Current Transplantation Reports

, Volume 3, Issue 3, pp 185–191 | Cite as

Update on Chronic Lung Allograft Dysfunction

  • Jason M. Gauthier
  • Ramsey R. Hachem
  • Daniel KreiselEmail author
Thoracic Transplantation (J Kobashigawa, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Thoracic Transplantation


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.


Chronic lung allograft dysfunction Bronchiolitis obliterans Bronchiolitis obliterans syndrome Azithromycin responsive allograft dysfunction Neutrophilic reversible allograft dysfunction Restrictive allograft syndrome 


Compliance with Ethical Standards

Conflict of Interest

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.

Human and Animal Rights and Informed Consent

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


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

  1. 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.CrossRefPubMedGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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 CrossRefPubMedGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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 CrossRefPubMedGoogle Scholar
  9. 9.
    Leung AN, Fisher K, Valentine V, et al. Bronchiolitis obliterans after lung transplantation: detection using expiratory HRCT. Chest. 1998;113(2):365–70.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.PubMedGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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.Google Scholar
  23. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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 CrossRefPubMedGoogle Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 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 CrossRefPubMedGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 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.CrossRefPubMedGoogle Scholar
  38. 38.
    Parada MT, Alba A, Sepúlveda C. Everolimus in lung transplantation in Chile. Transplant Proc. 2010;42(1):328–30.CrossRefPubMedGoogle Scholar
  39. 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.CrossRefPubMedGoogle Scholar
  40. 40.
    Martin SI, Fishman JA. Pneumocystis pneumonia in solid organ transplantation. Am J Transplant. 2013;13(Suppl 4):272–9.CrossRefPubMedGoogle Scholar
  41. 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 CrossRefPubMedGoogle Scholar
  42. 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.PubMedGoogle Scholar
  43. 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.CrossRefPubMedGoogle Scholar
  44. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 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.CrossRefPubMedGoogle Scholar
  46. 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.CrossRefPubMedGoogle Scholar
  47. 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.CrossRefPubMedGoogle Scholar
  48. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 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.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Schrepfer S, Deuse T, Hoyt G, et al. Experimental orthotopic tracheal transplantation: the Stanford technique. Microsurgery. 2007;27(3):187–9.CrossRefPubMedGoogle Scholar
  51. 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.CrossRefPubMedGoogle Scholar
  52. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 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.CrossRefPubMedGoogle Scholar
  54. 54.
    Allan JS, Wain JC, Schwarze ML, et al. Modeling chronic lung allograft rejection in miniature swine. Transplantation. 2002;73(3):447–53.CrossRefPubMedGoogle Scholar
  55. 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.CrossRefPubMedGoogle Scholar
  56. 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.CrossRefPubMedGoogle Scholar
  57. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 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 CrossRefPubMedGoogle Scholar
  59. 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.CrossRefPubMedGoogle Scholar
  60. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 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.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Jason M. Gauthier
    • 1
  • Ramsey R. Hachem
    • 2
  • Daniel Kreisel
    • 1
    • 3
    • 4
    Email author
  1. 1.Department of SurgeryWashington University in St. LouisSaint LouisUSA
  2. 2.Department of MedicineWashington University in St. LouisSaint LouisUSA
  3. 3.Department of Pathology & ImmunologyWashington University in St. LouisSaint LouisUSA
  4. 4.Washington University School of MedicineSt. LouisUSA

Personalised recommendations