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Beeckmans H, Kerckhof P, Acet Öztürk N, Zajacova A, Van Slambrouck J, Bos S, Vermant M, Van Dieren LO, Goeminne T, Vandervelde C, Bardyn J, Willems E, Lauriers S, Brusselmans M, Langenhoven LV, Emonds MP, De Pelsmaeker S, Kerkhofs J, Sadeleer LD, Godinas L, Dupont LJ, Raemdonck DEV, Ceulemans LJ, Vanaudenaerde BM, Vos R. Clinical predictors for restrictive allograft syndrome: A nested case-control study. Am J Transplant 2025; 25:1319-1338. [PMID: 39892791 DOI: 10.1016/j.ajt.2025.01.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 01/21/2025] [Accepted: 01/22/2025] [Indexed: 02/04/2025]
Abstract
Risk factors for restrictive allograft syndrome (RAS), a severe phenotype of chronic lung allograft dysfunction (CLAD) after lung transplantation, are currently not well known. In this retrospective nested case-control-study, we analyzed 69 patients with RAS and 69 matched non-CLAD controls to identify clinical risk factors for RAS. Patients with RAS demonstrated overall higher blood eosinophils (P = .02), increased bronchoalveolar eosinophils (P < .001) and lymphocytes (P = .03), and higher incidence of infections, particularly Pseudomonas species infection (P = .003), invasive fungal disease (P < .001, mainly due to Aspergillus species), SARS-CoV-2 (P < .001), and cytomegalovirus infection (P = .04), compared with non-CLAD controls. Antihuman leukocyte antigen (anti-HLA) antibodies, especially persistent donor-specific antibodies (P < 0.001), specifically targeting HLA-DQ and HLA-DR loci, and antibody-mediated rejection (P < .001), were strongly associated with later RAS. Histopathologic lung injury patterns on transbronchial biopsy (P < .001), and persistent chest computed tomography opacities in absence of pulmonary dysfunction (P < .001) were identified as early indicators of later RAS. Proactive detection and management of these risk factors could help mitigate future decline in allograft function and reduce progression to clinical RAS. Future studies should explore early treatment strategies targeting these modifiable factors to preserve allograft function and improve long-term outcomes for lung transplant recipients.
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Affiliation(s)
- Hanne Beeckmans
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of CHROMETA, KU Leuven, Leuven, Belgium; Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.
| | - Pieterjan Kerckhof
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of CHROMETA, KU Leuven, Leuven, Belgium
| | - Nilufer Acet Öztürk
- Department of Pulmonology, Uludağ University Faculty of Medicine, Bursa, Turkey
| | - Andrea Zajacova
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of CHROMETA, KU Leuven, Leuven, Belgium; Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Jan Van Slambrouck
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of CHROMETA, KU Leuven, Leuven, Belgium; Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Saskia Bos
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Marie Vermant
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of CHROMETA, KU Leuven, Leuven, Belgium; Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Lyne O Van Dieren
- Department of Internal Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Tessa Goeminne
- Department of Internal Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Christelle Vandervelde
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of CHROMETA, KU Leuven, Leuven, Belgium
| | - Josephine Bardyn
- Department of Internal Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Elisabeth Willems
- Department of Internal Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Sam Lauriers
- Department of Internal Medicine, University Hospitals Leuven, Leuven, Belgium
| | | | | | - Marie Paule Emonds
- Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross Flanders, Mechelen, Belgium; Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Steffi De Pelsmaeker
- Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross Flanders, Mechelen, Belgium
| | - Johan Kerkhofs
- Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross Flanders, Mechelen, Belgium
| | - Laurens De Sadeleer
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of CHROMETA, KU Leuven, Leuven, Belgium; Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Laurent Godinas
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of CHROMETA, KU Leuven, Leuven, Belgium; Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Lieven J Dupont
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of CHROMETA, KU Leuven, Leuven, Belgium; Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Dirk E Van Raemdonck
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of CHROMETA, KU Leuven, Leuven, Belgium; Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Laurens J Ceulemans
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of CHROMETA, KU Leuven, Leuven, Belgium; Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Bart M Vanaudenaerde
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of CHROMETA, KU Leuven, Leuven, Belgium
| | - Robin Vos
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of CHROMETA, KU Leuven, Leuven, Belgium; Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
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Tanaka S, Tanimine N, Nakakura A, Uchida K, Sakanoue I, Kayawake H, Takahashi M, Nishikawa S, Yutaka Y, Yamada Y, Ohsumi A, Hamaji M, Nakajima D, Chen-Yoshikawa TF, Tanaka Y, Ohdan H, Date H. Activation of anti-donor CD8 alloimmune response in clinically diagnosed acute rejection early after living-donor lobar lung transplantation and its impact on outcome. Transpl Immunol 2025; 90:102201. [PMID: 39988210 DOI: 10.1016/j.trim.2025.102201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 02/19/2025] [Accepted: 02/19/2025] [Indexed: 02/25/2025]
Abstract
BACKGROUND The characteristics and prognostic impacts of early graft infiltration after lung transplantation and clinically diagnosed acute rejection remain unclear. Furthermore, the alloimmune response status in lung transplantation remains uninvestigated. METHODS In this retrospective cohort study, we evaluated 92 living-donor lobar lung transplantations (LDLLT) to establish the effect of graft infiltration-diagnosed as acute rejection-within one-month post-transplantation (cAR), on chronic lung allograft dysfunction (CLAD)-free LDLLT survival. The alloimmune response was evaluated using the carboxyfluorescein diacetate succinimidyl ester (CFSE)-mixed lymphocyte reaction (MLR) in lymphocytes isolated from donor and recipient blood one week after LDLLT. The anti-donor proliferation of CD4+ and CD8+ T cells was determined using flow cytometry. RESULTS cAR was observed in 54 (58.7 %) patients who underwent LDLLT. The median postoperative day of cAR occurrence was 7 days (ranging between 5 and 28 days). Only one episode of cAR occurred in 51 patients (94.4 %). CLAD-free survival was significantly lower in patients who underwent cAR, especially within 2 years after LDLLT (p = 0.016). Thirteen CFSE-MLR assays were performed in seven consecutive LDLLT cases (six bilateral and one unilateral LDLLT). Increased anti-donor proliferation of CD8+ T cells, but not CD4+ T cells, was associated with cAR, irrespective of human leukocyte antigen (HLA) class I mismatch. CONCLUSION Early lung graft infiltration after LDLLT increases the risk of the early development of CALD. Augmented anti-donor CD8 + response was also associated with graft infiltration, which could not be predicted from HLA mismatches but could be monitored using MLR in LDLLT.
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Affiliation(s)
- Satona Tanaka
- Department of Thoracic Surgery, Kyoto University Hospital, 54, Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
| | - Naoki Tanimine
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-0037, Japan
| | - Akiyoshi Nakakura
- Center for Clinical and Translational Research, Kyushu University Hospital, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Koichiro Uchida
- Center for Immunotherapy and Diagnosis, Juntendo University, 3-1-3, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Ichiro Sakanoue
- Department of Thoracic Surgery, Kyoto University Hospital, 54, Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hidenao Kayawake
- Department of Thoracic Surgery, Kyoto University Hospital, 54, Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Mamoru Takahashi
- Department of Thoracic Surgery, Kyoto University Hospital, 54, Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shigeto Nishikawa
- Department of Thoracic Surgery, Kyoto University Hospital, 54, Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yojiro Yutaka
- Department of Thoracic Surgery, Kyoto University Hospital, 54, Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yoshito Yamada
- Department of Thoracic Surgery, Kyoto University Hospital, 54, Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Akihiro Ohsumi
- Department of Thoracic Surgery, Kyoto University Hospital, 54, Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Masatsugu Hamaji
- Department of Thoracic Surgery, Kyoto University Hospital, 54, Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Daisuke Nakajima
- Department of Thoracic Surgery, Kyoto University Hospital, 54, Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Toyofumi F Chen-Yoshikawa
- Department of Thoracic Surgery, Nagoya University Hospital, 65, Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8560, Japan
| | - Yuka Tanaka
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-0037, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-0037, Japan
| | - Hiroshi Date
- Department of Thoracic Surgery, Kyoto University Hospital, 54, Shogoinkawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
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McDermott JK, Castaneda SJ, Mietz SM, Lawson CK, Gerlach JA, Hadley RJ, Sathiyamoorthy G, Krishnan S, Murphy ET, Girgis RE. Preemptive Treatment of De Novo Donor Specific Anti-HLA Antibodies With IVIG Monotherapy after Lung Transplantation. Transpl Int 2024; 37:13431. [PMID: 39364119 PMCID: PMC11446803 DOI: 10.3389/ti.2024.13431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 09/11/2024] [Indexed: 10/05/2024]
Affiliation(s)
- Jennifer K. McDermott
- Richard DeVos Heart and Lung Transplant Program, Corewell Health and Michigan State University College of Human Medicine, Grand Rapids, MI, United States
| | - Skye J. Castaneda
- Richard DeVos Heart and Lung Transplant Program, Corewell Health and Michigan State University College of Human Medicine, Grand Rapids, MI, United States
| | - Sarah M. Mietz
- Richard DeVos Heart and Lung Transplant Program, Corewell Health and Michigan State University College of Human Medicine, Grand Rapids, MI, United States
| | - Cameron K. Lawson
- Richard DeVos Heart and Lung Transplant Program, Corewell Health and Michigan State University College of Human Medicine, Grand Rapids, MI, United States
| | - John A. Gerlach
- Biomedical Laboratory Diagnostics Program, Department of Medicine, Michigan State University College of Human Medicine, East Lansing, MI, United States
| | - Ryan J. Hadley
- Richard DeVos Heart and Lung Transplant Program, Corewell Health and Michigan State University College of Human Medicine, Grand Rapids, MI, United States
| | - Gayathri Sathiyamoorthy
- Richard DeVos Heart and Lung Transplant Program, Corewell Health and Michigan State University College of Human Medicine, Grand Rapids, MI, United States
| | - Sheila Krishnan
- Richard DeVos Heart and Lung Transplant Program, Corewell Health and Michigan State University College of Human Medicine, Grand Rapids, MI, United States
| | - Edward T. Murphy
- Richard DeVos Heart and Lung Transplant Program, Corewell Health and Michigan State University College of Human Medicine, Grand Rapids, MI, United States
| | - Reda E. Girgis
- Richard DeVos Heart and Lung Transplant Program, Corewell Health and Michigan State University College of Human Medicine, Grand Rapids, MI, United States
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Aburahma K, de Manna ND, Kuehn C, Salman J, Greer M, Ius F. Pushing the Survival Bar Higher: Two Decades of Innovation in Lung Transplantation. J Clin Med 2024; 13:5516. [PMID: 39337005 PMCID: PMC11432129 DOI: 10.3390/jcm13185516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/13/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
Survival after lung transplantation has significantly improved during the last two decades. The refinement of the already existing extracorporeal life support (ECLS) systems, such as extracorporeal membrane oxygenation (ECMO), and the introduction of new techniques for donor lung optimization, such as ex vivo lung perfusion (EVLP), have allowed the extension of transplant indication to patients with end-stage lung failure after acute respiratory distress syndrome (ARDS) and the expansion of the donor organ pool, due to the better evaluation and optimization of extended-criteria donor (ECD) lungs and of donors after circulatory death (DCD). The close monitoring of anti-HLA donor-specific antibodies (DSAs) has allowed the early recognition of pulmonary antibody-mediated rejection (AMR), which requires a completely different treatment and has a worse prognosis than acute cellular rejection (ACR). As such, the standardization of patient selection and post-transplant management has significantly contributed to this positive trend, especially at high-volume centers. This review focuses on lung transplantation after ARDS, on the role of EVLP in lung donor expansion, on ECMO as a principal cardiopulmonary support system in lung transplantation, and on the diagnosis and therapy of pulmonary AMR.
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Affiliation(s)
- Khalil Aburahma
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
| | - Nunzio Davide de Manna
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
| | - Christian Kuehn
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
- German Centre for Lung Research (DZL/BREATH), 35392 Hannover, Germany
| | - Jawad Salman
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
- German Centre for Lung Research (DZL/BREATH), 35392 Hannover, Germany
| | - Mark Greer
- German Centre for Lung Research (DZL/BREATH), 35392 Hannover, Germany
- Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, 30625 Hannover, Germany
| | - Fabio Ius
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
- German Centre for Lung Research (DZL/BREATH), 35392 Hannover, Germany
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5
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Righi I, Barone I, Rosso L, Morlacchi LC, Rossetti V, Caffarena G, Limanaqi F, Palleschi A, Clerici M, Trabattoni D. Immunopathology of lung transplantation: from infection to rejection and vice versa. Front Immunol 2024; 15:1433469. [PMID: 39286256 PMCID: PMC11402714 DOI: 10.3389/fimmu.2024.1433469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 08/14/2024] [Indexed: 09/19/2024] Open
Abstract
Lung transplantation offers a lifesaving option for patients with end-stage lung disease, but it is marred by a high risk of post-transplant infections, particularly involving multidrug-resistant bacteria, Cytomegalovirus, and fungal pathogens. This elevated infection rate, the highest among solid organ transplants, poses a significant challenge for clinicians, particularly within the first year post-transplantation, where infections are the leading cause of mortality. The direct exposure of lung allografts to the external environment exacerbates this vulnerability leading to constant immune stimulation and consequently to an elevated risk of triggering alloimmune responses to the lung allograft. The necessity of prolonged immunosuppression to prevent allograft rejection further complicates patient management by increasing susceptibility to infections and neoplasms, and complicating the differentiation between rejection and infection, which require diametrically opposed management strategies. This review explores the intricate balance between preventing allograft rejection and managing the heightened infection risk in lung transplant recipients.
