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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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Early high-grade acute rejections (pathologic grade A2 or A3) in recipients of lung allografts are a major risk factor for the subsequent development of obliterative bronchiolitis (OB). We analyzed the risk factors for high-grade acute rejections in 152 recipients of single (100) or bilateral (52) lung allografts transplanted at our institution between 1990 and 1996. Using Kaplan-Meier product limit estimate analysis, there was a 50% probability of grade A2 or A3 rejection by 1 yr after transplant. By univariate analysis, the only significant predictor of early high-grade rejections was the presence of one or more mismatches at the HLA-DR locus (p = 0.038). This association was confirmed using the Cox proportional hazards model for multivariable analysis, with HLA-DR locus mismatch being the only risk factor identified for high-grade rejection (p = 0.036). Using repeated rejection analysis, recipients with one or more matches at the HLA-DR locus had a lower cumulative rate of grade A2 or A3 rejections during the first year compared with recipients with no matches at the HLA-DR locus (0.73 versus 1.32). In addition, recipients with one or more HLA-B locus matches had a lower cumulative rate of grade A2 or A3 rejections in the first year than did recipients with no matches at the HLA-B locus (0.59 versus 1.30). These results indicate that mismatches between donors and recipients at the HLA-DR and HLA-B loci are important risk factors for early high-grade rejections after lung transplantation. Immunosuppressive protocols that are more effective in preventing recipient T-cell activation by donor alloantigens are likely to reduce the rate of high-grade acute rejections in recipients of lung transplants, and may directly impact on the time to onset of OB.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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After lung transplantation, there is a high incidence of acute and chronic rejection that appears to be higher than that observed with other solid organ allografts (1). Although acute allograft rejection episodes are common, they are rarely fatal and tend to respond favorably to augmented immunosuppression. In contrast, obliterative bronchiolitis (OB), which is generally considered to represent chronic allograft rejection, responds poorly to augmented immunosuppression, and is the major cause of long-term morbidity and mortality after lung transplantation (4). A number of studies have identified multiple and high-grade acute rejection episodes as the major risk factors for OB (5), although the pathogenic mechanisms linking acute perivascular rejection to chronic airway obliteration remain undefined. At the present time, there are no guidelines for optimal surveillance and treatment of acute rejections in order to prevent OB.
To begin dissecting the pathogenic mechanisms of OB, we undertook the present study to identify, by univariate and multivariable analyses, the various risk factors for acute rejection after lung transplantation. In particular, we sought to determine whether donor and/or recipient HLA loci influence the development of acute rejection. Since high-grade acute rejections, grade A2 or A3, are known to be particularly powerful predictors of OB (5), these were the clinical end points specifically chosen for study.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Transplant Population
The study population consisted of 152 consecutive patients who underwent lung transplantation (100 single lung, 52 bilateral lung) at our institution between 1990 and 1996. Eighty-two (54%) transplant recipients were women and 70 (46%) were men. The mean age at the time of surgery was 45 ± 15 (SD) yr. Underlying diseases were emphysema (45%), cystic fibrosis (20%), pulmonary fibrosis (16%), pulmonary hypertension (13%), and miscellaneous (6%).
After transplantation, patients were monitored by regular visits in the outpatient department. Complete evaluations were performed weekly for the first 2 mo, biweekly for the next 3 mo, and then monthly thereafter. Mean follow-up time after transplantation was 25 ± 22 (SD) mo and follow-up was complete for all patients.
Immunosuppression
Standard maintenance immune suppression consisted of cyclosporine or tacrolimus, azathioprine, and prednisone. Cyclosporine dosage was adjusted to maintain trough whole-blood cyclosporine levels near 350 ng/ml (TDx; Abbot, Abbott Park, IL) and to maintain a serum creatinine level of 175 mmol/L or less. After the first six postoperative months, trough cyclosporine levels were maintained near 250 ng/ml, and by 1 yr after transplantation levels were maintained near 200 ng/ ml. Tacrolimus dosage was adjusted to maintain trough whole-blood levels between 5 and 15 ng/ml (IMx; Abbot). Prednisone (1 mg/kg/d) was begun immediately postoperatively and tapered to 0.1-0.15 mg/ kg/d by 3 mo after surgery. Azathioprine (2 mg/kg/d) was adjusted to maintain the white blood cell count above 4,000/mm3 and the platelet count above 100,000/mm3.
