LUNG TRANSPLANTATION

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ADVANCED LUNG DISEASE

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LUNG TRANSPLANTATION A Disease-Specific Approach Jeffrey D. Edelman, MD, and Robert M. Kotloff, MD

Advances in surgical technique, immunosuppression, and perioperative care have permitted successful application of lung transplantation to a variety of nonmalignant pulmonary disorders of the airways, lung parenchyma, and pulmonary vasculature. This option is available to selected candidates under the age of 65 years whose life expectancy and functional status are severely limited because of advanced lung disease but who remain ambulatory and free of significant comorbid disease. The majority of transplant recipients experience marked improvement in quality of life, but long-term survival remains an elusive goal for many patients. Five-year survival following lung transplantation is only 45y0.l~ With the increasingly diverse indications for lung transplantation, it has become evident that the nature of the underlying disease process must be taken into account in many facets of candidate selection and recipient management. In this regard, an intimate appreciation of the natural history and prognostic indices of the individual disease states is essential in making appropriate decisions about the timing of transplantation. The decision to replace one or both lungs may rest on the particular pathophysiology of the underlying disease and the implications of leaving a native lung in place. Finally, the post-transplant course may be complicated by factors

related to the native disease rather than those generic to transplantation and immunosuppression. This article provides a disease-specific approach to lung transplantation, highlighting issues particular to the primary diseases for which transplantation is commonly performed. CHRONIC OBSTRUCTIVE PULMONARY DISEASE Given the high prevalence of chronic obstructive pulmonary disease (COPD) in the general population, it is not surprising that it represents the most frequent indication for lung transplantation. Together with the less common variant, a,-antitrypsin (a,-AT) deficiency, COPD underlies approximately 40% of the transplants performed ~ o r l d w i d e . ' ~ Survival rate following transplantation for emphysema is the highest of any patient population. Despite extensive experience with this disease, questions related to timing of transplantation, optimal procedure, and the role of alternative or adjuvant therapies (lung volume reduction surgery, post-transplant a,AT enzyme replacement) remain. Timing of Transplantation The literature is replete with studies examining the natural history of COPD in an at-

From the Program for Advanced Lung Disease and Lung Transplantation, Pulmonary and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

CLINICS IN CHEST MEDICINE

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VOLUME 18 * NUMBER 3 SEPTEMBER 1997

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tempt to identify prognostic indices. To date, the best single predictor of survival has been the postbronchodilator forced expiratory volume in 1 second (FEV,). In a study that predated the routine use of chronic home supplemental oxygen therapy, median survival in patients under 65 years of age with an FEV, less than 30% of predicted was slightly under 3 years.94The presence or absence of cor pulmonale added independently to the prognostic value of the FEV,. For those with a FEV, of less than 30%, median survival was 5.1 years in the absence and only 2.2 years in the presence of cor pulmonale. Patients with a less severe degree of airflow obstruction (FEV, between 30% and 40%) had a favorable prognosis in the absence of cor pulmonale (median survival of 8.8 years) but the outlook was far more ominous in its presence (median survival of 2.9 years). Two more recent trials have demonstrated a more favorable prognosis for a given decrement in FEV,. In the Intermittent Positive Pressure Breathing Trial, which excluded hypoxemic patients, 3-year survival exceeded 70% in patients under age 65 with an FEV, less than 30% of predicted.,, 36 Similar 3-year survival was documented in the Nocturnal Oxygen Therapy Trial (NOTT), which included only hypoxemic patients, when hypoxemia was corrected with continuous supplemental oxygen.', 69 Notably, survival was far inferior in a second patient group of the NOTT, whose hypoxemia was inadequately treated with nocturnal oxygen only. The use of continuous supplemental oxygen therefore appears to fully negate the detrimental impact of hypoxemia on survival. This underscores the importance of assessing patients for the need for supplemental oxygen, but also argues against using this need as an independent factor in dictating the timing of transplantation. Even in patients receiving long-term supplemental oxygen, the presence of pulmonary hypertension remains a poor prognostic sign. Oswald-Mammosser and c011eagues~~ examined outcomes of 84 patients with COPD and a mean FEV, of 852 mL. The cumulative survival rate for the group, as a whole, was 71% at 3 years and 48% at 5 years. Subgroup analysis, however, revealed a 5-year survival of 62% when the mean pulmonary artery pressure was less than or equal to 25 mm Hg and only 36% when mean pressure exceeded that level. The natural history of a,-AT deficiency has

also been scrutinized and the FEV, similarly found to be the most reliable predictor of mortality. In one study from Sweden, 5-year survival associated with a FEV, greater than 30% exceeded 80% but fell to 40% with a FEV, of 30% or less."9 In a study from Denmark, median survival was 10.5 years for those with a FEV, of 25% to 49% and 6.3 years for those with a FEV, below 25%." Seersholm and colleaguess2found that mortality at 2 years was negligible until the FEV, fell below 35%. Two-year mortality increased exponentially below that level, reaching 50% in association with a FEV, less than 15% predicted. Taken in sum, the studies of COPD and a,AT deficiency demonstrate a highly variable and protracted natural history, typically evolving over many years in an insidious fashion. Even at an advanced stage, long-term survival is possible. As a result, determining the point in a patient's course at which the risk of death from COPD exceeds that associated with transplantation is somewhat problematic. Clearly, the FEV, must be well below 30% predicted before the survival curves of native disease and transplantation cross. Although the precise point cannot be accurately defined from available literature, we rarely offer transplantation until the FEV, falls to a level of 25% or below. The presence of pulmonary hypertension is an ominous sign and mandates consideration of transplantation independent of the FEV,. In the face of prognostic uncertainty, the patient's functional status and quality of life, assessed after pulmonary rehabilitation, should be factored into the decision. Choice of Procedure

The choice of single versus bilateral lung transplantation for COPD remains a matter of some debate. To date, single lung transplantation represents the most commonly used technique, accounting for nearly 80% of the procedures performed in this patient pop~lation.'~ Factors relevant to the issue include physiologic considerations, donor organ scarcity, functional outcomes, and survival benefits. Early attempts at single lung transplantation for COPD resulted in severe ventilation/ perfusion derangements. In two well-documented cases, ventilation was preferentially directed toward the highly compliant native

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lung, leading to progressive hyperinflation and encroachment on the a l l ~ g r a f t . ~ Con" versely, the poorly ventilated allograft received the preponderance of blood flow, presumably reflecting the lower resistance of its vascular bed, resulting in shunt physiology. Based on this experience, it was concluded that single lung transplantation was physiologically unsuitable for treatment of COPD5,90 and replacement of both lungs via heart-lung or bilateral lung techniques emerged as the procedure of choice. That bias persisted until the late 1980s and early 1990s, when advances in the field of lung transplantation emboldened a number of investigators to reattempt single lung transplantation for COPD, this time with successful 62, 64, 75, 92 In the absence of early allograft dysfunction, ventilation/perfusion imbalance is typically mild and of little clinical consequence. Arterial oxygen and carbon dioxide tensions normalize, although the average partial pressure of oxygen (Po2) achieved is slightly below that following bilateral transplantati~n.~~ Hyperinflation of the native lung may still pose a problem following single lung transplantation but, fortunately, this complication is uncommon. In the immediate postoperative period, the use of positive-pressure ventilation, in combination with the development of significant allograft edema, magnifies the compliance differential between native and

