ABSTRACT
Primary graft dysfunction (PGD) is a form of early lung graft dysfunction that is
a major cause of early morbidity and mortality following lung transplantation. Survivors
of PGD have decreased long-term lung function and an increased risk of developing
bronchiolitis obliterans syndrome (BOS), a manifestation of chronic graft dysfunction.
This article reviews the current definition, contributing factors, and guidelines
for grading clinical PGD, as well as controversies surrounding them. The current literature
examining clinical risk factors for PGD is summarized, as are studies exploring molecular
and biochemical markers for PGD prediction and severity. Studies examining the short-
and long-term effects of PGD on lung transplant outcomes are reviewed. Lastly, we
highlight the emerging concepts in lung transplantation that will potentially impact
PGD incidence and outcomes.
KEYWORDS
Primary graft dysfunction - ischemia-reperfusion injury - lung transplantation
REFERENCES
- 1
Christie J D, Bavaria J E, Palevsky H I et al..
Primary graft failure following lung transplantation.
Chest.
1998;
114
51-60
- 2
King R C, Binns O A, Rodriguez F et al..
Reperfusion injury significantly impacts clinical outcome after pulmonary transplantation.
Ann Thorac Surg.
2000;
69
1681-1685
- 3
Christie J D, Kotloff R M, Pochettino A et al..
Clinical risk factors for primary graft failure following lung transplantation.
Chest.
2003;
124
1232-1241
- 4
Arcasoy S M, Kotloff R M.
Lung transplantation.
N Engl J Med.
1999;
340
1081-1091
- 5
Christie J D, Van Raemdonck D, de Perrot M ISHLT Working Group on Primary Lung Graft
Dysfunction et al.
Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part I: introduction
and methods.
J Heart Lung Transplant.
2005;
24
1451-1453
- 6
Arcasoy S M, Fisher A, Hachem R R, Scavuzzo M, Ware L B. ISHLT Working Group on Primary
Lung Graft Dysfunction .
Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part V: predictors
and outcomes.
J Heart Lung Transplant.
2005;
24
1483-1488
- 7
Christie J D, Kotloff R M, Ahya V N et al..
The effect of primary graft dysfunction on survival after lung transplantation.
Am J Respir Crit Care Med.
2005;
171
1312-1316
- 8
Christie J D, Carby M, Bag R, Corris P, Hertz M, Weill D. ISHLT Working Group on Primary
Lung Graft Dysfunction .
Report of the ISHLT Working Group on Primary Lung Graft Dysfunction, II: Definition.
A consensus statement of the International Society for Heart and Lung Transplantation.
J Heart Lung Transplant.
2005;
24
1454-1459
- 9
Daud S A, Yusen R D, Meyers B F et al..
Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans
syndrome.
Am J Respir Crit Care Med.
2007;
175
507-513
- 10
Barr M L, Kawut S M, Whelan T P ISHLT Working Group on Primary Lung Graft Dysfunction
et al.
Report of the ISHLT Working Group on Primary Lung Graft Dysfunction, IV: Recipient-related
risk factors and markers.
J Heart Lung Transplant.
2005;
24
1468-1482
- 11
Whitson B A, Nath D S, Johnson A C et al..
Risk factors for primary graft dysfunction after lung transplantation.
J Thorac Cardiovasc Surg.
2006;
131
73-80
- 12
Prekker M E, Nath D S, Walker A R et al..
Validation of the proposed International Society for Heart and Lung Transplantation
grading system for primary graft dysfunction after lung transplantation.
J Heart Lung Transplant.
2006;
25
371-378
- 13
Prekker M E, Herrington C S, Hertz M I, Radosevich D M, Dahlberg P S.
Early trends in PaO(2)/fraction of inspired oxygen ratio predict outcome in lung transplant
recipients with severe primary graft dysfunction.
Chest.
2007;
132
991-997
- 14
Oto T, Levvey B J, Snell G I.
Potential refinements of the International Society for Heart and Lung Transplantation
primary graft dysfunction grading system.
J Heart Lung Transplant.
2007;
26
431-436
- 15
Christie J, Keshavjee S, Orens J ISHLT Working Group on PGD et al.
Potential refinements of the International Society for Heart and Lung Transplantation
primary graft dysfunction grading system.
J Heart Lung Transplant.
2008;
27
138
- 16
Oto T, Griffiths A P, Levvey B J, Pilcher D V, Williams T J, Snell G I.
