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Ann Thorac Surg 1995;60:1346-1347
© 1995 The Society of Thoracic Surgeons
DR THOMAS M. EGAN (Chapel Hill, NC): I congratulate Dr Sundaresan for a very concise presentation, which represents an extensive audit of their program to establish the incidence and prevalence of posttransplantation bronchiolitis obliterans syndrome, or BOS. They have brought to our attention the alarming frequency of development of this complication, and they have also emphasized the heterogeneity of this clinical syndrome.
Our data at the University of North Carolina are similar. Among 72 lung transplant recipients surviving longer than 3 months who are at risk, the distribution of prevalence is 39 patients in whom BOS has not developed and 33 patients in whom BOS or biopsy-proven obliterative bronchiolitis has developed. There are 3 patients in grade 1, 8 in grade 2, and 15 in grade 3; 14 of the 33 patients with BOS have died.
Rather than assess these data by quartile, we have calculated the actuarial freedom from BOS, and I believe that the current report would be strengthened by inclusion of this analysis. This depicts the time course to development of BOS, and it is clear that in most patients, BOS will begin to develop between 6 and 30 months. A good study raises additional questions, and this one is no exception. This study clearly begs the question, why do so many patients have development of BOS? Perhaps the better query is why BOS does not develop in some patients.
I have several questions for Dr Sundaresan. Have you performed any multivariate analyses to identify risk factors for the development of BOS? Although you have noted a higher risk of mortality among patients with BOS, how many of your BOS patients remained stable and what is the incidence of progression from grade 1 to 2, from 2 to 3, and so on? Could you elaborate on specifically when to treat patients whose FEV1 begins to fall and when to resort to cytolytic therapy? Given that some patients progress and that many patients succumb before a grade 3 diagnosis is made, could you comment on the utility of the current BOS grading system? Do you have any suggestions to improve it based on this analysis?
And finally, I take issue with the concluding statement in the manuscript that BOS poses the most serious problem in clinical lung transplantation today. Although it is the greatest source of late mortality after lung transplantation, we have had far more patients than 14 die before transplantation because of the critical shortage of suitable pulmonary donors. And, parenthetically, we could perhaps offer retransplantation to patients with severe BOS if we could solve the donor shortage.
DR RICHARD J. NOVICK (London, Ontario, Canada): I also congratulate Dr Sundaresan on his presentation. The pulmonary retransplant registry was established in 1991 to document the outcome and predictors of survival after retransplantation. Approximately 55% of the 150 patients in the registry have had retransplantation for OB.
At 1 year after retransplantation for OB, 66% of patients have normal pulmonary function, whereas 14% have recurrent, stage 3 (ie, severe) OB. At 2 years only half the patients have normal pulmonary function, whereas 33% have severe OB.
Absolute FEV1 declined 11% and 27% at 1 and 2 years after retransplantation, respectively, compared with baseline values after retransplantation.
The two questions I have are similar to those of Dr Egan. First, do you have actuarial data on the prevalence of BOS stages 1, 2, and 3 in your patients after primary lung transplantation, as we do after retransplantation? Second, in view of the fact that Dr Cooper's article last year did not demonstrate a correlation between the number of acute early rejection episodes and the development of OB, have you performed a multivariate analysis to determine which factors correlate with the subsequent development of OB after lung transplantation?
DR DAVID J. SUGARBAKER (Boston, MA): I enjoyed your report very much. I would like to ask you if you could correlate the incidence of BOS with the number or severity of acute rejection episodes in the immediate postoperative period. There are some data from the solid-organ transplant groups showing that the number and severity of acute rejection episodes do correlate with long-term development of BOS.
DR ROBERT J. KEENAN (Pittsburgh, PA): I enjoyed your presentation very much, and we too have made the same surprising finding that single lung and bilateral lung transplants seem to do just as well after the diagnosis of OB, which is not something that we would have intuitively thought. I wonder whether the early patients were somewhat discriminated against because BOS was only recently described, so that the people in the third and fourth quartiles of your analysis might have been treated more aggressively after this syndrome was recognized, as opposed to those in the first or the second quartile?
The other issue I would address with you is whether the more aggressive treatment of this syndrome might have come at a cost of infectious complications, such as what we have seen at Pittsburgh, with a surprising frequency of fungal or opportunistic viral infections after giving aggressive cytolytic therapy.
DR CHRISTOPHER G. A. McGREGOR (Rochester, MN): Again, I congratulate Dr Sundaresan on a fine presentation. Could I ask him to allude briefly to the current management strategy for this problem at St. Louis? It is clearly a depressing medium-term survival after lung transplantation, and I would be grateful for some guidance as to their current management strategy. I would briefly mention that we are now undertaking a protocol of total lymphoid irradiation in selected patients with OB to try to mitigate the progression of this disease.