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Affiliation(s)
- Ilaria Righi
- Thoracic Surgery and Lung Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Ivan Barone
- Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Lorenzo Rosso
- Thoracic Surgery and Lung Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Letizia Corinna Morlacchi
- Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Valeria Rossetti
- Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giovanni Caffarena
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
- Department of Thoracic Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Fiona Limanaqi
- Department of Biomedical and Clinical Sciences (DIBIC), University of Milan, Milan, Italy
| | - Alessandro Palleschi
- Thoracic Surgery and Lung Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Mario Clerici
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
- Fondazione Don C. Gnocchi IRCCS, Milan, Italy
| | - Daria Trabattoni
- Department of Biomedical and Clinical Sciences (DIBIC), University of Milan, Milan, Italy
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Messika J, Belousova N, Parquin F, Roux A. Antibody-Mediated Rejection in Lung Transplantation: Diagnosis and Therapeutic Armamentarium in a 21st Century Perspective. Transpl Int 2024; 37:12973. [PMID: 39170865 PMCID: PMC11336419 DOI: 10.3389/ti.2024.12973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 07/10/2024] [Indexed: 08/23/2024]
Abstract
Humoral immunity is a major waypoint towards chronic allograft dysfunction in lung transplantation (LT) recipients. Though allo-immunization and antibody-mediated rejection (AMR) are well-known entities, some diagnostic gaps need to be addressed. Morphological analysis could be enhanced by digital pathology and artificial intelligence-based companion tools. Graft transcriptomics can help to identify graft failure phenotypes or endotypes. Donor-derived cell free DNA is being evaluated for graft-loss risk stratification and tailored surveillance. Preventative therapies should be tailored according to risk. The donor pool can be enlarged for candidates with HLA sensitization, with strategies combining plasma exchange, intravenous immunoglobulin and immune cell depletion, or with emerging or innovative therapies such as imlifidase or immunoadsorption. In cases of insufficient pre-transplant desensitization, the effects of antibodies on the allograft can be prevented by targeting the complement cascade, although evidence for this strategy in LT is limited. In LT recipients with a humoral response, strategies are combined, including depletion of immune cells (plasmapheresis or immunoadsorption), inhibition of immune pathways, or modulation of the inflammatory cascade, which can be achieved with photopheresis. Altogether, these innovative techniques offer promising perspectives for LT recipients and shape the 21st century's armamentarium against AMR.
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Affiliation(s)
- Jonathan Messika
- Thoracic Intensive Care Unit, Foch Hospital, Suresnes, France
- Physiopathology and Epidemiology of Respiratory Diseases, UMR1152 INSERM and Université de Paris, Paris, France
- Paris Transplant Group, Paris, France
| | - Natalia Belousova
- Paris Transplant Group, Paris, France
- Pneumology, Adult Cystic Fibrosis Center and Lung Transplantation Department, Foch Hospital, Suresnes, France
| | - François Parquin
- Thoracic Intensive Care Unit, Foch Hospital, Suresnes, France
- Paris Transplant Group, Paris, France
| | - Antoine Roux
- Paris Transplant Group, Paris, France
- Pneumology, Adult Cystic Fibrosis Center and Lung Transplantation Department, Foch Hospital, Suresnes, France
- Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, France
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7
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Bogyó LZ, Török K, Illés Z, Szilvási A, Székely B, Bohács A, Pipek O, Madurka I, Megyesfalvi Z, Rényi-Vámos F, Döme B, Bogos K, Gieszer B, Bakos E. Pseudomonas aeruginosa infection correlates with high MFI donor-specific antibody development following lung transplantation with consequential graft loss and shortened CLAD-free survival. Respir Res 2024; 25:262. [PMID: 38951782 PMCID: PMC11218249 DOI: 10.1186/s12931-024-02868-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 06/05/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND Donor-specific antibodies (DSAs) are common following lung transplantation (LuTx), yet their role in graft damage is inconclusive. Mean fluorescent intensity (MFI) is the main read-out of DSA diagnostics; however its value is often disregarded when analyzing unwanted post-transplant outcomes such as graft loss or chronic lung allograft dysfunction (CLAD). Here we aim to evaluate an MFI stratification method in these outcomes. METHODS A cohort of 87 LuTx recipients has been analyzed, in which a cutoff of 8000 MFI has been determined for high MFI based on clinically relevant data. Accordingly, recipients were divided into DSA-negative, DSA-low and DSA-high subgroups. Both graft survival and CLAD-free survival were evaluated. Among factors that may contribute to DSA development we analyzed Pseudomonas aeruginosa (P. aeruginosa) infection in bronchoalveolar lavage (BAL) specimens. RESULTS High MFI DSAs contributed to clinical antibody-mediated rejection (AMR) and were associated with significantly worse graft (HR: 5.77, p < 0.0001) and CLAD-free survival (HR: 6.47, p = 0.019) compared to low or negative MFI DSA levels. Analysis of BAL specimens revealed a strong correlation between DSA status, P. aeruginosa infection and BAL neutrophilia. DSA-high status and clinical AMR were both independent prognosticators for decreased graft and CLAD-free survival in our multivariate Cox-regression models, whereas BAL neutrophilia was associated with worse graft survival. CONCLUSIONS P. aeruginosa infection rates are elevated in recipients with a strong DSA response. Our results indicate that the simultaneous interpretation of MFI values and BAL neutrophilia is a feasible approach for risk evaluation and may help clinicians when to initiate DSA desensitization therapy, as early intervention could improve prognosis.
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Affiliation(s)
- Levente Zoltán Bogyó
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Rath Gyorgy u. 7-9, Budapest, 1122, Hungary
- National Korányi Institute of Pulmonology, Koranyi Frigyes ut 1, Budapest, 1121, Hungary
| | - Klára Török
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Rath Gyorgy u. 7-9, Budapest, 1122, Hungary
- National Korányi Institute of Pulmonology, Koranyi Frigyes ut 1, Budapest, 1121, Hungary
| | - Zsuzsanna Illés
- Hungarian National Blood Transfusion Service, Budapest, Hungary
| | - Anikó Szilvási
- Hungarian National Blood Transfusion Service, Budapest, Hungary
| | - Bálint Székely
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Rath Gyorgy u. 7-9, Budapest, 1122, Hungary
| | - Anikó Bohács
- Department of Pulmonology, Semmelweis University, Budapest, Hungary
| | - Orsolya Pipek
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Rath Gyorgy u. 7-9, Budapest, 1122, Hungary
- Department of Physics of Complex Systems, Eotvos Loránd University, Budapest, Hungary
| | - Ildikó Madurka
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Rath Gyorgy u. 7-9, Budapest, 1122, Hungary
- National Korányi Institute of Pulmonology, Koranyi Frigyes ut 1, Budapest, 1121, Hungary
| | - Zsolt Megyesfalvi
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Rath Gyorgy u. 7-9, Budapest, 1122, Hungary
- National Korányi Institute of Pulmonology, Koranyi Frigyes ut 1, Budapest, 1121, Hungary
- Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Ferenc Rényi-Vámos
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Rath Gyorgy u. 7-9, Budapest, 1122, Hungary
- National Korányi Institute of Pulmonology, Koranyi Frigyes ut 1, Budapest, 1121, Hungary
- National Institute of Oncology and National Tumor Biology Laboratory, Budapest, Hungary
| | - Balázs Döme
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Rath Gyorgy u. 7-9, Budapest, 1122, Hungary
- National Korányi Institute of Pulmonology, Koranyi Frigyes ut 1, Budapest, 1121, Hungary
- Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- National Institute of Oncology and National Tumor Biology Laboratory, Budapest, Hungary
- Department of Translational Medicine, Lund University, Lund, Sweden
| | - Krisztina Bogos
- National Korányi Institute of Pulmonology, Koranyi Frigyes ut 1, Budapest, 1121, Hungary.
| | - Balázs Gieszer
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Rath Gyorgy u. 7-9, Budapest, 1122, Hungary.
- National Korányi Institute of Pulmonology, Koranyi Frigyes ut 1, Budapest, 1121, Hungary.
| | - Eszter Bakos
- Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Rath Gyorgy u. 7-9, Budapest, 1122, Hungary
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Abdulqawi R, Alawwami M, Aldosari O, Aldosari Z, Alhuqbani M, Saleh RA, Esendagli D, Aldakhil H, De Vol EB, Alkattan K, Marquez KAH, Saleh W, Sandoqa S, Al-Mutairy EA. Intravenous Immunoglobulins Alone for the Desensitization of Lung Transplant Recipients with Preformed Donor Specific Antibodies and Negative Flow Cytometry Crossmatch. Clin Transplant 2024; 38:e15374. [PMID: 38979724 DOI: 10.1111/ctr.15374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/08/2024] [Accepted: 05/24/2024] [Indexed: 07/10/2024]
Abstract
BACKGROUND The lack of evidence regarding optimal desensitization strategies for lung transplant candidates with preformed donor specific anti-human leukocyte antigen antibodies (DSAs) has led to varying approaches among centers towards this patient group. Our institution's desensitization protocol for recipients with preformed DSAs and negative flow cytometry crossmatch (FCXM) consists of intravenous immunoglobulin (IVIG) as the sole therapy. The study aimed to determine outcomes using this approach. METHODS This retrospective study included adults who underwent lung-only transplantation for the first time between January 2015 and March 2022 at a single center. We excluded patients with positive or missing FCXM results. Transplant recipients with any DSA ≥ 1000 MFI on latest testing within three months of transplant were considered DSA-positive, while recipients with DSAs <1000 MFI and those without DSAs were assigned to the low-level/negative group. Graft survival (time to death/retransplantation) and chronic lung allograft dysfunction (CLAD)-free times were compared between groups using Cox proportional hazards models. RESULTS Thirty-six out of 167 eligible patients (22%) were DSA-positive. At least 50% of preformed DSAs had documented clearance (decrease to <1000 MFI) within the first 6 months of transplant. Multivariable Cox regression analyses did not detect a significantly increased risk of graft failure (aHR 1.04 95%CI 0.55-1.97) or chronic lung allograft dysfunction (aHR 0.71 95%CI 0.34-1.52) in DSA-positive patients compared to patients with low-level/negative DSAs. Incidences of antibody-mediated rejection (p = 1.00) and serious thromboembolic events (p = 0.63) did not differ between study groups. CONCLUSION We describe a single-center experience of administering IVIG alone to lung transplant recipients with preformed DSAs and negative FCXM. Further studies are required to confirm the efficacy of this strategy against other protocols.
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Affiliation(s)
- Rayid Abdulqawi
- Lung Health Centre Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Moheeb Alawwami
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
- Kidney and Pancreas Health Centre Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Omar Aldosari
- College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Zyad Aldosari
- College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | | | - Rana A Saleh
- Lung Health Centre Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Dorina Esendagli
- Chest Diseases Department, Faculty of Medicine, Baskent University, Ankara, Turkey
| | - Haifa Aldakhil
- Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Edward B De Vol
- Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Khaled Alkattan
- Lung Health Centre Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Kris Ann H Marquez
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Waleed Saleh
- Lung Health Centre Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Sahar Sandoqa
- Kidney and Pancreas Health Centre Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Eid A Al-Mutairy
- Lung Health Centre Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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9
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Hanks J, Girard C, Sehgal S. Acute rejection post lung transplant. Curr Opin Pulm Med 2024; 30:391-397. [PMID: 38656281 DOI: 10.1097/mcp.0000000000001078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
PURPOSE OF REVIEW To review what is currently known about the pathogenesis, diagnosis, treatment, and prevention of acute rejection (AR) in lung transplantation. RECENT FINDINGS Epigenomic and transcriptomic methods are gaining traction as tools for earlier detection of AR, which still remains primarily a histopathologic diagnosis. SUMMARY Acute rejection is a common cause of early posttransplant lung graft dysfunction and increases the risk of chronic rejection. Detection and diagnosis of AR is primarily based on histopathology, but noninvasive molecular methods are undergoing investigation. Two subtypes of AR exist: acute cellular rejection (ACR) and antibody-mediated rejection (AMR). Both can have varied clinical presentation, ranging from asymptomatic to fulminant ARDS, and can present simultaneously. Diagnosis of ACR requires transbronchial biopsy; AMR requires the additional measuring of circulating donor-specific antibody (DSA) levels. First-line treatment in ACR is increased immunosuppression (pulse-dose or tapered dose glucocorticoids); refractory cases may need antibody-based lymphodepletion therapy. First line treatment in AMR focuses on circulating DSA removal with B and plasma cell depletion; plasmapheresis, intravenous human immunoglobulin (IVIG), bortezomib, and rituximab are often employed.
