Immunosuppression: What's Standard and What's New?

 

 Buy Article Permissions and Reprints

Abstract

Lung transplantation is the ultimate treatment option for patients with end-stage lung disease. Chronic rejection, in the form of bronchiolitis obliterans syndrome, and noncytomegalovirus infections are the major causes of morbidity and mortality beyond the first year after transplantation. Most lung transplant recipients are treated lifelong with a three-drug immunosuppression regimen consisting of a calcineurin inhibitor, an antimetabolite, and low-dose corticosteroids. However, induction and maintenance immunosuppression strategies vary widely between centers, and a consensus on the ideal management of this patient population remains elusive. Over the past 20 years, several studies comparing the calcineurin inhibitors cyclosporine and tacrolimus and other studies comparing the antimetabolites azathioprine and mycophenolate mofetil have been performed. Additionally, the role of mammalian target of rapamycin (mTOR) inhibitors in the treatment of lung transplant recipients and the utility of azithromycin to treat and prevent bronchiolitis obliterans syndrome are areas of active investigation. This review discusses induction and traditional maintenance immunosuppressive agents and regimens and the evidence that exists to help guide therapy. Newer research involving the use of mTOR inhibitors in place of calcineurin inhibitors or antimetabolites and azithromycin for the treatment and prevention of bronchiolitis obliterans syndrome is also explored.

• References

• 1 Dalton ML. The first lung transplant. Am Surg 2004; 70 (4) 364-365
  PubMedGoogle Scholar
• 2 Hardy JD. The first lung transplant in man (1963) and the first heart transplant in man (1964). Transplant Proc 1999; 31 (1-2) 25-29
  CrossrefPubMedGoogle Scholar
• 3 Date H. Current status and future of lung transplantation. Intern Med 2001; 40 (2) 87-95
  CrossrefPubMedGoogle Scholar
• 4 Borel JF, Feurer C, Gubler HU, Stähelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 1976; 6 (4) 468-475
  CrossrefPubMedGoogle Scholar
• 5 Snell GI, Westall GP. Immunosuppression for lung transplantation: evidence to date. Drugs 2007; 67 (11) 1531-1539
  CrossrefPubMedGoogle Scholar
• 6 Bhorade SM, Stern E. Immunosuppression for lung transplantation. Proc Am Thorac Soc 2009; 6 (1) 47-53
  CrossrefPubMedGoogle Scholar
• 7 Cooper JD, Pearson FG, Patterson GA , et al. Technique of successful lung transplantation in humans. J Thorac Cardiovasc Surg 1987; 93 (2) 173-181
  PubMedGoogle Scholar
• 8 Christie JD, Edwards LB, Kucheryavaya AY , et al; International Society of Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report-2012. J Heart Lung Transplant 2012; 31 (10) 1073-1086
  CrossrefPubMedGoogle Scholar
• 9 Korom S, Boehler A, Weder W. Immunosuppressive therapy in lung transplantation: state of the art. Eur J Cardiothorac Surg 2009; 35 (6) 1045-1055
  CrossrefPubMedGoogle Scholar
• 10 Caillat-Zucman S, Blumenfeld N, Legendre C , et al. The OKT3 immunosuppressive effect. In situ antigenic modulation of human graft-infiltrating T cells. Transplantation 1990; 49 (1) 156-160
  CrossrefPubMedGoogle Scholar
• 11 Perico N, Remuzzi G. Prevention of transplant rejection: current treatment guidelines and future developments. Drugs 1997; 54 (4) 533-570
