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.

(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 75-5 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.

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

(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.)

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

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.

(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 75-9 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.

(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.)

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.

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.

Donor Selection and Management

The LAS assigns donor lungs to transplant candidates by use of a scoring system determined by medical urgency and net transplant benefit (predicted posttransplantation survival minus predicted wait list survival). Since its implementation in the United States in 2005, median waiting times have shortened markedly. Unfortunately, a scarcity of donated organs remains a limiting problem, leading to use of non–heart-beating donors (Table 75-4), ex vivo donor lung resuscitation, use of “bridges to transplant,” and development of different types of lung grafts (Table 75-5).

Table 75-4 Maastricht Classification for Non–Heart-Beating Donors*

* Controlled non–heart-beating donors may be eligible for lung donation.

Table 75-5 Types of Lung Grafts

From Wang D, Zhou X, Liu X, et al: Wang-Zwische double-lumen cannula—toward a percutaneous and ambulatory paracorporeal artificial lung, ASAIO J 54(6):606–611, 2008.

Currently, the Ideal Donor Selection Criteria are more stringent than those used for selecting other solid organs. In light of the scarcity of available lung grafts, many suggest that donor criteria be made more flexible to expand the existing donor pool. Alternate criteria include donor age older than 55 years, an initial PaO₂/FIO₂ ratio less than 300, the presence of pulmonary infiltrates on chest imaging, purulent secretions, and a positive history of use of tobacco or other inhalant drug (Table 75-6 and Box 75-1). Retrospective studies suggest similar outcomes for ideal and extended lung allograft recipients, specifically with respect to perioperative complications, ICU stay, requirements for mechanical ventilation, and 1-year survival rate (higher than 80% for both groups). Improved donor management also is under careful investigation, because it may help improve marginal donors and optimize them into ideal candidates. Optimizing donor status with reversal of any limiting physiologic insults is becoming the standard of care in most transplant centers (Figure 75-10). Common respiratory insults are caused by aspiration, atelectasis, infection, pulmonary edema, and the hemodynamic instability associated with neurologic dysfunction. Ventilatory strategies to improve alveolar ventilation may be implemented, along with therapeutic bronchoscopy to suction excess secretions and reexpand atelectatic lung. Small-volume bronchoalveolar lavage (BAL) can minimize the amount of alveolar flooding. Adequate tissue perfusion and cardiac function should be aided with vasoactive medications when needed. Repletion of cortisol, vasopressin, and thyroid hormone also may be of benefit (Figure 75-11).

Table 75-6 Donor Selection Guidelines

* Partial pressure of arterial oxygen tension (PaO₂) is measured on a fraction of inspired oxygen of 1.0 and a positive end-expiratory pressure of 5 cm H₂O.

Figure 75-10 Critical pathway of organ donor management.

(From Critical pathway for the organ donor, Richmond, Va, United Network for Organ Sharing, 2006 [poster online]: http://www.Unos.Org/Resources/Pdfs/Criticalpathwayposter.pdf.)

Figure 75-11 Critical pathway of organ donor management. CVP, central venous pressure; EF, ejection fraction; Hgb, hemoglobin; PT, prothrombin time; PTT, partial thromboplastin time; PWCP, pulmonary capillary wedge pressure; SVR, systemic vascular resistance.

(From Critical pathway for the organ donor, Richmond, Va, United Network for Organ Sharing, 2006 [poster online]: http://www.Unos.Org/Resources/Pdfs/Criticalpathwayposter.pdf.)

Donor Graft Management

Graft ischemic time begins after the lungs have been extracted from the donor. The lungs are flushed with a cold heparinized preservation solution—modified Euro-Collins, low potassium dextran solution (LPD), and University of Wisconsin solutions are the most commonly used—and hypothermic preservation is maintained during transport at 4° C. These solutions have helped reduce the severity of ischemic injury. Additives such as surfactant and platelet and thrombin inhibitors are still under investigation. Donor lungs are matched according to compatibility in size and ABO blood group. A growing trend is for use of prospective lymphocyte and human leukocyte antigen (HLA) cross-matching, especially in sensitized persons. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) cross-matching is not routine, because such testing often is impractical. Each matching procedure has its supporters for certain situations, however.

Lung Allograft Implantation

The implantation of a lung allograft (Figure 75-12) depends on the planned procedure, surgical experience, and the previous surgical history of the recipient. Before all transplant procedures, the recipient’s pulmonary function should be maximized, and management should continue through surgery (e.g., continuing pulmonary vasodilators).

