit should not be confusedwitha lackofclinicaleffectiveness insomepatients.Atrialofoxygentherapymaystillbewarrantedinselectedpatients with moderate exertional hypoxemia andintractablebreathlessnessdespiteappropriateevidence-basedtreatmentotherwise.

3.The LOTT was an unblinded study which may haveconfoundedtheresults.

4.Meanoxygenusewas15.1hoursperdayinthe24-hourgroup and 11.3 hours per day in the sleep-exercisegroup. The possibility that longer exposures to oxygenmighthavegivendifferentresultscannotbeexcluded.

5.At this time, there has been no change in Medicarereimbursement guidelines for supplemental oxygen inpatientswithCOPD.

DUAL BRONCHODILATORS AND COPD EXACERBATIONSWedzicha JA, Banerji D, Chapman KR, Vestbo J, RocheN,AyersRT,ThachC,FogelR,PatalanoF,VogelmeierCFfortheFLAMEInvestigators.Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD.N Engl J Med 2016;374:2222-34.]

SummaryWhile there an increasing number of LABA/LAMA (longacting beta agonist / long acting muscarinic antagonist)combination inhalers available on the market for COPD,their role in the treatment of COPD and in particulartheir effectiveness in the prevention of exacerbations ascompared to ICS/LABA (inhaled corticosteroid / LABA)therapy has been less clear. The FLAME trial was a3,362 person, 52-week study comparing the efficacy ofa LABA/LAMA (indacaterol/glycopyrronium) with an ICS/LABA (fluticasone propionate / salmeterol) in decreasingtheannual rateofCOPDexacerbations.Thisstudy foundan 11% lower rate of exacerbations in the indacaterol/glycopyrronium treated group as compared to thesalmeterol/fluticasone group (rate ratio 0.89, p=0.0003).Those treated with indacaterol/glycopyrronium also hada longer time to first exacerbation (71 days vs. 51 days;p<0.001) and a lower annual rate ofmoderate or severeexacerbations(rateration0.83,p<0.001).Theexacerbationsremained lower in the indacaterol-glycopyrronium treatedarmregardlessofthebaselinebloodeosinophilcount.Theincidenceofpneumoniawasalsolowerintheindacaterol/glycopyrroniumtreatedsubjects,3.2%vs.4.8%,p=0.02.

Comments1.Data fromFLAMEhelped to inform theupdatedGOLD2017 statement that recommends LABA/LAMA as firstchoicetherapyforGOLDpatients.

2.Among individuals with greater than or equal to 2%blood eosinophils, the rate of moderate or severeexacerbations was still significantly lower in theindacaterol/glycopyrronium treated group than thesalmeterol/fluticasone group, rate ratio 0.85, p=0.01.Additional analyses examining other eosinophil cutoffsdemonstratedsimilarresults.

3.Thesedata should be interpreted in the context of theWISDOM study (Withdrawal of Inhaled Steroids duringOptimized Bronchodilator Management) trial wherepost hoc analyses demonstrated that withdrawal of


COPDMONDAY, MAY 22

inhaledglucocorticoidsdidincreasetherateofmoderateand severe exacerbations among individuals with abloodeosinophil countof 4%orhigheror anabsoluteeosinophilcountofatleast300cellspermicroliter.

4.The definition for a moderate exacerbation requiringtreatmentwithsystemiccorticosteroidsorantibioticsorboth and severe requiring hospitalization is consistentwithotherstudies.However, itshouldbenotedthatanelectronic diary, completed by the patient twice daily,was also used to assess symptoms and if diary datasuggestedworsening of symptoms, the diary triggeredanalarmforthepatienttocontactthesite.Itispossibleuseoftheelectronicdiaryinfluencedtherateandtypesofexacerbationsreported.

5.More data are still need on longer term outcomescomparing LABA/LAMA to ICS/LABA and on whetherthere are subgroups of patients whomight experiencegreaterbenefitfromtreatmentwithonetreatmentregimenovertheother.

ICS/LABA AND CARDIOVASCULAR MORTALITY IN COPD VestboJ,Anderson.JA,BrookRD,CalverleyPM,CelliBR,Crim C, Martinez F, Yates J, Newby DE for the SUMMITInvestigators. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial.Lancet2016;387:1817-26

SummaryWhile studies to date suggest good efficacy of inhaledtherapies in COPD for symptom improvement andexacerbationreduction,nostudytodatehasdemonstratedanimpactoftherapyonmortality.SUMMITwasadouble-blind,randomizedclinicaltrialperformedat1,368centersin43countriesof16,590patients tocompare fluticasonefuroate/vilanterol to fluticasone furoate alone, vilanterolalone and placebo with respect to all-cause mortality.Inclusion criteria included FEV1% predicted between50-70%,mMRCscoreoftwoorgreaterandeitherhistoryoforincreasedriskforcardiovasculardisease.Nodifferencewas seen in all-cause mortality in any of the treatmentarms as compared to placebo.However, in pre-specifiedsecondaryanalyses,rateofFEV1declinewasreducedbyICS/LABA therapy by 8ml per year. All active treatmentarmsreducedtherateofexacerbations.Nodifferencesinriskofpneumoniaorcardiovasculareventswerereportedinanyofthetreatmentgroups.

Comments1.The SUMMIT study designwas informed by results ofthe TORCH trial where post-hoc analyses suggesteda reduction in cardiovascular mortality with ICS/LABAtherapy.

2.ThereductionsinFEV1declinearenearlyidenticaltothatseeninpost-hocsubgroupanalysisofGOLD2patientsintheUPLIFTstudycomparingtiotropiumtoplacebo.

3.Nodataonbaselinebloodeosinophilswerecollectedaspartofthistrial.

4.Whilemaximumlengthoffollow-upwasfouryears,manypatientsunderwentsignificantlyshorterfollow-upasthiswas an event-driven study where follow-up continueduntilatleast1000deathsoccurred.

5.Concomitantuseofalong-actingmuscarinicantagonistatbaselinewasnotallowed.

EFFICACY OF ICS/LABA IN A “REAL WORLD” SETTING Vestbo J, LeatherD,DiarBakerlyN,New J,Gibson JM,McCorkindale S, Collier S, Crawford J, Frith L, HarveyC,SvedsaterH,WoodcockA for theSalfordLungStudyInvestigators. Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice.N Engl J Med 2016;375:1253-1260.

SummaryTreatment studies inCOPDhavebeencriticized for strictinclusion criteria that may not relate to “real world”COPD patient populations. The Salford Lung Study wasa randomized, open label study conducted to compareonce-dailyfluticasonefuroate-vilanteroltousualcareinanunrestrictedCOPDpatientpopulationrecruitedfromclinicsinSalfordandSouthManchester,England.Thiscommunityisunique in that it isservedprimarilybyasinglehospitaland a single electronic health record connecting primaryandsecondarycare.Thegoalof the trialwas tosimulateaclinicalpracticeenvironmentwheretrialconductionandmonitoring was incorporated into routine care delivery.In this study of 2,799 patients, the rate of moderateor severe exacerbations was lowered with fluticasonefuroate-vilanterolascomparedtousualcareby8.4%overa one-year period. No significant difference was seen inthe annual rate of COPD-related contacts to primary orsecondarycare.Nodifferenceintimetofirstmoderateorsevereexacerbationwasseenbetweentreatmentgroups.Noexcessseriousadverseeventsofpneumoniawereseeninthefluticasonetreatedgroup.

Comments1.Asasignificantproportionofpatients in theusualcarearm were also on ICS-LABA inhalers, the reduction inexacerbation frequency seen in the treatment armmaybe due to the once-daily frequency of the medicationwhichmayhaveimprovedadherence.

2.Itisalsopossiblethatoutcomeswereinfluencedbybiasintroducedbytheunblindednatureofthetrial.

3.Diagnosis of COPD was based on physician reporteddiagnosisandnotspirometry.

4.Inthefluticasonefuroate/vilanterolarmofthestudy,22%ofthepatientsswitchedbacktotheirpriortreatmentvs.11% in the usual care group making the results moredifficulttointerpret.


COPDMONDAY, MAY 22

OTHER ARTICLES OF INTERESTEPIDEMIOLOGYAllinson JP, Hardy R, Donaldson GC, Shaheen SO, Kuh D,WedzichaJA.The Presence of Chronic Mucus Hypersecretion across Adult Life in Relation to Chronic Obstructive Pulmonary Disease Development.Am J Respir Crit Care Med2016;193(6):662-72.

DIAGNOSISJordanRE,PeymaneA,SitchA,EnocsonA,BlissettD, JowettS,MarshJ,RileyRD,MillerMR,CooperBG,TurnerAM,JollyK,AyresJG,HaroonS,StockleyR,GreenfieldS,SiebertS,DaleyAJ,ChengKK,FitzmauriceD.Targeted case finding for chronic obstructive pulmonary disease versus routine practice in primary care (Target COPD): a cluster-randomised controlled trial.Lancet Respir Med.2016;4(9):720-730.

MartinezFJ,ManninoD,LeidyNK,MalleyKG,BacciED,BarrRG,BowlerRP,HanMK,HoufekJF,MakeB,MeldrumCA,RennardS,ThomashowB,WalshJ,YawnBP;High-Risk-COPDScreeningStudy Group.A New Approach for Identifying Patients with Undiagnosed COPD. Am J Respir Crit Care Med 2016 [epubaheadofprint].

TREATMENTSciurbaFC,CrinerGJ,StrangeC,ShahPL,MichaudG,ConnollyTA, Deslée G, Tillis WP, Delage A, Marquette CH, Krishna G,KalhanR,FergusonJS,JantzM,MaldonadoF,McKennaR,MajidA,RaiN,GayS,DransfieldMT,Angel L,MaxfieldR,Herth FJ,WahidiMM,MehtaA,SlebosDJ;RENEWStudyResearchGroup.Effect of Endobronchial Coils vs. Usual Care on Exercise Tolerance in patients with Severe Emphysema: The RENEW Randomized Clinical Trial.JAMA2016;315(20):2178-89.

Lindson-Hawley N, Banting M, West R, Michie S, DPhil BS,AveyardP.Gradual versus Abrupt Smoking Cessation.Annals of Internal Medicine.2016;164:585-592.

Pascoe S, Locantore N, DransfieldMT, Barnes NC, Pavord ID.Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials.Lancet Respir Med.2015;3(6):435-42.

Martinez FJ, Rabe KF, Sethi S, Pizzichin E, McIvor A, AnzuetoA,AlagappanVK,SiddiquiS,RekedaL,MillerCJ,ZetterstrandS, Reisner C, Rennard SI. Effect of Roblumilast and Inhaled Corticosteroid/Long-Acting Beta2-Agonist on COPD exacerbations (RE(2)SPOND). A randomized Clinical Trial.Am J Respir Crit Care Med2016;194(5):559-64.

PavordI,LettisS,AnzuetoA,BarnesN.Blood Eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis. Lancet Respir Med. 2016;4(9):681-683.

SinghD,PapiA,CorradiM,Pavlišová I,Montagna I, FranciscoC,CohuetG,VezzoliS,ScuriM,VestboJ.Single inhaler triple therapy versus inhaled corticosteroid plus long-acting Beta2-agonist therapy for COPD (TRILOGY): a double-blind, parallel group, randomized controlled trial.The Lancet.2016;388.

MECHANISMBhatt SP, Soler X, Wang X, Murray S, Anzueto AR, Beaty TH,Boriek AM, Casaburi R, Criner GJ, Diaz AA, Dransfield MT,Curran-EverettD,GalbánCJ,HoffmanEA,HoggJC,KazerooniEA,KimV,KinneyGL,LagsteinA,LynchDA,MakeBJ,MartinezFJ,RamsdellJW,ReddyR,RossBD,RossiterHB,SteinerRM,StrandMJ,vanBeekEJ,WanES,WashkoGR,WellsJM,WendtCH, Wise RA, Silverman EK, Crapo JD, Bowler RP, Han MK;COPDGene Investigators. Association between Functional Small Airway Disease and FEV1 Decline in COPD.Am J Respir Crit Care Med.2016;194(2):178-84.

Wain LV, ShrineN,Miller S, Jackson VE, Ntalla I, Soler ArtigasM, Billington CK, Kheirallah AK, Allen R, Cook JP, Probert K,ObeidatM, Bossé Y, Hao K, PostmaDS, Paré PD, RamasamyA;UKBrainExpressionConsortium (UKBEC).,MägiR,MihailovE, Reinmaa E, Melén E, O’Connell J, Frangou E, Delaneau O;OxGSKConsortium.,FreemanC,PetkovaD,McCarthyM,SayersI, Deloukas P, Hubbard R, Pavord I, Hansell AL, Thomson NC,ZegginiE,MorrisAP,MarchiniJ,StrachanDP,TobinMD,HallIP.Novel insights into the genetics of smoking behavior, lung function, and chronic obstructive pulmonary disease (UKI BiLEVE): a genetic association study in UK Biobank.Lancet Respir Med. 2015;3(10):769-81.

Dransfield MT, Kunisaki KM, Strand MJ, Anzueto A, Bhatt SP,Bowler RP, Criner GJ, Curtis JL, Hanania NA, Nath H, PutchaN, Roark SE, Wan ES, Washko GR, Wells JM, Wendt CH,Make BJ; COPDGene Investigators.Acute Exacerbations and Lung Function Loss in Smokers with and without Chronic Obstructive Pulmonary Disease.Am J Respir Crit Care Med.2016Aug24[epubaheadofprint].

REVIEWSHanMK,MartinezCH,AuDH,BourbeauJ,BoydCM,BransonR,CrinerGJ,KalhanR,KallstromTJ,KingA,KrishnanJA,LareauSC,LeeTA,LindellK,ManninoDM,MartinezFJ,MeldrumC,PressVG,ThomashowB,TyconL,SullivanJL,WalshJ,WilsonKC,WrightJ, Yawn B, Zueger PM, Bhatt SP, Dransfield MT. Meeting the challenge of COPD care delivery in the USA: a multiprovider perspective.Lancet Respir Med2016;4(6):473-526.

Beran D, Zar HJ, Perrin C, Menezes AM, Burney P; Forum ofInternational Respiratory Societies working group collaboration.Burden of asthma and COPD and access to essential medicines in low-income and middle-income countries.Lancet Respir Med.2015;3(2):159-70.


MONDAY, MAY 22 PULMONARY VASCULAR DISEASES

Anna R. Hemnes, MDVanderbiltUniversityMedicalCenter

DepartmentofAllergy,PulmonaryandCriticalCareMedicineNashville,TN

NEW UNDERSTANDING OF PAH MECHANISMSRhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC,HadinnapolaC,WatsonG,BledaM,HaimelM,CoghlanG,CorrisPA,HowardLS,KielyDG,PeacockAJ,Pepke-ZabaJ,ToshnerMR,WortSJ,GibbsJS,LawrieA,GräfS,MorrellNW,Wilkins MR. Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension. Circulation, 2016;135:460-475

SummaryAlthoughinsulinresistanceandlipidmetabolismareknowntobealteredinpulmonaryarterialhypertension(PAH),thefullbreadthofmetabolicabnormalitieshavenotpreviouslybeendescribedandgiven thewell-described relationshiplinkingmitochondrialmetabolismandPAH, thiswouldbehighly informativeonpathways amenable to intervention.Inthismanuscript,Rhodesandcolleaguescomparedover1300metabolites in theplasmaof116PAHpatientsandcontrols (diseaseandhealthy)usinganon-targetedmassspectrometry-based platform. They found 53metabolitesdistinguished idiopathic and heritable PAH patients fromcontrolsand62thatwereprognosticofsurvivalinPAH.Apathway-basedanalysisidentifiedenergymetabolismandstressresponsepathwaysareperturbedinPAH.Correctionof several metabolites correlated with a good clinicalresponse.Interestingly,patientswithaclinicalresponsetocalciumchannelblockershadmetaboliteprofilessimilartohealthycontrols,suggestingadifferentdiseaseetiologyinthiscohort.

Comments1.Metabolite profiles in plasma can distinguish PAH fromhealthyanddiseasecontrols.

2.MetaboliteprofilesandtheirchangeovertimemaybeusefulinpredictingoutcomesandresponsetotherapyinPAH.

3.ThisstudyhighlightedstressresponsesasakeyfeatureofalteredmetabolisminPAH.

4.PatientswithPAHwhoaresuccessfullytreatedwithcalciumchannelblockersmayhaveadifferentdiseaseetiologyfromthegreatmajorityofPAHpatientswhodonot respond tothesemedications.

NEW PAH THERAPIESKawut SM, Archer-Chicko CL, CeMichele A, Fritz JS,KKlinger JR, Ky B, Palevsky HI, Palmisciano AJ, PatelM,PinderD,PropertKH,SmithKA,StanczykF,TracyR,Vaidya A, Whittenhall ME, Ventetuolo CE. Anastrozole

in pulmonary arterial hypertension: A randomized, double-blind, placebo-controlled trial.Am J Respir Crit Care Med 2017;195:360-8

SummaryIt has longbeen recognized thatwomen are at higher riskfor PAH than men, even in the context of heritable PAH.There has been tremendous growth in the past decadein understanding how estrogen and its metabolites maypromotePAHandanimalmodelshaveevensuggestedthatanti-estrogen therapiesmaybebeneficial forPAHbut alsomay be a detriment to right ventricular function. Thus far,however, therehavebeennotrialsofanti-estrogentherapyinhumanswithPAH.Inthisimportantpilotstudy,Kawutandcolleagues treated 18 patients with PAHwith 3months ofplacebo or anastrozole, which prevents the conversion ofandrogenstoestrogeninperipheraltissues.Importantly,theauthorsincludedonlymenandpost-menopausalwomenintheirstudy.Theco-primaryendpointwaschangeinplasmaestradiol levels and change in TAPSE as amarker of rightventricularfunctioninasafetyassessment.First,anastrozoleappeared to be safe and well tolerated in this cohortof patients and did not reduce right ventricular functionas measured by TAPSE. Anastrozole did reduce plasmaestradiol levels.Second, therewasastatisticallysignificantincrease in six minute walk distance in the cohort treatedwith anastrozole compared with placebo. This study is animportanttranslationofmanylinesofbasicsciencestudiesontheroleofestrogen inPAHtobeginningtotreathumandisease. Further study of anastrozole in larger numbersof patients will be required before it can be confidentlyprescribedasatreatmentforPAH,however.

Comments1.Femalesex is thestrongestpredictor fordevelopmentofPAH.

2.EstrogensappeartoplayaroleindevelopmentofPAHinrodentmodels.

3.Anastrozoleappearstoincreasesixminutewalkdistancemorethanplacebointhispilotstudy

4.Anastrozoleappearssafeandwelltolerated.5.A large-scalemulticenter trial of anastrozole in PAH iswarranted.


MONDAY, MAY 22 PULMONARY VASCULAR DISEASES

CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSIONDelcroixM,Lang I,Pepke-ZabaJ,JansaP,D’ArminiAM,SnijderR,BresserP,TorbicikiA,MellemkjaerS,LewczukJ,SimknovaI,BarberaJA,dePerrotM,HoeperMM,GaineS,SpeichR,Gomez-SanchezMA,KovacsG,JaisX,AmbrozD,TreacyC,Morsolini,JenkinsD,LindnerJ,DartevelleP,MayerE,SimonneauG.Long-term outcomes of patients with chronic thromboembolic pulmonary hypertension: Results from an international prospective registry.Circulation2016;133:859-71.

SummaryChronic thromboembolic pulmonary hypertension isrecognized as a not uncommon cause of pulmonaryhypertension that, importantly, can be cured orsignificantly improved in most patients with pulmonarythromboendarterectomy.Theprocedureisonlyrecommendedafterconfirmationofchronicthromboembolicdiseaseusingradiologyproceduressuchaspulmonaryangiographyandshouldonlybecarriedoutatexpertcenterswithexperienceinevaluationandmanagementofthiscomplexcondition.OfflabelPAH-directedtherapieshavebeenusedinpatientswithchronicthromboembolicpulmonaryhypertensionincludingPDE5 inhibitors, endothelin receptors and prostaglandinsandriociguathasrecentlybeenFDA-approvedforpatientswith post-pulmonary thromboendarterectomy pulmonaryhypertensionandinoperabledisease.Thisrecentpublicationfrom the largest registry of chronic thromboembolicpulmonaryhypertensionevaluated long-termpredictorsofsurvival in this disease, both in operated and medically-managedpatients.Thekeyfindingsofthisimportantworkare that in the 679 newly diagnosed patients enrolled inthisstudy,60%percentwereconsideredtohaveoperablediseaseandunderwentpulmonarythromboendarterectomy.Ofthenotoperatedcohort,61%weretreatedwithmedicaltherapy using standard PAH treatments. 12% of patientswhoweretreatedsurgicallywereNYHAfunctionalclassIV,highlighting that this is not a contraindication to surgery.However, inbothoperatedandnot-operatedpatients, thestrongestpredictorofmortalitywasbeingNYHAfunctionalclass IV. In this registry, survivalwas improved at all timepointsuptothreeyearsintheoperatedcohortvs.thenot-operatedgroup(3yearsurvival89%vs.70%).TheuseofbridgingPAHtherapywasassociatedwithhighermortalityafter pulmonary thromboendarterectomy though this maytrackcloselywithpatientswithmoreseveredisease, (e.g.NYHAfunctionalclassIV).Overall,thismanuscriptstronglysupportsoperativemanagementofchronicthromboembolicpulmonary hypertension when appropriate and highlightsimportant risk factors fordeath (e.g.advanceddisease) inbothoperatedandnot-operatedpatients.

Comments1.SurvivalisimprovedinpatientswithCTEPHtreatedwithpulmonary thromboendarterectomy compared with notoperatedpatients.

2.ThestrongestpredictorofmortalityinbothoperatedandnotoperatedgroupsisNYHAfunctionalclassIVstatus.

3.Approximately20-25%ofpatientsinbothcohortshadnoidentifiedprioracutevenousthromboembolismevent.

4.Bridging PAH therapy to surgical procedure wasassociatedwithhighermortalityattwoyears.

MECHANISMS OF RIGHT VENTRICULAR FAILURE IN PH Brittain EL, Talati M, Fessel JP, Zhu H, Penner N, CalcuttMW, West JD, Funke M, Lewis GD, Gerszten RE, HamidR, PughME, Austin ED, Newman JH, Hemnes AR. Fatty acid metabolic defects and right ventricular lipotoxicity in human pulmonary arterial hypertension. Circulation 2016;133:136-44.

