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The Impact of Bronchiolitis Obliterans on Late Morbidity and Mortality After Single and Bilateral Lung Transplantation for Pulmonary Hypertension
The Impact of Bronchiolitis Obliterans on Late Morbidity and Mortality After Single and Bilateral Lung Transplantation for Pulmonary Hypertension Sudhir Sundaresan Primary pulmonary hypertension (PPH) is a rare cardiovascular disease with a variable course; however, in gene ral, its prognosis is poor. Among the various treatment options available, transplantation (initially heart-lung transplantation, and later isolated single or bilateral lung transpl antation) has become an accepted modal ity. Heart-lung transplantation is necessary only in a minority of patients because right ventricular recovery has been gratifying after isolated lung transplantation. Furthermore, the scarcity of suitable donor organs mandates the achievement of the maximal number of heart and lung transplants from the limited donor pool. Available published data show that both single and bilateral lung transplantation are suitable alternatives for the majority of patients with pulmonary hypertension. Bronchiolitis obliterans syndrome (BaS), the main cause of late mortality and morbidity in lung transplant recipients, affects pulmonary hypertensive patients as it does other recipient subgroups. The available data regarding the impact of BaS on single versus bilateral lung recipients with pulmonary hypertension are somewhat scanty. Although some have suggested that BaS is more prevalent among PPH recipients, this is not uniformly supported through the literature. Other reports have documented severe ventilation-perfusion imbalance associated with graft dysfunction secondary to BaS in single lung transplant recipients w ith PPH. Despite this, t here are no available data to document a significant survival benefit for PPH patients receiving bilateral versus single lung transplantation. Our own transplantation experience at Washington University in St . Louis with pulmonary hypertension shows a trend toward better survival in bilateral lung recipients, although this difference is not significant. Ultimately, both single and bilateral lung replacement seem to be satisfactory transplant options in PPH. Both recipient groups are affected by BaS, and longer follow-up of larger numbers of patients may document superior survival and functional outcome w ith bilateral lung replacement. Copyright © 1998 by W.B. Saunders Company Key words: Primary pulmonary hypertension, heart and lung transplantation, bronchiolitis obliterans syndrome.
P
rimary pu lmonary hypertension (PPH) is a rar e and complex cardiovascular lesion. Alth ough the natural history of this condition is somewha t variable, it is a serious problem , and in gen er al ca rries a poor prognosis. Data from The Na tiona l Institutes of H ealth Primary Pulmonary Hypertension Registry have shown a median survival of 2.8 years and a I-year survival of 68% from the time of diagnosis.' In this study, mortality was found to be a From the Department flf Surgery, Washington University School if Medicine, St. Louis, MO. Address reprint requests to Sudhir Sundaresan, J ill, Division if Cardiothoracic S urgery, BamesJewish Hospital Plam, Quem)!Tower, Suite 3108, St . Louis, MO 63110. Co~right © 1998 by HI.E. Saunders Company' 1043-0679/98/1002-0010$08.00/0
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function of the hemodynamic indices and New York H eart Associa tion functional class. Furthermore, a formula was created to pr edict survival, and this was bas ed primarily on hemodynamic param et ers. Although the first successful isolated lung tr ansplantation is credited to th e Toronto Lung Transplant Group (who performed a right single lung transplantation in a patient with idiopathic pulm onary fibrosis in 1983), th e first successful clinical lung transplantation was in fact achi eved by Reitz et ai, who in 1982, re port ed successful combined heart lung tr ansplantation in advanced PPH.2With improved success in th e field ofl ung transplantati on over th e ensuing decad e, th is field of solid organ tr an splantation has "come of age". Hospital survival rat es and ea rly functional results are, in gen er al, exceilent.v' Unfortunately,
Semi nars in Th oracic and Cardiovascular S urgery, Vol lO, No 2 (Ap ril), 1998: pp 152-159
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late survival and function for lung allograft recipients are clouded by the development of opportunistic infections and/or chronic rejection as manifested by obliterative bronchiolitis. Until these problems are completely sorted out, lung transplantation cannot be viewed as a definitive "cure" for PPH or any other end-stage pulmonary disease. This realization, in the face of a very scarce donor lung pool, has focused considerable attention on understanding the natural history of PPH, response of this condition to various medical therapeutic strategies and, in general, exploring alternative therapies. A prospective study by Rich et al showed that high doses of calcium channel blockers in patients with PPH who respond with reductions in pulmonary vascular resistance may produce improved survival.> A retrospective study from the Mayo Clinic showed a favorable influence on survival ofPPH patients with the use of anticoagulant therapy," Finally, continuous intravenous epoprostenol (prostacyclin) was evaluated in a prospective randomized trial." This trial showed improved survival, superior quality of life, and several objective improvements (including improved pulmonary artery pressure, pulmonary vascular resistance, and 6-minute walk distance) in patients with severe PPH receiving epoprostenol. Available data from the final update of The St. Louis International Lung Transplant Registry from January 1997 showed that only 434 transplantations of a total of 6,126 reported transplantations (or about 7%) have been done for PPH (unpublished data). The declining frequency of lung transplantation for PPH may in fact be related to the favorable response achieved with continuous epoprostenol therapy.