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Affiliation(s)
- Justin Hanks
- Department of Pulmonary Medicine, Integrated Hospital Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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10
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Auner S, Hillebrand C, Boehm PM, Boecker J, Koren D, Schwarz S, Kovacs Z, Murakoezy G, Fischer G, Aigner C, Hoetzenecker K, Jaksch P, Benazzo A. Impact of Transient and Persistent Donor-Specific Antibodies in Lung Transplantation. Transpl Int 2024; 37:12774. [PMID: 38779355 PMCID: PMC11110840 DOI: 10.3389/ti.2024.12774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 04/15/2024] [Indexed: 05/25/2024]
Abstract
Lung transplantation (LuTx) is an established treatment for patients with end-stage lung diseases, however, outcomes are limited by acute and chronic rejection. One aspect that has received increasing attention is the role of the host's humoral alloresponse, particularly the formation of de novo donor-specific antibodies (dnDSAs). The aim of this study was to investigate the clinical significance of transient and persistent dnDSAs and to understand their impact on outcomes after LuTx. A retrospective analysis was conducted using DSA screening data from LuTx recipients obtained at the Medical University of Vienna between February 2016 and March 2021. Of the 405 LuTx recipients analyzed, 205 patients developed dnDSA during the follow-up period. Among these, 167 (81%) had transient dnDSA and 38 (19%) persistent dnDSA. Persistent but not transient dnDSAs were associated with chronic lung allograft dysfunction (CLAD) and antibody-mediated rejection (AMR) (p < 0.001 and p = 0.006, respectively). CLAD-free survival rates for persistent dnDSAs at 1-, 3-, and 5-year post-transplantation were significantly lower than for transient dnDSAs (89%, 59%, 56% vs. 91%, 79%, 77%; p = 0.004). Temporal dynamics of dnDSAs after LuTx have a substantial effect on patient outcomes. This study underlines that the persistence of dnDSAs poses a significant risk to graft and patient survival.
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Affiliation(s)
- S. Auner
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - C. Hillebrand
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - P. M. Boehm
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - J. Boecker
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - D. Koren
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - S. Schwarz
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Z. Kovacs
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - G. Murakoezy
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - G. Fischer
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - C. Aigner
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - K. Hoetzenecker
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - P. Jaksch
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - A. Benazzo
- Vienna Lung Transplant Program, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
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11
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Battle R, Pritchard D, Peacock S, Hastie C, Worthington J, Jordan S, McCaughlan JA, Barnardo M, Cope R, Collins C, Diaz-Burlinson N, Rosser C, Foster L, Kallon D, Shaw O, Briggs D, Turner D, Anand A, Akbarzad-Yousefi A, Sage D. BSHI and BTS UK guideline on the detection of alloantibodies in solid organ (and islet) transplantation. Int J Immunogenet 2023; 50 Suppl 2:3-63. [PMID: 37919251 DOI: 10.1111/iji.12641] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 10/04/2023] [Indexed: 11/04/2023]
Abstract
Solid organ transplantation represents the best (and in many cases only) treatment option for patients with end-stage organ failure. The effectiveness and functioning life of these transplants has improved each decade due to surgical and clinical advances, and accurate histocompatibility assessment. Patient exposure to alloantigen from another individual is a common occurrence and takes place through pregnancies, blood transfusions or previous transplantation. Such exposure to alloantigen's can lead to the formation of circulating alloreactive antibodies which can be deleterious to solid organ transplant outcome. The purpose of these guidelines is to update to the previous BSHI/BTS guidelines 2016 on the relevance, assessment, and management of alloantibodies within solid organ transplantation.
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Affiliation(s)
- Richard Battle
- Scottish National Blood Transfusion Service, Edinburgh, UK
| | | | - Sarah Peacock
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | | | - Sue Jordan
- National Blood Service Tooting, London, UK
| | | | - Martin Barnardo
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Rebecca Cope
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | | | | | - Luke Foster
- Birmingham Blood Donor Centre, Birmingham, UK
| | | | - Olivia Shaw
- Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - David Turner
- Scottish National Blood Transfusion Service, Edinburgh, UK
| | - Arthi Anand
- Imperial College Healthcare NHS Trust, London, UK
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12
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Matsumoto H, Suzuki H, Yamanaka T, Kaiho T, Hata A, Inage T, Ito T, Kamata T, Tanaka K, Sakairi Y, Motohashi S, Yoshino I. Anti-CD20 Antibody and Calcineurin Inhibitor Combination Therapy Effectively Suppresses Antibody-Mediated Rejection in Murine Orthotopic Lung Transplantation. Life (Basel) 2023; 13:2042. [PMID: 37895424 PMCID: PMC10608275 DOI: 10.3390/life13102042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/07/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Antibody-mediated rejection (AMR) is a risk factor for chronic lung allograft dysfunction, which impedes long-term survival after lung transplantation. There are no reports evaluating the efficacy of the single use of anti-CD20 antibodies (aCD20s) in addition to calcineurin inhibitors in preventing AMR. Thus, this study aimed to evaluate the efficacy of aCD20 treatment in a murine orthotopic lung transplantation model. Murine left lung transplantation was performed using a major alloantigen strain mismatch model (BALBc (H-2d) → C57BL/6 (BL/6) (H-2b)). There were four groups: isograft (BL/6→BL/6) (Iso control), no-medication (Allo control), cyclosporine A (CyA) treated, and CyA plus murine aCD20 (CyA+aCD20) treated groups. Severe neutrophil capillaritis, arteritis, and positive lung C4d staining were observed in the allograft model and CyA-only-treated groups. These findings were significantly improved in the CyA+aCD20 group compared with those in the Allo control and CyA groups. The B cell population in the spleen, lymph node, and graft lung as well as the levels of serum donor-specific IgM and interferon γ were significantly lower in the CyA+aCD20 group than in the CyA group. Calcineurin inhibitor-mediated immunosuppression combined with aCD20 therapy effectively suppressed AMR in lung transplantation by reducing donor-specific antibodies and complement activation.
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Affiliation(s)
- Hiroki Matsumoto
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
- Department of Thoracic Surgery, Kimitsu Chuo Hospital, 1010 Sakurai, Kisarazu 292-8535, Japan
| | - Hidemi Suzuki
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
| | - Takahiro Yamanaka
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
| | - Taisuke Kaiho
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
| | - Atsushi Hata
- Department of General Thoracic Surgery, Chiba Cancer Center, Chiba 260-8717, Japan; (A.H.); (T.I.)
| | - Terunaga Inage
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
| | - Takamasa Ito
- Department of General Thoracic Surgery, Chiba Cancer Center, Chiba 260-8717, Japan; (A.H.); (T.I.)
| | - Toshiko Kamata
- Department of Thoracic Surgery, International University of Health and Welfare Atami Hospital, Shizuoka 413-0012, Japan;
| | - Kazuhisa Tanaka
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
| | - Yuichi Sakairi
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
| | - Shinichiro Motohashi
- Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;
| | - Ichiro Yoshino
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (H.M.); (T.Y.); (T.K.); (T.I.); (K.T.); (Y.S.); (I.Y.)
- Department of General Thoracic Surgery, International University of Health and Welfare Narita Hospital, Chiba 286-8520, Japan
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13
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January SE, Fester KA, Halverson LP, Witt CA, Byers DE, Vazquez-Guillamet R, Alexander-Brett J, Tague LK, Kreisel D, Gelman A, Puri V, Bahena RN, Takahashi T, Hachem RR, Kulkarni HS. Tocilizumab for antibody-mediated rejection treatment in lung transplantation. J Heart Lung Transplant 2023; 42:1353-1357. [PMID: 37268051 PMCID: PMC10529998 DOI: 10.1016/j.healun.2023.05.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 03/08/2023] [Accepted: 05/20/2023] [Indexed: 06/04/2023] Open
Abstract
Tocilizumab (TCZ), an IL-6 inhibitor, has shown promise in the treatment of donor-specific antibodies (DSA) and chronic antibody-mediated rejection (AMR) in renal transplant recipients. However, its use in lung transplantation has not been described. This retrospective case-control study compared AMR treatments containing TCZ in 9 bilateral lung transplant recipients to 18 patients treated for AMR without TCZ. Treatment with TCZ resulted in more clearance of DSA, lower recurrence of DSA, lower incidence of new DSA, and lower rates of graft failure when compared to those treated for AMR without TCZ. The incidence of infusion reactions, elevation in transaminases, and infections were similar between the 2 groups. These data support a role for TCZ in pulmonary AMR and establish preliminary evidence to design a randomized controlled trial of IL-6 inhibition for the management of AMR.
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Affiliation(s)
- Spenser E January
- Department of Pharmacy, Barnes-Jewish Hospital , Saint Louis, Missouri.
| | - Keith A Fester
- Department of Pharmacy, Barnes-Jewish Hospital , Saint Louis, Missouri
| | - Laura P Halverson
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri
| | - Chad A Witt
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri
| | - Derek E Byers
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri
| | - Rodrigo Vazquez-Guillamet
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri
| | - Jennifer Alexander-Brett
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri
| | - Laneshia K Tague
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri
| | - Daniel Kreisel
- Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri
| | - Andrew Gelman
- Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri
| | - Varun Puri
- Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri
| | - Ruben Nava Bahena
- Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri
| | - Tsuyoshi Takahashi
- Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri
| | - Ramsey R Hachem
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri
| | - Hrishikesh S Kulkarni
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri
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14
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Goldsby J, Beermann K, Frankel C, Parish A, Stauffer N, Schandert A, Erkanli A, Reynolds JM. Preemptive immune globulin therapy in sensitized lung transplant recipients. Transpl Immunol 2023; 80:101904. [PMID: 37499884 PMCID: PMC10631014 DOI: 10.1016/j.trim.2023.101904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 07/17/2023] [Accepted: 07/22/2023] [Indexed: 07/29/2023]
Abstract
BACKGROUND Sensitized lung transplant recipients are at increased risk of developing donor-specific antibodies, which have been associated with acute and chronic rejection. Perioperative intravenous immune globulin has been used in sensitized individuals to down-regulate antibody production. METHODS We compared patients with a pre-transplant calculated panel reactive antibody ≥25% who did not receive preemptive immune globulin therapy to a historical control that received preemptive immune globulin therapy. Our cohort included 59 patients, 17 patients did not receive immune globulin therapy and 42 patients received therapy. RESULTS Donor specific antibody development was numerically higher in the non-immune globulin group compared to the immune globulin group (58.8% vs 33.3%, respectively, odds ratio 2.80, 95% confidence interval [0.77, 10.79], p = 0.13). Median time to antibody development was 9 days (Q1, Q3: 7, 19) and 28 days (Q1, Q3: 7, 58) in the non-immune globulin and immune globulin groups, respectively. There was no significant difference between groups in the incidence of primary graft dysfunction at 72 h post-transplant or acute cellular rejection, antibody-mediated rejection, and chronic lung allograft dysfunction at 12 months. CONCLUSION These findings are hypothesis generating and emphasize the need for larger, randomized studies to determine association of immune globulin therapy with clinical outcomes.
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Affiliation(s)
- Jessica Goldsby
- Department of Pharmacy, Duke Health, DUHS Box 3089, Durham, NC 27710, United States
| | - Kristi Beermann
- Department of Pharmacy, Duke Health, DUHS Box 3089, Durham, NC 27710, United States.
| | - Courtney Frankel
- Division of Pulmonary, Allergy, and Critical Care Medicine, Duke Health, 330 Trent Drive, Box 102352, Durham, NC 27710, United States
| | - Alice Parish
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, 2424 Erwin Road, Suite 1102, Hock Plaza Box 2721, Durham, NC 27710, United States
| | - Nicolas Stauffer
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, 2424 Erwin Road, Suite 1102, Hock Plaza Box 2721, Durham, NC 27710, United States
| | - Amanda Schandert
- Department of Pharmacy, Duke Health, DUHS Box 3089, Durham, NC 27710, United States
| | - Alaattin Erkanli
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, 2424 Erwin Road, Suite 1102, Hock Plaza Box 2721, Durham, NC 27710, United States
| | - John M Reynolds
- Division of Pulmonary, Allergy, and Critical Care Medicine, Duke Health, 330 Trent Drive, Box 102352, Durham, NC 27710, United States
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15
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Brandon W, Dunn C, Bollineni S, Joerns J, Lawrence A, Mohanka M, Timofte I, Torres F, Kaza V. Management of donor-specific antibodies in lung transplantation. FRONTIERS IN TRANSPLANTATION 2023; 2:1248284. [PMID: 38993917 PMCID: PMC11235237 DOI: 10.3389/frtra.2023.1248284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/23/2023] [Indexed: 07/13/2024]
Abstract
The formation of antibodies against donor human leukocyte antigens poses a challenging problem both for donor selection as well as postoperative graft function in lung transplantation. These donor-specific antibodies limit the pool of potential donor organs and are associated with episodes of antibody-mediated rejection, chronic lung allograft dysfunction, and increased mortality. Optimal management strategies for clearance of DSAs are poorly defined and vary greatly by institution; most of the data supporting any particular strategy is limited to small-scale retrospective cohort studies. A typical approach to antibody depletion may involve the use of high-dose steroids, plasma exchange, intravenous immunoglobulin, and possibly other immunomodulators or small-molecule therapies. This review seeks to define the current understanding of the significance of DSAs in lung transplantation and outline the literature supporting strategies for their management.
