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1 Johns Hopkins Hospital, Baltimore, Maryland; and 2 The University of Chicago Medical Center, Chicago, Illinois
Correspondence and requests for reprints should be addressed to Jonathan B. Orens, M.D., Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Blalock Room 910, Baltimore, MD 21287. E-mail: jorens{at}jhmi.edu
ABSTRACT
Lung transplantation is an established treatment option for patients with a wide variety of end-stage lung diseases. For patients with end-stage lung disease, lung transplant can prolong life substantially; however, the survival statistics for lung transplants still pale compared with other solid organ transplants. Acute cellular rejection (ACR) is common after lung transplantation occurring in up to 90 percent of patients. Chronic allograft rejection, manifest as bronchiolitis obliterans syndrome (BOS), remains the "Achilles heel" to the long-term success of lung transplantation. Unfortunately, BOS is common after lung transplantation, occurring in a majority of patients by 5 years after transplant. Candidates for lung transplantation should have near–end-stage lung disease with a limited life expectancy. Allocation of organs today is based upon need and survivability of the operation, and there is a high likelihood of improvement in quality of life. Details of the advances in this fascinating field are included in the several articles in this issue.
Key Words: lung transplantation • organ allocation • surgery • selection
HISTORY
Lung transplantation is an established treatment option for patients with a wide variety of end-stage lung diseases. Although early attempts at human lung transplantation in the 1960s and 1970s yielded extremely poor results, the experience since the 1980s has been much more promising. Looking back in time, Vladimir P. Demikhov, a Soviet researcher, performed the first experimental lung transplants in animals in the 1940s and 1950s (1, 2). It took 20 years before moving from animals to humans when James Hardy and colleagues performed the first attempt at a human lung transplant in 1963 at the University of Mississippi (3). The recipient was a prisoner with severe emphysema who had lung cancer but could not tolerate resection of the tumor due to the severity of his underlying lung disease. While the technical aspects of the operation were successful, the patient died on Postoperative Day 18. Interestingly, the donor was declared dead in the operating theater after cessation of heartbeat followed by rapid removal of the organs, making this also the first lung transplant from a non–heart-beating donor. Over the next 20 years, there were no fewer than 38 attempts at isolated human lung transplants without any long-term survivors. With so many failures, it was thought that lung transplantation would never become a viable therapeutic option. However, in 1981, after years of additional work in the animal laboratory (Figure 1), Bruce Reitz and Norman Shumway performed the first successful combined heart-lung transplant in a patient with end-stage primary pulmonary hypertension (4). This operation literally opened the door to the possibility of future isolated lung transplantation in humans. Not only was this operation a technical success, but the patient, a newspaper executive from Arizona, survived for many years and wrote a wonderful book detailing the story of this amazing medical accomplishment (5). In May of 1986, Joel Cooper and the team from the Toronto Lung Transplant Group published their experience with the first two successful human single-lung transplants (6). The recipients had end-stage pulmonary fibrosis and at the time of the publication both were alive at 14 and 26 months. Not only did the patients survive, but they both enjoyed marked improvement in lung function associated with normal resting arterial blood gas measurements and no inducible oxygen desaturation with exercise. One year later, the Cooper team published their further experience with a total of five single-lung transplants for patients with end-stage pulmonary fibrosis resulting in four long-term survivors (7). After the initial experience by the Toronto group in the early 1980s, there was exponential growth in the number of cadaveric donor lung transplants performed worldwide through the 1990s. However, the volume of transplants performed leveled off from the mid- to late 1990s to the present time (Figure 2), primarily due to the limited number of available donor lungs. Motivated by the limited number of available donor organs, Starnes and coworkers performed the first living lobar donor lung transplants in the early 1990s, primarily in children with cystic fibrosis (8). Recent innovations have attempted to address the donor shortage, often using lungs that were formerly not acceptable. Today, programs around the world are working aggressively to better understand how to prevent and or treat some of the major complications associated with lung transplants.
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WHAT CAN BE EXPECTED
Expectations with lung transplants vary based on many conditions that the recipient and the donor bring to the process. That improved survival has happened is clear from Figure 3 (9), which shows separation of the survival curves by era since data collection began (9). Of particular note is the improvement in early postoperative survival as the technical difficulties with lung surgery have been addressed, so that first-month mortality has declined steadily since the late 1980s. Also of note, however, are the nearly parallel slopes of the later survival curves, demonstrating loss of life at equivalent rates since lung transplant data have been collected. This represents graft and patient loss due to late complications of the operation, mostly bronchiolitis obliterans syndrome (BOS), which (when combined with recurrent lung infection) is responsible for the majority of deaths in those who have survived at least 1 year (9).
