Impact of Allograft Injury Time of Onset on the Development of Chronic Lung Allograft Dysfunction After Lung Transplantation.
The impact of allograft injury time of onset on the risk of chronic lung allograft dysfunction (CLAD) remains unknown. We hypothesized that episodes of late-onset (≥6 months) allograft injury would produce an augmented CXCR3/ligand immune response, leading to increased CLAD. In a retrospective single-center study, 1894 transbronchial biopsy samples from 441 lung transplant recipients were reviewed for the presence of acute rejection (AR), lymphocytic bronchiolitis (LB), diffuse alveolar damage (DAD), and organizing pneumonia (OP). The association between the time of onset of each injury pattern and CLAD was assessed by using multivariable Cox models with time-dependent covariates. Bronchoalveolar lavage (BAL) CXCR3 ligand concentrations were compared between early- and late-onset injury patterns using linear mixed-effects models. Late-onset DAD and OP were strongly associated with CLAD: adjusted hazard ratio 2.8 (95% confidence interval 1.5-5.3) and 2.0 (1.1-3.4), respectively. The early-onset form of these injury patterns did not increase CLAD risk. Late-onset LB and acute rejection (AR) predicted CLAD in univariable models but lost significance after multivariable adjustment for late DAD and OP. AR was the only early-onset injury pattern associated with CLAD development. Elevated BAL CXCR3 ligand concentrations during late-onset allograft injury parallel the increase in CLAD risk and support our hypothesis that late allograft injuries result in a more profound CXCR3/ligand immune response.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
M Y
MY
Shino
Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
S S
SS
Weigt
Department of Biomathematics, University of California at Los Angeles, Los Angeles, CA.
N
N
Li
Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
A
A
Derhovanessian
Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
D M
DM
Sayah
Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
R H
RH
Huynh
Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
R
R
Saggar
Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
A L
0000-0001-6806-0868
AL
Gregson
Division of Cardiothoracic Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA.
A
A
Ardehali
Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
D J
DJ
Ross
Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
J P
JP
Lynch
Department of Biomathematics, University of California at Los Angeles, Los Angeles, CA.
R M
RM
Elashoff
Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
J A
JA
Belperio
D055371:Acute Lung Injury / Q000175:diagnosis / Q000209:etiology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000175:diagnosis / Q000209:etiology*; D006085:Graft Survival; D006801:Humans; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011650:Pulmonary Alveoli / Q000473:pathology*; D012189:Retrospective Studies; D014184:Transplantation, Homologous
chemokines/chemokine receptors; clinical research/practice; immunobiology; lung (allograft) function/dysfunction; lung failure/injury; lung transplantation/pulmonology; rejection: acute; rejection: chronic; translational research/science
Nat Med. 2002 Jun;8(6):567-73
12042806
J Heart Lung Transplant. 1998 Dec;17(12):1255-63
9883768
Transplantation. 2006 May 27;81(10):1415-20
16732179
Am J Respir Crit Care Med. 2004 Nov 1;170(9):1022-6
15297270
Transplantation. 2005 Nov 27;80(10):1406-13
16340783
Am J Respir Crit Care Med. 2013 Nov 1;188(9):1117-25
24063316
Thorax. 2011 Sep;66(9):748-54
21429899
Transplantation. 2008 Feb 27;85(4):547-53
18347533
Transplantation. 2008 Sep 27;86(6):811-9
18813106
Nature. 2006 May 11;441(7090):235-8
16648838
J Thorac Cardiovasc Surg. 1997 Aug;114(2):195-202
9270635
Am J Transplant. 2012 Jul;12(7):1831-8
22682332
J Heart Lung Transplant. 2009 Sep;28(9):888-93
19716040
J Heart Lung Transplant. 2011 Oct;30(10):1104-22
21962018
Am J Respir Crit Care Med. 2013 Mar 1;187(5):518-26
23328531
PLoS One. 2015 Feb 17;10(2):e0117618
25689405
Am J Transplant. 2009 Aug;9(8):1903-11
19459819
Am J Transplant. 2012 Feb;12(2):438-46
22151926
J Thorac Cardiovasc Surg. 2005 May;129(5):1144-52
15867792
Am J Respir Crit Care Med. 2008 May 1;177(9):1033-40
18263803
Am J Transplant. 2012 Feb;12(2):477-84
22152000
Eur Respir J. 2009 Sep;34(3):676-86
19386686
J Heart Lung Transplant. 2002 Nov;21(11):1206-12
12431494
Am J Transplant. 2005 Aug;5(8):2022-30
15996255
Am J Respir Crit Care Med. 2007 Mar 1;175(5):507-13
17158279
J Immunol. 2003 Nov 1;171(9):4844-52
14568964
Am J Respir Crit Care Med. 2004 Jul 15;170(2):181-7
15130908
Exp Ther Med. 2015 Mar;9(3):1006-1012
25667668
J Heart Lung Transplant. 1996 Dec;15(12):1200-8
8981205
J Heart Lung Transplant. 2002 May;21(5):559-66
11983546
Am J Transplant. 2016 Feb;16(2):640-9
26461171
J Heart Lung Transplant. 2012 Apr;31(4):354-63
22330935
J Immunol. 2002 Jul 15;169(2):1037-49
12097412
Transplantation. 2008 Mar 15;85(5):771-4
18337673
Chest. 1996 Nov;110(5):1150-4
8915212
J Heart Lung Transplant. 1993 Sep-Oct;12(5):713-6
8241207
Eur Respir J. 2008 Apr;31(4):707-13
18057058
J Immunol. 1986 Apr 1;136(7):2348-57
2419430
J Exp Med. 1996 Sep 1;184(3):963-9
9064356
J Exp Med. 1998 Jun 15;187(12):2009-21
9625760
Am J Pathol. 2001 May;158(5):1703-11
11337368
Am J Transplant. 2008 Jul;8(7):1512-22
18513272
Nat Immunol. 2000 Jul;1(1):47-53
10881174
J Heart Lung Transplant. 2002 Mar;21(3):297-310
11897517
J Heart Lung Transplant. 1999 Sep;18(9):828-37
10528744
Am J Surg Pathol. 1993 May;17(5):491-6
8470763
J Heart Lung Transplant. 2006 Nov;25(11):1358-62
17097501
Immunity. 1999 Aug;11(2):163-71
10485651
Am J Transplant. 2012 Mar;12(3):745-52
22123337
J Heart Lung Transplant. 2002 Feb;21(2):271-81
11834356
Transplant Proc. 2012 Jan;44(1):164-6
22310605
Exp Ther Med. 2014 Jul;8(1):237-242
24944628
Am J Respir Crit Care Med. 1999 Mar;159(3):829-33
10051258
Science. 2014 Oct 3;346(6205):98-101
25170049
J Immunol. 2000 Jul 1;165(1):461-72
10861085
Am J Respir Crit Care Med. 2002 Jan 15;165(2):277-304
11790668
J Immunol. 1999 Aug 15;163(4):2267-75
10438971
J Heart Lung Transplant. 2001 Feb;20(2):167
11250258
J Heart Lung Transplant. 1996 Jan;15(1 Pt 1):1-15
8820078
J Heart Lung Transplant. 2007 Dec;26(12):1229-42
18096473
Am J Physiol Lung Cell Mol Physiol. 2004 Jun;286(6):L1129-39
15136293