Other Treatments for Bronchiolitis Obliterans Syndrome

  • Ramsey HachemEmail author
Part of the Respiratory Medicine book series (RM, volume 8)


Bronchiolitis obliterans syndrome (BOS) remains the leading obstacle to better long-term outcomes after lung transplantation. The incidence of BOS approaches 50 % within 4 years of transplantation, and the median survival after the diagnosis of BOS is approximately 3 years. Because BOS is generally thought to represent chronic alloimmune-mediated rejection, the mainstay of therapy has been intensifying immunosuppression. However, the response to treatment is poor, and the typical clinical course is characterized by progressive allograft dysfunction. Total lymphoid irradiation (TLI) and extracorporeal photopheresis (ECP) are used at some centers, although they are usually reserved as salvage treatments for refractory BOS. Re-transplantation is the ultimate treatment option, but the donor organ shortage and generally marginal outcomes have limited its widespread use.


Bronchiolitis obliterans syndrome Total lymphoid irradiation Extracorporeal photopheresis Forced expiratory volume in one second (FEV1Survival 


  1. 1.
    Estenne M, Hertz MI. Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med. 2002;166:440–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Belperio JA, Weigt SS, Fishbein MC, Lynch JP. Chronic lung allograft rejection. Mechanisms and therapy. Proc Am Thorac Soc. 2009;6:108–21.PubMedCrossRefGoogle Scholar
  3. 3.
    Weigt SS, Wallace WD, Derhovanessian A, Saggar R, Saggar R, Lynch JP, et al. Chronic allograft rejection: epidemiology, diagnosis, pathogenesis, and treatment. Semin Respir Crit Care Med. 2010;31:189–207.PubMedCrossRefGoogle Scholar
  4. 4.
    Daud SA, Yusen RD, Meyers BF, Chakinala MM, Walter MJ, Aloush AA, et al. Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2007;175:507–13.PubMedCrossRefGoogle Scholar
  5. 5.
    Davis RD, Lau CL, Eubanks S, Messier RH, Hadjiliadis D, Steele MP, et al. Improved lung allograft function in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg. 2003;125:533–42.PubMedCrossRefGoogle Scholar
  6. 6.
    Khalifah AP, Hachem RR, Chakinala MM, Schechtman KB, Patterson GA, Schuster DP, et al. Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death. Am J Respir Crit Care Med. 2004;170:181–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Christie JD, Edwards LB, Kucheryavaya AY, Benden C, Dobbels F, Kirk R, et al. The registry of the International Society for Heart and Lung Transplantation: Twenty-eighth adult lung and heart-lung transplant report—2011. J Heart Lung Transplant. 2011;30:1104–22.PubMedCrossRefGoogle Scholar
  8. 8.
    Fuks Z, Strober S, Bobrove AM, Sasazuki T, McMichael A, Kaplan HS. Long term effects of radiation on T and B lymphocytes in peripheral blood of patients with Hodgkin’s disease. J Clin Invest. 1976;58:803–14.PubMedCrossRefGoogle Scholar
  9. 9.
    Waer M, Vanrenterghem Y, Roels L, Verberckmoes R, Hauglustaine D, van der Schueren E, et al. Renal cadaveric transplantation in diabetics using total lymphoid irradiation or cyclosporine A. A controlled randomized study. Leuven Collaborative Transplantation Group. Transpl Int. 1988;1:64–8.PubMedGoogle Scholar
  10. 10.
    Saper V, Chow D, Engleman ED, Hoppe RT, Levin B, Collins G, et al. Clinical and immunological studies of cadaveric renal transplant recipients given total lymphoid irradiation and maintained on low-dose prednisone. Transplantation. 1988;45:540–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Strober S, Slavin S, Gottlieb M, Zan-Bar I, King DP, Hoppe RT, et al. Allograft tolerance after total lymphoid irradiation (TLI). Immunol Rev. 1979;46:87–112.PubMedCrossRefGoogle Scholar
  12. 12.
    Strober S, Modry DL, Hoppe RT, Pennock JL, Bieber CP, Holm BI, et al. Induction of specific unresponsiveness to heart allografts in mongrel dogs treated with total lymphoid irradiation and antithymocyte globulin. J Immunol. 1984;132:1013–8.PubMedGoogle Scholar
  13. 13.