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What Figure 3 above does not show is the reported improvement in both symptomatology and overall QOL. While the literature is pretty thin in these areas, those investigators who have studied symptoms and QOL find marked improvement in the majority of surviving patients (12, 13) at most time points after transplant. Investigators have used many survey tools to assess multiple domains of patient well-being apart from survival (13–15). All reported improved patient functioning in areas like physical, emotional, and general health. Also demonstrated was that scores remained improved after transplant even after onset of BOS, as long as the patient remained better than pre-transplant by his/her own estimate.
Despite all of the potential benefits associated with lung transplantation, this intervention is indeed associated with several shortcomings. These include: infection, acute and chronic rejection, the need for lifelong potent immunosuppressive medications, and the side effects associated with these medications. Such side effects include but are not limited to renal failure, liver toxicity, hypertension, diabetes mellitus, neurological insults, and malignancy.
SURVIVAL
For patients with end-stage lung disease, lung transplant can prolong life substantially; however, the survival statistics for lung transplants still pale compared with other solid organ transplants. While heart, kidney, and liver transplants enjoy a half-life of around 10 years, lung transplants are still limited to a half life of around 5 years (9). Data from the 2007 International Society For Heart and Lung Transplantation Registry Report show an overall survival of 78% at 1 year, 62% at 3 years, 50% at 5 years, and 26% at 10 years (9, 16). While these data are inclusive of the early experience in lung transplantation, the overall survival has improved between the eras 1995 to 1999 and 2000 to June of 2005, in which the 1- and 5-year survival rate has increased from 74 and 47% to 81 and 52%, respectively (9). These data are inclusive of all recipients and also show significant survival differences related to the underlying disease. For example, patients with a diagnosis of chronic obstructive pulmonary disease (COPD) have a 1-, 3-, and 5-year unadjusted survival rate of 86.4%, 68.7%, and 51.1%, while patients with IPF have a 1-, 3-, and 5-year survival of 80.4%, 64.2%, and 48.5% (16). It is important to note that these survival data are for recipients who were transplanted with the old organ allocation system, in which priority was based on time accrued on the waiting list. In May of 2005, the LAS was initiated, prioritizing patients on the basis of the risk of death on the waiting list (urgency) and the chance of surviving 1 year after transplant (utility) (17). Accordingly, the LAS is, in part, a score based on severity of illness, which may have a significant impact on the characteristics of patients transplanted and survival outcomes. Since the system is relatively new, additional time is needed to collect data to assess its impact on survival outcomes. At least preliminarily it appears that the LAS has not led to a major decline in overall survival as sicker patients are done first, except for some change noted among those with the highest LAS scores (18).
PRIMARY GRAFT DYSFUNCTION
With every transplant there is injury to the graft by means of removing the organ from its natural blood supply, warm/cold ischemia, organ manipulation, and then subsequent reperfusion. The net result of this injury in lung transplants is a process now defined as primary graft dysfunction (PGD) (formerly ischemia reperfusion injury or primary graft failure) (19). The clinical hallmarks of PGD are hypoxemia and diffuse radiographic infiltrates associated with capillary leak into the graft. Pathologically, there is alveolar and interstitial edema early in the process. Subsequently, hyaline membranes develop analogous to the pathology seen in adult respiratory distress syndrome (ARDS) or other forms of acute lung injury (19). This process may range in severity from very mild with barely visible radiographic infiltrates and relatively normal alveolar to arterial oxygen gradients (A-a gradient) to severe and life-threatening with dense infiltrates and profound abnormalities of gas exchange. While most patients survive this process, this is a leading cause of perioperative mortality in lung transplant recipients. More importantly, there is now evidence suggesting that severe PGD is associated with decreased long-term survival (20). The pathogenesis involved with this process is the focus of ongoing investigation.
