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Current Transplantation Reports

, Volume 3, Issue 3, pp 192–198 | Cite as

Lung Transplant Rejection and Surveillance in 2016: Newer Options

  • Mark Benzimra
  • Allan R. Glanville
Thoracic Transplantation (J Kobashigawa, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Thoracic Transplantation

Abstract

Lung allograft rejection is a major risk factor for the development of chronic lung allograft dysfunction. It is a significant cause of morbidity and mortality, and limits survival post lung transplantation, which is lower than any other solid organ transplant. The invasive nature of current methods of diagnosis which consists of histological diagnosis via transbronchial biopsy and the lack of sensitivity of clinical surveillance warrants the search for novel less invasive and more accurate methods of diagnosis. This review aims to highlight recent changes to current methods of surveillance and diagnosis as well as present some of the novel methods that are becoming available.

Keywords

Lung transplant Rejection Surveillance Acute cellular rejection Antibody-mediated rejection 

Notes

Compliance with Ethical Standards

Conflict of Interest

Mark Benzimra and Allan Glanville declare that they have 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.

Glossary

ACR

Acute cellular rejection

AMR

Antibody-mediated rejection

BALF

Bronchoalveolar lavage fluid

BOS

Bronchiolitis obliterans syndrome

CLAD

Chronic lung allograft dysfunction

Col-V

Collagen V

DSA

Donor specific HLA antibodies

HLA

Human leucocyte antigen

Kα1T

K-alpha-1 tubulin

LTX

Lung transplantation

MFI

Mean fluorescence intensity

miRNA

Micro-ribonucleic acid

OB

Obliterative bronchiolitis

RCLAD

Restrictive chronic lung allograft dysfunction

SAB

Single-antigen beads

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Yusen RD, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Dobbels F, 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
  2. 2.
    Weigt SS, DerHovanessian A, Wallace WD, Lynch 3rd JP, Belperio JA. Bronchiolitis obliterans syndrome: the Achilles’ heel of lung transplantation. Semin Respir Crit Care Med. 2013;34(3):336–51.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Gardiner BJ, Snydman DR. Editorial commentary: chronic lung allograft dysfunction in lung transplant recipients: another piece of the puzzle. Clin Infect Dis. 2016;62(3):320–2.CrossRefPubMedGoogle Scholar
  4. 4.
    McManigle W, Pavlisko EN, Martinu T. Acute cellular and antibody-mediated allograft rejection. Semin Respir Crit Care Med. 2013;34(3):320–35.CrossRefPubMedGoogle Scholar
  5. 5.
    Yousem SA, Berry GJ, Cagle PT, Chamberlain D, Husain AN, Hruban RH, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant. 1996;15(1 Pt 1):1–15.PubMedGoogle Scholar
  6. 6.
    Baz MA, Layish DT, Govert JA, Howell DN, Lawrence CM, Davis RD, et al. Diagnostic yield of bronchoscopies after isolated lung transplantation. Chest. 1996;110(1):84–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Stephenson A, Flint J, English J, Vedal S, Fradet G, Chittock D, et al. Interpretation of transbronchial lung biopsies from lung transplant recipients: inter- and intra-observer agreement. Can Respir J. 2005;12(2):75–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Wallace WA, Bellamy CO, Rassl DM, Harrison DJ. Transplant histopathology for the general histopathologist. Histopathology. 2003;43(4):313–22.CrossRefPubMedGoogle Scholar
  9. 9.
    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.CrossRefPubMedGoogle Scholar
  10. 10.
    Yousem SA, Berry GJ, Brunt EM, Chamberlain D, Hruban RH, Sibley RK, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Lung Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant. 1990;9(6):593–601.Google Scholar
  11. 11.
    Cooper JD, Billingham M, Egan T, Hertz MI, Higenbottam T, Lynch J, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 1993;12(5):713–6.PubMedGoogle Scholar
  12. 12.
    Estenne M, Hertz MI. Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med. 2002;166(4):440–4.CrossRefPubMedGoogle Scholar
  13. 13.
    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.CrossRefPubMedGoogle Scholar
  14. 14.
    Vanaudenaerde BM, Meyts I, Vos R, Geudens N, De Wever W, Verbeken EK, 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.•
    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. 2011;30(7):735–42. This study was the first to recognise a restrictive form of chronic allograft dysfunction which exhibited peripheral lung fibrosis and significantly affected survival negatively.CrossRefPubMedGoogle Scholar
  16. 16.•
