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Human Leukocyte Antigen Mismatches Predispose to the Severity of Bronchiolitis Obliterans Syndrome After Lung Transplantation^*

^* From the Division of Pulmonary Diseases and Critical Care Medicine (Drs. Chalermskulrat, Neuringer, Randell, and Aris), Department of Medicine, Department of Pathology and Laboratory Medicine (Dr. Schmitz), School of Medicine, and Department of Biostatistics (Dr. Catellier and Mr. Gurka), School of Public Health, University of North Carolina, Chapel Hill, NC.

Correspondence to: Robert M. Aris, MD, Associate Professor of Medicine Division of Pulmonary Diseases and Critical Care Medicine, 420 Burnett-Womack Building, CB No. 7020 Chapel Hill, NC 27599; e-mail: aris{at}med.unc.edu

Background: Obliterative bronchiolitis (OB) is the most important cause of long-term morbidity and mortality in lung transplant recipients, and probably results from alloimmune airway injury. Bronchiolitis obliterans syndrome (BOS), defined as a staged decline in pulmonary function, is the clinical correlate of OB.

Objective: Evaluation of the risk and severity of BOS on the basis of the incompatibility of donor and recipient human leukocyte antigen (HLA) molecules.

Design: Retrospective cohort study.

Setting: Large university hospital.

Participants: Lung transplant recipients between January 1990 and January 2000.

Measurements: We determined the BOS stage using internationally promulgated guidelines with a minor modification on all recipients at their 4-year transplant anniversary. Recipients whose graft function had deteriorated or who died due to causes other than BOS were excluded from the study. HLA loci mismatches and other covariables, including recipient age, donor age, cytomegalovirus (CMV) mismatch, cold ischemic time, use of cardiopulmonary bypass, ventilatory days, episodes of acute rejection and CMV pneumonitis, mean trough cyclosporin A (CsA) level, episodes of subtherapeutic CsA levels, and histopathology of OB and diffuse alveolar damage were entered into the analysis of BOS predictors.

Results: Sixty-four patients met the inclusion and exclusion criteria of the study at the 4-year posttransplant time point. In univariate analyses, the number of combined HLA-A and HLA-B mismatches was strongly associated with the stage of BOS at 4 years (p = 0.002). This association remained significant after the inclusion of other potential risk factors for BOS in multiple linear regression models. Pretransplant and posttransplant proportional odds models confirmed that the increasing number of combined HLA-A and HLA-B mismatches increased the overall severity of BOS (adjusted odds ratio, 1.84 [p = 0.035] vs 1.69 [p = 0.067], respectively). A trend toward significance was seen with HLA-DR mismatching (p = 0.17).

Conclusions: The degree of HLA class I mismatching between donors and recipients predisposes lung transplant recipients to the development and severity of BOS.

Key Words: bronchiolitis obliterans syndrome • human leukocyte-associated antigen • lung transplant • obliterative bronchiolitis

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