SummaryRecentworkhashighlightedtheroleofmetabolicdiseasein PAH, suggesting that insulin resistance and lipiddysregulationarecommoninpatientswithpulmonaryarterialhypertension. The right ventricle is the most importantpredictorofmortality inPAHand isahighlymetabolicallyactive tissue,making it likely tobeaffectedbymetabolicdisease.WhileanimalandhumanstudieshaveshownhighratesofglucoseoxidationinthePAHrightventricle,theroleoffatmetabolismintheRVhasbeenlittlestudied,despitetheknowledgethatfattyacidoxidationisthemajorsourceof ATP in the normal right ventricle. In this manuscript,BrittainandcolleaguesusedbloodsamplesfromPAHandcontrolpatients todemonstrate increased free fattyacidscirculating inPAHandusedametabolomicsapproach todemonstratethatacylcarnitines,keytransportersoffatintothe mitochondria are elevated in PAH plasma comparedto controls. In the myocardium, there was increasedtriglycerideinautopsyPAHRVcomparedtocontrols.TheythenwentontomeasurelipiddepositioninvivoincontrolsandPAHpatientsusingmagneticresonancespectroscopyandfound7foldhigherlipidcontentinthePAHmyocardiumcompared to controls. In rodent models, they were ableto demonstrate a failure of RV myocardium to augmentfatty acid oxidation when supplied with palmitate. Takentogether, these data support the hypothesis that lipidmetabolismisabnormalinPAHandmaycontributetoRVdysfunction through lipotoxicity. As there are metabolicinterventions, such as metformin, that may address thispathobiology, the translation of these data to new rightventricle-directedtherapiesinPAHshowshighpotential.

Comments1.PAH patients have high levels of insulin resistance andcirculatingfattyacids.


PULMONARY VASCULAR DISEASESMONDAY, MAY 22

2.Acylcarnitines, which transport fat into mitochondria, arealteredinPAHpatients’bloodandintheirhearts.

3.Living patients with PAH have markedly increased rightventricularlipidcontentcomparedtocontrols.

4.Mitochondrial fatty acid oxidation is impaired in the PAHrightventricle.

5.Metabolicinterventionsinhumanpatientsneedtobetestedtodetermine if they improve right ventricular functionandoutcomesinPAH.

CHALLENGING DEFINITION OF PULMONARY HYPERTENSIONMaronBA,HessE,MaddoxTM,OptowskyAR,TedfordRJ,Lahm T, Joynt KE, Kass DJ, Stephens T, Stainislawski MA,SwensonER,GoldsteinRH,LeopoldJA,ZamanianRT,ElwingJM, Plomondon ME, Grunwald GK, Baron AE, RumsfeldJS, Choudhary G. Association of borderline pulmonary hypertension with mortality and hospitalization in a large patient cohort: insights from the veterans affairs clinical assessment, reporting and tracking program. Circulation2016;133:1240-1248.

SummaryIntheoriginalWHOcategorizationofpulmonaryhypertension,ameanpulmonaryarterialpressureof>or=25mmHgwaschosen as a cutoff for pulmonary hypertension. Thoughthis number was admittedly arbitrarily selected, it wasbased on the expertise of the participants. This cutoff haspersistedsince1973.RecentWorldSymposiaonPulmonaryHypertension have maintained this cutoff, and definedpatients with mean pulmonary arterial pressure between20-24mmHg as “borderline.” Recent work by Maron etal has challenged this dogma. In this analysis of nearly22,000 veterans with right heart catheterization data, theyfoundincreasedmortalityinpatientswithpulmonaryarterialpressures beginning at 19mmHg and rising continuouslythereafter.Theyexamineddemographiccharacteristicsofthecohortwithmeanpressureof19-24comparedwithpatientswhose mean pressure was below 19mmHg or 25mmHgor higher. They found that patients with this intermediatephenotypeweremorelikelytobeolderandAfricanAmericanandtohavehigherprevalenceofmetabolicdisease,suchasobesity,diabetes,systemichypertensionandleftheartfailure.While the association of mortality with mean pulmonaryartery pressure is strong, there is no data demonstratingthattherapyinthispopulationwouldimprovesurvivalorthatpatientswiththisintermediatephenotypeultimatelygoontomeetthecurrentdefinitionofpulmonaryhypertension.

Comments1.In this VA cohort, mean pulmonary artery pressure of19mmHgorgreater,previouslynotdefinedasabnormal,isassociatedwithincreasedmortality.

2.Patientswith ameanpressure of 19-24mmHgweremorelikelytobeolderandAfricanAmericanthanpatientswhosemeanpressurewaslessthan19mmHg.

3.It isunknownifpatientswiththis intermediatephenotypeprogress to meet criteria for pulmonary hypertension(meanpulmonaryarterialpressureof>or=25mmHg)orifthesepatientswouldbenefitfrompulmonary–vascularspecifictherapies.

NEW PULMONARY HYPERTENSION PHENOTYPESOpitz CF, Hoeper MM, Gibbs JSR, Kaemmerer H, et al.Pre-capillary, combined and post-capillary pulmonary hypertension: A pathophysiological continuum.J Am Coll Cardiol 2016;68:368-78

SummaryThephenotypeofpatientswithmixedGroup1andGroup2 has recently been recognized, but little is known abouthow these patients are different or similar to traditionalpulmonaryhypertensionphenotypes,specificallypulmonaryarterial hypertension and group 2, pulmonary venoushypertension. Inthismanuscript,theauthorsusedregistrydata to compare clinical phenotypes and outcomes intraditionalidiopathicPAH(IPAH),patientswithatypicalPAH,definedby3ormoreriskfactorsforleftheartdisease,andthosewithGroup2PHtreatedwithPAH-directedtherapy.TheyfoundthatpatientswithatypicalPAHwereolderandmoreobese,buthadsimilarhemodynamicsincludingmeanpulmonary arterial pressure and cardiac index. Treatmenteffects,measuredbychangeinexercisecapacity,functionalclass and natriuretic peptides, were present in all groupsat 12 months, but the effects were most pronounced intypicalIPAH,leastintheGroup2PHandintermediatedintheatypicalPAHgroup.Thesedatasuggestthatwhattheauthors call “atypical PAH” likely is a distinct phenotypebothdiagnosticallyandprognostically.

Comments1.A substantial portion of patients do not meet traditionalguidelinesforspecificdiagnosisofpulmonaryhypertensionwith features of both Group 1 and Group 2 pulmonaryhypertension.

2.Patients with atypical PAH phenotype have more obesityandcomorbiditiesbutsimilarhemodynamics.

3.Patients with idiopathic PAH appear to derive the mostbenefitfromPAH-directedtherapies.

4.Patientswith heart failurewith preserved ejection fractionbenefittheleastfromPAH-directedtherapies.

OTHER ARTICLES OF INTERESTBASIC SCIENCE IN PHSaS,GuM,ChappellJ,ShaoNYetal.iPSC model of pulmonary arterial hypertension reveals novel gene expression and patient specificity.Am J Respir and Crit Care Med.2016

YanL,ChenX,TalatiM,NunleyBW,GladsonS,BlackwellT,CoganJ,AustinE,WheelerF,LoydJ,WestJ,HamidR.Bone Marrow-derived Cells Contribute to the Pathogenesis of Pulmonary


PULMONARY VASCULAR DISEASESMONDAY, MAY 22

Arterial Hypertension. Am J Respir Crit Care Med. 2016 Apr15;193(8):898-909.doi:10.1164/rccm.201502-0407OC.

HurstLA,DunmoreBJ,LongL,CrosbyA,Al-LamkiR,DeightonJ,SouthwoodM,YangX,NikolicMZ,HerreraB,InmanGJ,BradleyJR,RanaAA,UptonPD,MorrellNW.TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling.Nat Commun. 2017 Jan 13;8:14079.doi:10.1038/ncomms14079.

GuignabertC,PhanC,SeferianA,HuertasA,TuL,ThuilletR,SattlerC,LeHiressM,TamuraY,JutantEM,ChaumaisMC,BouchetS,Manéglier B, Molimard M, Rousselot P, Sitbon O, Simonneau G,MontaniD,HumbertM.Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension.J Clin Invest.2016Sep1;126(9):3207-18.

INSIGHTS IN RIGHT VENTRICULAR FAILURE AND THERAPYTalati MH, Brittain EL, Fessel JP, Penner N, Atkinson J, FunkeM, Grueter C, Jerome WG, Freeman M, Newman JH, WestJ, Hemnes AR. Mechanisms of Lipid Accumulation in the Bone Morphogenetic Protein Receptor Type 2 Mutant Right Ventricle.Am J Respir Crit Care Med.2016Sep15;194(6):719-28

WestJD,VossBM,PavlivL,deCaesteckerM,HemnesAR,CarrierEJ. Antagonism of the thromboxane-prostanoid receptor is cardioprotective against right ventricular pressure overload.Pulm Circ.2016Jun;6(2):211-23.

Frump AL, Goss KN, Vayl A, Albrecht M, Fisher A, TursunovaR,FierstJ,WhitsonJ,CucciAR,BrownMB,LahmT.Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones.Am J Physiol Lung Cell Mol Physiol. 2015May1;308(9):L873-90.

vanderBruggenCE,HappéCM,DorfmüllerP,TripP,SpruijtOA,RolN,HoevenaarsFP,HouwelingAC,GirerdB,MarcusJT,MercierO,HumbertM,HandokoML,vanderVeldenJ,VonkNoordegraafA,BogaardHJ,GoumansMJ,deManFS.Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension: A View on the Right Ventricle.Circulation.2016May3;133(18):1747-60.

CLINICAL ASSESSMENT AND CARE OF PATIENTS WITH PHMontaniD,GirerdB,JaïsX,LevyM,AmarD,SavaleL,DorfmüllerP, Seferian A, Lau EM, EyriesM, Le Pavec J, Parent F, Bonnet D,Soubrier F, Fadel E, SitbonO, SimonneauG,HumbertM.Clinical phenotypes and outcomes of heritable and sporadic pulmonary veno-occlusive disease: a population-based study.Lancet Respir Med. 2017Feb;5(2):125-134

SavaleL,SattlerC,CoillyA,ContiF,RenardS,FrancozC,BouvaistH,FerayC,BorentainP, JaïsX,MontaniD,ParentF,O’ConnellC,HervéP,HumbertM,SimonneauG,SamuelD,CalmusY,DuvouxC,DurandF,Duclos-ValléeJC,SitbonO.Long-term outcome in liver transplantation candidates with portopulmonary hypertension.Hepatology.2016Dec20.doi:10.1002/hep.28990.

Assad TR, Hemnes AR, Larkin EK, Glazer AM, Xu M, Wells QS,Farber-EgerEH,ShengQ,ShyrY,Harrell FE,NewmanJH,BrittainEL.Clinical and Biological Insights Into Combined Post- and Pre-Capillary Pulmonary Hypertension. J Am Coll Cardiol. 2016 Dec13;68(23):2525-2536

CTEPHBrenot P, Garcia Alonso C, Gerardin B, Bourkaib R, Jais X,SimonneauG,FadelE.TCT-89 Balloon pulmonary angioplasty for chronic thromboembolic hypertension: report of a two-year experience in a surgical center.J Am Coll Cardiol.2016Nov1;68(18S):B36.

SimonneauG,D’ArminiAM,GhofraniHA,GrimmingerF,JansaP,KimNH,MayerE,PulidoT,WangC,ColoradoP,FritschA,MeierC,NikkhoS,HoeperMM.Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016May;4(5):372-80.

CannonJE,SuL,KielyDG,PageK,ToshnerM,SwietlikE,TreacyC,PonnaberanamA,CondliffeR,ShearesK,et.al.Dynamic Risk Stratification of Patient Long-Term Outcome After Pulmonary Endarterectomy: Results From the United Kingdom National Cohort. Circulation.2016May3;133(18):1761-71.


ASTHMAMONDAY, MAY 22

Eugene R. Bleecker, MDUniversityofArizona

DepartmentofMedicineTucson,AZ

ASTHMA PATHOGENESISStein MM, Hrusch CL, Gozdz J, Igartua C, Pivniouk V,MurraySE,LedfordJG,MarquesdosSantosM,AndersonRL,MetwaliN,NeilsonJW,MaierRM,GilbertJA,HolbreichM, Thorne PS, Martinez FD, von Mutius E, Vercelli D,OberC,SperlingAI. Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children.N Engl J Med.2016Aug4;375(5):411-21.doi:10.1056/NEJMoa1508749.PMID:27518660

SummaryTwo isolated populationswith similar lifestyles butmajordifferences inasthmaprevalencewerestudied(Hutteritesand Amish). The populations are genetically similar butthe prevalence of asthma and allergic sensitization was4-6 times lower in Amish children compared toHutteritechildren of a similar age. In addition, there are majordifferencesinfarmingpracticeswiththeAmishpracticingtraditional methods (single family farms with livestock)while the Hutterites have large industrialized communalfarms. The authors observed that median endotoxinlevelswere significantly higher inAmish housedustwithdifferences inmicrobialcomposition.More importantly, inamousemodelofallergicasthma,theintranasalinstillationofthehousedustfromtheAmishwasfoundtosignificantlyinhibitairwayhyperreactivityandeosinophilia(comparedtotheHutterites).TheprotectiveeffectsoftheAmishhousedust were not observed in mice deficient in moleculesimportant in innate immune signaling (MyD88 and Trif).The authors postulate that the Amish home environmentisprotectiveofdevelopingasthmaby‘shapingtheinnateimmuneresponse.”

Comments1.Thisworkisanimportantextensionofpreviousfindingsthatchildrenraisedontraditionaldairyfarmshavealowfrequency of asthma suggesting a protective effect ofcontactwithfarmanimalsandhighmicrobialexposures.

2.The two isolatedpopulations (AmishandHutterites)donotdiffergeneticallyrulingoutgeneticdifferencesasthecausefortheobserveddifferencesinasthmaprevalence.

3.Althoughtheirlifestyleinrespecttomultipleriskfactorsfor asthma and allergic diseases are similar in manyways, there are important differences in their farmingpractices with the Amish children having increasedexposuretofarmanimals.

4.Key to this study was the testing of the effects ofthe Amish house dust in a murine model of asthmademonstrating the role of innate immunity which mayin the future lead to prevention of disease instead oftreatmentafterasthmadevelops.

Peters MC, McGrath KW, Hawkins GA, Hastie AT, LevyBD,IsraelE,PhillipsBR,MaugerDT,ComhairSA,ErzurumSC, JohanssonMW, Jarjour NN, Coverstone AM,CastroM, Holguin F, Wenzel SE, Woodruff, PG, Bleecker ER,Fahy JV for the National Heart Lung and Blood InstituteSevereAsthmaResearchProgram.Plasma interleukin-6 concentrations, metabolic dysfunction and asthma severity: a cross-sectional analysis of two cohorts.Lancet Respir Med 2016; 4:574-84. PMID: 27283230PMCID:PMC5007068

SummaryMostoftheemphasisinunderstandingthepathogenesisofasthmahasemphasizedeosinophilic (type2) inflammatorymechanisms. Targeting these inflammatory mechanismshasbeenthegoalofmostofthecurrentbiologictherapiesin asthma. The importance of this paper by Peters andco-workersisthatitemphasizesthepotentialroleofnonT2mechanismsinmoresevereasthma.TheauthorsextendedpreviousobservationsonthepotentialroleoftheIL6pathwayinmoresevereasthmasub-phenotypes(Hawkins,et.al,JACI2012; 130:510-515) to more general asthma populations(636asthmapatientsfromtwopopulations:UCSFandSARPreplicatesamplesand93normalcontrols).Thesecohortshaddatarelatedtometabolicdisorders(hypertension,diabetes,obesity,aswellasasthmaseverityandType2inflammation).IL6relatedoutcomeswereassessedinblood,sputum,andquantitative gene expressionwas performed to determinerelationships between IL6, metabolic health, and asthmaseverity.Basedonanupper95thcortilevalueestablishedin the normal controls, elevated IL6 levels were found in14%ofUCSFand26%ofSARPsubjects,amoresevereasthmacohort.PlasmaIL6levelswerenotassociatedwithsputum IL6proteinor transcript levels inblood,or type2inflammationbutwerecorrelatedwithC-reactiveproteinandneutrophils.ThehighIL6asthmaticshadhigherBMI,higherprevalence of metabolic disorders, lower lung functionandmore frequent asthma exacerbations. Seventy five%of high IL6 patients were obese, 63% of obese subjectswere IL6 low. Non-obese IL6 high asthmatics had morefrequent exacerbations. Thus, systemic IL6 inflammation



andmetabolicdysfunctionwerefoundinanasthmasubsetandinasmallsubsetofnon-obeseasthma.

Comments1.Study demonstrates the importance of non-Type 2inflammationinsevereasthma.

2.Findingssupportthepotentialvalueofevaluatinganti-IL6pathwaytherapyinasmallsubsetofnon-Th2asthmaticswhich could further inform on mechanisms underlyingsevereasthma.

3.ThereisaquestionofwhetherIL6causessevereasthmaor is additive to other pathophysiologicmechanisms inasthma.

4.ItispossiblethattheseIL6findingsmayreflectcomplexinteractions with IL6R and other IL6 pathway proteins,someofwhichareundergeneticcontrol.

ASTHMA PHENOTYPESLefaudeux D, De Meulder B, Loza MJ, Peffer N, RoweA, Baribaud F, Bansal AT, Lutter R, Sousa AR, CorfieldJ, Pandis I, Bakke PS, CarusoM, Chanez P, Dahlén SE,Fleming LJ, Fowler SJ, Horvath I, Krug N, MontuschiP, Sanak M, Sandstrom T, Shaw DE, Singer F, SterkPJ, Roberts G, Adcock IM, Djukanovic R, Auffray C,ChungKF;U-BIOPREDStudyGroup.U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics. J Allergy Clin Immunol. 2016Oct 20. pii: S0091-6749(16)31185-doi.10.1016/j.jaci.2016.08.048. [Epubaheadofprint]PMID:27773852

SummaryIt is well known that asthma is a heterogeneous diseaseand multiple investigators have previously performedanalyses to define subgroups of subjects with differingclinical phenotypes and/or differing endotypes. In thismanuscript, theauthorsanalyzeaverywellcharacterizedcohortofadultswithasthma.Theydividedthecohortintoatrainingandvalidationsetandshouldreproduciblyoftheirclusters in the two data sets. They defined four clusterswithdifferingphenotypes;T1)wellcontrolledmoderatetosevere asthma, T2) late onset with a history of smokingand chronic airflow obstruction, T3) similar to clusterT2 but nonsmokers and T4) mainly obese females withuncontrolledasthmadespiterelativelynormallungfunction.Inaddition,theauthorsobservedsignificantdifferencesinbothsputumproteomicsandtranscriptomicsbetweentheclusters further defining disease heterogeneity. Themoresevere clusters (T2, T3, T4) compared to cluster T1 hadhigher sputum eosinophils with no differences in sputumneutrophils, exhaled nitric oxide or serum IgE levels.In summary, four stable and reproducible clusters withdifferentphenotypesandendotypeswereobservedfurtherdefiningtheunderlyingbasisforasthmaheterogeneity.

Comments1.Further understanding of asthma heterogeneity isimportant in understanding the variable response toasthmatherapiesandthedevelopmentofseveredisease.

2.Major prior studies of asthmawhich have not includedsubjects with a significant prior or current history ofsmokingwouldnothaveobservedclusterT2whichmaybeconfoundedwithACOSorCOPD.

3.Characterizing the phenotypic derived clusters bysputumcellcounts(eosinophilsandneutrophils)aswellas thecommonbiomarkersofexhalednitricoxideandserum IgE levels is an important next step in definingasthmaheterogeneity.

BIOLOGIC THERAPY OF SEVERE ASTHMAOrtegaHG,YanceySW,MayerB,GunsoyNB,KeeneON,BleeckerER,BrightlingCE,PavordID.Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016Jul;4(7):549-56. doi: 10.1016/S2213-2600(16)30031-5.Epub2016May10.PMID:27177493

SummaryThis paper reports on two Phase 3b studies on theefficacyof lebrikizumab,an IL13 inhibitor, inpatientswithmoderatetosevereasthma.IL13isaType2inflammatorycytokinethatcouldcontributetoseveralpathophysiologiccharacteristics observed in asthma including, mucousproduction,smoothmusclehyperplasia, fibrous,bronchialhyper-responsiveness, IgE synthesis and eosinophilicairway inflammation. An earlier phase 2 study with thisdrug showed efficacy improving lung function better in abiomarker high group (periostin or FeNO) (Corren ital. NEng J Med 2011; 365: 1088-1098). Periostin is an IL13inducedmatricellularproteinsecretedinbronchialepithelialcellsanddetectedinserum.Morethan2100patientswithmoderate to severe asthmawere studied in two identicaltrials(LavoltaIandII).InclusioncriteriaweretreatmentwithmoderatetohighdoseICS,oneadditionalcontroller,aFEV1between 40-80%with a bronchodilator response and anACQ-5greaterthan1.5.Therewerenorequirementsforapriorexacerbationorspecifiedbiomarkers.Thestudyfailedtoprovideconsistent results for theprimaryexacerbationendpoint nor did it show the expected improvements inFEV1orACQ-5.Resultswerestratifiedbyhighperiostinorhigh eosinophil levelsdid not consistently identify benefitfromthisantiIL13.

Comments1.The subjects were recruited without specified priorexacerbations and the overall exacerbation rates werelowsoperhapsa therapeuticsignalwas lostusing thisstudydesignstrategy.


2.There is the possibility that IL13 blockade alone is notsufficient to reduce asthma exacerbations and onlyeffectslungfunction.

3.The chosen biomarker may not be predicative andothers,perhapsFeNOshouldbeevaluated.

4.AsthmaisheterogeneousandthecorrectsubpopulationresponsivetoIL13inhibitionmaynothavebeenidentified.

WenzelS,CastroM,CorrenJ,MasperoJ,WangL,ZhangB,PirozziG, SutherlandER, EvansRR, JoishVN, EckertL,GrahamNM,StahlN,YancopoulosGD,Louis-TisserandM, Teper A. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial.Lancet.2016Jul2;388(10039):31-44.doi:10.1016/S0140-6736(16)30307-5.Epub2016Apr27.PMID:27130691

SummaryThisphase2bstudyevaluatesdupilumab,afullyhumanizedanti IL4Ramonoclonal antibody that blocks both IL4 andIL13 signaling inmoderate to severeuncontrolledasthma.PatientswererecruitedthatweretreatedwithmoderatetohighdoseICS,asecondcontrolleranddespitethistherapyremained poorly controlled (ACQ greater than 1.5). Theywerealso required tohaveatoneasthmaexacerbationorhospitalizationrequiringtherapywithsystemiccorticosteroidsinthepastyear.769patientswererandomized.Thelargestimprovement in lung function and exacerbations wereobserved with every two week therapy. Therapy with thisIL4Ra antagonist reduced severe asthma exacerbations(70%) in the overall population and marginally better inthehighbloodeosinophil subgroup. Improvement inFEV1wasobserved in theoverallgroupand thehigheosinophilgroupshowedsomewhatbetter improvementthanthe loweosinophilgroup.OverallIL4/13Rawithdupilumabimprovedpulmonary function and reduced severe exacerbations inmoderatetosevereuncontrolledasthmapatientsirrespectiveofbaselineeosinophilcount.