Transplantation Options in Pulmonary Vascular Disease As mentioned previously, heart-lung transplantation (HLT) was the original transplantation option for patients with end-stage pulmonary hypertension." Subsequently however, important observations were made in pulmonary hypertensive patients undergoing thromboendarterectomy for chronic thromboembolic pulmonary hypertension," These patients were noted to sustain significant hemodynamic improvement and also recovery of right ventricular function postoperatively. On this basis, lung transplantation alone was considered as a potentially effective alternative to HLT for pulmonary hypertension. Consequently, a very different transplantation approach, namely single lung transplantation (SLT), was advo-
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cated. The early reports describing this clinical approach came from Levine et al'' and Pasque et al.lO,11 These reports provided early follow-up data in small numbers of patients, but showed impressive hemodynamic improvements with respect to pulmonary artery pressure, pulmonary vascular resistance, cardiac index, and right ventricular ejection fraction. Levine et al showed that pulmonary function tests, arterial blood gases, and maximal exercise testing in these patients gave results comparable with those achieved following HLT in PPH.9 Pasque et al documented an impressive improvement in functional status, such that all recipients were in New York Heart Association (NYHA) class ill or IV preoperatively, but improved to class I or II posttransplantation. Both of these groups documented a specific ventilation-perfusion pattern posttransplantation. Because the pulmonary allograft has essentially normal pulmonary vascular resistance, the vast majority of perfusion was directed to the transplanted lung. However, because the compliance of the two sides was quite similar, ventilation was relatively equally divided between the two lungs. This created a situation of a low ventilation/perfusion ratio in the transplanted lung, and some degree of dead space ventilation in the native lung. However, despite these findings, these early reports showed that this physiological result would still result in sufficient pulmonary reserve to allow normal activities of daily living and also an impressive exercise response. On this basis, SLT in PPH was touted as a viable option, and further evaluation was advocated to assess the longterm durability of the hemodynamic improvement, and also to see if the hemodynamic improvement translated into a survival benefit. Ultimately, SLT for patients with PPH is a technically much simpler procedure than HLT. The SLT approach also makes better use of donor heart-lung blocks, so that more patients can receive heart and lung transplants from the severely limited donor pool. For example, in a long-term follow-up study of SLT for PPH, Pasque et al showed that 31 donors yielded the 34 single lung transplants for PPH in their study, as well as a further 28 cardiac and 20 lung transplant procedures, thereby ultimately achieving 82 transplant procedures in 82 separate patients.F Because of the prevailing rules governing allocation of donor organs, the use of isolated lung transplantation in PPH also shortens the time on the waiting list, which in turn may have a favorable impact on the mortality rate for PPH patients on the waiting list for heart-lung blocks. In a recent review by Trulock,13
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the current role of HLT in patients with PPH was thought to be limited to the following situations: associated coronary artery disease; significant left ventricular dysfunction (in addition to the expected right ventricular dysfunction); and complex/uncorrectable congenital cardiac defects. With greater experience, it has been further appreciated that isolated lung transplantation, along with cardiac repair, is a viable option for selected patients with pulmonary hypertension secondary to congenital cardiac lesions. 14,15
Bronchiolitis Obliterans Syndrome Following Lung Transplantation With the achievement of improved early survival in lung transplantation, bronchiolitis obliterans syndrome (BOS) has emerged as the main cause of late mortality and morbidity for these patients.l'' BOS refers to a late syndrome of chronic lung allograft dysfunction, and is widely regarded to represent chronic rejection of the lung graft, and therefore be the result of an immune-mediated process. According to a working formulation for the clinical staging of chronic lung allograft dysfunction devised by a working group of The International Society for Heart and Lung Transplantation.l" the term BOS was applied to those lung transplant recipients with a 20% or greater decline in their forced expiratory volume in 1 second (FEV I ) relative to their best posttransplantation baseline FEV j value. BOS was also applied to those patients with characteristic
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histological changes, and these typically included dense eosinophilic submucosal scar tissue that partiallyor totally obliterates the lumen of small (2-mm) airways, specifically the terminal and respiratory bronchioles. For the term BOS to apply, the deterioration of pulmonary function after lung transplantation should not be accounted for by other factors such as infection, acute rejection, or bronchial anastomotic complications. From a functional standpoint, BOS is characterized by a progressive decline in FEV 1 and mimics the inexorable progression of chronic obstructive pulmonary disease. The potentially deleterious impact of BOS on PPH patients who have received single lung transplants was outlined by Levine et al.!? This group reported late ventilation-perfusion changes arising in one patient with acute rejection and another patient with chronic rejection/obliterative bronchiolitis, both occurring approximately 4 months after SLT for PPH. Both of these patients exhibited abnormalities that were discrepant with the expected ventilationperfusion changes associated with rejection in SLT recipients who underwent transplantation for obstructive or restrictive lung disease. Whereas the predominant change previously noted was a reduction in graft perfusion with perhaps a mild decrease in ventilation," Levine et al noted a very slight decrease in graft perfusion, with the major change being a large reduction in graft ventilation'? (Fig 1). This led to a profound ventilation-perfusion mismatch, and was associated with dyspnea and hypoxemia. This unfavor-
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Figure 1. Quantitative ventilation-perfusion lung scans showing posterior views after right single lung transplantation for primary pulmonary hypertension. Early posttransplantation study showed 91% of perfusion (lower left) and 48% of ventilation (upper left) distributed to the right lung graft. Later study was obtained 4 months posttransplantation, at which time obliterative bronchiolitis was documented pathologically. At this point, 81% of perfusion (lower right) but only 35% of ventilation (upper right) are distributed to the right lung graft. (Reprinted with permission.!")
Bronchiolitis Obliterans andLung Transplantation
able ventilation-perfusion ratio was conceptually depicted by Bando et al in another report (Fig 2).20 Levine et al therefore cautioned that these findings represented a serious and potentially limiting factor that could complicate the use ofSLT in patients with pulmonary vascular disease. In light of the severe ventilation-perfusion mismatch that results from rejection of single lung allografts in PPH, bilateral lung transplantation (BLT) has been proposed as another transplantation option. BLT in patients with pulmonary vascular disease might be potentially better than SLT in the long run, because any late graft problem, like BOS, carries the potential for graft impairment and the previously mentioned ventilation-perfusion changes. However, this is an unproven supposition and, clearly, long-term follow-up data would be necessary to confirm this notion.