  CrossrefPubMedGoogle Scholar
• 12 Bourdage JS, Hamlin DM. Comparative polyclonal antithymocyte globulin and antilymphocyte/antilymphoblast globulin anti-CD antigen analysis by flow cytometry. Transplantation 1995; 59 (8) 1194-1200
  CrossrefPubMedGoogle Scholar
• 13 Knoop C, Haverich A, Fischer S. Immunosuppressive therapy after human lung transplantation. Eur Respir J 2004; 23 (1) 159-171
  CrossrefPubMedGoogle Scholar
• 14 Gaber AO, Monaco AP, Russell JA, Lebranchu Y, Mohty M. Rabbit antithymocyte globulin (thymoglobulin): 25 years and new frontiers in solid organ transplantation and haematology. Drugs 2010; 70 (6) 691-732
  CrossrefPubMedGoogle Scholar
• 15 Boothpur R, Hardinger KL, Skelton RM , et al. Serum sickness after treatment with rabbit antithymocyte globulin in kidney transplant recipients with previous rabbit exposure. Am J Kidney Dis 2010; 55 (1) 141-143
  CrossrefPubMedGoogle Scholar
• 16 Onrust SV, Wiseman LR. Basiliximab. Drugs 1999; 57 (2) 207-213 , discussion 214
  CrossrefPubMedGoogle Scholar
• 17 Wiseman LR, Faulds D. Daclizumab: a review of its use in the prevention of acute rejection in renal transplant recipients. Drugs 1999; 58 (6) 1029-1042
  CrossrefPubMedGoogle Scholar
• 18 Hengster P, Pescovitz MD, Hyatt D, Margreiter R. Roche Study Group. Cytomegalovirus infections after treatment with daclizumab, an anti IL-2 receptor antibody, for prevention of renal allograft rejection. Transplantation 1999; 68 (2) 310-313
  CrossrefPubMedGoogle Scholar
• 19 Nashan B, Moore R, Amlot P, Schmidt AG, Abeywickrama K, Soulillou JP. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group. Lancet 1997; 350 (9086) 1193-1198
  CrossrefPubMedGoogle Scholar
• 20 Xia MQ, Tone M, Packman L, Hale G, Waldmann H. Characterization of the CAMPATH-1 (CDw52) antigen: biochemical analysis and cDNA cloning reveal an unusually small peptide backbone. Eur J Immunol 1991; 21 (7) 1677-1684
  CrossrefPubMedGoogle Scholar
• 21 Xia MQ, Hale G, Lifely MR , et al. Structure of the CAMPATH-1 antigen, a glycosylphosphatidylinositol-anchored glycoprotein which is an exceptionally good target for complement lysis. Biochem J 1993; 293 (Pt 3) 633-640
  PubMedGoogle Scholar
• 22 Weaver TA, Kirk AD. Alemtuzumab. Transplantation 2007; 84 (12) 1545-1547
  CrossrefPubMedGoogle Scholar
• 23 McCurry KR, Iacono A, Zeevi A , et al. Early outcomes in human lung transplantation with thymoglobulin or Campath-1H for recipient pretreatment followed by posttransplant tacrolimus near-monotherapy. J Thorac Cardiovasc Surg 2005; 130 (2) 528-537
  CrossrefPubMedGoogle Scholar
• 24 Trulock EP. Lung transplantation. Am J Respir Crit Care Med 1997; 155 (3) 789-818
  CrossrefPubMedGoogle Scholar
• 25 Cai J, Terasaki PI. Induction immunosuppression improves long-term graft and patient outcome in organ transplantation: an analysis of United Network for Organ Sharing registry data. Transplantation 2010; 90 (12) 1511-1515
  CrossrefPubMedGoogle Scholar
• 26 Palmer SM, Miralles AP, Lawrence CM, Gaynor JW, Davis RD, Tapson VF. Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study. Chest 1999; 116 (1) 127-133
  CrossrefPubMedGoogle Scholar
• 27 Hartwig MG, Snyder LD, Appel III JZ , et al. Rabbit anti-thymocyte globulin induction therapy does not prolong survival after lung transplantation. J Heart Lung Transplant 2008; 27 (5) 547-553
