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Ann Thorac Surg 2002;73:1041-1048
© 2002 The Society of Thoracic Surgeons
a Division of Thoracic and Cardiovascular Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA
* Address reprint requests to Dr Kron, Department of Thoracic and Cardiovascular Surgery, University of Virginia Health Sciences Center, Lee St, Rm 2753, Charlottesville, VA 22908, USA
e-mail: ikron{at}virginia.edu
Presented at the Forty-eighth Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 8–10, 2001.
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Abstract |
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Methods. Data on 134 patients who had lung transplantation between January 1, 1990 and January 1, 2000, was used for univariate and multivariate logistic regression analysis.
Results. After lung transplantation, 115 patients (115 of 134, 86%) survived more than 3 months. In that group, 41 patients developed BOS, of which 23 had progressive disease. Univariate analysis revealed that ischemia-reperfusion injury (p = 0.017) and two or more acute rejection episodes (p = 0.032) were predictors of BOS onset, whereas ischemia-reperfusion injury (p = 0.011) and cytomegalovirus infection (p = 0.009) predicted progressive BOS. Multivariate logistic regression analysis showed that ischemia-reperfusion injury was an independent predictor for both BOS development and BOS progression. Two or more acute rejection episodes were also an independent predictor of BOS development, whereas cytomegalovirus infection was an independent predictor of progressive BOS.
Conclusions. Ischemia-reperfusion injury increases the risk of BOS after lung transplantation.
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Introduction |
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Acute pulmonary graft dysfunction secondary to ischemia-reperfusion injury continues to be the most common cause of early mortality after lung transplantation [6–8]. Ischemia-reperfusion injury involves neutrophil infiltration into lung tissue followed by release of oxygen radicals and proteases that can damage the surrounding parenchyma [9, 10]. This can result in severe acute pulmonary dysfunction in the early postoperative period [11]. This damage, however, may also result in a permanent lung injury that could predispose patients to late BOS. Our hypothesis was that ischemia-reperfusion injury after lung transplantation increases the risk of late BOS. To test this hypothesis, we performed a multivariate analysis of our lung transplant population in the early and late postoperative periods.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentDiscussionReferences |
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2 and Student’s t tests. Multivariate logistic regression analysis was also performed using all variables that showed at least a trend (p < 0.20) toward an increased risk of either BOS development or progressive BOS based on univariate analysis. Data are expressed as mean ± standard error of the mean with p values less than or equal to 0.05 considered significant.
Perioperative immunosuppresion and infection prophylaxis
Induction immunosuppressive therapy consisted of cyclosporin (3 to 6 mg/kg), azathioprine (2.5 mg/kg), antithymocyte globulin (ATGAM 15 mg/kg; Upjohn, Kalamazoo, MI), and 500 mg of methylprednisone. The initial dose of methylprednisone was followed by a gradual steroid taper. The initial dose of ATGAM was followed by a 10-mg/kg dose on postoperative day 1 and 7.5 mg/kg doses on postoperative days 2 and 3. Long-term immunosuppression was started with a triple drug regimen of prednisone, cyclosporin, and azathioprine.
Perioperative antibacterial agents consisted of cefazolin for the first 24 hours after transplant. Patients who received lungs having a predominate organism in the donor bronchus were changed to appropriate antibiotic coverage. Recipients who were CMV negative who received CMV positive lungs were considered to be at risk for CMV infection and received appropriate prophylaxis with postoperative ganciclovir. Postoperative and long-term Pneumocystis carinii prophylaxis was achieved with either trimethoprim/sulfamethoxazole or aerosolized pentamidine.
Ischemia-reperfusion injury
The requirements for the diagnosis of ischemia-reperfusion injury were clinical suspicion, appropriate chest roentgenogram findings, and at least moderate pulmonary dysfunction (oxygenation index, > 7) in the first 24 hours after transplantation. The oxygenation index was determined using the equation: 
[12]. Calculation of the oxygenation index started after the patient was transferred from the operating room to the intensive care unit.
Acute rejection
Treatment strategies for acute rejection have gradually evolved since the early (1990 to 1995) transplant era at our institution. For the majority of patients in the early transplant era, the diagnosis of acute rejection was based on biopsy findings. During more recent years, however, clinical suspicion has been used with increasing frequency to diagnose patients with acute rejection. Thus for this study, acute rejection episodes were defined by one of two methods. Patients with lung biopsies showing least grade 2A perivascular lymphocyte infiltration were considered to have acute rejection. Patients diagnosed with acute rejection based on clinical suspicion followed by an appropriate response to high dose steroids or OKT3 were also included in the study. Patients with two or more acute rejection episodes within the first 6 months after transplantation were considered to have significantly more rejection episodes than their counterparts and were used for statistical analysis.
