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Ann Thorac Surg 2006;81:286-291
© 2006 The Society of Thoracic Surgeons
a Department of Cardiothoracic Surgery, Stanford University, Stanford, California
b Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California
Accepted for publication August 15, 2005.
* Address correspondence to Dr Reitz, Department of Cardiothoracic Surgery, Stanford School of Medicine, CVRB Falk Research Building, 300 Pasteur Dr, Stanford, CA 94305–5407 (Email: breitz{at}stanford.edu).
Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.
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Abstract |
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METHODS: Heart-lung and bilateral sequential double-lung transplant recipients were reviewed retrospectively from 1990 to 2000 using the Stanford Transplant Database. The heart-lung transplant group consisted of 77 heart-lung transplant recipients and the double-lung transplant group consisted of 51 double-lung transplant recipients. The rates of BOS, survival, acute rejection, and cytomegalovirus infection at 1, 3, and 5 years were measured.
RESULTS: There were no significant differences in patient demographics between the two groups. Rates of survival and acute rejection were similar in the two transplant groups. The incidence of cytomegalovirus infection was significantly higher in heart-lung transplant recipients. Freedom from BOS was similar in the two transplant groups. Risk factors for the development of BOS in the heart-lung and double-lung transplant recipients included male donor, younger recipient age, a diagnosis other than cystic fibrosis, nonuse of cardiopulmonary bypass, and the use of OKT3 induction therapy.
CONCLUSIONS: Heart-lung transplant recipients exhibit BOS at a rate similar to double-lung transplant recipients. The immunoprotective effect the lung allograft presumably provides the heart is not reciprocated by the heart in preventing the development of BOS.
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Introduction |
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Despite improved outcomes in both heart-lung and double-lung transplantation, chronic rejection in the form of bronchiolitis obliterans syndrome (BOS) remains the main cause of morbidity and mortality [4–7]. The target of the immune response appears to be the bronchial epithelium, resulting in luminal obliteration and fibrous scarring of small airways [4]. Heart-lung transplant recipients, although plagued with BOS, appear to be spared from cardiac allograft vasculopathy both clinically and in animal models [8–10]. Whether or not heart-lung transplant recipients are also protected from BOS has not been previously established.
The search for the cause of BOS in both heart-lung and lung transplant recipients has been extensive [6, 11–16]. Potential causes have included cytomegalovirus (CMV) infection, early and late acute rejection, ischemic–reperfusion injury, human leukocyte antigen mismatches, organizing pneumonias, and nonuse of induction therapy. We have reviewed our data to identify donor and recipient risk factors in the development of BOS.
Therefore, we have reviewed our experience to determine whether the heart allograft protects heart-lung transplant recipients from developing BOS as compared with double-lung transplant recipients. We have also identified risk factors for the development of BOS to further our understanding and treatment.
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Patients and Methods |
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Heart-Lung and Lung Procurement and Implantation
Donor heart-lung and double-lung preservation consisted of 500 micrograms of prostaglandin E1 that was given directly into the pulmonary artery followed by an infusion of 4 L of ice-cold Euro-Collins solution. Cardiac preservation consisted of 250 mL of cold hyperkalemic crystalloid Stanford Cardioplegia Solution to achieve diastolic arrest and 10 L of ice-cold topical saline. The heart-lung or lung block was placed in cold saline for transport. All allograft ischemic times were less than 6 hours.
Allograft implantation was performed with cardiopulmonary bypass for heart-lung transplantation and for the majority of double-lung transplants. The techniques of heart-lung and double-lung transplantation were previously described by Reitz and associates [1] and Kaiser and coworkers [17].
Immunosuppressive Regimen
Between 1990 and 1993, recipients of both HLT and DLT received rabbit antithymocyte globulin (RATG) or OKT3 induction therapy based on the availability of the locally produced RATG. As of December 1993, RATG was routinely used at a dose of 1.5 mg/kg given intravenously on posttransplant days 1, 2, 3, 5, and 7 after premedication with diphenhydramine and acetaminophen. OKT3 (5 mg/kg) was given intravenously on posttransplant days 1 through 5 with similar premedication.
