Non-Bronchiolitis Obliterans Syndrome Forms of Chronic Lung Allograft Dysfunction

  • Gregory I. SnellEmail author
  • Bronwyn J. Levvey
  • Glen P. Westall
Part of the Respiratory Medicine book series (RM, volume 8)


The bronchiolitis obliterans syndrome (BOS) has been described as the clinical correlate of chronic lung allograft rejection and defined as irreversible airflow obstruction in the absence of other causes. However, it has become apparent that BOS does not explain all chronic lung allograft dysfunction (CLAD) and that a variety of other etiologies with a mixed obstructive and restrictive pattern on spirometry, or even a pure restrictive picture (restrictive allograft syndrome, or RAS), are also identifiable. Surgical, mechanical, vascular obstructive, infectious, and infiltrative processes, as well as a whole range of chronic lung allograft rejection entities need to be considered in making a diagnosis of CLAD. The performance of any lung allograft is really the sum-of-the-parts of all of these processes, and considering non-BOS CLAD in all its forms may potentially provide more therapeutic options than just considering BOS alone as the explanation for declining lung function.


Lung transplantation Bronchiolitis obliterans syndrome Chronic lung allograft dysfunction Obliterative bronchiolitis Restrictive lung allograft syndrome Allograft rejection Chronic rejection 



Support for this work comes from the Margaret Pratt Foundation.