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transplanted lungs and may lead to marked overdistention of the native lung, with attendant hypoxemia, hypercapnia, and hemodynamic compromise (Fig. 1). This lifethreatening complication has been managed successfully with independent lung ventilation.26,86 Beyond the perioperative period, a mild and stable degree of hyperinflation and contralateral mediastinal shift is typical. Rarely, however, hyperinflation of the native lung may be insidiously progressive and may be associated with delayed deterioration in pulmonary function caused by restriction of the allograft. In situations in which other causes of late graft dysfunction have been excluded (e.g., obliterative bronchiolitis, anastomotic stenosis, infection), volume reduction of the native lung has been reported to partially rectify the situation.51, 53. 54 From a technical perspective, single lung transplantation is a more straightforward and less rigorous procedure than its bilateral counterpart, making it an appealing procedure for older and more tenuous patients. Cardiopulmonary bypass is only rarely required; in one large series, bypass was used in only 2% of single lung procedures, compared with 20% of bilateral transplant^.^^ Single lung transplantation also allows two recipients to benefit from a single donor, using the scarce allograft pool in a maximally effi-

Figure 1. A, Chest radiograph of a patient with chronic obstructive pulmonary disease immediately following left single lung transplantation. The patient was on positive pressure mechanical ventilation with a standard endotracheal tube in place. Note the marked hyperinflation of the native right lung with contralateral shift of the mediastinum and compression of the allograft (partially obscured by the patient's arm). 6,Chest radiograph of the same patient after insertion of a double lumen endotracheal tube and institution of independent lung ventilation, utilizing a low respiratory rate and prolonged expiratory time for the emphysematous lung and positive end expiratory pressure for the edematous allograft.

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cient manner. On the other hand, transplantation of a single lung places greater constraints on donor organ selection than bilateral replacement. Typically, the lung must be oversized with respect to the recipient and there may be a greater reluctance to utilize marginal allografts. Functional outcomes following single and bilateral lung transplantation have been thoroughly scrutinized and compared.6,55, 60, 75, 92, 97 Although both procedures effect dramatic improvement in the FEVI, the magnitude of improvement is far greater following bilateral transplantation (Fig. 2). Despite the superior outcomes in pulmonary function, bilateral transplantation confers only a modest advantage over single lung replacement with respect to exercise tolerance. We and others6* 92 have observed a slightly greater 6-minute walk distance in our bilateral lung recipients (see Fig. Z), but this may, in part, reflect agerelated and not procedure-related influences. Peak exercise performance, as assessed by progressive cardiopulmonary exercise testing, is reduced to a similar degree in single and bilateral transplant recipients, with a maximum oxygen consumption (VoZmax) in the range of 40% to 60% of predicted?, 58, 75, 97 In neither group is exercise limitation ventilatory in nature; peripheral muscle dysfunction attributable to chronic deconditioning and cyclosporine34has been implicated. Perioperative mortality approximates 10%

for both single and bilateral procedures and roughly 80% of patients in each group are Beyond the first year, bilatalive at 1 year.13*74 eral transplantation appears to confer a survival advantage that approaches statistical significance at year four (65%versus 51% survival for single and bilateral transplantation, respectively; P = 0.056).13 This survival differential has commonly been ascribed to the greater functional reserve afforded by the bilateral procedure, permitting recipients to better tolerate the detrimental impact of chronic rejection. Because bilateral transplantation is typically offered to younger patients, differences in age and accompanying comorbidity may also play a role. In sum, the technical ease and efficient use of the limited donor pool are the major assets of single lung transplantation. It appears well-suited for older patients who likely could not withstand the rigors of the more extensive bilateral procedure. With functional outcomes permitting resumption of a normal lifestyle in all but the most vigorous patients, a strong argument can be made to preferentially use the single lung procedure in the majority of COPD patients. Should the trend toward poorer long-term survival in single lung transplant recipients prove to be significant, however, it would have to be viewed as ultimately inferior to bilateral replacement, forcing the medical community to choose between the competing interests of maximizing

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Figure 2. Peak functional outcomes achieved within the first year following uncomplicated lung transplantation for COPD. Shown are mean pre- and postoperative A, FEV, and 6,6-minute walk test distance (6MWT) for 21 single lung transplant (SLT) and 17 bilateral lung transplant (BLT) recipients at the University of Pennsylvania Medical Center. ' P < 0.001 comparing SLT and BLT postoperative FEV,. t P < 0.05 comparing SLT and BLT postoperative 6MWT distance. Square = SLT; circle = BLT.

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the allocation of a scarce resource versus optimizing the outcome of the individual patient. Role of Alternative or Adjuvant Therapies

Lung Volume Reduction Surgery

Lung volume reduction surgery (LVRS) recently emerged as a potential surgical option for the treatment of advanced emphysema, resulting in improved pulmonary function, gas exchange, exercise tolerance, and perceived dyspnea in some, but not all, patients who undergo the procedure (see article by Benditt and Albert). Although functional outcomes following LVRS are inferior to those 48 the proceachieved with tran~plantation,2~, dure is potentially available to a greater number of patients, carries a significantly lower perioperative mortality rate, and avoids the risks posed by immunosuppression and rejection. At present, LVRS is being used in patients whose pulmonary disease is not sufficiently severe to warrant transplantation or in patients deemed unsuitable for transplantation because of advanced age or comorbid conditions. For potential transplant candidates, LVRS is offered as a "bridge" to transplantation, intended to improve function sufficiently to permit patients to tolerate the prolonged waiting period until donor organs become available or to actually defer the need Iol The ultimate role to for transplantation.25* be played by LVRS in the management strategy of patients with advanced emphysema awaits further demonstration of its efficacy in the upcoming multicenter trial sponsored by the National Heart, Lung, and Blood Institute. Antitrypsin Replacement Therapy

Lung transplantation effectively treats the pulmonary manifestations of a,-AT deficiency but the underlying antiprotease-deficient state persists. This raises the question of whether these patients are at risk for recurrent protease-mediated injury to the allograft and, in turn, whether a,-AT replacement therapy is warranted in the post-transplant period. Because the development of emphysema in nonsmoking au,-AT-deficient patients evolves over many decades, far exceeding the currently anticipated life expectancy of transplant recipients, it is not clear that enzyme replacement would prolong life or preserve

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graft function. There are no reports of the reappearance of emphysema in lung allografts following transplantation for al-AT deficiency. In 4-year follow-up, post-transplant survival in al-AT deficient patients is identical to that of nondeficient COPD patients.74 At present, therefore, there is no compelling reason to advocate institution of chronic enzyme replacement therapy following transplantation. A recent study by King and colleagues45 documented adequate antiprotease activity in bronchoalveolar lavage fluid recovered from 11 healthy a,-AT-deficient transplant recipients. During periods characterized by severe lower respiratory tract inflammation (acute lung injury, pneumonia), however, free elastase activity was demonstrated in several patients, indicating that antiprotease function had been overwhelmed. This study provides a rationale for the limited use of replacement therapy during periods of acute inflammation but corroborating data based on larger numbers of patients are necessary before such a policy can be adopted as standard care. CYSTIC FIBROSIS