    Evans MA, Schomberg PJ, Rodeheffer RJ, Katzmann JA, Schnell Jr WA, Tazelaar HD, et al. Total lymphoid irradiation: a novel and successful therapy for resistant cardiac allograft rejection. Mayo Clin Proc. 1992;67:785–90.PubMedCrossRefGoogle Scholar
  14. 14.
    Salter SP, Salter MM, Kirklin JK, Bourge RC, Naftel DC. Total lymphoid irradiation in the treatment of early or recurrent heart transplant rejection. Int J Radiat Oncol Biol Phys. 1995;33:83–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Ross HJ, Gullestad L, Pak J, Slausaon S, Valantine HA, Hunt SA. Methotrexate or total lymphoid radiation for treatment of persistent or recurrent allograft cellular rejection: a comparative study. J Heart Lung Transplant. 1997;16:179–89.PubMedGoogle Scholar
  16. 16.
    Lim TS, O’Driscoll G, Freund J, Peterson V, Hayes H, Heywood J. Short-course total lymphoid irradiation for refractory cardiac transplantation rejection. J Heart Lung Transplant. 2007;26:1249–54.PubMedCrossRefGoogle Scholar
  17. 17.
    Valentine VG, Robbins RC, Wehner JH, Patel HR, Berry GJ, Theodore J. Total lymphoid irradiation for refractory acute rejection in heart-lung and lung allografts. Chest. 1996;109:1184–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Diamond DA, Michalski JM, Lynch JP, Trulock EP. Efficacy of total lymphoid irradiation for chronic allograft rejection following bilateral lung transplantation. Int J Radiat Oncol Biol Phys. 1998;41:795–800.PubMedCrossRefGoogle Scholar
  19. 19.
    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;5:537–43.PubMedCrossRefGoogle Scholar
  20. 20.
    Yeoh K, Mikhaeel NG. Role of radiotherapy in modern treatment of Hodgkin’s lymphoma. Advances in Hematology 2011; 2011: Article ID: 258797.Google Scholar
  21. 21.
    Verleden GM, Lievens Y, Dupont LJ, Van Raemdonck DE, De Vleeschauwer SI, Vos R, et al. Efficacy of total lymphoid irradiation in azithromycin nonresponsive chronic allograft rejection after lung transplantation. Transplant Proc. 2009;41:1816–20.PubMedCrossRefGoogle Scholar
  22. 22.
    Edelson R, Berger C, Gasparro F, Jegasothy B, Heald P, Wintroub B, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. N Engl J Med. 1987;316: 297–303.PubMedCrossRefGoogle Scholar
  23. 23.
    Heald P, Rook A, Perez M, Wintroub B, Knobler R, Jegasothy B, et al. Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy. J Am Acad Dermatol. 1993;28:1023–4.CrossRefGoogle Scholar
  24. 24.
    Yoo EK, Rook AH, Elenitsas R, Gasparro FP, Vewels BR. Apoptosis induction of ultraviolet A and photochemotherapy in cutaneous T-cell lymphoma; relevance to mechanism of therapeutic action. J Invest Dermatol. 1996;107:235–42.PubMedCrossRefGoogle Scholar
  25. 25.
    Berger CL, Hanlon D, Kanada D, Girardi M, Edelson RL. Transimmunization, a novel approach for tumor immunotherapy. Transfus Apher Sci. 2002;26:205–16.PubMedCrossRefGoogle Scholar
  26. 26.
    Menkes CJ, Andreu J, Heshmati f, Hillikquin P. Treatment of refractory rheumatoid arthritis by extracorporeal photochemotherapy. Br J Rheumatol. 1992;31:789–90.PubMedCrossRefGoogle Scholar
  27. 27.
    Rook AH, Freundich B, Jegasothy BV, Perez MI, Barr WG, Jimenez SA, et al. Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial. Arch Dermatol. 1992;128:337–46.PubMedCrossRefGoogle Scholar
  28. 28.
    Knobler RM. Extracorporeal photochemotherapy for the treatment of lupus erythematosus: preliminary observations. Springer Semin Immunopathol. 1994;16:323–5.PubMedCrossRefGoogle Scholar
  29. 29.
    Rook AH, Jgasothy BV, Heald P, Nahass GT, Ditre C, Witmer WK, et al. Extracorporeal photochemotherapy for drug resistant pemphigus vulgaris. Ann Intern Med. 1990;112:303–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Dall’Amico R, Messina C. Extracorporeal photochemotherapy for the treatment of graft-versus-host disease. Ther Apher. 2002;6:296–304.PubMedCrossRefGoogle Scholar
  31. 31.