Diagnosis of Rejection
Surveillance fiberoptic bronchoscopy with transbronchial biopsies was performed on a schedule of 3 wk, 3 mo, 6 mo, 9 mo, and 1 yr after transplantation. In addition, biopsies were performed at any time in the presence of clinical indications, such as cough, fever, and dyspnea; an abnormal chest radiograph; or a decline in spirometry. Follow-up biopsies were performed 4 wk after treated rejection to ensure resolution of rejection. During the second postoperative year, surveillance biopsies were performed every 4 mo, and thereafter, biopsies were obtained every 6 mo.
The bronchoscopic procedure was performed under local lidocaine anesthesia by the transnasal approach, using an Olympus BF P-20 bronchoscope (Olympus Corporation of America, New Hyde Park, NY). At least six and usually eight specimens were obtained from different subsegments and immediately placed in formalin for routine histopathology. Biopsies were graded according to the standard criteria of the Lung Rejection Study Group (8). In this system, acute cellular rejection is defined by the presence of perivascular mononuclear cell infiltration. Acute rejection varies from minimal (grade A1) and mild (grade A2) to moderate (grade A3) and severe (grade A4). Normal pulmonary parenchyma without perivascular infiltrates is considered to have no rejection (grade A0). Airway inflammation is designated grade B; OB is designated grade C. Only histologically proved episodes of high-grade acute perivascular rejection (grade A2 or A3) were included in this analysis. Of the total episodes, 74% were grade A2 and only 24% were grade A3. There were no episodes of grade A4 rejection.
Treatment of Rejection
Episodes of rejection grade A2 or A3 were treated with daily infusion of methylprednisolone, 1 g intravenously, for 3 d. Rejections that persisted after methylprednisolone therapy were treated with OKT3 or anti-thymocyte globulin.
HLA Typing
Recipients and donors were typed for HLA-A, -B, and -DR antigens using monospecific anti-HLA sera from our laboratory together with HLA typing trays for ethnic subgroups obtained from One Lambda, Inc. (Los Angeles, CA). HLA typing was performed using purified T cells for detection of HLA class I antigens and purified B cells for detection of HLA class II antigens. Complete HLA typing for both donor and recipient was available in 93% of cases. Zero, one, and two mismatches occurred at the HLA-A locus in 1, 44, and 55%, respectively; at the HLA-B locus in 0, 22, and 78%, respectively; at the HLA-DR locus in 1, 35, and 64%, respectively.
Analyzed Variables
Variables applied in univariate and multivariable analyses were grouped in five broad categories:
- Preoperative donor variables: Donor age, sex, race, smoking, Gram stain, HLA type, cytomegalovirus (CMV) status
- Preoperative recipient variables: Recipient age, sex, race, diagnosis, preoperative corticosteroids, HLA type, CMV status
- Preoperative donor-recipient matching: Age, sex, race, HLA type, CMV status
- Intraoperative variables: Ischemic time, single versus bilateral lung transplant, cardiopulmonary bypass, surgeon
- Postoperative complications: Ischemia-reperfusion injury, postoperative pneumonia, bronchial ischemia, bronchial dehiscence, bronchial stenosis, diaphragmatic paralysis, CMV pneumonitis
Ischemia-reperfusion was assessed by hypoxemia (PaO2/FIO2) (FIO2, fraction of inspired oxygen) and lung injury scores (9). The diagnosis of pneumonia was based on the presence of a new intrathoracic opacity (other than atelectasis) and either (1) culture, serologic, cytologic, or histopathologic evidence of a specific organism or organisms, or (2) a clinical course in which pulmonary infection appeared highly likely (10). Bronchial ischemia was defined by bronchoscopic visualization of dark, necrotic mucosa overlying the bronchial anastomosis (11). Anastomotic dehiscence was defined as disruption of more than 25% of the circumferential suture line observed at bronchoscopy (11). Stenosis was defined as narrowing of the bronchial lumen to less than 4.9 mm in diameter (the outer diameter of the bronchoscope) (11).
Statistical Analysis
Risk factors for acute rejection were evaluated by two different methods. For the analysis of time-related events, data were analyzed by the Kaplan-Meier product-limit estimate (univariate analysis), and by the Cox proportional hazards model (multivariable analysis). These approaches examined time to first rejection and censored individuals at the time of death. For the analysis of repeated rejections, we used the generalized estimation equations (GEE) approach developed by Zeger and Liang, which allows repeated measures analysis of discrete data, and corrects for correlation among observations in the same individual (12). This approach considered only individuals who survived at least 1 yr after transplantation. All data were analyzed using SAS system software (SAS Institute, Cary, NC).
