The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Clinical features and allograft failure rates of pulmonary antibody-mediated rejection categories

Published:September 19, 2022DOI:


      Pulmonary antibody-mediated rejection (AMR) consensus criteria categorize AMR by diagnostic certainty. This study aims to define the clinical features and associated outcomes of these recently defined AMR categories.


      Adjudication committees reviewed clinical data of 335 lung transplant recipients to define clinical or subclinical AMR based on the presence of allograft dysfunction, and the primary endpoints, time from transplant to allograft failure, a composite endpoint of chronic lung allograft dysfunction and/or death. Clinical AMR was subcategorized based on diagnostic certainty as definite, probable or possible AMR if 4, 3, or 2 characteristic features were present, respectively. Allograft injury was assessed via plasma donor-derived cell-free DNA (ddcfDNA). Risk of allograft failure and allograft injury was compared for AMR categories using regression models.


      Over the 38.5 months follow-up, 28.7% of subjects developed clinical AMR (n = 96), 18.5% developed subclinical AMR (n = 62) or 58.3% were no AMR (n = 177). Clinical AMR showed higher risk of allograft failure and ddcfDNA levels compared to subclinical or no AMR. Clinical AMR included definite/probable (n = 21) or possible AMR (n = 75). These subcategories showed similar clinical characteristics, ddcfDNA levels, and risk of allograft failure. However, definite/probable AMR showed greater measures of AMR severity, including degree of allograft dysfunction and risk of death compared to possible AMR.


      Clinical AMR showed greater risk of allograft failure than subclinical AMR or no AMR. Subcategorization of clinical AMR based on diagnostic certainty correlated with AMR severity and risk of death, but not with the risk of allograft failure.