Definitions of primary graft dysfunction after lung transplantation: differences between
bilateral and single lung transplantation.
J Thorac Cardiovasc Surg.
2006;
132
140-147
- 17
de Perrot M, Liu M, Waddell T K, Keshavjee S.
Ischemia-reperfusion-induced lung injury.
Am J Respir Crit Care Med.
2003;
167
490-511
- 18
Carter Y M, Gelman A E, Kreisel D.
Pathogenesis, management, and consequences of primary graft dysfunction.
Semin Thorac Cardiovasc Surg.
2008;
20
165-172
- 19
Frank M M.
Complement in the pathophysiology of human disease.
N Engl J Med.
1987;
316
1525-1530
- 20
de Perrot M, Bonser R S, Dark J ISHLT Working Group on Primary Lung Graft Dysfunction
et al.
Report of the ISHLT Working Group on Primary Lung Graft Dysfunction, III: Donor-related
risk factors and markers.
J Heart Lung Transplant.
2005;
24
1460-1467
- 21
Lee J C, Christie J D.
Primary graft dysfunction.
Proc Am Thorac Soc.
2009;
6
39-46
- 22
Meyer D M, Bennett L E, Novick R J, Hosenpud J D.
Effect of donor age and ischemic time on intermediate survival and morbidity after
lung transplantation.
Chest.
2000;
118
1255-1262
- 23
Oto T, Griffiths A P, Levvey B et al..
A donor history of smoking affects early but not late outcome in lung transplantation.
Transplantation.
2004;
78
599-606
- 24
Lee J CKC, Hadjiliadis D, Aahya V N et al..
Risk factors for early vs late primary graft dysfunction [abstract].
Am J Respir Crit Care Med.
2008;
177
A396
- 25
King R C, Binns O A, Rodriguez F et al..
Reperfusion injury significantly impacts clinical outcome after pulmonary transplantation.
Ann Thorac Surg.
2000;
69
1681-1685
- 26
Thabut G, Vinatier I, Stern J B et al..
Primary graft failure following lung transplantation: predictive factors of mortality.
Chest.
2002;
121
1876-1882
- 27
Covarrubias M, Ware L B, Kawut S M Lung Transplant Outcomes Group et al.
Plasma intercellular adhesion molecule-1 and von Willebrand factor in primary graft
dysfunction after lung transplantation.
Am J Transplant.
2007;
7
2573-2578
- 28
Kawut S M, Okun J, Shimbo D et al..
Soluble P-selectin and the risk of primary graft dysfunction after lung transplantation.
Chest.
2009;
136
237-244
- 29
Lee J C, Kuntz C, Kawut S M et al..
Clinical risk factors for the development of primary graft dysfunction [abstract].
J Heart Lung Transplant.
2008;
27
S67-S68
- 30
Cassivi S D, Meyers B F, Battafarano R J et al..
Thirteen-year experience in lung transplantation for emphysema.
Ann Thorac Surg.
2002;
74
1663-1669
discussion 1669-1670
- 31
Fiser S M, Kron I L, McLendon Long S, Kaza A K, Kern J A, Tribble C G.
Early intervention after severe oxygenation index elevation improves survival following
lung transplantation.
J Heart Lung Transplant.
2001;
20
631-636
- 32
Hadjiliadis D, Chaparro C, Reinsmoen N L et al..
Pre-transplant panel reactive antibody in lung transplant recipients is associated
with significantly worse post-transplant survival in a multicenter study.
J Heart Lung Transplant.
2005;
24(7, Suppl)
S249-S254
- 33
Yoshida S, Haque A, Mizobuchi T et al..
Anti-type V collagen lymphocytes that express IL-17 and IL-23 induce rejection pathology
in fresh and well-healed lung transplants.
Am J Transplant.
2006;
6
724-735
- 34
Bobadilla J L, Love R B, Jankowska-Gan E et al..
Th-17, monokines, collagen type V, and primary graft dysfunction in lung transplantation.
Am J Respir Crit Care Med.
2008;
177
660-668
- 35
Sommers K E, Griffith B P, Hardesty R L, Keenan R J.
Early lung allograft function in twin recipients from the same donor: risk factor
analysis.
Ann Thorac Surg.
1996;
62
784-790
- 36
Szeto W Y, Kreisel D, Karakousis G C et al..
