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11th banff conference lung transplant pathology
 

11th banff conference lung transplant pathology

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Summary presentation by Carol F. Farver, MD

Summary presentation by Carol F. Farver, MD
and W. Dean Wallace, MD, Co-Chairs, 11th Banff Conference-Lung, Paris, France
June 2011.

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  • Traditionally, lung rejection has been regarded as a T-cell mediated process And standard immunosuppression targeting T-cell proliferation and function has improved graft survival and made transplantation a clinical reality But a potential role for antibodies in rejection has long been suspected since HLA antibodies are detected in patients with rejection HLA antibodies are known to cause different syndromes of rejection after kidney transplantation And HLA antibodies are associated with acute cellular rejection and BOS after lung transplantation But AMR remains enigmatic after LTX
  • The association between the development of HLA antibodies and BOS was recognized in the late 90s The development of AB preceded the diagnosis of BOS by an average of 20 months Multiple centers corroborated these findings and AB to both class I and class II molecules were associated with BOS These findings underscore the role of humoral immunity in graft rejection after lung transplantation
  • The purpose of this study is to review a series of cases of AMR from our center and describe the clinicopathological findings
  • All patients had circulating DSA detected at the time of diagnosis The DSA was to Class I only in 2 of 19; to Class II only in 13 of 19; and to Class I and II in 4 of 19 DSA mean MFI 5841; range: 975-14232
  • Pneumonitis with fibrin deposition and diffuse alveolar damage Neutrophilic interstitial infiltration Alveolar hemorrhage
  • Neutrophils in alveolar septa
  • Focal capillary endothelial C4d deposition
  • Overall, 9 of the 12 patients with persistent DSA died compared to 1 of the 7 patients who cleared the DSA
  • Overall, 10 of the 19 patients have died 5 died acutely of refractory AMR 4 of BOS 1 of pneumonia
  • AMR may be the cause of acute graft failure But a high index of suspicion is necessary for the diagnosis Less severe cases may not result in clinical graft dysfunction similar to most cases of acute cellular rejection & may be unrecognized Yet, these cases may have an impact on BOS development

11th banff conference lung transplant pathology 11th banff conference lung transplant pathology Presentation Transcript

  • 11 th Banff Conference on Allograft Pathology Carol F. Farver, MD Cleveland Clinic W. Dean Wallace, MD UCLA Co-Chairs, 11 th Banff Conference-Lung June 2011
  • Lung Session Topics
    • Antibody-mediated Rejection
    • Infections in Lung Transplant
    • Non-BOS Graft Dysfunction
    • Endothelial Cells in the Lung Allograft
  • Antibody-mediated Rejection Lung
    • Clinical
      • Diagnostic criteria
      • Effect on survival
      • Role in etiology of BOS
  • CLINICAL FEATURES OF AMR IN LUNG TRANSPLANTATION Ramsey Hachem, MD June 7, 2011
  • Humoral immunity
    • Rejection T-cell mediated
    • Role for antibodies in rejection
      • HLA antibodies in lung transplantation
      • AMR in kidney transplantation
    • AMR in lung transplantation is enigmatic
    • “ In 2006, no histologic features for antibody-mediated rejection in the lung were agreed upon”
    J Heart Lung Transplant 2007; 26: 1229
  • HLA antibodies
    • HLA AB & BOS
    • AB precede BOS
    • AB & lymphocytic bronchiolitis
    • Underscore role of humoral immunity
    Transplantation 1998; 65: 648 Transplantation 1999; 67: 1155 J Heart Lung Transplant 2004; 23: 1135 Am J Transplant 2005; 5: 131
  • AMR study
    • Retrospective cohort study of acute AMR
    • Between 1/1/06 & 1/1/11
    • Follow-up through 4/1/11
    • AMR diagnosis fulfilling all 4 criteria
      • DSA, C4d, pathology, & graft dysfunction
    • 19 patients
  • Donor-specific antibodies
    • 19/19 had circulating DSA
    • Immunodominant DSA MFI
  • Neutrophilic pneumonitis: n=10
  • b Capillaries injury with pneumonitis: n=9
  • +C4d staining: n=19
  • Early outcomes
    • 14/19 (74%) improved & discharged
      • 8/9 (89%) with capillary injury improved
      • 6/10 (60%) without capillary injury improved
    • 5/19 ( 26%) did not respond, died of refractory AMR
  • DSA clearance Persistent DSA Cleared DSA log rank p = 0.005
  • BOS (Survived AMR: n=14)
    • 1 pt: Pre-existing BOS
    • 8/13 pts: Developed BOS within 1 year of AMR diagnosis.
