(Chest. 2003;123:1825-1831.)
© 2003
American College of Chest Physicians
Human Leukocyte Antigen Mismatches Predispose to the Severity of Bronchiolitis Obliterans Syndrome After Lung Transplantation*
Worakij Chalermskulrat, MD;
Isabel P. Neuringer, MD, FCCP;
John L. Schmitz, PhD;
Diane J. Catellier, PhD;
Matthew J. Gurka, MS;
Scott H. Randell, PhD and
Robert M. Aris, MD
* 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
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Abstract
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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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Introduction
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Lung transplantation has become an established therapeutic option for patients with end-stage lung disease. Despite a reasonable 1-year posttransplant actuarial survival rate of 73.5%, the 5-year actuarial survival rates of single and double lung transplants are 45.1% and 50.0%, respectively,1
and are not as auspicious as those rates achieved after the transplantation of other solid organs. Obliterative bronchiolitis (OB), which is generally considered to be synonymous with chronic lung allograft rejection, is the most significant cause of long-term morbidity and mortality.1
The standardization of nomenclature and staging of chronic lung allograft dysfunction due to OB has been developed2
and updated.3
The clinical entity of OB has been termed bronchiolitis obliterans syndrome (BOS) and is staged using fractional declines in the FEV1 from baseline values. Once the presence of BOS is established, however, pulmonary function losses rarely are regained, and progressive graft deterioration and death are common despite therapeutic efforts.1
Identifying the risk factors will guide future research in the areas of pathogenesis and therapy for BOS. Meanwhile, mitigating the risk factors for BOS is essential to improve lung transplant outcomes.
Human leukocyte antigen (HLA) matching of donors and recipients clearly improves outcomes after hematopoietic cell, kidney, and heart transplantation. Several smaller studies and, a more recent, larger study have noted an association between HLA mismatching and lung graft survival,4
5
patient survival,6
7
acute rejection,8
9
and the presence or absence of BOS.10
11
12
13
However, the association between HLA mismatches and BOS has been controversial in the literature, as there are more studies showing no association than those finding an association.7
10
11
12
13
14
15
16
17
As a result, the most recent consensus from the International Society of Heart and Lung Transplantation does not recognize HLA mismatching as an established risk factor for BOS.3
The conflicting results on this subject are due predominantly to the small sample sizes and methodological differences among studies. Many previous analyses have largely viewed patients with BOS as being homogeneous, irrespective of the time of onset, severity, or progression of BOS or were limited by an insufficient length of follow-up time. For example, a patient may be staged as BOS 0 at 4 months posttransplant and yet the same patient may be at BOS stage 3 at 2 years posttransplant. The length of follow-up in such a case would affect the analysis of any predictor of BOS. We hypothesized that immune responses are involved in the development of BOS and that mismatched donor HLA alloantigens provide the immunologic stimulus that increases the advent and, more importantly, the severity of BOS. Using the same cohort, we studied the associations between other pretransplant and posttransplant risk factors and the severity of BOS. The independent risk factors for the severity of BOS were integrated into two proportional odds models, one of which included pretransplant and posttransplant variables and the other of which included only pretransplant variables. These models provided us with invaluable tools with which to predict objectively the development and severity of BOS in lung transplant recipients.
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Materials and Methods
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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.18
19
A cross-sectional analysis of BOS stage was determined at two time points (the 3-year and 4-year transplant anniversaries) using internationally promulgated guidelines2
3
with a minor modification (which allowed transplant recipients who were affected early by BOS and had died before 3 or 4 years to remain in the analysis as BOS stage 4) [Table 1 ]. While choosing the 3-year and 4-year transplant anniversaries was somewhat arbitrary, selecting a specific time point to analyze BOS severity may eliminate potential inaccuracies in assessing patients who had different posttransplant follow-up times and dissimilar rates of progression of BOS. Patients were included in this study if they had survived to the anniversary time points or had died of BOS beforehand. They were excluded from the study if they had died of non-BOS causes, their immunosuppression therapy had been reduced for the treatment of posttransplant lymphoproliferative disorders (PTLDs), they had undergone a retransplant, or HLA data were not available. Pulmonary function results were obtained utilizing a laboratory or home spirometer, both of which generated data meeting the American Thoracic Society standards.20
21
This study was conducted in accordance with the guidelines of the Committee on the Protection of the Rights of Human Subjects of the University of North Carolina at Chapel Hill.