ACUTE REJECTION
Acute cellular rejection (ACR) is common after lung transplantation, occurring in up to 90 percent of patients (21). ACR is most likely to occur during the fist postoperative year (22). Although it appears to be a common problem, the true incidence is not entirely clear since many cases may be clinically silent and only discovered by surveillance bronchoscopic biopsies, which are not consistently performed from center to center. Treatment for ACR is reported in 40 to 50 percent of patients during the first year (9). However, it is important to recognize that most centers do not treat minimal rejection, which is a common finding in asymptomatic patients. Although ACR is a common problem, it typically responds quickly to treatment with simple augmentation of the immunosuppression with corticosteroids. The nonspecific clinical presentation of ACR varies depending on the severity of the process from completely asymptomatic to manifestations of fever, diffuse pulmonary infiltrates, and hypoxemia. The possibility of ACR occurring in asymptomatic patients may be detected by a drop in spirometry, measured at home as part of the standard daily monitoring routine (23). ACR is typically diagnosed by bronchoscopic transbronchial biopsies with histology showing perivascular and interstitial lymphocytic infiltrates. The severity of ACR is divided into none, minimal, moderate, and severe based on the extent of the lymphocytic infiltrates using the International Society for Heart and Lung Transplant grading system (24). Under this system there is a severity grade for both the perivascular/interstitial component (a-grade) and airway component (b-grade). The most important consequence of ACR is the association with chronic rejection. Numerous studies show that frequent and severe episodes of ACR are associated with a higher incidence of bronchiolitis obliterans syndrome, the clinical hallmark of chronic allograft rejection (25–29).
CHRONIC REJECTION
Chronic allograft rejection remains the "Achilles heel" to the long-term success of lung transplantation. Chronic rejection is the leading cause of long-term morbidity and mortality and it is characterized pathologically as obliterative bronchiolitis (OB) (24, 25). Clinically, patients with chronic rejection present with progressive airflow obstruction that may be associated with dyspnea and cough (25). Patients with chronic rejection ultimately die from either respiratory failure or secondary infection. While the diagnosis of OB is most confidently established with a surgical biopsy, most patients are diagnosed on clinical grounds alone. The term "bronchiolitis obliterans syndrome" (BOS) is used to describe patients with progressive airflow obstruction that can't be ascribed to any specific cause (30). Specifically, acute rejection, infection, or large airway stenosis must be excluded by bronchoscopy with bronchoalveolar lavage and transbronchial biopsies (30). BOS is diagnosed when there is at least a persistent 20% drop in FEV1 and the other issues outlined above have been excluded (25, 30).
Unfortunately, BOS is common after lung transplantation, occurring in up to 64% of patients by 5 years after transplant (31). Survival is reduced in patients with BOS compared with those who are free of this process (31). The rate of progression of BOS is quite heterogeneous in its presentation. Some patients may develop a sudden drop in lung function that may remain stable for years, while others may present with a very rapid and progressive loss of lung function leading to death within a few months. To date, there is no proven effective treatment for BOS. Many treatment strategies have been tried, including augmentation of immunosuppression, total lymphoid irradiation, and photophoresis (32). None of these have proven to be effective. Recently, two approaches seem to show some promise. The groups from Duke University and the University of Toronto showed an association between gastroesophageal reflux disease (GERD) and BOS (33). Aggressive treatment for GERD, including surgical esophageal wrapping, has improved lung function in several reported patients (34). The oral antibiotic azithromycin has also recently been shown to improve lung function in some patients with BOS (35). The mechanism for improvement remains the subject of ongoing research.
INFECTION
Infection is the leading cause of mortality during the first year and remains a major cause of morbidity and mortality over the long term after lung transplantation (9, 36). In addition to the increased susceptibility to infection induced by the immunosuppressive medications that are common to all solid organ transplants, lung transplants have additional susceptibility to infection. Because they are uniquely exposed to the outside world, lung allografts are at increased risk of exposure to infection through direct inhalation. Other factors that increase the risk of infection in lung allografts include denervation and therefore inhibited cough reflex to foreign stimuli and abnormal airway mucosal function limiting removal of foreign material from the lungs. Taken together, these factors markedly increase the risk for primary infection of the allografts. Indeed, all categories of infection are seen in lung transplant recipients, including bacterial, viral, and fungal agents. In an early study by Maurer and colleagues (37), bacterial infections were the most common (32 out of 51 episodes of infection), followed by viral and fungal infections. Overall, the lung was the most frequent site of infection, with pneumonia occurring in over half of the cases reported (37). Each of these infections can be responsible for acute morbidity and mortality, but there is also major concern about the relationship of infections to future graft function. Several studies document the association between chronic graft dysfunction/BOS and viral infections (38, 39). It is not entirely clear what the mechanism is for graft damage, be it direct injury from the infection, or a combination of direct injury plus immune reaction, ultimately leading to the development of BOS.
