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Update on Chronic Lung Allograft Dysfunction

  • Thoracic Transplantation (J Kobashigawa, Section Editor)
  • Published:
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Abstract

Chronic lung allograft dysfunction (CLAD) encompasses a range of pathologies that cause a transplanted lung to not achieve or maintain normal function. CLAD manifests as airflow restriction and/or obstruction and is predominantly a result of chronic rejection. Three distinct phenotypes of chronic rejection are now recognized: bronchiolitis obliterans, neutrophilic reversible allograft dysfunction, and restrictive allograft syndrome. Recent investigations have revealed that each phenotype has a unique pathology and histopathological findings, suggesting that treatment regimens should be tailored to the underlying etiology. CLAD is poorly responsive to treatment once diagnosed, and therefore, the prevention of the factors that predispose a patient to develop CLAD is critically important. Small and large animal models have contributed significantly to our understanding of CLAD, and more studies are needed to develop treatment regimens that are effective in humans.

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References

Papers of Particular Interest, Published recently, Have Been Highlighted as: • of Importance •• of Major Importance

  1. Grossman RF, Frost A, Zamel N, et al. Results of single-lung transplantation for bilateral pulmonary fibrosis. The Toronto lung transplant group. N Engl J Med. 1990;322(11):727–33.

    Article  CAS  PubMed  Google Scholar 

  2. Yusen RD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report--2014; focus theme: retransplantation. J Heart Lung Transplant. 2014;33(10):1009–24.

    Article  PubMed  Google Scholar 

  3. Moyron-quiroz JE, Rangel-moreno J, Kusser K, et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med. 2004;10(9):927–34.

    Article  CAS  PubMed  Google Scholar 

  4. Meyer KC, Raghu G, Verleden GM, et al. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome. Eur Respir J. 2014;44:1479–503.

    Article  PubMed  Google Scholar 

  5. Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. A new classification system for chronic lung allograft dysfunction. J Heart Lung Transplant. 2014;33(2):127–33 .This manuscript was the first to provide a specific, comprehensive clinical definition of CLAD

    Article  PubMed  Google Scholar 

  6. Kroshus TJ, Kshettry VR, Savik K, John R, Hertz MI, Bolman RM. Risk factors for the development of bronchiolitis obliterans syndrome after lung transplantation. J Thorac Cardiovasc Surg. 1997;114(2):195–202.

    Article  CAS  PubMed  Google Scholar 

  7. Daud SA, Yusen RD, Meyers BF, et al. Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2007;175(5):507–13.

    Article  PubMed  Google Scholar 

  8. Verleden SE, Vos R, Mertens V, et al. Heterogeneity of chronic lung allograft dysfunction: insights from protein expression in broncho alveolar lavage. J Heart Lung Transplant. 2011;30(6):667–73 .The realization that patients responsive to AZT have a different pathology than AZT non-responders paved the way for the modern understanding of NRAD

    Article  PubMed  Google Scholar 

  9. Leung AN, Fisher K, Valentine V, et al. Bronchiolitis obliterans after lung transplantation: detection using expiratory HRCT. Chest. 1998;113(2):365–70.

    Article  CAS  PubMed  Google Scholar 

  10. Worthy SA, Park CS, Kim JS, Müller NL. Bronchiolitis obliterans after lung transplantation: high-resolution CT findings in 15 patients. AJR Am J Roentgenol. 1997;169(3):673–7.

    Article  CAS  PubMed  Google Scholar 

  11. Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant. 2002;21(3):297–310.

    Article  PubMed  Google Scholar 

  12. Kramer MR, Stoehr C, Whang JL, et al. The diagnosis of obliterative bronchiolitis after heart-lung and lung transplantation: low yield of transbronchial lung biopsy. J Heart Lung Transplant. 1993;12(4):675–81.

    CAS  PubMed  Google Scholar 

  13. Stewart S, Fishbein MC, Snell GI, et al. Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant. 2007;26(12):1229–42.

    Article  PubMed  Google Scholar 

  14. Vanaudenaerde BM, Meyts I, Vos R, et al. A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy. Eur Respir J. 2008;32(4):832–43.