Figure 75-12 Comparison of the four standard lung replacement techniques, including their common indications.

A single-lung transplant often is placed through an anterolateral or posterolateral thoracotomy. Bilateral lung implantation may be performed by means of a transverse sternotomy “clamshell” incision, at the level of the fourth or fifth intercostal spaces, whereas HLTx usually is done through a midsternotomy. Bilateral sequential lung transplantation (BSLT) also can be performed through bilateral anterior thoracotomies; this approach may be preferred because it does not split the sternum and is associated with less chest wall instability. The surgical history of the recipient is important, because previous pleurodesis or cardiothoracic surgery results in fibrous bands and adhesions. This makes resection difficult and may alter the anatomy. When a single-lung transplant procedure is to be performed, the intact side is preferred.

In most instances, the cold ischemic time for a single-lung transplant is approximately 4 hours and for a bilateral lung transplant is less than 6 hours. Pleural tubes are placed before closure and maintained in place until drainage is less than 200 mL/day. Bronchoscopic evaluation of the airway mucosa, anastomotic sites, and therapeutic suctioning of secretions is performed to document graft viability and optimize function.

Intraoperative and postoperative management of patients with end-stage pulmonary disease is challenging because of poor pulmonary gas exchange, elevated pulmonary vascular resistance, and right ventricular overload. Analgesia is controlled with multiple medications, with avoidance of narcotics if possible because of their effects of decreased respiratory drive and sedative properties. A thoracic epidural often is placed in preparation for surgery to adequately control pain and optimize postoperative lung function. Endotracheal intubation is performed with the largest-diameter dual-lumen tube possible to facilitate clearance of secretions. Mechanical ventilation can increase pulmonary vascular resistance and decrease venous return, leading to systemic hypotension. This potential for such effects is important to consider, because anesthetics used during rapid-sequence induction and surgery should be administered cautiously to avoid a precipitous drop in systemic vascular resistance. In most cases, infusions with propofol and fentanyl are used and combined with a neuromuscular blocker such as pancuronium. A fraction of inspired oxygen at 1.0 is used initially, to reduce hypoxic pulmonary vasoconstriction and limit right-sided heart afterload. Cardiopulmonary bypass is not used routinely and should generally be avoided unless hemodynamic instability arises or simultaneous cardiac surgery is necessary. If bypass is used, aprotinin (which slows fibrinolysis) may be administered to help control the coagulopathic disturbance created by the activation of multiple cytokines from the bypass procedure (although recent studies have suggested aprotinin may be associated with increased thrombotic complications). When single-lung ventilation commences, hypoxia and hypoventilation may ensue. Capnography, along with serial arterial blood gases, can help detect signs of failing single-lung ventilation. This deficit may be corrected with independent dual-lung ventilation and tolerance of moderate respiratory acidosis so long as hemodynamics and oxygenation remain stable.

Pulmonary vasodilators such as inhaled nitric oxide (iNO) are used commonly in the perioperative setting. The effects of iNO at relatively low levels (less than 20 parts per million) are not completely understood, but this agent is preferred because of the selective pulmonary vasodilation occurring at sites receiving adequate alveolar ventilation. iNO also seems to inhibit endothelial dysfunction and capillary leak, suppress oxygen radical formation, and ameliorate ischemia-reperfusion injury to the lung allograft. These benefits could then extend to improvement in early graft function. The adverse effects of iNO at higher concentration levels include methemoglobinemia, pulmonary edema, and cardiac contractile dysfunction. Prostacyclin, in either intravenous or aerosolized form, also is used as a direct pulmonary vasodilator.

The goal of hemodynamic management is to reach a negative fluid balance and limit pulmonary edema. The pulmonary artery occlusion pressure is kept under 10 mm Hg to ensure adequate preload. In most cases, immediate normalization of pulmonary arterial pressures and right ventricular function is expected after transplantation. To prevent alveolar damage, hyperinflation, pulmonary vascular hypertension, and anastomotic dehiscence, peak airway pressures are kept under 40 cm H₂O, with a positive end-expiratory pressure close to 5 cm H₂O. Liberation from mechanical ventilation usually is accomplished in the first 1 to 3 days after transplantation.

