Research Article: The prognostic importance of CXCR3 chemokine during organizing pneumonia on the risk of chronic lung allograft dysfunction after lung transplantation

Date Published: July 7, 2017

Publisher: Public Library of Science

Author(s): Michael Y. Shino, S. Samuel Weigt, Ning Li, Vyacheslav Palchevskiy, Ariss Derhovanessian, Rajan Saggar, David M. Sayah, Richard H. Huynh, Aric L. Gregson, Michael C. Fishbein, Abbas Ardehali, David J. Ross, Joseph P. Lynch, Robert M. Elashoff, John A. Belperio, Udai P. Singh.

http://doi.org/10.1371/journal.pone.0180281

Abstract

Since the pathogenesis of chronic lung allograft dysfunction (CLAD) remains poorly defined with no known effective therapies, the identification and study of key events which increase CLAD risk is a critical step towards improving outcomes. We hypothesized that bronchoalveolar lavage fluid (BALF) CXCR3 ligand concentrations would be augmented during organizing pneumonia (OP) and that episodes of OP with marked chemokine elevations would be associated with significantly higher CLAD risk.

All transbronchial biopsies (TBBX) from patients who received lung transplantation between 2000 to 2010 were reviewed. BALF concentrations of the CXCR3 ligands (CXCL9, CXCL10 and CXCL11) were compared between episodes of OP and “healthy” biopsies using linear mixed-effects models. The association between CXCR3 ligand concentrations during OP and CLAD risk was evaluated using proportional hazards models with time-dependent covariates.

There were 1894 bronchoscopies with TBBX evaluated from 441 lung transplant recipients with 169 (9%) episodes of OP and 907 (49%) non-OP histopathologic injuries. 62 (37%) episodes of OP were observed during routine surveillance bronchoscopy. Eight hundred thirty-eight (44%) TBBXs had no histopathology and were classified as “healthy” biopsies. There were marked elevations in BALF CXCR3 ligand concentrations during OP compared with “healthy” biopsies. In multivariable models adjusted for other injury patterns, OP did not significantly increase the risk of CLAD when BAL CXCR3 chemokine concentrations were not taken into account. However, OP with elevated CXCR3 ligands markedly increased CLAD risk in a dose-response manner. An episode of OP with CXCR3 concentrations greater than the 25th, 50th and 75th percentiles had HRs for CLAD of 1.5 (95% CI 1.0–2.3), 1.9 (95% CI 1.2–2.8) and 2.2 (95% CI 1.4–3.4), respectively.

This study identifies OP, a relatively uncommon histopathologic finding after lung transplantation, as a major risk factor for CLAD development when considered in the context of increased allograft expression of interferon-γ inducible ELR- CXC chemokines. We further demonstrate for the first time, the prognostic importance of BALF CXCR3 ligand concentrations during OP on subsequent CLAD risk.

Partial Text

Chronic lung allograft dysfunction (CLAD) is the leading cause of death after the first year post-lung transplantation and the major factor limiting long-term survival.[1] There is increasing evidence that CLAD has two distinct phenotypes: restrictive allograft syndrome (RAS) and bronchiolitis obliterans syndrome (BOS).[2–4] RAS is characterized by restrictive physiology on pulmonary function testing with parenchymal infiltrates, sub-pleural reticulation and septal / pleural thickening on high resolution CT scan (HRCT) of the chest, whereas BOS is characterized by obstructive physiology due to fibro-obliteration of the small airways with air trapping evident on chest HRCT. RAS has been associated with significantly higher mortality compared with BOS.[3,5,6] The pathogenesis of CLAD or its phenotypes, RAS and BOS, remains poorly understood with no effective treatment options. The identification and study of key events which increase CLAD and its phenotypes is a critical first step towards understanding its pathogenesis.

With IRB approval, we performed a retrospective review of all lung transplant recipients (LTRs) at UCLA between January 1, 2000 and December 31, 2010. Participants provided full written consent for their medical records to be reviewed for this study. LTRs received a surveillance bronchoscopy with bronchoalveolar lavage (BALF) and transbronchial biopsy (TBBX) at 1, 3, 6 and 12 months post-transplant, as well as during episodes of clinical deterioration. One of three pulmonary pathologists interpreted the biopsies according to the International Multidisciplinary Consensus Statement on Idiopathic Interstitial Pneumonias (OP and DAD)[27], and the International Society for Heart and Lung Transplantation criteria (AR and LB)[28,29] Biopsy data were coded for the presence or absence of OP, DAD, LB and AR (grade A1 or greater). TBBXs with no histopathologic evidence of allograft injury were considered “healthy”. Ungradable biopsies were considered to be a missing value. Study participants were aged 20 to 79 with a mean age of 60.

The identification and study of key risk factors of CLAD pathogenesis is a critical step towards improving outcomes after lung transplantation. Prior studies have established AR, LB and DAD as strong risk factors for CLAD development [9,13,14,23,24]. However, there is a paucity of studies evaluating the association between OP and CLAD. In this study, we evaluated the association between OP and CLAD using multivariable analysis adjusting for other allograft injury patterns (DAD, AR, LB) as well as the prognostic significance of BALF CXCR3 chemokine concentrations. We evaluated 690 BALF samples from 324 recipients and found marked elevations in all three CXCR3 ligands during OP compared with “healthy” samples. In multivariable models adjusted for other injury patterns, OP did not significantly increase the risk of CLAD when BAL CXCR3 chemokine concentrations were not taken into account. However, OP with elevated CXCR3 ligands markedly increased CLAD risk in a dose-response manner. An episode of OP with CXCR3 concentrations greater than the 25th, 50th and 75th percentiles had HRs for CLAD of 1.5 (95% CI 1.0–2.3), 1.9 (95% CI 1.2–2.8) and 2.2 (95% CI 1.4–3.4), respectively. This study identifies OP, a relatively uncommon histopathologic finding after lung transplantation as a major risk factor for CLAD development when considered in the context of increased allograft expression of interferon-γ inducible ELR- CXC chemokines. Furthermore, it demonstrates for the first time, the prognostic importance of BALF CXCR3 ligand concentrations during OP on subsequent CLAD risk.

 

Source:

http://doi.org/10.1371/journal.pone.0180281

 

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