Comments1.Overall,verypromisingclinicalresultswereobservedforIL4/13inhibitiontherapyinsevereasthma.

2.This raises the question of whether IL4Ra blockadethateffectsboth IL13and IL4signaling isnecessary incomparisontoIL13blockadealone(Hanania2016).

3.Anotherpotential question is thatpatients in this studymayhavebeenlessseveresincetheyarenotrequiredtohaveexperiencedatleastonesevereasthmaexacerbationinthepastyear.

4.It isdifficulttodirectlycomparetheresultswithantiIL5therapysincethepopulationinthistrialmayhavebeensomewhat less severe than those included in the IL5registrationtrials.

5.An important question to address is whether there aresevereasthmasubpopulationsorendotypesthatmaybemore responsible to IL5 versus IL13/4 inhibition (or dotheytargetthesamesubjects).

6.Furtherinvestigationofpredictivebiomarkersisnecessary



TUESDAY, MAY 23 TUBERCULOSIS AND NONTUBERCULOUS MYCOBACTERIA

Charles L. Daley, MDNationalJewishHealthandtheUniversityofColoradoDenver

DepartmentofMedicineDenver,CO

LATENT TUBERCULOSIS INFECTIONMancuso JD, Diffenderfer JM, Ghassemieh BJ, HorneDJ, Kao TC. The prevalence of latent tuberculosis infection in the United States.Am J Respir Crit Care Med2016;194:501-509.

SummaryIndividuals with latent TB infection (LTBI) representa reservoir from which active cases of disease arisecontinuing the spread of M. tuberculosis. In the UnitedStates (U.S.), targeted testing and treatment of LTBI isa major focus of TB control. In order to estimate theprevalenceofLTBIintheU.S.,investigatorsusedTSTandinterferon-gamma release assay data from the NationalHealth and Nutrition Examination Survey (NHANES). Thepatientpopulation included6,083peopleaged≥6 yearswho had a TST andQuantiFERON-TBGold In-Tube test(QFT-GIT).TheestimatedprevalenceofLTBIin2011-2012was4.4%asmeasuredbyTSTand4.8%byQFT-GITthatcorresponds to 12,398,000 and 13,628,000 individuals,respectively.Prevalencedeclinedslightlycomparedtothe2000surveyamong theU.S.-bornbut remainedconstantamong foreign-born. Higher risk groups included theforeign-born,closecontactstoactiveTBcasesandcertainracial/ethnic groups. Asian individuals had the highestprevalenceofLTBI(25%hadapositiveTSTand18%hadapositiveQFT-GIT).UseoftheQFT-GITresultedinhigherprevalence of LTBI in U.S.-born and lower prevalence inforeign-born persons likely due to BCG vaccination inthe latter.Foreign-bornpersons representan increasinglylargerproportionofthepoolofLTBI(73%).

Comments1.The prevalence of LTBI has remained stable between2000 and 2012 although the number of those infectedhasincreasedby1.2millionto12.4million.

2.TheprevalenceofLTBIwas4.4%byTSTand4.8%byQFT-GIT.

3.QFT-GITresulted inahigherprevalenceestimate intheU.S.-bornbutlowerestimateintheforeign-born.

4.Other high-risk groups included contacts to activecases, older individuals (cohort) and certain racial andethnicgroups.

5.Incarceratedandhomeless individualsarenot includedinNHANESandBCGvaccination,durationofresidenceoutsidetheU.S.,andgeographicregionoforiginamongthosebornoutsidetheU.S.werenotavailable.

SCREENING AND TREATMENT OF LATENT TB INFECTIONUSPreventive Services Task Force.Screening or latent tuberculosis infection in adults. US Preventive Services Task Force Recommendation Statement. JAMA 2016;316(9);962-969.

SummaryThe USPSTF makes recommendations about theeffectiveness of specific preventive services for patientswithoutobviousrelatedsignsorsymptomsofdisease. Itsrecommendations are based on the evidence of benefitsandharmsoftheserviceandasassessmentofthebalance.Costsarenotconsidered.AfterreviewingtheevidenceonscreeningforLTBIinasymptomaticadultsseeninprimarycare,theUSPSTFmadethefollowingrecommendation:TheUSPSTF recommends screening for LTBI in populationsat increased risk (B recommendation). The evidencereport included72studieswith51,711patients.Nostudyevaluated the benefits and harms of screening comparedwith no screening. Populations at increased risk for LTBIincludepersonswhowerebornin,orareformerresidentsof countries with increased tuberculosis prevalence andpersonswho live in,orhave lived inhigh-riskcongregatesettings (e.g., homeless, correctional facilities). ScreeningtestsincludetheMantouxtuberculinskintestandinterferon-gamma release assays which are moderately sensitiveand highly specific for the detection of LTBI. TreatmentshouldfollowCDCguidelines.Isoniazidhadhigherratesofhepatotoxicitythanplaceboorrifampin.

Comments1.TheUSPSTFrecommendationisasignificantstepintheright direction toward eliminationof TB in theU.S. buttargeted testing is a critical but insufficient step in TBprevention.

2.InordertoeliminateTB,theU.S.willhavetomovemuchofthescreeningforLTBIandtreatmentofLTBIintotheprivatesector.

3.The recommendation addressed two specific high-riskgroupsbutdidnotaddresspersonswithHIVinfectionorcontactsto infectiousTBcasesasthe latter is likely tobeseeninpublichealthsettings.

4.ThePatientProtectionandAffordableCareActrequiresprivate health plans to cover services recommendedwitheitheranAorBrecommendationatnocosttotheconsumer.

5.Inorderforthisrecommendationtobesuccessful,theremustbelinkagetoaccessibleandaffordabletreatment.



TREATMENT AND PREVENTION OF TB/HIVHosseinipourMC,BissonGP,MiyaharaS,etal.Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomized controlled trial.Lancet2016;387:1198-1209.

SummaryMortalitywithinthefirst6monthsafterinitiatingantiretroviraltherapyisoftenduetotuberculosis(TB)inresource-limitedsettings.DifferentiationofsubclinicalTBfromlatentTBoractive disease can be difficult in these settings. In ordertoevaluatewhetherempiricalTB treatmentwould reduceearly mortality compared with isoniazid (INH) preventivetherapy, investigators conducted a multi-country open-labelrandomizedcontrolledtrial.HIVinfectedpatientswithCD4countsof<50cells/microL from tencountrieswererandomized to antiretroviral therapy (ART) and empiricalTBtreatmentorARTandINHtreatment.850patientswereenrolledbetween2011and2014.ThemedianCD4countwas 18 cells/microL. At 24 weeks, 22 (5%) participantsfromeachgroupdiedorwereofunknownstatus.However,there was an increase in incident TB and HIV diseaseprogressionintheempiricalgroup.Grade3or4signsandsymptoms occurred in 50 (12%) in the empirical groupversus46(11%)intheINHgroup.INHpreventivetherapywaswelltoleratedandassociatedwithlowermortalitythaninpreviousstudies.

Comments1.UptakeofWHOguidelinesrecommendingINHtreatmentofHIVinfectedpatientswithadvanceddiseasehasbeenlow inpartdue to theconcern for identifyingactiveTBdiseaseandthepossibilityofgeneratingdrugresistance.

2.This study showed no difference in survival betweenthe empirically treated group and the INH preventivetreatment group although in the former there was ahigherrateofTBandAIDSprogression.

3.Therewasnodifferenceinadversesymptoms,signs,orlaboratoryvaluesbetweengroups.

4.INHcouldbesafelygiventoHIVinfectedindividualswithadvancedHIVdisease.

5.In settings where routine symptom screening is donein outpatients presenting for ART therapy, there is nobenefit to empirical TB therapy compared with WHOrecommendedINHpreventivetherapy.

NONTUBERCULOUS MYCOBACTERIA AND CYSTIC FIBROSIS Bryant JM, Grogono DM, Rodriguez-Rincon D, et al.Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacteria.Science 2016;354:751-758.

SummaryPatients with cystic fibrosis (CF) are at high risk ofdevelopinglunginfectionduetoMycobacteriumabscessus.NTM are typically acquired from the environment andtransmission fromperson topersonhasbeenconsideredhighly unusual. In order to evaluate the possibility oftransmissionofM.abscessusgroupbetweenCFpatients,investigators performed whole genome sequencing of1080 isolates from 517 patients collected from sites inthe United Kingdom, United States, Republic of Ireland,Denmark, Sweden, Netherlands and Australia. Multiplecladesofnear-identicalisolateswereidentifiedsuggestingtransmission of circulating clones. Most patients wereinfectedwith“clustered”isolates.UsingBayesiananalysis,the investigatorsestimated that themost recentcommonancestor infecting patients arose around 1978. Througha series of experiments, the investigators were able toshowexamplesofpotentialpersontopersontransmissionand that the clones were better able to survive withinmacrophages,causemorevirulent infections inmice,andwereassociatedwithworsetreatmentoutcomesinhumans.

Comments1.M. abscessus infections are increasing in CF patientsandcreatesignificantmorbidity.

2.ThisstudywasabletoidentifygeneticallyhighlysimilarstrainsofM.abscessusandM.massilienseincountriesconsistentwithpersontopersontransmission.

3.Theisolatesshowedincreasedvirulence/pathogenicityinmacrophagesandmice.

4.Treatment outcomes were worse but the details oftreatmentwerenotprovided.

TREATMENT OF PULMONARY MYCOBACTERIUM AVIUM COMPLEXOlivier KN, Griffith DE, Eagle G, et al.Randomized trial of liposomal amikacin for inhalation of nontuberculous mycobacterial lung disease.Am J Respir Crit Care Med 2016;Oct17.[Epubaheadofprint].

SummaryPulmonaryinfectionsduetonontuberculousmycobacteria(NTM) are on the rise but there are no drugs that areapproved for treatment. A phase 2 study investigatedefficacy and safety of liposomal amikacin for inhalation(LAI) in treatment of refractory pulmonary NTM disease.Patients were randomly assigned to LAI (590 mg) orplaceboadministeredoncedailyfor84dayswiththeoptionof an additional 84 days of open label use. The primaryendpointwaschangefrombaselinetoday84onasemi-quantitative growth scale with other endpoints includingsputumconversion,6-minutewalkdistance, andadverseevents.Themodifiedintent-to-treatpopulationincluded89patients(44LAI,45placebo).Theprimaryendpointwasnotachieved(p=0.072)however,agreaterproportionoftheLAI



groupdemonstrated≥1negativesputumculture(32%vs9%,p=0.006)anddemonstratedimprovementin6-minutewalktest(+20.6vs-25.0meters,p=0.017).NopatientwhoanMICofgreaterthan64μg/mloramolecularlydeterminedamikacin mutation achieved culture conversion. Seriousadverseeventsoccurredin18.2%ofthosereceivingLAIvs8.9%onplacebo.Seven(15.9%)patientsintheLAIgroupandnoneintheplacebogroupdiscontinuedstudydrugfortreatment-emergentadverseevents.

Comments1.ThestudyshowedsignificantactivityofLAIoverplaceboinpatientswithrefractorypulmonaryMACasmeasuredbysecondaryendpoints.

2.Thestudyshowedbothamycobacteriologicimprovement(cultureconversionat84days)thatwassustainedaswellasimprovementin6-minutewalk.

3.AdverseeffectsweremorecommonwithLAIthanplaceboandLAIwasdiscontinuedmorefrequentlythanplacebo.

4.AdditionalstudyofLAIwithotherNTMandinCFpatientsiswarranted.

HEAT-COOLER UNIT-RELATED DISSEMINATED MYCOBACTERIUM CHIMAERA ChandM, Lamagni T, Kranzer K, et al. Insidious risk of severe Mycobacterium chimaera infection in cardiac surgery patients.Clin Infect Dis2017;64:335-342.

SummaryInvasiveM.chimaerainfectionsrelatedtoheater-coolerunits(HCU) usedduring cardiopulmonarybypass surgery havebeenreportedfromseveralcountrieswiththeinitialreportscoming fromSwitzerland.Wholegenomesequencinghasdemonstrated remarkable similarity between HCU andpatient isolates. This study evaluated the risk of invasiveM.chimaera infection in theU.K. throughamultiprongedinvestigative approach using national laboratory andhospital admission data, cohort study, microbiologicaland aerobiological investigations of HCU, and wholegenomesequencingofclinicalandenvironmentalisolates.Eighteen probable cases of cardiopulmonary bypass-associated infection were identified; all had undergonevalve replacement in 11 hospitals between 2007 and2015,amedianof19monthsprior toonset (3monthsto5years).Risk increasedafter2010from<0.2to1.65per10,000 person-years in 2013. Endocarditis was themostcommonpresentation(n=11).Ninepatientshaddied.Theinvestigators demonstrated that aerosol was releasedthrough holes in the HCU tanks. M. chimaera and otherpathogenswereisolatedfromwaterandairsamples.Wholegenomesequencingdemonstratedhighlysimilarstrains.

Comments1.DisseminatedM.chimaerainfectionshavebeenreportedfrommultiplecountriesincludingtheU.S.andCanada.

2.Thisstudy foundareason theHCUthatcould result inleakageandaerosolizationofinfectedwater.

3.Whole genome sequencing was able to match HCUisolateswithpatientisolateswithhighdegreeofcertainty.

4.Overallmortalitywashighasreportedinotherstudies.

OTHER ARTICLES OF INTERESTLATENT TUBERCULOSIS INFECTIONMiramontesR,HillAN,YelkWRS,LambertLA,NavinTR,CastroKG, LoBue PA. Tuberculosis infection in the United States: prevalence estimates from the National Health and Nutrition Examination Survey, 2011-2012.PLoS One2015:10:e0140881.

Ghassemieh GJ, Attia EF, Koelle DM, Mancuso JD, Narita M,HorneDJ.Latent tuberculosis infection test agreement in the National Health and Nutrition Examination Survey.Am J Respir Crit Care Med 2016;194:493-500.

SCREENING AND TREATMENT OF LATENT TB INFECTIONKahwatiLC,FeltnerC,HalpernM,etal.Primary Care Screening and Treatment for Latent Tuberculosis Infection in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA.2016Sep6;316(9):970-83.

RevesR,DaleyCL.Screening for latent tuberculosis infection: A key step toward achieving tuberculosis elimination in the United States.JAMA Intern Med.2016Oct1;176(10):1439-1440

NONTUBERCULOUS MYCOBACTERIA AND CYSTIC FIBROSIS Bryant JM, Grogono DM, Greaves D, et al. Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fibrosis: a retrospective cohort study. Lancet.2013May4;381(9877):1551-60.

AitkenML,LimayeA,PottingerP,etal.Respiratory outbreak of Mycobacterium abscessus subspecies massiliense in a lung transplant and cystic fibrosis center. Am J Respir Crit Care Med. 2012Jan15;185(2):231-2.

TREATMENT OF PULMONARY MYCOBACTERIUM AVIUM COMPLEXOlivier KN, Shaw PA, Glaser TS, et al. Inhaled amikacin for treatment of refractory pulmonary nontuberculous mycobacterial disease.Ann Am Thorac Soc.2014Jan;11(1):30-5.

HEAT-COOLER UNIT-RELATED DISSEMINATED MYCOBACTERIUM CHIMAERA Sax H, Bloemberg G, Hasse B, et al. Prolonged outbreak of Mycobacterium chimaera infection after open-chest heart surgery. Clin Infect Dis.2015Jul1;61(1):67-75.

KohlerP,KusterSP,BloembergG,etal.Healthcare-associated prosthetic heart valve, aortic vascular graft, and disseminated Mycobacterium chimaera infections subsequent to open heart surgery.Eur Heart J.2015Oct21;36(40):2745-53.


TUESDAY, MAY 23 THE HOST MICROBIOME IN LUNG DISEASE

ASTHMADurack J, LynchSV,NariyaS,BhaktaNR,BeigelmanA,CastroM,DyerAM, IsraelE,KraftM,MartinRJ,MaugerDT,RosenbergSR,Sharp-KingT,WhiteSR,WoodruffPG,Avila PC, Denlinger LC, Holguin F, Lazarus SC, LugogoN,MooreWC,PetersSP,QueL,SmithLJ,SorknessCA,WechslerME,WenzelSE,BousheyHA,HuangYJ;NationalHeart,LungandBlood Institute’s “AsthmaNet”.Features of the bronchial bacterial microbiome associated with atopy, asthma, and responsiveness to inhaled corticosteroid treatment. J Allergy Clin Immunol. 2016Nov10.pii:S0091-6749(16)31283-0.

SummaryAsthma is clinically heterogeneous and microbial factorshave long been postulated to play a role in asthma.Prior studies found significant associations betweenfeaturesofmoresevereasthmaandpatternsofbronchialmicrobiotacomposition.However,theinfluenceofinhaledcorticosteroiduseandbackgroundatopyonsuchfindingshas been unclear. In a multi-center investigation by theNHLBI AsthmaNet, investigators studied the bronchialbacterialmicrobiome in threegroups:atopicmildasthmapatientsnotoninhaledsteroidtherapy,atopic(aeroallergen-sensitized)subjectswithoutasthma,andnon-atopichealthyindividuals. Asthmatic subjects were then randomized toinhaled fluticasone or placebo inhaler treatment for sixweeks, after which the microbiome was re-examined.Bacterialmicrobiotawereanalyzedusing16S rRNAgenesequencing, and the functional potential of the bacterialcommunity determined using inferred metagenomicanalysis. Significant differences in the bronchial bacterialmicrobiomewereobservedbetweenthegroups,includingdiscretedifferencesassociatedwithasthmaorwithatopyalone. Predicted bacterial functions associated withasthma included increased representation of pathwaysfor amino acid, short-chain fatty acid, and xenobioticmetabolism. Type 2-“high” asthma subjects harboredsignificantly less bronchial bacterial burden than type2-“low”subjects.Fluticasonetreatment led tochanges inbacterialcommunitycomposition,andnon-responsivenessto fluticasonewasassociatedwithdifferences inbaselinecommunitycomposition.

Comments1. Steroid-naïve mild asthma is itself associated withalterationsinthebronchialbacterialmicrobiome.

2. The amount of type 2 airway inflammation present islinkedtodifferencesinbronchialbacterialcontent.

3.Controllingforallergicstatusisanimportantconsiderationforstudiesoftherespiratorymicrobiome.

4.Analysisoffluticasoneeffectsonthebronchialmicrobiomewaslimitedbyarelativelysmallnumberofsubjectswithadequatepairedbrushsamplesforcomparison.

5. The presence of non-bacterial microbiota (i.e. fungi,viruses)wasnotassessedduetotechnicallimitations.

COPDWang Z, Bafadhel M, Haldar K, Spivak A, Mayhew D,Miller BE, Tal-Singer R, Johnston SL, Ramsheh MY,Barer MR, Brightling CE, Brown JR. Lung microbiome dynamics in COPD exacerbations.Eur Respir J. 2016Apr;47(4):1082-92.

SummaryBacterial or viral infections are implicated in 70-80% ofacute COPD exacerbations. Little is known about therole of broader changes in the airway microbiome inCOPDexacerbations. This study applied 16S rRNAgenesequencingmethods to characterizebacterial communitychanges in sputum collected from 87 subjects duringclinical stability, at exacerbation, and post-treatment.Exacerbationphenotypeswereclassifiedusingpreviouslydefinedmicrobiologicalandclinicalcriteria(bacterial,viral,eosinophilic,andpauci-inflammatoryphenotypes).Overall,exacerbation samples demonstrated reduced alpha-diversity with non-significant increases in the relativeabundance of Proteobacteria members (3-5% changein Haemophilus and Moraxella spp.) and a decreasein Firmicutes (Streptococcus). Segregating eventsby exacerbation phenotype demonstrated significantdifferences in bacterial community composition betweenbacterial and eosinophilic exacerbations, with the abovedifferences seen mainly in the bacterial phenotype.Consistent with prior reports, treatment with antibioticsversus oral corticosteroids alone was found to havecontrastingeffectsonsputumbacterialcomposition,withsteroid treatment resulting in Proteobacteria enrichment.Analysis for relationships between sputum inflammatorymediatorsandthebacterialcommunityidentifiednegativecorrelations between CXCL8/IL-8, alpha-diversity andthe relative abundance of several taxa representingHaemophilus,MoraxellaandStreptococcusmembers..

Yvonne J. Huang, MDUniversityofMichigan

DivisionofPulmonaryandCriticalCareMedicine,DepartmentofInternalMedicineAnnArbor,MI



Comments1.Resultsofthisculture-independentanalysisoftheCOPDsputum microbiome confirm a bacterial exacerbationphenotype as previously defined by sputum cultureresults.

2.Eosinophilic exacerbations were not associated withevidentchangesinthesputumbacterialcommunitybutbacterial interactionsarepossiblegivenobservations intheothercombinedphenotypes.

3.ThislargerstudyconfirmspreviousreportsthattreatmentwithoralcorticosteroidsaloneleadstoairwayenrichmentinProteobacteria,thelong-termconsequencesofwhichareunknown.

4.No healthy or non-exacerbating COPD control groupswerestudied,sothespecificityofthebacterialcommunitydynamicsobservedtoacuteexacerbationsisunclear.

MICROASPIRATION AND THE LUNG MICROBIOMESegalLN,ClementeJC,TsayJC,KoralovSB,KellerBC,WuBG,LiY,ShenN,GhedinE,MorrisA,DiazP,HuangL,WikoffWR,UbedaC,ArtachoA,RomWN,StermanDH,CollmanRG,BlaserMJ,WeidenMD.Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype.Nat Microbiol. 2016Apr4;1:16031.

SummaryMicroaspiration is common even in healthy individuals,andgastroesophagealrefluxcancomplicatelungdiseasesincludingcysticfibrosis,asthma,andpulmonaryfibrosis.Apriorsmallinvestigationfoundthatbronchoalveolarlavagefluid enriched in predominantly supraglottic bacteria, i.e.oral-relatedanaerobes likePrevotellaandVeillonella,wasassociated with increased numbers of BAL lymphocytesand neutrophils. In this study characteristics of this BALmicrobiomephenotype, termed “pneumotype-SPT,”werefurtherdissectedusingamulti-omictranslationalapproach.Acellular BAL samples from 49 healthy subjects derivedfrom three cohorts were analyzed. Subjects weremostlymale (64%), had normal lung function and reported norespiratorysymptoms.63%hadacurrentorformerhistoryof smoking. Unsupervised hierarchical cluster analysis of16SrRNAgenesequencedatademonstratedtwodistinctbacterialcommunityprofiles,asseenbefore.Pneumotype-SPTwasassociatedwithasignificantlydifferentfunctionalprofile by several assessments including predictedmetagenomiccontent,metabolitecorrelationsandelevationin Th17-related BAL cytokines. Similarity of the BALmicrobiome toupperairwaysamplesalsocorrelatedwithahigherpercentageofIL17+CD4+BALcells,andalveolarmacrophages from pneumotype-SPT subjects displayedbluntedTLR4 responses.Thestudyconcludes that lungsenrichedinpneumotype-SPT-associatedbacteriadisplayapro-inflammatoryphenotypecharacterizedbyTh17-relatedimmuneresponses.