DR JOHN R. BENFIELD (Sacramento, CA): You say that the true pathogenesis of bronchiolitis obliterans is unknown. That is true. But I do not think that the true pathogenesis of bronchiolitis obliterans in conjunction with lung transplantation is unknown. It seems to me that it is chronic transplant rejection. Is that too sweeping a statement? What is wrong with changing the terminology from bronchiolitis obliterans to chronic transplant rejection syndrome?
DR SUNDARESAN: I thank Dr Benfield and all the other discussants for their remarks. If I can just discuss Dr Benfield's questions first, I think there is an overwhelming amount of evidence that suggests that this syndrome, BOS, is the result of an immune-mediated allograft injury. However, a lot of that evidence is indirect in a variety of ways. And although the pathology of this entity resembles that seen in other solid-organ allografts, it has not been definitively proved that this is an immune-mediated phenomenon. I think, however, that most of us do treat it as such.
I agree with Dr Egan's remark that it is a very intriguing question, not only why so many patients get BOS but also, in looking at those who have survived for a long period without it, why those patients do not get it. Second, he asked, as did Dr Novick, I believe, whether we have done a multivariate analysis. In a fairly detailed analysis of the first 112 consecutive transplantations done at Barnes, we compared a group of 54 patients without BOS to a group of 40 with BOS using the same criteria as in this study. We looked at a number of clinical factors, including the ones that I showed here today, as well as graft ischemic time and use of cardiopulmonary bypass for the transplantation. However, the focus of that study was to see whether we could find any immunologic indices that correlated with the development of BOS. So we looked at human lymphocyte antigen tissue typing (that is, A, B, and DR antigen mismatches), the incidence of positive donor-specific cross match, as well as the development of lymphocytotoxic anti–human lymphocyte antigen antibodies by the panel reactive antibody method. We did not do a multivariate analysis in that study, but after systematic analysis of all those variables, the development of these anti–human lymphocyte antigen antibodies was the only factor to emerge as correlating with the development of BOS.
I think Dr Egan also wanted to know about the progression of patients once they are diagnosed with BOS. For example, if we identify 20 patients who are in BOS stage 1 today, what is their fate in 3 months or 6 months, or even 12 months from now? That is actually the subject of a study just being completed by my colleagues. I do not have precise data to show you, but I can just summarize the overall result by saying that virtually all patients identified with BOS do, with time, move to worse stages. It is a distinct minority that actually move to lower stages of BOS over time.
Another question Dr Egan asked was when to treat a patient when the FEV1 declines. This question coincides with Dr McGregor's question regarding management of BOS, so I will deal with these together. In our program, when a patient is found to manifest signs of declining spirometry, the patient undergoes fiberoptic bronchoscopy, mainly to rule out other specific causes of their dysfunction. Once anastomotic and septic problems have been ruled out, these patients receive treatment with bolus administration of steroids as well as a course of cytolytic therapy, and then they are followed up very carefully with pulmonary function tests at approximately 2-week intervals.
Doctor Egan asked about ways that we could try to improve the staging system. The main comment I have is that the current staging system has improved our understanding of this whole phenomenon, mainly because it deals not only with pathologically proven disease but also with the aspect of physiologic decline. I think this actually is a strong point in favor of the current system that is being used.
Doctor Egan took exception to my last statement that BOS is the most pressing problem of clinical lung transplantation. I certainly have to agree that the shortage of donors, making it such a scarce resource, is clearly right up there.
Doctor Novick asked me about actuarial data for patients in stages 1, 2, and 3. I think I have partly dealt with that issue already. In general, I would agree that an actuarial approach to our data would be very useful. The main impact of our presentation here is that we can state an absolute prevalence of this problem given a sufficient period of follow-up, which in our experience was about 2.5 years.
Doctor Keenan asked whether the early patients in our series were perhaps disadvantaged with respect to their treatment. I probably would have to agree, because at that time it was not truly appreciated that their graft dysfunction was the consequence of this entity. He also asked about whether the aggressive augmented immunosuppression protocol we use is associated with infectious complications, and I think that that is indeed the case in our experience. In fact, data from our lung transplant registry show that the most common causes of late death in lung allograft recipients are not only this entity, BOS, but also the septic events that ensue as a complication of augmented immunosuppression therapy.
Related Article
Ann. Thorac. Surg. 1995 60: 1341-1346.
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