Cytomegalovirus infection
Cytomegalovirus infections were diagnosed by a variety of methods. Patients with lung biopsy specimens showing characteristic CMV inclusions in association with an inflammatory infiltrate were considered to have CMV pneumonitis. Cytomegalovirus infections diagnosed by CMV culture, serologic demonstration of a significant increase in CMV immunoglobulin G, or new onset of CMV antigenemia based on the early antigen fluorescent foci test were also included in the CMV infection group. The presence of CMV infection within the first 6 months after transplantation was considered as a possible risk factor for BOS development. Patients with CMV infection were given at least 6 weeks of intravenous ganciclovir.
Pneumonia
The diagnosis of pneumonia required clinical suspicion, appropriate chest roentgenogram findings, substantiating microbiologic results, and institution of appropriate antibiotic therapy. Isolated cultures not requiring treatment were excluded. Patients that were believed to be colonized with an organism were likewise not considered to have pneumonia. Patients receiving antibiotic treatment for organisms isolated from the donor bronchus at the time of transplantation were also not considered to have pneumonia. Patients diagnosed with bronchitis were similarly excluded.
Bronchiolitis obliterans syndrome
Pulmonary function tests were used to identify patients with BOS as outlined by the International Society of Heart and Lung Transplantation guidelines for clinical staging of chronic dysfunction in lung allografts [13]. Briefly, baseline forced expiratory volume in 1 second (FEV1) was determined by taking the average of the two highest consecutive FEV1 values after lung transplantation, with such measurements being obtained 3 to 6 weeks apart. Patients with a subsequent unexplained decrease in FEV1 to 66% to 80% of baseline value for two consecutive measurements, obtained at least 3 weeks apart, met criteria for mild BOS (stage I). Patients with an unexplained decrease in FEV1 to 51% to 65% and 50% or less of baseline value for two consecutive measurements, obtained at least 3 weeks apart, were considered to have moderate (stage II) and severe (stage III) BOS, respectively. Time until onset of BOS was defined as the time until initial decline in pulmonary function tests (PFT) to the corresponding BOS stage after transplantation.
Patients referred to as having progressive disease are those that deteriorated to stage II or stage III BOS based on PFT data. Patients who did not have adequate PFT criteria for progressive disease but died from BOS (n = 4) were also considered to have progressive disease. Patients who had stage I BOS but died secondary to other causes were not considered to have progressive disease.
The BOS staging system used in the study is a reflection of the current status of the lung transplant population. Patients who had an unexplained deterioration to stage II or III BOS but who returned to stage I by the time of the study (March 1, 2000) were considered to have stage I disease. Patients who died of BOS based on autopsy but did not have the PFT data necessary for the diagnosis were considered to have both BOS onset and progressive BOS starting on the day of death.
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Results |
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Bronchiolitis obliterans syndrome
Of the 115 survivors, 48 (48 of 115, 42%) developed at least stage I BOS. Twenty-three of the patients who had stage I BOS (29 of 48, 50%) developed progressive disease (stage II BOS, stage III BOS, or death from BOS). For the 48 patients who developed at least stage I BOS, mean time to onset of BOS was 804.9 ± 87.9 days (2.3 years; range, 133 to 2,196 days). Patients who eventually had progressive BOS developed stage I disease earlier (601.7 ± 60.2 days; 1.65 years) than those that did not have progressive disease (1,164.6 ± 122.3 days; 3.2 years, p < 0.001). For the 29 patients who had progressive disease, mean time to onset was 745.9 ± 80.4 days (2.0 years) after transplantation. Of that group, 23 patients were in stage I, 2 patients were in stage II, and no patients were in stage III disease at the time of initial BOS diagnosis based on PFT data. Four other patients without PFT criteria for BOS died of BOS based on findings at autopsy.
Ischemia-reperfusion injury
Of the patients who survived more than 3 months, 23 (20%) had previously had clinically significant ischemia-reperfusion injury after lung transplantation. Of the 23 patients who had previous ischemia-reperfusion injury, 14 (60%) developed at least stage I BOS. Ten (43%) of these patients went on to develop progressive BOS. Nine of the 14 patients (64%) with reperfusion injury who went on to have BOS had oxygenation indices more than 10, which is considered to be severe pulmonary dysfunction. Four of the 9 patients (44%) with reperfusion injury who did not develop BOS had oxygenation indices more than 10. There was no statistical difference between these two groups.