  CrossrefPubMedGoogle Scholar
• 28 Hachem RR, Edwards LB, Yusen RD, Chakinala MM, Alexander Patterson G, Trulock EP. The impact of induction on survival after lung transplantation: an analysis of the International Society for Heart and Lung Transplantation Registry. Clin Transplant 2008; 22 (5) 603-608
  CrossrefPubMedGoogle Scholar
• 29 Jaksch P, Wiedemann D, Augustin V , et al. Antithymocyte globulin induction therapy improves survival in lung transplantation for cystic fibrosis. Transpl Int 2013; 26 (1) 34-41
  CrossrefPubMedGoogle Scholar
• 30 Hachem RR, Chakinala MM, Yusen RD , et al. A comparison of basiliximab and anti-thymocyte globulin as induction agents after lung transplantation. J Heart Lung Transplant 2005; 24 (9) 1320-1326
  CrossrefPubMedGoogle Scholar
• 31 Brock MV, Borja MC, Ferber L , et al. Induction therapy in lung transplantation: a prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab. J Heart Lung Transplant 2001; 20 (12) 1282-1290
  CrossrefPubMedGoogle Scholar
• 32 Ailawadi G, Smith PW, Oka T , et al. Effects of induction immunosuppression regimen on acute rejection, bronchiolitis obliterans, and survival after lung transplantation. J Thorac Cardiovasc Surg 2008; 135 (3) 594-602
  CrossrefPubMedGoogle Scholar
• 33 Clinckart F, Bulpa P, Jamart J, Eucher P, Delaunois L, Evrard P. Basiliximab as an alternative to antithymocyte globulin for early immunosuppression in lung transplantation. Transplant Proc 2009; 41 (2) 607-609
  CrossrefPubMedGoogle Scholar
• 34 Shyu S, Dew MA, Pilewski JM , et al. Five-year outcomes with alemtuzumab induction after lung transplantation. J Heart Lung Transplant 2011; 30 (7) 743-754
  CrossrefPubMedGoogle Scholar
• 35 Parekh K, Trulock E, Patterson GA. Use of cyclosporine in lung transplantation. Transplant Proc 2004; 36 (2, Suppl): 318S-322S
  CrossrefPubMedGoogle Scholar
• 36 Kahan BD. Cyclosporine. N Engl J Med 1989; 321 (25) 1725-1738
  CrossrefPubMedGoogle Scholar
• 37 Wiederrecht G, Lam E, Hung S, Martin M, Sigal N. The mechanism of action of FK-506 and cyclosporin A. Ann N Y Acad Sci 1993; 696: 9-19
  CrossrefPubMedGoogle Scholar
• 38 Tedesco D, Haragsim L. Cyclosporine: a review. J Transplant 2012; 2012: 230386
  PubMedGoogle Scholar
• 39 Burdmann EA, Andoh TF, Yu L, Bennett WM. Cyclosporine nephrotoxicity. Semin Nephrol 2003; 23 (5) 465-476
  CrossrefPubMedGoogle Scholar
• 40 Ekberg H, Tedesco-Silva H, Demirbas A , et al; ELITE-Symphony Study. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357 (25) 2562-2575
  CrossrefPubMedGoogle Scholar
• 41 Curtis JJ. Hypertensinogenic mechanism of the calcineurin inhibitors. Curr Hypertens Rep 2002; 4 (5) 377-380
  CrossrefPubMedGoogle Scholar
• 42 Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int 2000; 13 (5) 313-326
  CrossrefPubMedGoogle Scholar
• 43 Jaksch P, Kocher A, Neuhauser P , et al. Monitoring C2 level predicts exposure in maintenance lung transplant patients receiving the microemulsion formulation of cyclosporine (Neoral). J Heart Lung Transplant 2005; 24 (8) 1076-1080
  CrossrefPubMedGoogle Scholar
• 44 Iversen M, Nilsson F, Sipponen J , et al. Cyclosporine C2 levels have impact on incidence of rejection in de novo lung but not heart transplant recipients: the NOCTURNE study. J Heart Lung Transplant 2009; 28 (9) 919-926
  CrossrefPubMedGoogle Scholar