COST
Solid organ transplantation always raises the issue of cost as it relates to benefit, both to the individual and to society as a whole. Clearly the costs are more easily borne if the transplant is uncomplicated, and much more difficult to bear if rocky in its course. It is an inherently expensive process that exacts its toll emotionally, physically, and financially. The emotional load is palpable from the start, as recipient candidates maneuver through the medical system while significantly disabled, even with the help of loved ones. The most obvious emotional weight is felt from the donor side, where family and friends deal with the devastation of a death and the heartfelt request for donation. These issues are the subject of many publications, including Strange Harvest, in which the author describes the "tyranny of the gift" that drives some of the process (40).
On the financial side, more detailed cost analysis is possible. The University Health Systems Consortium (UHC) collects data from participating institutions to compare costs, outcomes, complications, and other valuable information. Reported quarterly, the data give a snapshot view of lung transplantation as practiced in the United States (41). From these data can be gleaned median length of stay (LOS), median cost, rates of certain complications, and so on. As expected, basic costs vary tremendously by center and geographic location. The main finding is that LOS affects cost. The median case cost associated with lung transplant through 2007 for 33 centers and 766 cases is approximately $140,000, with mean length of stay approximately 18 days. It is also clear that uncomplicated cases cost less than others, with fewer patient readmissions and fewer complications that need intervention. Follow-up costs for lung transplantation are high, but quite difficult to document. Clearly the financial load is not for the faint of heart, yet comparisons with annual infusion therapy for pulmonary hypertension or alpha-1 antitrypsin deficiency show annual charges in excess of $100,000 each. That being said, it is still desirable to avoid transplantation until medically necessary. Analysis of cost-benefit by estimating quality-adjusted life years, or QUALY, is nascent and hence little information exists to inform the community about its value in lung transplantation.
CANDIDACY
Candidates for lung transplantation should have near–end stage lung disease with a limited life expectancy. While transplantation has the potential to improve both survival and quality of life, the major driving force for this procedure is to prolong survival. Fortunately, with a successful transplant there is also marked improvement in quality of life as measured in multiple domains (14, 42). Disease-specific guidelines for lung transplantation are published in the Journal for Heart and Lung Transplantation (43) and are discussed more extensively in another section of this issue (pp. 20–27). There are both inclusion and exclusion criteria. The best candidates for lung transplantation are individuals aged 65 years or less who have no comorbidities (43). Candidates should be compliant with their medical care and be psychologically and socially capable of handling complex lifelong medical regimens (43). Absolute contraindications include significant chronic disease of other organs (i.e., heart, liver, kidney) and untreatable chronic infections (i.e., chronic active hepatitis, human immunodeficiency virus infection) (43). In addition to the medical issues, patients must have adequate financial resources, either through insurance or other means, to afford the surgery and an extensive number of costly medications for the remainder of life.
TIMING
It is important to recognize that to achieve the best survival benefit, transplantation needs to be properly timed in relation to the progression of the underlying disease. Ideally, transplantation should not be performed prematurely, nor should it be offered too late. A premature transplant may shorten a patient's life, while a transplant offered too late may result in the patient not surviving long enough to find a proper donor or being too ill to survive the transplant. The appropriate timing for transplantation depends on the underlying disease. For patients with diseases such as idiopathic pulmonary fibrosis (IPF) that may progress rapidly, transplantation should occur relatively early in the course of the disease. For patients with diseases that progress very slowly, such as chronic obstructive pulmonary disease (COPD), transplantation should be offered much later, when it is clear that there is a significant chance of death without transplantation. Indeed, one study showed that for patients with COPD, there was no survival benefit for those who received lung transplantation when compared with patients who continued to wait (10). Yet, patients with COPD have the best short- and medium-term survival for lung transplantation when compared with those with other underlying diseases (9). It therefore stands to reason that the major reason for the lack of a survival benefit for patients with COPD in this study was premature transplantation, before they were at significant risk for dying from their disease.
