History

The pioneering experiments of numerous researchers who attempted to transplant heart, lung, and combined heart-lung blocks in different animal models laid the foundation for thoracic organ transplantation. In the 1950s, successful canine experiments performed by Demikhov, Metras, Hardin, and Kittle made lung transplantation a reality. In 1963, Dr. James Hardy and his team at the University of Mississippi Medical Center performed the first successful human lung homotransplantation. The recipient was a man with severe emphysema and a nonresectable left-sided lung cancer. His donor had recently died from a massive myocardial infarction. As with most early lung transplant procedures, the allograft was harvested from a non–heart-beating donor, an approach that is currently reemerging as a partial solution for the organ shortage. Immediately after the operation, which lasted less than 3 hours, the patient’s oxygen saturation improved, providing the first evidence of adequate allograft function. Unfortunately, the initial success was met with failure, because the recipient died 18 days later from renal failure. Nearly 45 different transplantation attempts followed over the next 20 years. In almost all cases, failure seemed to stem from a lack of adequate bronchial perfusion to the anastomosed airways, which led to necrosis, dehiscence, and infection, in concert with lack of medications adequate to prevent acute rejection.

In the early 1980s, lung transplantation entered a new era. Dr. Bruce Reitz and the Stanford transplant group were able to achieve long-term survival with their series of combined heart-lung transplantations. Part of their success was attributed to the lack of bronchial ischemia as a result of performing the combined heart-lung approach that left the coronary circulation intact to provide collateral blood flow to the main airways after the bronchial artery had been ligated. The concurrent use of cyclosporine, the first effective T cell suppressor drug approved for use in solid organ transplantation in the United States, helped ameliorate acute rejection episodes. Dr. Joel Cooper and the Toronto transplant group also documented success with single-lung transplants and then with en bloc bilateral lung transplants. Improved bronchial healing was achieved with omentopexy (i.e., wrapping omentum around the anastomosis to facilitate neovascularization). Omentopexy has been replaced, first by the telescoping bronchial anastomosis technique first described by Dr. Frank Veith in 1969, and then by the end-to-end technique. In the late 1980s, the bilateral sequential single-lung transplant technique, as developed by the Toronto and San Antonio programs, became the procedure of choice for double-lung transplantation.

Over the next 2 decades, the state of lung transplantation grew sporadically, but quickly, and has now stabilized. The most recent reports from multiple lung transplant centers throughout the world indicate that bilateral and single-lung transplants continue to account for most procedures performed. Heart-lung transplants are now rare and reserved primarily for those patients with the Eisenmenger anomaly or severe primary pulmonary hypertension.

Current Trends in Lung Transplantation

In the United States, the United Network for Organ Sharing (UNOS) has been operating the Organ Procurement and Transplantation Network (OPTN) since 1984. The International Society for Heart and Lung Transplantation (ISHLT), in collaboration with UNOS, created a worldwide registry of all heart and heart-lung transplant procedures in 1982. The Twenty-seventh Report documents that more than 32,000 lung transplant procedures have been performed since that time, with 2769 lung transplant procedures done in 2008 by 158 transplant centers worldwide. Most current transplant procedures involve bilateral sequential or double-lung transplants (Figure 75-2). Seventy-three heart-lung transplant procedures were done during that same year.

Figure 75-2 Number of lung transplants reported by year and procedure type.

Although the number of lung transplant procedures has increased substantially in the past 2 decades, the leading indications for lung transplantation remain relatively unchanged: chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), α₁-antitrypsin (A1A) deficiency with emphysema, and pulmonary arterial hypertension (PAH) (Figure 75-3). The type of transplant a patient receives is dictated in part by the recipient’s underlying disease: Recipients with COPD and IPF tend to receive single-lung as often as double-lung transplants, whereas those with CF and PAH almost always receive bilateral lung transplants (Figure 75-4). Over the past several years, a trend toward performing double-lung transplants and transplanting older people in the 55 to 65 age range has emerged (Figure 75-5).