• 45 Sawada S, Suzuki G, Kawase Y, Takaku F. Novel immunosuppressive agent, FK506. In vitro effects on the cloned T cell activation. J Immunol 1987; 139 (6) 1797-1803
  PubMedGoogle Scholar
• 46 Peters DH, Fitton A, Plosker GL, Faulds D. Tacrolimus: a review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 1993; 46 (4) 746-794
  CrossrefPubMedGoogle Scholar
• 47 Taylor JL, Palmer SM. Critical care perspective on immunotherapy in lung transplantation. J Intensive Care Med 2006; 21 (6) 327-344
  CrossrefPubMedGoogle Scholar
• 48 Horning NR, Lynch JP, Sundaresan SR, Patterson GA, Trulock EP. Tacrolimus therapy for persistent or recurrent acute rejection after lung transplantation. J Heart Lung Transplant 1998; 17 (8) 761-767
  PubMedGoogle Scholar
• 49 Hachem RR, Yusen RD, Chakinala MM , et al. A randomized controlled trial of tacrolimus versus cyclosporine after lung transplantation. J Heart Lung Transplant 2007; 26 (10) 1012-1018
  CrossrefPubMedGoogle Scholar
• 50 Keenan RJ, Konishi H, Kawai A , et al. Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Ann Thorac Surg 1995; 60 (3) 580-584 , discussion 584–585
  CrossrefPubMedGoogle Scholar
• 51 Fan Y, Xiao YB, Weng YG. Tacrolimus versus cyclosporine for adult lung transplant recipients: a meta-analysis. Transplant Proc 2009; 41 (5) 1821-1824
  CrossrefPubMedGoogle Scholar
• 52 Zuckermann A, Reichenspurner H, Birsan T , et al. Cyclosporine A versus tacrolimus in combination with mycophenolate mofetil and steroids as primary immunosuppression after lung transplantation: one-year results of a 2-center prospective randomized trial. J Thorac Cardiovasc Surg 2003; 125 (4) 891-900
  CrossrefPubMedGoogle Scholar
• 53 Treede H, Glanville AR, Klepetko W , et al; European and Australian Investigators in Lung Transplantation. Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: results of a prospective, randomized international trial in lung transplantation. J Heart Lung Transplant 2012; 31 (8) 797-804
  CrossrefPubMedGoogle Scholar
• 54 Bush EL, Lin SS. Lung transplantation: advances in immunosuppression. Thorac Surg Clin 2006; 16 (4) 421-433
  CrossrefPubMedGoogle Scholar
• 55 Shapiro R, Young JB, Milford EL, Trotter JF, Bustami RT, Leichtman AB. Immunosuppression: evolution in practice and trends, 1993-2003. Am J Transplant 2005; 5 (4 Pt 2) 874-886
  CrossrefPubMedGoogle Scholar
• 56 Orens JB, Shearon TH, Freudenberger RS, Conte JV, Bhorade SM, Ardehali A. Thoracic organ transplantation in the United States, 1995-2004. Am J Transplant 2006; 6 (5, Pt 2) 1188-1197
  CrossrefPubMedGoogle Scholar
• 57 Hopkins PM, McNeil K. Evidence for immunosuppression in lung transplantation. Curr Opin Organ Transplant 2008; 13 (5) 477-483
  CrossrefPubMedGoogle Scholar
• 58 Sollinger HW. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995; 60 (3) 225-232
  CrossrefPubMedGoogle Scholar
• 59 Kobashigawa J, Miller L, Renlund D , et al; Mycophenolate Mofetil Investigators. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation 1998; 66 (4) 507-515
  CrossrefPubMedGoogle Scholar
• 60 McNeil K, Glanville AR, Wahlers T , et al. Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients. Transplantation 2006; 81 (7) 998-1003
  CrossrefPubMedGoogle Scholar
• 61 Palmer SM, Baz MA, Sanders L , et al. Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection. Transplantation 2001; 71 (12) 1772-1776