Methylprednisolone, 500 mg intravenously, was given to all patients immediately before reperfusion. Cyclosporin was started postoperatively when hemodynamics and renal function were stable. Azathioprine was started on posttransplant day 1. Maintenance immunosuppression consisted of cyclosporin (Sandimmune or Neoral), 5 mg/kg orally daily, to maintain whole blood levels of approximately 300 ng/mL, azathioprine (Imuran), 2 mg/kg orally daily, and prednisone, 0.6 mg/kg orally daily, starting on day 8.
Long-Term Follow-Up and Management
Surveillance bronchoscopy with transbronchial biopsy was performed at 2, 4, 8, and 12 weeks and then at 6 months and 1 year after transplant. Long-term follow-up included bronchoscopy every 6 months to 1 year or when clinically indicated. Pulmonary function tests and chest roentgenogram were performed at each follow-up visit or when clinically warranted. Acute rejection was defined as any episode of grade II rejection or greater on transbronchial biopsy. Heart-lung transplant recipients underwent endomyocardial biopsy twice in the first 6 months after transplant and annually thereafter. Coronary angiography was performed at odd-numbered annual transplant anniversaries or when clinically indicated. Rejection was treated with methylprednisolone, 1 g intravenously, daily for 3 days and an increase in the prednisone dose.
Infection Prophylaxis
Infection was defined as any infectious event that required treatment. As of December 1993, all CMV-mismatched donor–recipient pairs received intravenous ganciclovir, 5 mg/kg intravenously twice daily for 14 days and 6 mg/kg twice daily for the subsequent 20 days, Cytovene (oral ganciclovir), 1,000 mg orally three times a day for 6 weeks, and CytoGam (immunoglobulin G), 150 mg/kg 72 hours after transplant, 100 mg/kg weeks 2, 4, 6, and 8 after transplant, and 50 mg/kg weeks 12 and 16. Before the introduction of Cytovene and CytoGam in 1993, all CMV-mismatch recipients received intravenous ganciclovir alone.
Pneumocystic carinii pneumonia prophylaxis consisted of trimethoprim/sulfamethoxazole DS twice daily, Monday, Wednesday, and Friday. Aspergillus prophylaxis consisted of aerosolized amphotericin B, 20 mg twice daily, while hospitalized and itraconazole, 200 mg orally every morning and 100 mg orally every night for 90 days. Donor-positive toxoplasmosis was treated with pyrimethamine, 25 mg orally, and folinic acid orally daily for 6 weeks.
Definition of Bronchiolitis Obliterans Syndrome
Bronchiolitis obliterans syndrome is defined by the ISHLT as a greater than 20% decline in forced expiratory volume in 1 second or in forced expiratory flow, midexpiratory phase, in the absence of acute rejection or infection [7]. Individual charts were reviewed, and a diagnosis of BOS was based on either a decline in lung function that was demonstrated on two separate visits at least 2 weeks apart or histologic evidence of obliterative bronchiolitis from transbronchial biopsies.
Data Collection and Statistics
Patient data was assembled by Stanford transplant nurse coordinators and entered into theTransplant Database. Continuous variables were reported as mean ± standard deviation and categorical variables were reported as proportion and percentage. Comparisons between continuous variables were made using the unpaired two-tailed Student's t test. Categorical variables were compared using the 
2 test. The actuarial life-table method was used to generate survival estimates, which are reported with 95% confidence limits. A log-rank test was used to compare survival estimates between groups. To identify independent risk factors for the development of BOS, a multivariable forward stepwise Cox proportional hazards model was used after exploratory analysis of all available recipients and donor variables (Appendix). The p values for inclusion and retention of variables in the models were 0.1 and 0.08, respectively. All statistical analyses were performed with the SPSS program (version 10.0; SPSS Inc, Chicago, IL).
