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William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil
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William Dean Wallace Lung Summary Banff 2013 Meeting in Brazil

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Lung summary from 12th Banff Conference on Transplant Pathology from the meeting in Comandatuba-Bahia, Brazil on August 23rd, 2013 http://cybernephrology.ualberta.ca/banff/2013

Lung summary from 12th Banff Conference on Transplant Pathology from the meeting in Comandatuba-Bahia, Brazil on August 23rd, 2013 http://cybernephrology.ualberta.ca/banff/2013

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  • 1
  • The presence of all 4 criteria in lung tx patient is rare althought the routine diagnosis of AMR with suffiencent sensitivity and specificity remains elusive multiple cases with a convincing constellation of DSA, tissue injury and vascular C4d completmentnt staining have been described
  • Wash U: Clinical Coordinating Site
  • We conducted a prospective multicenter observational study to Standardize DSA monitoring & HLA testing adnf Determine the incidence of DSA development & characterize DSA profiles early after lung transplantation
  • After enrollment and transplant, 7 (of the 126 patients) were ineligible; 119 were eligible and included in HALT The most common reasons for patients not being enrolled were: Treatment with desensitization pre-tx, having a previous tx, treatment with IVIG or cytogam, or being too sick to approach for the study Among those enrolled and transplanted, 7 were ineligible because of either a positive XM or requiring treatment with IVIG or cytogam
  • 44 of 68 (65%) DSA negative patients had at least 1 episode of ACR grade ≥ A1 compared to 25 of 36 (69%) DSA+ patients This was not statistically significant 26 of 68 (38%) DSA negative patients had at least 1 episode of ACR grade ≥ A2 compared to 16 of 36 (44%) DSA+ patients This was not statistically significant
  • There were 4 cases of AMR. These have not been adjudicated by the study adjudication committee yet. The cases presented at these time points after LTX and all presented with acute allograft dysfunction All had DSA; 1 patient had pre-tx DSA with MFI 1300, the MFI of this DSA increased to 10,000 and a new DSA was found at AMR. The other 3 patients had de novo DSA Biopsies were done in 2 of the 4 cases; the other 2 cases did not have biopsies because the patients were too sick. The 2 biopsies showed alveolar septal neutrophilia, but immunostaining for C4d and C3d was negative in both cases. In all cases there was clinical response to IVIG and high-dose steroids.
  • Transcript

    • 1. ISHLT Pathology Council & Pulmonary AMR 12th Banff Conference on Allograft Pathology Thursday, August 22, 2013 GERRY BERRY
    • 2. Pulmonary AMR in 2013 • Historical Highlights • 2012 ISHLT Survey of Pathology Practices • Recommendations from ISHLT 2012 in Prague • Future Directions
    • 3. 2012 Survey of Current Practices in Diagnosis and Reporting of Pulmonary AMR • Survey modeled on successful approach by AECVP for Cardiac AMR * • Survey consisted of 33 questions created in REDCap and supported by Stanford Center for Clinical Informatics in Stanford SOM • Survey sent to 38 institutions in North America, Europe and Australia * Burke M, Andersen C, Ashworth M, et al. J Heart Lung Transplant 2010; 29:S37-38.
