Acute and Chronic Acute and Chronic RejectionRejection

Jessie S. Wilt, MDJessie S. Wilt, MDAssistant Professor of Clinical MedicineAssistant Professor of Clinical Medicine

Associate Medical DirectorAssociate Medical Director--Lung TransplantationLung TransplantationColumbia UniversityColumbia University

The RThe R---------------- WordWord

Know the difference between acute and Know the difference between acute and chronic rejectionchronic rejectionUnderstand how each is diagnosedUnderstand how each is diagnosedUnderstand treatment optionsUnderstand treatment options

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Interval % Survival 1 Month 85% 6 Month 67% 1 Year 61% UNOS 1Year 79 % 3 Year 42% UNOS 3 Year 62%

Interval % Survival 1 Month 98% 6 Month 94% 1 Year 93% UNOS 1Year 79 % 3 Year 78% UNOS 3 Year 62%

UNOS 1YR

UNOS 3YR

UNOS 1YR

UNOS 3YR

CPMC

CPMC

ColumbiaColumbia--Presbyterian Medical CenterPresbyterian Medical Center ColumbiaColumbia--Presbyterian Medical CenterPresbyterian Medical CenterKaplanKaplan--Meier Meier -- Patient Patient SurvivalSurvival EstimatesEstimates KaplanKaplan--Meier Meier -- Patient Patient SurvivalSurvival EstimatesEstimatesLung Transplantation Lung Transplantation –– 7/01/1997 to 6/30/2001 Lung Transplantation 7/01/1997 to 6/30/2001 Lung Transplantation –– 7/01/2001 to 12/08/20057/01/2001 to 12/08/2005(n = 92)(n = 92) (n = 136)(n = 136)

PrePre--Program RestructureProgram Restructure Post Program Restructure Post Program Restructure

ADULT LUNG TRANSPLANT RECIPIENTS: Cause Of ADULT LUNG TRANSPLANT RECIPIENTS: Cause Of

DeathDeath (Deaths: January 1992(Deaths: January 1992-- June 2004)June 2004)

CAUSE OF DEATHCAUSE OF DEATH00--30 Days 30 Days (N = 1146)(N = 1146)

31 Days 31 Days -- 1 1 Year Year

(N = 1,717)(N = 1,717)

>1 Year >1 Year -- 3 3 Years Years

(N = 1,428)(N = 1,428)

>3 Years >3 Years -- 5 5 Years Years

(N = 800)(N = 800)

MALIGNANCY, MALIGNANCY, OTHEROTHER 1 (0.1%)1 (0.1%) 44 (2.6%)44 (2.6%) 78 (5.5%)78 (5.5%) 60 (7.5%)60 (7.5%) 70 (8.4%)70 (8.4%)

CMVCMV 00 65 (3.8%)65 (3.8%) 20 (1.4%)20 (1.4%) 4 (0.5%)4 (0.5%) 3 (0.4%)3 (0.4%)

>5 Years >5 Years (N = 829)(N = 829)

BRONCHIOLITISBRONCHIOLITIS 5 (0.4%)5 (0.4%) 82 (4.8%)82 (4.8%) 378 (26.5%)378 (26.5%) 231 (28.9%)231 (28.9%) 225 (27.1%)225 (27.1%)

ACUTE ACUTE REJECTIONREJECTION 63 (5.5%)63 (5.5%) 35 (2.0%)35 (2.0%) 25 (1.8%)25 (1.8%) 4 (0.5%)4 (0.5%) 5 (0.6%)5 (0.6%)

LYMPHOMALYMPHOMA 1 (0.1%)1 (0.1%) 47 (2.7%)47 (2.7%) 32 (2.2%)32 (2.2%) 11 (1.4%)11 (1.4%) 27 (3.3%)27 (3.3%)

INFECTION, NONINFECTION, NON--CMVCMV

245 245 (21.4%)(21.4%) 639 (37.2%)639 (37.2%) 352 (24.6%)352 (24.6%) 162 (20.3%)162 (20.3%) 150 (18.1%)150 (18.1%)