Noninfectious Complications

The most common problems in the immediate posttransplantation period are the same as those occurring in most postsurgical patients. Hypoxemia may stem from poor cardiac output, endotracheal tube displacement, or obstruction of uncleared secretions, leading to lobar atelectasis. Additional complications that are unique to lung transplantation include hyperacute rejection, graft dysfunction, and cardiac failure; each may be difficult to differentiate from the others (Table 75-7). A suggested reading by Ahya and Kawut has been listed.

Acute Rejection

Acute rejection (AR) is a cell-mediated event activated by donor antigens. It occurs in about 40% of transplant recipients in the first year alone with the highest incidence at 6 months after lung transplantation and is irrespective of specific induction treatment. Figure 75-13 shows the reported rejection between discharge and 1-year follow-up stratified by immunosuppressive regimen. It manifests with presence of alveolar infiltrates on the chest radiograph, hypoxemia, and fever, but many patients may be asymptomatic. Histologic examination (Figure 75-14) is required to diagnose AR, because the clinical presentation mimics that in pulmonary infection, and increasing immunosuppression empirically can lead to toxicity, infection, and malignancy.

Figure 75-13 Reported rejection between discharge and 1-year follow-up for adult lung transplant follow-ups from July 2004 through June 2010, stratified by maintenance immunosuppressive regimen. Rejection is classified as treated (lighter color) or untreated (darker color). AZA, azathioprine; CyA, cyclosporine A; MMF, mycophenolate mofetil; TAC, tacrolimus. Analysis is limited to patients who were alive at the time of the follow-up.

(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 75-14 Transbronchial lung biopsy specimen showing acute rejection. The lymphocytes surround an arteriole and the infiltrate spreads into surrounding alveolar walls (grade A3).

AR is associated with an increased risk for development of chronic rejection. For this reason, serial surveillance with fiberoptic bronchoscopy, BAL, and transbronchial biopsy is often routine during the first year after transplantation. Current recommendations are to obtain at least five separate samples that contain both alveolated lung and bronchioles (because both are necessary to grade the level of AR). Treatment centers on increasing the level of immunosuppression by administration of high-dose corticosteroids and optimizing the use of the standard agents. In addition, antithymocyte globulin, photochemotherapy, and lymphoid irradiation may be used.

Bronchial Anastomotic Complications

Bronchial anastomotic dehiscence may result from ischemic injury, infection, or poor healing. Bronchial artery interruption during the transplant procedure disrupts perfusion to the large airways. High doses of corticosteroids impair wound healing, potentially leading to bronchomalacia and stenosis (Figure 75-15). Dehiscence may manifest as pneumomediastinum, pneumopericardium, and/or pneumothorax (Figure 75-16). Fiberoptic bronchoscopy is necessary to ensure that all bronchial anastomoses are intact. Correction consists of treating any underlying infection and maintenance of adequate tissue perfusion. Bronchial stent placement, laser ablation, and balloon dilatation often are used in management; rarely is reoperation considered.

Figure 75-15 CT scan of bilateral bronchial stenosis (distal main bronchi) after bilateral sequential lung transplantation. Poor anastomotic perfusion from septic shock and bacterial pneumonia complicated the immediate postoperative course.

Figure 75-16 Chest radiograph showing pneumopericardium arising as a manifestation of bronchial dehiscence after lung transplantation.

Hyperinflation

Hyperinflation of the native lung may be seen in patients with COPD and unilateral lung transplantation as a result of the higher lung compliance, more severe airway obstruction, and air trapping that occurs in the remaining emphysematous lung. The hyperinflated lung can compress the transplanted lung and/or the mediastinal structures, causing a substantial reduction in function (Figure 75-17).

Figure 75-17 Chest radiograph showing right single-lung transplant for emphysema. Severe hyperinflation with mediastinal shift caused by overinflation of the native lung with compression of the transplanted right lung is evident.

Infectious Complications

Infectious complications in the immediate postoperative period are the same as those associated with other major cardiothoracic surgery. Blood-borne infections from indwelling catheters, urinary tract, and wound complications are common. Pneumonia in the acute posttransplantation phase requires careful assessment of the donor’s and recipient’s microbiologic and clinical histories, including previous bacterial colonization or recent infections. Clinical history is relevant, because it may detect risks for aspiration, nosocomial, and ventilator-associated pathogens (Table 75-9). Physiologic abnormalities in the transplanted lung also predispose to infection. Impaired mucociliary clearance, denervation of the cough reflex, and disruption of the pulmonary lymphatic and vascular outflow all may act in combination. Infection of the allograft results in inflammation and graft damage. Although prophylaxis seems logical in preventing future infection, strong clinical evidence to support universal use of prophylaxis is lacking, with variable findings among different transplant centers worldwide.