Interest in applying lung transplantation to the cystic fibrosis (CF) population was initially tempered by consideration of a number of potential problems unique to the disease. Of paramount concern was the manner in which these chronically infected patients would fare in the face of post-transplant immunosuppression, recognizing that the upper airway and sinuses would remain as reservoirs of virulent bacteria. The systemic nature of the disease raised concern that the CF defect could recur in the lung allograft. Finally, it was anticipated that the surgery would be technically challenging in the face of dense pleural adhesions, a frequent feature resulting from years of chronic pulmonary infection. Over a decade of experience in transplantation surgery in patients with CF has demonstrated those concerns to be exaggerated. Worldwide, approximately 1000 CF patients have undergone lung or heart-lung transplantation, with outcomes similar to those achieved in other patient populations. Timing of Transplantation

Uncertainty in predicting the natural history of CF has resulted in a trend toward late

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referral for transplantation and a consequent high mortality rate among CF patients 47 A recent study awaiting tran~plantation.'~, by Kerem and c011eagues~~ identified prognostic indices that may facilitate more timely referral to a transplant center. In a retrospective review of more than 600 patients, Kerem found a FEV, of less than 30% of predicted, a Po2 of less than 55 mm Hg, and a partial pressure of carbon dioxide (Pco2)exceeding 50 mm Hg to be associated with a 2-year mortality of approximately 50%. Age and gender were also identified as important risk factors. For a given FEVI, patients younger than 18 years and female patients had a higher 2-year mortality rate than their older and male counterparts, respectively. Based on this study, a FEV, below 30% predicted should prompt consideration of referral for transplantation, with earlier referral of female patients and those under 18 years of age. Although not scrutinized in Kerem's study, additional factors we believe should enter into the decision to refer include (1) rapid decline in lung function despite maximum medical therapy, (2) increasing need for hospitalizations and parenteral antibiotic administration, (3) presence of pulmonary hypertension, (4) progressive weight loss, and (5) unacceptably poor quality of life.

Pretransplant Considerations

Liver Disease Up to 5% of patients with CF develop clinically significant biliary cirrhosis, characterized by hepatosplenomegaly, ascites, portal hypertension, and hyperbilirubinemia. The presence of significant liver dysfunction increases the risk of perioperative infection and bleeding, and impairs clearance of the numerous hepatically metabolized drugs used in the post-transplant period. Although a contraindication to isolated lung transplantation, the concurrent presence of advanced liver and lung disease has been successfully treated with combined lung (or heart-lung) and liver tran~plantation.'~, For the occasional CF patient who develops end-stage liver disease while maintaining adequate lung function, isolated liver transplantation has been performed successfully.88 Surprisingly, the suppurative lungs, which remain in place, have not commonly served as a nidus for overwhelming infection follow-

ing liver transplantation. On the contrary, pulmonary function has been reported to improve or stabilize in that circumstance,sspossibly related to the mitigating effects of immunosuppressive therapy on airways inflammation. Diabetes Mellitus Clinically overt diabetes mellitus develops in approximately 10% of adults with CF and an equal or greater percentage have latent glucose intolerance that can be unmasked by steroid administration. Unless particularly difficult to control or associated with significant end-organ damage (e.g., renal insufficiency), diabetes is not a contraindication to transplantation. Madden and colleagues61 found no difference in 2-year post-transplant survival between CF patients with and without diabetes. Nutrition Malnutrition, resulting from chronic infection and malabsorption, is a common feature of advanced CF. Based on data suggesting increased perioperative mortality in underweight CF transplant recipients (<80% of ideal body weight), attempts to aggressively correct severe nutritional deficiencies prior to transplantation seem j~stified.'~ The use of nocturnal enteral supplementation via a percutaneously placed gastric tube is an effective strategy in patients refractory to standard oral supplements. Persistently poor nutritional status despite these interventions should be viewed as a contraindication to transplantation. Sinusitis Similar to the lower respiratory tract, the sinuses are invariably infected in CF patients and serve as a potential reservoir for organisms in the post-transplant period. This has prompted some clinicians to advocate surgical drainage or lavage of the sinuses prior to transplantation but the recommendation remains contr0versial.5~In the absence of firm evidence implicating the sinuses as a source of post-transplant pulmonary infection, and for fear that even a minimally invasive procedure such as endoscopic sinus surgery could precipitate respiratory failure in the tenuous CF population, we have opted not to pursue this approach.

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Prior Thoracic Procedures

Chemical or surgical pleurodesis is often used in the management of recurrent CF-related pneumothoraces. Although resulting in the formation of pleural adhesions, these procedures no longer contraindicate transplantation at most experienced centers. Rarely, CF patients referred for transplantation have previously undergone lobectomy for control of persistent, localized infection or massive hemoptysis. When postsurgical changes are minimal, transplantation can still be offered. In cases in which marked volume loss and extensive pleural reaction are present, however, the task of pneumonectomy becomes so formidable as to preclude transplantation. Pretransplant Mechanical Ventilation

Experience has shown that CF patients who develop respiratory failure in the absence of an acute, reversible process (e.g., pneumothorax, hemoptysis) rarely wean from mechanical ventilation, leading some experienced CF caregivers to advocate against the use of this intervention on the basis of its medical futility.21The availability of lung transplantation as a life-saving intervention for the CF patient with respiratory failure potentially alters the futility argument, however. Indeed, transplantation has been performed successfully in a small number of mechanically ventilated CF patients, with short-term outcomes similar to th,ose achieved in the more conventional 66 In Europe and Cantransplant population.23* ada, where lungs are preferentially allocated to intubated patients, the option of mechanical ventilation appears reasonable for patients listed for transplantation. In contrast, lung allocation in the United States is blinded to severity of illness and initiation of mechanical ventilation does not guarantee prompt transplantation. The possibility of transplantation therefore should enter into the decision to institute mechanical ventilation only for listed patients whose accrued time defines them as senior members on the waiting list. When mechanical ventilation is used in that setting, it must be made clear to the patient and family that the development of serious intercurrent complications or profound debility would necessitate removal of the patient from the active waiting list. Nocturnal noninvasive ventilatory support has been reported to stabilize some CF patients with worsening hypercapnic respira-

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tory failure, permitting them to survive to tran~plantation.~~ Patient intolerance and impaired pulmonary toilet limit the utility and widespread application of the technique, however. Colonization with Highly Resistant Organisms