    • 4. Demographics
    • 5. Experience in Reading Biopsies
    • 6. Monthly Transbronchial Biopsy Load
    • 7. Antibodies used in IHC
    • 8. Conclusions #1 • Group (90%) composed of experienced pathologists (> 5 yrs experience) • > 80% of groups evaluating > 10 TBBx/mo • Primary indications for immunostaining are clinical and histopathological findings • Few centers (25%) perform immunostaining according to protocols
    • 9. Conclusions #2 Indications of performing Immunostains • Acute Lung Injury Pattern (66%) • Neutrophilic Margination (70%) • Acute Capillaritis (85%) • Unexplained Graft Dysfunction (2/3) • High Grade ACR (22%)
    • 10. J Heart & Lung Transplant 2013; 32:14-21
    • 11. Histopathologic Indications for Immunopathologic Staining • Neutrophilic Capillaritis • Neutrophilic Septal Margination • High Grade ACR • Persistent/Recurrent ACR • Acute Lung Injury Pattern/DAD • High Grade LB (B2R) • Persistent low grade LB (Grade B1R) • Obliterative Bronchiolitis (Grade C1) • Arteritis in the Absence of Infection or ACR • Graft Dysfunction without Morphologic Explanation • Any Histologic Findings in setting of de novo +ve DSA
    • 12. Interpretative Issues in AMR • Distribution of C4d Staining: – Multifocal/Diffuse staining >50% of microvasculature: POSITIVE – Focal or <50% staining: NEGATIVE – Any C4d staining should be discussed with clinicians as findings might warrant DSA studies and more frequent clinical monitoring
    • 13. Diagnostic Terminology • Like ACR, AMR is diagnosis of exclusion • Requires clinical dysfunction, circulating DSA and C4d immunoreactivity “No Evidence of AMR” “Findings Suggestive of AMR” • Insufficient experience for making recommendations for follow-up intervals
    • 14. Summary & Future Directions • Diagnosis of pulmonary AMR requires multidisciplinary approach • Histopathological findings are nonspecific patterns of injury; patterns should trigger immunostaining • Qualified terminology should be used with final clinical diagnosis incorporating all modalities • For centers that do not routinely obtain DSA, studies should be done at or near time of biopsy • Centers are encouraged to develop protocols that will promote investigations addressing issues of time to onset of AMR, incidence, prevalence, spectrum of temporal, morphological and immunopathological changes, clinical outcomes and risk for chronic allograft dysfunction • Digital pathology slide technology will be used to promote educational and collaborative efforts
    • 15. Adriana Zeevi PhD (D) ABHI Professor of Pathology, Surgery and Immunology University of Pittsburgh Medical Center Serology of Lung AMR
    • 16. Summary  Recurrent ACR, refractory to increased immunosuppression is associated with development of de-novo DSA.  The most frequent DSAs in LTx were HLA-DQ specific including Abs towards DQB, DQA and combination of DQB/DQA pairs.  Persistent DQ specific DSAs with C1q reactivity are demonstrated prior to diagnosis of AMR.  Response to AMR treatment is associated with Diminished and/ or Loss of C1q reactive DSAs.
    • 17. Summary/Conclusions  Pre-formed and de-novo DSA are associated with various forms of antibody injury to allograft  Non HLA antibodies need to be evaluated for the impact on LTX  Early detection of DSA post LTx and systematic monitoring with sensitive solid-phase platforms is recommended  Antibody depletion protocols need to be evaluated: when and how
    • 18. Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation Survival was significantly worse in recipients who had persistent DSA than in those who cleared the DSA. Ramsey R. Hachem, MD, et al J Heart Lung Transplant 2010;29:973–80
    • 19. Clinical Overview of Pulmonary AMR Marie M. Budev DO MPH FCCP Medical Director Lung and Heart Lung Transplant Program Cleveland Clinic Cleveland, OH
    • 20. Triple Test - Diagnosis of Pulmonary AMR Serologic Evidence Donor Specific Antibody + Graft Dysfunction Histological Evidence Histopathology + C4d staining +
    • 21. AAMR and SurvivalAAMR and Survival • Survival afterSurvival after AMR is poorAMR is poor • Cleared DSACleared DSA significantlysignificantly better survivalbetter survival Witt CA. In Press : J Heart Lung Transplant. 2013