Opportunistic Infections

Opportunistic infections are uncommon before the first month after transplantation. They are directly related to the immunosuppressed state that leads to the reactivation of latent infections and an inadequate response to otherwise nonvirulent pathogens. Prophylaxis against Pneumocystis, the Herpesviridae family of viruses, and Aspergillus will reduce the frequencies of these infections; however, opportunistic infection is a common contributor to posttransplantation morbidity.

Cytomegalovirus (Human Herpesvirus Type 5)

CMV is found in latent stage in nearly 60% of all adults. Routine screening of donor and recipient for CMV IgG allows stratification of patients at highest risk for CMV reactivation and pneumonitis. Primary CMV infection occurs when a CMV-seronegative recipient becomes infected from a CMV-positive graft or blood product. Because primary CMV infection is associated with the highest risk for severe morbidity and mortality, matching CMV-negative recipients to CMV-negative donors is preferred but sometimes is impractical. In cases in which CMV-naive recipients receive a CMV-positive graft, passive immunization with intravenous CMV IgG can be given, followed by inhibition of viral replication with ganciclovir. Other anti-CMV agents include valganciclovir, cidofovir, foscarnet, and leflunomide. These may be used in refractory or resistant cases. Secondary CMV infection and CMV superinfection can cause reactivation pneumonitis in CMV-seropositive recipients; however, these types of infections are not as severe as primary CMV infection. An oral prodrug for cidofovir may be available soon for therapy or prevention.

CMV pneumonitis can be diagnosed by the presence of intranuclear viral inclusion bodies on histologic examination. This condition may be an indirect cause of rejection and the bronchiolitis obliterans syndrome (Figure 75-18). CMV prophylaxis often is given routinely and may delay acute infection (Table 75-10). This practice, however, may result in the evolution of resistant strains and predispose the patient to antiviral toxicity, as well as increasing the current cost of care. Alternatively, preemptive monitoring and treatment of infection can be implemented. CMV replication can be detected early by rising serum CMV antigen levels or quantitative CMV polymerase chain reaction (PCR) assay results.

Figure 75-18 The direct and indirect effects of cytomegalovirus infection. The activation of latent cytomegalovirus (CMV) alters many aspects of the innate and adaptive immune response. The indirect effects include predisposition to opportunistic infections, activation of other latent viruses, and graft rejection or graft-versus-host disease. EBV, Epstein-Barr virus; ICAM1, intercellular adhesion molecule-1; MHC, major histocompatibility complex; TNF-α, tumor necrosis factor-α; VCAM, vascular cell adhesion molecule; vWF, von Willebrand factor.

(From Ison MG, Fishman JA: Cytomegalovirus pneumonia in transplant recipients, Clin Chest Med 26:691–705,viii [Figure 1], 2005.)

Table 75-10 Suggested CMV Prophylaxis After Lung Transplantation

CMV Status	Recipient +	Recipient −
Donor +	• Treatment duration is 3 months 1. Days 1-14: Valganciclovir 900 mg PO bid 2. Days 15-90: Valganciclovir 900 PO mg daily

• Donor +/Recipient − are the highest risk for CMV disease

• Prophylaxis may have advantage over preemptive therapy

• Treatment duration is typically 6 months

1. Days 1-14: Valganciclovir 900 mg PO bid

2. Days 15-180: Valganciclovir 900 mg PO daily*

Donor −

• Treatment duration is 3 months

1. Days 1-14: Valganciclovir 900 mg PO bid

2. Days 15-90: Valganciclovir 900 PO mg daily

• Risk of CMV disease is increased with extensive blood transfusion

• Leukodepleted and CMV seronegative blood products are recommended

• If extensive transfusions are necessary, CMV prophylaxis should be considered

• Monitoring weekly for CMV PCR should be considered

• We use Acyclovir or Valacyclovir for HSV prophylaxis days 1-90

CMV, cytomegalovirus; HSV, herpes simplex virus; PCR, polymerase chain reaction.

* When used as prophylaxis, the dose of Valganciclovir is 900 mg daily, versus treatment dose which is 900 mg twice daily.