Acute rejection
After lung transplantation, acute rejection was a common occurrence (Table 2).
Fifty patients (50 of 115, 43%) had 83 episodes of acute rejection in the first 6 months after lung transplantation. Of these episodes, 44 were diagnosed with lung biopsy and 39 were diagnosed clinically with improvement in symptoms after treatment. Five patients required treatment with OKT3 for refractory rejection. Of the patients with acute rejection, 21 had two or more episodes of acute rejection. Of the 21 patients who had at least two episodes of acute rejection, 13 (62%) developed stage I BOS. Seven (33%) of these patients went on to develop progressive BOS.
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Pneumonia
Bacterial pneumonia was diagnosed in 30 patients who had 37 episodes of pneumonia within the first 6 months after lung transplantation, of whom 6 patients had two or more episodes. Table 3
gives the relative frequency of predominating organisms. Fourteen (43%) of the patients diagnosed with pneumonia developed at least stage I BOS, of which 8 (27%) went on to have progressive disease.
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Comment |
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Acute rejection has been consistently marked as one of the prime contributors to the development of BOS. In a large study from Cambridge [3], 230 lung transplant recipients were analyzed. In that series the number of rejection episodes progressively increased the risk of developing BOS per episode of acute rejection. Other investigations have demonstrated that both severity of acute rejection, based on acute rejection scores, and number of acute rejection episodes are directly associated with a progressive increase in risk of BOS onset [4, 5, 16–18].
Cytomegalovirus infection has been shown to be a risk factor for BOS in the present study and in studies by other researchers, although the data are not as consistent as those found for acute rejection. Kroshus and associates [16] showed a significant correlation between CMV pneumonitis and BOS onset. In the study from Cambridge [3], both positive CMV status and CMV pneumonitis were associated with an increased risk of BOS. Studies by both Cooper [19] and Ettinger [20] and their colleagues, however, showed no increased risk of BOS in patients suffering from CMV infection.
Although not observed in the present series (which may represent a type II error), pulmonary bacterial or fungal infection has also been correlated with an increased risk of developing BOS. Girgis and associates [18] found that the presence of bacterial or fungal pneumonia within the first 6 months of lung transplantation significantly increased the risk of BOS onset. Similarly, in the series from Cambridge [3], patients with episodes of bacterial lung infection within the first 6 months of lung transplantation were more likely to develop BOS.
In addition to acute rejection and CMV infection, the current series shows a significant correlation between ischemia-reperfusion injury and the development of BOS. Other studies directly correlating ischemia-reperfusion injury with the development of BOS are limited.
Although the exact mechanism of ischemia-reperfusion injury is not fully understood, circulating neutrophils have been strongly implicated, to the extent that lung biopsies showing influx of circulating neutrophils is currently one of the most accurate means for identifying patients with acute ischemia-reperfusion injury [18]. Influx of neutrophils into the lung parenchyma, with the subsequent release of proteases and oxygen radicals, has been shown to be at least partially responsible for the respiratory decline associated with ischemia-reperfusion injury [9, 10]. Activation of the inflammatory system against transplanted lungs may also result in the generation of an allogenic immune response that predisposes patients to long-term complications, such as BOS. Interestingly, we and other investigators have shown that ischemia time (at least less than 8 hours) does not increase the risk of reperfusion injury after lung transplantation [21].
In addition to acute rejection, there may be an increased risk of chronic rejection after lung transplant reperfusion injury. Although formal animal experiments investigating the effects of reperfusion injury on subsequent chronic rejection are lacking, this correlation has been suggested in a limited number of clinical studies. In one study from the University of Pittsburgh [4], the impact of ischemic injury on BOS onset was investigated. In that study, patients underwent early postoperative bronchoscopy for airway assessment. Ischemic injury was defined as the presence of intensely erythematous, friable, edematous airways in lung allografts without any evidence of airway infection. These changes were found to usually resolve within 2 to 3 weeks after transplantation. Patients with evidence of airway ischemic injury were more likely to develop BOS compared to the rest of the transplant population (p = 0.004). In another study from Stanford [18], lung biopsies were obtained within the first 30 days of lung transplantation and assessed for ischemia-reperfusion injury, as indicated by the presence of interstitial neutrophil sequestration. A strong trend toward increased risk of late BOS was found (p = 0.09). This method, however, may have missed some patients with significant ischemia-reperfusion injury who had recovered from the initial neutrophil-mediated event by the time the biopsy was taken.