GRAFT FAILUREGRAFT FAILURE 331 331 (28.9%)(28.9%) 307 (17.9%)307 (17.9%) 244 (17.1%)244 (17.1%) 137 (17.1%)137 (17.1%) 127 (15.3%)127 (15.3%)

CARDIOVASCULACARDIOVASCULARR

121 121 (10.6%)(10.6%) 72 (4.2%)72 (4.2%) 50 (3.5%)50 (3.5%) 36 (4.5%)36 (4.5%) 46 (5.5%)46 (5.5%)

TECHNICALTECHNICAL 96 (8.4%)96 (8.4%) 44 (2.6%)44 (2.6%) 11 (0.8%)11 (0.8%) 2 (0.3%)2 (0.3%) 3 (0.4%)3 (0.4%)

OTHEROTHER 283 283 (24.7%)(24.7%) 382 (22.2%)382 (22.2%) 238 (16.7%)238 (16.7%) 153 (19.1%)153 (19.1%) 173 (20.9%)173 (20.9%)

JHLT 2005, Vol 24; 948JHLT 2005, Vol 24; 948--982982

PERCENTAGE OF ADULT LUNG TRANSPLANT PERCENTAGE OF ADULT LUNG TRANSPLANT RECIPIENTS TREATED FOR REJECTION IN 1ST YEARRECIPIENTS TREATED FOR REJECTION IN 1ST YEARStratified by Type of Induction (Transplants: January 1, 2000 Stratified by Type of Induction (Transplants: January 1, 2000 -- June 30, 2003)June 30, 2003)

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JHLT 2005, Vol 24; 948JHLT 2005, Vol 24; 948--982982

NUMBER OF REJECTION EPISODES FOR ADULT LUNG NUMBER OF REJECTION EPISODES FOR ADULT LUNG TRANSPLANT RECIPIENTS TREATED FOR REJECTION IN TRANSPLANT RECIPIENTS TREATED FOR REJECTION IN 1ST YEAR1ST YEARStratified by Type of Induction (Transplants: January 1, 2000 Stratified by Type of Induction (Transplants: January 1, 2000 -- June 30, 2003)June 30, 2003)

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Acute Lung RejectionAcute Lung Rejection

A0 A0 No infiltratesNo infiltratesA1A1 Rare perivascular infiltratesRare perivascular infiltratesA2A2 Perivascular infiltrates notable Perivascular infiltrates notable

at at low magnificationlow magnificationA3A3 Infiltrates extend into septaeInfiltrates extend into septaeA4A4 Diffuse infiltrates and alveolar Diffuse infiltrates and alveolar

damagedamage-- With/Without Grade BWith/Without Grade B

AJT 2005, 5; 2022AJT 2005, 5; 2022--20302030

Minimal Acute Cellular Minimal Acute Cellular RejectionRejection

Clinical FeaturesClinical Features

AsymptomaticAsymptomatic–– Surveillance transbronchial biopsySurveillance transbronchial biopsy

NonspecificNonspecific–– FeverFever–– MalaiseMalaise–– DyspneaDyspnea–– CoughCough–– SputumSputum

Clinical FindingsClinical Findings

Chest radiographChest radiograph–– ClearClear–– Focal infiltrateFocal infiltrate–– Diffuse hazy opacitiesDiffuse hazy opacities

SpirometrySpirometry–– NormalNormal–– Decline from postDecline from post--operative baselineoperative baseline

Differential DiagnosisDifferential Diagnosis

Acute RejectionAcute RejectionInfectionInfection–– BacterialBacterial–– ViralViral

CMVCMV

–– FungalFungal

Graft dysfunctionGraft dysfunction–– VascularVascular

DiagnosisDiagnosis

Fiberoptic bronchoscopyFiberoptic bronchoscopy–– Bronchoalveolar lavageBronchoalveolar lavage–– Transbronchial biopsyTransbronchial biopsy

1010--12 specimens12 specimensAt least 5 pieces, >100 alveoli, bronchiolesAt least 5 pieces, >100 alveoli, bronchioles