      AMR (Antibody-Mediated Rejection), CLAD (Chronic lung allograft dysfunction), DSA (donor-specific antibodies), ddcfDNA (donor-derived cell-free DNA), FEV1 (forced expiratory volume in one second), FVC (forced vital capacity), HLA (human leukocyte antigen), MFI (mean fluorescent intensity)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Heart and Lung Transplantation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Takemoto SK
        • Zeevi A
        • Feng S
        • et al.
        National conference to assess antibody-mediated rejection in solid organ transplantation.
        Am J Transplant. 2004; 4: 1033-1041
        • Levine DJ
        • Glanville AR
        • Aboyoun C
        • et al.
        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
        • Roux A
        • Levine DJ
        • Zeevi A
        • et al.
        Banff Lung Report: current knowledge and future research perspectives for diagnosis and treatment of pulmonary antibody-mediated rejection (AMR).
        Am J Transplant. 2019; 19: 21-31
        • Hachem RR
        • Kamoun M
        • Budev MM
        • et al.
        Human leukocyte antigens antibodies after lung transplantation: primary results of the HALT study.
        Am J Transplant. 2018; 18: 2285-2294
        • Verleden SE
        • Vanaudenaerde BM
        • Emonds MP
        • et al.
        Donor-specific and -nonspecific HLA antibodies and outcome post lung transplantation.
        Eur Respir J. 2017; 50: 1-8
        • Brugiere O
        • Roux A
        • Le Pavec J
        • et al.
        Role of C1q-binding anti-HLA antibodies as a predictor of lung allograft outcome.
        Eur Respir J. 2018; 521701898
        • Iasella CJ
        • Ensor CR
        • Marrari M
        • et al.
        Donor-specific antibody characteristics, including persistence and complement-binding capacity, increase risk for chronic lung allograft dysfunction.
        J Heart Lung Transplant. 2020; 39: 1417-1425
        • DeNicola MM
        • Weigt SS
        • Belperio JA
        • Reed EF
        • Ross DJ
        • Wallace WD.
        Pathologic findings in lung allografts with anti-HLA antibodies.
        J Heart Lung Transplant. 2013; 32: 326-332
        • Aguilar PR
        • Carpenter D
        • Ritter J
        • et al.
        The role of C4d deposition in the diagnosis of antibody-mediated rejection after lung transplantation.
        Am J Transplant. 2018; 18: 936-944
        • Gogenur M
        • Burcharth J
        • Gogenur I.
        The role of total cell-free DNA in predicting outcomes among trauma patients in the intensive care unit: a systematic review.
        Crit Care. 2017; 2114
        • Hou YQ
        • Liang DY
        • Lou XL
        • Zhang M
        • Zhang ZH
        • Zhang LR.
        Branched DNA-based Alu quantitative assay for cell-free plasma DNA levels in patients with sepsis or systemic inflammatory response syndrome.
        J Crit Care. 2016; 31: 90-95
        • Wang Z
        • Cheng Y
        • An T
        • et al.
        Detection of EGFR mutations in plasma circulating tumour DNA as a selection criterion for first-line gefitinib treatment in patients with advanced lung adenocarcinoma (BENEFIT): a phase 2, single-arm, multicentre clinical trial.
        Lancet Respir Med. 2018; 6: 681-690
        • Garcia Moreira V
        • Prieto Garcia B
        • Baltar Martin JM
        • Ortega Suarez F
        • Alvarez FV
        Cell-free DNA as a noninvasive acute rejection marker in renal transplantation.
        Clin Chem. 2009; 55: 1958-1966
        • Knight SR
        • Thorne A
        • Lo Faro ML.
        Donor-specific Cell-free DNA as a Biomarker in Solid Organ Transplantation. A systematic review.
        Transplantation. 2019; 103: 273-283
        • Agbor-Enoh S
        • Wang Y
        • Tunc I
        • et al.
        Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation.
        EBioMedicine. 2019; 40: 541-553
        • von Elm E
        • Altman DG
        • Egger M
        • et al.
        The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies.
        PLoS Med. 2007; 4e296
        • Verleden GM
        • Glanville AR
        • Lease ED
        • et al.
        Chronic lung allograft dysfunction: definition, diagnostic criteria, and approaches to treatment-A consensus report from the pulmonary council of the ISHLT.
        J Heart Lung Transplant. 2019; 38: 493-503
        • Stewart S
        • Fishbein MC
        • Snell GI
        • et al.
        Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection.
        J Heart Lung Transplant. 2007; 26: 1229-1242
        • De Vlaminck I
        • Martin L
        • Kertesz M
        • et al.
        Noninvasive monitoring of infection and rejection after lung transplantation.
        Proc Natl Acad Sci U S A. 2015; 112: 13336-13341
        • Jang MK
        • Tunc I
        • Berry GJ
        • et al.
        Donor-derived cell-free DNA accurately detects acute rejection in lung transplant patients, a multicenter cohort study.
        J Heart Lung Transplant. 2021; 40: 822-830
        • Agbor-Enoh S
        • Jackson AM
        • Tunc I
        • et al.
        Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: evidence from cell-free DNA analysis.
        J Heart Lung Transplant. 2018; 37: 925-932
        • Lobo LJ
        • Aris RM
        • Schmitz J
        • Neuringer IP.
        Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cystic fibrosis after lung transplantation.
        J Heart Lung Transplant. 2013; 32: 70-77
        • Roux A
        • Bendib Le Lan I
        • Holifanjaniaina S
        • et al.
        Antibody-mediated rejection in lung transplantation: clinical outcomes and donor-specific antibody characteristics.
        Am J Transplant. 2016; 16: 1216-1228
        • Safavi S
        • Robinson DR
        • Soresi S
        • Carby M
        • Smith JD.
        De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation.
        J Heart Lung Transplant. 2014; 33: 1273-1281
        • Witt CA
        • Gaut JP
        • Yusen RD
        • et al.
        Acute antibody-mediated rejection after lung transplantation.
        J Heart Lung Transplant. 2013; 32: 1034-1040
        • Neuhaus K
        • Hohlfelder B
        • Bollinger J
        • Haug 3rd, M
        • Torbic H.
        Antibody-mediated rejection management following lung transplantation.
        Ann Pharmacother. 2021; 10600280211012410
        • Ensor CR
        • Yousem SA
        • Marrari M
        • et al.
        Proteasome inhibitor carfilzomib-based therapy for antibody-mediated rejection of the pulmonary allograft: use and short-term findings.
        Am J Transplant. 2017; 17: 1380-1388
        • Berry G
        • Burke M
        • Andersen C
        • et al.
        Pathology of pulmonary antibody-mediated rejection: 2012 update from the pathology council of the ISHLT.
        J Heart Lung Transplant. 2013; 32: 14-21