Comments1.This larger study of acellular BAL from asymptomaticsubjects from three different cohorts extends thepreviouslyreportedassociationbetweenlungprevalenceofcertainoral-relatedbacteriaandlunginflammation.

2.The health versus disease consequences of theserelationships are unclear since themajority of subjectshadanat-risksmokinghistory.

3.The species of Prevotella and Veillonella linked to theobserved lung responses are not known but would beof interest to further investigate and understand theirfunctions.

4.Whilemicrobiota-metabolite correlations suggest directlinkswithinacompartment, itcanbedifficulttoresolvelocalvs.distantgenerationofmetabolitesdetectedinthelungandtheirquantification.

LUNG TRANSPLANTATIONBernasconi E, Pattaroni C, Koutsokera A, Pison C,KesslerR,BendenC,SoccalPM,MagnanA,Aubert JD,Marsland BJ, Nicod LP; SysCLAD Consortium. Airway Microbiota Determines Innate Cell Inflammatory or Tissue Remodeling Profiles in Lung Transplantation.Am J Respir Crit Care Med.2016Nov15;194(10):1252-1263

SummaryChronic lung allograft dysfunction is a significant barrierto long-term survival after transplant, and control ofinflammationandtissueremodelingareimportantunderlyingprocesses. The influence of lungmicrobiota and bacterialcommunity dynamics on these processes in the first yearpost-transplant was assessed using BALs collected from112 patients, coupled with host gene expression studiesand in vitro studies of bacterial effects on monocyte-derived macrophages. Bacterial profiles were determinedby 16S rRNA-basedmethods, andBAL cellularRNAwasusedtoassessexpressionofinnateimmunecellfunctionslinked to inflammatory, intermediate (immunoregulatory)orremodeling profiles. Lung microbiota were characterizedby three dysbiotic patterns defined by dominance ofBacteroidetes, Firmicutes, or Proteobacteria, and a non-dysbiotic group with a balanced composition. Thesemicrobiota characteristics were associated with distinctgene expression profiles; Proteobacteria or Firmicutes-related dysbiosis was more prevalent in samples withpro-inflammatory profiles, whereas Bacteroidetes-relateddysbiosiswasmoreprevalentinsampleswitharemodelingprofile.Theserelationshipswerefurtherexaminedusingfourbacterial species representative of the microbiota groupsin single andco-culture studiesof their effectsonhumanmonocytic cell line-derived macrophages (THP-DM). Theco-culturestudiesdemonstratedattenuatingeffectsof“non-dysbiotic”bacterialspeciesontheinflammationelicitedbyspeciesfromtheFirmicutes/Proteobacteriaphyla.



Comments1.The study findings highlight the likely importance oflung microbiota interactions in shaping innate immuneresponsesinthetransplantedlungmicroenvironment.

2.Inasubsetofpairedsamples, temporalshifts in innateimmune response profiles were observed as well astransitions from one bacterial community pattern toanother, suggesting dynamic interactions between thetwofeatureslongitudinally.

3.Thecollectiontimeframeofthesamplesanalyzeddidnotallowforinsightsintoassociationswithchronicrejection.

4.Theeffectsofantimicrobial therapieson themicrobiotapatterns could not be evaluated due to large clinicalvariation.

5.Primary immune cells from the transplanted lung werenot used for the exposure experiments and wouldbe of interest to assess similarity of responses to themicrobiota.

IDIOPATHIC PULMONARY FIBROSISHuang Y, Ma SF, Espindola MS, Vij R, Oldham JM,HuffnagleGB,Erb-DownwardJR,FlahertyKR,MooreBB,WhiteES,ZhouT,LiJ,LussierYA,HanMK,KamniskiN,Garcia JG, HogaboamCM,Martinez FJ, Noth I; COMETInvestigators. Microbies associate with host innate immune response in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med.2017Feb3,inpress.

SummaryPrior studies have identified relationships betweenpolymorphisms in host defense genes and IPF risk orsurvival.Thisstudyappliedasystemsbiologyapproachtoexamine relationships between BAL bacterial microbiotaandtranscriptionalpatternsinperipheralbloodmononuclearcells. 68 IPF patients from the COMET study had pairedspecimensavailablefor16SrRNAgenesequencinganalysisofBALandmicroarrayanalysisofPBMCgeneexpression.Inaddition,asubsetofpatientshadsamplesusedtostudylung fibroblast responsiveness to TLR9 stimulation (CpG-ODN) and circulating leukocyte phenotypes. Interactionnetworkswereconstructedbasedonthecollectiveresultsandclinicaloutcomes.Higherbacterialspeciesrichnesswasassociatedwithdown-regulationofinnateimmuneresponsepathways (NOD, TLR, and RIG-I-like receptor pathways)that in turn were associated with worse progression-freesurvival.Severalbacterial taxademonstratedpositivecorrelationswithvariousimmunepathways,includingNOD-like receptor signaling (Streptococcus), TLR expression/TLRsignaling(StaphylococcusandPrevotella)andTOLLIPexpression (Pseudomonas). Additional associations wereidentified between specific bacterial genusmembers andfibroblastresponsivenesstoCpG-ODNandphenotypesofcirculatingT-cells.

Comments1.These results provide function-oriented evidence insupportofbacterial-hostinteractionsinthepathogenesisofIPFandsurvivaloutcomes.

2.The associations involving several bacterial OTUshighlight that a collection of bacterial-host interactionsmay be important in IPF progression, although causaldirectioncannotbedetermined.

3.It is unclear if similar associations exist between theidentified microbiota members and innate immuneresponsesinIPFlungcells(e.g.alveolarmacrophages).

4.Whetherspecificlungmicrobiotamodulateexistinghostdefensealterations in IPFand functionallycontribute todiseaseprogressionisuncertain.

NON-CYSTIC FIBROSIS BRONCHIECTASISTaylorSL,WoodmanRJ,ChenAC,BurrLD,GordonDL,McGuckinMA,WesselinghS,RogersGB.FUT2 genotype influences lung function, exacerbation frequency and airway microbiota in non-CF bronchiectasis. Thorax.2016Aug8.pii:thoraxjnl-2016-208775.

SummaryNon-CFbronchiectasispatientssuffersignificantmorbidityfrom complications of chronic airway infection includingexacerbations. Bacterial colonization patterns commonlyinclude culture isolation of Haemophilus influenzae andPseudomonas aeruginosa. It is unclear if the broadercompositionofairwaymicrobiotainfluencesexacerbationsin non-CFbronchiectasis and further,whethermicrobiotapatternsareassociatedwithhost-specificmucosalfactorsthat shape susceptibility to infections such as variabilityinmucosalglycanexpression.Loss-of-functionmutationsin theFUT2gene result inan inability toexpressglycanson mucosal surfaces; such individuals are known as“non-secretors” whereas “secretors” carry at least onefunctional copy. Here, sputum collected at baseline fromsubjects in the BLESS trial was analyzed using 16SrRNAgene pyrosequencing and fungal and virus-specificQ-PCR. Paired FUT2 genotype (23 “non-secretors”, 48heterozygoteand22homozygote“secretors”)andsputumbacterialcommunitydataweredetermined in93patients.Sputum profiles were dominated by eitherP. aeruginosa (n=25),H. influenzae (n=33),orotherspecies(n=35).Non-secretors demonstrated significantly lower prevalence ofP.aeruginosa-dominated airway infections, higher lungfunctionandfewerexacerbationsduringthetrial,comparedto secretor genotypes. The prevalence of non-dominantbacterial taxaor thepresenceof testedfungi (C. albicans and A. fumigatus) and viruses, however, did not differbetweennon-secretorsandsecretors.



Comments1.Stratificationofnon-CFbronchiectasispatientsbyFUT2genotype may have prognostic value in identifyingpatients at increased risk for exacerbation anddiseaseprogression.

2.SputummicrobiotarelationshipstoFUT2genotypewerelimited to associations with P. aeruginosa dominance,leaving unclear what microbiota interactions underlieexacerbations and outcomes in non-Pseudomonas-dominated,non-secretorpatients.

3.The study was likely underpowered technically todiscriminate relationships between less abundantmembersofthemicrobiotaandsecretorstatus.

OTHER ARTICLES OF INTERESTCribbs SK, Uppal K, Li S, Jones DP, Huang L, Tipton L, FitchA, Greenblatt RM, Kingsley L, Guidot DM, Ghedin E,Morris A.Correlation of the lung microbiota with metabolic profiles in bronchoalveolar lavage fluid in HIV infection.Microbiome.2016Jan20;4:3.

Denner DR, Sangwan N, Becker JB, Hogarth DK, Oldham J,CastilloJ,SperlingAI,SolwayJ,NaureckasET,GilbertJA,WhiteSR.Corticosteroid therapy and airflow obstruction influence the bronchial microbiome, which is distinct from that of bronchoalveolar lavage in asthmatic airways. J Allergy Clin Immunol.2016May;137(5):1398-1405.e3

Dickson RP, Singer BH, Newstead MW, Falkowski NR, Erb-Downward JR, Standiford TJ, Huffnagle GB. Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome.Nat Microbiol. 2016 Jul18;1(10):16113.

Korten I, Mika M, Klenja S, Kieninger E, Mack I, BarbaniMT, Gorgievski M, Frey U, Hilty M, Latzin P. Interactions of Respiratory Viruses and the Nasal Microbiota during the First Year of Life in Healthy Infants.mSphere.2016Nov23;1(6).

MolyneauxPL,WillisOwenSA,CoxMJ, JamesP,CowmanS,Loebinger M, Blanchard A, Edwards LM, Stock C, Daccord C,Renzoni EA, Wells AU, Moffatt MF, Cookson WO, Maher TM.Host-Microbial Interactions in Idiopathic Pulmonary Fibrosis.Am J Respir Crit Care Med.2017Jan13.

Prevaes SM, de Winter-de Groot KM, Janssens HM, deSteenhuijsenPitersWA,Tramper-StrandersGA,WyllieAL,HasratR,TiddensHA,vanWestreenenM,vanderEntCK,SandersEA,BogaertD.Development of the Nasopharyngeal Microbiota in Infants with Cystic Fibrosis.Am J Respir Crit Care Med.2016Mar1;193(5):504-15.

ShenoyMK, Iwai S, Lin DL,WorodriaW, Ayakaka I, ByanyimaP,KaswabuliS,FongS,StoneS,ChangE,DavisJL,FaruqiAA,SegalMR,HuangL,LynchSV.Immune Response and Mortality Risk Relate to Distinct Lung Microbiomes in Patients with HIV and Pneumonia. Am J Respir Crit Care Med. 2017 Jan1;195(1):104-114.

Sverrild A, Kiilerich P, Brejnrod A, Pedersen R, Porsbjerg C,Bergqvist A, Erjefält JS, Kristiansen K, Backer V. Eosinophilic airway inflammation in asthmatic patients is associated with an altered airway microbiome. J Allergy Clin Immunol.2016Dec29.pii:S0091-6749(16)32475-7.


TUESDAY, MAY 23 BRONCHIECTASIS

James D. Chalmers, MD, PhDUniversityofDundee

ScottishCentreforRespiratoryResearchDundee,UnitedKingdom

PATIENT CHARACTERISTICS IN THE UNITED STATESAksamitTR,O’DonnellAE,BarkerA,OlivierKN,WinthropKL,DanielsML, JohnsonM, EdenE,GriffithD,KnowlesM,MeterskyM,SalatheM,ThomashowB,TinoG,TurinoG,CarrettaB,DaleyCL.Adult bronchiectasis patients: a first look at the United States Bronchiectasis Research Registry. Chest2016;Nov23.pii:S0012-3692(16)62354-1.doi:10.1016/j.chest.2016.10.055.

Summary Bronchiectasis is a heterogeneous disorder caused bya wide range of different underlying diseases and withdiverse patient characteristics. As an “orphan” disease,its characteristics and natural history have not beenwelldocumented.TherearelimiteddataregardingbronchiectasisfromtheUnitedStates.Multicenter registriessuchas theUnited States Bronchiectasis Research Registry and theEuropean EMBARC registry provide the opportunity tobettercharacterizethedisease.

This article presents the first data from theU.S. registry,describing data on 1826 patients recruited from 2008to 2014. Patients were predominantly female and neversmokers with moderate lung function impairment. A keyfinding of this study was that 63% of patients had ahistoryofisolationofnon-tuberculousMycobacteria.Otheraetologiesandcomorbiditiesincludedpneumoniainnearly70%,COPDin20%andrheumatologicaldiseasesin8%.The first data on treatment of bronchiectasis in the U.S.is presented with the most frequent treatments beinginhaled bronchodilators (61%), corticosteroids (39%) andsuppressiveantibiotics(39%).

Comments1.ThehighfrequencyofNTMdiseaseintheU.S.contrastswithEuropeandata,andsuggeststhat investigationforNTM should be mandatory for bronchiectasis patientspresentingintheUnitedStates.

2.Thisstudyshowsahighburdenofdisease,withameanof3exacerbationsinthepast2yearsandahighburdenofsymptoms

3.1/3ofpatientshavePseudomonasaeruginosainfectionat baseline in the registry- a population we know hasmoreseverediseaseandaworseoutcome.

4.Thereareno licensed therapies forbronchiectasis,andalltreatmentsdescribedinthisregistryareofflabel.Themostfrequentlyuseddrugs,suchasbronchodilatorsandinhaledsteroids,havenosupportingtrialevidence.

5.The Registry alongwith other longitudinal internationalstudies will provide the opportunity to understandoutcomes and the impact of different patientcharacteristics and therapies, while also supportingrandomizedtrials.

A LINK BETWEEN BRONCHIECTASIS AND CARDIOVASCULAR DISEASENavaratnamV,Millett ER,Hurst JR, ThomasSL,SmeethL,HubbardRB,Brown J,Quint JK.Bronchiectasis and the risk of cardiovascular disease: a population-based study. Thorax. 2017 Feb;72(2):161-166. doi: 10.1136/thoraxjnl-2015-208188.

SummaryWe have learned from other respiratory diseases,particularlyCOPD,thatmuchofthemortalityisattributableto comorbidities rather than directly due to respiratoryfailure.Bronchiectasisisasystemicinflammatorydisorder,andiscloselyassociatedwithcomorbiditiesthathavebeenlinked to increased cardiovascular complications. A linkbetween bronchiectasis and cardiovascular disease, has,however,notbeenclearlyestablished.

Navaratnam and colleagues used a large electronicdatabasewith10,942patientswitharecordeddiagnosisofbronchiectasis to establish a linkbetweenbronchiectasisand cardiovascular events. After a median of 5.6 yearsfollow-up, comparing patients with bronchiectasis tocontrolswithoutbronchiectasis,firstcardiovasculareventsoccurredmorefrequentlyinbronchiectasispatients(hazardratio 1.42 95%CI 1.25-1.60,p<0.001). Stroke rates werealso69%higherinbronchiectasispatientsvscontrols.Thesame effects were observed after excluding co-existingCOPDandthosewithahistoryofsmoking.

Theauthorsconclude thatbronchiectasis likely increasesthe risk of cardiovascular disease and stroke. This hasimportant implications forwholisticcareof thesepatientswheremanagementofcomorbiditiesmayhaveanimportantimpactonoutcome

Comments1.Routine datasets give an entirely different view ofbronchiectasis compared to registries or cohorts fromspecialistcenters,withhigherratesofCOPDandasthmaassociateddiseaseandahigherrateofsmokers


BRONCHIECTASISTUESDAY, MAY 23

2.Theincreasedratesofcardiovasculardiseaseandstrokeobserved in this study are clinically important. Themechanismisunclearandshouldbefurtherinvestigatedwithpossibilities includingsystemic inflammationor theeffectofexacerbations.

3.Limitations of routine datasets include a lack of CTvalidation of the bronchiectasis diagnosis and limitedcollection of confounders, so conclusions should betreatedwithcaution.

4.There are currently no data on prevention of cardiaceventsinpatientswithbronchiectasis.

5.Bronchiectasis is a heterogeneous disorder and thisdatasetdoesnotcontainsufficientphenotypicdetail toidentifythepatientgroupsathighestrisk.

COMORBIDITIES AND OUTCOMESMcDonnell MJ, Aliberti S, Goeminne PC, Restrepo MI,Finch S, Pesci A, Dupont LJ, Fardon TC, Wilson R,LoebingerMR,SkrbicD,ObradovicD,DeSoyzaA,WardC,LaffeyJG,RutherfordRM,ChalmersJD.Comorbidities and the risk of mortality in patients with bronchiectasis: an international multicentre cohort study.Lancet Respir Med. 2016 Dec;4(12):969-979. doi: 10.1016/S2213-2600(16)30320-4.

SummaryThe majority of bronchiectasis patients are elderly andtherefore frequently have comorbidities. Approximately50%ofpatientshaveanunderlyingdisorderpredisposingto bronchiectasis, such as rheumatological disease,inflammatory bowel disease, ciliary disorders and allergicbronchopulmonary aspergillosis. The impact of thesecomorbidities and aetiologies on clinical presentation andoutcomes of bronchiectasis have not been defined. ThisEuropean cohort study of 986 patients usedmultivariableanalysis to identify risk factors formortality over 5 years.Thestudyidentifiedthatcomorbiditieswerecommon,withamedianof4comorbiditiesperpatient,andshowed thatmultiplecomorbiditiesincludinghaematologicalmalignancy,COPD< inflammatory bowel disease, connective tissuediseasesandasthmawereassociatedwithhighermortality.Amodelbasedonthesecharacteristicswasmoreaccurateat predicting mortality than disease severity scores. Thestudyconcludesthatpatientswithspecificaetiologiesandcomorbiditiessuchas thoseaboveshouldbe followed-upmore carefully and the treatable comorbidities should beidentifiedandmanagedtoimproveoutcomes.

Comments1.Anumberofcomorbiditiesandaetiologiesareassociatedwith worse outcomes in bronchiectasis, includingmortalityandsevereexacerbations.

2.Scoring systems such as the bronchiectasis severityindex and the aetiology and comorbidity index can

predictdiseaseoutcomeswithahighdegreeofaccuracy,andhavebeenindependentlyvalidated.

3.Anassociationwasdemonstratedbetweencomorbiditiesand exacerbations, while patients with Pseudomonasaeruginosa infection also had more frequentcomorbidities, suggesting a link between comorbiditiesandlungdisease.

4.PredictionmodelshavepredominantlyonlybeentestedinEurope, and require further validation in other healthcaresystemsincludingtheUnitedStates

BRONCHIECTASIS IN COPD Diaz AA, Young TP, Maselli DJ, Martinez CH, Gill R,Nardelli P, Wang W, Kinney GL, Hokanson JE, WashkoGR, San Jose Estepar R.Quantitative CT measures of bronchiectasis in smokers. Chest. 2016 Nov 24. pii:S0012-3692(16)62460-1.doi:10.1016/j.chest.2016.11.024.[Epubaheadofprint]

SummaryBronchiectasis is increasingly reported in patients withCOPD. Some have suggested that bronchiectasis mayinfluenceoutcomesormaybea“phenotype”ofCOPD.ThismanuscripthasimportantimplicationsforourunderstandingofbronchiectasisinCOPD.UsingdatafromtheCOPDGenestudy, Diaz and colleagues sought to use quantitativeCT to objectively measure airway and vascular size andassociated features in 21 smokers with a radiologicaldiagnosisofbronchiectasis (including17withCOPD)and21neversmokingcontrols.

Inhealth,thebronchusshouldbesmallerthantheadjacentvessel at every level on CT. Therefore a bronchial:arterialratio (BA ratio) >1 indicates “dilatation” and may bereported as bronchiectasis. This study, however, reportsthatsubjectswithbronchiectasishad increasedBA ratiosprimarily driven by reductions in the vessel diameter.Subjectswith“bronchiectasis”didnothavemajorincreasesin bronchial diameter compared to healthy subjects atthe same level, but had smaller blood vessels giving the“artificial” appearance of bronchiectasis. Wall thicknesswas associated with sputum production, the definingsymptom of clinical bronchiectasis, and inversely relatedto FEV1, but BA ratio was not. Oxygen saturations werecorrelatedtobronchialarterydiametersleadingtheauthorstospeculatethatreducedvesselsizemayindicatehypoxicvasoconstriction.

These findings are intriguing, as we see more and morepatientswithbronchiectasisCOPDoverlap.Thisisasmallstudy and it is important to point out that larger studieswillbeneeded.Nevertheless,thesituationisclearlynotassimpleassomehavesuggestedwithbronchiectasisasaninfectiondriven“phenotype”ofCOPD.


BRONCHIECTASISTUESDAY, MAY 23

Comments1.Radiologicalbronchiectasisisnotalwaysduetobronchialdilatation,butmayalsoreflectpulmonaryvasculardisease.

2.Asradiologicalbronchiectasisdoesnotnecessarilyreflect“clinical bronchiectasis” its role in guiding treatment islikelytobelimited.

3.Considerairwayinfection,pulmonaryvasculardiseaseandNTMinfectioninpatientswithCOPDandbronchiectasis,but also be aware that bronchiectasis may reflect anincidentalfindingwithnoclinicalsignificance.

4.Bronchial wall thickness may be a useful radiologicalindicatorofactiveinflammation.

5.Thesedatashouldbeinterpretedwithcautiongiventhesmallsamplesize.

RISING DISEASE PREVALENCE IN THE U.K.Quint JK, Millett ER, Joshi M, Navaratnam V, ThomasSL, Hurst JR, Smeeth L, Brown JS. Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population-based cohort study. Eur Respir J. 2016 Jan;47(1):186-93. doi:10.1183/13993003.01033-2015.

SummaryBronchiectasis was previously thought to be a rare ororphan disease. Accurate assessment of prevalence ofbronchiectasishelpstounderstanddiseaseburdenaswellascharacterizethepatients.UsingroutinehealthcaredatafromtheU.K.,Quintandcolleaguesdescribetheprevalenceof the disease from 2004 to 2013. They observed anincreaseofapproximately40%intheprevalenceoverthatnearly 10 year period, rising to a prevalence of 485 per100,000inmenand566per100,000infemaleattheendofthestudyperiod.

Interestingly,30%ofpatientswerecurrentsmokers,whichis at odds with rates reported in the U.S. bronchiectasisregistry and European cohorts. 42% of patients had aprior history of asthma while 36% had a prior history ofCOPD.Nootheraetiologiesaccountformorethan10%ofbronchiectasiscases.

Thisdatasetdidnotallowexplorationofwhytheprevalencewasincreasingsorapidly.

Comments1.Bronchiectasis prevalence is increasing rapidly,particularly in individualswith a past history of asthmaandCOPD.

2.Possible reasons for the increasing prevalence includeincreasing use of CT, increased disease awareness ortheagingpopulation,asbronchial/arterialratioincreaseswithage.

3.Mortality rates in this population for bronchiectasispatients were more than twice the mortality rate in

the general population, independent of age and otherconfounders.