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Affiliation(s)
- William Brandon
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Colin Dunn
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Srinivas Bollineni
- Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - John Joerns
- Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Adrian Lawrence
- Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Manish Mohanka
- Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Irina Timofte
- Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Fernando Torres
- Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Vaidehi Kaza
- Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
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16
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Kayawake H, Tanaka S, Yutaka Y, Yamada Y, Ohsumi A, Hamaji M, Nakajima D, Yurugi K, Hishida R, Date H. Impact of Spousal Donation on Postoperative Outcomes of Living-donor Lobar Lung Transplantation. Transplantation 2023; 107:1786-1794. [PMID: 36895091 DOI: 10.1097/tp.0000000000004579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Abstract
BACKGROUND The effect of human leukocyte antigen mismatches between donors and recipients on postoperative outcomes of lung transplantation remains controversial. We retrospectively reviewed adult recipients receiving living-donor lobar lung transplantation (LDLLT) to examine the difference in de novo donor-specific antibody (dnDSA) development and clinically diagnosed unilateral chronic lung allograft dysfunction per graft (unilateral CLAD) between lung grafts donated by spouses (nonblood relatives) and nonspouses (relatives within the third degree). We also investigated the difference in prognoses between recipients undergoing LDLLTs including spouse donors (spousal LDLLTs) and not including spouse donors (nonspousal LDLLTs). METHODS In this study, 63 adult recipients undergoing LDLLTs (61 bilateral and 2 unilateral LDLLTs from 124 living donors) between 2008 and 2020 were enrolled. The cumulative incidence of dnDSAs per lung graft was calculated, and prognoses were compared between recipients undergoing spousal and nonspousal LDLLTs. RESULTS The cumulative incidence of both dnDSAs and unilateral CLAD in grafts donated by spouses was significantly higher than that in grafts donated by nonspouses (5-y incidence of dnDSAs: 18.7% versus 6.4%, P = 0.038; 5-y incidence of unilateral CLAD: 45.6% versus 19.4%, P = 0.011). However, there were no significant differences in the overall survival or chronic lung allograft dysfunction-free survival between recipients undergoing spousal and nonspousal LDLLTs ( P > 0.99 and P = 0.434, respectively). CONCLUSIONS Although there were no significant differences in prognoses between spousal and nonspousal LDLLTs, more attention should be paid to spousal LDLLTs because of the higher development rate of dnDSAs and unilateral CLAD.
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Affiliation(s)
- Hidenao Kayawake
- Department of Thoracic Surgery, Kyoto University, Kyoto, Japan
- Department of Thoracic Surgery, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Satona Tanaka
- Department of Thoracic Surgery, Kyoto University, Kyoto, Japan
| | - Yojiro Yutaka
- Department of Thoracic Surgery, Kyoto University, Kyoto, Japan
| | - Yoshito Yamada
- Department of Thoracic Surgery, Kyoto University, Kyoto, Japan
| | - Akihiro Ohsumi
- Department of Thoracic Surgery, Kyoto University, Kyoto, Japan
| | | | | | - Kimiko Yurugi
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Rie Hishida
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Hiroshi Date
- Department of Thoracic Surgery, Kyoto University, Kyoto, Japan
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Stoker A, Hicks A, Wright MC, Ali A, Klapper J, Poisson J, Zaffiri L, Chen D, Hartwig M, Ghadimi K, Welsby I, Bottiger B. Development of New Donor-Specific and Human Leukocyte Antigen Antibodies After Transfusion in Adult Lung Transplantation. J Cardiothorac Vasc Anesth 2023:S1053-0770(23)00274-4. [PMID: 37263806 DOI: 10.1053/j.jvca.2023.04.038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 06/03/2023]
Abstract
OBJECTIVES The development of new human leukocyte antigens (HLAs) and donor-specific antibodies (DSAs) in patients are associated with worse outcomes following lung transplantation. The authors aimed to examine the relationship between blood product transfusion in the first 72 hours after lung transplantation and the development of HLA antibodies, including DSAs. DESIGN A retrospective observational study. SETTING At a single academic tertiary center. PARTICIPANTS Adult lung transplant recipients who underwent transplantation between September 2014 and June 2019. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A total of 380 patients were included in this study, and 87 (23%) developed de novo donor-specific antibodies in the first year after transplantation. Eighty-five patients (22%) developed new HLA antibodies that were not donor-specific, and 208 patients (55%) did not develop new HLA antibodies in the first year after transplantation. Factors associated with increased HLA and DSA development included donor pulmonary infection, non-infectious indication for transplant, increased recipient body mass index, and a preoperative calculated panel reactive antibody value above 0. Multivariate analysis identified platelet transfusion associated with an increased risk of de novo HLA antibody development compared to the negative group (odds ratio [OR; 95% CI] 1.18 [1.02-1.36]; p = 0.025). Cryoprecipitate transfusion was associated with de novo DSA development compared to the negative group (OR [95% CI] 2.21 [1.32-3.69] for 1 v 0 units; p = 0.002). CONCLUSIONS Increased perioperative transfusion of platelets and cryoprecipitate are associated with de novo HLA and DSA development, respectively, in lung transplant recipients during the first year after transplantation.
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Affiliation(s)
- Alexander Stoker
- Department of Anesthesiology, Cardiothoracic Anesthesiology Division, Duke University Medical Center, Durham, NC
| | - Anne Hicks
- Department of Anesthesiology, Cardiothoracic Anesthesiology Division, Duke University Medical Center, Durham, NC
| | - Mary Cooter Wright
- Department of Anesthesiology, Biostatistics, Duke University Medical Center, Durham, NC
| | - Azfar Ali
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, NC
| | - Jacob Klapper
- Department of Cardiothoracic Surgery, Duke University Medical Center, Durham, NC
| | - Jessica Poisson
- Department of Pathology, Duke University Medical Center, Durham, NC
| | - Lorenzo Zaffiri
- Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, NC
| | - Dongfeng Chen
- Department of Pathology, Duke University Medical Center, Durham, NC
| | - Matthew Hartwig
- Department of Cardiothoracic Surgery, Duke University Medical Center, Durham, NC
| | - Kamrouz Ghadimi
- Department of Anesthesiology, Cardiothoracic Anesthesiology Division, Duke University Medical Center, Durham, NC; Department of Anesthesiology, Critical Care Medicine Division, Duke University Medical Center, Durham, NC
| | - Ian Welsby
- Department of Anesthesiology, Cardiothoracic Anesthesiology Division, Duke University Medical Center, Durham, NC; Department of Anesthesiology, Critical Care Medicine Division, Duke University Medical Center, Durham, NC
| | - Brandi Bottiger
- Department of Anesthesiology, Cardiothoracic Anesthesiology Division, Duke University Medical Center, Durham, NC.
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Keller M, Yang S, Ponor L, Bon A, Cochrane A, Philogene M, Bush E, Shah P, Mathew J, Brown AW, Kong H, Charya A, Luikart H, Nathan SD, Khush KK, Jang M, Agbor-Enoh S. Preemptive treatment of de novo donor-specific antibodies in lung transplant patients reduces subsequent risk of chronic lung allograft dysfunction or death. Am J Transplant 2023; 23:559-564. [PMID: 36732088 PMCID: PMC10079558 DOI: 10.1016/j.ajt.2022.12.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 01/20/2023]
Abstract
The development of donor-specific antibodies after lung transplantation is associated with downstream acute cellular rejection, antibody-mediated rejection (AMR), chronic lung allograft dysfunction (CLAD), or death. It is unknown whether preemptive (early) treatment of de novo donor-specific antibodies (dnDSAs), in the absence of clinical signs and symptoms of allograft dysfunction, reduces the risk of subsequent CLAD or death. We performed a multicenter, retrospective cohort study to determine if early treatment of dnDSAs in lung transplant patients reduces the risk of the composite endpoint of CLAD or death. In the cohort of 445 patients, 145 patients developed dnDSAs posttransplant. Thirty patients received early targeted treatment for dnDSAs in the absence of clinical signs and symptoms of AMR. Early treatment of dnDSAs was associated with a decreased risk of CLAD or death (hazard ratio, 0.36; 95% confidence interval, 0.17-0.76; P < .01). Deferring treatment until the development of clinical AMR was associated with an increased risk of CLAD or death (hazard ratio, 3.00; 95% confidence interval, 1.46-6.18; P < .01). This study suggests that early, preemptive treatment of donor-specific antibodies in lung transplant patients may reduce the subsequent risk of CLAD or death.
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Affiliation(s)
- Michael Keller
- Laboratory of Applied Precision Omics (APO),National Heart,Lung and Blood Institute (NHLBI),National Institutes of Health,Bethesda,Maryland,USA; Laboratory of Transplantation Genomics, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland, USA; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland, USA; Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA; Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Song Yang
- Office of Biostatistics Research, National Heart, Lung and Blood Institute, Bethesda, Maryland, USA
| | - Lucia Ponor
- Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland, USA; Division of Hospital Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, USA
| | - Ann Bon
- Laboratory of Applied Precision Omics (APO),National Heart,Lung and Blood Institute (NHLBI),National Institutes of Health,Bethesda,Maryland,USA; Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | | | - Mary Philogene
- Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA; Johns Hopkins Immunogenetics Laboratory, Baltimore, Maryland, USA
| | - Errol Bush
- Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland, USA; Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Pali Shah
- Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland, USA; Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Joby Mathew
- Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland, USA; Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Anne W Brown
- Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland, USA; Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Hyesik Kong
- Laboratory of Applied Precision Omics (APO),National Heart,Lung and Blood Institute (NHLBI),National Institutes of Health,Bethesda,Maryland,USA; Laboratory of Transplantation Genomics, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland, USA; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland, USA
| | - Ananth Charya
- Division of Pulmonary and Critical Care Medicine, University of Maryland Medical Center, Baltimore, Maryland, USA
| | - Helen Luikart
- Genome Transplant Genomics (GTD), Stanford University School of Medicine, Palo Alto, California, USA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California, USA; Department of Pathology, Stanford University School of Medicine, Palo Alto, California, USA
| | - Steven D Nathan
- Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland, USA; Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Kiran K Khush
- Genome Transplant Genomics (GTD), Stanford University School of Medicine, Palo Alto, California, USA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California, USA
| | - Moon Jang
- Laboratory of Applied Precision Omics (APO),National Heart,Lung and Blood Institute (NHLBI),National Institutes of Health,Bethesda,Maryland,USA; Laboratory of Transplantation Genomics, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland, USA; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland, USA
| | - Sean Agbor-Enoh
- Laboratory of Applied Precision Omics (APO),National Heart,Lung and Blood Institute (NHLBI),National Institutes of Health,Bethesda,Maryland,USA; Laboratory of Transplantation Genomics, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland, USA; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland, USA; Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.
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19
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Halverson LP, Hachem RR. Antibody-Mediated Rejection: Diagnosis and Treatment. Clin Chest Med 2023; 44:95-103. [PMID: 36774172 PMCID: PMC10148231 DOI: 10.1016/j.ccm.2022.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Antibody-mediated rejection (AMR) is a form of lung allograft rejection that is emerging as an important risk factor for chronic lung allograft dysfunction and decreased long-term survival. In this review, we provide a brief overview of our current understanding of its pathophysiology with an emphasis on donor-specific antibodies before moving on to focus on the current diagnostic criteria and treatment strategies. Our goal is to discuss the limitations of our current knowledge and explore how novel diagnostic and therapeutic options aim to improve outcomes through earlier definitive diagnosis and preemptive targeted treatment.
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Affiliation(s)
- Laura P Halverson
- Division of Pulmonary & Critical Care, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8052, Saint Louis, MO 63108, USA.
| | - Ramsey R Hachem
- Division of Pulmonary & Critical Care, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8052, Saint Louis, MO 63108, USA
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20
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Sharma D, Sharma N, Subramaniam KG. Curbing Proteastasis to Combat Antibody-Mediated Rejection Post Lung Transplant. INDIAN JOURNAL OF TRANSPLANTATION 2023; 17:12-15. [DOI: 10.4103/ijot.ijot_33_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 01/30/2023] [Indexed: 04/03/2023] Open
Abstract
Lung transplantation (LTx) has emerged as the treatment of choice for patients suffering from end-stage lung disease all over the past 35 years. Despite ameliorated early survival with a median survival of 6.5 years, its long-term outcomes are dissatisfactory. Although antibody-mediated rejection (AMR) remained “the Achilles heel of LTx,” yet we have not attained consensus on the optimal therapeutic approach. The aim of this review article is to address the upcoming role of proteasome inhibitor drugs in managing AMR post-LTx.
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Affiliation(s)
- Dhruva Sharma
- Department of Cardiothoracic and Vascular Surgery, SMS Medical College and Attached Hospitals, Jaipur, Rajasthan, India
| | - Neha Sharma
- Department of Pharmacology, SMS Medical College and Attached Hospitals, Jaipur, Rajasthan, India
| | - Krishnan Ganapathy Subramaniam
- Department of Cardiothoracic and Vascular Surgery, Sri Padmavathi Children Heart Centre, Tirupati, Andhra Pradesh, India
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21
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Calabrese DR, Chong T, Singer JP, Rajalingam R, Hays SR, Kukreja J, Leard L, Golden JA, Lanier LL, Greenland JR. CD16 + natural killer cells in bronchoalveolar lavage are associated with antibody-mediated rejection and chronic lung allograft dysfunction. Am J Transplant 2023; 23:37-44. [PMID: 36695619 PMCID: PMC10018437 DOI: 10.1016/j.ajt.2022.10.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 09/12/2022] [Accepted: 10/10/2022] [Indexed: 01/13/2023]
Abstract
Acute and chronic rejections limit the long-term survival after lung transplant. Pulmonary antibody-mediated rejection (AMR) is an incompletely understood driver of long-term outcomes characterized by donor-specific antibodies (DSAs), innate immune infiltration, and evidence of complement activation. Natural killer (NK) cells may recognize DSAs via the CD16 receptor, but this complement-independent mechanism of injury has not been explored in pulmonary AMR. CD16+ NK cells were quantified in 508 prospectively collected bronchoalveolar lavage fluid samples from 195 lung transplant recipients. Associations between CD16+ NK cells and human leukocyte antigen mismatches, DSAs, and AMR grade were assessed by linear models adjusted for participant characteristics and repeat measures. Cox proportional hazards models were used to assess CD16+ NK cell association with chronic lung allograft dysfunction and survival. Bronchoalveolar lavage fluid CD16+ NK cell frequency was associated with increasing human leukocyte antigens mismatches and increased AMR grade. Although NK frequencies were similar between DSA+ and DSA- recipients, CD16+ NK cell frequencies were greater in recipients with AMR and those with concomitant allograft dysfunction. CD16+ NK cells were associated with long-term graft dysfunction after AMR and decreased chronic lung allograft dysfunction-free survival. These data support the role of CD16+ NK cells in pulmonary AMR.