  • Overall Survival (n=19 patients) 10/19 (53%) died AMR, n = 5 BOS, n = 4 Pneumonia, n = 1
  • Conclusions
    • AMR may cause acute graft failure
    • Index of suspicion
    • Less severe cases may be unrecognized
      • “ Subclinical humoral rejection” & potential impact on BOS
      • Unknown incidence
    • Subsequent BOS
  • Antibody-mediated Rejection Lung
    • Clinical
      • Diagnostic criteria
      • Effect on survival
      • Role in etiology of BOS
    • Immunology
      • Role of DSA
      • HLA vs non-HLA antibodies
  • Immunology of AMR in Lung Transplantation 11 th Banff Conference | June 7, 2011 Medhat Askar, MD, PhD Director, Allogen Laboratories, Cleveland Clinic Associate Professor, Department of Surgery Cleveland Clinic Lerner College of Medicine at Case Western Reserve University School of Medicine
  • Outline
    • Pre-transplant Immunologic risk assessment
    • Post-transplant immunological monitoring
      • DSA
      • C4d
    • Non-HLA targets for humoral immune responses
  • RESULTS Pre-transplant DSA
  • RESULTS Positive Pre-Tx DSA Reference Group P Value ACR (≥ ISHLT grade II) 43% 29% 0.0009 ACR/100 Pt./Yr 20.6 7.7
  • (+)Post-Tx DSA with (+) C4d
    • >1000 consecutive lung transplant biopsies at CCF were stained for C4d and C3d (IF)
      • Surveillance and Clinical indication
    • Four (4) were + C4d
      • All in the setting of clinical disease
      • Acute and organizing DAD (x3); Capillary injury (x1)
    • All 4 were + DSA (post-transplant)
    • None were + C3d
  • Pos C4d
  • Pos C4d
  • Pos C4d
  • Non-HLA Antibodies
  • MHC Class I-related chain A (MICA) Antibodies
    • 6/116 (5%)Reference were Pos for MICA Ab
    • 4/35 (11%) patients with Pos DSA were also pos for MICA Ab
    • None were DSA MICA
  • Antibody-mediated Rejection Lung
    • Clinical
      • Diagnostic criteria
      • Effect on survival
      • Role in etiology of BOS
    • Immunology
      • Role of DSA
      • HLA vs non-HLA antibodies
    • Pathology
      • Importance of C4d staining
      • Pathologic pattern of injury
  • W. Dean Wallace, M.D. Associate Professor of Pathology David Geffen School of Medicine UCLA Medical Center Pathology of Antibody-Mediated Rejection of the Lung Allograft
    • Putative Stages of Humoral Response to an Organ Graft – 2003 NIH recommendations
    • I: Latent humoral response
    • Circulating antibody alone (but without biopsy findings or graft dysfunction)
    • II: Silent humoral reaction (accommodation vs pre-rejection state)
    • Circulating antibody, C4d deposition (but without histologic changes or graft dysfunction)
    • III: Sub-clinical humoral rejection
    • Circulating antibody, C4d deposition, tissue pathology (but without graft dysfunction)
    • IV: Humoral rejection
    • Circulating antibody, C4d deposition, tissue pathology, graft dysfunction
    Takemoto SK, et al. National conference to assess antibody-mediated rejection in solid organ transplantation. Am J Transplant 2004;4:1033–41.
  • Complement deposition – ISHLT Lung Rejection Study Group
    • Historically associated with hyperacute rejection.
    • Serum anti-HLA antibodies and complement deposition support the concept of AMR in the lung.
    • Some of the suggested clinical-pathologic features of AMR, extrapolated from findings in other organ allografts including deposition of C3d and C4d, may serve as a marker AMR.
    • Low specificity limits use in protocol biopsies.
    Stewart S, et al. Revision of the 1996 working formulation….lung rejection. J Heart Lung Transplant 2007; 26:1229-42.