4.SimilardatahavebeenreportedfromGermanyandtheU.S., suggesting a global increase in bronchiectasisimpact.

OTHER ARTICLES OF INTERESTDiaz AA, Young TP,Maselli DJ,Martinez CH,Maclean ES, YenA, Dass C, Simpson SA, Lynch DA, Kinney GL, Hokanson JE,WashkoGR,SanJoséEstéparR.Bronchoarterial ratio in never-smokers adults: Implications for bronchial dilation definition. Respirology.2017Jan;22(1):108-113.doi:10.1111/resp.12875.

McDonnellMJ,AlibertiS,GoeminnePC,DimakouK,ZucchettiSC,DavidsonJ,WardC,LaffeyJG,FinchS,PesciA,DupontLJ,FardonTC,SkrbicD,ObradovicD,CowmanS,LoebingerMR,RutherfordRM, De Soyza A, Chalmers JD. Multidimensional severity assessment in bronchiectasis: an analysis of seven European cohorts. Thorax. 2016 Aug 11. pii: thoraxjnl-2016-208481. doi:10.1136/thoraxjnl-2016-208481.[Epubaheadofprint]

Burr LD, Rogers GB, Chen AC, Hamilton BR, Pool GF, TaylorSL, Venter D, Bowler SD, Biga S, McGuckin MA. Macrolide Treatment Inhibits Pseudomonas aeruginosa Quorum Sensing in Non-Cystic Fibrosis Bronchiectasis. An Analysis from the Bronchiectasis and Low-Dose Erythromycin Study Trial.Ann Am Thorac Soc.2016Oct;13(10):1697-1703

AlibertiS,MasefieldS,PolverinoE,DeSoyzaA,LoebingerMR,MenendezR,RingshausenFC,VendrellM,PowellP,ChalmersJD;EMBARCStudyGroup.Research priorities in bronchiectasis: a consensus statement from the EMBARC Clinical Research Collaboration. Eur Respir J. 2016 Sep;48(3):632-47. doi:10.1183/13993003.01888-2015.

Rademacher J,RingshausenFC,SuhlingH,FugeJ,MarschG,WarneckeG,HaverichA,WelteT,GottliebJ.Lung transplantation for non-cystic fibrosis bronchiectasis. Respir Med. 2016Jun;115:60-5.doi:10.1016/j.rmed.2016.04.007.

SpinouA,FragkosKC,LeeKK,ElstonC,SiegertRJ,LoebingerMR,WilsonR,GarrodR,BirringSS.The validity of health-related quality of life questionnaires in bronchiectasis: a systematic review and meta-analysis.Thorax.2016Aug;71(8):683-94.doi:10.1136/thoraxjnl-2015-207315.

ChalmersJD,McDonnellMJ,RutherfordR,DavidsonJ,FinchS,CrichtonM,DupontL,HillAT,FardonTC,DeSoyzaA,AlibertiS,GoeminneP.The generalizability of bronchiectasis randomized controlled trials: A multicentre cohort study.Respir Med.2016Mar;112:51-8.doi:10.1016/j.rmed.2016.01.016.

Aliberti S, Lonni S, Dore S, McDonnell MJ, Goeminne PC,Dimakou K, Fardon TC, Rutherford R, Pesci A, Restrepo MI,SotgiuG,Chalmers JD.Clinical phenotypes in adult patients with bronchiectasis.Eur Respir J.2016Apr;47(4):1113-22.doi:10.1183/13993003.01899-2015.


TUESDAY, MAY 23 LUNG TRANSPLANTATION

Lianne G. Singer, MDUniversityHealthNetwork,UniversityofToronto

DepartmentofMedicineToronto,ON,Canada

ANTIBODY-MEDIATED REJECTIONLevineDJ,GlanvilleAR,AboyounC,BelperioJ,BendenC,BerryGJ,HachemR,HayesDJr,NeilD,ReinsmoenNL,SnyderLD,SweetS,TyanD,VerledenG,WestallG,YusenRD, Zamora M, Zeevi A. Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2016;35:397-406.

Summary Antibody-mediatedrejection(AMR)hasbeendefinedinothertransplantedorgansbuttherehasnotbeenastandardizeddefinition in lung transplants. A working group of theInternational Society of Heart and Lung Transplantation(ISHLT) developed aworking definition to facilitate furtherresearchandimproveclinicalidentificationofthissyndrome,thoughmanygapsinknowledgecurrentlyexist.Evidenceofallograftdysfunctionisaprerequisitefor“clinicalAMR”andis broadly defined as alterations in pulmonary physiology,gasexchange,radiologicfeaturesorfunctionalperformance.The level of certainty in AMR diagnosis depends on thenumberofdiagnosticcriteriapresent.DefiniteAMRincludes3/3ofthefollowingfactorswhileprobableAMRincludes2/3of:(1)circulatingdonor-specificanti-HLAantibodies(DSA),(2) histopathologic changes consistent with AMR; and (3)C4d staining of interstitial alveolar capillaries in a linearpatternasevidenceofcomplement fixation.Othercausesof graft dysfunction such as infection should generallybe excluded, but probable AMR may be diagnosed withconcurrent causes of graft dysfunction if other diagnosticcriteriaarepresent.Thereportalso includesdefinitionsfor“subclinicalAMR”whereallograftdysfunctionisnotpresent.

Comments1.Similar to prior ISHLT consensusdefinitions of primarygraftdysfunctionandbronchiolitisobliteranssyndrome,this is an empiric definition which will be useful infacilitating furtherdialogueanddiscoveryandwill likelyberevisedovertimeasknowledgegapsareaddressed.

2.The optimal approach to treating clinical AMR (or themorecontentious“subclinicalAMR”wheregraftfunctionispreserved)isunclearandtheconsensusreportdidnotincludetreatmentrecommendations.

3.The report and accompanying supplementary materialhighlight many areas for further research includingimmunologic testing for DSA and non-HLA antibodies,standardization of the pathology of AMR, and refiningclinicalaspectsofAMRdiagnosisandtreatment.

ACCESS TO TRANSPLANTATIONSell JL, Bacchetta M, Goldfarb SB, Park H, HeffernanPV,RobbinsHA,ShahL,RazaK,D’Ovidio F,Sonett JR,Arcasoy SM, Lederer DJ. Short stature and access to lung transplantation in the United States. A cohort study.Am J Respir Crit Care Med2016;193:681-8.

SummaryLungtransplantcentersfrequentlyattempttomatchdonorlungstorecipientsbasedonheightortotal lungcapacity.The authors hypothesized that this may disadvantagetransplant candidates of below-average height. Thisretrospective cohort study included 13,346 adults listedfor lung transplantation in the United States between2005 and 2011. Associations between recipient heightand outcomes on the waiting list and post-transplantwereevaluatedusingmultivariablecompetingrisksurvivalmodels.Comparedwithcandidatesofaverageheight(170-176.5cm),candidates in the lowestheightquartile (<162cm)hada34%lowerrateoftransplantation,a62%higherrateofdeathorremovalfromthewaitinglistduetoclinicaldeterioration,anda42%higher rateof respiratory failureonthewaitinglist.Womencomprised93%ofindividualsinthelowestheightquartile.Heightwasnotassociatedwithsurvivalaftertransplantation.

Comments1.Shorterindividualsaresubjectedtoadisparityinaccesstotransplantation;thisdisparityparticularlyaffectswomenwhomayalsobedisadvantagedbyallosensitization.

2.Onepotentialsolutionisreappraisalofacceptedsurgicalpractices to increase transplantation of “oversized”organs, or “downsizing” of donor lungs through lobartransplantationornon-anatomicvolumereduction.

3.Theauthorsalsoadvocate forearlier transplant referralofshortindividuals,andinclusionofcandidateheightinthelungallocationalgorithm.

4.Thisworkaddstootherrecent literaturedemonstratinggeographicandsocial(insurancestatus,socioeconomicstatus) barriers to transplantation; recognition ofthese disparities may prompt earlier referral for lungtransplantationandguideadvocacyeffortstopromoteamoreequitablehealthcaresystem.


LUNG TRANSPLANTATIONTUESDAY, MAY 23

CHRONIC LUNG ALLOGRAFT DYSFUNCTION PHENOTYPESDerHovanessian A, Todd JL, Zhang A, Li N, Mayalall A,FinlenCopelandCA,ShinoM,PavliskoEN,WallaceDW,GregsonA,RossDJ,SaggarR,LynchJP,BelperioJ,SnyderLD, Palmer SM, Weigt SS. Validation and refinement of chronic lung allograft dysfunction phenotypes in bilateral and single lung recipients.Ann Am Thorac Soc2016;13:637-635

Summary It is now well-recognized that chronic lung allograftdysfunction can present with a restrictive phenotype(termedrestrictiveallograftsyndrome,orrestrictiveCLAD)which carries aworse prognosis than themore commonobstructivephenotypeofbronchiolitisobliteranssyndrome.This restrictive phenotype has been defined by loss oftotal lung capacity in bilateral lung transplant recipients.This two-center retrospective cohort study examined thepredictive validity of an alternatedefinitionof forced vitalcapacity (FVC) loss in single andbilateral lung transplantrecipients, and examined the additional utility of pleuralor parenchymal fibrosis on chest computed tomography(CT).389recipientswithCLADwereincludedinthestudy.CLADwasdefinedby>20%FEV1lossandsub-classifiedbypresenceorabsenceof concomitant>20%FVC loss.Subjects with FVC loss had a higher mortality risk, andthisappliedtobothbilateral(HR=2.75,95%CI2.02-3.73)and single (HR=1.80, 95% CI 1.09-2.98) lung transplantrecipients. In subjectswithout FVC loss, CT fibrosiswasalsoassociatedwithahighermortality risk inbothsingleandbilateralrecipients.

Comments1.ValidationoftheproposedFVClossdefinitionofrestrictiveCLAD phenotype in single lung transplant recipients isimportant,asitwasunclearwhethernativelungFVClosscould limit theprognosticutilityofPFTchanges in thissetting.

2.Pleural orparenchymal fibrotic changesonCTmaybeespecially useful in single lung transplant recipients,since it is easier to identify whether changes haveoccurredinthenativeorthetransplantedlung.

3.One important caveat is that FVC loss may not beindicativeofrestrictioniftheFVCisbeingreducedbyairtrapping;lungvolumeswerenotmeasuredinthisstudyand so could not be used to validate this definition ofrestrictivephysiology.

4.Itispossiblethatcombinationsofimagingandpulmonaryfunctionmeasurementswill have the highest predictivevalue;seeadditionalreferencesforalternateapproachestoCLADphenotyping.

5.Irrespective of measurement method used, otherwiseunexplainedlossofgraftfunctioninarestrictivepatternisanominousdevelopmentwhichis largelyuntreatableand should prompt consideration of re-transplantation,although this may also be associated with inferioroutcomes.

LONG-TERM COMPLICATIONSManshM,BinstockM,WilliamsK,HafeezF,KimJ,GliddenD,BoettgerR,HaysS, Kukreja J,Golden J, AsgariMM,Chin-HongP,SingerJP,ArronST.Voriconazole exposure and risk of cutaneous squamous cell carcinoma, Aspergillus colonization, invasive aspergillosis and death in lung transplant recipients. Am J Transplant 2016;16:262-70.

Summary Some lung transplant programs use voriconazole forprophylaxis of Aspergillus infections in lung transplantrecipients; however it is not known whether the benefitsof this practice outweigh the risks. This single-centerretrospective cohort study included 455 lung recipientstransplantedbetween1991-2012inSanFrancisco.84.5%of subjects were exposed to voriconazole. Multivariatesurvivalmodelswereusedtoexamineassociationsbetweenvoriconazole exposure andoutcomes includingdiagnosisofcutaneoussquamouscellcarcinoma(SCC),Aspergilluscolonization,invasiveaspergillosisandall-causemortality.There were several changes in immunosuppressiveprotocols and approach to prophylaxis and treatment ofAspergillus infections during this period; however, theauthors attempted to adjust for these changes. Duringthestudyperiod,19%ofsubjectsdevelopedat leastoneSCC, 26% developed Aspergillus colonization, and 17%developed invasive aspergillosis. Voriconazole exposurewas associatedwith an increased risk of SCC (HR 1.73,95% CI 1.04-2.88) and this effect was dose-dependent.VoriconazoleexposurewasassociatedwithalowerriskofAspergillus colonization, but not of invasive aspergillosis.Voriconazole exposure was associated with reduced all-causemortalityamongsubjectswhodevelopedAspergilluscolonization (HR=0.34,95%CI0.13-0.91)butnotamongthosewho did not develop colonization.Other antifungalagentsincludinginhaledamphotericinBandposaconazolewerenotassociatedwithanincreasedriskofSCC.

Comments 1.There were several important limitations to this workincluding the observational design, high prevalenceof voriconazole exposure, and inability to account forknown confounders including smoking, skin type, sunexposure,andintensityofimmunosuppression.

2.Nevertheless,thisstudydemonstratesthata“one-size-fits-all” approach to prophylaxis may be inappropriateand confer increased risks of SCC without reducinginfectionormortalityrisk.

3.This study suggests that targeted prophylaxis ofindividuals who are colonized with Aspergillus may bebeneficial,butthisshouldbestudiedinthecontextofarandomizedtrial.

4.It is possible that other biomarkers such as BALgalactomannanmayhelp further refine theapproach to


TUESDAY, MAY 23

targetedprophylaxisandlimitantifungaltherapytothosewithafavorablerisk-benefitratio.

5.Sunprotectioncounsellingandregularskinsurveillanceare also very important in themanagement of all lungtransplant recipients,butespecially thoseathigher riskbyvirtueofpriorskincancerhistory,fairskintype,age,malesex,residenceinaregionofhighsunexposureandexposuretophotosensitizingmedications.

INNOVATIVE CLINICAL CARE MODELSDeVitoDabbsA,SongMK,MyersBA,LiR,HawkinsRP,PilewskiJM,BermudezCA,AubrechtJ,BegeyA,ConnollyM, Alrawashdeh M, DewMA.A randomized controlled trial of a mobile health intervention to promote self-management after lung transplantation.Am J Transplant 2016;16:2172-80.

Summary Given thehigh frequencyofadverseoutcomesafter lungtransplantation,patientsareencouragedtotakeanactiverole in monitoring their health, hoping this will promotemedicationadherenceandearlieridentificationoftreatablecomplications. This single-center randomized controlledtrial assigned 201 first-time lung recipients at hospitaldischargetoeitherusualcare(includingrecordingofhealthindicators in paper logs) or a mobile health (mHealth)interventionwhichconsistedofasmartphoneprogrammedtoallow recordingofhealth indicators (e.g. lung function,vitalsigns),viewingof trends in indicatorsover time,andautomatedfeedbacktocontactthecoordinatorifindicatorsfelloutsidenormalparameters.Smartphonedatawerenotautomatically sharedwith the transplant team.Outcomeswere assessed up to 12 months post-transplant. ThemHealthgroupdemonstratedmoreself-monitoring,betteradherence,andmorefrequentreportingofabnormalresultsthan the standard care group. However, there was nodifference in re-hospitalization rates ormortality betweenthe two groups. In a follow-up report of 182 survivorsof the 12-month trial (see additional references) with amedian followupof 5.7 years post-transplant, therewasno difference in BOS rates between the intervention andcontrolgroups.Intheentirecohortirrespectiveoftreatmentassignment, self-monitoring and reporting of abnormalresultstothehealthcareteaminthefirst12monthswereassociatedwithlowersubsequentrisksofdeathandBOS.

Comments 1.Ofnote,bothgroupsshowedadeclineinself-managementbehaviors over time, which perhaps contributed to thelackofdifferencenotedinhealthoutcomesbetweenthetwogroups.

2.Limitations to generalizability include the relatively oldpatient cohort (eithermainly or exclusively in their 50sand 60s with a high prevalence of COPD), whereasnonadherencemay be more prevalent among younger

patients; the provision of smartphones and the use ofoldertechnology.

3.The follow up analysis did show that early self-managementbehaviorsandreportingofabnormalhealthindicators were subsequently associated with betteroutcomes.

4.It is possible that technologies which embed self-management into patients’ own smartphones and/or automatically report poor self-management orabnormalresultstotransplantteamswillprovideearlieropportunitiesforinterventionandimproveoutcomes,butthisarticleillustratesthatmobiletechnologiescannotbeautomaticallyassumedtobeeffective.

SAFETY OF ANTIFIBROTIC MEDICATIONSDelanote I, Wuyts W, Yserbyt J, Verbeken EK, VerledenGM, Vos R. Safety and efficacy of bridging to lung transplantation with antifibrotic drugs in idiopathic pulmonary fibrosis: a case series. BMC Pulm Med 2016;16:156.

Summary Withthelong-awaitedadventofeffectivetherapiestodelayprogression of idiopathic pulmonary fibrosis, transplantprograms have lacked information about whether thesedrugs are safe to continue in patients on thewaiting listfor transplantation. This single-center case series of 9patients is the largest reported experience to date. Theseriesincludepatientswhoreceivedlungtransplantswhiletaking nintedanib or pirfenidone. They were comparedwith a small group of 6 contemporaneously transplantedcontrolpatientswhodidnotreceiveantifibrotics.Moderatedeclinesinlungfunctiononthewaitinglistwereobservedin both treated and control patients. Significant weightloss occurred in treated patients. Therewere no obviousindications of increased perioperative or post-transplantrisksofantifibroticswithrespecttobleeding,woundhealing,anastomoticcomplications,primarygraftdysfunction,earlyCLADorsurvivalafteramedian19.8monthfollowup.

Comments 1.While no patients died on the waiting list while takingantifibroticdrugs, theauthorsdidnot reporthowmanypatients had to discontinue these drugs after listingfor side effects such as weight loss, GI intolerance orhepatitis.

2.Several patients were enrolled in randomized clinicaltrials post-transplant, which may have had effects onobservedoutcomes.

3.Whilemoreexperienceisneededtodrawfirmconclusionsabout thesafetyof thesedrugs, thesepreliminarydataprovidesomereassurance.

4.While thesamegrouphaspreviouslypublishedacasereportontreatmentofrestrictiveallograftsyndromewithpirfenidone,itisnotclearwhetherthesedrugshaveanybenefitinthepost-transplantsetting.

LUNG TRANSPLANTATION


TUESDAY, MAY 23 LUNG TRANSPLANTATION

OTHER ARTICLES OF INTERESTDONOR-SPECIFIC ANTIBODIES

Tikkanen JM, Singer LG, Kim SJ, Li Y, Binnie M, Chaparro C,ChowCW,MartinuT,AzadS,KeshavjeeS,TinckamK.DeNovoDQ.Donor-Specific Antibodies Are Associated with Chronic Lung Allograft Dysfunction after Lung Transplantation.Am J Respir Crit Care Med2016;194(5):596-606.

WallaceWD,LiN,AndersenCB,ArrossiAV,AskarM,BerryGJ,DeNicolaMM,NeilDA,PavliskoEN,ReedEF,RemmelinkM,WeigtSS,WeynandB,ZhangJQ,BudevMM,FarverCF.Banff study of pathologic changes in lung allograft biopsy specimens with donor-specific antibodies.J Heart Lung Transplant2016;35:40-8.

ACCESS TO TRANSPLANTATION

RamosKJ,QuonBS,PsoterKJ, LeaseED,Mayer-HamblettN,AitkenML,GossCH.Predictors of non-referral of patients with cystic fibrosis for lung transplant evaluation in the United States.J Cyst Fibros2016;15(2):196-203

Egan TM, Edwards LB. Effect of the lung allocation score on lung transplantation in the United States. J Heart Lung Transplant2016;35:433-9.

TsuangWM;ChanKM;SkeansMA;PykeJ;HertzMI; IsraniAJ;Robbins-CallahanL;VisnerG;WangX;WozniakTC;ValapourM.Broader geographic sharing of pediatric donor lungs improves pediatric access to transplant.Am J Transplant2016;16:930-7.

CHRONIC LUNG ALLOGRAFT DYSFUNCTION PHENOTYPES AND PROGNOSIS

SaitoT,HorieM,SatoM,NakajimaD,ShoushtarizadehH,BinnieM, Azad S, Hwang DM, Machuca TN, Waddell TK, Singer LG,Cypel M, Liu M, Paul NS, Keshavjee S. Low-dose computed tomography volumetry for subtyping chronic lung allograft dysfunction. J Heart Lung Transplant2016;35:59-66.

Suhling H, Dettmer S, Greer M, Fuehner T, Avsar M, HaverichA, Welte T, Gottlieb J. Phenotyping chronic lung allograft dysfunction using body plethysmography and computed tomography.Am J Transplant2016;16:3163-3170.

Belloli EA, Degtiar I, Wang X, Yanik GA, Stuckey LJ, VerledenSE, Kazerooni EA, Ross BD, Murray S, Galban CJ, Lama VN.Parametric response mapping as an imaging biomarker in lung transplant recipients.Am J Respir Crit Care Med 2016Oct25.[Epubaheadofprint].

VerledenSE,RuttensD,VandermeulenE,BellonH,DubbeldamA,DeWeverW,DupontL,VanRaemdonckDE,VanaudenaerdeBM, Verleden GM, Benden C, Vos R. Predictors of survival in restrictive chronic lung allograft dysfunction after lung transplantation.J Heart Lung Transplant 2016:35;1078-84.

CHRONIC LUNG ALLOGRAFT DYSFUNCTION PREVENTION

RuttensD,VerledenSE,VandermeulenE,BellonH,VanaudenaerdeBM, Somers J, Schoonis A, Schaevers V, Van RaemdonckDE, Neyrinck A, Dupont LJ, Yserbyt J, Verleden GM, Vos R.Prophylactic azithromycin therapy after lung transplantation: Post hoc analysis of a randomized controlled trial. Am J Transplant 2016;16:254-61.

StrueberM,WarneckeG,FugeJ,SimonAR,ZhangR,WelteT,HaverichA,GottliebJ.Everolimus vs. mycophenolate mofetil de novo after lung transplantation: a prospective, randomized open-label trial. Am J Transplant2016;16:3171-3180.

Gottlieb J; Zamora MR; Hodges T; Musk AW; SommerwerkU; Dilling D; Arcasoy S; DeVincenzo J; Karsten V; Shah S;Bettencourt BR; Cehelsky J; Nochur S; Gollob J; VaishnawA; Simon AR; Glanville AR. ALN-RSV01 for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients. J Heart Lung Transplant2016:35;213-21.

INNOVATIVE CLINICAL CARE MODELS

Rosenberger EM,DeVitoDabbsAJ,DiMartini AF, LandsittelDP,Pilewski JM,DewMA.Long-term follow up of a randomized controlled trial evaluating a mobile health intervention for self-management in lung transplant recipients. Am J Transplant 2016Sep24(Epubaheadofprint).