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Affiliation(s)
- Daniel R Calabrese
- Department of Medicine, University of California, San Francisco, California, USA; Medical Service, Veterans Affairs Health Care System, San Francisco, California, USA.
| | - Tiffany Chong
- Department of Medicine, University of California, San Francisco, California, USA
| | - Jonathan P Singer
- Department of Medicine, University of California, San Francisco, California, USA
| | - Raja Rajalingam
- Department of Surgery, University of California, San Francisco, California, USA
| | - Steven R Hays
- Department of Medicine, University of California, San Francisco, California, USA
| | - Jasleen Kukreja
- Department of Surgery, University of California, San Francisco, California, USA
| | - Lorriana Leard
- Department of Medicine, University of California, San Francisco, California, USA
| | - Jeffrey A Golden
- Department of Medicine, University of California, San Francisco, California, USA
| | - Lewis L Lanier
- Department of Microbiology and Immunology and the Parker Institute for Cancer Immunotherapy, University of California, San Francisco, California, USA
| | - John R Greenland
- Department of Medicine, University of California, San Francisco, California, USA; Medical Service, Veterans Affairs Health Care System, San Francisco, California, USA
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22
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Abstract
BACKGROUND Donor-specific antibodies (DSAs) have been associated with antibody-mediated rejection, chronic lung allograft dysfunction (CLAD), and increased mortality in lung transplant recipients. Our center performs transplants in the presence of DSA, and we sought to evaluate the safety of this practice with respect to graft loss, CLAD onset, and primary graft dysfunction (PGD). METHODS We reviewed recipients transplanted from 2010 to 2017, classifying them as DSA positive (DSA+) or negative. We used Kaplan-Meier estimation to test the association between DSA status and time to death or retransplant and time to CLAD onset. We further tested associations with severe PGD and rejection in the first year using logistic regression and Fisher exact testing. RESULTS Three hundred thirteen patients met inclusion criteria, 30 (10%) of whom were DSA+. DSA+ patients were more likely to be female, bridged to transplant, and receive induction therapy. There was no association between DSA status and time to death or retransplant (log rank P = 0.581) nor death-censored time to CLAD onset (log rank P = 0.278), but DSA+ patients were at increased risk of severe PGD (odds ratio 2.88; 95% confidence interval, 1.10-7.29; P = 0.031) and more frequent antibody-mediated rejection in the first posttransplant year. CONCLUSIONS Crossing DSA at time of lung transplant was not associated with an increased risk of death or CLAD in our cohort, but patients developed severe PGD and antibody-mediated rejection more frequently. However, these risks are likely manageable when balanced against the benefits of expanded access for sensitized candidates.
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23
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Bos S, Milross L, Filby AJ, Vos R, Fisher AJ. Immune processes in the pathogenesis of chronic lung allograft dysfunction: identifying the missing pieces of the puzzle. Eur Respir Rev 2022; 31:31/165/220060. [PMID: 35896274 DOI: 10.1183/16000617.0060-2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/19/2022] [Indexed: 11/05/2022] Open
Abstract
Lung transplantation is the optimal treatment for selected patients with end-stage chronic lung diseases. However, chronic lung allograft dysfunction remains the leading obstacle to improved long-term outcomes. Traditionally, lung allograft rejection has been considered primarily as a manifestation of cellular immune responses. However, in reality, an array of complex, interacting and multifactorial mechanisms contribute to its emergence. Alloimmune-dependent mechanisms, including T-cell-mediated rejection and antibody-mediated rejection, as well as non-alloimmune injuries, have been implicated. Moreover, a role has emerged for autoimmune responses to lung self-antigens in the development of chronic graft injury. The aim of this review is to summarise the immune processes involved in the pathogenesis of chronic lung allograft dysfunction, with advanced insights into the role of innate immune pathways and crosstalk between innate and adaptive immunity, and to identify gaps in current knowledge.
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Affiliation(s)
- Saskia Bos
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK.,Institute of Transplantation, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | - Luke Milross
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK
| | - Andrew J Filby
- Flow Cytometry Core and Innovation, Methodology and Application Research Theme, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Robin Vos
- Dept of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium.,University Hospitals Leuven, Dept of Respiratory Diseases, Leuven, Belgium
| | - Andrew J Fisher
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK .,Institute of Transplantation, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
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24
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Sharma D, Krishnan GS, Sharma N, Chandrashekhar A. Current perspective of immunomodulators for lung transplant. Indian J Thorac Cardiovasc Surg 2022; 38:497-505. [PMID: 36050971 PMCID: PMC9424406 DOI: 10.1007/s12055-022-01388-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 06/09/2022] [Accepted: 06/14/2022] [Indexed: 11/25/2022] Open
Abstract
Lung transplantation is an effective treatment option for selected patients suffering from end-stage lung disease. More intensive immunosuppression is enforced after lung transplants owing to a greater risk of rejection than after any other solid organ transplants. The commencing of lung transplantation in the modern era was in 1983 when the Toronto Lung Transplant Group executed the first successful lung transplant. A total of 43,785 lung transplants and 1365 heart-lung transplants have been performed from 1 Jan 1988 until 31 Jan 2021. The aim of this review article is to discuss the existing immunosuppressive strategies and emerging agents to prevent acute and chronic rejection in lung transplantation.
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Affiliation(s)
- Dhruva Sharma
- Department of Cardiothoracic and Vascular Surgery, SMS Medical College & Attached Hospitals, J L N Marg, Jaipur, 302001 Rajasthan India
| | - Ganapathy Subramaniam Krishnan
- Institute of Heart and Lung Transplant and Mechanical Circulatory Support, MGM Healthcare, No. 72, Nelson Manickam Road, Aminjikarai, Chennai, 600029 Tamil Nadu India
| | - Neha Sharma
- Department of Pharmacology, SMS Medical College & Attached Hospitals, J L N Marg, Jaipur, 302001 Rajasthan India
| | - Anitha Chandrashekhar
- Institute of Heart and Lung Transplant and Mechanical Circulatory Support, MGM Healthcare, No. 72, Nelson Manickam Road, Aminjikarai, Chennai, 600029 Tamil Nadu India
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25
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Carfilzomib versus rituximab for treatment of de novo donor-specific antibodies in lung transplant recipients. Transpl Immunol 2022; 75:101703. [PMID: 36049718 DOI: 10.1016/j.trim.2022.101703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 08/24/2022] [Accepted: 08/24/2022] [Indexed: 11/24/2022]
Abstract
INTRODUCTION De novo donor-specific antibodies (DSAs) increase the risk of chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs). Both carfilzomib (CFZ) and rituximab (RTX) lower the mean fluorescent intensity (MFI) of DSAs, but comparative data are lacking. We compared CLAD-free survival and the degree and duration of DSA depletion after treatment of LTRs with CFZ or RTX. METHODS LTRs that received CFZ or RTX for DSA depletion between 08/01/2015 and 08/31/2020 were included. The primary outcome was CLAD-free survival. Secondary outcomes were change in MFI at corresponding loci within 6 months of treatment (ΔMFI), time to DSA rebound, and change in % predicted FEV1 6 months after treatment (ΔFEV1). RESULTS Forty-four LTRs were identified, 7 of whom had ≥2 drug events; therefore, 53 drug events were divided into 2 groups, CFZ (n = 17) and RTX (n = 36). Use of plasmapheresis, immunoglobulin, and mycophenolate augmentation was equivalent in both groups. CLAD-free survival with a single RTX event was superior to that after ≥2 drug events (p = 0.001) but comparable to that with a single CFZ event (p = 0.399). Both drugs significantly lowered the MFI at DQ locus, and the median ΔMFI was comparable. Compared to the RTX group, the CFZ group had a shorter median interval to DSA rebound (p = 0.015) and a lower ΔFEV1 at 6 months (p = 0.014). CONCLUSION Although both CFZ and RTX reduced the MFI of circulating DSAs, RTX prolonged the time to DSA rebound. Despite more pronounced improvement in FEV1 with RTX, comparable CLAD-free survival between the 2 groups suggests that both drugs offer a reasonable treatment strategy for DSAs in LTRs.
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26
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Ravichandran R, Bansal S, Rahman M, Sureshbabu A, Sankpal N, Fleming T, Bharat A, Mohanakumar T. Extracellular Vesicles Mediate Immune Responses to Tissue-Associated Self-Antigens: Role in Solid Organ Transplantations. Front Immunol 2022; 13:861583. [PMID: 35572510 PMCID: PMC9094427 DOI: 10.3389/fimmu.2022.861583] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
Transplantation is a treatment option for patients diagnosed with end-stage organ diseases; however, long-term graft survival is affected by rejection of the transplanted organ by immune and nonimmune responses. Several studies have demonstrated that both acute and chronic rejection can occur after transplantation of kidney, heart, and lungs. A strong correlation has been reported between de novo synthesis of donor-specific antibodies (HLA-DSAs) and development of both acute and chronic rejection; however, some transplant recipients with chronic rejection do not have detectable HLA-DSAs. Studies of sera from such patients demonstrate that immune responses to tissue-associated antigens (TaAgs) may also play an important role in the development of chronic rejection, either alone or in combination with HLA-DSAs. The synergistic effect between HLA-DSAs and antibodies to TaAgs is being established, but the underlying mechanism is yet to be defined. We hypothesize that HLA-DSAs damage the transplanted donor organ resulting in stress and leading to the release of extracellular vesicles, which contribute to chronic rejection. These vesicles express both donor human leukocyte antigen (HLA) and non-HLA TaAgs, which can activate antigen-presenting cells and lead to immune responses and development of antibodies to both donor HLA and non-HLA tissue-associated Ags. Extracellular vesicles (EVs) are released by cells under many circumstances due to both physiological and pathological conditions. Primarily employing clinical specimens obtained from human lung transplant recipients undergoing acute or chronic rejection, our group has demonstrated that circulating extracellular vesicles display both mismatched donor HLA molecules and lung-associated Ags (collagen-V and K-alpha 1 tubulin). This review focuses on recent studies demonstrating an important role of antibodies to tissue-associated Ags in the rejection of transplanted organs, particularly chronic rejection. We will also discuss the important role of extracellular vesicles released from transplanted organs in cross-talk between alloimmunity and autoimmunity to tissue-associated Ags after solid organ transplantation.
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Affiliation(s)
| | - Sandhya Bansal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Mohammad Rahman
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Angara Sureshbabu
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Narendra Sankpal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Timothy Fleming
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Ankit Bharat
- Department of Surgery-Thoracic, Northwestern University, Chicago, IL, United States
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27
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Abstract
Chronic lung allograft dysfunction (CLAD) is a syndrome of progressive lung function decline, subcategorized into obstructive, restrictive, and mixed phenotypes. The trajectory of CLAD is variable depending on the phenotype, with restrictive and mixed phenotypes having more rapid progression and lower survival. The mechanisms driving CLAD development remain unclear, though allograft injury during primary graft dysfunction, acute cellular rejection, antibody-mediated rejection, and infections trigger immune responses with long-lasting effects that can lead to CLAD months or years later. Currently, retransplantation is the only effective treatment.
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Affiliation(s)
- Aida Venado
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California, San Francisco, 505 Parnassus Ave, M1093A, San Francisco, CA 94143-2204, USA.
| | - Jasleen Kukreja
- Division of Cardiothoracic Surgery, Univeristy of California, San Francisco, 500 Parnassus Ave, MU 405W Suite 305, San Francisco, CA 94143, USA
| | - John R Greenland
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California, San Francisco, SF VAHCS Building 2, Room 453 (Mail stop 111D), 4150 Clement St, San Francisco CA 94121, USA
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28
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Subramani MV, Pandit S, Gadre SK. Acute rejection and post lung transplant surveillance. Indian J Thorac Cardiovasc Surg 2022; 38:271-279. [PMID: 35340687 PMCID: PMC8938213 DOI: 10.1007/s12055-021-01320-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 12/09/2021] [Accepted: 12/16/2021] [Indexed: 12/05/2022] Open
Abstract
Purpose The purpose of this review is to summarize the current evidence on the evaluation and treatment of acute rejection after lung transplantation. Results Despite significant progress in the field of transplant immunology, acute rejection remains a frequent complication after transplantation. Almost 30% of lung transplant recipients experience at least one episode of acute cellular rejection (ACR) during the first year after transplant. Acute cellular rejection, lymphocytic bronchiolitis, and antibody-mediated rejection (AMR) are all risk factors for the subsequent development of chronic lung allograft dysfunction (CLAD). Acute cellular rejection and lymphocytic bronchiolitis have well-defined histopathologic diagnostic criteria and grading. The diagnosis of antibody-mediated rejection after lung transplantation requires a multidisciplinary approach. Antibody-mediated rejection may cause acute allograft failure. Conclusions Acute rejection is a risk factor for development of chronic rejection. Further investigations are required to better define risk factors, surveillance strategies, and optimal management strategies for acute allograft rejection.