    Todd JL, Jain R, Pavlisko EN, Finlen Copeland CA, Reynolds JM, Snyder LD, et al. Impact of forced vital capacity loss on survival after the onset of chronic lung allograft dysfunction. Am J Respir Crit Care Med. 2014;189(2):159–66. This paper demonstrated that patients with restrictive physiology with associated FVC decline at CLAD onset had significantly worse survival after CLAD when compared with those with preserved FVC.Google Scholar
  17. 17.
    Sato M, Hwang DM, Waddell TK, Singer LG, Keshavjee S. Progression pattern of restrictive allograft syndrome after lung transplantation. J Heart Lung Transplant. 2013;32(1):23–30.CrossRefPubMedGoogle Scholar
  18. 18.•
    Verleden SE, Todd JL, Sato M, Palmer SM, Martinu T, Pavlisko EN, et al. Impact of CLAD phenotype on survival after lung retransplantation: a Multicenter Study. Am J Transplant. 2015;15(8):2223–30. This study showed that patients re-transplanted for rCLAD had worse survival outcomes than those re-transplanted for BOS.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    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.CrossRefPubMedGoogle Scholar
  20. 20.
    Verleden SE, de Jong PA, Ruttens D, Vandermeulen E, van Raemdonck DE, Verschakelen J, et al. Functional and computed tomographic evolution and survival of restrictive allograft syndrome after lung transplantation. J Heart Lung Transplant. 2014;33(3):270–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Belloli EA, Wang X, Murray S, Forrester G, Weyhing A, Lin J, et al. Longitudinal forced vital capacity monitoring as a prognostic adjunct after lung transplantation. Am J Respir Crit Care Med. 2015;192(2):209–18.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Glanville AR. The role of bronchoscopic surveillance monitoring in the care of lung transplant recipients. Semin Respir Crit Care Med. 2006;27(5):480–91.CrossRefPubMedGoogle Scholar
  23. 23.
    Swarup V, Rajeswari MR. Circulating (cell-free) nucleic acids—a promising, non-invasive tool for early detection of several human diseases. FEBS Lett. 2007;581(5):795–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Lo YM, Rainer TH, Chan LY, Hjelm NM, Cocks RA. Plasma DNA as a prognostic marker in trauma patients. Clin Chem. 2000;46(3):319–23.PubMedGoogle Scholar
  25. 25.•
    Snyder TM, Khush KK, Valantine HA, Quake SR. Universal noninvasive detection of solid organ transplant rejection. Proc Natl Acad Sci U S A. 2011;108(15):6229–34. This study demonstrate that cell-free DNA can be used to detect an organ-specific signature that correlates with rejection in heart transplant recipients.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.•
    De Vlaminck I, Valantine HA, Snyder TM, Strehl C, Cohen G, Luikart H, et al. Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection. Sci Transl Med. 2014;6(241):241ra77. In this study the utility of cell-free donor DNA was tested by comparing with positive endomyocardial biopsies. They were able to show that the sensitivity and specificity of measuring cell free donor DNA was comparable to the biopsy itself.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Deng MC, Eisen HJ, Mehra MR, Billingham M, Marboe CC, Berry G, et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant. 2006;6(1):150–60.CrossRefPubMedGoogle Scholar
  28. 28.
    Pham MX, Teuteberg JJ, Kfoury AG, Starling RC, Deng MC, Cappola TP, et al. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med. 2010;362(20):1890–900.CrossRefPubMedGoogle Scholar
  29. 29.
    Sigdel TK, Vitalone MJ, Tran TQ, Dai H, Hsieh SC, Salvatierra O, et al. A rapid noninvasive assay for the detection of renal transplant injury. Transplantation. 2013;96(1):97–101.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Glanville AR. Bronchoscopic monitoring after lung transplantation. Semin Respir Crit Care Med. 2010;31(2):208–21.CrossRefPubMedGoogle Scholar
  31. 31.•
    De Vlaminck I, Martin L, Kertesz M, Patel K, Kowarsky M, Strehl C, et al. Noninvasive monitoring of infection and rejection after lung transplantation. Proc Natl Acad Sci U S A. 2015;112(43):13336–41. This study showed that levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0.9).CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Neujahr DC. Lung microvessicles may hold clues to lung transplant failure. Transplantation. 2015;99(11):2243–4.CrossRefPubMedGoogle Scholar
  33. 33.
    Harms A, Fuehner T, Warnecke G, Haverich A, Gottlieb J, Trummer A. Epithelial and erythrocyte microvesicles from bronchoalveolar lavage fluid are elevated and associated with outcome in chronic lung allograft dysfunction. Transplantation. 2015;99(11):2394–400.CrossRefPubMedGoogle Scholar
  34. 34.•