EX-VIVO LUNG PERFUSION

Yeung JC, Krueger T, Yasufuku K, de Perrot M, Pierre AF,WaddellTK,SingerLG,KeshavjeeS,CypelM.Outcomes after transplantation of lungs preserved for more than 12 h: a retrospective study. Lancet Respir Med; 2016 Nov 17 (Epubaheadofprint).


WEDNESDAY, MAY 24 THORACIC ONCOLOGY

Lynn T. Tanoue, MDYaleSchoolofMedicine

DepartmentofInternalMedicineSectionofPulmonary,CriticalCareandSleepMedicine

NewHaven,CT

LUNG CANCER SCREENINGKatkiHA,KovalchikSA,BergCDetal.Development and Validation of Risk Models to Select Ever-Smokers for CT Lung Cancer Screening. JAMA Intern Med. 2017; 177:399-406.

SummaryWhileastraightforwarddefinitionof“highrisk”isnecessaryforthepracticalpurposesofclinicaltrialssuchastheNLST,inclinicalpractice,weknowthatlungcancerriskestimationincludes factors beyond age and smoking. Risk-basedstrategies argue that screening recommendations shouldaccommodate “equal management of people at equalrisk.” Risk assessment of the NLST population identifiessubgroupswith varying risks,with themajority of benefit(decreased lung cancer deaths) occurring in the highestriskgroups,andrelativelylittlebenefitrealizedinthelowestrisk groups. Katki and colleagues developed models forlungcancerincidenceanddeathinever-smokersfromtheProstate,Lung,Colorectal,andOvarianCancerScreeningTrial (PLCO)controlgroup,using theassumption that theNLST mortality reduction of 20.4% would be applicableto ever-smokers independent of exposure level. ThesewerevalidatedinthechestradiographyarmsofthePLCOand NLST; the death model was additionally validatedin the National Health Interview Survey population. Theyconcludethatscreening9millionever-smokersages50-80identified by modeling as at highest 5-year risk of lungcancer (>1.9%)would result ina20%relative increase inCT-preventabledeathscomparedtoscreeningthe9millionAmericanseligiblebyUSPSTFrecommendations.

Comments1.Screening the 9 million Americans eligible by USPSTFrecommendationswasprojectedtoresultinthepreventionof 46,488 (95%CI, 43,924-49,053) lung cancer deathsover5years,vs.screening9millionever-smokersaged50-80identifiedasathighest5-yearriskoflungcancer(>1.9%)bytheriskmodels,whichwasprojectedtoprevent55,717(95%CI,53,033-58,400)lungcancerdeathsover5years(P<.001).

2.Compared with USPSTF recommendations, the riskmodel-based strategy was projected to have greaterestimated screening effectiveness [Number Needed toScreen to prevent one lung cancer death: 194 (95%CI,187-201)vs162(95%CI,157-166);P<.001],andgreaterestimated screening efficiency [fewer false-positivescreeningexaminationsperpreventeddeath:133(95%CI,128-137)vs.116(95%CI,113-119);P<.001].

3.The results suggest that application of risk-basedstrategies would preferentially replace the low-risk,low-benefit USPSTF-eligible population with a readilyidentifiable high-risk, high-benefit USPSTF-ineligiblepopulation.

4.At present, the Centers for Medicare and MedicaidServices will only support lung cancer screening forindividualswhomeettheUSPSTFlungcancerscreeningrecommendationcriteria.

5.Whether lung cancer risk predictivemodels should beused indeterminingwhoshouldbescreeneddeservesfurtherstudy.

LUNG CANCER SCREENING: IMPLEMENTATIONKinsingerLS,AndersonC,KimJ,LarsonM,ChanSH,KingHA,RiceKL,SlatoreCG,TannerNT,PittmanK,MonteRJ,McNeilRB,GrubberJM,KelleyMJ,Provenzale,DattaSK,Sperber NS, Barnes L, Abbott DH, Sims KJ, Whitley RL,Wu RR, Jackson GL. Implementation of Lung Cancer Screening in the Veterans Health Administration.JAMA Intern Med. 2017; 177:399-406.

SummaryImplementation of high quality lung cancer screening ischallenging, as demonstrated by this Veterans HealthAdministration(VHA)clinicaldemonstrationproject.Amonga total primary care population of 93,033 individuals at8 VHA hospitals, 4246 met USPSTF screening criteria.Accuratesmokinghistoryinformationwasdifficulttoobtainfrom the electronic health record, andonly 2106 (57.7%)patientsagreedtobescreened.Clinicalcarecoordination(scheduling, patient education, shared decision making,communicatingresults,followup,etc.)requiredafull-timecoordinator at each site. Multiple revisions of protocols,electronictools,andeducationalmaterialswerenecessary.UsingtheFleischnerSocietypulmonarynoduleguidelines,59.7%of screenedpatientshadpositive findings;66.5%of nodules were < 6 mm in diameter. A wide range ofnodular findings among the 8 siteswasnoted (30.7% to85%), raising the possibilities of geographic differencesor substantial variation in radiologist reporting. 40% ofpatientshadotherincidental,non-nodulefindings.Therateoflungcancerontheprevalencescanwas1.4%.This observational study should not be interpreted asarguing against lung cancer screening. It does point outthat implementation of screening is a complex process,and ideally should be undertaken by a committed teamusingstandardizedapproachesandalgorithms.


THORACIC ONCOLOGYWEDNESDAY, MAY 24

Comments1.High quality lung cancer screening requires amultidisciplinary effort to rigorously structure selectionof patients, radiology reporting, identification of lungnodules, standardized lung nodule management, anddatacollectionandreporting.

2.TheAmericanCollegeofRadiologyrecommendsradiologyreportingforLDCTlungcancerscreeningstudiesbedonewith Lung-RADS,which provides structured algorithmsfor nodule reporting and management, and aims tominimizefalsepositivefindings.

3.ThepolicystatementfromtheAmericanThoracicSocietyandtheAmericanCollegeofChestPhysiciansarticulatesthe components necessary to develop and implementhighqualitylungcancerscreening;thesearerecapitulatedinthememofromtheCentersforMedicareandMedicaidServicesoutliningtherequirementsforauthorizationandreimbursementoflungcancerscreening.

4.Nearly half of patients in this demonstration projectwhomet USPSTF criteria elected not to undergo lungcancerscreening;thereasonsforthisshouldbefurtherinvestigated.

PULMONARY NODULESMacMahonH,NaidichDP,GooJM,LeeKS,LeungANC,MayoJR,MehtaAC,OhnoY,PowellCA,ProkopM,RubinGD, Schaefer-Prokop CM Travis WD, Van Schil PE, andBankier AA. Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017. Radiology 2017. http://pubs.rsna.org/doi/abs/10.1148/radiol.2017161659 (aheadofprint).

SummaryPulmonary nodules are exceedingly common incidentalfindingsonCTimaging.Anestimated1.5millionindividualsin theUSwill have a pulmonary nodule identified byCTscanning annually, of which only a small, albeit notable,minority will be diagnosed with lung cancer. The 2017FleischnerSocietyGuidelinesforManagementofIncidentalPulmonaryNodulesDetectedonCT Images replaces theprevious 2005 and 2013 guidelines for incidental solidandsubsolidnodules.Thisstandardizationofapproachisintended to reduce unnecessary follow-up examinationsforfindingsunlikelytobesignificantorharmfultopatients,withoutproscribingclinicalcarethatshouldbeinformedbyindividualpatientcharacteristics.It is important to recognize that these guidelines referspecifically to pulmonary nodules identified incidentallyon CT imaging. This is in distinction to patients whoundergo low-dose chest CT for lung cancer screening,who comprise a different population with distinct lungcancerrisk,andforwhomaseparatespecificguidelineforinterpretationoffindingsshouldbeused.Thenewguidelinesincludemultiplesubstantivechangesinrecommendationsforbothsolidandsubsolidnodules,onlya few ofwhich are outlined below.Given the prevalence

of incidentalpulmonarynodules,athoroughreviewoftheentireguidelinesisstronglyencouraged.Comments1.The guidelines recommend that all chest CT scans bereconstructedandarchivedwithcontiguousthinsections(<1.5 mm) to enable accurate measurement, and thatthedefinitionofthediameterofanoduleshouldbetheaverageoflong-andshort-axisdiametersmeasuredontheCTimagewiththelargestnoduledimensions.

2.The threshold size for solid noduleswarranting routinefollowuphasbeenincreasedfrom4mmto6mm;solidnodules<5mmdonot require routine follow-upunlessthere is specific concern for higher risk because ofnodulemorphologyorlocation.

3.The threshold size for subsolid (pure ground glass orpart-solid)noduleshasbeenchangedto6mm;selectedsubsolidnoduleswithdiameterlessthanbutcloseto6mminsizewithconcerningmorphologyorotherpatientrisk factorsmaymerit followup,with consideration forlongerintervalsbetweenimaging(2-and4-years).

4.Forsubsolidnodules,puregroundglassnodules>6mmin diameter that demonstrate stability at 6-12 monthsshould have longer interval imaging follow up (2-year)for 5 years; part-solid nodules > 6 mm with a solidcomponent < 6 mm that demonstrate stability at 3-6monthsshouldhaveannualfollowupfor5years.

5.Theseguidelinesarenotintendedforuseinthefollowinggroupsofpatients:1)personsundergoingCTscanningfor the purpose of lung cancer screening; 2) patientswith known primary cancers at risk for metastases;3) children and adults younger than 35 years; 4)immunocompromisedpatientsatriskforinfection.

Kakinuma R, Noguchi M, Ashizawa K, Kuriyama K,MaeshimaAM,KoizumiN,KondoT,MatsugumaH,NittaN,OhmatsuH,OkamiJ,SuehisaH,YamajiT,KodamaK,MoriK,YamadaK,MatsunoY,MurayamS,MurataK.Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study.J Thorac Oncol2016;11(7):1012-1028.

SummarySubsolid pulmonary nodules present several challenges:they lackastandardized radiographicnomenclature, theirnaturalhistoryispoorlyunderstood,andtheyhaveahighlikelihoodofbeingpre-malignantormalignantlesions,butoftendisplaylessaggressivebiologicbehavior.Kakinuma and colleagues describe the natural history ofsubsolid pulmonary nodules in this prospective study of975 patients with 1229 subsolid nodules. They proposethree practical definitions: pure ground glass nodules(PGGN); heterogeneous ground glass nodules (HGGN):solid component detected only on lung windows andnot on mediastinal windows; part-solid nodules: solidcomponent detected on both lung and mediastinalwindows. Mean nodule diameter at enrollment was 7.8+ 3.4mm.Over amean follow up of 4.3 years, 1.2%ofPGGNsdeveloped intoHGGNs,and5.4% intopart-solidnodules; median time for the latter was 3.8 + 2 years.


WEDNESDAY, MAY 24

19.8% of HGGNs developed into part-solid nodules;median time to development was 2.1 + 2.3 years. 35 of977PGGNsand7of 78HGGNswere resected; allwereatypical adenomatous hyperplasia, adenocarcinoma insitu(AIS),orminimally invasiveadenocarcinoma(MIA).49of174part-solidnoduleswereresected;12wereinvasiveadenocarcinomas.AlltumorswereStage1(78StageIA;2StageIB).Comments 1.On the basis of a receiver operating characteristicanalysis for differentiating AIS and MIA from invasiveadenocarcinoma, the cutoff value of the maximaldiameterofasolidcomponentwas3.3mm (sensitivity61%,specificity91%).

2.Theminimumperiodsforthedevelopmentofpart-solidnodules with a solid component 3.3 mm or larger inmaximaldiameterwere1.8yearsfornodulesthatbeganas PGGNs, and 2.5 years for nodules that began asHGGNs.

3.The thoracic community should establish standardizedcriteriaforradiographicdescriptionofsubsolidnodules,includingstandardizationoftheCTslicethicknessusedtoevaluatethesenodules.

4.Observation of subsolid nodules appears to be anappropriate initial strategy, with the intervals betweenimaginginformedbythepresenceorabsenceofasolidcomponentonlungand/ormediastinalwindows,andthedevelopmentorlackthereofofasolidcomponentduringfollowup.

5.Thevariationbetweenmedicalguidelinerecommendationsfor duration of follow up for part-solid nodules (ACCP:surveillanceCTforatleast3yearsforpuregroundglassnodule,and3-5yearsforpart-solidnodules;FleischnerSociety: surveillance CT for at least 5 years for puregroundglasslesionsandnoduleswithsolidcomponent≤ 5 mm; NCCN: annual low-dose CT scanning untilthepatient is no longer eligible fordefinitive treatment)reflectstheneedforfurtherstudyinthisarea.

LUNG CANCER STAGINGDetterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The Eighth Edition Lung Cancer Stage Classification. Chest 2017;151(1):193-203.Summary Thepurposeofstageclassificationformalignancyistoprovideacommonlanguagethatconsistentlydescribestheanatomicextentofdisease.Thestagingnomenclaturefacilitatesreliablecommunicationabouttumorstage,providesprognosticinformation,andidentifieshomogeneouspopulationsforclinicaltrials.Itisimportanttorecognizethatstageclassificationdoesnotincludetumormolecularinformation,shouldnotbeusedasatreatmentalgorithm,andcannotbeusedtodefineanindividualpatient’sprognosis,whichwillbeinfluencedbymanyfactorsotherthananatomicextentofdisease.Periodicrevisionsofthestagingclassificationsforcancersarenecessary,toupdateoutcomesinmorecurrentpatient

populationsthatreflectadvancesinstagingtechnologiesandcancertreatment.TheInternationalAssociationfortheStudyofLungCancer(IASLC)amassedaglobaldatabasetoinformthenewstagingclassification,including94,708patientsfrom16countriesdiagnosedfrom1999–2010.RecommendationsforrevisionsoftheTumor(T),Node(N),andMetastasis(M)descriptors,andstagegroupings(TNM)werebasedondifferencesinoutcomes.ThisreviewofthenewEighthEditionsummarizestheeffortsofseveralgroupsforIASLC,identifieskeychangesinthestagingclassification,andclarifiesthesubgroupofpatientswithmultiplepulmonarysitesoflungcancer.Comments1.The new Eighth Edition of the stage classification forlungcancerwasimplementedgloballyinJanuary,2017,except intheUnitedStates,wheretheanticipateddateofimplementationisJanuary,2018.

2.While stage is often used to define groups for whomspecific treatments are recommended, treatment fora given patient must be individualized, influenced byan array of factors, including age, histologic subtype,treatment rendered, thepresenceofcomorbiditiesand/or competing causes of death, patient access to careandthequalityofthecaredelivered,etc.

3.Key changes in the staging classification: the Tdescriptor has undergone several revisions, includingnewdefinitionsforT1–T4basedonsizeandcentrality;theNdescriptorremainslargelyunchanged,exceptthattheanatomicmidlinewasshiftedtotheleftparatrachealborder and the extent of the subcarinal station wasexpanded; the M descriptor now differentiatesoligometastaticdisease(M1b)fromdiseasewithmultipledistantmetastases(M1c).

4.TheassignmentofTNMgroupsintodifferentstageswasdeterminedbyclinicaloutcomes.

5.Stagingforpatientswithmultiplepulmonarysitesoflungcancerwasmorerigorouslydefinedinfourcategories:1)Secondprimarylungcancer;2)Primarylungcancerwithoneormoreseparate,relatedtumornodules;3)Multipleground glass or lepidic nodules; 4) “Pneumonic-type”lungcancer.

LUNG CANCER TREATMENTReckM,Rodriguez-AbreuD,RobinsonAG,HuiR,CsosziT,FulopA,GottfriedM,PeledN,TafreshiA,CuffeS,O’BrienM,RaoS,HottaK,LeibyMA,LubinieckiGM,ShentuY,RangwalaRBrahmerJR.Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-1833.

SummaryTheprogrammeddeath-1(PD-1)pathwayisbeingintenselyinvestigatedasatherapeutictargetfornon-smallcelllungcancer(NSCLC).ActivatedBandTcellsexpressPD-1,animmunecheckpointinhibitorthatnormallydown-regulatesexcessive immune responses.PD-L1, oneof two ligands

THORACIC ONCOLOGY



identified for PD-1, is highly expressed by approximatelyone-fourthofNSCLCs.Blockingtumorimmunecheckpointinhibition with anti-PD-1 antibodies presumably restorestheabilityoftheimmunesystemtorecognizeandrespondtotumorneoantigens,whichareabundantintumorssuchas smoking-associated lung cancers that typically harborlargesequentialmutationalburden.This randomized multi-center study demonstrated thattherapy with pembrolizumab, a humanized anti-PD-1monoclonal antibody, was superior to platinum-basedcombination chemotherapy as first-line treatment foradvanced NSCLC. The study population was limited toNSCLC patientswith high PD-L1 tumor proportion score(PD-L1expressionon>50%of tumorcells);patientswithsensitizing EGFR mutations or ALK translocations wereexcluded. Treatment with pembrolizumab compared tostandard cytotoxic chemotherapy resulted in significantlylongerprogression-freesurvival[HRfordiseaseprogressionor death, 0.50 (95%CI, 0.37-0.68); P<0.001], improvedoverall survival [HR for death, 0.60 (95%CI, 0.41-0.89);P=0.005],andfewerserioustreatmentsideeffects(rateofgrade3-5adverseevents:26.6%vs.53.3%).

Comments 1.Thisisthefirstrandomizedtrialtodemonstratesuperiorityofimmunotherapycomparedtocytotoxicchemotherapyas first-line therapy for advanced NSCLC with highPD-L1tumorexpression.

2.Longerprogression-freesurvivalandoverallsurvivalwithanti-PD1therapywereobservedinbothnon-squamousand squamous histologies, and is particularly notablefor the latter, considering the relative lack of treatmentoptionsforthisgroup.

3.PriorstudieshavedemonstratedthatPD-L1isusefulasa biomarker, as a significantly increased response rateto pembrolizumab is observed in patients with PD-L1expressiononatleast50%oftumorcells.

4.Theefficacyofpembrolizumabinpatientswithlowtumorproportion score is unknown, but nivolumab, anothercheckpoint inhibitor, has been demonstrated to be ofbenefitassecond-linetherapyinnon-biomarkerenrichedpopulationsofpatientswithadvancedNSCLC.

5.First-line treatment of advanced NSCLC can now beapproachedmorestrategically,withthedecisiontoinitiatetherapy targeted to EGFR sensitizing mutations, ALKtranslocationsorROS1rearrangements,immunotherapy,orplatinum-basedchemotherapybasedonadeeperandmore personalized understanding of the biology of anindividualpatient’stumor.

LUNG CANCER QUALITY OF LIFEWrightAA,KeatingNL,AyanianJZ,ChrischillesEA,KahnKL,RitchieCS,WeeksJC,EarleCCLandrumMB.Family Perspectives on Aggressive Cancer Care Near the End of Life.JAMA2016;315:284-292.

SummaryDespite important treatmentadvances,many lungcancerpatientswill stilldie from theirdisease.Most terminally illpatientsareconsistentintheirgoalstohaverelieffrompainandtodieathome.Thirtyyearsago,70%ofcancerdeathsintheU.S.occurredinacutecarehospitals.Forlungcancer,thisrate isnow20%, likelyreflectinganappreciationthatless aggressive care and enhanced services addressingendoflifeneedsandgoalscontributetoimprovedqualityoflifeneardeath.This study investigated quality of life and attainment ofpatient endof life goals asperceivedby familymembersof1146patientswithadvanced lungorcolorectalcancer.Medicareclaimsdatawereused toassesscare renderedin the 6months preceding death. Next-of-kin or patient-identified family member/close friend were interviewedafter the patient’s death regarding their perceptions ofpatient goal-congruent care, including preferred site ofdeath, and their assessment of quality of care. 51.3%reportedexcellentendoflifecare.Amongmultiplevariablesmeasured,ICUadmissionwithin30daysofdeath,<3daysofhospicecare,anddeathoccurring in thehospitalwereassociated with a lower likelihood that patients receivedpreference-congruentcareand largerdifferences in familymember-reportedqualityofcare.Comments1.Improvingthequalityoftheendoflifefortheover150,000people in the U.S. and the hundreds of thousands ofpeopleintheworldwhowilldiefromlungcancerin2017isanimportantandnecessarygoal.

2.Careforpatientswithadvanced-stagelungcancershouldbecongruentwith theirpreferences,andshould includecounselingtounderstandthosepreferencesandgoals.

3.The study suggests that earlier hospice enrollment,avoidance of ICU admissions, and allowing death tooccur at the patient’s preferred site may improve thequalityofendoflifecare.

4.The National Quality Form (NQF) and the AmericanSociety of Clinical Oncology have endorsed indicatorsofoverlyaggressiveendof lifecare, includingrepeatedhospitalizations,emergencydepartmentvisits,admissiontoanICUwithinthelastmonthoflife,patientreceiptofchemotherapywithin2weekspriortodeath,andlateorabsenthospicereferrals.

OTHER ARTICLES OF INTERESTLUNG CANCER SCREENING

Fucito LM, Czabafy S, Hendricks PS, Kotsen C, RichardsonD, Toll BA, Association for the Treatment of Tobacco Use andDependence/Society for Research on Nicotine and TobaccoSynergyCommittee.Pairing smoking-cessation services with lung cancer screening: A clinical guideline from the Association for the Treatment of Tobacco Use and Dependence and the Society for Research on Nicotine and Tobacco.Cancer2016;122:1150-1159.



GouldMK.Who Should Be Screened for Lung Cancer? And Who Gets to Decide?JAMA2016;315:2279-2281.

TammemagiMC.Applications of risk prediction models to lung cancer screening: a review.J Thorac Imaging2015;30:88-100.

Tanner,NT,KanodraNM,GebregziabherM,PayneE,HalbertCH,WarrenGW,EgedeLE,SilvestriGA.The Association between Smoking Abstinence and Mortality in the National Lung Screening Trial.Am J Respir Crit Care Med2016;193:534-541.

WilleMM,DirksenA,AshrafH,SaghirZ,BachKS,BrodersenJ,ClementsenPF,HansenH,LarsenKR,MortensenJ,RasmussenJF,SeersholmN,SkovBG,ThomsenLH,TonnesenP,PedersenJH.Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling.Am J Respir Crit Care Med 2016;193:542-551

PULMONARY NODULES

Sawada S, Yamashita N, Sugimoto R, Ueno T, Yamashita M.Long-term Outcomes of Patients with Ground-Glass Opacities Detected Using CT Scanning.Chest2017;151:308-315.

Detterbeck FC. Achieving Clarity About Lung Cancer and Opacities.Chest2017;151:252-254.

LUNG CANCER STAGING

Asamura H, Chansky K, Crowley J, Goldstraw P, Rusch VW,VansteenkisteJF,WatanabeH,WuYL,ZielinskiM,BallD,Rami-PortaR.The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the forthcoming 8th Edition of the TNM Classification for Lung Cancer.J Thorac Oncol2015;10:1675-1684.

BalekianAA,Fisher JM,GouldMK.Brain Imaging for Staging of Patients With Clinical Stage IA Non-small Cell Lung Cancer in the National Lung Screening Trial: Adherence With Recommendations From the Choosing Wisely Campaign.Chest2016;149:943-950.