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Results |
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Cytomegalovirus Infection Rates in Heart-Lung and Double-Lung Transplant Recipients
The overall infection rate for recipients of HLT was 84%, 87%, and 87% as compared with 83% for the DLT recipients at 1, 3, and 5 years, respectively (not significantly different). This included viral, bacterial, and fungal infections. The CMV infection rate for recipients of DLT was 45%, 47%, and 47%, at 1, 3, and 5 years, respectively. Comparatively, the CMV infection rate for recipients of HLT was significantly higher at 58%, 59%, and 62%, at 1, 3, and 5 years, respectively (p < 0.05; Fig 1).
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionFootnotesReferences |
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Other animal experiments looking at reduced heart allograft rejection have been helpful to further discern the requirement for donor lymphocytes in a functionally active state [10, 20, 21]. Again, using a completely mismatched rat heart transplant model, heart allografts were transplanted in the presence of syngeneic or donor-specific lung or spleen grafts with or without cyclosporin treatment. In the presence of cyclosporin and either donor lung or spleen, heart grafts survived indefinitely; this phenomenon was coined the combi-effect. Heart graft prolongation was not seen if the donor spleen was lymphocyte depleted or if the spleen was from a third party. On the basis of these results, in combination with earlier work, it was concluded that the protective effect of donor tissue was dependent on the presence of active donor lymphocytes in a finite quantity. In addition, cyclosporin was required to get a strong combi-effect, further emphasizing the requirement of a controlled immune response. Tolerance to heart allografts in the presence of a renal allograft has recently been shown to be the result of regulatory cells that are present in innate recipient thymic tissue as well as cells generated by way of immunoselection in the grafted tissue [22]. Tolerance is therefore likely as a result of an active regulatory process rather than simple deletion or anergic mechanisms [22]. Baldwin and colleagues [8] have further suggested that in addition to lymphocytes, the lymphoid tissue framework of the lung or spleen may actually filter anti–graft-reactive lymphocytes out of the blood circulation so that they do not reach the heart allograft.
Once realizing that the incidence of BOS was similar in HLT and DLT recipients, donor and recipient factors were analyzed using Cox regression analysis to identify risk factors for developing BOS. Although 25 donor and recipient variables were tested for, only five were found to be significant. Younger recipient age may suggest the presence of a more active immature immune system. A diagnosis other than cystic fibrosis as a risk factor suggests that cystic fibrosis patients, with ongoing chronic pulmonary infections and generally poor nutrition, may be less immunoreactive and therefore somewhat protected from a chronic rejection process. Not using cardiopulmonary bypass for implantation may indicate that uncontrolled reperfusion of organs, when bypass is not used, is detrimental and may initiate a negative immunologic process early after transplantation. The use of OKT3 for induction therapy has been controversial, with many centers using RATG, daclizumab, or no induction therapy [23, 24]. That our results indicate that the use of OKT3 is associated with an increased risk of developing BOS is contrary to the argument for using OKT3. Proponents of OKT3 induction therapy feel that it prevents acute rejection and subsequent BOS [24]. Our results suggest that OKT3 actually enhances the chronic immune response; the nonspecific lymphocyte activity of OKT3 may hinder the generation of a regulatory immunosuppressive response.
Strategies to prevent the development of BOS have included surveillance transbronchial biopsies on routine biopsies, adequate treatment of CMV-mismatched patients, use of cytolytic therapy, and changing immunosuppressive drug regimens [25–28]. Our data revealed that HLT recipients suffered higher rates of CMV infection as compared with DLT recipients. This was probably because of the fact that a larger proportion of HLT procedures (36 of 77) were performed before 1993 when compared with the number of DLT procedures performed before 1993 (12 of 51). Nonetheless, this higher incidence of CMV infection in HLT recipients did not translate into higher rates of BOS. It is important to note, however, that the higher CMV rates in the HLT recipients may have masked any protective effect the heart could have had on the lung allografts. To analyze this possibility one would have to look at only HLT and DLT recipients after 1993 who had all received similar CMV prophylaxis regimens. A better understanding of both donor and recipient risk factors in combination with potential causes of BOS after transplantation will help to reduce the risk of developing BOS.