Clinical Reviews of Heart-Lung and Lung Transplantation for Pulmonary Vascular Disease There have been two clinical reviews comparing heart-lung, single, and bilateral lung transplantation for pulmonary hypertension,19,20 and a third report from Washington University by Pasque et al providing late follow-up on 34 patients undergoing single lung transplantation for pulmonary hypertension.I'' Unfortunately, the report by Chapelier et al did not yield sufficient data to assess the differential effect of BOS on SLT versus BLT recipients with pulmonary hypertension. Their review dealt with 30 patients 1.0
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who underwent transplantation for pulmonary hypertension, of which 24 had PPH (21 HLT, 8 BLT, and only 1 SLT). The investigators emphasized that the sole SLT recipient in this report suffered severe perioperative pulmonary edema, had residual pulmonary hypertension documented at late follow-up, and ultimately sustained a severe ventilation-perfusion mismatch, with graft perfusion being 70%, and graft ventilation being 30%. The investigators acknowledged that the poor ventilation of the transplanted lung may have been exacerbated by the presence of a significant bronchial anastomotic complication that eventually necessitated bronchial stenting. This report did show fairly equivalent rates ofBOS development in HLT and BLT recipients (38% in HLT vs 25% in BLT) with an identical 50% case fatality rate secondary to BOS, for the HLT and BLT groups. The report by Bando et apo dealt with 57 consecutive patients who underwent transplantation for pulmonary vascular disease (27 with PPH, 30 with Eisenmenger's syndrome) between 1989 and 1993. Twenty-four patients received HLT, 22 received BLT, and 11 received SLT. The investigators pointed out that HLT was reserved for recipients with coronary artery disease, left ventricular impairment (with left ventricular ejection fraction less than 35%), or complex and irreparable congenital heart disease. The investigators also pointed out that their selection of BLT or SLTwas based only on donor organ availability. Bando et apo noted superior hemodynamic improvements (ie, in terms of cardiac index, mean pulmonary artery pressure, and pulmonary vascular resistance index) in the BLT and HLT groups compared with those in the SLT groups. With respect to late functional outcome, recipient survival tended to be worse in the SLT group at 1year after transplantation, although this difference did not achieve statistical significance; a much greater percentage of late deaths in the SLT group was graft-related as compared with the BLT and HLT groups, and consequently the l-year actuarial graft survival rate was significantly worse in the SLT group (Figs 3A and B). The Washington University report by Pasque et al reported on 34 consecutive patients (24 with PPH, 10 with secondary pulmonary hypertension) undergoing SLT for pulmonary hypertension between 1989 and 1994. In earlier reports.l's!' this group had shown an immediate and virtually complete resolution of the pulmonary hypertension and right ventricular dysfunction in pulmonary hypertensive patients receiving SLT. In the follow-up report.l? these investigators reported on the long-term durability of this improve-
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100
patients; furthermore, although 23 of the current survivors were in NYHA class ill or N pretransplantation, 16 survivors were in class I and 5 were in class II posttransplantation. Nineteen of the 23 current survivors (83%) enjoyed full- or part-time working or student status. All of these data lend credibility to the application ofSLT for pulmonary hypertension. However, it is important to evaluate more specifically the impact ofBOS on the SLT and BLT groups.
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Figure 3. (A) Actuarial recipient survival; (B) actuarial allograft survival. One-year survival in SLT recipients was lower than that for BLT recipients, but this difference did not achieve significance. (B) Forty-six percent of SLT recipients died after transplantation, and all deaths were graft-related. Because only 16% of BLT recipients died of graft-related causes, I-year graft survivalwas significantly lower after SLT than after BLT. (Reprinted with permission.i")
ment, noting that the improved pulmonary hemodynamics and right ventricular ejection fraction persisted beyond 4 years. In evaluating the causes of late death for the recipients in this series, these investigators pointed out that late deaths were not cardiovascular in nature, but in fact were due to complications associated with lung transplantation, not pulmonary hypertension. Furthermore, they showed that the actuarial survival for the transplantation group was significantly better than the predicted survival for this same patient cohort based on the National Institutes of Health PPH Registry formula. Based on these data, Pasque et al made a compelling argument in favor of SLT as a long-term transplantation strategy for patients with pulmonary hypertension. In addition to the uniform and durable improvement in hemodynamics, the investigators showed that SLT conferred a significant survival advantage for these
Impact of BOS on Long-Term Outcome of Lung Transplantation for Pulmonary Hypertension One of the questions that arises is the following: Is the incidence or prevalence of BOS similar for PPH patients compared with other patient subgroups undergoing lung transplantation? This question was specifically addressed by Kshettry et al at the University of Minnesota." This group reviewed a series of 125 consecutive lung transplant recipients between 1986 and 1994. One hundred and seven of these recipients survived at least 3 months posttransplantation, putting them at risk for developing BOS. Twentythree recipients underwent transplantation for PPH, whereas 84 underwent transplantation for other indications. These investigators found a significantly higher prevalence ofBOS (defined by positive histology) in the PPH subgroup (9 of 23,39% vs 16 of 84, 19%; P = .044), and that the PPH patients tended to develop BOS more rapidly. In a multivariate analysis of risk factors for developing BOS, they found a pretransplantation diagnosis of PPH to be a significant independent predictor ofdeveloping BOS. Their analysis showed that actuarial survival was significantly worse for lung transplant recipients with BOS compared with those free ofBOS, although actuarial survival for PPH recipients did not differ significantly from that of the non-PPH recipients. The investigators explained this observed discrepancy by the small number of PPH recipients and the relatively short duration of available follow-up. Available data from other sources do not corroborate the notion that PPH recipients are more prone to developing BOS. In a retrospective analysis of nearly 200 lung transplant recipients at risk for BOS at Washington University.f we reported a comparable proportion of PPH patients in the group with and without BOS (18.2% of the recipients free of BOS vs 15.6% of the group with BOS; P = .360). A more recent analysis of the Barnes]ewish Hospital experience reported on 334 lung transplantation
157
Bronchiolitis Obliterans andLung Transplantation
patients, with 296 at risk for BOS (data not published). Nineteen of 32 (59%) recipients with PPH developed BOS, and the case fatality rate was 6 of 19 (32%). For the entire group overall, 159 of296 at risk (54%) developed BOS, and the overall case fatality rate was 72 of 159 (45%) (P = NS). A more important question is the impact of BOS on survival and function of lung allograft recipients with PPH. As mentioned previously, Kshettry et aF] found a higher incidence ofBOS and earlier development ofBOS in lung transplant recipients with PPH. However, although they found a worse actuarial survival for BOS positive recipients compared with BOS negative recipients, they did not find actuarial survival to be worse for PPH recipients compared with non-PPH recipients. In their report, they pointed out that their PPH recipients were far more likely to undergo HLT or BLT than the non-PPH recipients. They reported HLT in 12 of23 PPH recipients (52%) compared with 16 of 84 non-PPH recipients (19%). BLT was used in 7 of 23 PPH recipients (30%) versus only 11 of 84 non-PPH recipients (13%). Conversely, SLTwas much more commonly used in the non-PPH group (57 of 84 [68%] us 4 of 23 with PPH [17%]; P <.001). These investigators explained the lack of a significant survival difference between the PPH and non-PPH groups on the basis of the small number of PPH patients and the short duration of follow-up. Unfortunately, they did not stratify survival according to the type of transplantation performed in the PPH group. Therefore, one could conjecture that the higher proportion of PPH recipients with two lung allografts (82%, compared with only 32% in the non-PPH group) was the basis for a survival advantage for these PPH recipients. In other words, although the PPH group had a higher incidence of BOS, the presence of two lung allografts in the majority provided greater pulmonary reserve after the onset of physiological decline associated with BOS, thereby averting BOS-related mortality. Unfortunately, the data provided in their report do not permit this to be stated as a definitive conclusion. In a recent update of the Barnes-jewish Hospital experience (data not published), actuarial survival of a series of35 pulmonary hypertensive patients receiving SLT was compared with a series of 15 similar patients receiving BLT. Actuarial survival curves are shown in Fig 4. Although actuarial survival tended to be superior in the BLT group in the long term, these survival differences did not achieve statistical significance. Furthermore, the trend toward better late survival in the BLT group was achieved at the cost of
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BOS stage II (FEV! between 50% and 65% of their best posttransplantation baseline value). Only I had BOS stage III (FEV! <50% of the best posttransplantation baseline value). Similarly, 3 of the 4 BOS recipients from the earlier report had BOS stage II. None of this group had progressed to BOS stage III. Again, these data may lead one to conjecture that it is virtually impossible for PPH patients receiving SLT to progress to advanced stages of BOS (ie, stage III) simply because the ensuing severe degree of ventilation-perfusion mismatch would not be compatible with survival at this stage. Unfortunately, once again, the available data do not permit this statement to be made as a definitive conclusion.