  1. 1.
    Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz M, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant. 2002;21(3):297–310.PubMedCrossRefGoogle Scholar
  2. 2.
    Verleden SE, Verleden GM, Vanaudenaerde BM. Phenotyping BOS could improve understanding of mechanisms involved. J Heart Lung Transplant. 2010;30(1):112.PubMedCrossRefGoogle Scholar
  3. 3.
    Todd JL, Palmer SM. Bronchiolitis obliterans syndrome: the final frontier for lung transplantation. Chest. 2011;140(2):502–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Verleden GM, Vos R, Verleden SE, De Wever W, De Vleeschauwer SI, Willems-Widyastuti A, et al. Survival determinants in lung transplant patients with chronic allograft dysfunction. Transplantation. 2011;92(6):703–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Woodrow JP, Shlobin OA, Barnett SD, Burton N, Nathan SD. Comparison of bronchiolitis obliterans syndrome to other forms of chronic lung allograft dysfunction after lung transplantation. J Heart Lung Transplant. 2010;29(10):1159–64.PubMedCrossRefGoogle Scholar
  6. 6.
    Williams TJ, Snell GI. Early and long-term functional outcomes in unilateral, bilateral, and living-related transplant recipients. Clin Chest Med. 1997;18(2):245–57.PubMedCrossRefGoogle Scholar
  7. 7.
    Fitton TP, Bethea BT, Borja MC, Yuh DD, Yang SC, Orens JB, et al. Pulmonary resection following lung transplantation. Ann Thorac Surg. 2003;76(5):1680–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Hadjiliadis D, Hutcheon MA. Detection of bronchiolitis obliterans syndrome (BOS) in single lung transplant recipients. J Heart Lung Transplant. 2003;22(7):829–30.PubMedCrossRefGoogle Scholar
  9. 9.
    Ferrer J, Roldan J, Roman A, Bravo C, Monforte V, Pallissa E, et al. Acute and chronic pleural complications in lung transplantation. J Heart Lung Transplant. 2003;22(11):1217–25.PubMedCrossRefGoogle Scholar
  10. 10.
    Kono C, Yamaguchi T, Yamada Y, Hoshi S, Amano H, Minami M, et al. [A case of bronchostenosis in the allograft after lung transplantation in pulmonary lymphangioleiomyomatosis]. Nihon Kokyuki Gakkai Zasshi. 2004;42(2):170–5.PubMedGoogle Scholar
  11. 11.
    Santacruz JF, Mehta AC. Airway complications and management after lung transplantation: ischemia, dehiscence, and stenosis. Proc Am Thorac Soc. 2009;6(1):79–93.PubMedCrossRefGoogle Scholar
  12. 12.
    Kahan ES, Petersen G, Gaughan JP, Criner GJ. High incidence of venous thromboembolic events in lung transplant recipients. J Heart Lung Transplant. 2007;26(4):339–44.PubMedCrossRefGoogle Scholar
  13. 13.
    Regueiro F, Roche P, Regueiro MV, Lozano R. The importance of histology in the evaluation of pulmonary transplantation: carcinomatous lymphangitis. Thorac Cardiovasc Surg. 2005;53(2):122–3.PubMedCrossRefGoogle Scholar
  14. 14.
    Rossi SE, Erasmus JJ, McAdams HP, Sporn TA, Goodman PC. Pulmonary drug toxicity: radiologic and pathologic manifestations. Radiographics. 2000;20(5):1245–59.PubMedGoogle Scholar
  15. 15.
    Orens JB, Estenne M, Arcasoy S, Conte JV, Corris P, Egan JJ, et al. International guidelines for the selection of lung transplant candidates: 2006 update–a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006;25(7):745–55.PubMedCrossRefGoogle Scholar
  16. 16.
    Esmore DS, Brown R, Buckland M, Briganti EM, Fetherston GJ, Rabinov M, et al. Techniques and results in bilateral sequential single lung transplantation. The National Heart & Lung Replacement Service. J Card Surg. 1994;9(1):1–14.PubMedCrossRefGoogle Scholar
  17. 17.
    Snell GI, Westall GP. The contribution of airway ischemia and vascular remodelling to the pathophysiology of bronchiolitis obliterans syndrome and chronic lung allograft dysfunction. Curr Opin Organ Transplant. 2010;15(5):558–62.PubMedCrossRefGoogle Scholar
  18. 18.
    Boffa DJ, Mason DP, Su JW, Murthy SC, Feng J, McNeill AM, et al. Decortication after lung transplantation. Ann Thorac Surg. 2008;85(3):1039–43.PubMedCrossRefGoogle Scholar
  19. 19.
    Ng YL, Paul N, Patsios D, Walsham A, Chung TB, Keshavjee S, et al. Imaging of lung transplantation: review. AJR Am J Roentgenol. 2009;192(3 Suppl):S1–13.PubMedGoogle Scholar
  20. 20.
    Martinu T, Howell DN, Davis RD, Steele MP, Palmer SM. Pathologic correlates of bronchiolitis obliterans syndrome in pulmonary retransplant recipients. Chest. 2006;129(4):1016–23.PubMedCrossRefGoogle Scholar
  21. 21.
    Konen E, Weisbrod GL, Pakhale S, Chung T, Paul NS, Hutcheon MA. Fibrosis of the upper lobes: a newly identified late-onset complication after lung transplantation? AJR Am J Roentgenol. 2003;181(6):1539–43.PubMedCrossRefGoogle Scholar
  22. 22.
    Snell GI, Boehler A, Glanville AR, McNeil K, Scott JP, Studer SM, et al. Eleven years on: a clinical update of key areas of the 1996 lung allograft rejection working formulation. J Heart Lung Transplant. 2007;26(5):423–30.PubMedCrossRefGoogle Scholar
  23. 23.
    Stewart S, Fishbein MC, Snell GI, Berry GJ, Boehler A, Burke MM, 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.PubMedCrossRefGoogle Scholar
  24. 24.