    Gregson AL, Hoji A, Injean P, Poynter ST, Briones C, Palchevskiy V, et al. Altered exosomal RNA profiles in bronchoalveolar lavage from lung transplants with acute rejection. Am J Respir Crit Care Med. 2015;192(12):1490–503. Findings in this study validated the use of bronchoalveolar lavage fluid exosomal shuttle RNA as a source for understanding the pathophysiology of AR and for biomarker discovery in lung transplantation.CrossRefPubMedGoogle Scholar
  35. 35.
    Gimino VJ, Lande JD, Berryman TR, King RA, Hertz MI. Gene expression profiling of bronchoalveolar lavage cells in acute lung rejection. Am J Respir Crit Care Med. 2003;168(10):1237–42.CrossRefPubMedGoogle Scholar
  36. 36.
    Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007;27(1):91–105.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Booton R, Lindsay MA. Emerging role of microRNAs and long noncoding RNAs in respiratory disease. Chest. 2014;146(1):193–204.CrossRefPubMedGoogle Scholar
  38. 38.
    Anglicheau D, Sharma VK, Ding R, Hummel A, Snopkowski C, Dadhania D, et al. MicroRNA expression profiles predictive of human renal allograft status. Proc Natl Acad Sci U S A. 2009;106(13):5330–5.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Sun Y, Tawara I, Zhao M, Qin ZS, Toubai T, Mathewson N, et al. Allogeneic T cell responses are regulated by a specific miRNA-mRNA network. J Clin Invest. 2013;123(11):4739–54.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Takahashi H, Kanno T, Nakayamada S, Hirahara K, Sciume G, Muljo SA, et al. TGF-beta and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat Immunol. 2012;13(6):587–95.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Trotta R, Chen L, Ciarlariello D, Josyula S, Mao C, Costinean S, et al. miR-155 regulates IFN-gamma production in natural killer cells. Blood. 2012;119(15):3478–85.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Wei L, Wang M, Qu X, Mah A, Xiong X, Harris AG, et al. Differential expression of microRNAs during allograft rejection. Am J Transplant. 2012;12(5):1113–23.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Nana-Sinkam SP, Hunter MG, Nuovo GJ, Schmittgen TD, Gelinas R, Galas D, et al. Integrating the microRNome into the study of lung disease. Am J Respir Crit Care Med. 2009;179(1):4–10.CrossRefPubMedGoogle Scholar
  44. 44.
    Wilflingseder J, Regele H, Perco P, Kainz A, Soleiman A, Muhlbacher F, et al. miRNA profiling discriminates types of rejection and injury in human renal allografts. Transplantation. 2013;95(6):835–41.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Duong Van Huyen JP, Tible M, Gay A, Guillemain R, Aubert O, Varnous S, et al. MicroRNAs as non-invasive biomarkers of heart transplant rejection. Eur Heart J. 2014;35(45):3194–202.CrossRefPubMedGoogle Scholar
  46. 46.•
    Levine DJ et al. Antibody mediated rejection of the An ISHLT Consensus Report. J Heart Lung Transplant Lung. 2016. This report is the first document published by the ISHLT providing guidance on daignostic criteria and classification of AMR.Google Scholar
  47. 47.
    Slavcev A. Prediction of organ transplant rejection by HLA-specific and non-HLA antibodies—brief literature review. Int J Immunogenet. 2013;40(2):83–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Yabu JM, Higgins JP, Chen G, Sequeira F, Busque S, Tyan DB. C1q-fixing human leukocyte antigen antibodies are specific for predicting transplant glomerulopathy and late graft failure after kidney transplantation. Transplantation. 2011;91(3):342–7.CrossRefPubMedGoogle Scholar
  49. 49.
    Tait BD, Susal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, et al. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation. 2013;95(1):19–47.CrossRefPubMedGoogle Scholar
  50. 50.
    Hachem RR, Tiriveedhi V, Patterson GA, Aloush A, Trulock EP, Mohanakumar T. Antibodies to K-alpha 1 tubulin and collagen V are associated with chronic rejection after lung transplantation. Am J Transplant. 2012;12(8):2164–71.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Saini D, Weber J, Ramachandran S, Phelan D, Tiriveedhi V, Liu M, et al. Alloimmunity-induced autoimmunity as a potential mechanism in the pathogenesis of chronic rejection of human lung allografts. J Heart Lung Transplant. 2011;30(6):624–31.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Goers TA, Ramachandran S, Aloush A, Trulock E, Patterson GA, Mohanakumar T. De novo production of K-alpha1 tubulin-specific antibodies: role in chronic lung allograft rejection. J Immunol. 2008;180(7):4487–94.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Mark Benzimra
    • 1
  • Allan R. Glanville
    • 1
  1. 1.St Vincent’s HospitalSydneyAustralia

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