The majority of scientific evidence suggests that obliterans bronchiolitis results from an immunologically mediated injury directed against pulmonary vascular endothelium and airway epithelium [2]. One of the important events leading to obliterans bronchiolitis seems to be the upregulation of donor HLA antigens and presentation of these complexes to recipient lymphocytes [22–24]. Activation of lymphocytes by HLA antigens then causes the release of cytokines that facilitate the activation of inflammatory cells and the production of antidonor antibodies by stimulated B-cells. The net effect of these processes is a direct inflammatory or immune injury to pulmonary endothelial and airway epithelial cells. The repair and remodeling response to this injury results in clinically apparent obliterans bronchiolitis [2]. A few important observations in patients who have developed obliterans bronchiolitis help support this theory. First, there seems to be heightened immune activity in these patients, as assessed by the primed lymphocyte test and cell-mediated cytotoxicity [25, 26]. Second, these patients have enhanced expression of major histocompatability complex (MHC) class II antigens on bronchial epithelium and pulmonary endothelium [27]. Third, increased numbers and activity of dendritic cells, which bear class II HLA receptor-antigen complexes, are present in patients who have obliterans bronchiolitis [28].
Given this theory, processes that result in the upregulation of donor MHC antigens could increase the risk of bronchiolitis obliterans. Acute rejection, specifically, has been suggested to induce BOS as a result of a direct immunologic lung injury mediated by T lymphocytes. Animal models have shown that acute rejection episodes result in increased expression of class II HLA antigens and increased numbers of antigen-presenting cells in lung grafts [29, 30]. Similarly, CMV infection results in an inflammatory response that is followed by the upregulation of MHC class I and II antigens on endothelial and epithelial cells. The CMV infection also increases the activity and number of antigen-presenting cells, immune responses, and allograft reactivity [27, 31]. Bacterial or fungal pneumonia can also induce an inflammatory response that may result in an increased risk for the development of obliterans bronchiolitis [32]. Certainly pneumonia causes an acute inflammation and it has been previously shown that cytokines and other mediators of inflammation increase the expression of MHC class II antigens in transplanted lungs [2]. Finally, ischemia-reperfusion injury may also result in an immune response that leads to the development of bronchiolitis obliterans.
Studies have shown that ischemia-reperfusion injury after lung transplantation is associated with the upregulation of cytokines, such as interleukin-2, tumor necrosis factor-
, and interferon-
, which contribute to the induction of an inflammatory response in the lung allograft [4, 15]. In addition to mediating the inflammatory response to reperfusion injury, these upregulated cytokines and recruited cells may also have a role in the expression of HLA antigens. Evidence for this is provided by animal models investigating ischemia-reperfusion injury. Serrick and associates [33] demonstrated increased expression of MHC class II antigens after ischemia-reperfusion injury in an experiment using mongrel dogs. Waddell and colleagues [34] also demonstrated that severe ischemia-reperfusion injury leads to a significant increase in MHC class I and II antigen expression using a rat model. Thus, in addition to acute lung dysfunction after reperfusion injury, upregulation of MHC class II antigens in patients with ischemia-reperfusion injury may provide a mechanism for chronic allograft failure.
One drawback of this study is given the relatively small number of patients in the series, the possibility of a type II error certainly exists. Many studies examining lung transplant populations suffer from this problem. However, we still believe that it is important to examine and try to make comparisons within the population we have to work with.
In summary, the development of BOS can result from several different pathologic processes that seem to lead to a heightened allograft immune response. Several studies have shown the importance of acute rejection and infection in BOS. In addition, however, patients with ischemia-reperfusion injury perioperatively are at increased risk for BOS. Given this, prevention of perioperative pulmonary graft dysfunction may have an impact on both short- and long-term outcomes after lung transplantation.
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Appendix |
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BOS = bronchiolitis obliterans syndrome; CMV = cytomegalovirus;IR = ischemia/reperfusion.
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Discussion |
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The investigators from the University of Virginia are suggesting that perhaps the number one problem may actually be ischemic reperfusion injury, which significantly contributes to the development of bronchiolitis obliterans. We have also been interested in this mechanism as a contributing factor for the development of accelerated atherosclerosis in the transplanted heart.
One of our pathologists, Dr Ralph Hruban, looked retrospectively at the first cardiac biopsy and graded the ischemic injury. We then compared these data with the subsequent development of coronary artery disease in our patients and found a very significant correlation between the degree of ischemic injury and the development of accelerated coronary artery disease. I noticed in your manuscript, which is, by the way, very well written, that you did routine biopsies on early transplant patients. Have you compared the histological degree of ischemic injury, which is a more objective finding and which has its hallmark as the infiltration of neutrophils, with the subsequent development of bronchiolitis obliterans?