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RESULTS |
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Time-related Acute Rejection
The probability of high-grade acute rejection (grade A2 or A3) after lung transplantation is shown in Figure 1. The data indicate that 42% of patients developed at least one high-grade acute rejection by 6 mo after transplantation, and that 50% of patients had a high-grade acute rejection by 1 yr after transplantation. The probability of acute rejection appeared to stabilize after the first postoperative year.
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The major risk factors for grade A2 or A3 acute rejection are listed in Table 1. By univariate analysis, only mismatching between recipient and donor at the HLA-DR locus (p = 0.038) was a significant risk factor for acute rejection. Mismatching at the HLA-B locus showed a trend as a risk factor for acute rejection, but did not achieve statistical significance (p = 0.180). In addition, recipients with cystic fibrosis showed a trend (p = 0.084) as a risk factor for acute rejection. Mismatching at the HLA-A locus showed no statistical association with acute rejection, nor did any of the postoperative complications such as reperfusion injury, bronchial ischemia, postoperative pneumonia, or CMV pneumonitis.
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The influence of mismatching between the donor and recipient at the HLA-DR locus on the probability of grade A2 or A3 acute rejection is shown in Figure 2. The upper curve represents recipients with one match at the HLA-DR locus, whereas the lower curve represents recipients with no matches at the HLA-DR locus. The curves are significantly different (p [log-rank] = 0.034). The data show that by 1 yr after transplant, 54% of recipients with no matches at the HLA-DR locus developed high-grade acute rejection, compared with 41% of recipients with one match at the HLA-DR locus (Figure 2).
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By Cox proportional hazards modeling, the only risk factor for acute rejection was mismatching between donor and recipient at the HLA-DR locus (p = 0.036). The risk of acute rejection associated with complete HLA-DR mismatch was 1.8 relative to that associated with one or more matches at the HLA-DR locus (confidence intervals, 1.1 to 2.9).
Cumulative Acute Rejections
The histogram in Figure 3 shows the rate of grade A2 or A3 acute rejections per patient broken down into four quarters, representing those recipients who survived at least 1 yr after transplantation (n = 94). The data demonstrate a high rate of grade A2 or A3 acute rejections during the first year, especially in the first quarter after lung transplantation, with a cumulative rate of 1.2 grade A2 or A3 rejections per patient in the first year.
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The influence of mismatching between the donor and recipient at the HLA-DR locus on the rate of grade A2 or A3 acute rejection is shown in Figure 4. Recipients with one match at the HLA-DR locus had a lower rate of grade A2 or A3 rejections as compared with recipients with no matches at the HLA-DR locus. The cumulative rate of grade A2 or A3 rejection per year was 0.73 for those with one match at the HLA-DR locus as compared with 1.32 for recipients with no matches at the HLA-DR locus.
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The influence of mismatching between the donor and recipient at the HLA-B locus on the rate of grade A2 or A3 acute rejection is shown in Figure 5. Recipients with one match at the HLA-B locus had a lower rate of grade A2 or A3 rejection as compared with recipients with no matches at the HLA-B locus, especially in the first quarter. The cumulative rate of grade A2 or A3 rejection per year was 0.59 for those with one match at the HLA-B locus as compared with 1.30 for recipients with no matches at the HLA-B locus.
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By GEE modeling, two significant risk factors were found for acute rejection: mismatching between donor and recipient at the HLA-B locus (p = 0.03) and mismatching at the HLA-DR locus (p = 0.06) Mismatching at the HLA-A locus showed no statistical association with cumulative acute rejection, nor did any of the other tested variables.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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This study reports data from a single institution examining the various risks factors for acute rejection after lung transplantation. We focused the analysis on high-grade acute rejection, pathologic grade A2 or A3, since these are the known major risk factors for OB (5). The data were analyzed by time-related analysis to include all recipients until the time of death, as well as by repeated rejection analysis to evaluate the effect of repeated episodes of rejection during the first year after transplantation. The data show that grade A2 or A3 acute rejection episodes are common during the first year after lung transplantation, and that mismatches between donors and recipients at the HLA-DR and HLA-B loci are important variables determining postoperative rejection.
The overall incidence of acute rejection in the study population was quite high. The probability of developing at least one episode of high-grade acute rejection by 1 yr after transplantation was 50%, and the cumulative number of high-grade rejections per person per year was 1.2. This high rate of acute rejection after lung transplantation is at the upper end of the range of 43-55% reported from other lung transplant centers (1, 5). The detection of a high rate of acute rejections in the present series may reflect our practice of performing routine surveillance bronchoscopic examination at regular intervals after surgery in the absence of clinical symptoms.