Cardiopulmonary bypass for bilateral sequential lung transplantation in patients with
chronic obstructive pulmonary disease without adverse effect on lung function or clinical
outcome.
J Thorac Cardiovasc Surg.
2002;
124
241-249
- 37
Wang Y, Kurichi J E, Blumenthal N P et al..
Multiple variables affecting blood usage in lung transplantation.
J Heart Lung Transplant.
2006;
25
533-538
- 38
Webert K E, Blajchman M A.
Transfusion-related acute lung injury.
Transfus Med Rev.
2003;
17
252-262
- 39
Christie J D, Shah C V, Kawut S M Lung Transplant Outcomes Group et al.
Plasma levels of receptor for advanced glycation end products, blood transfusion,
and risk of primary graft dysfunction.
Am J Respir Crit Care Med.
2009;
180
1010-1015
- 40
dos Santos C C, Okutani D, Hu P et al..
Differential gene profiling in acute lung injury identifies injury-specific gene expression.
Crit Care Med.
2008;
36
855-865
- 41
Li J, Nie J, Chen G et al..
Gene expression profile of pulmonary tissues in different phases of lung ischemia-reperfusion
injury in rats.
J Huazhong Univ Sci Technolog Med Sci.
2007;
27
564-570
- 42
Ray M, Dharmarajan S, Freudenberg J, Zhang W, Patterson G A.
Expression profiling of human donor lungs to understand primary graft dysfunction
after lung transplantation.
Am J Transplant.
2007;
7
2396-2405
- 43
Anraku M, Cameron M J, Waddell T K et al..
Impact of human donor lung gene expression profiles on survival after lung transplantation:
a case-control study.
Am J Transplant.
2008;
8
2140-2148
- 44
Kaneda H, Waddell T K, de Perrot M et al..
Pre-implantation multiple cytokine mRNA expression analysis of donor lung grafts predicts
survival after lung transplantation in humans.
Am J Transplant.
2006;
6
544-551
- 45
Calfee C S, Budev M M, Matthay M A et al..
Plasma receptor for advanced glycation end-products predicts duration of ICU stay
and mechanical ventilation in patients after lung transplantation.
J Heart Lung Transplant.
2007;
26
675-680
- 46
Kawut S M, Okun J, Shimbo D Lung Transplant Outcomes Group et al.
Soluble p-selectin and the risk of primary graft dysfunction after lung transplantation.
Chest.
2009;
136
237-244
- 47
Hoffman S A, Wang L, Shah C V Lung Transplant Outcomes Group et al.
Plasma cytokines and chemokines in primary graft dysfunction post-lung transplantation.
Am J Transplant.
2009;
9
389-396
- 48
Fisher A J, Donnelly S C, Hirani N et al..
Elevated levels of interleukin-8 in donor lungs is associated with early graft failure
after lung transplantation.
Am J Respir Crit Care Med.
2001;
163
259-265
- 49
De Perrot M, Sekine Y, Fischer S et al..
Interleukin-8 release during early reperfusion predicts graft function in human lung
transplantation.
Am J Respir Crit Care Med.
2002;
165
211-215
- 50
Krenn K, Klepetko W, Taghavi S, Lang G, Schneider B, Aharinejad S.
Recipient vascular endothelial growth factor serum levels predict primary lung graft
dysfunction.
Am J Transplant.
2007;
7
700-706
- 51
Christie J D, Robinson N, Ware L B et al..
Association of protein C and type 1 plasminogen activator inhibitor with primary graft
dysfunction.
Am J Respir Crit Care Med.
2007;
175
69-74
- 52
Justice A C, Covinsky K E, Berlin J A.
Assessing the generalizability of prognostic information.
Ann Intern Med.
1999;
130
515-524
- 53
Khan S U, Salloum J, O'Donovan P B et al..
Acute pulmonary edema after lung transplantation: the pulmonary reimplantation response.
Chest.
1999;
116
187-194
- 54
Burton C M, Iversen M, Milman N et al..
Outcome of lung transplanted patients with primary graft dysfunction.
Eur J Cardiothorac Surg.
2007;
31
75-82
- 55
Whitson B A, Prekker M E, Herrington C S et al..
Primary graft dysfunction and long-term pulmonary function after lung transplantation.
J Heart Lung Transplant.
2007;
26
1004-1011
- 56
Christie J D, Sager J S, Kimmel S E et al..
Impact of primary graft failure on outcomes following lung transplantation.