The presence of chronic infection of the respiratory tract distinguishes CF from other end-stage lung diseases amenable to transplantation. Pseudomonas aeruginosa is the pathogen most commonly cultured in the adult CF population. Patients referred for transplantation frequently harbor multidrugresistant strains of the organism, a result of the selective pressures induced by repeated administration of broad-spectrum antibiotic therapy. The presence of highly resistant bacterial species has been associated with excessive morbidity and mortality following transplantation. At the University of Pittsburgh, 1year post-transplant survival was only 40% for CF patients infected with pan-resistant organisms preoperatively, compared with an 84% 1-year survival in patients with sensitive As a result, some centers consider the presence of pan-resistant organisms to be an absolute contraindication to transplantation. Of great concern is the recent emergence of Burkholderia (Pseudomonas) cepacia as a significant airways pathogen in the CF population. Acquisition of this organism impacts negatively on the natural history of CF, resulting in accelerated decline in lung function and increased short-term mortality. Moreover, this organism has plagued the posttransplant course of some patients by re-emerging to cause devastating and, frequently, lethal infections in the transplant recipient. Snell and colleaguess7reported that 14 of 15 patients infected with B. cepacia had at least one serious post-transplant infection attributable to the organism and the infection proved lethal in five patients. Of eight patients at the University of North Carolina harboring B. cepacia preoperatively, two died of lethal post-transplant infections with the organism and several others developed nonfatal 22, 89 Eminfections or recurrent colonization.20, ploying sophisticated molecular fingerprinting techniques, investigators were able to demonstrate that postoperative infection was caused by persistence of the preoperative strain rather than acquisition of a new

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strain.89Finally, Noyes and colleagues70reported two cases of B. cepacia empyema necessitatis following lung transplantation for CF; both patients had been colonized preoperatively. It now appears that certain strains of B. cepacia are more virulent than othersg1and therefore may carry greater risk of post-transplantation infection. Until further insight is gained into the role of virulence factors in predicting behavior of the organism, policies regarding transplantation of patients colonized with B. cepacia will remain reflective of center-specific experiences. Many centers now exclude all patients harboring the organism whereas others consider patients whose organism remains sensitive to at least one antibiotic agent. Aspergillus sp commonly colonize the bronchiectatic airways of CF patients. Flume and colleaguesz2reported a 63% rate of recovery of Aspergillus from sputum cultures obtained in 27 CF patients prior to transplantation. Although the organism was recovered in 33% of patients following transplantation, that was attributed to colonization rather than active infection and treatment was not deemed necessary in any patient. Despite a paucity of information on the risks posed by preoperative colonization with Aspergillus, most centers do not view it as a contraindication to transplantation. Choice of Procedure

Because of concerns related to leaving a chronically infected lung in place, single lung transplantation is not an option for CF patients. The problem could be circumvented by performance of single lung transplantation and contralateral pneumonectomy, the feasibility of which was suggested in a recent case report,s4 but this approach allows for little reserve in the event of severe allograft dysfunction and is not advocated. Both heart-lung and bilateral lung transplantation have been employed successfully in the CF population. Heart-lung transplantation was the first to be applied in the treatment of CF and it remains a favored procedure in some British centers. It offers the advantage of a low incidence of airway complications (because of the partial preservation of the donor bronchial circulation) but mandates use of cardiopulmonary bypass, with its attendant bleeding risks, and needlessly

subjects the recipient to the potential risks of cardiac allograft rejection and accelerated arteriosclerosis. Perhaps the greatest limitation of the procedure is the severe shortage of intact heart-lung blocs in the United States because of the preferential allocation of hearts to "status 1" cardiac patients. As a result, heart-lung transplantation has largely been supplanted by bilateral lung transplantation, a technique that avoids many of the drawbacks of the former technique while providing comparable survival and functional outcomes.47 In most cases, bilateral transplantation can be accomplished without use of cardiopulmonary bypass by sustaining the patient on the contralateral native lung during implantation of the first allograft which, in turn, is ventilated to permit completion of the second graft. The limited availability of organs and the high mortality rate of CF patients awaiting lung transplantation provided the impetus for the development of living-related donor bilateral lobar transplantation. This technique, pioneered and most strongly advocated by Starnes, involves the donation of a lower lobe from each of two ABO-compatible donors, typically the parents of the recipient. Through August of 1996,54 such procedures had been performed in the United States.96 There have been no reported deaths among the donors and morbidity has been limited chiefly to prolonged air leaks." Donors experience an average decrease in FEV, and forced vital capacity of approximately 20%.11 In a preliminary study involving 10 recipients of bilateral lobar transplantation, the FEV, improved from a preoperative value of 19 4% predicted to 51 15% predicted at 3 months post-transplant, with a further increase to 70 2 15% in the four patients followed to 1 year? A l-year actuarial survival of 66% was reported by Starne~,4~ a figure comparable to that achieved with standard heart-lung and bilateral lung technique^.'^, 35 Nonetheless, the technique of living-related donor transplantation remains controversial and not yet widely embraced by the transplant community, largely because of ethical concerns related to placing two healthy individuals at risk for a procedure that is unlikely to confer upon the recipient a long-lasting benefit given the current state of the art.

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Outcomes and Post-transplant Considerations

One and 5-year actuarial survival following lung transplantation for CF is 70% and 4870,

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re~pectively.'~ Contrary to initial predictions, the incidence of bacterial infections following transplantation does not differ significantly from that of non-CF population^.'^, 22 The systemic nature of the disease should not be overlooked in the post-transplant period. Patients remain predisposed to nonpulmonary CF-related problems, including malabsorption, diabetes mellitus, distal intestinal obstruction syndrome (meconium ileus equivalent), and sinusitis.

Does the Cystic Fibrosis Defect Recur After Transplantation? At the time lung transplantation was first attempted in patients with CF, the pathogenesis of the disease was uncertain, leading to fears that the disease might recur in the allografts. The subsequent demonstration that the bioelectrical defect that characterizes CF epithelium could not be detected up to 2 years following transplantation served to allay 98 With the identification of those the genetic defect that underlies this disease, the issue has been fully laid to rest. Because epithelial cell renewal in the transplanted lungs is of donor, not recipient, lineage, the abnormal CF gene is permanently replaced.

Altered Cyclosporine Kinetics The bioavailability of orally administered cyclosporine in CF patients is roughly one third that in non-CF patients and drug absorption is generally more erratic.j2.93 Oral cyclosporine is delivered in an oily vehicle and its decreased bioavailability may relate, in part, to pancreatic insufficiency, which is highly prevalent among the CF population. This view has been challenged by the demonstration that bioavailability does not improve with the concurrent administration of pancreatic enzymes, leading to speculation that poor cyclosporine absorption may arise from abnormal bile acid composition and secretion rather than from pancreatic insufficiency.12 Several strategies have been used successfully, singularly or in combination, to reduce the total oral cyclosporine requirement and stabilize blood levels: (1)use of a three-times rather than twice-daily dosing schedule, (2) conversion to the newer oral microemulsion preparation (Neoral, Sandoz Pharmaceuti-

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cals), and (3) concurrent use of agents such as erythromycin, diltiazem, verapamil or azole antifungal agents that impair cyclosporine metabolism via the hepatic P450 enzyme system.27, 43, 84

