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. 2017 Jul 7;12(7):e0180281.
doi: 10.1371/journal.pone.0180281. eCollection 2017.

The Prognostic Importance of CXCR3 Chemokine During Organizing Pneumonia on the Risk of Chronic Lung Allograft Dysfunction After Lung Transplantation

Free PMC article

The Prognostic Importance of CXCR3 Chemokine During Organizing Pneumonia on the Risk of Chronic Lung Allograft Dysfunction After Lung Transplantation

Michael Y Shino et al. PLoS One. .
Free PMC article


Rationale: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Fig 1
Fig 1. Study profile.
OP = organizing pneumonia; DAD = diffuse alveolar damage; LB = lymphocytic bronchiolitis; AR = Acute rejection (Grade A1 or higher); BALs = bronchoalveolar lavage.
Fig 2
Fig 2
Immunohistochemistry demonstrating A) CXCL9 and B) CXCL10 expressed from allograft alveolar pneumocytes (green arrows) and interstitial infiltrating mononuclear cells (black arrows). C) CXCL11 expressed from allograft pulmonary vascular endothelial cells (red arrows). D) CXCR3 expressed from allograft infiltrating mononuclear cells (black arrows) and macrophages (blue arrows).
Fig 3
Fig 3. Kaplan-Meier plot for freedom from chronic lung allograft dysfunction (CLAD) by lung transplant recipients who: 1) Never had any allograft injury, 2) Developed OP with “low” BAL CXCR3 ligand concentrations (“low” ≤ median first principal component (PC) of three CXCR3 ligands), 3) Developed OP with “high” BAL CXCR3 ligand concentrations (“high” > median PC of three ligands).

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    1. Christie JD, Edwards LB, Kucheryavaya AY, Benden C, Dobbels F, et al. (2011) The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Lung and Heart-Lung Transplant Report—2011. J Heart Lung Transplant 30: 1104–1122. doi: 10.1016/j.healun.2011.08.004 - DOI - PubMed
    1. Crespo E, Lucia M, Cruzado JM, Luque S, Melilli E, et al. (2015) Pre-transplant donor-specific T-cell alloreactivity is strongly associated with early acute cellular rejection in kidney transplant recipients not receiving T-cell depleting induction therapy. PLoS One 10: e0117618 doi: 10.1371/journal.pone.0117618 - DOI - PMC - PubMed
    1. Sato M, Waddell TK, Wagnetz U, Roberts HC, Hwang DM, et al. (2011) Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant 30: 735–742. doi: 10.1016/j.healun.2011.01.712 - DOI - PubMed
    1. Verleden SE, Ruttens D, Vandermeulen E, Vaneylen A, Dupont LJ, et al. (2013) Bronchiolitis obliterans syndrome and restrictive allograft syndrome: do risk factors differ? Transplantation 95: 1167–1172. doi: 10.1097/TP.0b013e318286e076 - DOI - PubMed
    1. Todd JL, Jain R, Pavlisko EN, Finlen Copeland CA, Reynolds JM, et al. (2014) Impact of forced vital capacity loss on survival after the onset of chronic lung allograft dysfunction. Am J Respir Crit Care Med 189: 159–166. - PMC - PubMed

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