Concomitant diagnosesConcomitant diagnoses–– Concurrent infectionConcurrent infection

CFCFCMVCMV

TreatmentTreatment

Oral corticosteroidsOral corticosteroids–– Boost with taperBoost with taper

Intravenous methylprednisoloneIntravenous methylprednisolone–– 1010--15 mg/kg/day (50015 mg/kg/day (500--1000 mg/day)1000 mg/day)

Augmentation of immunosuppressionAugmentation of immunosuppression–– Change calcineurin inhibitorChange calcineurin inhibitor–– Add mycophenolateAdd mycophenolate

Lympholytic therapyLympholytic therapy

LARGOLARGO

Lung Allograft Gene Expression Lung Allograft Gene Expression Observational StudyObservational Study14 centers U.S., Canada, Europe14 centers U.S., Canada, EuropeEnrolled > 600 patientsEnrolled > 600 patients

CARGOCARGOAlloMapAlloMapTMTM

–– NPV 98NPV 98--99%99%

POSTPOST--LUNG TRANSPLANT MORBIDITY FOR LUNG TRANSPLANT MORBIDITY FOR ADULTSADULTSCumulative Prevalence in Cumulative Prevalence in SurvivorsSurvivors within 1 and 5 Years within 1 and 5 Years PostPost--Transplant Transplant (Follow(Follow--ups: April 1994 ups: April 1994 -- June 2004)June 2004)

Outcome Within 1 Year

Total number with known response

Within 5 Years

Total number with known response

Hypertension 51.1% (N = 6,994) 85.9% (N = 1,490) Renal Dysfunction 25.7% (N = 7,008) 39.4% (N = 1,596) Abnormal Creatinine < 2.5 mg/dl 16.2% 22.7% Creatinine > 2.5 mg/dl 7.6% 12.8% Chronic Dialysis 1.9% 3.2% Renal Transplant 0.0% 0.7% Hyperlipidemia 17.7% (N = 7,362) 46.8% (N = 1,645)

Diabetes 21.5% (N = 6,995) 30.9% (N = 1,467) Bronchiolitis Obliterans 8.8% (N = 6,407) 33.0% (N = 1,178)

ObliterativeObliterative BronchiolitisBronchiolitis

Narrowing of the small airwaysNarrowing of the small airwaysLittle inflammatory infiltrateLittle inflammatory infiltrateIrreversibleIrreversibleProgressive airflow obstructionProgressive airflow obstruction

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Diagnosis of OBDiagnosis of OB

Diagnosis of EXCLUSIONDiagnosis of EXCLUSION–– Exclude infectionsExclude infections–– Exclude airway abnormalitiesExclude airway abnormalities–– Exclude acute rejectionExclude acute rejection

Reduction in Reduction in PFTsPFTs from the from the BESTBEST postpost--transplant baselinetransplant baseline

PFTsPFTs postpost--transplanttransplant

What should your lung function be?What should your lung function be?–– AgeAge–– GenderGender–– HeightHeight–– Donor?Donor?

When are the When are the PFTsPFTs ““the BESTthe BEST””..

BOS BOS –– BronchiolitisBronchiolitisObliteransObliterans SyndromeSyndrome

Once all other diagnoses are excludedOnce all other diagnoses are excludedMany names:Many names:–– BOS, Chronic rejection, Graft failureBOS, Chronic rejection, Graft failure

Clinical DiagnosisClinical Diagnosis–– TransbronchialTransbronchial biopsy cannot detect the biopsy cannot detect the

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TreatmentTreatment

Treatment OptionsTreatment Options

Augment immunosuppressive medicationsAugment immunosuppressive medicationsAntiAnti--inflammatory medicationinflammatory medication–– AdvairAdvair–– LipitorLipitor–– AzithromycinAzithromycin

AntiAnti--lymphocyte therapylymphocyte therapy–– PhotopheresisPhotopheresis

ReRe--transplanttransplant

Thank YouThank You