Primary and Secondary Outcomes Measurement
All outcome measurements were obtained from a comprehensive electronic database at University of North Carolina hospitals that captured all clinical, pathologic, and radiologic data during the study period. HLA typing was performed by standard complement-dependent cytotoxicity testing.22
Recipient peripheral blood mononuclear cells, donor lymph node cells, or peripheral blood mononuclear cells were used for class I typing, while magnetic bead-purified B lymphocytes were used for class II typing. Split antigens were defined, when possible, and, when applicable, matching was based on the broad designations. All lung biopsy specimens during the first 2 postoperative years were reviewed. Acute and chronic rejection were diagnosed by testing of lung biopsy specimens using standard nomenclature.23
The number of grade 2 or higher acute perivascular rejection episodes was used in the analysis. Acute airway rejection was not included due to the low sensitivity of transbronchial biopsy. Cytomegalovirus (CMV) pneumonitis was defined by the presence of characteristic cytopathology. Cold ischemic time was defined as the (mean) interval from the application of the aortic cross-clamp during harvesting until reperfusion of the graft in the recipient. The degree of ischemia-reperfusion injury was assessed by the use of cardiopulmonary bypass (CPB), the number of ventilation days, and the presence of diffuse alveolar damage (DAD) on lung biopsy specimens during the first 30 days. Whole blood, trough cyclosporin A (CsA; Abbott Laboratories; Abbott Park, IL) levels of < 200 ng/mL were defined as subtherapeutic. Clinically significant subtherapeutic CsA level was defined when > 10% of all measured levels fell to < 200 ng/mL during the first year.
Statistical Analysis
Univariate analyses were performed to determine whether there were associations between BOS stage at 4 years and potential predictor variables. Spearman correlation coefficients and the Mantel-Haenszel nonparametric test were used to assess the associations between BOS stage and continuous variables (ie, recipient and donor age, ischemic time, ventilator days, CsA level, and acute rejection) and categoric variables (ie, HLA mismatches, CPB, DAD, CMV pneumonitis, clinical subtherapeutic CsA, and OB).
Pretransplant and posttransplant variables were included in the multivariate analyses to determine the risk of different BOS severity stages. Backward stepwise proportional odds models were used to obtain a reduced set of the most influential variables. Age was kept in our models due to the broad age distribution in our cohort. In these pretransplant and posttransplant models, the odds ratios of fatal BOS (stage 4) relative to nonfatal BOS (stages 1, 2, or 3) or no BOS (stage 0), and nonfatal BOS relative to no BOS were assumed and were tested to be constant. Score tests were used to verify the assumption of the proportionality of odds.24
Therefore, these models analyzed general trends toward more severe BOS stages. Analyses were performed using a statistical software package (SAS, version 8.0124; SAS Institute; Cary, NC).
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Results
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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 were excluded due to missing HLA data (six patients), altered immunosuppression for PTLD (one patient), or retransplantation (one patient). Thus, 64 patients remained for the final analysis at the 4-year anniversary time point. In a similar fashion, 72 patients remained for analysis at the 3-year anniversary time point. Since the third and fourth year anniversary analyses produced similar results, the data in this report pertain only to the patients who were staged for BOS at the 4-year anniversary (64 patients). The characteristics of these patients are shown in Table 2
and reflect those who received transplants but were not included in these analyses.
Univariate Analysis
HLA Mismatches and BOS:
Total HLA mismatches were strongly associated with BOS stage at 4 years (p = 0.004). Individually, HLA-B and HLA-A mismatches were more strongly correlated with BOS stage at 4 years (p = 0.005 and 0.052, respectively) than were mismatches at the HLA-DR locus (p = 0.170). Further analysis of the number of combined HLA-A and HLA-B mismatches showed a stronger association with BOS stage (p = 0.002) than did mismatches at any single HLA locus (Table 3
, Fig 1
).