PULMONARY HYPERTENSION

Pulmonary hypertension, either primary or secondary to congenital cardiac defects (Eisenmenger's syndrome), has been the indication for approximately 10% of lung transplants and 60% of heart-lung transplants performed worldwide.13,35 The approach to this group of patients has evolved significantly over the past 15 years. New therapeutic modalities have altered the natural history of primary pulmonary hypertension. Experience with repair of congenital defects concurrent with lung transplantation and observation of the reversal of right ventricular dysfunction with normalization of pulmonary artery pressures have obviated the need for heart-lung transplantation in the majority of patients. Nonetheless, the transplant procedure of choice for this difficult patient population remains controversial and the perioperative period remains precarious. Pretransplant Evaluation and Management

Primary Pulmonary Hypertension In 1991, the Patient Registry for Characterization of Primary Pulmonary Hypertension reported a median survival of 2.8 years for patients with primary pulmonary hypertension.15 Survival was shown to correlate with functional status and indices of right ventricular hemodynamic function. Patients categorized as New York Heart Association (NYHA) class I or I1 had a median survival of 59 months, whereas patients who were NYHA class I11 or IV had median survivals of 32 and 6 months, respectively. A regression equation was developed to describe the relationships among pulmonary arterial pressure, right atrial pressure, cardiac index, and mortality.I5Survival predictions based upon those data, however, may no longer be valid, given subsequent advances in medical therapy. Patients who respond favorably to calciumchannel blockers appear to have improved survival. In a study by Rich and colleagues77

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of high-dose calcium-channel blocker therapy, 25% of patients demonstrated a reduction of greater than 20% in both mean pulmonary artery pressure and pulmonary vascular resistance. The 3-year survival of those patients was %%, whereas their predicted 3year survival from the Patient Registry equation was 55%. Anticoagulation also appears to confer a survival benefit, particularly in patients who do not exhibit a response to calcium-channel blockers.z4,77 Prostacyclin was recently approved by the Food and Drug Administration for treatment of patients with primary pulmonary hypertension with NYHA class I11 or IV functional status. This drug has been shown to improve hemodynamics, exercise tolerance, and survival in such patient^.^,^,^^ In a recent 12-week prospective randomized study of NYHA class I11 and IV patients, survival was 100% in the prostacyclin-treated group, compared with 80% in the group randomized to conventional the rap^.^ In another study, 3-year survival of NYHA class 111 and IV patients treated with prostacyclin was 63%, whereas that of similar historical controls was 41?’0.~ There is no standardized approach for referral and listing of primary pulmonary hypertension patients for transplantation. Given the potential for medical therapy to improve survival and the significant risks of transplantation for this population, only patients who fail medical therapy should undergo transplantation. Unfortunately, it is difficult to predict which patients will demonstrate a long-term response to pharmacologic intervention. We believe a reasonable approach is to evaluate all NYHA class I and I1 patients for medical therapy alone, consisting of calcium-channel blockers plus anticoagulation. NYHA class I11 and IV patients should be evaluated for medical therapy, including the continuous infusion of prostacyclin, and concurrently listed for transplantation if otherwise deemed to be suitable candidates. Limited pulmonary rehabilitation should also be considered for patients being evaluated for or actively awaiting transplantation. Although some have advanced the view that pulmonary hypertension is a contraindication to such a program, we have found a carefully monitored rehabilitation program to be safe and beneficial. As patients may subsequently demonstrate a marked response to medical and rehabilitative therapy, the necessity for active status on the waiting list needs to be continually reviewed.

Eisenmenger’s Syndrome

Patients with pulmonary hypertension attributable to Eisenmenger’s syndrome-most commonly in the setting of an atrial septal defect, ventricular septal defect, patent ductus arteriosis, or aortopulmonary windowrequire a somewhat different approach than patients with primary pulmonary hypertension. Survival in such patients is difficult to predict and many are surprisingly well adapted to chronic hypoxemia in the setting of right-to-left shunting of blood. In this population, patients who demonstrate progressive functional decline or evidence of right ventricular failure should be maintained on a transplant waiting list. There is no defined role for vasodilator therapy in this population. Anticoagulation should be considered in light of the potential for thrombus formation in an enlarged and poorly functioning right atrium and ventricle, with risk of embolization to the systemic circulation, as well as the risk of in situ thrombosis in the pulmonary vasculature. Some patients may also require periodic phlebotomy to maintain hemoglobin levels at the upper limit of normal and minimize the risk of cerebrovascular events.

Preoperative Hepatic Dysfunction

As right ventricular function worsens, patients with pulmonary hypertension manifest signs of hepatic dysfunction resulting from passive congestion of the liver. Liver dysfunction, if not rapidly reversible following transplantation, carries serious potential consequences including bleeding, infection, and drug toxicity. Kramer and colleague^^^ explored the implications of preoperative liver function on postoperative outcome in 62 patients undergoing heart-lung transplantation for pulmonary hypertension. Preoperative hyperbilirubinemia was found to be most predictive; a bilirubin level exceeding 2.1 mg/dL was associated with a 58% early postoperative mortality rate, compared with mortality rates of 27% for those with levels of 1.1 to 2 mg/dL and 16% with less than 1 mg/ dL. Massive hemorrhage contributed to half the deaths in the group with the highest bilirubin levels but none of the deaths in the patients with normal or mildly elevated levels. We have observed similarly poor out-

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comes in patients with preoperative coagulopathies attributable to passive congestion. Based on the aforementioned experiences, we believe that significant liver dysfunction refractory to diuretic therapy and pharmacologic treatment of pulmonary hypertension should be viewed as a contraindication to transplantation. Choice of Procedure

Successful heart-lung transplantation for pulmonary vascular disease was first reThe ported in 1982 by Reitz and technique effects replacement of both diseased lungs and eliminates the need for cardiac repair in the setting of congenital anomalies. It permits the development of coronary-bronchial collaterals after transplantation, which provide a nurturing blood supply to the donor airway and minimize the risk of anastomotic complications. Heart-lung transplantation is clearly required for patients with complex, irreparable cardiac anomalies or decreased left ventricular systolic function, and may be considered if significant coronary artery disease is present.2 As previously discussed, the scarcity of suitable donor organs is clearly a problem that limits the utility of the procedure. From this standpoint, the disadvantages of heartlung transplantation are twofold: Waiting times for a heart-lung transplant are longer than those for single or double lung transplantation and organs that could potentially benefit two or three individuals are used for a single recipient. Using the heart from a heart-lung transplant recipient in a ”domino” procedure offsets this inefficiency and may allow patients with intrinsic pulmonary vascular disease secondary to left ventricular dysfunction to undergo cardiac transplantation with reduced risk of acute right heart failure.42, Heart-lung transplantation carries the added risks of acute cardiac rejection and accelerated coronary artery disease, although these risks are rarely lifethreatening and are greatly overshadowed by the more frequently encountered complication of obliterative bronchiolitis.80 Single and bilateral lung transplantation have more recently emerged as acceptable alternatives to heart-lung transplantation for pulmonary hypertension. Both techniques preserve the recipient heart, with its dilated, hypertrophied, and functionally impaired