Figure 75-3 Adult lung transplantation major indications by year (%). Alpha-1, α₁-antitrypsin deficiency; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; IPAH, idiopathic pulmonary arterial hypertension; IPF, idiopathic pulmonary fibrosis; Re-Tx, repeat transplantation.

(Adapted from Christie JD, Edwards LB, Kucheryavaya AY: The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth adult lung and heart-lung transplant report—2011, J Heart Lung Transplant 30:1104–1122, 2011.)

Figure 75-4 Adult lung transplantation procedure types according to indication and year of transplantation. AT Def, α1-antitrypsin deficiency emphysema; COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis; IPAH, idiopathic pulmonary arterial hypertension.

Figure 75-5 Age distribution of adult lung transplant recipients by era.

In March 2011, UNOS estimated a total of 1790 patients on the active waiting list in the United States. The median waiting time for those listed in the period 2003 to 2004 was approximately 2 years. The most recent waiting list time is not yet known, but after the implementation of the Lung Allocation Score (LAS), median waiting times seem to have shortened. Twenty-five percent of patients undergo transplantation within 3 months. Today, donors selected for lung donation are older, with a mean age of 38 years, and more donors older than the age of 59 are now accepted.

Survival

Achieving successful outcomes and maximal survival in the lung transplant population starts with the proper selection of transplant candidates. This entails an understanding of the natural history of the recipient’s lung disease and the projected survival with optimal medical and surgical therapy. Identifying potential candidates must be based on their current quality of life and the potential for improvement with and without transplantation. The median survival for lung transplant recipients has improved dramatically over the past several years. Transplant procedures performed from 2000 to 2004 were associated with a median survival of 5 years, significantly higher than for previous years (Figure 75-6). The survival curve is not linear, however, because approximately 20% of all recipients die in the first year after transplantation, with most occurring in the first 90 days. After this rapid decline, survival then stabilizes and follows a more linear trajectory, with an estimated 6% mortality rate per year. First-year mortality is attributable to postoperative graft complications, infection, cardiac failure, rejection, and early toxicity from immunosuppressive medications (Figure 75-7).

Figure 75-6 Kaplan-Meier survival by era for adult lung transplants performed between January 1988 and June 2009. Conditional half-life is the time to 50% survival for the recipients who were alive 1 year after transplantation.

Figure 75-7 Cause of death in time periods after transplantation based on data from transplants performed between January 1997 and June 2009.

Several independent factors also seem to affect survival, including older age, higher body mass index (BMI), severe pulmonary hypertension, the type of transplant procedure performed, and the recipient’s native pulmonary disease. In recipients older than 65, the expected 5-year median survival is 3.4 years, considerably lower than the overall average 5-year median survival. This is one reason why age older than 65 is considered to be a relative contraindication (Table 75-1).

Table 75-1 General Contraindications to Lung Transplantation

Absolute	Relative
Malignancy within 5 years (except SCC and BCC) Untreatable multiorgan dysfunction Active hepatitis B and C and HIV infection Severe spinoskeletal deformity Current substance addiction Severe osteoporosis Mechanical ventilation Poor social support and medical adherence	Age older than 65 years Unstable clinical condition Poor rehabilitation potential Pan-resistant colonization (Burkholderia cepacia genomovar III) BMI >30 kg/m²

BCC, basal cell cancer; BMI, body mass index; HIV, human immunodeficiency virus; SCC, squamous cell cancer.

Modified from Orens JB, Estenne M, Arcasoy SM, et al: International guidelines for the selection of lung transplant candidates: 2006 update—a consensus report from the Pulmonary Scientific Council of the International Society of Heart and Lung Transplantation, J Heart Lung Transplant 25:745–755, 2006.