Summary In summary, both single and bilateral lung replacement for pulmonary hypertension have been evaluated in long-term follow-up studies and have been found to be suitable transplantation alternatives. Although the concerns about potentially severe ventilation-perfusion mismatch associated with BOS in the transplanted lung of SLT recipients have been clinically recognized and are not simply theoretical, the data from Pasque et al continue to show very acceptable late survival and functional outcome after SLT. In our experience at Barnes-jewish Hospital, bilateral lung replacement was associated with a slightly higher perioperative risk, but then trended toward better late survival. This superiority in late survival is presumably owing to the greater pulmonary reserve afforded by two lung allografts after the eventual onset ofBOS. Unfortunately, available published data evaluating this specific question are somewhat scanty, so that both SLT and BLT must continue to be touted as acceptable transplantation alternatives for the significant majority of patients with advanced pulmonary hypertension. Ultimately, the scarcity of suitable donor lungs, and the logistics of donor lung availability would likely be the deciding factor between these two transplantation options. Longer duration of follow-up of larger numbers of patients receiving BLT for PPH may eventually conclusively show the superiority of this approach over single lung transplantation in pulmonary hypertension.
Acknowledgment The author gratefully acknowledges the expert assistance of Richard B. Schuessler in performing the statistical analysis.
References 1. D'Alonzo GE, Barst R], Ayres SM, et al: Survival in patients
with primary pulmonary hypertension. Results from a National Prospective Registry. Ann Intern Med 115:343-349, 1991 2. Reitz BA,Wallwork], Hunt SA,et al: Heart-lung transplantation: Successful therapy for patients with pulmonary vascular disease.N Engl] Med 306:557-564, 1982 3. deHoyos AL, Patterson GA, Maurer JR, et al: Pulmonary transplantation. Early and late results.] Thorac Cardiovasc Surg 103:295-306, 1992 4. Cooper]D, Patterson GA, Trulock EP, et al: Results of single and bilateral lung transplantation in 131 consecutive recipients.] Thorac CardiovascSurg 107:460-471, 1994 5. Rich S, Kaufman E, Levy PS: The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension.N EnglJ Med 327:76-81, 1992 6. Fuster V, Steele PM, Edwards WD, et al: Primary pulmonary hypertension:Natural historyand the importance of thrombosis.Circulation 70:580-587, 1984 7. Barst R], Rubin L], Long WA, et al: A comparison of continuous intravenous epoprostenol (Prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl]Med334:296-301,1996 8. Moser KM, DailyPO, Peterson K, et al: Thromboendarterectomy for chronic, major vessel thromboembolic pulmonary hypertension:Immediate and long-term results in 42 patients. Ann Intern Med 107:560-565, 1987 9. LevineSM,Gibbons"'CT, BryanCL, et al:Singlelung transplantation for primary pulmonary hypertension. Chest 98:1107115,1990 10. Pasque MK, Kaiser LR, Dresler CM, et al: Single lung transplantation for pulmonary hypertension: Technical aspects and immediate hemodynamicresults.] Thorac CardiovaseSurg 103:475-482, 1992 11. Pasque MK, Trulock EP, Kaiser LR, Cooper]D: Single lung transplantation for pulmonary hypertension: Three-month hemodynamicfollow-up. Circulation 84:2275-2279, 1991 !2. Pasque MK, Trulock EP, Cooper JD, et al: Single lung transplantation for pulmonary hypertension. Single institution experiencein 34 patients. Circulation 92:2252-2258, 1995 13. Trulock EP:Lung transplantation. AmJ RespirCrit Care Med 155:789-818, 1997 14. Aeba R, Griffith BP, Hardesty RL, et al: Isolated lung transplantation for patients with Eisenmenger's syndrome. Circulation 88:452-455, 1993 15. Lupinetti FM, Bolling SF, Bove EL, et al: Selective lung or heart-lung transplantation for pulmonaryhypertensionassociated with congenital cardiac anomalies. Ann Thorac Surg 57:1545-1549,1994 16. Cooper]D, Billingham], Egan T, et al: Aworkingformulation for the standardization of nomenclature and for clinical staging of chronicdysfunctionin lung allografts.] Heart Lung Transplant, 12:713-716, 1993 17. Levine SM, Jenkinson SG, Bryan CL, et al: Ventilationperfusioninequalitiesduring graft rejectionin patients undergoing single lung transplantation for primary pulmonary hypertension.Chest 101:401-405, 1992 18. Grossman RF, Frost A, Zamel N, et al: Results of single lung transplantation for bilateral pulmonary fibrosis. N EnglJ Med 322:727-733,1990
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19. C hapelier A, Vouhe 1', Macchiar ini P, et al: Comparative
21. Kshet try YR, Kroshus lJ, Savik K, et al: Primary pulmonary
outcome of heart-l ung and lung tr ansplantat ion for pulmonary hypertension.] Th orac Ca rdiovasc Surg 106:299-307,
hypertension as a risk factor for the development of obliterative bronchiolitis in lun g allograft recipients. Chest 110:704-
1993 20. Bando K, Armi tageJM, Paradis IL, et al: Indications for and results of single, bilateral and hear t-lung tr ansplantation for pulmonary hypert ension.] Thorac Ca rdiovasc Surg IOB:56-65,
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709,1996 22. Sundar esan S, Trulock EP, Mohanakumar '1', et al and Th e Washington Universi ty Lung Transplant Group: Prevalence and out come of bron chiolitis obliterans syndrome after lung tr ansplant at ion. Ann Th orac Surg 60:1341-1347, 1995
P
rimary pu lmonary hypertension (PPH) is a rar e and complex cardiovascular lesion. Alth ough the natural history of this condition is somewha t variable, it is a serious problem , and in gen er al ca rries a poor prognosis. Data from The Na tiona l Institutes of H ealth Primary Pulmonary Hypertension Registry have shown a median survival of 2.8 years and a I-year survival of 68% from the time of diagnosis.' In this study, mortality was found to be a From the Department flf Surgery, Washington University School if Medicine, St. Louis, MO. Address reprint requests to Sudhir Sundaresan, J ill, Division if Cardiothoracic S urgery, BamesJewish Hospital Plam, Quem)!Tower, Suite 3108, St . Louis, MO 63110. Co~right © 1998 by HI.E. Saunders Company' 1043-0679/98/1002-0010$08.00/0
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function of the hemodynamic indices and New York H eart Associa tion functional class. Furthermore, a formula was created to pr edict survival, and this was bas ed primarily on hemodynamic param et ers. Although the first successful isolated lung tr ansplantation is credited to th e Toronto Lung Transplant Group (who performed a right single lung transplantation in a patient with idiopathic pulm onary fibrosis in 1983), th e first successful clinical lung transplantation was in fact achi eved by Reitz et ai, who in 1982, re port ed successful combined heart lung tr ansplantation in advanced PPH.2With improved success in th e field ofl ung transplantati on over th e ensuing decad e, th is field of solid organ tr an splantation has "come of age". Hospital survival rat es and ea rly functional results are, in gen er al, exceilent.v' Unfortunately,