EberhardtWE,MitchellA,CrowleyJ,KondoH,KimYT,TurrisiA,3rd,GoldstrawP,Rami-PortaR.The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M Descriptors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol2015;10:1515-1522.

GoldstrawP,ChanskyK,CrowleyJ,Rami-PortaR,AsamuraH,Eberhardt WE, Nicholson AG, Groome P, Mitchell A, BolejackV. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification of Lung Cancer.J Thorac Oncol 2016;11:39-51.

Rami-PortaR,BolejackV,CrowleyJ,BallD,KimJ,LyonsG,RiceT,SuzukiK,ThomasCF,Jr.,TravisWD,WuYL.The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol2015;10:990-1003

LUNG CANCER TREATMENT

BernickerE.Next-Generation Sequencing and Immunotherapy Biomarkers: A Medical Oncology Perspective.Arch Pathol Lab Med 2016;140:245-248.

Herbst RS, Baas P, KimDW, Felip E, Perez-Gracia JL,Han JY,Molina J, Kim JH, Arvis CD, AhnMJ,MajemM, Fidler MJ, deCastroGJr.,GarridoM,LubinieckiGM,ShentuY, ImE,Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial.Lancet2016;387:1540-1550.

Mok TS, Loong HH. Are we ready for immune checkpoint inhibitors for advanced non-small-cell lung cancer? Lancet2016;387:1488-1490.

SteuerCE,BeheraM,BerryL,KimS,RossiM,SicaG,OwonikokoTK, Johnson BE, Kris MG, Bunn PA, Khuri FR, Garon EB,RamalingamSS.Role of Race in Oncogenic Driver Prevalence and Outcomes in Lung Adenocarcinoma: Results from the Lung Cancer Mutation Consortium.Cancer2016;122:766-772.

Swanton C, Govindan R. Clinical Implications of Genomic Discoveries in Lung Cancer.N Engl J Med2016;374:1864-1873.

LUNG CANCER QUALITY OF LIFE

Bekelman JE, Halpern SD, Blankart CR, Bynum JP, Cohen J,Fowler R, Kaasa S, Kwietniewski L, Melberg HO, Onwuteaka-PhilipsenB,Oosterveld-VlugM,PringA,SchreyoggJ,UlrichCM,VerneJ,WunschH,EmanuelEJ.Comparison of Site of Death, Health Care Utilization, and Hospital Expenditures for Patients Dying With Cancer in 7 Developed Countries. JAMA 2016;315:272-283.


Simon L.F. Walsh, MD, MRCPKing’sCollegeHospitalFoundationTrust

DepartmentofRadiologyLondon,UnitedKingdom

COMPUTER-AIDED EVALUATION OF HRCT FOR PROGNOSIS IN IPFJacobJ,BartholmaiBJ,RajagopalanS,KokosiM,NairA,KarwoskiR,etal.Mortality prediction in IPF: evaluation of automated computer tomographic analysis with conventional severity measures.Eur Respir J.2016.

Summary In this study of 283 IPF patients, Jacob et al. comparedCALIPER-derived measures of disease severity withsemiquantitative visual CT evaluation and pulmonaryfunction. A noteworthy feature of this study was themeasurementofpulmonaryvascularvolume(PVV),anovelCT variable that captures the volumes of the pulmonaryarteriesandveinsasapercentageofthetotallungvolume.On multivariate analysis, the only CT-derived variables,which were independently predictive of mortality, werehoneycombing(HR1.21,p=0.0004,95%CI1.09-1.34)andPVV (HR 1.39, p<0.0001, 95%CI 1.25-1.54) as assessedbyCALIPER.Theonlyphysiologicalvariableretainedintheanalysiswas thecompositephysiological index (CPI) (HR1.05, p<0.0001, 95%CI 1.02-1.07). These findings wereextended to create two 3-stage categorical scores; onebasedonCALIPER-derivedhoneycombing,PVVandtheCPI(CALIPER-CPIscore)andonebasedonCALIPER-derivedhoneycombingandthePVV(CALIPER-onlyscore).Bothofthese CALIPER-derived composite scores demonstratedimproved mortality prediction and goodness of fit whencomparedtothecategoricalGAPstagingsystem.Comments1.For prognostication, CALIPER outperformssemiquantitativevisualCTevaluation.

2.CALIPER-derived CT pattern scores may be used instagingsystems,whichprovidestrongermortalitysignalwhencomparedtothecategoricalGAPstagingsystem.

3.Pulmonary vascular volume, a novel CT variable is asignificantindependentpredictorofmortalityinIPF.

COMPUTER-AIDED EVALUATION OF HRCT FOR PROGNOSIS IN CONNECTIVE TISSUE DISEASE-RELATED INTERSTITIAL LUNG DISEASEJacobJ,BartholmaiBJ,RajagopalanS,BrunAL,EgashiraR, Karwoski R, et al. Evaluation of computer-based computer tomography stratification against outcome models in connective tissue disease-related interstitial lung disease: a patient outcome study. BMC Med.2016;14(1):190.

Summary ThisstudyevaluatedtheutilityofCALIPERasaprognostictoolinacohortof203patientswithall-comersconnectivetissue disease-related interstitial lung disease (CTD-ILD).A strength of this study was that by testing CALIPER ina mixed population of patients with different CTDs, theinvestigators overcome difficulties applying their data todifferentCTDsubgroupsorpatientswithoverlappingCTDfeatures.UsingCALIPER-derivedCTvariables,theauthorsstratified thecohort into threeoutcomegroupseachwithdistinct morphological characteristics (as measured byCALIPER) and function profiles (as measured by lungfunction). The authors improved mortality prediction bysubstituting FVC and DLco in the GAP staging model(HR1.74p<0.000195%CI1.45-2.08)with thisCALIPER-generatedpatientstratification(HR2.00,p<0.000195%CI1.63-2.45).CombiningtheGAPstagingsystemandpatientstratificationaugmentedprognosticationfurther.Asecondkey finding was that similar to IPF; pulmonary vascularvolume was the most powerful independent predictor ofmortalityinall-comersCTD-ILD(HR1.57,p<0.000195%CI1.35-1.82).

Comments 1.Computer-aided analysis of ILD combined with lungfunction can be used to stratify patientswithCTD-ILDinto prognostically distinct groups regardless of theirunderlyingCTDdiagnosis.

2.As in IPF, pulmonary vascular volume, a novel CTvariableisasignificantindependentpredictorofmortalityinconnectivetissuedisease-relatedILD.

CLINICAL AND RADIOGRAPHIC PREDICTORS OF HISTOPATHOLOGIC UIPBrownell R, Moua T, Henry TS, Elicker BM, White D,Vittinghoff E, et al. The use of pretest probability increases the value of high-resolution CT in diagnosing usual interstitial pneumonia.Thorax.2017.

Summary Thisstudyexaminedthetestcharacteristicsofnon-definiteUIP patterns on HRCT for UIP on lung biopsy using allpatients evaluated at the University of California at SanFrancisco ILD from September 2002 to July 2015. Onlypatients with a prospectively scored lung biopsy wereincluded.PatientswithdefiniteUIPonHRCT,aconnectivetissue disease or cystic lung disease were excluded.Patientswith a possibleUIPpattern onHRCT showed aspecificityof91.2%(95%CI87.2%to94.3%),apositive

THORACIC IMAGINGWEDNESDAY, MAY 24


predictivevalue(PPV)of62.5%(95%CI49.5%to74.3%)andlikelihoodratio(LR+)of4.01(95%CI2.54to6.33)fordefinite/probableUIPonsurgicalbiopsy.AcombinationofpossibleUIPonHRCT,malegender,age≥60years,andincreasing severity of traction bronchiectasis increasedthe PPV to 95% but reduced sensitivity to 16.8%. Age(stratified into50-59,≥60),malegenderandpossibleUIPwithatractionbronchiectasisscoreof≥4were identifiedaspredictorsofUIPonsurgicallungbiopsyandcombinedto create a “UIP-score.” This score demonstrated highdiscriminative performance for identifying histopathologicUIPonsurgicallungbiopsy(Cstatistic0.74,95%CI0.69to 0.78). The combination of “inconsistent with UIP” onHRCTandcandidatepredictorsdidnotprovideadequatepredictivepowerto“rulein”histopathologicUIP(maximumPPV achieved was 38%). The UIP-score demonstratedsimilar predictive power for histopathologic UIP in avalidationcohortmadeupoffibroticlungdiseasepatientsfromtheMayoClinic,Rochester.Comments 1.AgeisasignificantclinicalpredictorofIPF.2.When the HRCT pattern is that of “possible UIP,”the presence of traction bronchiectasis predictshistopathologicUIP.

3.Apredictionmodelcanbegeneratedusingage,gender,HRCTpatternandthepresenceoftractionbronchiectasis,whichdemonstrateshighdiscriminativeperformanceforidentifyinghistopathologicUIPonsurgicallungbiopsy.

4.These findings together corroborate thoseof Fell et al.(AJRCCM 2010;181:832) and support recent subgroupanalysisfromtheInpulsistrials(RaghuGetal.AJRCCM2017;195:78-85).].

CLINICAL AND RADIOGRAPHIC PREDICTORS OF A CLINICAL DIAGNOSIS OF IPFSalisburyML,XiaM,MurrayS,BartholmaiBJ,KazerooniEA,MeldrumCA,etal.Predictors of idiopathic pulmonary fibrosis in absence of radiologic honeycombing: A cross sectional analysis in ILD patients undergoing lung tissue sampling.Respir Med.2016;118:88-95

Summary This study evaluated 200 patients enrolled in the LungTissue Research Consortium with a diagnosis of fibroticlungdisease.Allpatientsunderwentsurgical lungbiopsy,andthosewithadiagnosisofaconnectivetissuediseasewereexcluded.Candidatevariablesincludingage,gender,smoking status, forced vital capacity andHRCT featureswerecombined to formadiagnosticmodel forpredictinga clinical diagnosis of IPF. In this study, a model-basedprobability of IPF was 80% or greater in patients of 60yearsormore,andwithreticularpatternsoccupyingmorethan one-third of their total lung volume on HRCT. Thespecificity for IPF inpatientsmeetingorexceeding these

criteriawas96%(95%CI91-100%),anduseofthismodelresultedin16%oflungbiopsiesbeingavoided.Comments1.AgeisasignificantclinicalpredictorofIPF.2.In the absence of honeycombing, the combination ofreticular patterns (greater than one third the total lungvolume)andage(60yearsormore)maypredictaclinicaldiagnosisofIPFwithaprobabilityof80%.

3.The use of this predictive model resulted in 16% ofsurgical lung biopsies being avoided in patients withsuspectedIPF.

INTERSTITIAL LUNG ABNORMALITIESArakiT,PutmanRK,HatabuH,GaoW,DupuisJ,LatourelleJC, et al.Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study.Am J Respir Crit Care Med.2016;194(12):1514-22.

Summary Several recent analyses of antifibrotic therapy in IPFhavedemonstrated identical treatment effects aboveandbelow FVC thresholds of 70% and 80%. These findingshave stimulated interest in identifying subclinical IPFfor the purpose of early intervention. Recent studies ofsubclinical “interstitial lung abnormalities” (ILA) provide abasis for IPFscreening,butuntilnow, thesestudieshavebeenconfined to lungcancerscreeningdata.Arakietal.investigated prevalence and patterns of progression ofILA’s inageneralpopulationofpatientsderived from theFraminghamHeartStudy(FHS).Outof1867patients,118(6%)hadILA’s,whichprogressed(12).Increasingageandincreasingcopiesof theMUC5Bpromoterpolymorphismwere associated with ILA progression. ILA progressionwas associatedwith a greater FVC decline compared toparticipants without ILA (20 ml; SE, 66 ml; P = 0.0005)andwithparticipantswithoutprogression (25ml;SE,611ml; P = 0.03). ILA progression was also associated withincreased risk of deathwhen compared to thosewithoutILA’s (median follow-up time four years, HR 3.9; 95%confidenceinterval,1.3–10.9;p=0.01).

Comments1.These results support the growing body of evidenceindicatingthatILA’sareclinicallysignificantandthattheiridentificationmayplayaroleinearlyIPFdiagnosis.

2.ILA prevalence (which is an order ofmagnitude higherthanIPFprevalence)isanimportantissuethatneedstobestudiedfurther.

3.SinceILA’scanbecharacterizedmorphologically,futurestudieswillneedtoselectivelyevaluateILApatternsthatare most likely to represent early IPF (e.g. subpleuralreticularILAs)ratherthanstudyILA’sasasingleentity.

WEDNESDAY, MAY 24 THORACIC IMAGING


OTHER ARTICLES OF INTERESTEgashira R, Jacob J, Kokosi MA, Brun AL, Rice A, NicholsonAG, Wells AU, Hansell DM. Diffuse Pulmonary Ossification in Fibrosing Interstitial Lung Diseases: Prevalence and Associations. Radiology 2017, Feb 9. DOI: http://dx.doi.org/10.1148/radiol.2017152419

RaghuG,Wells AU, Nicholson AG, Richeldi L, Flaherty KR, LeMaulfF,etal.Effect of Nintedanib in Subgroups of Idiopathic Pulmonary Fibrosis by Diagnostic Criteria.Am J Respir Crit Care Med. 2017;195:78-85.

SalisburyML, Lynch DA, van Beek EJR, Kazerooni EA, Guo J,XiaM,MurrayS,AnstromKJ,YowE,MartinezFJ,HoffmanEA,FlahertyKR.IPFnetInvestigators.Idiopathic Pulmonary Fibrosis: Adaptive Multiple Features Method Fibrosis Association with Outcomes.Am J Respir Crit Care Med2016;Oct21,DOI:http://dx.doi.org/10.1164/rccm.201607-1385OC

Walsh SL, Wells AU, Desai SR, Poletti V, Piciucchi S, et.al.Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case cohort study. Lancet Respir Med.2016;4:557-65

WalshSLF,Calandriello L, SverzellatiN,WellsAU,HansellDM,Consort UIP. Interobserver agreement for the ATS/ERS/JRS/ALAT criteria for a UIP pattern on CT.Thorax2016;71:45-51.

WEDNESDAY, MAY 24 THORACIC IMAGING


IMPACT OF THE AFFORDABLE CARE ACTSommersBD,BlendonRJ,OravEJ,EpsteinAM.Changes in utilization and health among low-income adults after Medicaid expansion or expanded private insurance.JAMA Internal Medicine2016,176:1501-1509

SummaryMore than 30 states expanded Medicaid under theAffordableCare Act (ACA). Although the ACA resulted inincreasedhealthcarecoverage formillions, its impactonutilization and health remain less clear. To address this,the investigators evaluated survey data from November2013 throughDecember2015ofU.S.citizensages19 to64 years with incomes below 138% of the federal pov-erty level inKentucky,Arkansas,andTexas(totaling8676subjects). The investigators found no differences in sex,income,ormaritalstatus.Asexpected,by2015,theyfoundthat expansion was associated with reduced uninsuredratecompared tonon-expansion. Interestingly,expansionwasassociatedwith increases inaccess toprimarycare,fewer skippedmedicationdue tocost; reductions inout-of-pocket spending, likelihood of emergency departmentvisits;andincreasedoutpatientvisits.Screeningfordiabe-tes,glucosetesting,andregularcareforchronicconditionsalsoincreased.Qualityofcareratingsimprovedasdidtheshare of adults reporting excellent health. Comparisonsbetween Arkansas versus Kentucky showed increasedprivatecoverage inArkansas,with increasedMedicaid inKentucky. However, other than higher diabetic glucosetestingratesinKentucky,nootherdifferenceswereidenti-fiedwhencomparingtypeofexpansion.

Comment1.TheauthorsconcludethatKentucky’sMedicaidprogramand Arkansas’s private option were associated withsignificant increases in outpatient utilization, preventivecare, and improved health care quality; reductions inemergencydepartmentuse;andimprovedself-reportedhealth.

2.Although dependent on self-reported outcomes, thismanuscript is one of the few manuscripts examiningthe impactof theACAonhealth utilizationand relatedoutcomes.

3.The comparison of a state with Medicaid expansion(Kentucky)toaprivateoption(Arkansas)andtoastatewithnoexpansion(Texas)representsastrength.

4.Of interest, the investigators found improvements inreceipt of checkups, care for chronic conditions, and

qualityofcareeveninareaswithprimarycareshortages,suggestingthatinsuranceexpansionhashadanimpacteveninareaswithrelativeshortagesperhapsthroughtheuseof“safetynetproviders.”

5.A subgroup analysis suggested that racial/ethnicminorities may be differentially affected by alternativeexpansionapproaches.

6.The studyhas limitations including theuseof random-digit dialing telephone survey, which may introducebias, and that annual family income was used todefine the study sample, which does not necessarilymeasure ACA-related eligibility. Of course, no clearcausalinterpretationscanbemade.

IMPACT OF GENETIC DIAGNOSIS ON HEALTH DISPARITIESManraiAK,FunkeBH,RehmHL,OlesenMS,MaronBA,SzolovitsP,MarguliesDM,LoscalzoJ,KohaneIS.Genetic misdiagnoses and the potential for health disparities.NEJM,2016,375:655-665.

SummaryToday, access to genetic testing has improved chancesof early diagnosis of complex disorders. One example ishypertrophic cardiomyopathy. Using sequencing results,clinicians can assess the risk of hypertrophic cardiomy-opathy in patients’ relatives and diagnose the conditionin patients with ambiguous presentations. However, theimpactofsuchapproachonheathdisparitiesisunclear.Toaddressthis, theauthorsusedapubliclyavailableexomedatabaseand identifiedvariants thathadpreviouslybeenconsideredcausalinhypertrophiccardiomyopathyandthatare overexpressed in the general population. Importantly,they studied these variants in diverse populations andfound that patients of African American or unspecifiedancestry receivedpositive resultswith variantsmisclassi-fiedaspathogenic.Later,allofthesevariantswerere-cat-egorizedasbenign.ItturnsoutthatthevariantsthatweremostcommoninthegeneralpopulationweresignificantlymorecommonamongblackAmericansthanamongwhiteAmericans.Furthermore, theauthorsshowedthatsimula-tionsrevealedthattheinclusionofevensmallnumbersofblack Americans in control cohorts would have probablypreventedsuchmisclassifications.

Comments1.Theauthorsconcludethatthereisaneedforsequencingthegenomesofdiversepopulations,bothinasymptomatic

HEALTH DISPARITIESWEDNESDAY, MAY 24

Jesse Roman, MDUniversityofLouisvilleandRobleyRexVAMedicalCenter

DepartmentofMedicineLouisville,Kentucky



controls and the tested patient population, to avoidmisdiagnoses.

2.The use of ancestry-matched controls to interpret anyidentifiedvariantsisrecommended.

3.Further studies in additional populations of differentancestry backgrounds are expected to result inreclassificationsofcertainvariants.

4.Thisstudyshowsthatdisparitiesmayresult fromerrorsrelated neither to access to care nor to proposedphysiologicaldifferences.

5.In addition to black Americans, studies should beconducted using genomic data fromNative Americans,AsianAmericans,andotherpopulations.

DISPARITIES IN LEADING CAUSES OF DEATH ChangMH,MoonesingheR,AtharHM,TrumanBI.Trends in disparity by sex and race/ethnicity for the leading causes of death in the United States-1999-2010.J Public Health Manag Pract.2016,22(Supp1):S13-S24.

SummaryTherearedatasuggestingsignificant trends indisparitiesrelatedtotheleadingcausesofdeathwithinUnitedStatesdemographicsubgroups,butthesedataseemlimitedandoutdated.Toaddressthis,theauthorsusedcauseofdeathandpopulationestimatesfromtheNationalVitalStatisticsSystem to calculate age-adjusted death rates for the 10leadingcausesofdeathduring1999-2010.Theyfoundthatofthe10leadingcausesofdeath,age-adjusteddeathratesbysexandrace/ethnicitydeclinedduringtheperiodofstudyfor6causes,butincreasedfor4causes.Interestingly,sexandracial/ethnicdisparitiesbetweengroupspersistentforeachyearandcauseofdeath.Thedecreasing trendwasgreatest for cerebrovascular disease and the increasingtrendwasgreatest forAlzheimer’s disease. For each sexandyear,thedisparityindeathratesbetweenAsian/PacificIslanders and other groups varies by cause of death. In2010,theAsian/Pacific Islander-non-Hispanicblackdis-paritywaslargestforheartdisease,malignantneoplasms,cerebrovasculardisorders,andnephritis.TheAsian/Pacific-AlaskaNativedisparitywaslargestforunintentionalinjury,diabetesmellitus, influenza, andpneumonia, andsuicide.The Asian/Pacific Islander - non-Hispanic white dispar-itywas largest forchronic lower respiratorydiseasesandAlzheimerdisease.

Comments1.Age-adjusted death rates have improved for someleadingcausesofdeath,buthavedecreasedforothers.

2.Disparitiesinage-adjusteddeathratesvaryaccordingtocauseofdeathandrace/ethnicancestry.

3.Theauthorsconcludethatthesefindingscanbeusedtoimprovepoliciesandpracticesandtoevaluateprogressineliminatingdisparitiesandtheirsocialdeterminantsinvulnerablepopulations.

DISPARITIES IN LUNG CANCER INCIDENCETabatabai MA, Kengwoung-Keumo J-J, Oates GR,GuemmegneJT,AkinlawonA,EkadiG,FouadMN,SinghKP. Racial and gender disparities in incidence of lung and bronchus cancer in the United States: A longitudinal analysis. PLOS one. 2016, 1-19, DOI:10.1371/journal.pone.0162949.(September)

SummaryIt is well known that certain populations in the UnitedStates carry a disproportionate burden of cancer. Theseinvestigatorsusedworkmodelstoanalyzelungandbron-chuscancerage-adjustedincidenceratesbyrace,gender,andprevalenceofsmokingin38statesandtheDistrictofColumbia, and across geographic regions from 1999 to2012.Theyfoundthatinthisperiodoftime,age-adjustedincidence rates in lung cancer decreased in all statesand regions. However, Whites continue to have lowerage-adjusted incidence rates for lungcancer thanBlacksin all states and in five of the eight geographic regions.Interestingly, disparities in incidence ratesbetweenBlackandWhitemenwere found tobesignificantly larger thanthosefoundbetweenBlackandWhitewomen.Evenmoreinterestingarethedatageneratedbymodelingwhichpre-dictthatthegendergapinthe incidenceratesforWhiteswoulddisappearbymid-2018,andforBlacksby2026,butthe racial gapwill remain. The investigators also found adownwardtrendintheprevalenceofdailysmokinginbothgenders,althoughmaleshaveahigherratethanfemales.Thehighestand lowestprevalenceofdailysmokingwerefoundintheMid-SouthandNewEngland,respectively.Asexpected,asignificantcorrelationwasfoundbetweenlungcancerincidenceratesandsmokingprevalence.