    • 22. Clinical Points AAMR StudyClinical Points AAMR Study • Survival is poor after AAMRSurvival is poor after AAMR • Survival is better if DSA clearedSurvival is better if DSA cleared • AAMR may be a reversible cause ofAAMR may be a reversible cause of allograft failureallograft failure • High index of suspicion with protocolHigh index of suspicion with protocol for surveillance in place including HLAfor surveillance in place including HLA testingtesting - C4d still controversialC4d still controversial • Role of C1qRole of C1q
    • 23. HLA ANTIBODIES AFTER LUNGHLA ANTIBODIES AFTER LUNG TRANSPLANTATION: EARLYTRANSPLANTATION: EARLY RESULTS OF THE HALT STUDYRESULTS OF THE HALT STUDY The HALT InvestigatorsThe HALT Investigators
    • 24. HALT: Multicenter StudyHALT: Multicenter Study • Washington UniversityWashington University – R. Hachem, R. Yusen, K. Schechtman, J. Gaut, T. MohanakumarR. Hachem, R. Yusen, K. Schechtman, J. Gaut, T. Mohanakumar • Cleveland ClinicCleveland Clinic – M. Budev, C. Farver, M. AskarM. Budev, C. Farver, M. Askar • University of PennsylvaniaUniversity of Pennsylvania – V. Ahya, J. Lee, L. Litzky, M. KamounV. Ahya, J. Lee, L. Litzky, M. Kamoun • UTHSC San AntonioUTHSC San Antonio – D. Levine, S. Werner-Abboud, M. PollackD. Levine, S. Werner-Abboud, M. Pollack • Stanford UniversityStanford University – G. Dhillon, D. Weill, G. Berry, D. TyanG. Dhillon, D. Weill, G. Berry, D. Tyan • University of California San FranciscoUniversity of California San Francisco – L. Leard, J. Golden, K. Jones, L. Baxter-LoweL. Leard, J. Golden, K. Jones, L. Baxter-Lowe
    • 25. MethodsMethods • Pilot prospective multicenterPilot prospective multicenter observational studyobservational study • Standardize DSA monitoringStandardize DSA monitoring • Determine incidence of DSADetermine incidence of DSA development (DSA profiles)development (DSA profiles) • Enrollment 12/2011 – 6/2012Enrollment 12/2011 – 6/2012 • 4 months follow-up after transplant4 months follow-up after transplant • LABScreen® Single Antigen assayLABScreen® Single Antigen assay - Days: 10, 30, 60, 90, 120Days: 10, 30, 60, 90, 120 - Allograft dysfunctionAllograft dysfunction
    • 26. Patient flow diagram
    • 27. Acute cellular rejectionAcute cellular rejection • At least 1 episode of ACR grade ≥ A1At least 1 episode of ACR grade ≥ A1 - DSA-: 44/68 (65%)DSA-: 44/68 (65%) - DSA+: 25/36 (69%)DSA+: 25/36 (69%) • At least 1 episode of ACR grade ≥ A2At least 1 episode of ACR grade ≥ A2 - DSA-: 26/68 (38%)DSA-: 26/68 (38%) - DSA+: 16/36 (44%)DSA+: 16/36 (44%) • CARS: sum of all A scoresCARS: sum of all A scores - DSA-: mean = 1.5 ± 1.5, median = 1.0DSA-: mean = 1.5 ± 1.5, median = 1.0 - DSA+: mean = 1.7 ± 1.6, median = 1.5DSA+: mean = 1.7 ± 1.6, median = 1.5 P = 0.63 P = 0.54 P = 0.70
    • 28. Antibody-mediated rejectionAntibody-mediated rejection • 4 cases of AMR (adjudicated)4 cases of AMR (adjudicated) • Occurred on POD 22, 46, 75, and 92Occurred on POD 22, 46, 75, and 92 • Clinical allograft dysfunctionClinical allograft dysfunction • DSA to class I & II (n = 4)DSA to class I & II (n = 4) – Pre-tx DSA (n = 1): higher MFI and new DSAPre-tx DSA (n = 1): higher MFI and new DSA – De novoDe novo DSA (n = 3)DSA (n = 3) • Alveolar septal neutrophilia (n = 2), no biopsy (n =Alveolar septal neutrophilia (n = 2), no biopsy (n = 2)2) – C4d & C3d negative (n = 2)C4d & C3d negative (n = 2) • Clinical response to IVIG, high-dose steroidsClinical response to IVIG, high-dose steroids
    • 29. ConclusionsConclusions • DSA is common early afterDSA is common early after transplantationtransplantation • DSA to HLA class II more commonDSA to HLA class II more common • HALT follow-up too short to examineHALT follow-up too short to examine impact on clinical outcomesimpact on clinical outcomes • Some patients did clear DSA duringSome patients did clear DSA during follow-upfollow-up • Long-term follow-up is necessary &Long-term follow-up is necessary & planned with HALT II Trialplanned with HALT II Trial