Semi nars in Th oracic and Cardiovascular S urgery, Vol lO, No 2 (Ap ril), 1998: pp 152-159
Bronchiolitis Obliterans andLung Transplantation
late survival and function for lung allograft recipients are clouded by the development of opportunistic infections and/or chronic rejection as manifested by obliterative bronchiolitis. Until these problems are completely sorted out, lung transplantation cannot be viewed as a definitive "cure" for PPH or any other end-stage pulmonary disease. This realization, in the face of a very scarce donor lung pool, has focused considerable attention on understanding the natural history of PPH, response of this condition to various medical therapeutic strategies and, in general, exploring alternative therapies. A prospective study by Rich et al showed that high doses of calcium channel blockers in patients with PPH who respond with reductions in pulmonary vascular resistance may produce improved survival.> A retrospective study from the Mayo Clinic showed a favorable influence on survival ofPPH patients with the use of anticoagulant therapy," Finally, continuous intravenous epoprostenol (prostacyclin) was evaluated in a prospective randomized trial." This trial showed improved survival, superior quality of life, and several objective improvements (including improved pulmonary artery pressure, pulmonary vascular resistance, and 6-minute walk distance) in patients with severe PPH receiving epoprostenol. Available data from the final update of The St. Louis International Lung Transplant Registry from January 1997 showed that only 434 transplantations of a total of 6,126 reported transplantations (or about 7%) have been done for PPH (unpublished data). The declining frequency of lung transplantation for PPH may in fact be related to the favorable response achieved with continuous epoprostenol therapy.
Transplantation Options in Pulmonary Vascular Disease As mentioned previously, heart-lung transplantation (HLT) was the original transplantation option for patients with end-stage pulmonary hypertension." Subsequently however, important observations were made in pulmonary hypertensive patients undergoing thromboendarterectomy for chronic thromboembolic pulmonary hypertension," These patients were noted to sustain significant hemodynamic improvement and also recovery of right ventricular function postoperatively. On this basis, lung transplantation alone was considered as a potentially effective alternative to HLT for pulmonary hypertension. Consequently, a very different transplantation approach, namely single lung transplantation (SLT), was advo-
153
cated. The early reports describing this clinical approach came from Levine et al'' and Pasque et al.lO,11 These reports provided early follow-up data in small numbers of patients, but showed impressive hemodynamic improvements with respect to pulmonary artery pressure, pulmonary vascular resistance, cardiac index, and right ventricular ejection fraction. Levine et al showed that pulmonary function tests, arterial blood gases, and maximal exercise testing in these patients gave results comparable with those achieved following HLT in PPH.9 Pasque et al documented an impressive improvement in functional status, such that all recipients were in New York Heart Association (NYHA) class ill or IV preoperatively, but improved to class I or II posttransplantation. Both of these groups documented a specific ventilation-perfusion pattern posttransplantation. Because the pulmonary allograft has essentially normal pulmonary vascular resistance, the vast majority of perfusion was directed to the transplanted lung. However, because the compliance of the two sides was quite similar, ventilation was relatively equally divided between the two lungs. This created a situation of a low ventilation/perfusion ratio in the transplanted lung, and some degree of dead space ventilation in the native lung. However, despite these findings, these early reports showed that this physiological result would still result in sufficient pulmonary reserve to allow normal activities of daily living and also an impressive exercise response. On this basis, SLT in PPH was touted as a viable option, and further evaluation was advocated to assess the longterm durability of the hemodynamic improvement, and also to see if the hemodynamic improvement translated into a survival benefit. Ultimately, SLT for patients with PPH is a technically much simpler procedure than HLT. The SLT approach also makes better use of donor heart-lung blocks, so that more patients can receive heart and lung transplants from the severely limited donor pool. For example, in a long-term follow-up study of SLT for PPH, Pasque et al showed that 31 donors yielded the 34 single lung transplants for PPH in their study, as well as a further 28 cardiac and 20 lung transplant procedures, thereby ultimately achieving 82 transplant procedures in 82 separate patients.F Because of the prevailing rules governing allocation of donor organs, the use of isolated lung transplantation in PPH also shortens the time on the waiting list, which in turn may have a favorable impact on the mortality rate for PPH patients on the waiting list for heart-lung blocks. In a recent review by Trulock,13
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Sudhir Sundaresan
the current role of HLT in patients with PPH was thought to be limited to the following situations: associated coronary artery disease; significant left ventricular dysfunction (in addition to the expected right ventricular dysfunction); and complex/uncorrectable congenital cardiac defects. With greater experience, it has been further appreciated that isolated lung transplantation, along with cardiac repair, is a viable option for selected patients with pulmonary hypertension secondary to congenital cardiac lesions. 14,15
Bronchiolitis Obliterans Syndrome Following Lung Transplantation With the achievement of improved early survival in lung transplantation, bronchiolitis obliterans syndrome (BOS) has emerged as the main cause of late mortality and morbidity for these patients.l'' BOS refers to a late syndrome of chronic lung allograft dysfunction, and is widely regarded to represent chronic rejection of the lung graft, and therefore be the result of an immune-mediated process. According to a working formulation for the clinical staging of chronic lung allograft dysfunction devised by a working group of The International Society for Heart and Lung Transplantation.l" the term BOS was applied to those lung transplant recipients with a 20% or greater decline in their forced expiratory volume in 1 second (FEV I ) relative to their best posttransplantation baseline FEV j value. BOS was also applied to those patients with characteristic