  • C4d staining in lung transplant biopsies
    • Saint Martin (1996)
      • C3, IgM, IgG
    • Magro (2003)
      • +C4d with septal injury
      • 22 pts with (-) PRA
    • Magro (2003)
      • +C4d with septal injury
      • 25 lung pts. With (-) PRA, (-) HLA-Abs
    • Magro (2003)
      • +C4d with bronchial epithelial injury
    • Girnita Al, (2006)
      • 2 pts.
      • +DSA, +C4d
    • Wallace (2005)
      • +C4d
    • Hachem et al (unpublished)
      • C4d+
      • 19 lung tx pts.
  • Post capillary venule Nonspecific background staining Nonspecific C4d staining
  • Nonspecific C4d staining Nonspecific elastic staining Hyaline membranes in DAD
  • Capillaritis in transplant patient with acute pneumonia
  • the transbronchial biopsy…
    • ISHLT study group recommends 5 pieces of alveolar tissue
    • Unlike in the kidney, heart and liver, lung biopsies are very easily crushed and distorted.
    • Biopsies are frequently inadequate.
    • Procedural hemorrhage can make the biopsy technically difficult to perform and interpret.
    • Distinction between normal, infection, aspiration and alloimmune rejection can be very difficult.
    • Putative Stages of Humoral Response to an Organ Graft – 2003 NIH recommendations
    • I: Latent humoral response
    • Circulating antibody alone (without biopsy findings or graft dysfunction)
    • II: Silent humoral reaction (accommodation vs pre-rejection state)
    • Circulating antibody, (without histologic changes or graft dysfunction)
    • III: Sub-clinical humoral rejection
    • Circulating antibody, tissue pathology (without graft dysfunction)
    • IV: Humoral rejection
    • Circulating antibody, tissue pathology, graft dysfunction
    Takemoto SK, et al. National conference to assess antibody-mediated rejection in solid organ transplantation. Am J Transplant 2004;4:1033–41. C4d deposition C4d deposition, C4d deposition,
  • Putative Stages of Humoral Response to an Organ Graft – 2003 NIH recommendations I: Latent humoral response/Silent humoral reaction Circulating antibody alone (without biopsy findings or graft dysfunction) III: Sub-clinical humoral rejection Circulating antibody, (without graft dysfunction) IV: Humoral rejection Circulating antibody, graft dysfunction tissue pathology tissue pathology,
  • I: Latent humoral response/Silent humoral reaction/Sub-clinical humoral rejection Circulating antibody alone (without biopsy findings or graft dysfunction) II: Humoral rejection Circulating antibody, graft dysfunction Where is the pathologist?
  • Clinical-Pathologic Diagnosis of AMR in the Lung Allograft
    • Objective
      • Determine if there is a specific histopathologic or immunohistochemical finding that is characteristic of patients with de-novo DSA and AMR.
    • Criteria for AMR
      • Detection of circulating DSA
      • Compatible tissue pathology
        • Intravascular neutrophils
        • C3d/C4d deposition?
      • Graft dysfunction
    Matt DeNicola, Sam Weigt, W. Dean Wallace. UCLA David Geffen School of Medicine
  • Study design
    • Case control study:
      • Since 1/1/2006, lung txp recipients screened for DSA at surveillance time-points.
      • Inclusion required Tbbx within 30 days of de-novo DSA or negative screening test for DSA:
        • 16 cases with de-novo anti-HLA DSA
        • 30 controls never developing DSA – bx selected to achieve a similar range of duration post-transplant
          • 9 with de-novo anti-HLA, not donor specific (Non-DSA)
          • 21 without any anti-HLA ab
  • Study Design
    • Biopsies assessed by pathologist blind to any clinical data including the presence or absence of DSA.
      • Capillary neutrophilia graded on 0-4 scale
        • 0 Normal
        • 1+ Mild increase in PMN
        • 2+ Increase of PMNs with groups of 2
        • 3+ Increase of PMNs with groups of 3 or more
        • 4+ Capillaritis
      • DAD
      • Pathology suspicious for AMR was defined as > 2+ neutrophilia, or “unexplained” DAD.