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Figure 1. BOS stage category at 4 years vs the number of combined HLA-A and HLA-B mismatches. In univariate analysis, BOS stage category (No BOS [stage 0], nonfatal BOS [stages 1, 2, and 3], and fatal BOS [stage 4]) was strongly associated with the number of combined HLA-A and HLA-B mismatches, which is shown as the percentage of patients in each HLA mismatch category (ie, 0 to 1, 2, 3, or 4) [p = 0.002]. After adjusting for potential covariables, the posttransplant proportional odds model confirms this association (AOR, 1.84; p = 0.04).
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Recipient Age, Acute Rejection, and BOS:
Recipient age was inversely correlated with BOS stage at 4 years (p = 0.015) [Table 3
]. This association remained after adjusting for underlying lung disease (cystic fibrosis). The number of episodes of grade 2 or higher acute rejection was strongly associated with BOS stage (p = 0.002) [Table 3
].
Nonpredictors of BOS:
Other variables available to clinicians pretransplant (ie, donor age and cold ischemic time) and posttransplant (ie, mechanical ventilator days, presence of DAD, presence of CMV pneumonitis, mean CsA level, and clinically significant subtherapeutic CsA levels) were not significantly associated with BOS stage at 4 years (p > 0.2 for each). However, there was a nonsignificant trend suggesting that the use of CPB was associated with BOS (p = 0.12; Table 3
).
Other Important Correlations:
Total HLA mismatches were significantly associated with the number of grade 2 or higher acute rejection episodes (p = 0.001). There were too few histologically confirmed cases of OB to analyze its potential association with HLA mismatches. However, BOS stage at 4 years was associated with the histopathologic diagnosis of OB in lung specimens obtained during the first 2 years (p = 0.001).
Multivariate Analyses
Pretransplant Proportional Odds Model:
The pretransplant proportional odds model (using only variables available pretransplant) showed that the effect of increasing numbers of combined HLA-A and HLA-B mismatches increased the overall severity of BOS at 4 years. With each increment in the number of combined HLA-A and HLA-B mismatches, the recipient age-adjusted odds for developing a more severe BOS stage increased by a factor of 1.84 (p = 0.035) [Table 4
]. No other pretransplant variable, including recipient age, was found to be independently predictive of BOS stage.
Posttransplant Proportional Odds Model:
For the model using variables that were available both pretransplant and posttransplant, the number of episodes of grade 2 or higher acute rejection was associated with BOS stage at 4 years (adjusted odds ratio [AOR], 1.70; p = 0.026) [Table 4
]. There was also a strong trend suggesting that a greater number of HLA-A and HLA-B mismatches was associated with higher BOS stage at 4 years (AOR, 1.69; p = 0.067) [Table 4
] even after adjusting for acute rejection.
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Discussion
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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 point after lung transplant when the prevalence of BOS is high. Our novel statistical approach improved our power to detect an association between BOS stage and HLA mismatches, and our data are consistent with larger databases obtained from kidney and heart transplant recipients. While the best time point to conduct these analyses is debatable, we found similar results at 3 and 4 years posttransplant, time points at which the majority of lung transplant recipients who will develop BOS already have done so.
The influence of HLA molecules and/or HLA peptides on inducing an alloimmune response is likely not uniform across different HLA antigens or among different organ grafts and has not been well-defined after lung transplantation. Our results are in agreement with those of several previous studies showing that mismatches at the HLA class I loci were associated with BOS,10
11
12
13
describing the associations between BOS and anti-HLA alloantibodies directed against donor-mismatched class I peptides,10
25
and demonstrating that indirect allorecognition of HLA class I peptides initiated BOS.26
We have extended these results by showing that HLA class I mismatches also increase the risk of more severe BOS after lung transplantation. As a simple example, one HLA-A and HLA-B mismatch between recipient and donor will create a 1.84 times higher chance of the recipient experiencing a higher stage of BOS after lung transplantation than recipients with complete HLA-A and HLA-B matching (Table 4)
. Although others have reported12
that HLA-A mismatches predicted the occurrence of BOS using a posttransplant model, our analysis showed, for the first time, that prior to the time of transplant, one can objectively, albeit imperfectly, predict the severity of posttransplant BOS solely on the basis of donor-recipient HLA incompatibility. This finding, if authenticated, may yield an important strategy (ie, donor-recipient HLA matching) to mitigate the influence of BOS on the premature demise of lung transplant recipients.