Epstein-Barr Virus

EBV is also routinely screened for in both recipients and donors. Similar to CMV, it carries a high risk for reactivation and can lead to posttransplantation lymphoproliferative disorder (PTLD). PTLD is believed to occur in almost half of the patients who are EBV-seronegative and receive an EBV-seropositive graft. Matching EBV-negative status is therefore extremely important, but often difficult, because few donor agencies screen for EBV. PTLD may manifest as a pulmonary nodule, mass, or infiltrate and requires tissue biopsy for diagnosis. Unfortunately, commonly used chemotherapy directed against lymphoproliferative malignancies has not been very successful in treating PTLD. EBV prophylaxis in patients at highest risk is covered by antiviral treatment directed against CMV and herpes simplex virus (HSV). As with all other opportunistic complications, reduction in the level of immunosuppression remains the single most important management strategy, if PTLD occurs.

Aspergillus Spp.

Aspergillus infection is a common infection after solid organ transplantation. It may manifest in a variety of ways, including a bronchial inflammatory disorder, necrotizing airway infection (with pseudomembrane formation), and invasive pulmonary parenchymal aspergillosis. Invasive fungal infection is difficult to diagnose, because it is angiocentric and not detected on routine BAL or TBB. Surgical biopsy often is necessary to make a definite diagnosis. Prophylaxis with oral amphotericin B, itraconazole, voriconazole, or intravenous liposomal amphotericin may be administered to persons at highest risk for infection. The azoles must be used carefully, because they can interfere with the metabolism of calcineurin inhibitors.

A chronology for the common infectious and noninfectious complications that occur after transplantation over time is presented in Figure 75-19.

Figure 75-19 The chronology of pulmonary complications in the lung transplant recipient. Some complications occur during a defined time span in the early posttransplantation period, but others occur throughout the follow-up period.

Chronic Rejection

Chronic Lung Allograft Dysfunction

Bronchiolitis obliterans syndrome (BOS) is a common clinicopathologic syndrome of progressive and irreversible airway obstruction with a declining DLCO that occurs as a late complication in graft function with an incidence of almost 50% by the fifth year after transplantation (Figure 75-20). On histopathologic examination, BOS is represented by obliterative bronchiolitis (OB)—specifically, fibrosis of the small airways with intimal thickening and sclerosis of its accompanying vessel that lead to near-complete occlusion of the bronchiolar lumen and small airway obstruction (Figure 75-21). Chest imaging should yield normal findings in the early stages of BOS, which remains a diagnosis of exclusion at that time. Acute rejection, infection, drug-induced pneumotoxicity, and bronchial anastomotic obstruction must be excluded. Advanced BOS may appear as peripheral bronchiectasis with a loss of vascularity and atelectasis. A staging system has been created to aid in the diagnosis of BOS by the International Society of Heart and Lung Transplantation (Tables 75-11 and 75-12). Of importance, not all graft dysfunction is due to OB. A restrictive pattern is present in a significant minority of patients. Imaging may suggest peripheral encroachment of the lung volume and restrictive pulmonary function tests (PFTs). Therefore, the phraseology “chronic lung allograft dysfunction” (CLAD) is coming into use to account for more than one manifestation of chronic graft failure.

Figure 75-20 Freedom from bronchiolitis obliterans syndrome in adult lung recipients for follow-up assessments between April 1994 and June 2010, conditional on survival to 14 days.

(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 75-21 Open lung biopsy specimen showing obliterative bronchiolitis. The bronchiolar lumen is obliterated by organizing fibrin, myofibroblasts, and lymphocytes.

Table 75-11 Histologic Classification and Grading of Pulmonary Allograft Rejection

Acute Rejection
Grade 0—none	No significant abnormality
Grade 1—minimal	Infrequent perivascular mononuclear cell infiltrates mainly surrounding venules that are 2-3 cells deep
Grade 2—mild	More frequent infiltrates, 5 cells or more deep, involving venules and arterioles
Grade 3—moderate	More exuberant mononuclear cell infiltrate that extends from the perivascular space into the alveolar
	Interstitium
Grade 4—severe	Infiltrate extending into the alveolar space with pneumocyte damage and at times necrosis of vessels and lung parenchyma
Airway inflammation	Lymphocytic bronchitis/bronchiolitis; pathologist may grade
Chronic Rejection
Chronic airway rejection Active Inactive
Chronic vascular rejection–accelerated graft vascular sclerosis