The observed effect of mismatching at the HLA-DR and HLA-B loci on acute rejection after lung transplantation is similar to that observed after transplantation of other solid organs (13). In several series of heart transplant recipients, an absence of HLA-DR mismatch delayed the time to first rejection, reduced the chance of severe rejection, and may have reduced the incidence of transplant-related coronary artery disease (14). In another series of heart transplant recipients, combined mismatch at both HLA-DR and -B loci was associated with higher rejection rates and greater rejection severity (17). These associations were detected in large series of heart transplant recipients, in which such statistical relationships are easier to demonstrate. By comparison, our study was relatively small, and many trends in the data did not achieve statistical significance.
Our analysis of risk factors for acute rejection did not identify certain risk factors that have been previously reported by
others (1). In a large series of lung and heart-lung recipients from Pittsburgh, older donor age (> 40 yr), CMV mismatch
(D+/R
), CMV disease, single-lung transplants, and recipients
with pulmonary hypertension were identified by multivariable
analysis as significant risk factors for acute rejection (1). In
our series, CMV disease may not have emerged as a risk factor
in the time-related analysis since CMV pneumonitis often followed acute rejection. In addition, all recipients (except D/R)
received ganciclovir prophylaxis at the time of augmented immune suppression. No association between rejection and donor age, single-lung transplants, or recipients with pulmonary
hypertension was found. On the other hand, our data did show
a trend for increased rejection in patients with cystic fibrosis.
This may relate to erratic absorption of cyclosporine associated with gastrointestinal dysfunction (18).
The observed association between HLA-DR locus mismatch and increased risk of high-grade rejection implicates an
underlying mechanism of recipient T-cell allorecognition of
donor HLA-DR alloantigens on lung vascular endothelium.
Such a mechanism needs to take into account the absence of
constitutive HLA-DR antigen expression by quiescent endothelium, and provide a rationale as to why donor endothelium
might be activated under certain circumstances, thereby aberrantly expressing DR molecules. Although there is experimental evidence to suggest that early lung injury such as reperfusion edema or postoperative pneumonitis may upregulate the
expression of surface HLA antigens and adhesion molecules (19), our data did not provide any statistical correlation between these complications and acute rejection episodes. Induction of HLA-DR molecules on donor endothelium could be the result,
initially, of elaboration of interferon 
(IFN-) or additional cytokines by recipient CD8 T cells directly recognizing constitutively expressed allogeneic MHC class I molecules, particularly
those originating from the HLA-B locus. Ultimately, these interactions would result in a process of enhanced direct alloantigen recognition by CD4 helper T cells. Elaboration of interleukin 2 (IL-2) by these cells would then amplify the CD8
cytotoxic response to major histocompatibility complex class I
donor alloantigens, resulting in fulminant cellular rejection of
the organ.
The approximately twofold higher frequency of acute rejection for HLA-DR and -B mismatches in this study does not yet justify prospective matching of lung transplant recipients, as is currently done for kidney transplant recipients. Nevertheless, retrospective knowledge of mismatching may be useful in certain situations that currently represent difficult clinical decisions in the management of lung transplant recipients. For example, are there certain subsets of patients in whom follow-up biopsies are necessary after treatment of grade A2 or A3 rejection to ensure that the rejection process has resolved? Should management differ according to the relative risk imposed by HLA-DR or -B locus mismatch status if lymphocytic infiltrates diminish after treatment but do not resolve completely? Recipients who are completely mismatched with their donors may define a high-risk group that requires augmented immune suppression or more vigorous surveillance for diagnosis and treatment of acute rejection.
Acute rejection episodes are readily treatable and rarely fatal. Since the high rate of acute rejections in the first postoperative year has ominous implications regarding subsequent development of OB, the ultimate goal of our analysis was to identify potential pathogenic risk factors for acute rejection in order to modify our current immunosuppressive regimen and reduce the incidence of OB. The data in the present study show that HLA-DR and -B mismatches between donors and recipients are important risk factors for acute rejection after lung transplantation. However, the high incidence of acute rejection episodes in fully HLA-mismatched and partially HLA-mismatched recipients underscores the need for more effective prevention of recipient T-cell activation by donor alloantigens to reduce the rate of rejections after lung transplantation, and, it is hoped, delay the time to onset of OB.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Larry L. Schulman, M.D., Department of Medicine, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032.
(Received in original form July 1, 1997 and in revised form February 10, 1998).
Presented at the ATS International Society Conference, May 1997, San Francisco, California.| |
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