    Foss FM, Divenuti GM, Chin K, Sprague K, Grodman H, Klein A, et al. Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors. Bone Marrow Transplant. 2005;45:1187–93.CrossRefGoogle Scholar
  32. 32.
    Costanzo-Nordin MR, Hubbell EA, O’Sullivan EJ, Johnson MR, Mullen GM, Heroux AL, et al. Photopheresis versus corticosteroids in the therapy of heart transplant rejection: preliminary clinical report. Circulation. 1992;86(5 suppl):II242–50.PubMedGoogle Scholar
  33. 33.
    Barr ML, Meiser BM, Eisen HJ, Roberts RF, Livi U, Dall’Amico R, et al. Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. N Engl J Med. 1998;339:1744–51.PubMedCrossRefGoogle Scholar
  34. 34.
    Di Renzo M, Rubegni P, Sbano P, Cuccia A, Castagnini C, Pompella G, et al. ECP-treated lymphocytes of chronic graft-versus-host disease patients undergo apoptosis which involves both the Fas/FasL system and the Bcl-2 protein family. Arch Dermatol Res. 2003;295:175–82.PubMedCrossRefGoogle Scholar
  35. 35.
    Bladon J, Taylor PC. Extracorporeal photopheresis: a focus on apoptosis and cytokines. J Dermatol Sci. 2006;43:85–94.PubMedCrossRefGoogle Scholar
  36. 36.
    Enk AH. Dendritic cells in tolerance induction. Immunol Lett. 2005;99:8–11.PubMedCrossRefGoogle Scholar
  37. 37.
    Lamioni A, Parisi F, Isacchi G, Giorda E, Di Cesare S, Landolfo A, et al. The immunological effects of extracorporeal photopheresis unraveled: induction of tolerogenic dendritic cells in vitro and regulatory T cells in vivo. Transplantation. 2005;79(7):846–50.PubMedCrossRefGoogle Scholar
  38. 38.
    Biagi E, Di Biaso I, Leoni V, Gaipa G, Rossi V, Bugarin C, et al. Extracorporeal photochemotherapy is accompanied by increasing levels of circulating CD4+ CD25+ GITR+Foxp3+CD62L+ functional regulatory T-cells in patients with graft- versus-host disease. Transplantation. 2007;84:31–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Bladon J, Taylor P. Extracorporeal photopheresis normalizes some lymphocyte subsets (including T regulatory cells) in chronic graft-versus-host-disease. Ther Apher Dial. 2008;12:311–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Meloni F, Cascina A, Miserere S, Perotti C, Vitulo P, Fietta AM. Peripheral CD4+CD25+ TREG cell counts and the response to extracorporeal photopheresis in lung transplant recipients. Transplant Proc. 2007;39:213–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Gorgun G, Miller KB, Foss FM. Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease. Blood. 2002;100:941–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Di Renzo M, Sbano P, De Aloe G, Pasqui AL, Rubegni P, Ghezzi A, et al. Extracorporeal photopheresis affects co-stimulatory molecule expression and interleukin-10 production by dendritic cells in graft-versus-host disease patients. Clin Exp Immunol. 2008;151:407–13.PubMedCrossRefGoogle Scholar
  43. 43.
    Slovis BS, Loyd JE, King LE. Photopheresis for chronic rejection of lung allografts. N Engl J Med. 1995;332:962–3.PubMedCrossRefGoogle Scholar
  44. 44.
    Salerno CT, Park SJ, Kreykes NS, Kulick DM, Savik K, Hertz MI, et al. Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis. J Thorac Cardiovasc Surg. 1999;117:1063–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Villanueva J, Bhorade SM, Robinson JA, Husain AN, Garrity ER. Extracorporeal photopheresis for the treatment of lung allograft rejection. Ann Transplant. 2000;5:44–7.PubMedGoogle Scholar
  46. 46.
    Benden C, Speich R, Hofbauer GF, Irani S, Eich-Wanger C, Russi EW, et al. Extracorporeal photopheresis after lung transplantation: a 10-year single-center experience. Transplantation. 2008;86:1625–7.PubMedCrossRefGoogle Scholar
  47. 47.
    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;29:424–31.PubMedCrossRefGoogle Scholar
  48. 48.