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Affiliation(s)
| | - Sumir Pandit
- Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue A-90, Cleveland, OH 44195 USA
| | - Shruti Kumar Gadre
- Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue A-90, Cleveland, OH 44195 USA
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Ohm B, Jungraithmayr W. B Cell Immunity in Lung Transplant Rejection - Effector Mechanisms and Therapeutic Implications. Front Immunol 2022; 13:845867. [PMID: 35320934 PMCID: PMC8934882 DOI: 10.3389/fimmu.2022.845867] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 02/10/2022] [Indexed: 12/14/2022] Open
Abstract
Allograft rejection remains the major hurdle in lung transplantation despite modern immunosuppressive treatment. As part of the alloreactive process, B cells are increasingly recognized as modulators of alloimmunity and initiators of a donor-specific humoral response. In chronically rejected lung allografts, B cells contribute to the formation of tertiary lymphoid structures and promote local alloimmune responses. However, B cells are functionally heterogeneous and some B cell subsets may promote alloimmune tolerance. In this review, we describe the current understanding of B-cell-dependent mechanisms in pulmonary allograft rejection and highlight promising future strategies that employ B cell-targeted therapies.
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Affiliation(s)
- Birte Ohm
- Department of Thoracic Surgery, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Wolfgang Jungraithmayr
- Department of Thoracic Surgery, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
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Anti-HLA immunization of patients qualified for lung transplantation – Single center study. Transpl Immunol 2022; 71:101553. [DOI: 10.1016/j.trim.2022.101553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 11/17/2022]
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Mangiola M, Marrari M, Xu Q, Sanchez PG, Zeevi A. Approaching the sensitized lung patient: risk assessment for donor acceptance. J Thorac Dis 2022; 13:6725-6736. [PMID: 34992848 PMCID: PMC8662510 DOI: 10.21037/jtd-2021-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 05/14/2021] [Indexed: 12/16/2022]
Abstract
The presence of HLA antibodies is widely recognized as a barrier to solid organ transplantation, and for lung transplant candidates, it has a significant negative impact on both waiting time and waiting list mortality. Although HLA antibodies have been associated with a broad spectrum of allograft damage, precise characterization of these antibodies in allosensitized candidates may enhance their accessibility to transplant. The introduction of Luminex-based single antigen bead (SAB) assays has significantly improved antibody detection sensitivity and specificity, but SAB alone is not sufficient for risk-stratification. Functional characterization of donor-specific antibodies (DSA) is paramount to increase donor accessibility for allosensitized lung candidates. We describe here our approach to evaluate sensitized lung transplant candidates. By employing state-of-the-art technologies to assess histocompatibility and determine physiological properties of circulating HLA antibodies, we can provide our Clinical Team a better risk assessment for lung transplant candidates and facilitate a "road map" to transplant. The cases presented in this paper illustrate the "individualized steps" taken to determine calculated panel reactive antibodies (cPRA), titer and complement-fixing properties of each HLA antibody present in circulation. When a donor is considered, we can better predict the risk associated with potentially crossing HLA antibodies, thereby allowing the Clinical Team to approach allosensitized lung patients with an individualized medicine approach. To facilitate safe access of sensitized lung transplant candidates to potential donors, a synergy between the histocompatibility laboratory and the Clinical Team is essential. Ultimately, donor acceptance is a decision based on several parameters, leading to a risk-stratification unique for each patient.
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Affiliation(s)
| | - Marilyn Marrari
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Qingyong Xu
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Pablo G Sanchez
- Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Adriana Zeevi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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Benazzo A, Auner S, Boehm PM, Morscher A, Schwarz S, Vidmar B, Dzubur F, Schweiger T, Hoda AM, Moser B, Matilla JR, Muraközy G, Lang G, Taghavi S, Klepetko W, Hoetzenecker K, Jaksch P. Outcomes with alemtuzumab induction therapy in lung transplantation: a comprehensive large-scale single-center analysis. Transpl Int 2021; 34:2633-2643. [PMID: 34738249 DOI: 10.1111/tri.14153] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 10/15/2021] [Accepted: 10/20/2021] [Indexed: 12/25/2022]
Abstract
Alemtuzumab is a monoclonal antibody targeting CD52, increasingly used as induction therapy after transplantation. The aim of this study was to analyze the outcomes of alemtuzumab induction therapy followed by a low-dose maintenance immunosuppression in a large single-center cohort of lung transplant recipients. All patients, who received alemtuzumab induction followed by a low-dose maintenance immunosuppression were included in the analysis. Short- and long-term outcomes were analyzed. 721 lung transplant recipients, transplanted between January 2008 and June 2019, were included in this retrospective study. Freedom from higher-grade ACR at 1, 5, and 10 years was 98%, 96%, and 96%, respectively. Thirty-nine patients (5%) developed clinical AMR. Twenty-one percent of patients developed high-grade CKD. A total of 1488 infections were recorded. Sixteen percent were diagnosed within the first 3 months. Sixty-two patients (9%) developed a malignancy during follow-up. Freedom from CLAD at 1, 5, and 10 years was 94%, 72%, and 53%, respectively. Overall survival rates at 1, 5, and 10 years were 85%, 71%, and 61%, respectively. Alemtuzumab induction combined with a low-dose tacrolimus protocol is safe and associated with low rates of acute and chronic rejection, as well as an excellent long-term survival.
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Affiliation(s)
- Alberto Benazzo
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Sophia Auner
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Panja M Boehm
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Annika Morscher
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Stefan Schwarz
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Bogdan Vidmar
- Division of Thoracic Surgery, Medical Center Ljubljana, Ljubljana, Slovenia
| | - Fedja Dzubur
- Clinical Center for Pulmonary Diseases, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Thomas Schweiger
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Ali M Hoda
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Bernhard Moser
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Jose R Matilla
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Gabriella Muraközy
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Georg Lang
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Shahrokh Taghavi
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Walter Klepetko
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Konrad Hoetzenecker
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Peter Jaksch
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
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McQuiston A, Emtiazjoo A, Angel P, Machuca T, Christie J, Atkinson C. Set Up for Failure: Pre-Existing Autoantibodies in Lung Transplant. Front Immunol 2021; 12:711102. [PMID: 34456920 PMCID: PMC8385565 DOI: 10.3389/fimmu.2021.711102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/12/2021] [Indexed: 11/17/2022] Open
Abstract
Lung transplant patients have the lowest long-term survival rates compared to other solid organ transplants. The complications after lung transplantation such as primary graft dysfunction (PGD) and ultimately chronic lung allograft dysfunction (CLAD) are the main reasons for this limited survival. In recent years, lung-specific autoantibodies that recognize non-HLA antigens have been hypothesized to contribute to graft injury and have been correlated with PGD, CLAD, and survival. Mounting evidence suggests that autoantibodies can develop during pulmonary disease progression before lung transplant, termed pre-existing autoantibodies, and may participate in allograft injury after transplantation. In this review, we summarize what is known about pulmonary disease autoantibodies, the relationship between pre-existing autoantibodies and lung transplantation, and potential mechanisms through which pre-existing autoantibodies contribute to graft injury and rejection.
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Affiliation(s)
- Alexander McQuiston
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States.,Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United States
| | - Amir Emtiazjoo
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United States
| | - Peggi Angel
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States
| | - Tiago Machuca
- Department of Surgery, University of Florida, Gainesville, FL, United States
| | - Jason Christie
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Carl Atkinson
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United States
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Young KA, Ali HA, Beermann KJ, Reynolds JM, Snyder LD. Lung Transplantation and the Era of the Sensitized Patient. Front Immunol 2021; 12:689420. [PMID: 34122454 PMCID: PMC8187850 DOI: 10.3389/fimmu.2021.689420] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 05/10/2021] [Indexed: 11/13/2022] Open
Abstract
Long term outcomes in lung transplant are limited by the development of chronic lung allograft dysfunction (CLAD). Within the past several decades, antibody-mediated rejection (AMR) has been recognized as a risk factor for CLAD. The presence of HLA antibodies in lung transplant candidates, "sensitized patients" may predispose patients to AMR, CLAD, and higher mortality after transplant. This review will discuss issues surrounding the sensitized patient, including mechanisms of sensitization, implications within lung transplant, and management strategies.
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Affiliation(s)
- Katherine A Young
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Hakim A Ali
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Kristi J Beermann
- Department of Pharmacy, Duke University Hospital, Durham, NC, United States
| | - John M Reynolds
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Laurie D Snyder
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
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Halverson LP, Hachem RR. Antibody-Mediated Rejection and Lung Transplantation. Semin Respir Crit Care Med 2021; 42:428-435. [PMID: 34030204 DOI: 10.1055/s-0041-1728796] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Antibody-mediated rejection (AMR) is now a widely recognized form of lung allograft rejection, with mounting evidence for AMR as an important risk factor for the development of chronic lung allograft dysfunction and markedly decreased long-term survival. Despite the recent development of the consensus diagnostic criteria, it remains a challenging diagnosis of exclusion. Furthermore, even after diagnosis, treatment directed at pulmonary AMR has been nearly exclusively derived from practices with other solid-organ transplants and other areas of medicine, such that there is a significant lack of data regarding the efficacy for these in pulmonary AMR. Lastly, outcomes after AMR remain quite poor despite aggressive treatment. In this review, we revisit the history of AMR in lung transplantation, describe our current understanding of its pathophysiology, discuss the use and limitations of the consensus diagnostic criteria, review current treatment strategies, and summarize long-term outcomes. We conclude with a synopsis of our most pressing gaps in knowledge, introduce recommendations for future directions, and highlight promising areas of active research.
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Affiliation(s)
- Laura P Halverson
- Division of Pulmonary and Critical Care, Washington University School of Medicine, Saint Louis, Missouri
| | - Ramsey R Hachem
- Division of Pulmonary and Critical Care, Washington University School of Medicine, Saint Louis, Missouri
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Amubieya O, Ramsey A, DerHovanessian A, Fishbein GA, Lynch JP, Belperio JA, Weigt SS. Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies. Semin Respir Crit Care Med 2021; 42:392-410. [PMID: 34030202 DOI: 10.1055/s-0041-1729175] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The primary factor that limits long-term survival after lung transplantation is chronic lung allograft dysfunction (CLAD). CLAD also impairs quality of life and increases the costs of medical care. Our understanding of CLAD continues to evolve. Consensus definitions of CLAD and the major CLAD phenotypes were recently updated and clarified, but it remains to be seen whether the current definitions will lead to advances in management or impact care. Understanding the potential differences in pathogenesis for each CLAD phenotype may lead to novel therapeutic strategies, including precision medicine. Recognition of CLAD risk factors may lead to earlier interventions to mitigate risk, or to avoid risk factors all together, to prevent the development of CLAD. Unfortunately, currently available therapies for CLAD are usually not effective. However, novel therapeutics aimed at both prevention and treatment are currently under investigation. We provide an overview of the updates to CLAD-related terminology, clinical phenotypes and their diagnosis, natural history, pathogenesis, and potential strategies to treat and prevent CLAD.
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Affiliation(s)
- Olawale Amubieya
- Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical Immunology, Department of Internal Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Allison Ramsey
- Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical Immunology, Department of Internal Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Ariss DerHovanessian
- Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical Immunology, Department of Internal Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Gregory A Fishbein
- Department of Pathology, The David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Joseph P Lynch
- Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical Immunology, Department of Internal Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, California
| | - John A Belperio
- Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical Immunology, Department of Internal Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, California
| | - S Samuel Weigt
- Division of Pulmonary, Critical Care Medicine, Allergy, and Clinical Immunology, Department of Internal Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, California
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Abstract
PURPOSE OF REVIEW The development of donor-specific antibodies (DSA) after lung transplantation has been recognized as an important risk factor for poor outcomes over the past 20 years. Recently, this has been a focus of intense research, and the purpose of this review is to summarize our current understanding of humoral responses and important recent findings as well as to identify areas of future research. RECENT FINDINGS Recent studies have identified donor-derived cell-free DNA (ddcfDNA) as an important biomarker associated with antibody-mediated rejection (AMR). Importantly, ddcfDNA levels are noted to be elevated approximately 3 months before the onset of clinical allograft dysfunction, making ddcfDNA a particularly appealing biomarker to predict the onset of AMR. Additional notable recent findings include the identification of an independent association between the isolation of Pseudomonas aeruginosa from respiratory specimens and the development of DSA. This finding provides potential insights into crosstalk between innate and alloimmune responses and identifies a potential therapeutic target to prevent the development of DSA. SUMMARY Progress in the field of humoral responses after lung transplantation has been slow, but ongoing and future research in this area are critically necessary to improve patient outcomes in the future.