    • Biopsies also stained for C4d and C3d and scored by pathologist
      • Any positive staining was used for correlation analyses
  • 2+ capillary neutrophilia
  • C4d
  • C4d does not correlate with pathology
  • Pathology does correlate with DSA
  • Pathology is associated with lung allograft survival
  • Pathology + DSA is associated with lung allograft survival
  • Suspected AMR (Pathology + DSA + dysfunction) is associated with lung allograft survival
  • Wallace Pathology Summmary
    • Pathology may be graded capillary injury with capillaritis at one end of spectrum
    • Capillary neutrophils ( > Grade +2) correlate with post-tx DSA, but not with +C4d
    • Almost all biopsies can demonstrate some form of C4d staining; therefore, C4d deposition is nonspecific and is probably not sensitive
    • All features are nonspecific in isolation
  • 11 th Banff Conference---Lung Session Discussion Points
    • DSA antibodies
      • Pre-transplant (memory) Abs vs post-transplant (de novo) antibodies
        • represent different processes/risks in the development of AMR
        • this needs to be explicit in literature/future studies
      • Timing of Abs appearance with the pathology of the biopsy is important
        • protocols that time blood sampling with lung biopsy are essential
    • Non-HLA antibodies need further study in lung transplantation patients
  • 11 th Banff Conference---Lung Session Discussion Points
    • Pathology
      • Methodologies for staining C4d are NOT standardized
      • Interpretation of C4d staining in the lung is probably subject to inter-observer variability
      • Defining (naming) the pathologic pattern of injury in biopsies of possible AMR in the lung is not consistent
        • Capillaritis
        • Capillary injury
        • Acute pneumonitis
        • Acute lung injury with neutrophils
  • 11 th Banff Conference---Lung Session Discussion Points
    • Pathology
      • Given the overlap of pathologic features of AMR with infection, the role of infection in the pathology has not been adequately assessed in many published studies
      • Incidence of biopsies with possible AMR in the lung (graft dysfunction, +DSA, +C4d) may be quite low
  • Conclusions
    • Published data to date are difficult to interpret given
      • Lack of standardization of methodology
        • Antibody (DSA) measurement
        • C4d staining/interpretation
      • Inconsistent pathologic descriptions
      • Other etiologies (infection, drug toxicity) not excluded
    • THE LUNG IS A MESS!
  • Background Studies Needed
    • Pathology:
      • Consensus for basic definitions of pathologic patterns of injury
        • Education around terminology
      • Standardization of methodology for staining and for pathologic interpretation of C4d
    • Immunology
      • Standardization of antibody measurement methodology
      • Routine measurement of both pre- and post- DSAs
  • Background Studies Needed
    • Clinical
      • Protocols that coordinate clinical evaluation (graft function), Ab measurement and biopsy results for accurate comparison of data from same time point.
      • Rigorous screening for other causes must be routinely done
        • Infections (cultures and tissue stains)
        • Drug toxicity
  • The journey of a thousand miles begins with a single step…… Lao-tzu, Chinese philosopher 604 BC - 531 BC
  • First Steps
    • Organize lung transplant pathologists (Farver and Wallace) with clinicians (Levine and Glanville) into AMR working group
    • Survey for interest
      • ISHLT
      • Banff
      • Pulmonary Pathology Society
  • 12 th Banff Conference
    • Working group of AMR in Lung Transplant
    • Collection of biopsy slides from possible AMR patients from pathologists
      • Digital pathology platforms
    • Standard methods for
      • C4d staining and interpretation
      • Standardization of pathology pattern of injury in AMR
        • ? grading system…..
  • Additional Topics
    • Infections in Lung Transplant (Stewart)
      • New infections with an update of molecular diagnostic techniques
      • Always in the differential diagnosis (esp. AMR)
    • Progressive, fibrosing parenchymal lung diseases post-transplantation (Iversen)
      • Is there parenchymal form of chronic rejection
    • Mechanism of endothelial injury in transplanted lungs (Belperio)
      • Chronic vascular rejection: small and large vessels
  • Conference Presenters
    • Lung Session
    • Medhat Askar, Cleveland Clinic (USA)
    • John Belperio, UCLA (USA)
    • Ramsey Hachem, Washington University (USA)
    • Martin Iversen, Copenhagen University Hospital, (Denmark)
    • Susan Stewart, Papworth Hospital (UK)
    • W. Dean Wallace, UCLA (USA)
    • Plenary Speakers
    • Andrew Fisher, Newcastle University (UK)
    • Adriana Zeevi, University of Pittsburgh (USA)
  •