    Lama VN, Murray S, Lonigro RJ, Toews GB, Chang A, Lau C, et al. Course of FEV1 after onset of bronchiolitis obliterans syndrome in lung transplant recipients. Am J Respir Crit Care Med. 2007;175:1192–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Yusen RD, Shearon TH, Quian Y, Kotloff R, Barr ML, Sweet S, et al. Lung transplantation in the United States, 1999–2008. Am J Transplant. 2010;10:1047–68.PubMedCrossRefGoogle Scholar
  50. 50.
    Novick RJ, Kaye MP, Patterson GA, Andreassian B, Klepetko W, Menkis AH, et al. Redo lung transplantation: A North American-European experience. J Heart Lung Transplant. 1993;12:5–15.PubMedGoogle Scholar
  51. 51.
    Novick RJ, Schafers HJ, Stitt L, Andreassian B, Duchatelle JP, Klepetko W, et al. Recurrence of obliterative bronchiolitis and determinants of outcome in 139 pulmonary retransplant recipients. J Thorac Cardiovasc Surg. 1995;110:1402–14.PubMedCrossRefGoogle Scholar
  52. 52.
    Novick RJ, Stitt LW, Al-Kattan K, Klepetko W, Schafers HJ, Duchatelle JP, et al. Pulmonary retransplantation: predictors of graft function and survival in 230 patients. Ann Thorac Surg. 1998;65:227–34.PubMedCrossRefGoogle Scholar
  53. 53.
    Brugiere O, Thabut G, Castier Y, Mal H, Dauriat G, Marceau A, et al. Lung retransplantation for bronchiolitis obliterans syndrome. Long-term follow-up in a series of 15 recipients. Chest. 2003;123:1832–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Strueber M, Fischer S, Gottleib J, Simon AR, Goerler H, Gohrbandt B, et al. Long-term outcome after pulmonary retransplantation. J Thorac Cardiovasc Surg. 2006;132:407–12.PubMedCrossRefGoogle Scholar
  55. 55.
    Osaki S, Maloney JD, Meyer KC, Cornwell RD, Edwards NM, De Oliveira NC. Redo lung transplantation for acute and chronic lung allograft failure: long-term follow-up in a single center. Eur J Cardiothorac Surg. 2008;34:1191–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Aigner C, Jaksch P, Taghavi S, Lang G, Reza-Hoda MA, Wisser W, Klepetko W. Pulmonary retransplantation: is it worth the effort? A long-term analysis of 46 cases. J Heart Lung Transplant. 2008;27:60–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Kawut SM, Lederer DJ, Keshavjee S, Wilt JS, Daly T, D’Ovidio F, et al. Outcomes after lung retransplantation in the modern era. Am J Respir Crit Care Med. 2008;177:114–20.PubMedCrossRefGoogle Scholar
  58. 58.
    Johnson BA, Iacono AT, Zeevi A, McCurry KR, Duncan SR. Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med. 2003;167:1271–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Weber J, Tiriveedhi V, Takenaka M, Lu W, Hachem R, Trulock E, et al. Inhibition of rennin angiotensin aldosterone system causes abrogation of obliterative airway disease through inhibition of tumor necrosis factor-α-dependent interleukin-17. J Heart Lung Transplant. 2012;31:419–26.PubMedCrossRefGoogle Scholar
  60. 60.
    Iuppa JA, Wills AR, Bowman LJ, Patterson GA, Trulock EP, Hachem RR. An evaluation of the impact of statin use on the progression to bronchiolitis obliterans in lung allografts [abstract]. J Heart Lung Transplant. 2011;30(Suppl):S150–1.CrossRefGoogle Scholar
  61. 61.
    Antus B, Sebe A, Fillinger J, Jeney C, Horvath I. Effects of blockade of the renin-angiotensin and endothelin systems on experimental bronchiolitis obliterans. J Heart Lung Transplant. 2006;25:1324–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Antus B, Fillinger J, Sebe A, Jeney C, Horvath I. Late treatment with angiotensin-converting enzyme inhibitors plus endothelin receptor antagonists ameliorates rat tracheal allograft rejection. Transpl Int. 2008;21:801–7.PubMedCrossRefGoogle Scholar
  63. 63.
    McKane BW, Fernandez F, Narayanan K, Marshbank S, Margolin S, Jendrisak M, et al. Pirfenidone inhibits obliterative airway disease in a murine heterotopic tracheal transplant model. Transplantation. 2004;77:664–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Washington University School of Medicine/Barnes-Jewish Hospital Pulmonary and Critical CareSt. LouisUSA

Personalised recommendations