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histological changes, and these typically included dense eosinophilic submucosal scar tissue that partiallyor totally obliterates the lumen of small (2-mm) airways, specifically the terminal and respiratory bronchioles. For the term BOS to apply, the deterioration of pulmonary function after lung transplantation should not be accounted for by other factors such as infection, acute rejection, or bronchial anastomotic complications. From a functional standpoint, BOS is characterized by a progressive decline in FEV 1 and mimics the inexorable progression of chronic obstructive pulmonary disease. The potentially deleterious impact of BOS on PPH patients who have received single lung transplants was outlined by Levine et al.!? This group reported late ventilation-perfusion changes arising in one patient with acute rejection and another patient with chronic rejection/obliterative bronchiolitis, both occurring approximately 4 months after SLT for PPH. Both of these patients exhibited abnormalities that were discrepant with the expected ventilationperfusion changes associated with rejection in SLT recipients who underwent transplantation for obstructive or restrictive lung disease. Whereas the predominant change previously noted was a reduction in graft perfusion with perhaps a mild decrease in ventilation," Levine et al noted a very slight decrease in graft perfusion, with the major change being a large reduction in graft ventilation'? (Fig 1). This led to a profound ventilation-perfusion mismatch, and was associated with dyspnea and hypoxemia. This unfavor-
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Figure 1. Quantitative ventilation-perfusion lung scans showing posterior views after right single lung transplantation for primary pulmonary hypertension. Early posttransplantation study showed 91% of perfusion (lower left) and 48% of ventilation (upper left) distributed to the right lung graft. Later study was obtained 4 months posttransplantation, at which time obliterative bronchiolitis was documented pathologically. At this point, 81% of perfusion (lower right) but only 35% of ventilation (upper right) are distributed to the right lung graft. (Reprinted with permission.!")
Bronchiolitis Obliterans andLung Transplantation
able ventilation-perfusion ratio was conceptually depicted by Bando et al in another report (Fig 2).20 Levine et al therefore cautioned that these findings represented a serious and potentially limiting factor that could complicate the use ofSLT in patients with pulmonary vascular disease. In light of the severe ventilation-perfusion mismatch that results from rejection of single lung allografts in PPH, bilateral lung transplantation (BLT) has been proposed as another transplantation option. BLT in patients with pulmonary vascular disease might be potentially better than SLT in the long run, because any late graft problem, like BOS, carries the potential for graft impairment and the previously mentioned ventilation-perfusion changes. However, this is an unproven supposition and, clearly, long-term follow-up data would be necessary to confirm this notion.
Clinical Reviews of Heart-Lung and Lung Transplantation for Pulmonary Vascular Disease There have been two clinical reviews comparing heart-lung, single, and bilateral lung transplantation for pulmonary hypertension,19,20 and a third report from Washington University by Pasque et al providing late follow-up on 34 patients undergoing single lung transplantation for pulmonary hypertension.I'' Unfortunately, the report by Chapelier et al did not yield sufficient data to assess the differential effect of BOS on SLT versus BLT recipients with pulmonary hypertension. Their review dealt with 30 patients 1.0
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155
who underwent transplantation for pulmonary hypertension, of which 24 had PPH (21 HLT, 8 BLT, and only 1 SLT). The investigators emphasized that the sole SLT recipient in this report suffered severe perioperative pulmonary edema, had residual pulmonary hypertension documented at late follow-up, and ultimately sustained a severe ventilation-perfusion mismatch, with graft perfusion being 70%, and graft ventilation being 30%. The investigators acknowledged that the poor ventilation of the transplanted lung may have been exacerbated by the presence of a significant bronchial anastomotic complication that eventually necessitated bronchial stenting. This report did show fairly equivalent rates ofBOS development in HLT and BLT recipients (38% in HLT vs 25% in BLT) with an identical 50% case fatality rate secondary to BOS, for the HLT and BLT groups. The report by Bando et apo dealt with 57 consecutive patients who underwent transplantation for pulmonary vascular disease (27 with PPH, 30 with Eisenmenger's syndrome) between 1989 and 1993. Twenty-four patients received HLT, 22 received BLT, and 11 received SLT. The investigators pointed out that HLT was reserved for recipients with coronary artery disease, left ventricular impairment (with left ventricular ejection fraction less than 35%), or complex and irreparable congenital heart disease. The investigators also pointed out that their selection of BLT or SLTwas based only on donor organ availability. Bando et apo noted superior hemodynamic improvements (ie, in terms of cardiac index, mean pulmonary artery pressure, and pulmonary vascular resistance index) in the BLT and HLT groups compared with those in the SLT groups. With respect to late functional outcome, recipient survival tended to be worse in the SLT group at 1year after transplantation, although this difference did not achieve statistical significance; a much greater percentage of late deaths in the SLT group was graft-related as compared with the BLT and HLT groups, and consequently the l-year actuarial graft survival rate was significantly worse in the SLT group (Figs 3A and B). The Washington University report by Pasque et al reported on 34 consecutive patients (24 with PPH, 10 with secondary pulmonary hypertension) undergoing SLT for pulmonary hypertension between 1989 and 1994. In earlier reports.l's!' this group had shown an immediate and virtually complete resolution of the pulmonary hypertension and right ventricular dysfunction in pulmonary hypertensive patients receiving SLT. In the follow-up report.l? these investigators reported on the long-term durability of this improve-
156
Sudhir Sundaresan
100
patients; furthermore, although 23 of the current survivors were in NYHA class ill or N pretransplantation, 16 survivors were in class I and 5 were in class II posttransplantation. Nineteen of the 23 current survivors (83%) enjoyed full- or part-time working or student status. All of these data lend credibility to the application ofSLT for pulmonary hypertension. However, it is important to evaluate more specifically the impact ofBOS on the SLT and BLT groups.