Bilateral lung transplantation (BLTx) is associated with a median survival of 5.6 years, compared with 4.3 years for single lung transplantation (SLTx) (Figure 75-8). Although heart-lung transplantation (HLTx) is associated with the lowest median survival rates of approximately 3 years, HLTx procedures also are the least commonly performed. Although it seems that bilateral lung transplant recipients have a better survival, specifically in the COPD group, this finding is controversial, because the observation is retrospective and uncontrolled. One contributing factor may be that older patients tend to receive single-lung transplants, whereas younger patients receive bilateral lung transplants. The highest survival rates are seen in patients with COPD and CF. The lowest survival rates are seen in patients with IPF and PAH, with a relative risk of death exceeding 2.0 in the first year after transplantation (Figure 75-9).

Figure 75-8 Kaplan-Meier survival by procedure type for adult lung transplants performed between January 1994 and June 2009. Conditional half-life is the time to 50% survival for the recipients who were alive 1 year after transplantation.

Figure 75-9 Kaplan-Meier survival by diagnosis for adult lung transplants performed between January 1990 and June 2009, conditioned on surviving to one year. Alpha-1, α1-antitrypsin–deficiency emphysema; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; IPAH, idiopathic pulmonary arterial hypertension; IPF, idiopathic pulmonary fibrosis.

General Selection Criteria

The International Consensus Guidelines for referral and selection of transplant candidates were published in 1998 as a joint effort from the American Society of Transplant Physicians, the American Thoracic Society, the European Respiratory Society, and the International Society for Heart and Lung Transplantation, to facilitate the appropriate timing of referral and proper selection of candidates most likely to benefit from transplantation while ensuring a fair allocation of limited organs. These guidelines were updated in 2006 (Table 75-2). In all instances, selected patients with end-stage pulmonary disease should have declining and irreversible lung function despite optimal medical and surgical management. To justify the risk of transplantation, patients should have an estimated survival of less than 2 years.

Table 75-2 International Guidelines for the Selection of Lung Transplant Candidates: 2006 Update

Two issues regarding this 2-year survival recommendation merit clarification. First, unique to lung transplantation, survival will vary as a function of the recipient’s primary disease. Within the first 2 years, survival rates stabilize and allow a more accurate prediction of subsequent survival. Second, the average waiting time for a transplant is close to 2 years. If transplanted prematurely, patients may lower their survival benefit and keep more terminal candidates from transplantation. Therefore, the most current projected prognosis of lung diseases, the average time on the waiting list, and the median survival after lung transplantation should be considered in determining timing for selection. The new Lung Allocation System in the United States also affects this planning, in that the time to transplantation seems to be shorter, but a median waiting time for patients has not yet been determined. In essence, this is a moving target that will take more time to define.

The typical age for HLTx is younger than 55 years, BLTx younger than 60, and SLTx younger than 65. Medical conditions associated with damage to other organs are considered absolute contraindications. The exception is in rare selected cases with potential for combined heart-lung, lung-kidney, or lung-liver transplantation. For this reason, diagnosis and management of hypertension, diabetes mellitus, gastroesophageal reflux, peptic ulcer disease, and osteoporosis should be aggressive. Renal impairment is considered an absolute contraindication to transplantation if the creatinine clearance is less than 50 mg/mL/minute.

Cancer screening includes mammography, Papanicolaou smear, PSA assay for prostate, and colonoscopy as medically indicated. A history of cancer is not an absolute contraindication. Eligibility is determined by cancer type and requires documentation of cure without evidence of recurrence or metastasis. In patients with a history of lymphoma, breast, colon, renal, or prostate cancer, a 5-year cancer-free period is required, because these cancers tend to have a longer recurrence period. Less aggressive skin cancers, such as squamous and basal cell, should be in remission for longer than 2 years.

Osteopenia and osteoporosis should be sought with bone densitometry measurements. Bone demineralization should be treated before transplantation by proper nutrition, calcium supplementation, vitamin D, bisphosphonates, and/or hormone replacement. Medications that increase bone resorption should be discontinued. Symptomatic osteoporosis is considered a relative contraindication. The future need for chronic steroid and immunosuppressive therapies will worsen bone loss. This can result in impaired ambulation and suboptimal rehabilitation and limit posttransplantation quality of life.