My other question, Dr Fiser, is do you constitute any therapeutic intervention when you suspect a patient is developing bronchiolitis?
You have made an important observation and it should restimulate interest into better preservation strategies for lung transplantation. Thanks again for asking me to review this manuscript.
DR FISER: We have not performed routine biopsies at least in the last six to seven years at our institution. Early on in our transplant experience we performed more biopsies when we suspected acute rejection, however finding consistency in reading the biopsies has been difficult, so we have tended to move away from getting routine biopsies and towards just treating acute rejection based on clinical suspicion.
We have tried to treat BOS with a whole host of immunosuppressive agents including OKT3 (Ortho Biotech, Raritan, NJ), ATGAM (Pharmacia Upjohn, Peapack, NJ), cyclosporine, Tacrolimus, Rapamune (Wyeth-Ayerst, Philadelphia, PA), and total lymphoid irradiation. However, we have not found any treatment that prevents the development of BOS or halts its progression.
DR ROBERT DAVIS (Durham, NC): I very much enjoyed your presentation. This is obviously an extremely important issue of the nonallogeneic effects on allogeneic responses. The problem with this analysis is that you are treating a time-dependent as a non-time-dependent variable. Are the patients who are suffering ischemic reperfusion part of your earlier cohort, or are they at the same duration of risk as the rest of your population?
Question number two I think you may have already answered. I gather you use clinical indications for determining the need for biopsy and therefore to make the diagnosis of acute rejection. The rate of acute rejection is one of the lowest that has been reported. Do you use an induction strategy? What is your immunosuppression protocol, because that type of rate is just not seen. Most reports of acute rejection rate are approximately 60% at six months.
A follow-up comment on this is that compared to other variables, acute rejection scores are much more strongly associated with the development of bronchiolitis in analysis that considers bronchiolitis as a time-dependent variable. That isn’t to say that ischemia reperfusion doesn’t have a strong role in priming the alloimmune response.
Again, I enjoyed your presentation very much.
DR FISER: Definitely bronchiolitis obliterans is a time-dependent variable. The longer these patients are followed, the more likely they are to develop BOS. What I can tell you, though, is that our incidence of reperfusion injury over the first five years of our transplant program compared to the second five years of our transplant program has been relatively the same. So given that we didn’t have more ischemia-reperfusion injury early on compared to later years, I think the observation that ischemia-reperfusion injury increases the risk of BOS is true.
As far as the second question, our induction immunosuppression, for the most part, I guess over the first six to seven years of our program, it has generally been cyclosporine, ATGAM, and Imuran. Over recent years we have switched to Tacrolimus (Faro Pharmaceuticals, San Diego, CA 92121). Patients are kept on maintenance immunosuppression with prednisone and cyclosporin or Tacrolimus. Additionally, our acute rejection rate is about 43% at six months. This may be lower than other reported values as a result of more aggressive immunosuppression or perhaps differences in definition. In any case, our seemingly lower incidence makes the association between acute rejection and BOS all the more compelling.
DR STEPHEN D. CASSIVI (St. Louis, MO): I appreciated listening to your presentation. At Washington University, we are also investigating ischemia-reperfusion as a cause of late graft dysfunction.
My first question pertains to the time course of your study. Over the 10-year period of your study, I was interested to know if you have made any adjustments in your preservation strategies. There are a number of new solutions being used in different centers. In our center, we have adopted a low potassium dextran solution for our lung preservation, and have been pleased with our results.
The other question I had is in relation to what Dr Davis discussed. Is there a difference in the mean follow-up of your two groups? Was there simply a shorter follow-up period in the group that developed less obliterative bronchiolitis and that given a longer follow-up period, they too would eventually have similar rates of BOS?
DR FISER: For the first question, we still continue to use Euro-Collins preservation solution at our institution. There has not been any clear evidence so far that suggests one solution is better than the rest for ischemic times less than 4 to 6 hours so we have not switched solutions such as University of Wisconsin solution or low potassium dextran.
As far as the difference in mean follow-up, obviously patients that had a transplant during our early transplant era (first five years of our program) are going to be more likely to develop BOS. But the variables we examined (acute rejection episodes, ischemia-reperfusion injury, cytomegalovirus infections) were not particularly increased in our early transplant experience compared to our more recent experience. Thus, I think the observation that these factors increase the risk of BOS holds true.
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