    Article  CAS  PubMed  Google Scholar 

  15. Palmer SM, Davis RD, Hadjiliadis D, et al. Development of an antibody specific to major histocompatibility antigens detectable by flow cytometry after lung transplant is associated with bronchiolitis obliterans syndrome. Transplantation. 2002;74(6):799–804.

    Article  CAS  PubMed  Google Scholar 

  16. Jaramillo A, Smith CR, Maruyama T, Zhang L, Patterson GA, Mohanakumar T. Anti-HLA class I antibody binding to airway epithelial cells induces production of fibrogenic growth factors and apoptotic cell death: a possible mechanism for bronchiolitis obliterans syndrome. Hum Immunol. 2003;64(5):521–9.

    Article  CAS  PubMed  Google Scholar 

  17. Denicola MM, Weigt SS, Belperio JA, Reed EF, Ross DJ, Wallace WD. Pathologic findings in lung allografts with anti-HLA antibodies. J Heart Lung Transplant. 2013;32(3):326–32.

    Article  PubMed  Google Scholar 

  18. Lobo LJ, Aris RM, Schmitz J, Neuringer IP. Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cystic fibrosis after lung transplantation. J Heart Lung Transplant. 2013;32(1):70–7.

    Article  PubMed  Google Scholar 

  19. Angaswamy N, Saini D, Ramachandran S, et al. Development of antibodies to human leukocyte antigen precedes development of antibodies to major histocompatibility class I-related chain a and are significantly associated with development of chronic rejection after human lung transplantation. Hum Immunol. 2010;71(6):560–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bharat A, Narayanan K, Street T, et al. Early posttransplant inflammation promotes the development of alloimmunity and chronic human lung allograft rejection. Transplantation. 2007;83(2):150–8.

    Article  CAS  PubMed  Google Scholar 

  21. Bharat A, Saini D, Steward N, et al. Antibodies to self-antigens predispose to primary lung allograft dysfunction and chronic rejection. Ann Thorac Surg. 2010;90(4):1094–101.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ius F, Sommer W, Kieneke D, et al. IgM-enriched human intravenous immunoglobulin-based treatment of patients with early donor specific anti-HLA antibodies after lung transplantation. Transplantation. 2015.

  23. Hachem RR, Yusen RD, Meyers BF, et al. Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation. J Heart Lung Transplant. 2010;29(9):973–80.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gerhardt SG, Mcdyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med. 2003;168(1):121–5.

    Article  PubMed  Google Scholar 

  25. Vos R, Vanaudenaerde BM, Verleden SE, et al. A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation. Eur Respir J. 2011;37(1):164–72.

    Article  CAS  PubMed  Google Scholar 

  26. Gottlieb J, Szangolies J, Koehnlein T, Golpon H, Simon A, Welte T. Long-term azithromycin for bronchiolitis obliterans syndrome after lung transplantation. Transplantation. 2008;85(1):36–41.

    Article  CAS  PubMed  Google Scholar 

  27. Corris PA, Ryan VA, Small T, et al. A randomised controlled trial of azithromycin therapy in bronchiolitis obliterans syndrome (BOS) post lung transplantation. Thorax. 2015;70(5):442–50.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Verleden GM, Vanaudenaerde BM, Dupont LJ, Van Raemdonck DE. Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2006;174(5):566–70.

    Article  CAS  PubMed  Google Scholar 

  29. D’ovidio F, Mura M, Tsang M, et al. Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation. J Thorac Cardiovasc Surg. 2005;129(5):1144–52.

    Article  PubMed  Google Scholar 

  30. Vos R, Vanaudenaerde BM, Verleden SE, et al. Anti-inflammatory and immunomodulatory properties of azithromycin involved in treatment and prevention of chronic lung allograft rejection. Transplantation. 2012;94(2):101–9.

    Article  CAS  PubMed  Google Scholar 

  31. Verleden SE, Vandermeulen E, Ruttens D, et al. Neutrophilic reversible allograft dysfunction (NRAD) and restrictive allograft syndrome (RAS). Semin Respir Crit Care Med. 2013;34(3):352–60.

    Article  PubMed  Google Scholar 

  32. Verleden GM, Vos R, Verleden SE, et al. Survival determinants in lung transplant patients with chronic allograft dysfunction. Transplantation. 2011;92(6):703–8.