    • 30. Banff Study of PathologicBanff Study of Pathologic Changes in Lung AllograftChanges in Lung Allograft Biopsies with Donor SpecificBiopsies with Donor Specific AntibodiesAntibodies Comandatuba, BrazilComandatuba, Brazil August 2013August 2013
    • 31. Banff 2011Banff 2011 Paris, FranceParis, France Lung Group DiscussionLung Group Discussion Data for pathology of lungData for pathology of lung AMR was limited/lackingAMR was limited/lacking The data on C4d wasThe data on C4d was inconsistent, probably unreliableinconsistent, probably unreliable AMR in lung allograft was not aAMR in lung allograft was not a pathologic diagnosis at that timepathologic diagnosis at that time Large study needed to gatherLarge study needed to gather pathologic data on lungpathologic data on lung transplant biopsiestransplant biopsies Should be multi-institutionalShould be multi-institutional Results to be presented at BanffResults to be presented at Banff 2013 in Brazil2013 in Brazil Mengel M, et al. Banff 2011 Meeting report: new concepts in antibody-mediated rejection. Am J Transplant. 2012 Mar;12(3):563-70.
    • 32. Banff StudyBanff Study • Team Leaders: Carol Farver, W. Dean WallaceTeam Leaders: Carol Farver, W. Dean Wallace • Lung transplant transbronchial biopsies were compiledLung transplant transbronchial biopsies were compiled from UCLA and Cleveland Clinicfrom UCLA and Cleveland Clinic • 253 lung transplant biopsies (62 biopsies have C4d stains)253 lung transplant biopsies (62 biopsies have C4d stains) – Mean age: 55.8, Range: 18-74Mean age: 55.8, Range: 18-74 – Gender: 111 females (43.9%), 142 males (56.1%)Gender: 111 females (43.9%), 142 males (56.1%) • Inclusion criteria:Inclusion criteria: – All biopsies have full serologic antibody studies performed withinAll biopsies have full serologic antibody studies performed within ((++) 30 days of biopsy) 30 days of biopsy • 98 de novo DSAs (38.7%)98 de novo DSAs (38.7%) • 46 non-DSAs (18.2%)46 non-DSAs (18.2%) • 109 never antibodies (43.1%)109 never antibodies (43.1%) – Full clinical/infectious disease work up dataFull clinical/infectious disease work up data – At least 1 year old at beginning of studyAt least 1 year old at beginning of study
    • 33. PathologistsPathologists • Biopsies are scanned for whole slide imageBiopsies are scanned for whole slide image analysis for ease of sharinganalysis for ease of sharing • Eleven pathologists participated in blinded studyEleven pathologists participated in blinded study – Carol Farver, Cleveland ClinicCarol Farver, Cleveland Clinic – W. Dean Wallace, UCLAW. Dean Wallace, UCLA – Claus B. Andersen, Rigshospitalet, CopenhagenClaus B. Andersen, Rigshospitalet, Copenhagen – Valeria Arrossi, Cleveland ClinicValeria Arrossi, Cleveland Clinic – Roberto Barrios, The Methodist Hospital, HoustonRoberto Barrios, The Methodist Hospital, Houston – Gerry Berry, StanfordGerry Berry, Stanford – Matthew DeNicola, UCLAMatthew DeNicola, UCLA – Desley Neil, Queen Elizabeth Hospital, Birmingham,Desley Neil, Queen Elizabeth Hospital, Birmingham, UKUK – Elizabeth Pavlisko, Duke UniversityElizabeth Pavlisko, Duke University – Myriam Remmelink, Brussels, BelgiumMyriam Remmelink, Brussels, Belgium – Birgit Weynand, Brussels, BelgiumBirgit Weynand, Brussels, Belgium
    • 34. Histologic VariablesHistologic Variables • Biopsy AdequacyBiopsy Adequacy • Acute Cellular RejectionAcute Cellular Rejection • Airway InflammationAirway Inflammation • Obliterative BronchiolitisObliterative Bronchiolitis • Acute Lung InjuryAcute Lung Injury • EndotheliitisEndotheliitis • Alveolar HemosiderosisAlveolar Hemosiderosis • Capillary InflammationCapillary Inflammation • Suspicion for Aspiration?Suspicion for Aspiration? • Other Infection?Other Infection? • C4d depositionC4d deposition