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Figure 3. (A) Actuarial recipient survival; (B) actuarial allograft survival. One-year survival in SLT recipients was lower than that for BLT recipients, but this difference did not achieve significance. (B) Forty-six percent of SLT recipients died after transplantation, and all deaths were graft-related. Because only 16% of BLT recipients died of graft-related causes, I-year graft survivalwas significantly lower after SLT than after BLT. (Reprinted with permission.i")
ment, noting that the improved pulmonary hemodynamics and right ventricular ejection fraction persisted beyond 4 years. In evaluating the causes of late death for the recipients in this series, these investigators pointed out that late deaths were not cardiovascular in nature, but in fact were due to complications associated with lung transplantation, not pulmonary hypertension. Furthermore, they showed that the actuarial survival for the transplantation group was significantly better than the predicted survival for this same patient cohort based on the National Institutes of Health PPH Registry formula. Based on these data, Pasque et al made a compelling argument in favor of SLT as a long-term transplantation strategy for patients with pulmonary hypertension. In addition to the uniform and durable improvement in hemodynamics, the investigators showed that SLT conferred a significant survival advantage for these
Impact of BOS on Long-Term Outcome of Lung Transplantation for Pulmonary Hypertension One of the questions that arises is the following: Is the incidence or prevalence of BOS similar for PPH patients compared with other patient subgroups undergoing lung transplantation? This question was specifically addressed by Kshettry et al at the University of Minnesota." This group reviewed a series of 125 consecutive lung transplant recipients between 1986 and 1994. One hundred and seven of these recipients survived at least 3 months posttransplantation, putting them at risk for developing BOS. Twentythree recipients underwent transplantation for PPH, whereas 84 underwent transplantation for other indications. These investigators found a significantly higher prevalence ofBOS (defined by positive histology) in the PPH subgroup (9 of 23,39% vs 16 of 84, 19%; P = .044), and that the PPH patients tended to develop BOS more rapidly. In a multivariate analysis of risk factors for developing BOS, they found a pretransplantation diagnosis of PPH to be a significant independent predictor ofdeveloping BOS. Their analysis showed that actuarial survival was significantly worse for lung transplant recipients with BOS compared with those free ofBOS, although actuarial survival for PPH recipients did not differ significantly from that of the non-PPH recipients. The investigators explained this observed discrepancy by the small number of PPH recipients and the relatively short duration of available follow-up. Available data from other sources do not corroborate the notion that PPH recipients are more prone to developing BOS. In a retrospective analysis of nearly 200 lung transplant recipients at risk for BOS at Washington University.f we reported a comparable proportion of PPH patients in the group with and without BOS (18.2% of the recipients free of BOS vs 15.6% of the group with BOS; P = .360). A more recent analysis of the Barnes]ewish Hospital experience reported on 334 lung transplantation
157
Bronchiolitis Obliterans andLung Transplantation
patients, with 296 at risk for BOS (data not published). Nineteen of 32 (59%) recipients with PPH developed BOS, and the case fatality rate was 6 of 19 (32%). For the entire group overall, 159 of296 at risk (54%) developed BOS, and the overall case fatality rate was 72 of 159 (45%) (P = NS). A more important question is the impact of BOS on survival and function of lung allograft recipients with PPH. As mentioned previously, Kshettry et aF] found a higher incidence ofBOS and earlier development ofBOS in lung transplant recipients with PPH. However, although they found a worse actuarial survival for BOS positive recipients compared with BOS negative recipients, they did not find actuarial survival to be worse for PPH recipients compared with non-PPH recipients. In their report, they pointed out that their PPH recipients were far more likely to undergo HLT or BLT than the non-PPH recipients. They reported HLT in 12 of23 PPH recipients (52%) compared with 16 of 84 non-PPH recipients (19%). BLT was used in 7 of 23 PPH recipients (30%) versus only 11 of 84 non-PPH recipients (13%). Conversely, SLTwas much more commonly used in the non-PPH group (57 of 84 [68%] us 4 of 23 with PPH [17%]; P <.001). These investigators explained the lack of a significant survival difference between the PPH and non-PPH groups on the basis of the small number of PPH patients and the short duration of follow-up. Unfortunately, they did not stratify survival according to the type of transplantation performed in the PPH group. Therefore, one could conjecture that the higher proportion of PPH recipients with two lung allografts (82%, compared with only 32% in the non-PPH group) was the basis for a survival advantage for these PPH recipients. In other words, although the PPH group had a higher incidence of BOS, the presence of two lung allografts in the majority provided greater pulmonary reserve after the onset of physiological decline associated with BOS, thereby averting BOS-related mortality. Unfortunately, the data provided in their report do not permit this to be stated as a definitive conclusion. In a recent update of the Barnes-jewish Hospital experience (data not published), actuarial survival of a series of35 pulmonary hypertensive patients receiving SLT was compared with a series of 15 similar patients receiving BLT. Actuarial survival curves are shown in Fig 4. Although actuarial survival tended to be superior in the BLT group in the long term, these survival differences did not achieve statistical significance. Furthermore, the trend toward better late survival in the BLT group was achieved at the cost of
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Figure 4. Kaplan-Meier estimation:Actuarial survival of 15 bilateral and 35 single lung recipients transplanted for pulmonary hypertension in The Washington University Lung Transplant Program between 1989 and 1997. Perioperative mortality was higher in the bilateral group; late survival tended to be better in the bilateral group,although this difference did not achieve significance. a significantly higher perioperative mortality rate for the BLT procedure in PPH (Fig 4). Even if bilateral lung replacement in pulmonary hypertensive patients is associated with complete reversal of their pulmonary hemodynamic and right ventricular functional abnormalities without any associated ventilation-perfusion mismatches as observed after SLT, one would still expect BOS to produce a progressive decline in spirometry in these recipients. This would therefore be expected to produce significant morbidity for the recipients, identical to that affecting other lung transplant recipient subgroups. It is more difficult to ascertain the functional impairment in pulmonary hypertensive patients who have received SLT, after the onset ofBOS. In the report by Pasque et al,'? the rate of BOS development was stated to be 35% overall (11 of 31 operative survivors). BOS was present in 6 of 23 current survivors (26%). Four of the 7 recipients in their early report!' were affiicted with BOS (57%). Pasque et al pointed out that mean pulmonary artery pressure, pulmonary vascular resistance, and right ventricular ejection fraction did not differ in a group of operative survivors without BOS compared with a corresponding group of survivors with BOS, although the data are not provided in their report. Interestingly, of the 6 current surviving recipients with BOS, 2 had BOS by histological criteria alone. Three had
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SudhirSundaresan
BOS stage II (FEV! between 50% and 65% of their best posttransplantation baseline value). Only I had BOS stage III (FEV! <50% of the best posttransplantation baseline value). Similarly, 3 of the 4 BOS recipients from the earlier report had BOS stage II. None of this group had progressed to BOS stage III. Again, these data may lead one to conjecture that it is virtually impossible for PPH patients receiving SLT to progress to advanced stages of BOS (ie, stage III) simply because the ensuing severe degree of ventilation-perfusion mismatch would not be compatible with survival at this stage. Unfortunately, once again, the available data do not permit this statement to be made as a definitive conclusion.