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right ventricle. Experience with thromboendarterectomy for chronic pulmonary thromboembolic disease demonstrated that a compromised right ventricle could recover after the resistance through the pulmonary vascular bed was reduced, providing the impetus for trials of lung transplantation in the setting of right ventricular d y ~ f u n c t i o n . ~Subse~ quent experience with single and bilateral lung transplantation for pulmonary hypertension has demonstrated immediate and sustained reduction in pulmonary vascular resistance and recovery of right ventricular systolic function in the majority of patients (Fig. 3).Z. 10, 50,56. 73, 79 In the setting of pulmonary hypertension, single or bilateral lung transplantation requires the use of cardiopulmonary bypass to avoid acute right ventricular distention and failure that would otherwise result from clamping of the pulmonary artery. Longstanding pulmonary hypertension may be complicated by marked dilatation of the main pulmonary arteries, which may make the creation of vascular anastamoses more difficult.1° Acute reduction in pulmonary pressures after lung transplantation may lead to a sudden reduction in the cavity size of an already hypertrophied right ventricle, rarely resulting 46,78 In in dynamic outflow tract obstruction.28, patients with Eisenmenger’s syndrome or a patent foramen ovale, intracardiac repair in conjunction with single lung transplantation is most easily accomplished when the right lung is transplanted.2 Following single lung transplantation, the remaining native lung in pulmonary hypertensive patients maintains normal static and dynamic compliance properties but persistent elevation of vascular resistance. This predisposes to significant ventilation-perfusion mismatch because ventilation is equally distributed between the two lungs but greater than 80% of blood flow is distributed to the allograft.2,73 In the immediate postoperative period, this may lead to exaggerated reperfusion pulmonary edema involving the allograft, which must bear the burden of nearly the entire cardiac output in the face of increased capillary permeability. Bando and colleagues2reported the development of allograft edema in 82% of pulmonary hypertensive patients following single lung transplantation, compared with 59% following bilateral and 33% following heart-lung procedures. Furthermore, the complication was poorly tolerated in the single lung group,

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Figure 3. A, Preoperative cardiac MR image of a patient with primary pulmonary hypertension.The right ventricle (asterisk) is markedly dilated and the interventricular septum bulges into the left ventricular cavity. 6, Cardiac M R image of the same patient obtained several months after right single lung transplantation. Both right and left ventricular cavities have assumed a more normal configuration. (Courtesy of Larry Kaiser, MD, Philadelphia, PA).

leading to hemodynamic instability, hypoxemia, and prolonged dependence on mechanical ventilation. Ventilation-perfusion mismatching has been shown to persist long-term but does not significantly limit activity or impair gas exchange in the setting of normal allograft function.73There is little reserve, however, and the development of acute or chronic rejection may lead to exaggerated degrees of hypoxemia and functional decline.57 Although the potential pitfalls have led some to advocate against the use of single lung transplantation for patients with pulmonary hypertension, others have reported excellent results, with the caveat that only organs deemed flawless at the time of harvest should be In the final analysis, heartlung, single lung, and bilateral lung trans-

plantation have all been successfully employed with equivalent functional outcomes and survival statistic^.'^, 35 Each is characterized by unique advantages and disadvantages, and no single procedure has clearly proven to be superior.

Outcomes One-year survival reported to the St. Louis International Registry is 62%, the lowest of the major patient populations for which transplantation is performed. This is attributable largely to an increased perioperative mortality rate in the pulmonary hypertensive group. Not surprisingly, outcomes differ among centers, likely reflecting variable expe-

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rience. The Washington University for example, has accrued one of the largest experiences in transplantation for pulmonary hypertension, and has reported l-year survival of 78% for all pulmonary hypertensive patients and 87% for patients with primary pulmonary hypertension. Beyond the first year, attrition among this group of patients approximates that of other populations. However a recent report52suggests a higher incidence and earlier onset of obliterative bronchiolitis in patients transplanted for primary pulmonary hypertension. IDIOPATHIC PULMONARY FIBROSIS

Lung transplantation has proven to be a major therapeutic advance in the management of idiopathic pulmonary fibrosis (IPF), a disease that tends to be relentlessly progressive despite pharmacologic intervention. IPF was the first disease for which long-term survival following lung transplantation was achieved and it represented the exclusive indication for lung transplantation in the early and mid-1980s. It remains the second most common indication for lung transplantation, accounting for approximately 15% of procedures performed wor1d~ide.l~ Pretransplant Considerations

The median survival of patients with IPF is under 5 years. An even more dismal prognosis is associated with male gender, a predominantly fibrotic (versus inflammatory) picture demonstrated on lung biopsy or suggested by high-resolution CT scan, and nonresponse to pharmacologic therapy. A trial of highdose corticosteroid therapy or cytotoxic therapy is warranted in most patients but only a small minority respond, typically modestly and transiently. In light of the poor prognosis of IPF and the low likelihood of response to medical management, early referral to a transplant center is appropriate in many cases. Guidelines for listing are imprecise but include progressive pulmonary impairment despite a trial of medical therapy, an increasing need for supplemental oxygen, and progressive limitation in exercise tolerance. Corticosteroids must be used judiciously in the potential transplant candidate; the protracted use of high doses can lead to marked weight gain

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and osteoporosis, which may jeopardize the eligibility of the patient. Steroids may also impact adversely on healing of the bronchial anastomosis at the time of transplant, although recent datas3suggest that daily doses of prednisone at or below 20 mg are acceptable. We favor the concurrent use of cytotoxic drugs (cyclophosphamide or azathioprine) to capitalize on their steroid-sparing effect.38 Pulmonary rehabilitation should be emphasized prior to transplantation but exercise is frequently limited by profound and refractory hypoxemia. Patients with IPF are poorly tolerant of the prolonged waiting times to transplantation and have the highest mortality rate of any primary disease group. Hayden and coll e a g u e ~reported ~~ a 6-month actuarial survival of only 38% for IPF patients awaiting transplantation, compared with 60% for primary pulmonary hypertension, 74% for CF, 81% for COPD, and 89% for Eisenmenger's. In recognition of their rapid disease course, IPF patients are now credited with 90 days at the time of listing, but this may be insufficient in the face of waiting times approximating 12 to 18 months at many centers. Choice of Procedure

The pathophysiologic features of IPF make that disease ideally suited for single lung t r a n ~ p l a n t a t i o n The . ~ ~ low compliance and high vascular resistance of the native lung ensure that both ventilation and perfusion are preferentially diverted to the allograft. Some clinicians favor bilateral transplantation for IPF patients with severe secondary pulmonary hypertension. Outcomes

As a group, patients with IPF fare less well following transplantation than the larger group of COPD patients. In one study,"j IPF patients undergoing single lung transplantation spent more time on the ventilator, required more tracheostomies for failure to wean, and had longer intensive care unit stays than COPD patients. In addition, actuarial survival is significantly below that of the COPD population. At 1 year, for example, actuarial survival for the IPF group is 64%, compared with 77% for patients with COPD.13 Nonetheless, successful transplantation for

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IPF results in marked improvements in lung function, gas exchange, and exercise tolerance, similar to those achieved in other 58