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Parquin F, Zuber B, Vallée A, Taupin JL, Cuquemelle E, Malard S, Neuville M, Devaquet J, Le Guen M, Fessler J, Beaumont L, Picard C, Hamid A, Colin de Verdière S, Grenet D, De Miranda S, Glorion M, Sage E, Pricopi C, De Wolf J, Brun AL, Longchampt E, Cerf C, Roux A, Brugière O. A virtual crossmatch-based strategy for perioperative desensitisation in lung transplant recipients with preformed donor-specific antibodies: 3-year outcome. Eur Respir J 2021; 58:13993003.04090-2020. [PMID: 34016620 DOI: 10.1183/13993003.04090-2020] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 04/08/2021] [Indexed: 11/05/2022]
Abstract
BACKGROUND Preformed donor-specific antibodies (DSAs) are associated with worse outcome after lung transplantation (LTx) and migvaht limit access to LTx. A virtual crossmatch (CXM)-based strategy for perioperative desensitisation protocol has been used for immunised LTx candidates since 2012 at Foch hospital. We compared the outcome of desensitised LTx candidates with high DSA mean fluorescence intensity (MFI) and those with low or no preformed DSAs, not desensitised. METHODS For all consecutive LTx recipients (January-2012/March-2018), freedom from CLAD and graft survival were assessed by Kaplan-Meier analysis and Cox multivariate analysis. RESULTS We compared outcomes for desensitised patients with high preformed DSAs (n=39) and those with no (n=216) or low pre-formed DSAs (n=66). The desensitisation protocol decreased the level of immunodominant DSA (class I/II) at 1, 3, and 6 month post-LTx (p<0.001, p<0.01, p<0.001, respectively). Freedom from CLAD and graft survival at 3 years was similar in the desensitised group as a whole and other groups. Nevertheless, incidence of CLAD was higher with persistent high- than cleared high-level (p=0.044) or no DSAs (p=0.014). Conversely, graft survival was better with cleared high DSAs than persistent high-, low-level, and no pre-formed DSAs (p=0.019, p=0.025, and p=0.044, respectively). On multivariate analysis, graft survival was associated with cleared high DSAs (HR: 0.12 [95%CI: 0.02-0.85] versus no DSAs, p=0.035) and CLAD with persistent DSAs (HR: 3.04 [1.02-9.17] versus no preformed DSAs, p=0.048). CONCLUSION The desensitisation protocol in LTx recipients with high preformed DSAs was associated with satisfactory outcome, with cleared high pre-formed DSAs after desensitisation identified as an independent predictor of graft survival.
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Affiliation(s)
- Francois Parquin
- Service de Réanimation médicale, Foch Hospital, Suresnes, France
| | - Benjamin Zuber
- Service de Réanimation médicale, Foch Hospital, Suresnes, France
| | - Alexandre Vallée
- Department of Clinical Research and Innovation, Foch Hospital, Suresnes, France
| | - Jean-Luc Taupin
- Laboratoire d'Immunologie et Histocompatibilité, Hôpital Saint-Louis, Paris, France
| | - Elise Cuquemelle
- Service de Réanimation médicale, Foch Hospital, Suresnes, France
| | - Stéphanie Malard
- Laboratoire d'Immunologie et Histocompatibilité, Hôpital Saint-Louis, Paris, France
| | | | - Jérôme Devaquet
- Service de Réanimation médicale, Foch Hospital, Suresnes, France
| | - Morgan Le Guen
- Service d'Anesthésie-Réanimation, Foch Hospital, Suresnes, France
| | - Julien Fessler
- Service d'Anesthésie-Réanimation, Foch Hospital, Suresnes, France
| | - Laurence Beaumont
- Service de Transplantation Pulmonaire et centre de compétence de la Mucoviscidose, Foch Hospital, Suresnes, France
| | - Clément Picard
- Service de Transplantation Pulmonaire et centre de compétence de la Mucoviscidose, Foch Hospital, Suresnes, France
| | - Abdulmonem Hamid
- Service de Transplantation Pulmonaire et centre de compétence de la Mucoviscidose, Foch Hospital, Suresnes, France
| | - Sylvie Colin de Verdière
- Service de Transplantation Pulmonaire et centre de compétence de la Mucoviscidose, Foch Hospital, Suresnes, France
| | - Dominique Grenet
- Service de Transplantation Pulmonaire et centre de compétence de la Mucoviscidose, Foch Hospital, Suresnes, France
| | - Sandra De Miranda
- Service de Transplantation Pulmonaire et centre de compétence de la Mucoviscidose, Foch Hospital, Suresnes, France
| | - Matthieu Glorion
- Service de Chirurgie Thoracique, Foch Hospital, Suresnes, France
| | - Edouard Sage
- Service de Chirurgie Thoracique, Foch Hospital, Suresnes, France
| | - Ciprian Pricopi
- Service de Chirurgie Thoracique, Foch Hospital, Suresnes, France
| | - Julien De Wolf
- Service de Chirurgie Thoracique, Foch Hospital, Suresnes, France
| | | | | | - Charles Cerf
- Service de Réanimation médicale, Foch Hospital, Suresnes, France
| | - Antoine Roux
- Service de Transplantation Pulmonaire et centre de compétence de la Mucoviscidose, Foch Hospital, Suresnes, France
| | - Olivier Brugière
- Service de Transplantation Pulmonaire et centre de compétence de la Mucoviscidose, Foch Hospital, Suresnes, France
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Klouda T, Vargas SO, Midyat L. Restrictive allograft syndrome after lung transplantation. Pediatr Transplant 2021; 25:e14000. [PMID: 33728767 DOI: 10.1111/petr.14000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/07/2021] [Accepted: 02/22/2021] [Indexed: 11/29/2022]
Abstract
Despite recent advances over the past decade in lung transplantation including improved surgical technique and immunotherapy, the diagnosis and treatment of chronic lung allograft dysfunction remains a significant barrier to recipient survival. Aside from bronchiolitis obliterans syndrome, a restrictive phenotype called restrictive allograft syndrome has recently been recognized and affects up to 35% of all patients with CLAD. The main characteristics of RAS include a persistent and unexplained decline in lung function compared to baseline and persistent parenchymal infiltrates on imaging. The median survival after diagnosis of RAS is 6 to 18 months, significantly shorter than other forms of CLAD. Treatment options are limited, as therapies used for BOS are typically ineffective at halting disease progression. Specific medications such as fibrinolytics are lacking large, multicenter prospective studies. In this manuscript, we discuss the definition, mechanism, and characteristics of RAS while highlighting the similarities and differences between other forms of CLAD. We also review the diagnoses along with current and potential treatment options that are available for patients. Finally, we discuss the existing knowledge gaps and areas for future research to improve patient outcomes and understanding of RAS.
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Affiliation(s)
- Timothy Klouda
- Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Sara O Vargas
- Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Levent Midyat
- Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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Neuhaus K, Hohlfelder B, Bollinger J, Haug M, Torbic H. Antibody-Mediated Rejection Management Following Lung Transplantation. Ann Pharmacother 2021; 56:60-64. [PMID: 33899550 DOI: 10.1177/10600280211012410] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Although antibody-mediated rejection (AMR) is described in other solid organ transplant populations, the literature describing the management following lung transplantation is limited. OBJECTIVE The purpose of this study is to evaluate the management strategies of AMR in lung transplant recipients. METHODS This single-center, retrospective study described the management of AMR in adult lung transplant recipients who received treatment with rabbit antithymocyte globulin, bortezomib, rituximab, intravenous immune globulin (IVIG), and/or plasmapheresis between September 2015 and June 2019. RESULTS A total of 270 medication orders for 55 patient admissions were included in the primary outcome analysis. The most commonly used regimen consisted of IVIG, plasmapheresis, and rituximab (49.1%; n = 27), followed by IVIG and plasmapheresis alone (27.3%, n = 15). A total of 51 patients (93%) received plasmapheresis as part of their AMR treatment, with a median of 4 [3, 5] sessions per encounter; 86% of patients with positive donor-specific antibodies (DSAs) had a reduction in DSAs following AMR treatment. Overall, 23.5% of patients had noted allograft failure or need for retransplantation. A total of 10 patients died during the AMR treatment hospital admission, and an additional 11 patients died within 1 year of the initial encounter. CONCLUSION AND RELEVANCE This represents the largest report describing management strategies of AMR in lung transplant recipients. Although practice varied, the most commonly used regimen consisted of plasmapheresis, IVIG, and rituximab.
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Desensitization and management of allograft rejection. Curr Opin Organ Transplant 2021; 26:314-320. [PMID: 33938468 DOI: 10.1097/mot.0000000000000878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Chronic lung allograft dysfunction (CLAD) limits the success of lung transplantation. Among the risk factors associated with CLAD, we recognize pretransplant circulating antibodies against the human leukocyte antigens (HLA), acute cellular rejection (ACR) and antibody-mediated rejection (AMR). This review will summarize current data surrounding management of desensitization, ACR, AMR, and CLAD. RECENT FINDINGS Strategies in managing in highly sensitized patients waiting for lung transplant include avoidance of specific HLA antigens and reduction of circulating anti-HLA antibodies at time of transplant. Several multimodal approaches have been studied in the treatment of AMR with a goal to clear circulating donor-specific antibodies (DSAs) and to halt the production of new antibodies. Different immunosuppressive strategies focus on influence of the host immune system, particularly T-cell responses, in order to prevent ACR and the progression of CLAD. SUMMARY The lack of significant evidence and consensus limits to draw conclusion regarding the impact of specific immunosuppressive regimens in the management of HLA antibodies, ACR, and CLAD. Development of novel therapeutic agents and use of multicenter randomized clinical trials will allow to better define patient-specific treatments and improve the length and quality of life of lung transplant recipients.
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Comparison of de novo donor-specific antibodies between living and cadaveric lung transplantation. J Heart Lung Transplant 2021; 40:607-613. [PMID: 34078558 DOI: 10.1016/j.healun.2021.03.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 02/24/2021] [Accepted: 03/20/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Despite growing interest in donor-specific antibodies (DSAs) and antibody-mediated rejection (AMR) in lung transplantation (LTx), no study evaluating the outcomes in recipients with de novo DSAs (dnDSAs) in living-donor lobar LTx (LDLLT) exists. We compared various characteristics of DSAs in LDLLT with those in cadaveric LTx (CLT) based on prospectively collected data. METHODS Between October 2009 and September 2019, 211 recipients underwent LTx (128 CLTs and 83 LDLLTs). We reviewed 108 CLTs and 74 LDLLTs to determine the characteristics and clinical impact of dnDSAs. Eighteen data-deficient cases, 7 cases with preformed DSAs, and 4 re-transplants were excluded. RESULTS There were significant differences between CLT and LDLLT patients in age, primary disease, ischemic time, and number of human leukocyte antigen mismatches per donor. The dnDSA incidence in LDLLT (6.8%) was significantly lower than that in CLT (19.4%, p = 0.02). The dnDSAs appeared later in LDLLT (mean 1,256 days) than in CLT (mean 196 days, p = 0.003). According to Cox models analyzed using dnDSA as a time-dependent covariate, dnDSA positivity was significantly associated with a poor overall survival (OS; hazard ratio [HR] 3.46, 95% confidence interval [CI] 1.59-7.57, p = 0.002) and poor CLAD-free survival in case of CLT (HR: 2.23, 95% CI: 1.08-4.63, p = 0.003). However, no such significant associations were noted in case of LDLLT. CONCLUSIONS The dnDSA occurrence was significantly lower and later in LDLLT than in CLT. Furthermore, dnDSA-positivity was significantly associated with worse OS and CLAD-free survival after CLT but not after LDLLT.
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Timofeeva OA, Choe J, Alsammak M, Yoon EJ, Geier SS, Mathew L, McCollick A, Carney K, Au J, Diamond A, Galli JA, Shenoy K, Mamary A, Sehgal S, Mulhall P, Toyoda Y, Shigemura N, Cordova F, Criner G, Brown JC. Guiding therapeutic plasma exchange for antibody-mediated rejection treatment in lung transplant recipients - a retrospective study. Transpl Int 2021; 34:700-708. [PMID: 33469943 DOI: 10.1111/tri.13825] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 11/09/2020] [Accepted: 01/15/2021] [Indexed: 11/29/2022]
Abstract
Antibody-Mediated Rejection (AMR) due to donor-specific antibodies (DSA) is associated with poor outcomes after lung transplantation. Currently, there are no guidelines regarding the selection of treatment protocols. We studied how DSA characteristics including titers, C1q, and mean fluorescence intensity (MFI) values in undiluted and diluted sera may predict a response to therapeutic plasma exchange (TPE) and inform patient prognosis after treatment. Among 357 patients consecutively transplanted without detectable pre-existing DSAs between 01/01/16 and 12/31/18, 10 patients were treated with a standardized protocol of five TPE sessions with IVIG. Based on DSA characteristics after treatment, all patients were divided into three groups as responders, partial responders, and nonresponders. Kaplan-Meier Survival analyses showed a statistically significant difference in patient survival between those groups (P = 0.0104). Statistical analyses showed that MFI in pre-TPE 1:16 diluted sera was predictive of a response to standardized protocol (R2 = 0.9182) and patient survival (P = 0.0098). Patients predicted to be nonresponders who underwent treatment with a more aggressive protocol of eight TPE sessions with IVIG and bortezomib showed improvements in treatment response (P = 0.0074) and patient survival (P = 0.0253). Dilutions may guide clinicians as to which patients would be expected to respond to a standards protocol or require more aggressive treatment.