    Kroegel C, Reissig A, Foerster M. Pulmonary fibrosis of the upper lobes after lung transplantation is associated with selective CD8+ T lymphocyte expansion. AJR Am J Roentgenol. 2005;184(3):1024–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Pakhale SS, Hadjiliadis D, Howell DN, Palmer SM, Gutierrez C, Waddell TK, et al. Upper lobe fibrosis: a novel manifestation of chronic allograft dysfunction in lung transplantation. J Heart Lung Transplant. 2005;24(9):1260–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Sato M, Hirayama S, Matsuda Y, Wagnetz D, Hwang DM, Guan Z, et al. Stromal activation and formation of lymphoid-like stroma in chronic lung allograft dysfunction. Transplantation. 2011;91(12):1398–405.PubMedCrossRefGoogle Scholar
  27. 27.
    Siddiqui MT, Garrity ER, Husain AN. Bronchiolitis obliterans organizing pneumonia-like reactions: a nonspecific response or an atypical form of rejection or infection in lung allograft recipients? Hum Pathol. 1996;27(7):714–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Gabbay E, Dark JH, Ashcroft T, Corris PA. Cryptogenic organizing pneumonia is an important cause of graft dysfunction and should be included in the classification of pulmonary allograft rejection. J Heart Lung Transplant. 1998;17(2):230–1.PubMedGoogle Scholar
  29. 29.
    Luckraz H, Goddard M, McNeil K, Atkinson C, Sharples LD, Wallwork J. Is obliterative bronchiolitis in lung transplantation associated with microvascular damage to small airways? Ann Thorac Surg. 2006;82(4):1212–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Herrera JM, McNeil KD, Higgins RS, Coulden RA, Flower CD, Nashef SA, et al. Airway complications after lung transplantation: treatment and long-term outcome. Ann Thorac Surg. 2001;71(3):989–93. discussion 93–4.PubMedCrossRefGoogle Scholar
  31. 31.
    Keating DT, Westall GP, Pham A, Whitford HM, Williams TJ, Snell GI. Proliferating bronchial webs after lung transplantation. Ann Thorac Surg. 2011;92(5):1893–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Vos R, Vanaudenaerde BM, De Vleeschauwer SI, Van Raemdonck DE, Dupont LJ, Verbeken EK, et al. Follicular bronchiolitis: a rare cause of bronchiolitis obliterans syndrome after lung transplantation: a case report. Am J Transplant. 2009;9(3):644–50.PubMedCrossRefGoogle Scholar
  33. 33.
    McManus TE, Milne DG, Whyte KF, Wilsher ML. Exudative bronchiolitis after lung transplantation. J Heart Lung Transplant. 2008;27(3):276–81.PubMedCrossRefGoogle Scholar
  34. 34.
    Verleden GM, Vos R, De Vleeschauwer S, Verleden S, Dupont L, Nevens F, et al. Neutrophilic reversible airways dysfunction after lung transplantation: a case report. Transplant Proc. 2011;43(5):2078–81.PubMedCrossRefGoogle Scholar
  35. 35.
    Sato M, Waddell TK, Wagnetz U, Roberts HC, Hwang DM, Haroon A, et al. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant. 2010;30(7):735–42.CrossRefGoogle Scholar
  36. 36.
    Glanville AR. Bronchoscopic monitoring after lung transplantation. Semin Respir Crit Care Med. 2009;31(2):208–21.CrossRefGoogle Scholar
  37. 37.
    Girnita AL, McCurry KR, Zeevi A. Increased lung allograft failure in patients with HLA-specific antibody. Clin Transpl. 2007:231–9.Google Scholar
  38. 38.
    Glanville AR. Antibody-mediated rejection in lung transplantation: myth or reality? J Heart Lung Transplant. 2009;29(4):395–400.CrossRefGoogle Scholar
  39. 39.
    Burke CM, Theodore J, Dawkins KD, Yousem SA, Blank N, Billingham ME, et al. Post-transplant obliterative bronchiolitis and other late lung sequelae in human heart-lung transplantation. Chest. 1984;86(6):824–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Baraut J, Michel L, Verrecchia F, Farge D. Relationship between cytokine profiles and clinical outcomes in patients with systemic sclerosis. Autoimmun Rev. 2010;10(2):65–73.PubMedCrossRefGoogle Scholar
  41. 41.
    Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010;2(52):52;72.Google Scholar
  42. 42.
    Willis BC, Borok Z. Epithelial-mesenchymal transition: potential role in obliterative bronchiolitis? Thorax. 2009;64(9):742–3.PubMedCrossRefGoogle Scholar
  43. 43.
    Ward C, Forrest IA, Murphy DM, Johnson GE, Robertson H, Cawston TE, et al. Phenotype of airway epithelial cells suggests epithelial to mesenchymal cell transition in clinically stable lung transplant recipients. Thorax. 2005;60(10):865–71.PubMedCrossRefGoogle Scholar
  44. 44.
    Coward WR, Saini G, Jenkins G. The pathogenesis of idiopathic pulmonary fibrosis. Ther Adv Respir Dis. 2010;4(6):367–88.PubMedCrossRefGoogle Scholar
  45. 45.
    Jiang X, Khan MA, Tian W, Beilke J, Natarajan R, Kosek J, et al. Adenovirus-mediated HIF-1alpha gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection. J Clin Invest. 2011;121(6):2336–49.PubMedCrossRefGoogle Scholar
  46. 46.
    Saggar R, Ross DJ, Saggar R, Zisman DA, Gregson A, Lynch 3rd JP, et al. Pulmonary hypertension associated with lung transplantation obliterative bronchiolitis and vascular remodeling of the allograft. Am J Transplant. 2008;8(9):1921–30.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Gregory I. Snell
    • 1
    Email author
  • Bronwyn J. Levvey
    • 1
    • 2
  • Glen P. Westall
    • 1
  1. 1.Department of Allergy, Immunology and Respiratory MedicineThe Alfred HospitalMelbourneAustralia
  2. 2.Faculty of Medicine, Nursing and Health SciencesMonash UniversityMelbourneAustralia

Personalised recommendations