Chest
Volume 123, Issue 6, June 2003, Pages 1825-1831
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Clinical Investigations
Bronchiolitis
Human Leukocyte Antigen Mismatches Predispose to the Severity of Bronchiolitis Obliterans Syndrome After Lung Transplantationa

https://doi.org/10.1378/chest.123.6.1825Get rights and content

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.

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.

Section snippets

Materials and Methods

Lung allograft recipients who received their transplants at our institution were studied. The selection criteria, operative techniques for the donors and recipients, and medical management have been published.1819A cross-sectional analysis of BOS stage was determined at two time points (the 3-year and 4-year transplant anniversaries) using internationally promulgated guidelines23with a minor modification (which allowed transplant recipients who were affected early by BOS and had died before 3

Patients

One hundred eighty-six lung transplants were performed between January 1990 and January 2000. Only 119 transplant recipients had accrued sufficient posttransplant time to reach their 4-year anniversary at the time of this study. Of these patients, 47 had died due to causes other than BOS (ie, graft failure within 90 days posttransplant, 24 patients; infections, 11 patients; sepsis, 4 patients; PTLDs, 3 patients; malignancy, 1 patient; stroke, 1 patient; and others, 3 patients). Eight patients

Discussion

The results in this study demonstrate that the degree of HLA class I loci mismatching independently predicted the severity of BOS at 4 years (or 3 years) after lung transplantation, irrespective of other pretransplant and/or posttransplant variables. We reasoned that the severity of immunologic injury and fibroproliferative response determines the onset, severity, and progression of BOS and took advantage of staging BOS in all patients uniformly at a single institution at a predesignated time

Acknowledgment

The authors thank Steve Wagoner for his continuing support, Cher R. Wilson for her assistance in validating the HLA data, and Drs. Thomas Egan and Frank Detterbeck and the Cardiothoracic Division in the Department of Surgery who performed all of the transplants from which our database is derived. We also thank our lung transplant coordinators, Judy McSweeney, Jean Rea, Kristi Gott, Brandi Mueller, and Ken Davis for their excellent care of the lung transplant candidates and recipients at The

References (29)

  • Y Iwaki et al.

    The HLA matching effect in lung transplantation

    Transplantation

    (1993)
  • K Bando et al.

    Analysis of time-dependent risks for infection, rejection, and death after pulmonary transplantation

    J Thorac Cardiovasc Surg

    (1995)
  • LL Schulman et al.

    Mismatches at the HLA-DR and HLA-B loci are risk factors for acute rejection after lung transplantation

    Am J Respir Crit Care Med

    (1998)
  • A Keogh et al.

    HLA mismatching and outcome in heart, heart-lung, and single lung transplantation

    J Heart Lung Transplant

    (1995)
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    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]).

    This research was funded, in parts, by the National and North Carolina Chapters of the American Lung Association and the Cystic Fibrosis Foundation.

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