    • 35. Primary questions to be asked…Primary questions to be asked… • Is there correlation with capillary inflammation and/orIs there correlation with capillary inflammation and/or acute lung injury and DSAs?acute lung injury and DSAs? • What is significance of C4d deposition?What is significance of C4d deposition? Secondary questions…Secondary questions… • Does ACR correlate with DSAs?Does ACR correlate with DSAs? • Is there correlation between endothelialitis and DSAs?Is there correlation between endothelialitis and DSAs? • Percent of biopsies suboptimal or inadequatePercent of biopsies suboptimal or inadequate • Percent of biopsies without airwaysPercent of biopsies without airways • What is inter-observer reliability for various histologicWhat is inter-observer reliability for various histologic categoriescategories
    • 36. Limitations of StudyLimitations of Study • Whole slide imaging not as good as glass slidesWhole slide imaging not as good as glass slides for capillary analysisfor capillary analysis • Only 1 level examinedOnly 1 level examined • Restriction of choices by dropdown menuRestriction of choices by dropdown menu • Variability in interpretation of ALI and capillaryVariability in interpretation of ALI and capillary inflammation (do we need better definitions?)inflammation (do we need better definitions?) • C4d performed at one institution onlyC4d performed at one institution only • Have not included antibody titer levelsHave not included antibody titer levels
    • 37. Acute Cellular RejectionAcute Cellular Rejection
    • 38. Frequency for pooled dataFrequency for pooled data
    • 39. Comparisons between D, A , and NComparisons between D, A , and N Average ACR Score 0.336 0.365 0.304
    • 40. Acute Lung InjuryAcute Lung Injury • Regarded as a spectrum from reactiveRegarded as a spectrum from reactive pneumocytes with interstitial/alveolar edemapneumocytes with interstitial/alveolar edema (above baseline) to diffuse alveolar damage(above baseline) to diffuse alveolar damage (DAD).(DAD). • Any degree of ALI less than DAD wasAny degree of ALI less than DAD was categorized as “ALI”.categorized as “ALI”. • Hyaline membranes indicated DADHyaline membranes indicated DAD • If acute inflammation consistent with acuteIf acute inflammation consistent with acute pneumonia, “Acute pneumonia, favor infection”pneumonia, “Acute pneumonia, favor infection”
    • 41. DSA
    • 42. Frequency of ALIFrequency of ALI
    • 43. Comparison Data Average ALI Score 0.187 0.322 0.128
    • 44. EndothelialitisEndothelialitis
    • 45. EndothelialitisEndothelialitis
    • 46. Capillary InflammationCapillary Inflammation • Capillary inflammation determined by degree ofCapillary inflammation determined by degree of neutrophils in alveolar capillaries.  neutrophils in alveolar capillaries.   • Does not include areas with hemorrhage or crushDoes not include areas with hemorrhage or crush artifact. artifact.  • Best area with preserved lung architecture. Best area with preserved lung architecture.  – 0=normal, generally few or no neutrophils. 0=normal, generally few or no neutrophils.  – 1=more than normal but no back-to-back (touching)1=more than normal but no back-to-back (touching) neutrophilsneutrophils – 2=more than baseline AND back-to-back neutrophils2=more than baseline AND back-to-back neutrophils – 3=frank capillaritis with karyorrhectic debris and hemorrhage3=frank capillaritis with karyorrhectic debris and hemorrhage
    • 47. Normal alveolar capillariesNormal alveolar capillaries
    • 48. Above baseline and 2 or moreAbove baseline and 2 or more neutrophils back-to-backneutrophils back-to-back
    • 49. Capillary InflammationCapillary Inflammation
    • 50. DSA
    • 51. DSA
    • 52. DSA
    • 53. DSA
    • 54. Non-DSA
    • 55. DSA vs NegativeDSA vs Negative
    • 56. Comparisons between D, A and NComparisons between D, A and N Average CI Score 0.264 0.362 0.224
    • 57. Capillary inflammation vs ALICapillary inflammation vs ALI
    • 58. C4d DepositionC4d Deposition • C4d measured as:C4d measured as: – NegativeNegative – Positive, <50%Positive, <50% – Positive, >50%Positive, >50% – Not performedNot performed • Measured in alveolar capillaries onlyMeasured in alveolar capillaries only • 62 biopsies had C4d stains62 biopsies had C4d stains • Full data from Cleveland Clinic 177 cases withFull data from Cleveland Clinic 177 cases with C4dC4d
    • 59. DSA
    • 60. C4d is correlated with ALI with DAD, increasing ACR and Capillary Inflammation but not ALI alone.