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Affiliation(s)
- Olga A Timofeeva
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Philadelphia, PA, USA.,Department of Pathology and Laboratory Medicine, Georgetown University School of Medicine, MedStar Georgetown University Hospital, Washington, DC, USA
| | - Jason Choe
- Department of Pharmacy Services, Temple University Hospital, Philadelphia, PA, USA
| | - Mohamed Alsammak
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Edward J Yoon
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Steven S Geier
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Leena Mathew
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Amanda McCollick
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Kevin Carney
- Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Jenny Au
- Department of Pharmacy Services, Temple University Hospital, Philadelphia, PA, USA
| | - Adam Diamond
- Department of Pharmacy Services, Temple University Hospital, Philadelphia, PA, USA
| | - Jonathan A Galli
- Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Kartik Shenoy
- Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Albert Mamary
- Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Sameep Sehgal
- Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Patrick Mulhall
- Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Yoshiya Toyoda
- Department of Surgery, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Norihisa Shigemura
- Department of Surgery, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Francis Cordova
- Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Gerald Criner
- Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - James C Brown
- Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Philadelphia, PA, USA
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Byrne D, Nador RG, English JC, Yee J, Levy R, Bergeron C, Swiston JR, Mets OM, Muller NL, Bilawich AM. Chronic Lung Allograft Dysfunction: Review of CT and Pathologic Findings. Radiol Cardiothorac Imaging 2021; 3:e200314. [PMID: 33778654 PMCID: PMC7978021 DOI: 10.1148/ryct.2021200314] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 11/02/2020] [Accepted: 11/06/2020] [Indexed: 04/14/2023]
Abstract
Chronic lung allograft dysfunction (CLAD) is the most common cause of mortality in lung transplant recipients after the 1st year of transplantation. CLAD has traditionally been classified into two distinct obstructive and restrictive forms: bronchiolitis obliterans syndrome and restrictive allograft syndrome. However, CLAD may manifest with a spectrum of imaging and pathologic findings and a combination of obstructive and restrictive physiologic abnormalities. Although the initial CT manifestations of CLAD may be nonspecific, the progression of findings at follow-up should signal the possibility of CLAD and may be present on imaging studies prior to the development of functional abnormalities of the lung allograft. This review encompasses the evolution of CT findings in CLAD, with emphasis on the underlying pathogenesis and pathologic condition, to enhance understanding of imaging findings. The purpose of this article is to familiarize the radiologist with the initial and follow-up CT findings of the obstructive, restrictive, and mixed forms of CLAD, for which early diagnosis and treatment may result in improved survival. Supplemental material is available for this article. © RSNA, 2021.
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Single-Center Experience of Outcomes and Prescribing Patterns of IV Immunoglobulin Use in Critically Ill Patients. Crit Care Explor 2021; 3:e0314. [PMID: 33458682 PMCID: PMC7803672 DOI: 10.1097/cce.0000000000000314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Supplemental Digital Content is available in the text. Previous literature has not compared prescribing practices of IV immunoglobulin in medical ICU survivors and nonsurvivors. The objective of this study was to study IV immunoglobulin use in patients admitted to a medical ICU evaluating differences between hospital survivors and nonsurvivors in regards to level of evidence supporting use, prescribing patterns, and cost.
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Aziz F, Tiwari A, Patel H, Chauhan R. Pretransplant histocompatibility testing algorithm: Laboratory and clinical approach in the Indian context. INDIAN JOURNAL OF TRANSPLANTATION 2021. [DOI: 10.4103/ijot.ijot_82_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Kayawake H, Chen-Yoshikawa TF, Gochi F, Tanaka S, Yurugi K, Hishida R, Yutaka Y, Yamada Y, Ohsumi A, Hamaji M, Nakajima D, Date H. Postoperative outcomes of lung transplant recipients with preformed donor-specific antibodies. Interact Cardiovasc Thorac Surg 2020; 32:616-624. [PMID: 33351064 DOI: 10.1093/icvts/ivaa311] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 10/19/2020] [Accepted: 10/27/2020] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVES Few studies have evaluated the outcomes of lung transplantation (LTx) in recipients with preformed donor-specific antibodies (DSAs). This study investigated the postoperative changes in preformed DSAs based on prospectively collected data of DSAs, and the influences of preformed DSAs on postoperative outcomes among LTx recipients. METHODS Between July 2010 and December 2019, 216 recipients underwent LTx (81 living-donor lobar lung transplants and 135 deceased-donor lung transplants). We reviewed 8 cases with preformed DSAs to determine postoperative changes in DSAs and compared postoperative outcomes between recipients with and without DSAs. RESULTS The preoperative mean fluorescence intensity of preformed DSAs ranged from 1141 to 14 695. Two recipients experienced antibody-mediated rejection within 2 weeks after LTx. DSAs disappeared in 7 recipients; however, 1 recipient experienced the relapse of DSAs and died from chronic lung allograft syndrome (CLAD), whereas 1 recipient had persisting DSAs within the study period and died from CLAD. Neither overall survival (OS) nor CLAD-free survival was significantly different between recipients with and without DSAs (P = 0.26 and P = 0.17, respectively). However, both OS and CLAD-free survival were significantly lower in recipients with DSAs against HLA class II than in those without these antibodies {5-year OS: 25.0% [95% confidence interval (CI): 0.9-66.5%] vs 72.1% (95% CI: 63.8-78.9%), P = 0.030 and 5-year CLAD-free survival: 26.7% (95% CI: 1.0-68.6%) vs 73.7% (95% CI: 66.5-79.5%), P = 0.002}. CONCLUSIONS Prognosis in recipients experiencing the relapse of preformed DSAs and those with persisting DSAs may be poor. The recipients with anti-HLA class II preformed DSAs had a significantly worse prognosis.
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Affiliation(s)
- Hidenao Kayawake
- Department of Thoracic Surgery, Kyoto University Graduate school of Medicine, Kyoto, Japan
| | | | - Fumiaki Gochi
- Department of Thoracic Surgery, Kyoto University Graduate school of Medicine, Kyoto, Japan
| | - Satona Tanaka
- Department of Thoracic Surgery, Kyoto University Graduate school of Medicine, Kyoto, Japan
| | - Kimiko Yurugi
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Rie Hishida
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
| | - Yojiro Yutaka
- Department of Thoracic Surgery, Kyoto University Graduate school of Medicine, Kyoto, Japan
| | - Yoshito Yamada
- Department of Thoracic Surgery, Kyoto University Graduate school of Medicine, Kyoto, Japan
| | - Akihiro Ohsumi
- Department of Thoracic Surgery, Kyoto University Graduate school of Medicine, Kyoto, Japan
| | - Masatsugu Hamaji
- Department of Thoracic Surgery, Kyoto University Graduate school of Medicine, Kyoto, Japan
| | - Daisuke Nakajima
- Department of Thoracic Surgery, Kyoto University Graduate school of Medicine, Kyoto, Japan
| | - Hiroshi Date
- Department of Thoracic Surgery, Kyoto University Graduate school of Medicine, Kyoto, Japan
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A Comprehensive Evaluation of Risk Factors for Pneumocystis Jirovecii Pneumonia in Adult Solid Organ Transplant Recipients: a Systematic Review and Meta-Analysis. Transplantation 2020; 105:2291-2306. [PMID: 33323766 DOI: 10.1097/tp.0000000000003576] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND There is no consensus guidance on when to reinitiate Pneumocystis jirovecii pneumonia (PJP) prophylaxis in solid organ transplant (SOT) recipients at increased risk. The 2019 American Society of Transplantation Infectious Diseases Community of Practice (AST IDCOP) guidelines suggested to continue or reinstitute PJP prophylaxis in those receiving intensified immunosuppression for graft rejection, CMV infection, higher dose of corticosteroids, or prolonged neutropenia. METHODS A literature search was conducted evaluating all literature from existence through April 22, 2020 using MEDLINE and EMBASE. (PROSPERO: CRD42019134204) RESULTS:: A total of 30 studies with 413 276 SOT recipients were included. The following factors were associated with PJP development: acute rejection (pooled odds ratio (pOR) = 2.35 (1.69, 3.26), study heterogeneity index (I)= 23.4%), cytomegalovirus (CMV)-related illnesses (pOR = 3.14 (2.30, 4.29), I=48%), absolute lymphocyte count < 500 cells/mm (pOR = 6.29[3.56, 11.13], I 0%), BK-related diseases (pOR = 2.59[1.22, 5.49], I 0%), HLA mismatch ≥ 3 (pOR = 1.83 [1.06, 3.17], I= 0%), rituximab use (pOR =3.03 (1.82, 5.04); I =0%) and polyclonal antibodies use for rejection (pOR = 3.92 [1.87, 8.19], I= 0%). On the other hand, sex, CMV mismatch, interleukin-2 inhibitors, corticosteroids for rejection, and plasmapheresis were not associated with developing PJP. CONCLUSION PJP prophylaxis should be considered in SOT recipients with lymphopenia, BK-related infections and rituximab exposure in addition to the previously mentioned risk factors in the AST IDCOP guidelines.
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Kaza V, Zhu C, Terada LS, Wang L, Torres F, Bollineni S, Mohanka M, Banga A, Joerns J, Mohanakumar T, Li QZ. Self-reactive antibodies associated with bronchiolitis obliterans syndrome subtype of chronic lung allograft dysfunction. Hum Immunol 2020; 82:25-35. [PMID: 33129576 DOI: 10.1016/j.humimm.2020.10.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 01/02/2023]
Abstract
BACKGROUND Chronic Lung Allograft Dysfunction (CLAD) remains the major limitation in long term survival after lung transplantation. Our objective is to evaluate for the presence of autoantibodies to self-antigens, which is a pathway along with complex interplay with immune as well as non-immune mechanisms that leads to a fibroproliferative process resulting in CLAD. METHODS Serum profiles of IgG autoantibodies were evaluated using customized proteomic microarray with 124 antigens. Output from microarray analyzed as antibody scores is correlated with bronchiolitis obliterans (BOS) subtype of CLAD using Mann-Whitney U test or Fisher exact test. Autoantibodies were evaluated for their predictive value for progressive BOS using a Cox proportional hazard model. BOS free survival and overall survival was analyzed using Kaplan-Meier survival analysis. RESULTS Forty- two patients included in the study are grouped into "stable BOS" and "progressive BOS" for comparisons. Pulmonary fibrosis is the major indication for lung transplantation in our cohort. Progressive BOS group had significantly worse survival (p < 0.005). Sixteen IgG autoantibodies are significantly elevated at baseline in progressive BOS group. Six among them correlated with worse BOS free survival (p < 0.05). In addition, these six IgG autoantibodies remain elevated at three months and one year after lung transplantation. CONCLUSION Pre-existing IgG autoantibodies correlate with progressive BOS and survival in a single center, small cohort of lung transplant recipients. Further validation with larger sample size, external cohort and confirmation with additional tissue, bronchoalveolar lavage samples are necessary to confirm the preliminary findings in our study.
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Affiliation(s)
- Vaidehi Kaza
- Division of Pulmonary Critical Care, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| | - Chengsong Zhu
- Department of Immunology, Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lance S Terada
- Division of Pulmonary Critical Care, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Li Wang
- Department of Immunology, Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Fernando Torres
- Division of Pulmonary Critical Care, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Srinivas Bollineni
- Division of Pulmonary Critical Care, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Manish Mohanka
- Division of Pulmonary Critical Care, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Amit Banga
- Division of Pulmonary Critical Care, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - John Joerns
- Division of Pulmonary Critical Care, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - T Mohanakumar
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA
| | - Quan-Zhen Li
- Department of Immunology, Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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Clinical Outcomes of Lung Transplantation in the Presence of Donor-Specific Antibodies. Ann Am Thorac Soc 2020; 16:1131-1137. [PMID: 31026404 DOI: 10.1513/annalsats.201812-869oc] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Rationale: There is significant variation in approach to pre-lung transplant donor-specific antibodies (DSA), with some centers declining to cross any DSA. We implemented a protocol for transplantation for candidates with pretransplant DSA so long as a prospective complement-dependent cytotoxicity crossmatch was negative, regardless of number, specificity, class, or mean fluorescence intensity.Objectives: To compare post-transplant outcomes including overall survival, chronic lung allograft dysfunction-free survival, antibody-mediated rejection, and acute cellular rejection in lung transplant recipients where pretransplant DSA was and was not present.Methods: This was a single-center retrospective cohort study. For recipients with pretransplant DSA, if the prospective complement-dependent cytotoxicity crossmatch was negative, the donor offer was accepted and plasmapheresis was performed within 24 hours of transplantation and continued until retrospective crossmatch results returned. Immunosuppression and post-transplant management were not otherwise modified.Results: Of the 203 included recipients, 18 (8.9%) had pretransplant DSA. The median DSA mean fluorescence intensity was 4,000 (interquartile range, 2,975-5,625; total range, 2,100-17,000). The median number of DSA present per patient was one (interquartile range, 1-2). The presence of pretransplant DSA was not associated with increased mortality (hazard ratio, 1.2; 95% confidence interval [CI], 0.4-3.4) or decreased chronic lung allograft dysfunction-free survival (hazard ratio, 1.1; 95% CI, 0.6-2.1). Recipients with pretransplant DSA were more likely to require prolonged mechanical ventilation (adjusted odds ratio, 7.0; 95% CI, 2.3-21.6) and to have antibody-mediated rejection requiring treatment (adjusted odds ratio, 7.5; 95% CI, 1.0-55.8).Conclusions: A protocol of accepting donor offers for lung transplant candidates with preformed, complement-dependent cytotoxicity crossmatch-negative DSA is associated with increased need for prolonged mechanical ventilation and antibody-mediated rejection without affecting short-term overall or chronic lung allograft dysfunction-free survival.
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