{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T17:33:04Z","timestamp":1778693584662,"version":"3.51.4"},"reference-count":33,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2019,2,13]],"date-time":"2019-02-13T00:00:00Z","timestamp":1550016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Research Foundation - Flanders","award":["12G8715N"],"award-info":[{"award-number":["12G8715N"]}]},{"name":"The Research Foundation - Flanders:","award":["1500617N"],"award-info":[{"award-number":["1500617N"]}]},{"DOI":"10.13039\/501100010648","name":"UZ Leuven","doi-asserted-by":"publisher","award":["STG\/15\/023"],"award-info":[{"award-number":["STG\/15\/023"]}],"id":[{"id":"10.13039\/501100010648","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004040","name":"KU Leuven","doi-asserted-by":"publisher","award":["C24\/15\/030"],"award-info":[{"award-number":["C24\/15\/030"]}],"id":[{"id":"10.13039\/501100004040","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Standard methods for detecting chronic lung allograft dysfunction (CLAD) and rejection have poor sensitivity and specificity and have conventionally required bronchoscopies and biopsies. Plasma cell-free DNA (cfDNA) has been shown to be increased in various types of allograft injury in transplant recipients and CXCL10 has been reported to be increased in the lung tissue of patients undergoing CLAD. This study used a novel cfDNA and CXCL10 assay to evaluate the noninvasive assessment of CLAD phenotype and prediction of survival from bronchoalveolar lavage (BAL) fluid. A total of 60 BAL samples (20 with bronchiolitis obliterans (BOS), 20 with restrictive allograft syndrome (RAS), and 20 with stable allografts (STA)) were collected from 60 unique lung transplant patients; cfDNA and CXCL10 were measured by the ELISA-based KIT assay. Median cfDNA was significantly higher in BOS patients (6739 genomic equivalents (GE)\/mL) versus STA (2920 GE\/mL) and RAS (4174 GE\/mL) (p &lt; 0.01 all comparisons). Likelihood ratio tests revealed a significant association of overall survival with cfDNA (p = 0.0083), CXCL10 (p = 0.0146), and the interaction of cfDNA and CXCL10 (p = 0.023) based on multivariate Cox proportional hazards regression. Dichotomizing patients based on the median cfDNA level controlled for the mean level of CXCL10 revealed an over two-fold longer median overall survival time in patients with low levels of cfDNA. The KIT assay could predict allograft survival with superior performance compared with traditional biomarkers. These data support the pursuit of larger prospective studies to evaluate the predictive performance of cfDNA and CXCL10 prior to lung allograft failure.<\/jats:p>","DOI":"10.3390\/jcm8020241","type":"journal-article","created":{"date-parts":[[2019,2,14]],"date-time":"2019-02-14T03:21:46Z","timestamp":1550114506000},"page":"241","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Cell-Free DNA and CXCL10 Derived from Bronchoalveolar Lavage Predict Lung Transplant Survival"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2410-7817","authenticated-orcid":false,"given":"Joshua Y.C.","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA"},{"name":"KIT Bio, 2000 University Avenue, Palo Alto, CA 94303, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stijn E.","family":"Verleden","sequence":"additional","affiliation":[{"name":"Leuven Lung Transplant Unit, Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arya","family":"Zarinsefat","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bart M.","family":"Vanaudenaerde","sequence":"additional","affiliation":[{"name":"Leuven Lung Transplant Unit, Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3468-9251","authenticated-orcid":false,"given":"Robin","family":"Vos","sequence":"additional","affiliation":[{"name":"Leuven Lung Transplant Unit, Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geert M.","family":"Verleden","sequence":"additional","affiliation":[{"name":"Leuven Lung Transplant Unit, Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reuben D.","family":"Sarwal","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tara K.","family":"Sigdel","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1927-5058","authenticated-orcid":false,"given":"Juliane M.","family":"Liberto","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Izabella","family":"Damm","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Drew","family":"Watson","sequence":"additional","affiliation":[{"name":"KIT Bio, 2000 University Avenue, Palo Alto, CA 94303, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minnie M.","family":"Sarwal","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA"},{"name":"KIT Bio, 2000 University Avenue, Palo Alto, CA 94303, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.healun.2013.10.022","article-title":"A new classification system for chronic lung allograft dysfunction","volume":"33","author":"Verleden","year":"2014","journal-title":"J. Heart Lung Transplant."