Our results would suggest that HLT recipients are not protected from developing BOS. In addition, our retrospective review has identified recipient and donor variables that, once understood, may be manipulated in an attempt to reduce the risk of developing BOS in both HLT and DLT recipients.
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Appendix |
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Recipient Demographics
Transplantation year
Age
Sex
Race
Indication for transplantation
Cystic fibrosis
Eisenmenger
Congenital
Primary pulmonary hypertension
Other
Previous sternotomy
Previous thoracotomy
Waiting time
Panel reactive antibodies > 10%
Donor Demographics
Age
Sex
Race
Weight
Cause of death
Trauma
Nontrauma
Donor older than 50 years
Mismatch sex (female donor to male recipient)
Mismatch race
CMV status
Mismatch CMV
Intraoperative Variables
Allograft ischemic time
Allograft ischemic time > 240 minutes
Cardiopulmonary bypass
Immunosuppression
OKT3 versus RATG
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionFootnotesReferences |
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DR MOFFATT-BRUCE: The majority of our double lungs are now are done on bypass. I think that our data just goes to support that that is the safest way, both acutely in the process of implanting the organ, as well as in the long term.
DR DECAMP: Have you looked at the outcomes just around the time of the transplant hospitalization in a bypass versus nonbypass comparison in terms of mortality, bleeding, and other complications?
DR MOFFATT-BRUCE: We have not looked at the mortality and morbidity. The number of nonbypass cases is very small. But it is an interesting question, and it would be interesting to go back and look at that.
DR DECAMP: Thank you.
DR ROBERT DUANE DAVIS (Durham, NC): Heart-lung transplants should be at least as susceptible to vagal nerve injury as lung transplants due to the technical aspects of removing the native heart and lungs, particularly given the more frequent previous operations in patients with congenital heart disease. The role that bypass might play in either initiating or protecting the allograft from subsequent immunologic injury is an interesting question. Personally, I view the use of bypass as it relates to patient safety, which is usually what will make the operating surgeon most comfortable. From an immunologic activation perspective, it is unclear how the use of bypass would be beneficial. With respect to an innate response that would start at the time of transplant and can lead to activation of an acquired immunologic response, bypass should be worse because there would be a lot of innate triggers that would be initiated by the blood extracorporeal surface interface. Regardless, the immunologic response is more likely to be related to the context in which antigen presentation occurs. If there is additional allograft injury such as an ischemia–reperfusion, viral infection, acute rejection, or gastroesophageal reflux, particularly if the injury is repetitive, then antigen presentation will occur in the context of a lot of costimulation and in the milieu of a proinflammatory cytokine environment. This should lead to a more robust alloimmune response and accelerated development of obliterative bronchiolitis. Unless the use of bypass may allow a more controlled reperfusion environment, which could lessen the ischemia–reperfusion injury, it is unclear how bypass would actually be protective for the development of obliterative bronchiolitis.
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Footnotes |
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References |
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This article has been cited by other articles:
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  T. Martinu, D.-F. Chen, and S. M. Palmer Acute Rejection and Humoral Sensitization in Lung Transplant Recipients Proceedings of the ATS, January 15, 2009; 6(1): 54 - 65. [Abstract] [Full Text] [PDF]
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) recipients was 58%, 59%, and 62% at 1, 3, and 5 years, respectively. The incidence of cytomegalovirus infection in the double-lung transplant (DLT; 
) recipients was significantly less at 45%, 47%, and 47% at 1, 3, and 5 years, respectively (p < 0.05).