    • 61. Cleveland Clinic DataCleveland Clinic Data
    • 62. Inter-Observer VariabilityInter-Observer Variability
    • 63. Where were we in 2011?Where were we in 2011?
    • 64. Putative Stages of Humoral Response toPutative Stages of Humoral Response to an Organ Graft – 2003 NIHan Organ Graft – 2003 NIH recommendationsrecommendations I: Latent humoral responseI: Latent humoral response Circulating antibody alone (without biopsy findings or graftCirculating antibody alone (without biopsy findings or graft dysfunction)dysfunction) II: Silent humoral reactionII: Silent humoral reaction (accommodation vs pre-rejection(accommodation vs pre-rejection state)state) Circulating antibody, (without histologicCirculating antibody, (without histologic changes or graft dysfunction)changes or graft dysfunction) III: Sub-clinical humoral rejectionIII: Sub-clinical humoral rejection Circulating antibody, tissue pathologyCirculating antibody, tissue pathology (without graft dysfunction)(without graft dysfunction) IV: Humoral rejectionIV: Humoral rejection Circulating antibody, tissue pathology, graftCirculating antibody, tissue pathology, graft dysfunctiondysfunction Takemoto SK, et al. National conference to assess antibody-mediated rejection in solid organ transplantation. Am J Transplant 2004;4:1033–41. C4d depositionC4d deposition C4d deposition,C4d deposition, C4d deposition,C4d deposition,
    • 65. Putative Stages of Humoral Response toPutative Stages of Humoral Response to an Organ Graft – 2003 NIHan Organ Graft – 2003 NIH recommendationsrecommendations I: Latent humoral response/Silent humoral reactionI: Latent humoral response/Silent humoral reaction Circulating antibody alone (without biopsy findings or graftCirculating antibody alone (without biopsy findings or graft dysfunction)dysfunction) III: Sub-clinical humoral rejectionIII: Sub-clinical humoral rejection Circulating antibody, (without graftCirculating antibody, (without graft dysfunction)dysfunction) IV: Humoral rejectionIV: Humoral rejection Circulating antibody, graft dysfunctionCirculating antibody, graft dysfunction tissue pathologytissue pathology tissue pathology,tissue pathology,
    • 66. I: Latent humoral response/Silent humoral reaction/Sub-I: Latent humoral response/Silent humoral reaction/Sub- clinical humoral rejectionclinical humoral rejection Circulating antibody alone (without biopsy findings or graftCirculating antibody alone (without biopsy findings or graft dysfunction)dysfunction) II: Humoral rejectionII: Humoral rejection Circulating antibody, graft dysfunctionCirculating antibody, graft dysfunction
    • 67. Where are we in 2013?Where are we in 2013?