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.healun.2016.09.001","article-title":"The Registry of the International Society for Heart and Lung Transplantation: Thirty-third adult lung and heart-lung transplant report-2016; Focus theme: Primary diagnostic indications for transplant","volume":"35","author":"Yusen","year":"2016","journal-title":"J. Heart Lung Transplant."},{"key":"ref_3","first-page":"675","article-title":"The diagnosis of obliterative bronchiolitis after heart-lung and lung transplantation: Low yield of transbronchial lung biopsy","volume":"12","author":"Kramer","year":"1993","journal-title":"J. Heart Lung Transplant."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5440","DOI":"10.21037\/jtd.2017.11.83","article-title":"Acute rejection","volume":"9","author":"Benzimra","year":"2017","journal-title":"J. Thorac. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1097\/TP.0b013e3182a6ee0a","article-title":"Elevated CXCL10 (IP-10) in bronchoalveolar lavage fluid is associated with acute cellular rejection after human lung transplantation","volume":"97","author":"Husain","year":"2014","journal-title":"Transplantation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1111\/ajt.12630","article-title":"Bronchoalveolar lavage cell immunophenotyping facilitates diagnosis of lung allograft rejection","volume":"14","author":"Greenland","year":"2014","journal-title":"Am. J. Transplant."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sacreas, A., Yang, J.Y.C., Vanaudenaerde, B.M., Sigdel, T.K., Liberto, J.M., Damm, I., Verleden, G.M., Vos, R., Verleden, E., and Sarwal, M.M. (2018). The common rejection module in chronic rejection post lung transplantation. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0205107"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2650","DOI":"10.21037\/jtd.2017.07.81","article-title":"Chronic lung allograft dysfunction phenotypes and treatment","volume":"9","author":"Verleden","year":"2017","journal-title":"J. Thorac. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1084\/jem.20122709","article-title":"A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation","volume":"210","author":"Khatri","year":"2013","journal-title":"J. Exp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1111\/j.1600-6143.2009.02645.x","article-title":"Urinary CXCL9 and CXCL10 levels correlate with the extent of subclinical tubulitis","volume":"9","author":"Schaub","year":"2009","journal-title":"Am. J. Transplant."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nrg.2017.12","article-title":"Transplant genetics and genomics","volume":"18","author":"Yang","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6229","DOI":"10.1073\/pnas.1013924108","article-title":"Universal noninvasive detection of solid organ transplant rejection","volume":"108","author":"Snyder","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sigdel, T., Archila, F., Constantin, T., Prins, S., Liberto, J., Damm, I., Towfighi, P., Navarro, S., Kirkizlar, E., and Demko, Z. (2018). Optimizing detection of kidney transplant injury by assessment of donor-derived cell-free DNA via massively multiplex PCR. J. Clin. Med., 8.","DOI":"10.3390\/jcm8010019"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1097\/TP.0b013e318295ee5a","article-title":"A rapid noninvasive assay for the detection of renal transplant injury","volume":"96","author":"Sigdel","year":"2013","journal-title":"Transplantation"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1023\/A:1006260319913","article-title":"Detection of circulating tumour DNA in the blood (plasma\/serum) of cancer patients","volume":"18","author":"Anker","year":"1999","journal-title":"Cancer Metastasis Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0305-7372(02)00077-4","article-title":"Circulating DNA: A new diagnostic gold mine?","volume":"28","author":"Ziegler","year":"2002","journal-title":"Cancer Treat. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13336","DOI":"10.1073\/pnas.1517494112","article-title":"Noninvasive monitoring of infection and rejection after lung transplantation","volume":"112","author":"Martin","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.humimm.2017.03.002","article-title":"Rapid detection of donor cell free DNA in lung transplant recipients with rejections using donor-recipient HLA mismatch","volume":"78","author":"Zou","year":"2017","journal-title":"Hum. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/j.healun.2018.01.1305","article-title":"Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis","volume":"37","author":"Jackson","year":"2018","journal-title":"J. Hear. Lung Transplant."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1183\/09031936.00107514","article-title":"An international ISHLT\/ATS\/ERS clinical practice guideline: Diagnosis and management of bronchiolitis obliterans syndrome","volume":"44","author":"Meyer","year":"2014","journal-title":"Eur. Respir. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1097\/MOT.0000000000000236","article-title":"Chronic lung allograft dysfunction: Evolving practice","volume":"20","author":"Vos","year":"2015","journal-title":"Curr. Opin. Organ Transplant."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"99","DOI":"10.2307\/3001913","article-title":"Comparing individual means in the analysis of variance","volume":"5","author":"Tukey","year":"1949","journal-title":"Biometric"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1111\/ajt.12091","article-title":"Bronchoalveolar lavage as a tool to predict, diagnose and understand bronchiolitis obliterans syndrome","volume":"13","author":"Kennedy","year":"2013","journal-title":"Am. J. Transplant"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2684","DOI":"10.21037\/jtd.2017.07.85","article-title":"Outcomes after lung transplantation","volume":"9","author":"Thabut","year":"2017","journal-title":"J. Thorac. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1111\/ajt.14557","article-title":"OPTN\/SRTR 2016 annual data report: Kidney","volume":"18","author":"Hart","year":"2018","journal-title":"Am. J. Transplant"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.healun.2017.07.019","article-title":"The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth adult heart transplantation report-2017; Focus theme: Allograft ischemic time","volume":"36","author":"Lund","year":"2017","journal-title":"J. Heart Lung Transplant."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1111\/tri.12341","article-title":"Mechanistic differences between phenotypes of chronic lung allograft dysfunction after lung transplantation","volume":"27","author":"Suwara","year":"2014","journal-title":"Transpl. Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1097\/TP.0000000000000269","article-title":"Differential cytokine, chemokine and growth factor expression in phenotypes of chronic lung allograft dysfunction","volume":"99","author":"Verleden","year":"2015","journal-title":"Transplantation"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e12898","DOI":"10.1111\/ctr.12898","article-title":"BALF cytokines in different phenotypes of chronic lung allograft dysfunction in lung transplant patients","volume":"31","author":"Berastegui","year":"2017","journal-title":"Clin. Transplant."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1164\/rccm.201305-0861OC","article-title":"CXCR3 ligands are associated with the continuum of diffuse alveolar damage to chronic lung allograft dysfunction","volume":"188","author":"Shino","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Shino, M.Y., Weigt, S.S., Li, N., Palchevskiy, V., Derhovanessian, A., Saggar, R., Sayah, D.M., Huynh, R.H., Gregson, A.L., and Fishbein, M.C. (2017). The prognostic importance of CXCR3 chemokine during organizing pneumonia on the risk of chronic lung allograft dysfunction after lung transplantation. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0180281"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1165\/rcmb.2015-0278OC","article-title":"Functional Toll-Like Receptor 9 expression and CXCR3 ligand release in pulmonary sarcoidosis","volume":"55","author":"Schnerch","year":"2016","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1164\/rccm.201203-0508OC","article-title":"CXCL10-CXCR3 enhances the development of neutrophil-mediated fulminant lung injury of viral and nonviral origin","volume":"187","author":"Ichikawa","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/2\/241\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:31:38Z","timestamp":1760185898000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/2\/241"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,13]]},"references-count":33,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2019,2]]}},"alternative-id":["jcm8020241"],"URL":"https:\/\/doi.org\/10.3390\/jcm8020241","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,13]]}}}