Comments1.The authors conclude that although age-adjustedincidenceratesinlungcancerhavedecreasedthroughouttheUnitedStates,racialandgenderdisparitiesremain.

2.Tobacco exposure continues to represent the mostimportant cause of lung cancer. Considering the datapresented, efforts directed at curtailing the impact oftobaccoshouldcontinue.

3.In addition to the longitudinal data, the study includesthe use of longitudinal lineal mixed-effects model thatdescribes thedynamicsof lungcancer incidence ratesby race, gender, and smoking prevalence. This modelshould be quite valuable in predicting future impact oflungcancerinvariousUnitedStatesregions.

DISPARITIES IN ACUTE RESPIRATORY FAILUREBime C, Poongkunram C, Borgstrom M, Natt B, DesaiH, Parthasarathy S, Garcia JG. Racial differences in mortality from severe acute respiratory failure in the United States, 2008-2012. Ann Am Thorac Soc.2016,13:2184-2189.


SummaryRacial disparities in acute critical illnesses such as sepsisand acute respiratory failure are increasingly recognized.To investigate this further, the authors used a large,representativeUnitedStatesnationwidedatabasetoexaminethehypothesisthatblackandHispanicpatientswithsevereacute respiratory failure have higher mortality rates whencomparedwithnon-Hispanicwhites.Theanalysisrevealedthat,afteradjustingforsex,age,race,diseaseseverity,typeof hospital, andmedian household income for patient ZIPcode,blackshadagreaterodds ratioof in-hospitaldeathwhen compared with non-Hispanic whites, and Hispanicshadagreateroddsratioofin-hospitaldeathwhencomparedtonon-Hispanicwhites.SimilartrendswerefoundforAsianandPacificIslandersandNativeAmericanswhencomparedwithnon-Hispanicwhites.

Comments1.TheauthorsconcludethatBlacks,Hispanics,andotherracialminoritiesintheUnitedStatesexhibitsignificantlyhigher in-hospital sepsis-related respiratory failureassociatedmortalitywhencomparedwithnon-Hispanicwhites.

2.The analysis was retrospective, but took advantage ofdatafromtheAgencyforHealthcareResearchandQuality,Nationwide Inpatient Sample, Healthcare Cost, andUtilizationProject.HospitalizationswithacuterespiratoryfailurewereidentifiedusingacombinationofInternationalClassificationofDiseases,NinthRevisioncodes.

3.Factorsresponsibleforthesedisparitiesareunclear.

GENETICS IN COPDBuschR,QiuW,Lasky-SuJ,MorrowJ,CrinerG,DeMeoD. Differential DNA methylation marks and gene comethylation of COPD in African Americans with COPD exacerbations. Respir Res, 2016, 17:143. DOI10.1186/s12931-016-0459-8

SummaryChronic obstructive pulmonary disease (COPD) carriessignificant morbidity in mortality and is the third-leadingcause of death worldwide. The authors hypothesizedthatCOPD-associatedDNAmethylationmarks in AfricanAmericansmightcontributetodiseasepathogenesisand,importantly, that their identification would help improveunderstandingofracialdisparitiesinthiscondition.Totestthis, they assessed DNA methylation from whole bloodsamples in 362AfricanAmerican smokers obtained fromthePA-SCOPEcohort.Theyfoundfivedifferentiallymeth-ylated CpG probes significantly associated with COPDamong African Americans. The top ranked gene asso-ciation was MAML1, which appears to affect NOTCH-dependentangiogenesisinmurinelung.Networkmodeling

yielded co-methylation modules associated with COPDwith enrichment for gene sets related to inflammatorypathwaysknowntoberelevantinCOPD.Othergeneswererelatedtolungdevelopmentprocesses.

Comments1.Theauthorsidentifiedatotalof12differentiallymethylatedCpG sites associated with COPD that mapped tobiologicallyplausiblegenes.

2.The genes identified might be contributing to racialdifferencesinCOPDsusceptibilityandseverity.

3.Whilemuchdatahavebeengenerated identifying racialdisparities in respiratory disorders, this work unveilspotentialtargetsforintervention.

4.Further research will be needed to understand thebiologicalconsequencesofsuchfindingsand,importantly,to identifymeaningfulapproaches for therapybasedonthesefindings.



PALLIATIVE CAREWEDNESDAY, MAY 24

Richard A. Mularski, MD, MSHS, MCRKaiserPermanenteNorthwest

TheCenterforHealthResearchandDeptofPulmonary/CriticalCarePortland,OR

FAMILY MEETING RANDOMIZED CLINICAL ICU TRIALCarsonSS,CoxCE,WallensteinS,HansonLC,DanisM,TulskyJA,ChaiE,NelsonJE.Effect of palliative care-led meetings for families of patients with chronic critical illness: A randomized clinical trial. JAMA 2016 Jul5;316(1):51-62

SummaryFamily caregivers of patients with chronic critical illnessarean importantand logical target for improving the ICUexperience,especiallyifitimprovespsychologicaldistress.In this multicenter randomized clinical trial supportingsurrogatedecisionmakersofpatientswithchroniccriticalillness, the study assessed whether augmenting theusual support of surrogates with at least two structuredconversations delivered by palliative care-trainedconsultantswoulddecrease familypsychologicaldistressat 3 months, improve perceptions of communicationquality,ordecreaseendoflifetreatmentintensity.Thetrialenrolled 365 surrogate decision-makers of adult patientsrequiring at least 7 days of mechanical ventilation. Theinterventiongroupreceivedteam-basedspecialtycarethatfocused on providing emotional support, communicatingvalidatedprognosticinformationabout1-yearsurvival,anddiscussingthepatient’svaluesandpreferences.Thestudyidentifiednodifferencebetweenstudygroupsfortheprimaryoutcomemeasureofsurrogates’symptomsofdepressionand anxiety 3 months after the patient’s hospitalization(Hospital Anxiety and Depression Scale mean scores of12.2intheinterventiongroupand11.4inthecontrolgroup)nordifferencesinsurrogates’perceptionsofthequalityofcommunication and end of life treatment intensity. Theydid observe increased surrogates’ posttraumatic stresssymptomsat3-monthfollow-upintheinterventiongroup.

Comments1.The authors conclude that among families of patientswithchroniccriticalillness,theuseofpalliativecare-ledinformationalandemotionalsupportmeetingscomparedwith usual care did not reduce anxiety or depressionsymptoms and may have increased post-traumaticstressdisordersymptoms.

2.Thestudywasboth rigorousandpragmatic in that theinterventionwas designed to be scalable andpromotewidespreadadoptionintopractice,buildingonovertwodecadesofworkinthisarea.

3.The study did not assess expectations or accuracy ofsurrogates’perceptionsofprognosisand thusmaynot

have fulfilled a change in the theoretical underpinningsthatimprovingsurrogates’prognosticexpectationswouldimprove the decision-making experience or persistentpsychologicalsequela.

4.Although mortality in each group was similarlyapproaching40%atonemonth,itisunclearifeffortstonormalize and present the options of comfort-focusedcaremayhavechangedtheeffect.

5.Thestudyfallsinlinewithmanyothersthatdemonstratehow difficult it is to improve complex decision-makingforthecriticallyillanddoesnotsupportroutinepalliativecare-led discussion of goals of care for all families ofpatientswithchroniccriticalillness.

PROGNOSTIC DISCORDANCE IN THE CRITICALLY ILLWhite DB, Ernecoff N, Buddadhumaruk P, Hong S,Weissfeld L, Curtis JR, Luce JM, Lo B. Prevalence of and factors related to discordance about prognosis between physicians and surrogate decision makers of critically ill patients.JAMA 2016May17;315(19):2086-94.

SummarySurrogates are called to participate in shared-decision-making for incapacitated critically ill patients and assuch should have decisional capacity that includes fullyunderstanding thecarechoices, the likelyoutcomes,andthealternativestoappreciateanddiscoursewiththecareteam on behalf of their loved ones. Thismixed-methodsstudy assessed comprehension of medical informationandmisperceptionsaboutprognosisbyindividualsmakingdecisions by exploring factors related to physician-surrogatediscordance–definedasadifferencebetweena physician’s and a surrogate’s prognostic estimates ofat least 20%. Using quantitative surveys and qualitativeinterviewsacrossmultipletypesofICUsinaU.S.medicalcenter,theauthorsdocumenteddiscordanceinoverhalfof229surrogatesand99physicians involved in thecareof174critically illpatients.Discordant reasons foroptimismidentified included loved-one’s need to maintain hope,beliefs that the patient had unique strengths unknownto the physician, and religious convictions. Uncertaintyin prognosis was demonstrated, as nearly 60% survivedand surrogate estimates were more pessimistic thanthose of physicians in 20%. The study demonstratesconcrete aspects involved in the challenges of end oflife decision-making in the ICU and provides targetsfor improved empathic communication in the face ofundeniableuncertainty.


WEDNESDAY, MAY 24

Comments1.Surrogatestendtobeoverlyoptimisticaboutprognosis,whichmay lead topersistingburdensome interventionswith limited benefit and delay more palliative carefocusedtherapy.

2.In 24 of the 122 discordant cases (20%), estimatesof surrogates were more pessimistic than those ofphysicians – surrogates attributed this to intrinsicoptimismbyphysiciansoralackoffullknowledgeofthepatient’sstatus.

3.ICU family discussions are emotional interactionsthat include the struggle to cope with uncomfortableprognostic information andcomplicated family roles assurrogatedecision-makers.

4.ThestudyhighlightstheneedforICUpractitionerstobeempathicactivelistenerswhenprovidinginformationandengagingfamiliesinunderstandingpossibleoutcomes.

VANTAGE POINTS TO ASSESS QUALITY OF PALLIATIVE CARE IN THE ICUMularski RA, Hansen L, Rosenkranz SJ, Leo MC, NagyP, Asch SM. Medical record quality assessments of palliative care for ICU patients: Do they match nurses’ and families’ perspectives? Ann Am Thorac Soc 2016May;13(5):690-698

SummaryIn ongoing efforts to understand and improve palliativecare provision in the intensive care unit, valid and broadmeasurementsof thequalityof caredelivered is needed.Inthenext inaseriestodevelopendorsedpalliativecareindicatorstatementsinitiatedbytheRobertWoodJohnsonFoundationEnd-of-LifePeerWorkgroup,theseinvestigatorsfully operationalized and tested a comprehensive qualityevaluationmeasure set using a rigorousmultidisciplinaryDelphi process focused on optimizing the validity andfeasibility of chart review-derived metrics. Fourteenprocessmeasures assessed the quality of care deliveredacross the established domains of palliative care for theICU. Additionally, data was triangulated from two otherperspectives: familysatisfactionreportsandnurseratingsfrom those providing care in the ICU. From 150 patientevaluationswithanaverageICUlengthofstayof7.5days,thestudydemonstratedthatICUpatientsreceived53%ofrecommended palliative care. Family satisfaction ratingswerehighandnotcorrelatedtomeasuredqualitydelivered.Nurses rated the quality of care higher than medicalrecordreviewandsimilarlyhadpoorcorrelationwithchartbasedprocessmeasures. Theauthors suggest that eachmeasurementvantagemayproviderelevantevaluationsofqualitytoguideimprovementandinnovationwork.

Comments1.Deficitswereidentifiedacrosssevendomainsoftechnicalqualitythatwerenotcorrelatedwitheithernurseorfamilyratings.

2.Differentperspectivesmaysupplementtechnicalqualityofcareasmeasuredthroughchart-basedmetrics.

3.ThefulloperationalizedmeasuresetisfreelyavailableinthepublicdomainatAnnalsATSwebpagehttp://www.atsjournals.org/doi/suppl/10.1513/AnnalsATS.201508-501OC/suppl_file/mularski_data_supplement.pdf

PALLIATIVE CARE IMPROVES OUTCOMESKavalieratos D, Corbelli J, Zhang D, Dionne-Odom JN,Ernecoff NC, Hanmer J, Hoydich ZP, Ikejiani DZ, Klein-FedyshinM,ZimmermannC,MortonSC,ArnoldRM,HellerL, Schenker Y.Association between palliative care and patient and caregiver outcomes: A systematic review and meta-analysis.JAMA.2016Nov22;316(20):2104-2114

SummaryIt has been over a decade since the AHRQ Evidence-basedPracticeProgramconductedthelastcomprehensiveevaluationof palliative care andprovided the fieldwith amassivesystematicreviewandmeta-analysis.Thiscurrenteffort sought to determine the association of palliativecarewithqualityof life (QOL), symptomburden, survival,and other outcomes for people with life-limiting illnessand for their caregivers by evaluating and synthesizingrandomized clinical trials reported through July 2016.Narrativesynthesisandrandom-effectsmeta-analysiswasconducted to translate estimates of QOL to comparableunitsexpressedbytheFunctionalAssessmentofChronicIllnessTherapy-palliativecarescale(FACIT-Pal)instrument[range, 0-184 (worst-best); minimal clinically importantdifference9points]andsymptomburdenexpressedbytheEdmontonSymptomAssessmentScale(ESAS)[range,0-90(best-worst);MCID5.7points].Forty-threeRCTsprovideddataon12,731patientsand2,479caregivers.Palliativecarewas associated with statistically and clinically significantimprovementsinpatientQOLatthe1-to3-monthfollow-up (SMD 0.46) with FACIT-Pal improvement of 11 pointsand ESAS improvement of -10 points. There was noassociationbetweenpalliativecareandsurvival.Palliativecare was associated consistently with improvements inadvancecareplanning,patientandcaregiversatisfaction,andlowerhealthcareutilization.

Comments1.In thismeta-analysis, palliative care interventions wereassociated with improvements in patient QOL andsymptomburden.

2.Findings for caregiver outcomeswere inconsistent andmany associations were no longer significant whenlimitedtotrialsatlowriskofbias.

PALLIATIVE CARE


WEDNESDAY, MAY 24

3.An accompanying editorial notes that negativestudies included in the analysis suggests caution thatprotocolized care delivered by specialists may not beeffective without regard to what makes palliative caremeaningful to many patients, families, and clinicians:frequent and longitudinal follow-up, close involvementwith the primary clinical team, and a focus on relief ofphysicalandpsychosocialdistress.

4.Investigators designing RCTs in the future would bewise tocarefullyexamine thenuancesof the trialsandmethodssummarizedinthiscomprehensivereview.

PALLIATIVE CARE IN COPDRush B, Hertz P, Bond A,McDermid RC, Celi L.Use of palliative care in patients with end-stage COPD and receiving home oxygen: National trends and barriers to care in the United States.Chest.2017;151(1):41-46

SummaryIn an effort to investigate the use of palliative care inpatients with end-stage COPD and exacerbations, theinvestigators used a large U.S. database (NationwideInpatient Sample inclusive 2006-2012) to conduct aretrospective nationwide cohort analysis on adult COPDpatientsreceivinghomeoxygenandadmittedtohospitalforanexacerbation.Identifyingover55millionhospitalizationswith 181,689 patients with COPD/home oxygen/hospitalexacerbation, the study foundonly 3,145patients (1.7%)also had palliative care contact. There was a 4.5-foldrelative increase in palliative referrals from 2006 (0.45%)to 2012 (2.56%). Patients receiving consultations wereolder,had longerhospitalizations,weremoreoftenwhite,had comorbid cancer diagnoses, andmore frequent useof invasiveornon-invasiveventilationuse,amongstotherfactors. Socioeconomic status and hospital type alsoassociated with palliative care referral. Having a Do NotResuscitate status also increased the odds of havingassociated palliative care consultation. During the sametime, comparable rates for palliative care in metastaticcancer were over 4 times higher. Although the authorsdemonstrated an increase in palliative care for COPDpatients over the study period, specialist palliative careoccurred in only a minority of patients with end-stageCOPDadmittedtohospitalwithanexacerbation.

Comments1.Despite that advanced care planning and referral topalliativecare for individualswithadvancedCOPD isalongstanding guideline recommendation, studies havedemonstratedlowuptakeinthispopulation.

2.Despiteencouragingtrendsinnationalhospiceratesforendoflifecareandavailabilityanduseofpalliativecarefor patients with chronic persistent disease, significantcaregapsexistinlungdiseases.

3.The present study with nearly 95% complete nationalsamplingacross theU.S. starklydocuments thedeficitin provision of palliative care for COPD patients withhospitalized exacerbations, the strongest predictor fornear-termfuturemortality.

4.Thestudyidentifiesanumberofbarriersthatshouldbetakenupbysubsequentinvestigationandpolicywork.

COPD AND ILD IN THE ICUBrownCE,EngelbergRA,NielsenEL,CurtisJR.Palliative care for patients dying in the intensive care unit with chronic lung disease compared with metastatic cancer.Ann Am Thorac Soc.2016May;13(5):684-9

SummaryTheinvestigatorsexploreddifferencesinreceiptofelementsof palliative care among patients with interstitial lungdisease (ILD) and chronic obstructive pulmonary disease(COPD) who died in ICU, compared with patients withcancer.Combiningdatafrom15Seattle-areahospitalsfromthe IntegratingPalliative andCriticalCare studybetween2003and2008,extensivemedicalrecordabstractionwasused to identify eight elements of palliative care delivery.Multivariable logistic and linear regression was used tocompare differences in receipt of elements of palliativecare and length of stay. The study found patients withisolated diagnoses of COPD (n = 592), ILD (n = 79), ormetastatic cancer (n = 158). Compared with patientswith cancer, patients with COPD were more likely toreceive cardiopulmonary resuscitation before death andpatientswith ILDwere less likely to have documentationofpainassessmentinthelastdayoflife.PatientswithILDand COPD were less likely to have a do-not-resuscitateorder in place at the time of death and less likely tohavedocumentationofdiscussionsaboutprognosis thanpatients with cancer. Patients with COPD had longerhospital lengthsofstay,andpatientswithCOPDand ILDhadlongerICUlengthsofstay.

Comments1.Palliativecareprovisionhasbeenshowntobehigherinpatientswithcancercompared topatientswithchroniclungdiseases,despitehighmorbidityandmortality.

2.The majority of deaths in intensive care units (ICUs)followdecisions towithhold orwithdraw life-sustainingtreatments, suggesting that palliative care is criticallyimportantinthissetting.

3.AmongpatientswhodieintheICU,patientswithILDandCOPDreceivefewerelementsofpalliativecareandhavelongerlengthsofstay.

4.Likethenationwidestudyandpriorsmallerexplorations,thesefindingsidentifyareasforimprovementincaringforpatientswithchroniclungdiseases.

PALLIATIVE CARE


OTHER ARTICLES OF INTERESTLUNG DISEASE

LiangZ,HoffmanLA,NouraieM,KassDJ,DonahoeMP,GibsonKF, SaulMI, Lindell KO.Referral to palliative care infrequent in patients with idiopathic pulmonary fibrosis admitted to an intensive care unit.J Palliat Med.2017Feb;20(2):134-140.

ICU CARE

Chang DW, Acosta D, Shapiro MF. Priority levels in medical intensive care at an academic public hospital. JAMA Intern Med. 2017;177(2):280-28

SwintonM,GiacominiM, ToledoF,Rose T,Hand-BreckenridgeT,BoyleA,WoodsA,ClarkeF,ShearsM,SheppardR,CookD.Experiences and expressions of spirituality at the end of life in the intensive care unit.Am J Respir Crit Care Med.2017Jan15;195(2):198-204.

TenoJM,GozaloP,KhandelwalN,CurtisJR,MeltzerD,EngelbergR, Mor V. Association of increasing use of mechanical ventilation among nursing home residents with advanced dementia and intensive care unit beds.JAMA Intern Med.2016Dec1;176(12):1809-1816.

CoxCE,CurtisJR.Using technology to create a more humanistic approach to integrating palliative care into the intensive care unit.Am J Respir Crit Care Med2016;193:242–250.

Zalenski RJ, Jones SS, Courage C,Waselewsky DR, KostaroffAS, Kaufman D, Beemath A, Brofman J, Castillo JW, KrayemH, Marinelli A, Milner B, Palleschi MT, Tareen M, Testani S,SoubaniA,WalchJ,WheelerJ,WilbornS,GranovskyH,WelchRD. Impact of palliative care screening and consultation in the ICU: A multihospital quality improvement project.J Pain Symptom Manage. 2017Jan;53(1):5-12.e3.

PRACTICE AND UTILIZATION

AldridgeMD,EpsteinAJ,BrodyAA, LeeEJ,CherlinE,BradleyEH. The impact of reported hospice preferred practices on hospital utilization at the end of life. Med Care. 2016Jul;54(7):657-63.

GrudzenCR,RichardsonLD,JohnsonPN,HuM,WangB,OrtizJM,KistlerEA,ChenA,MorrisonRS.Emergency department-initiated palliative care in advanced cancer: A randomized clinical trial. JAMA Oncol. 2016 Jan 14. doi: 10.1001/jamaoncol.2015.5252.

Horton JR, Morrison RS, Capezuti E, Hill J, Lee EJ, Kelley AS.Impact of inpatient palliative care on treatment intensity for patients with serious illness.J Palliat Med.2016Sep;19(9):936-42

GUIDELINE STATEMENTS

DavidsonJE,AslaksonRA,LongAC,PuntilloKA,KrossEK,HartJ,CoxCE,WunschH,WicklineMA,NunnallyME,et.al.Guidelines for Family-Centered Care in the Neonatal, Pediatric, and Adult ICU.Crit Care Med.2017Jan;45(1):103-128.

KonAA,DavidsonJE,MorrisonW,DanisM,WhiteDB.Shared Decision-Making in Intensive Care Units. Executive Summary of the American College of Critical Care Medicine and

American Thoracic Society Policy Statement.Am J Respir Crit Care Med.2016Jun15;193(12):1334-6.

ONGOING / FUTURE WORK

CourtrightKR,MaddenV,GablerNB,CooneyE,SmallDS,TroxelA,CasarettD,ErsekM,CasselJB,NicholasLH,EscobarG,HillSH,O’BrienD,VogelM,HalpernSD.Rationale and design of the randomized evaluation of default access to palliative services (REDAPS) trial. Ann Am Thorac Soc.2016Sep;13(9):1629-39.

CoxCE,WyshamNG,KamalAH,JonesDM,CassB,TobinM,WhiteDB,KahnJM,HoughCL,CarsonSS.Usability testing of an electronic patient-reported outcome system for survivors of critical illness.2016Jul;25(4):340-349.

WEDNESDAY, MAY 24 PALLIATIVE CARE

Printed on partially recycled paper, 100% recyclable.

AMERICAN THORACIC SOCIETY25 Broadway, 18th Floor | New York, NY 10004 USA

P. (212) 315 - 8600 | F. (212) 315 - 6498thoracic.org

CLINICAL YEAR IN REVIEW - American Thoracic Society · CLINICAL YEAR IN REVIEW ... AstraZeneca LP,...

Documents

Transcript of CLINICAL YEAR IN REVIEW - American Thoracic Society · CLINICAL YEAR IN REVIEW ... AstraZeneca LP,...