  CrossrefPubMedGoogle Scholar
• 62 Speich R, Schneider S, Hofer M , et al. Mycophenolate mofetil reduces alveolar inflammation, acute rejection and graft loss due to bronchiolitis obliterans syndrome after lung transplantation. Pulm Pharmacol Ther 2010; 23 (5) 445-449
  CrossrefPubMedGoogle Scholar
• 63 Terada N, Lucas JJ, Szepesi A, Franklin RA, Domenico J, Gelfand EW. Rapamycin blocks cell cycle progression of activated T cells prior to events characteristic of the middle to late G1 phase of the cycle. J Cell Physiol 1993; 154 (1) 7-15
  CrossrefPubMedGoogle Scholar
• 64 Cole OJ, Shehata M, Rigg KM. Effect of SDZ RAD on transplant arteriosclerosis in the rat aortic model. Transplant Proc 1998; 30 (5) 2200-2203
  CrossrefPubMedGoogle Scholar
• 65 Salminen US, Alho H, Taskinen E, Maasilta P, Ikonen T, Harjula AL. Effects of rapamycin analogue SDZ RAD on obliterative lesions in a porcine heterotopic bronchial allograft model. Transplant Proc 1998; 30 (5) 2204-2205
  CrossrefPubMedGoogle Scholar
• 66 Augustine JJ, Bodziak KA, Hricik DE. Use of sirolimus in solid organ transplantation. Drugs 2007; 67 (3) 369-391
  CrossrefPubMedGoogle Scholar
• 67 King-Biggs MB, Dunitz JM, Park SJ, Kay Savik S, Hertz MI. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation 2003; 75 (9) 1437-1443
  CrossrefPubMedGoogle Scholar
• 68 Groetzner J, Kur F, Spelsberg F , et al; Munich Lung Transplant Group. Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression. J Heart Lung Transplant 2004; 23 (5) 632-638
  CrossrefPubMedGoogle Scholar
• 69 Cattaneo D, Merlini S, Pellegrino M , et al. Therapeutic drug monitoring of sirolimus: effect of concomitant immunosuppressive therapy and optimization of drug dosing. Am J Transplant 2004; 4 (8) 1345-1351
  CrossrefPubMedGoogle Scholar
• 70 Gullestad L, Iversen M, Mortensen SA , et al. Everolimus with reduced calcineurin inhibitor in thoracic transplant recipients with renal dysfunction: a multicenter, randomized trial. Transplantation 2010; 89 (7) 864-872
  CrossrefPubMedGoogle Scholar
• 71 Parada MT, Alba A, Sepúlveda C. Everolimus in lung transplantation in Chile. Transplant Proc 2010; 42 (1) 328-330
  CrossrefPubMedGoogle Scholar
• 72 Roman A, Ussetti P, Zurbano F , et al. A retrospective 12-month study of conversion to everolimus in lung transplant recipients. Transplant Proc 2011; 43 (7) 2693-2698
  CrossrefPubMedGoogle Scholar
• 73 Parada MT, Alba A, Sepúlveda C, Melo J. Long-term use of everolimus in lung transplant patients. Transplant Proc 2011; 43 (6) 2313-2315
  CrossrefPubMedGoogle Scholar
• 74 Bhorade S, Ahya VN, Baz MA , et al. Comparison of sirolimus with azathioprine in a tacrolimus-based immunosuppressive regimen in lung transplantation. Am J Respir Crit Care Med 2011; 183 (3) 379-387
  CrossrefPubMedGoogle Scholar
• 75 Snell GI, Valentine VG, Vitulo P , et al; RAD B159 Study Group. Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial. Am J Transplant 2006; 6 (1) 169-177
  CrossrefPubMedGoogle Scholar
• 76 Snell GI, Levvey BJ, Chin W , et al. Sirolimus allows renal recovery in lung and heart transplant recipients with chronic renal impairment. J Heart Lung Transplant 2002; 21 (5) 540-546
  CrossrefPubMedGoogle Scholar
• 77 Euvrard S, Morelon E, Rostaing L , et al; TUMORAPA Study Group. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med 2012; 367 (4) 329-339