    Article  PubMed  Google Scholar 

  33. Sato M, Waddell TK, Wagnetz U, et al. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant. 2011;30(7):735–42 .The discovery of RAS has opened a new door for research in the field of lung transplant immunology. This paper was the first to show that RAS is a form of CLAD distinctly different from BO and NRAD, which has prompted investigation into the underlying etiology of this disease

    Article  PubMed  Google Scholar 

  34. Ofek E, Sato M, Saito T, et al. Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis. Mod Pathol. 2013;26(3):350–6.

    Article  CAS  PubMed  Google Scholar 

  35. Vos R, Verleden SE, Ruttens D, et al. Pirfenidone: a potential new therapy for restrictive allograft syndrome? Am J Transplant. 2013;13(11):3035–40 .This paper reports the case of a patient with RAS who had marked clinical and radiographic improvement after treatment with pirfenidone, which has previously been successful in treating IPF

    Article  CAS  PubMed  Google Scholar 

  36. Sivakumar P, Ntolios P, Jenkins G, Laurent G. Into the matrix: targeting fibroblasts in pulmonary fibrosis. Curr Opin Pulm Med. 2012;18(5):462–9.

    Article  CAS  PubMed  Google Scholar 

  37. Liu H, Drew P, Gaugler AC, Cheng Y, Visner GA. Pirfenidone inhibits lung allograft fibrosis through L-arginine-arginase pathway. Am J Transplant. 2005;5(6):1256–63.

    Article  CAS  PubMed  Google Scholar 

  38. Parada MT, Alba A, Sepúlveda C. Everolimus in lung transplantation in Chile. Transplant Proc. 2010;42(1):328–30.

    Article  CAS  PubMed  Google Scholar 

  39. Verleden GM, Verleden SE, Vos R, et al. Montelukast for bronchiolitis obliterans syndrome after lung transplantation: a pilot study. Transpl Int. 2011;24(7):651–6.

    Article  PubMed  Google Scholar 

  40. Martin SI, Fishman JA. Pneumocystis pneumonia in solid organ transplantation. Am J Transplant. 2013;13(Suppl 4):272–9.

    Article  CAS  PubMed  Google Scholar 

  41. Ruttens D, Verleden SE, Vandermeulen E, et al. Prophylactic azithromycin therapy after lung transplantation: post hoc analysis of a randomized controlled trial. Am J Transplant. 2016;16(1):254–61 .This study showed that prophylactic AZT reduces the prevalence of CLAD and improves CLAD-free survival, suggesting that there may be a role for prophylactic AZT in all lung transplant patients

    Article  CAS  PubMed  Google Scholar 

  42. Andreu G, Achkar A, Couetil JP, et al. Extracorporeal photochemotherapy treatment for acute lung rejection episode. J Heart Lung Transplant. 1995;14(4):793–6.

    CAS  PubMed  Google Scholar 

  43. Morrell MR, Despotis GJ, Lublin DM, Patterson GA, Trulock EP, Hachem RR. The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant. 2010;29(4):424–31.

    Article  PubMed  Google Scholar 

  44. Baskaran G, Tiriveedhi V, Ramachandran S, et al. Efficacy of extracorporeal photopheresis in clearance of antibodies to donor-specific and lung-specific antigens in lung transplant recipients. J Heart Lung Transplant. 2014;33(9):950–6.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Tallaj JA, Pamboukian SV, George JF, et al. Total lymphoid irradiation in heart transplantation: long-term efficacy and survival--an 18-year experience. Transplantation. 2011;92(10):1159–64.

    Article  PubMed  Google Scholar 

  46. Fisher AJ, Rutherford RM, Bozzino J, Parry G, Dark JH, Corris PA. The safety and efficacy of total lymphoid irradiation in progressive bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant. 2005;5(3):537–43.

    Article  PubMed  Google Scholar 

  47. Thomas M, Belli EV, Rawal B, Agnew RC, Landolfo KP. Survival after lung retransplantation in the United States in the current era (2004 to 2013): better or worse? Ann Thorac Surg. 2015;100(2):452–7.