The current standard of practice is for donor lungs and heart-lung blocs to be allocated to recipients without consideration of the extent of HLA mismatching. Because of its high polymorphicity, the likelihood that HLA loci will be well-matched between donor and recipient by chance is extremely small, as only 4.6% of the recipients in the International Society of Heart and Lung Transplantation registry received two or fewer total HLA mismatch lung grafts.7
In light of the acceptance of increasingly longer cold ischemic times for most lung grafts (with the possible exception of marginal donors),16
17
27
28
the ability to perform HLA matching may become a viable approach and have a considerable impact on lung transplant outcomes once the HLA typing technology is more advanced.
Our study found that acute rejection was an important clinical risk factor for BOS. As acute rejection has been shown to be associated with HLA mismatches in our study and in others,8
HLA mismatches and acute rejection are probably not truly independent. Yet, in our posttransplant multivariate analysis, adjusting for the occurrence of acute rejection did not fundamentally negate the relationship between HLA mismatches and BOS stage. We found no correlation between CMV pneumonitis and BOS stage at 4 years, nor did we find measures of ischemia-reperfusion injury, including number of ventilator days, histologic evidence of DAD, and the use of CPB, with which to predict BOS, confirming the observations of a previous study.10
Another possible cause of BOS is inadequate immunosuppression therapy. Although monitoring trough CsA levels has been generally accepted and practiced for the past decade, we found that neither the mean level nor the clinically significant subtherapeutic CsA levels during the first year posttransplant predicted BOS stage at 4 years. This result suggests that maintaining therapeutic trough CsA levels does not guarantee the prevention of BOS and that subtherapeutic levels may not necessarily promote BOS. In addition, our failure to find an association between subtherapeutic CsA levels and BOS suggests either that BOS is not associated with low CsA levels, that our study was underpowered to find this association given the strong influence of HLA mismatching, or that trough levels of CsA may not represent the best means with which to judge immunosuppression at the cellular level.
We recognize several shortcomings in our study, the major one being our relatively small patient number, which was primarily due to the expectedly low 4-year survival rate of lung transplant recipients. However, our rigorous approach, assessing the association between HLA mismatches and the severity of BOS instead of the presence or absence of BOS, has partially overcome the limitation of the small population size obtained from our institution. Second, our center is a national referral center for cystic fibrosis, which possibly could result in selection bias. Third, we found that the current definition and standardization for the staging of BOS, while very helpful to the clinician, is not without limitations. For example, any initial postoperative insult and inability to reach peak lung function may adversely affect the baseline spirometric values and, subsequently, the designated BOS stage. Moreover, BOS stage may be influenced by the type of transplant procedure (ie, single or bilateral) and/or the underlying lung disease.29
However, given the relative homogeneity of our study population, the staging of BOS in these patients was less disturbed by such factors. Last, using retrospective data on the serologic typing of HLA antigens, as used in our study, and in most studies, to assess the risk of HLA mismatches and other organ transplant survival factors may not be as accurate as other molecular methods that are currently being developed.
Given the rapid increase in the number of patients who are on the national lung transplant waiting list and a critically short graft supply, efficient graft allocation to the most suitable recipients is crucial for the best possible outcomes. Our findings are of particular importance in the reevaluation of the lung organ distribution schema. A multicenter retrospective analysis to confirm our results is the essential next step toward the possible modification of the allocation algorithm. Simultaneously, research into the areas of organ preservation and HLA typing technologies are vital. Meanwhile, lung transplant recipients who have received an allograft with a higher degree of HLA class I mismatches may deserve closer surveillance studies or more aggressive immunomodulation.
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Acknowledgements
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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 University of North Carolina at Chapel Hill.
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Footnotes
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Abbreviations: AOR = adjusted odds ratio; BOS = bronchiolitis obliterans syndrome; CMV = cytomegalovirus; CPB = cardiopulmonary bypass; CsA = cyclosporin A; DAD = diffuse alveolar damage; HLA = human leukocyte antigen; OB = obliterative bronchiolitis; PTLD = posttransplant lymphoproliferative disorders
This research was funded, in parts, by the National and North Carolina Chapters of the American Lung Association and the Cystic Fibrosis Foundation.
Received for publication June 27, 2002.
Accepted for publication December 17, 2002.
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References
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Abstract
Introduction