SARCOIDOSIS

The majority of patients with sarcoidosis follow a relatively benign course, characterized by mild and, often, self-limited disease. Approximately 10% of patients, however, progress to end-stage lung disease on the basis of widespread pulmonary fibrosis or, less commonly, severe airways obstruction. For this group, lung transplantation represents the only treatment option with the potential to restore the patient to a more normal functional status. To date, 80 patients with sarcoidosis have been reported to the St. Louis International Lung Transplant Registry, representing 1.5% of the transplant p0pu1ation.l~ Pretransplant Considerations In the absence of reliable prognostic indices specific to patients with sarcoidosis, indications for transplantation are generic-severe decrement in lung function, presence of pulmonary hypertension, increasing requirements for supplemental oxygen, and marked exercise limitation. Given the systemic nature of sarcoidosis, the potential transplant candidate must be scrutinized for evidence of significant extrapulmonary organ involvement that might compromise the patient’s suitability. Granulomatous involvement of the liver is present in the majority of patients but should not be viewed as a contraindication to transplantation unless associated with evidence of significant hepatocellular dysfunction or portal hypertension. Involvement of the heart is manifest by conduction abnormalities, arrhythmias, or dilated cardiomyopathy. When severe, heart-lung transplantation is the procedure of choice. Aspergillus, in the form of either mycetomas or semi-invasive disease, is particularly prevalent in patients with advanced sarcoidosis. The presence of Aspergillus is frequently associated with pleural thickening, the extent of which can be assessed most accurately by CT scan. When severe (Fig. 4), pleural thickening results in obliteration of normal tissue planes, making anatomic dissection and exploration of the native lung technically difficult, time-

consuming, and potentially bloody. Surgery in such cases also runs the risk of soiling the pleural space with fungal organisms. Defining the degree of pleural disease that contraindicates transplantation is a judgment call and is likely to vary depending upon the experience and aggressiveness of the transplant program. Outcomes

A distinctive feature of sarcoidosis is its propensity to recur following lung trans3i, 40, 41, 65, looThe incidence of recurrence cannot be assessed accurately at present but, in three small clinical series, recurrence was documented in 3 of 5, 2 of 3, and 2 of 11 patients, re~pectively.~~, 40, 41, loo Typically, noncaseating granulomas are noted incidentally on surveillance lung biopsies and are unassociated with symptoms or decline in lung function. Recurrence is frequently inapparent on chest radiographs. In several instances, micronodular changes in the upper lobes have been detected on high-resolution CT scans.4o,41, 65 The changes resolved when the corticosteroid dose was increased. Comparing the course of five sarcoid transplant recipients with that of a control recipient population, Johnson and colleague^^^ found that episodes of acute rejection within the first 3 months were histologically more severe in the sarcoid group. The investigators speculated that the upregulation of T-cell function that characterizes sarcoidosis may contribute to the greater severity of rejection episodes. The two groups were otherwise similar with respect to the frequency of obliterative bronchiolitis, pulmonary function, and survival, although mean follow-up was less than a year. The observations made on the course of sarcoidosis following lung transplantation are intriguing but are not sufficiently alarming to preclude consideration of that treatment option for patients with advanced disease. Should long-term follow-up of such patients demonstrate inferior outcomes, the wisdom of transplantation would have to be readdressed. LYMPHANGIOLEIOMYOMATOSIS

Lymphangioleiomyomatosis (LAM) is a rare disease of abnormal smooth muscle pro-

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Figure 4. CT scan of the chest in a patient with sarcoidosis demonstrating bilateral aspergillomas and marked pleural thickening. This patient was deemed unsuitable for lung transplantation because of concerns that the lungs could not be explanted without undue risk.

liferation that afflicts women of childbearing years and causes progressive pulmonary impairment. The disease typically evolves to an end-stage over approximately a decade! In addition to chronic airflow obstruction and hypoxemia, manifestations include recurrent pneumothoraces, chylothorax, and renal angiomyolipomas. The disease is believed to be hormonally mediated and therapy therefore is directed toward reduction in circulating estrogen levels. Unfortunately, disease progression despite those efforts is the rule. Lung transplantation has recently become an option for patients with end-stage disease, with 73 patients recorded in the St. Louis International Registry as of 1996.13 A recently published multicenter experience with 34 LAM patients undergoing lung transplantation sheds light on a number of important issues related to the timing of transplantation and problems particular to the patient population.* At the time of transplant evaluation, the majority of patients demonstrated evidence of severe obstructive lung disease, with an average FEV, of 24% of predicted. A minority of patients demonstrated a restrictive or mixed pattern. Diffusing capacity was reduced in all patients, averaging 26% of predicted, and mean room air arterial Po, was 56 mm Hg. Single lung transplantation was employed

in 27 patients, bilateral transplantation in six, and heart-lung in one. Extensive pleural adhesions were encountered during surgery in half the patients and could be attributed to prior pleurectomy or pleurodesis in fewer than a third of those instances. Notably, excessive bleeding from adhesions led to one intraoperative death and the need for re-exploration in two patients. Complications related to the native disease commonly plagued the post-transplant course. They included pneumothoraces in the native lung in five patients and chylothorax in three. In the reported series: renal angiomyolipomas did not contribute to post-transplant morbidity. In our own experience, however, we have encountered one episode of retroperitoneal hemorrhage from a renal angiomyolipoma, precipitated by the need to anticoagulate a patient with a thrombus at the left atrial suture line. Recurrence of the primary disease was observed in 1 of the 34 patients and was reported independently in a patient by another group.s, 71 Curiously, in both instances, the donor was a male. Both patients demonstrated progressive airflow obstruction, although only one had evidence of obliterative bronchiolitis, suggesting that recurrent LAM was responsible for compromised graft function in the other.

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One- and 2-year actuarial survivals reported in the multicenter series were 69% and 58%, respectively. With the possible exception of one intraoperative death caused by massive hemorrhage from pleural adhesions, all other lethal events related to complications generic to lung transplantation and immunosuppression and not to those attributable to the native disease. SUMMARY Lung transplantation has emerged as a viable option for the treatment of end-stage disease attributable to a wide spectrum of primary disorders. Although many aspects of patient management are indifferent to the underlying indication, important differences related to timing of transplantation, selection of candidates, choice of procedure, and posttransplant complications exist among the various primary disease groups. Optimal utilization of transplantation for these challenging patient populations with advanced lung disease mandates a thorough appreciation of those differences. References 1. Anthonisen N R Prognosis in chronic obstructive pulmonary disease: Results from multicenter clinical trials. Am Rev Respir Dis 14O[S]:95, 1989 2. Bando K, Armitage JM, Paradis IL, et a1 Indications for and results of single, bilateral, and heart-lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg 108:1056,1994 3. Barst RJ, Rubin LJ, Long WA, et al: A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 334296, 1996 4. Barst RJ, Rubin LJ, McGoon MD, et a1 Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 121:409,1994 5. Bates DV The other lung. N Engl J Med 282277, 1970 6. Bavaria JE, Kotloff R, Palevsky H, et al: Bilateral versus single lung transplantation for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 113:520, 1997 7. Bjnrtuft 0, Foerster A, Boe J, et al: Single lung transplantation as treatment for end-stage pulmonary sarcoidosis: Recurrence of sarcoidosis in two different lung allografts in one patient. J Heart Lung Transplant 13:24, 1994 8. Boehler A, Speich R, Russi EW, et al: Lung transplantation for lymphangioleiomyomatosis. N Engl J Med 335:1275, 1996 9. Chan K, Barbers R, Shapiro B, et al: Physiologic outcome following living-related lobar lung transplantation in cystic fibrosis patients. American Jour-