    Article  PubMed  Google Scholar 

  48. Verleden SE, Todd JL, Sato M, et al. Impact of CLAD phenotype on survival after lung retransplantation: a multicenter study. Am J Transplant. 2015;15(8):2223–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hertz MI, Jessurun J, King MB, Savik SK, Murray JJ. Reproduction of the obliterative bronchiolitis lesion after heterotopic transplantation of mouse airways. Am J Pathol. 1993;142(6):1945–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Schrepfer S, Deuse T, Hoyt G, et al. Experimental orthotopic tracheal transplantation: the Stanford technique. Microsurgery. 2007;27(3):187–9.

    Article  PubMed  Google Scholar 

  51. Kuo E, Bharat A, Goers T, et al. Respiratory viral infection in obliterative airway disease after orthotopic tracheal transplantation. Ann Thorac Surg. 2006;82(3):1043–50.

    Article  PubMed  Google Scholar 

  52. Jiang X, Khan MA, Tian W, et al. Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection. J Clin Invest. 2011;121(6):2336–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Dutly AE, Andrade CF, Verkaik R, et al. A novel model for post-transplant obliterative airway disease reveals angiogenesis from the pulmonary circulation. Am J Transplant. 2005;5(2):248–54.

    Article  PubMed  Google Scholar 

  54. Allan JS, Wain JC, Schwarze ML, et al. Modeling chronic lung allograft rejection in miniature swine. Transplantation. 2002;73(3):447–53.

    Article  PubMed  Google Scholar 

  55. Shoji T, Wain JC, Houser SL, et al. Indirect recognition of MHC class I allopeptides accelerates lung allograft rejection in miniature swine. Am J Transplant. 2005;5(7):1626–34.

    Article  CAS  PubMed  Google Scholar 

  56. Atanasova S, Hirschburger M, Jonigk D, et al. A relevant experimental model for human bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2013;32(11):1131–9.

    Article  PubMed  Google Scholar 

  57. Fan L, Benson HL, Vittal R, et al. Neutralizing IL-17 prevents obliterative bronchiolitis in murine orthotopic lung transplantation. Am J Transplant. 2011;11(5):911–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Suzuki H, Lasbury ME, Fan L, et al. Role of complement activation in obliterative bronchiolitis post-lung transplantation. J Immunol. 2013;191(8):4431–9 .Elucidating the role of IL-17 and the complement cascade in the development of BO may lead to new targeted therapies in humans

    Article  CAS  PubMed  Google Scholar 

  59. Oishi H, Martinu T, Sato M, et al. Halofuginone treatment reduces interleukin-17 A and ameliorates features of chronic lung allograft dysfunction in a mouse orthotopic lung transplant model. J Heart Lung Transplant. 2016;35(4):518–27.

    Article  PubMed  Google Scholar 

  60. De Vleeschauwer S, Jungraithmayr W, Wauters S, et al. Chronic rejection pathology after orthotopic lung transplantation in mice: the development of a murine BOS model and its drawbacks. PLoS One. 2012;7(1):e29802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gelman AE, Li W, Richardson SB, et al. Cutting edge: acute lung allograft rejection is independent of secondary lymphoid organs. J Immunol. 2009;182(7):3969–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Li W, Bribriesco AC, Nava RG, et al. Lung transplant acceptance is facilitated by early events in the graft and is associated with lymphoid neogenesis. Mucosal Immunol. 2012;5(5):544–54.

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Washington University in St. Louis, Saint Louis, MO, USA

    Jason M. Gauthier & Daniel Kreisel

  2. Department of Medicine, Washington University in St. Louis, Saint Louis, MO, USA

    Ramsey R. Hachem

  3. Department of Pathology & Immunology, Washington University in St. Louis, Saint Louis, MO, USA

    Daniel Kreisel

  4. Washington University School of Medicine, Campus Box 8234, 660 South Euclid Avenue, St. Louis, MO, 63110, USA

    Daniel Kreisel

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  1. Jason M. Gauthier
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  2. Ramsey R. Hachem
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Correspondence to Daniel Kreisel.

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Daniel Kreisel reports a patent (“Induction in tolerance of lung allograft transplantation”) issued to Washington University.

Jason Gauthier and Ramsey Hachem declare no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Thoracic Transplantation

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Gauthier, J.M., Hachem, R.R. & Kreisel, D. Update on Chronic Lung Allograft Dysfunction. Curr Transpl Rep 3, 185–191 (2016). https://doi.org/10.1007/s40472-016-0112-y

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