Summary In summary, both single and bilateral lung replacement for pulmonary hypertension have been evaluated in long-term follow-up studies and have been found to be suitable transplantation alternatives. Although the concerns about potentially severe ventilation-perfusion mismatch associated with BOS in the transplanted lung of SLT recipients have been clinically recognized and are not simply theoretical, the data from Pasque et al continue to show very acceptable late survival and functional outcome after SLT. In our experience at Barnes-jewish Hospital, bilateral lung replacement was associated with a slightly higher perioperative risk, but then trended toward better late survival. This superiority in late survival is presumably owing to the greater pulmonary reserve afforded by two lung allografts after the eventual onset ofBOS. Unfortunately, available published data evaluating this specific question are somewhat scanty, so that both SLT and BLT must continue to be touted as acceptable transplantation alternatives for the significant majority of patients with advanced pulmonary hypertension. Ultimately, the scarcity of suitable donor lungs, and the logistics of donor lung availability would likely be the deciding factor between these two transplantation options. Longer duration of follow-up of larger numbers of patients receiving BLT for PPH may eventually conclusively show the superiority of this approach over single lung transplantation in pulmonary hypertension.
Acknowledgment The author gratefully acknowledges the expert assistance of Richard B. Schuessler in performing the statistical analysis.
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with primary pulmonary hypertension. Results from a National Prospective Registry. Ann Intern Med 115:343-349, 1991 2. Reitz BA,Wallwork], Hunt SA,et al: Heart-lung transplantation: Successful therapy for patients with pulmonary vascular disease.N Engl] Med 306:557-564, 1982 3. deHoyos AL, Patterson GA, Maurer JR, et al: Pulmonary transplantation. Early and late results.] Thorac Cardiovasc Surg 103:295-306, 1992 4. Cooper]D, Patterson GA, Trulock EP, et al: Results of single and bilateral lung transplantation in 131 consecutive recipients.] Thorac CardiovascSurg 107:460-471, 1994 5. Rich S, Kaufman E, Levy PS: The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension.N EnglJ Med 327:76-81, 1992 6. Fuster V, Steele PM, Edwards WD, et al: Primary pulmonary hypertension:Natural historyand the importance of thrombosis.Circulation 70:580-587, 1984 7. Barst R], Rubin L], Long WA, et al: A comparison of continuous intravenous epoprostenol (Prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl]Med334:296-301,1996 8. Moser KM, DailyPO, Peterson K, et al: Thromboendarterectomy for chronic, major vessel thromboembolic pulmonary hypertension:Immediate and long-term results in 42 patients. Ann Intern Med 107:560-565, 1987 9. LevineSM,Gibbons"'CT, BryanCL, et al:Singlelung transplantation for primary pulmonary hypertension. Chest 98:1107115,1990 10. Pasque MK, Kaiser LR, Dresler CM, et al: Single lung transplantation for pulmonary hypertension: Technical aspects and immediate hemodynamicresults.] Thorac CardiovaseSurg 103:475-482, 1992 11. Pasque MK, Trulock EP, Kaiser LR, Cooper]D: Single lung transplantation for pulmonary hypertension: Three-month hemodynamicfollow-up. Circulation 84:2275-2279, 1991 !2. Pasque MK, Trulock EP, Cooper JD, et al: Single lung transplantation for pulmonary hypertension. Single institution experiencein 34 patients. Circulation 92:2252-2258, 1995 13. Trulock EP:Lung transplantation. AmJ RespirCrit Care Med 155:789-818, 1997 14. Aeba R, Griffith BP, Hardesty RL, et al: Isolated lung transplantation for patients with Eisenmenger's syndrome. Circulation 88:452-455, 1993 15. Lupinetti FM, Bolling SF, Bove EL, et al: Selective lung or heart-lung transplantation for pulmonaryhypertensionassociated with congenital cardiac anomalies. Ann Thorac Surg 57:1545-1549,1994 16. Cooper]D, Billingham], Egan T, et al: Aworkingformulation for the standardization of nomenclature and for clinical staging of chronicdysfunctionin lung allografts.] Heart Lung Transplant, 12:713-716, 1993 17. Levine SM, Jenkinson SG, Bryan CL, et al: Ventilationperfusioninequalitiesduring graft rejectionin patients undergoing single lung transplantation for primary pulmonary hypertension.Chest 101:401-405, 1992 18. Grossman RF, Frost A, Zamel N, et al: Results of single lung transplantation for bilateral pulmonary fibrosis. N EnglJ Med 322:727-733,1990
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19. C hapelier A, Vouhe 1', Macchiar ini P, et al: Comparative
21. Kshet try YR, Kroshus lJ, Savik K, et al: Primary pulmonary
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709,1996 22. Sundar esan S, Trulock EP, Mohanakumar '1', et al and Th e Washington Universi ty Lung Transplant Group: Prevalence and out come of bron chiolitis obliterans syndrome after lung tr ansplant at ion. Ann Th orac Surg 60:1341-1347, 1995