Chest.
2005;
127
161-165
- 57
Fiser S M, Tribble C G, Long S M et al..
Ischemia-reperfusion injury after lung transplantation increases risk of late bronchiolitis
obliterans syndrome.
Ann Thorac Surg.
2002;
73
1041-1047
discussion 1047-1048
- 58
Fisher A J, Wardle J, Dark J H, Corris P A.
Non-immune acute graft injury after lung transplantation and the risk of subsequent
bronchiolitis obliterans syndrome (BOS).
J Heart Lung Transplant.
2002;
21
1206-1212
- 59
Girgis R E, Tu I, Berry G J et al..
Risk factors for the development of obliterative bronchiolitis after lung transplantation.
J Heart Lung Transplant.
1996;
15
1200-1208
- 60
Hachem R R, Khalifah A P, Chakinala M M et al..
The significance of a single episode of minimal acute rejection after lung transplantation.
Transplantation.
2005;
80
1406-1413
- 61
Khalifah A P, Hachem R R, Chakinala M M et al..
Minimal acute rejection after lung transplantation: a risk for bronchiolitis obliterans
syndrome.
Am J Transplant.
2005;
5
2022-2030
- 62
Huang H J, Yusen R D, Meyers B F et al..
Late primary graft dysfunction after lung transplantation and bronchiolitis obliterans
syndrome.
Am J Transplant.
2008;
8
2454-2462
- 63
Halloran P F, Homik J, Goes N et al..
The “injury response”: a concept linking nonspecific injury, acute rejection, and
long-term transplant outcomes.
Transplant Proc.
1997;
29
79-81
- 64
Bharat A, Kuo E, Steward N et al..
Immunological link between primary graft dysfunction and chronic lung allograft rejection.
Ann Thorac Surg.
2008;
86
189-195
discussion 196-197
- 65
Burlingham W J, Love R B, Jankowska-Gan E et al..
IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis
in human lung transplants.
J Clin Invest.
2007;
117
3498-3506
- 66
Hornby K, Ross H, Keshavjee S, Rao V, Shemie S D.
Non-utilization of hearts and lungs after consent for donation: a Canadian multicentre
study.
Can J Anaesth.
2006;
53
831-837
- 67
Ware L B, Wang Y, Fang X et al..
Assessment of lungs rejected for transplantation and implications for donor selection.
Lancet.
2002;
360
619-620
- 68
Oto T.
Lung transplantation from donation after cardiac death (non-heart-beating) donors.
Gen Thorac Cardiovasc Surg.
2008;
56
533-538
- 69
Neyrinck A P, Van De Wauwer C, Geudens N et al..
Comparative study of donor lung injury in heart-beating versus non-heart-beating donors.
Eur J Cardiothorac Surg.
2006;
30
628-636
- 70
De Vleeschauwer S, Van Raemdonck D, Vanaudenaerde B et al..
Early outcome after lung transplantation from non-heart-beating donors is comparable
to heart-beating donors.
J Heart Lung Transplant.
2009;
28
380-387
- 71
Inci I, Zhai W, Arni S et al..
Fibrinolytic treatment improves the quality of lungs retrieved from non-heart-beating
donors.
J Heart Lung Transplant.
2007;
26
1054-1060
- 72
Loehe F, Preissler G, Annecke T, Bittmann I, Jauch K W, Messmer K.
Continuous infusion of nitroglycerin improves pulmonary graft function of non-heart-beating
donor lungs.
Transplantation.
2004;
77
1803-1808
- 73
Rega F R, Wuyts W A, Vanaudenaerde B M et al..
Nebulized N-acetyl cysteine protects the pulmonary graft inside the non-heart-beating
donor.
J Heart Lung Transplant.
2005;
24
1369-1377
- 74
Cypel M, Yeung J C, Hirayama S et al..
Technique for prolonged normothermic ex vivo lung perfusion.
J Heart Lung Transplant.
2008;
27
1319-1325
- 75
Cypel M YJ, Liu M, Chen F et al..
Normothermic human ex vivo lung perfusion (EVLP) for improved assessment of extended
criteria donor lungs for transplantation [abstract].
J Heart Lung Transplant.
2009;
28
S126
James C LeeM.D.
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania
School of Medicine
826 West Gates Bldg., 3400 Spruce St., Philadelphia, PA 19104
eMail: james.lee@uphs.upenn.edu