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Diagnosis of Acute Cellular Rejection Using Probe-based Confocal Laser Endomicroscopy in Lung Transplant Recipients

A Prospective, Multicenter Trial

Keller, Cesar A., MD1; Khoor, Andras, MD, PhD2; Arenberg, Douglas A., MD3; Smith, Michael A., MD4; Islam, Shaheen U., MD5

doi: 10.1097/TP.0000000000002306
Original Clinical Science—General
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Background Acute cellular rejection (ACR) in lung transplant recipients requires demonstration of perivascular lymphocytic infiltration in alveolar tissue samples from transbronchial biopsies (TBBs). Probe-based confocal laser endomicroscopy (pCLE) allows in vivo observation of alveolar, vascular, and cellular microstructures in the lung with potential to identify ACR. The objective of our prospective, blinded, multicenter observational study was to identify pCLE findings in patients with ACR diagnosed histopathologically by TBB.

Methods Lung transplant recipients undergoing diagnostic bronchoscopies within 1 year posttransplant for suspected ACR had pCLE video imaging obtained immediately prior to tissue sampling via TBB. Findings of 2 pCLE criteria, abundant alveolar cellularity and perivascular cellularity (PVC), were assessed by 4 investigators familiar with pCLE and compared with histopathologic criteria of ACR to derive sensitivity, specificity, area under the receiver operating characteristic curve, and accuracy. Interobserver agreement was assessed by calculating intraclass coefficient and Fleiss κ. Findings were analyzed before and after a consensus meeting of investigators on interpreting images.

Results Thirty pCLE procedures were performed on 24 patients, 8 showing ACR in TBB. Diagnostic performance and interobserver agreement using pCLE to identify PVC were significantly higher than those of abundant alveolar cellularity (P < 0.01). The number of blood vessels identified with PVC on pCLE was significantly correlated with histopathologic activity grading of ACR (P < 0.01). Perivascular cellularity agreement among investigators significantly improved after consensus meeting (P < 0.01).

Conclusions When found on pCLE, PVC is a feasible and reproducible criterion for assessment of ACR in vivo, but there is a learning curve for image interpretation.

Probe-based confocal laser endomicroscopy can identify acute cellular rejection (ACR) after lung transplantation noninvasively and perivascular cellularity is a feasible and reproducible criterion for assessment of ACR in vivo although there is a learning curve for image interpretation.

1 Department of Transplantation, Mayo Clinic, Jacksonville, FL.

2 Department of Laboratory Medicine & Pathology, Mayo Clinic, Jacksonville, FL.

3 Pulmonary Diseases and Critical Care Medicine Department, University of Michigan, Ann Arbor, MI.

4 Norton Thoracic Institute, Saint Joseph’s Hospital and Medical Center, Phoenix, AZ.

5 Division of Pulmonary and Critical Care Medicine, Medical College of Georgia at Augusta University, Augusta, GA.

Received 25 January 2018. Revision received 13 March 2018.

Accepted 4 April 2018.

None of the authors have disclosures pertaining to this study. Unrelated to the study, Dr. Smith serves as a VATS lobectomy course instructor for Ethicon Endosurgery, for which they contribute $1500 to Norton Thoracic Institute.

Mauna Kea Technologies, Paris, France.

Presented at the American Thoracic Society 2017 International Conference on May 2017, in Washington, DC.

Portions of this manuscript have been published in abstract form: Keller C, Arenberg DA, Smith M, Islam S. Probe-Based Confocal Laser Endomicroscopy in the Diagnosis of Acute Lung Rejection: Results of a Prospective Multicenter Trial. Am J Respir Crit Care Med. 2017;195:A7640.

©2017 Mayo Foundation for Medical Education and Research.

C.A.K. contributed to conception and design; experiments; collection, analysis, and interpretation of the data; generation/collection of the figures and tables; and writing and critical revision of the article. A.K. contributed to analysis and interpretation of the data and critical revision of the article. D.A.A. contributed to conception and design; experiments; collection, analysis, and interpretation of the data; collection of the images; and critical revision of the article. M.A.S. contributed to conception and design; experiments; collection, analysis, and interpretation of the data; collection of the images; and critical revision of the article. S.U.I. contributed to conception and design; experiments; collection, analysis, and interpretation of the data; collection of the images; and critical revision of the article.

Correspondence: Cesar A. Keller, MD, Lung Transplant Program, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224. (keller.cesar@mayo.edu).

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