  CrossrefPubMedGoogle Scholar
• 78 Adcock IM, Ito K. Molecular mechanisms of corticosteroid actions. Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace / Fondazione clinica del lavoro, IRCCS [and] Istituto di clinica tisiologica e malattie apparato respiratorio, Universita di Napoli. Seco 2000; 55: 256-266
  PubMedGoogle Scholar
• 79 Meyers BF, Lynch J, Trulock EP, Guthrie TJ, Cooper JD, Patterson GA. Lung transplantation: a decade of experience. Ann Surg 1999; 230 (3) 362-370 , discussion 370–371
  CrossrefPubMedGoogle Scholar
• 80 Retsema J, Fu W. Macrolides: structures and microbial targets. Int J Antimicrob Agents 2001; 18 (Suppl. 01) S3-S10
  CrossrefPubMedGoogle Scholar
• 81 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) 101-109
  PubMedGoogle Scholar
• 82 Kobayashi H, Ohgaki N, Takeda H. Therapeutic possibilities for diffuse panbronchiolitis. Int J Antimicrob Agents 1993; 3 (Suppl. 01) S81-S86
  CrossrefPubMedGoogle Scholar
• 83 Saiman L, Marshall BC, Mayer-Hamblett N , et al; Macrolide Study Group. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003; 290 (13) 1749-1756
  CrossrefPubMedGoogle Scholar
• 84 Anwar GA, Bourke SC, Afolabi G, Middleton P, Ward C, Rutherford RM. Effects of long-term low-dose azithromycin in patients with non-CF bronchiectasis. Respir Med 2008; 102 (10) 1494-1496
  CrossrefPubMedGoogle Scholar
• 85 Halldorsson S, Gudjonsson T, Gottfredsson M, Singh PK, Gudmundsson GH, Baldursson O. Azithromycin maintains airway epithelial integrity during Pseudomonas aeruginosa infection. Am J Respir Cell Mol Biol 2010; 42 (1) 62-68
  CrossrefPubMedGoogle Scholar
• 86 Murphy DM, Forrest IA, Corris PA , et al. Azithromycin attenuates effects of lipopolysaccharide on lung allograft bronchial epithelial cells. J Heart Lung Transplant 2008; 27 (11) 1210-1216
  CrossrefPubMedGoogle Scholar
• 87 Khalifah AP, Hachem RR, Chakinala MM , et al. Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death. Am J Respir Crit Care Med 2004; 170 (2) 181-187
  CrossrefPubMedGoogle Scholar
• 88 Vos R, Vanaudenaerde BM, De Vleeschauwer SI, Van Raemdonck DE, Dupont LJ, Verleden GM. De novo or persistent pseudomonal airway colonization after lung transplantation: importance for bronchiolitis obliterans syndrome?. Transplantation 2008; 86 (4) 624-625 , author reply 635–636
  PubMedGoogle Scholar
• 89 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) 566-570
  CrossrefPubMedGoogle Scholar
• 90 Verleden GM, Dupont LJ. Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation. Transplantation 2004; 77 (9) 1465-1467
  CrossrefPubMedGoogle Scholar
• 91 Yates B, Murphy DM, Forrest IA , et al. Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2005; 172 (6) 772-775
  CrossrefPubMedGoogle Scholar
• 92 Shitrit D, Bendayan D, Gidon S, Saute M, Bakal I, Kramer MR. Long-term azithromycin use for treatment of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant 2005; 24 (9) 1440-1443
  CrossrefPubMedGoogle Scholar
• 93 Jain R, Hachem RR, Morrell MR , et al. Azithromycin is associated with increased survival in lung transplant recipients with bronchiolitis obliterans syndrome. J Heart Lung Transplant 2010; 29 (5) 531-537
  CrossrefPubMedGoogle Scholar
• 94 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) 164-172
  CrossrefPubMedGoogle Scholar