    • 68. Recent StudiesRecent Studies • Yousem and ZeeviYousem and Zeevi (Am J Surg Pathol 2012;36:987–992).(Am J Surg Pathol 2012;36:987–992). – Found 23 pts with HLA Abs and lung dysfunctionFound 23 pts with HLA Abs and lung dysfunction – 17 had concurrent high grade ACR17 had concurrent high grade ACR – 18% had capillaritis18% had capillaritis – C4d seen in 76% (vs 24% of controls)C4d seen in 76% (vs 24% of controls) • DeNicola, Weigt, Wallace et al.DeNicola, Weigt, Wallace et al. (J Heart Lung(J Heart Lung Transplant 2013;32:326-332).Transplant 2013;32:326-332). – 41 pts, 16 with anti-HLA abs41 pts, 16 with anti-HLA abs – Capillary neutrophilic inflammation and DAD were tested asCapillary neutrophilic inflammation and DAD were tested as histologic markers for AMRhistologic markers for AMR
    • 69. ISHLT and BanffISHLT and Banff • G Berry, et al. Pathology of pulmonaryG Berry, et al. Pathology of pulmonary antibody-mediated rejection: 2012 update fromantibody-mediated rejection: 2012 update from the Pathology Council of the ISHLT. JHLTthe Pathology Council of the ISHLT. JHLT 2013; 32: 14-12.2013; 32: 14-12. • Banff StudyBanff Study
    • 70. Putative Stages of Humoral Response toPutative Stages of Humoral Response to an Organ Graft – 2003 NIHan Organ Graft – 2003 NIH recommendationsrecommendations I: Latent humoral responseI: Latent humoral response Circulating antibody alone (without biopsy findings or graftCirculating antibody alone (without biopsy findings or graft dysfunction)dysfunction) II: Silent humoral reactionII: Silent humoral reaction (accommodation vs pre-rejection(accommodation vs pre-rejection state)state) Circulating antibody, (without histologicCirculating antibody, (without histologic changes or graft dysfunction)changes or graft dysfunction) III: Sub-clinical humoral rejectionIII: Sub-clinical humoral rejection Circulating antibody, tissue pathologyCirculating antibody, tissue pathology (without graft dysfunction)(without graft dysfunction) IV: Humoral rejectionIV: Humoral rejection Circulating antibody, tissue pathology, graftCirculating antibody, tissue pathology, graft dysfunctiondysfunction Takemoto SK, et al. National conference to assess antibody-mediated rejection in solid organ transplantation. Am J Transplant 2004;4:1033–41. C4d depositionC4d deposition C4d deposition,C4d deposition, C4d deposition,C4d deposition,
    • 71. Putative Stages of Humoral Response toPutative Stages of Humoral Response to an Organ Graft – 2003 NIHan Organ Graft – 2003 NIH recommendationsrecommendations I: Latent humoral response/Silent humoral reactionI: Latent humoral response/Silent humoral reaction Circulating antibody alone (without biopsy findings or graftCirculating antibody alone (without biopsy findings or graft dysfunction)dysfunction) III: Sub-clinical humoral rejectionIII: Sub-clinical humoral rejection Circulating antibody, (without graftCirculating antibody, (without graft dysfunction)dysfunction) IV: Humoral rejectionIV: Humoral rejection Circulating antibody, graft dysfunctionCirculating antibody, graft dysfunction tissue pathologytissue pathology tissue pathology,tissue pathology,
    • 72. Is it that simple?Is it that simple? • NoNo • The histologic differences are significant but areThe histologic differences are significant but are neither sensitive nor specific for the presence ofneither sensitive nor specific for the presence of DSA.DSA. • Who would care if they were?Who would care if they were? • The question is:The question is: – Are the findings sensitive or specific for graftAre the findings sensitive or specific for graft deterioration in the setting of DSA????deterioration in the setting of DSA????
    • 73. InvestigatorsInvestigators • PathologistsPathologists – Carol FarverCarol Farver – W. Dean WallaceW. Dean Wallace – Claus B. AndersenClaus B. Andersen – Valeria ArrossiValeria Arrossi – Roberto BarriosRoberto Barrios – Gerry BerryGerry Berry – Matthew DeNicolaMatthew DeNicola – Desley NeilDesley Neil – Elizabeth PavliskoElizabeth Pavlisko – Myriam RemmelinkMyriam Remmelink – Birgit WeynandBirgit Weynand • UCLAUCLA – Sam WeigtSam Weigt – Ning LiNing Li – Elaine ReedElaine Reed – Jennifer ZhangJennifer Zhang • Cleveland ClinicCleveland Clinic – Marie BudevMarie Budev – Medhat AskarMedhat Askar – Rene SlawRene Slaw – Sol CristomoSol Cristomo

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