Nutritional state also affects outcome and postoperative rehabilitation. Candidates should weigh more than 70% but less than 130% of their ideal body weight. Generally speaking, a BMI between 18 and 30 kg/m² is acceptable. For patients whose BMI or weight is outside of these limits, a weight gain or weight loss program should be instituted with subsequent reevaluation for candidacy. Percutaneous enteral feeding may be necessary to achieve the desired nutritional goal. Total parenteral nutrition is an option but is not recommended with any enthusiasm because of the attendant risk of infection.

Dependence on tobacco, alcohol, or drugs must be treated, and patients should be substance-free for longer than 6 months. Disabling psychoaffective disorders, noncompliance, and lack of proper social support are relative contraindications. In our institution, social workers assess the support systems to maximize compliance with postoperative interventions and medications. Financial issues, including supplemental aid from hospital programs, insurance companies, and government agencies, as well as family and community support, must be explored preoperatively.

Invasive mechanical ventilation is considered a relative contraindication. Retrospective analyses suggest that acutely ventilated patients have a very high risk of perioperative complications, with a mortality rate surpassing 50%. On the other hand, chronically ventilated patients without other contraindications may have acceptable survival rates if they are otherwise good candidates.

Musculoskeletal disease that limits ambulation and breathing is an absolute contraindication. Less severe disease is acceptable if the recipient can undergo adequate rehabilitation and have a meaningful quality of life after transplantation. Restrictive anatomic deformities of the thorax and skeleton are considered relative contraindications.

Chronic active infection with human immunodeficiency virus (HIV), hepatitis B, and hepatitis C are considered absolute contraindications. Recipients colonized with multidrug-resistant Burkholderia cepacia complex (BCC) exhibit an extremely high rate of mortality and graft failure. BCC often is found in patients with CF, and many centers consider this to be an absolute contraindication. Survival in recipients with multidrug-resistant Pseudomonas aeruginosa is similar to that in noncolonized patients. Previously treated infection with Mycobacterium tuberculosis is not a contraindication. Treatment of various pulmonary infections may be started preoperatively in some patients in an attempt to decrease the pathogen burden. In others, postoperative prophylaxis may be instituted for those who are deemed to be at high risk for infection or reactivation (e.g., with Aspergillus colonization). A higher risk of infection still exists in colonized recipients who receive bilateral lung transplants, because many colonizing bacteria and fungi may spill down into the lung from sinuses, nasopharynx, and trachea.

Disease-Specific Considerations for Referral and Selection

Chronic Obstructive Pulmonary Disease

Patients with COPD (i.e., emphysema, chronic bronchitis, and obliterative bronchiolitis) have the highest survival rates after transplantation (emphysema related to A1A deficiency is considered a separate condition).

Survival benefit has not been documented in patients with COPD, even though transplantation confers substantial improvement in functional capacity and quality of life. One potential explanation for this discrepancy is that the forced expiratory volume in 1 second (FEV₁) may not be as reliable a referral parameter as, for example, the BODE index (determined by scoring for body mass index, airway obstruction, dyspnea, and exercise capacity) (Table 75-3). Patients with a BODE index between 7 and 10 should be selected for transplantation. Other criteria for selecting candidates with COPD include severe worsening of pulmonary function, shorter 6-minute walking distance capacity (less than 100 yards), weight loss (BMI less than 20 kg/m²), need for hospital admission (to the intensive care unit [ICU] in particular), and radiographically homogeneous emphysema. More severely affected patients will show chronic hypoventilation (i.e., PaCO₂ greater than 55 mm Hg and evidence of pulmonary hypertension despite oxygen therapy). All patients with COPD should be referred for pulmonary rehabilitation and treated with oxygen therapy, and use of an alternative approach such as lung volume reduction surgery should be either documented as not a viable option or proved to be ineffective.