EVALUATION AND LISTING
The evaluation process begins by referral to a lung transplant center. After an initial screening of the records by the transplant team, patients who meet the general candidacy guidelines (i.e., appropriate age and without known absolute contraindications) are further assessed in person at the transplant center. During this initial evaluation, a complete history and physical examination is performed and the patient is informed of the potential risks and benefits to transplantation. If the transplant physician deems the patient to be a potential candidate, a much more in-depth evaluation will be initiated. This includes a series of tests to assess severity of illness and to exclude comorbidities that could be a contraindication to transplantation. The candidate will also meet with other members of the transplant team such as the transplant surgeon, nurse coordinators, psychologist/psychiatrist, social worker, nutritionist, physical therapist, and financial specialist. Once all of the testing and individual team member assessments are completed, a candidacy decision is made by the entire team. Those deemed to be good candidates, and sick enough to warrant the risk of transplant, will be placed on the active waiting list. Some, however, will be deemed to be good candidates but not quite sick enough. These patients will typically be followed closely by the transplant team and placed on the active list after further progression of their disease, provided they have not developed any new contraindications. It is important to note that candidate selection criteria vary between centers and denial from one program does not necessarily exclude a patient from another center.
PRIORITY
All of solid organ transplantation depends upon availability of necessary organs. If the needed organs were routinely available, then recipients would be able to receive life-giving surgery when needed. Conversely, because there is a shortage of usable organs, rationing in the form of organ allocation has become essential. The ever-widening gap between organs needed and those available makes equitable allocation of this scarce resource highly desirable. It would also be ideal if quality of life data were robust enough to inform the organ allocation systems, but as of now, there is a dearth of information useful for this purpose. Quantitative, measurable data will for now have to suffice. The Lung Allocation System in the United States will serve as a key example below.
Lung transplantation has seen major changes in allocation. Within the United States until May 2005, lungs were allocated by waiting time with little regard for urgency. The practice of early listing became an expectation, leading to huge waitlists, frequent shuffling of the active and inactive candidates, and very long times to transplantation, often well over 2 or 3 years for patients with serious, life-threatening processes. These issues left some patients dying before transplant could be performed, while others with serious diseases but lower mortality rates survived to get transplants where the benefits were not so clear. Much controversy surrounded the older allocation waiting system because of its inability to account for urgency of patient need. With the development of the Lung Allocation System for the United States (17), a balanced system addressing pre-transplant urgency and transplant outcome has been adopted. Table 1 lists the clinical factors used to calculate the LAS for each patient. To this list will be added PCO2 and bilirubin as newer markers for waitlist mortality. Using Cox proportional hazards modeling, the score calculates the number of days a given recipient is expected to live in the next year, and the result is normalized to a scale from 0 to 100. Within blood types the next donor offer goes to the patient with the highest LAS, and potential ties are settled by time waiting.
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Spain is especially notable for having developed a particularly robust donor identification and management system that has allowed it to maintain leadership in population-based organ donation. Among many controversial topics in organ transplantation is the question of ownership of the resource, and Spain has answered it by making the donor a national resource to be shared, going beyond our hoped-for approach with primary consent by the donor in the United States. While others may wish to emulate this stance, the success of donation in Spain is nothing short of exceptional. If donation elsewhere were as successful, more organs would be accessible for transplants, waiting lists would be trimmed, and deaths of those waiting would decrease dramatically, while more patients could benefit from the gift of life. In the United States, it is estimated that an increase in organ donors to 75% of potential donors would quickly eliminate waiting lists (Organ Donor Collaborative). What a remarkable accomplishment that would be!
The view of the future is sometimes murky. Among the issues to discuss is the aggressive pursuit of organ donation after brain death, where some medical participants are willing to risk partial brain recovery by use of extracorporeal membrane oxygenator or cardiopulmonary bypass to aid in organ retrieval. The question asked becomes whether a person can die twice or even thrice in the process: once with the observed cardiac or brain death, once more if brain blood flow is restored and then stopped, and finally once more when the transplant recipient and organ expire (40). Another major learning opportunity centers on the minimization or complete withdrawal of immunosuppression, calling on immune tolerance for its benefits, however those benefits may happen. Other areas of significant interest include xenotransplantation, seemingly always a future state, and stem cell–based organ and tissue replacement. Improved drug therapy is also quite likely, but which less toxic medications will be used is not yet apparent. The future holds promise when these questions can be answered.
FOOTNOTES
Conflict of Interest Statement: J.B.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.R.G. is part of a consortium for a clinical trial funded by Astellas, 2003–2008. The total amount to consortium: $1.7 million. Funding had no influence on this manuscript.
(Received in original form July 24, 2008; accepted in final form August 28, 2008)
REFERENCES
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