nal of Respiratory and Critical Care Medicine 151:88, 1995 10. Chapelier A, Vouhe P, Macchiarini P, et al: Comparative outcome of heart-lung and lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg 106299, 1993 11. Cohen R, Barr M, Schenkel F, et al: Living-related donor lobectomy for bilateral lobar transplantation in patients with cystic fibrosis. Ann Thorac Surg 571423, 1994 12. Cooney G, Fiel S, Shaw L, et al: Cyclosporine bioavailability in heart-lung transplant candidates with cystic fibrosis. Transplantation 49:821, 1990 13. Cooper J D St. Louis international lung transplant registry-April 1996 report 14. Couetil JP, Houssin DP, Soubrane 0, et al: Combined lung and liver transplantation in patients with cystic fibrosis: A 4%-year experience. J Thorac Cardiovasc Surg 110:1415, 1995 15. DAlonzo GE, Barst RJ, Ayres SM, et al: Survival in patients with primary pulmonary hypertension: Results from a national prospective registry. Ann Intern Med 115:343, 1991 16. Davis RD, Trulock EP, Manley J, et al: Differences in early results after single lung transplantation. Ann Thorac Surg 58:1327, 1994 17. Dennis C, Caine N, Sharples L, et al: Heart-lung transplantation for end-stage respiratory disease in patients with cystic fibrosis at Papworth Hospital. J Heart Lung Transplant 12:893, 1993 18. Dennis CM, McNeil KD, Dunning J, et al: Heartlung-liver transplantation. J Heart Lung Transplant 15:536, 1996 19. deLeval M, Smyth R, Whitehead B, et a1 Heart and lung transplantation for terminal cystic fibrosis: A 4%-year experience. J Thorac Cardiovasc Surg 101:633, 1991 20. Egan T, Detterbeck F, Mill M, et al: Improved results of lung transplantation for patients with cystic fibrosis. J Thorac Cardiovasc Surg 109:224, 1995 21. Fiel S Heart-lung transplantation for patients with cystic fibrosis: A test of clinical wisdom. Arch Intern Med 151:870, 1991 22. Flume P, Egan T, Paradowski L, et al: Infectious complications of lung transplantation: Impact of cystic fibrosis. Am J Respir Crit Care Med 149:1601, 1994 23. Flume P, Egan T, Westerman JH, et al: Lung transplantation for mechanically ventilated patients. Journal of Heart and Lung Transplantation 1315, 1994 24. Fuster V, Steele I'M, Edwards WD, et al: Primary pulmonary hypertension: Natural history and the importance of thrombosis. Circulation 70:580, 1984 25. Gaissert HA, Trulock EP, Cooper JD, et al: Comparison of early functional results after volume reduction or lung transplantation for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 111296, 1996 26. Gavazzeni V, Iapichino G, Mascheroni D, et al: Prolonged independent lung respiratory treatment after single lung transplantation in pulmonary emphysema. Chest 103:96, 1993 27. Girault D, Haloun A, Viard L, et al: Sandimmune Neoral improves the bioavailability of cyclosporin A and decreases inter-individual variations in patients affected with cystic fibrosis. Transplant Proc 272488, 1995 28. Gorcsan J, Reddy SC, Armitage JM, et al: Acquired right ventricular outflow tract obstruction after lung

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49. Kramer MR, Marshall SE, Tiroke A, et al: Clinical significance of hyperbilirubinemia in patients with pulmonary hypertension undergoing heart-lung transplantation. J Heart Lung Transplant 10:317, 1990 50. Kramer MR, Valantine HA, Marshall SE, et al: Recovery of the right ventricle after single lung transplantation in pulmonary hypertension. Am J Cardiol 73494, 1994 51. Kroshus TJ, Bolman Rh4, Kshettry VR Unilateral volume reduction after single lung transplantation for emphysema. Ann Thorac Surg 62:363, 1996 52. Kshettry VR, Kroshus TJ, Savik K, et al: Primary pulmonary hypertension as a risk factor for the development of obliterative bronchiolitis in lung allograft recipients. Chest 110:704, 1996 53. Kuno R, Kanter KR, Torres WE, et al: Single lung transplantation followed by contralateral bullectomy for bullous emphysema. J Heart Lung Transplant 15:389, 1996 54. Le Pimpec-Barthes F, Debrosse D, Cuenod CA, et al: Late contralateral lobectomy after single-lung transplantation for emphysema. Ann Thorac Surg 61:231, 1996 55. Levine SM, Anzueto A, Peters JI, et al: Medium-term functional results of single lung transplantation for end-stage obstructive lung disease. American Journal of Respiratory and Critical Care Medicine 150:398, 1994 56. Levine SM, Gibbons WJ, Bryan CL, et al: Single lung transplantation for primary pulmonary hypertension. Chest 98:1107, 1990 57. Levine SM, Jenkinson SG, Bryan CL, et al: Ventilation-perfusion inequalities during graft rejection in patients undergoing single lung transplantation for primary pulmonary hypertension. Chest 101:401, 1992 58. Levy RD, Ernst P, Levine SM, et al: Exercise performance after lung transplantation. J Heart Lung Transplant 1297, 1993 59. Lewiston N, King V, Umetsu D, et a1 Cystic fibrosis patients who have undergone heart-lung transplantation benefit from maxillary sinus antrostomy and repeated sinus lavage. Transplant Proc 23:1207, 1991 60. Low DE, Trulock EP, Kaiser LR, et al: Morbidity, mortality, and early results of single versus bilateral lung transplantation for emphysema. J Thorac Cardiovasc Surg 103:1119, 1992 61. Madden B, Hodson M, Tsang V, et al: Intermediateterm results of heart-lung transplantation for cystic fibrosis. Lancet 339:1583, 1992 62. Ma1 H, Andreassian B, Pamela F, et al: Unilateral lung transplantation in end-stage pulmonary emphysema. Am Rev Respir Dis 140:797, 1989 63. Ma1 H, Sleiman C, Jebrak G, et al: Functional results of single lung transplantation for chronic obstructive lung disease. American Journal of Respiratory and Critical Care Medicine 149:1476, 1994 64. Marinelli WA, Hertz MI, Shumway SJ, et a1 Single lung transplantation for severe emphysema. J Heart Lung Transplant 11:577, 1992 65. Martinez FJ, Orens JB, Deeb M, et al: Recurrence of sarcoidosis following bilateral allogeneic lung transplantation. Chest 106:1597, 1994 66. Massard G, Shennib H, Metras D, et al: Double lung transplantation in mechanically ventilated patients with cystic fibrosis. Ann Thorac Surg 55:1087, 1993 67. Moser KM, Daily PO, Peterson K, et a1 Thromboendarterectomy for chronic, major vessel thromboem-

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Address reprint requests to Robert M. Kotloff, MD Pulmonary and Critical Care Division University of Pennsylvania Medical Center 3600 Spruce Street Philadelphia, PA 19104