Table 75-12 Comparison of Acute Rejection and Bronchiolitis Obliterans Syndrome

Feature	Acute Rejection	Bronchiolitis Obliterans Syndrome
Peak frequency	First 6 months	>3 months
Onset	Abrupt to subacute	Usually subtle
Symptoms/signs	Tightness in chest (immediate postoperative period) Cough (usually not productive) Dyspnea	Dyspnea with heavy exertion Cough (often productive)
Physiologic	Restrictive impairment Desaturation of arterial blood	Obstructive impairment Normoxia until late
Radiologic	Diffuse interstitial infiltrates Pleural effusions	No abnormality until disorder is far advanced Computed tomography evidence of bronchiectasis and mosaic pattern
Hematologic	Leukocytosis	Normal white blood cell count
Histologic	Perivascular mononuclear cell infiltrates Airway inflammation is variable	Obliterative bronchiolitis Atherosclerosis of pulmonary and bronchial arteries Pleural scarring
Response to treatment function	Majority of cases improve rapidly with intravenous corticosteroid	Forced expiratory volume in 1 second at best stabilized Majority of recipients show progressive decline in allograft

CLAD is believed to be caused by alloimmune tissue injury. Risk factors include a previous history of rejection episodes, viral infections, and the presence of lymphocytic bronchiolitis. Unfortunately, some patients with severe clinical BOS may not show histologic evidence of obliterative bronchiolitis on biopsy, whereas others with significant histologic evidence of BO may be asymptomatic. There is no effective treatment for BOS. Slowing of further progression may be possible with a trial of increased immunosuppression. This may be warranted in patients with an inflammatory-predominant stage of BOS. Retransplantation remains a potential option in a few selected cases. Treatments today do not differ between obstructive and restrictive CLAD.

Immunosuppression

The goal of immunosuppression in all patients undergoing solid organ transplantation arises from a two-phase host-versus-donor rejection model. In the initial acute posttransplantation period, donor antigen-presenting cells (APCs) activate T cells to react against graft antigens. B cells also are activated by graft antigens and form antibodies directed against them. This first phase, often attenuated, is associated with a high level of immunosuppression and is termed induction. Induction is directed against blocking the APC to T cell interaction, preventing T cell proliferation, and B cell alloimmunization. The second phase of immunosuppression is termed maintenance. During the maintenance phase, the host apparently adapts to the graft. Doses of immunosuppressants can be lowered to avoid toxicity and infectious complications while stabilizing the adaptive immune response.

Induction is accomplished with antibodies directed against human lymphoid cells. Antithymocyte globulin and monoclonal antibodies directed against specific CD receptors found on human lymphocytes are used, including muromonab-CD3, alemtuzumab, basiliximab, and daclizumab. Of these, basiliximab and daclizumab have gained favor, because they target activated T cells and have fewer, less severe side effects. Depleting antibodies are used in combination with high-dose methylprednisolone, a calcineurin inhibitor, and an antiproliferative drug such as an antimetabolite or an mTor (mammalian target of rapamycin) inhibitor.

Maintenance therapy is based on a triple-drug regimen that includes a calcineurin inhibitor, an antimetabolite, and a corticosteroid. This triple therapy has been chosen on the basis of studies performed on other solid organ transplants showing improved survival and lower graft rejection episodes over alternate regimens.

Calcineurin Inhibitors

Calcineurin inhibitors block the signal of activation between APCs and T cells. The classic agent in this group is cyclosporine, because it was the first effective immunosuppressant used in transplantation medicine. Tacrolimus is the second most commonly used calcineurin inhibitor and is now preferred in most lung transplant programs. Side effects of these drugs include nephrotoxicity, neurotoxicity, hemolytic uremic syndrome, posttransplantation diabetes mellitus, and hypertension.

Antimetabolites

The antimetabolites inhibit the proliferation of lymphocytes. They include inhibitors of purine synthesis such as mycophenolate mofetil (MMF) and azathioprine. MMF generally is preferred over azathioprine because of its better side effect profile. Recent studies suggest, however, that the two agents have a similar effectiveness. Accordingly, azathioprine is still preferred at some centers because of its relatively low cost.

Mammalian Target of Rapamycin Inhibitors

The mTOR inhibitors act by inhibiting the cell cycle and preventing T cell proliferation. Rapamycin, also known as sirolimus, is the classic mTOR inhibitor. Newer mTOR inhibitors include everolimus and temsirolimus. mTOR inhibitors used in conjunction with calcineurin inhibitors increase the incidence of nephrotoxicity and hemolytic uremic syndrome events. The mTOR inhibitors have antineoplastic properties and are used in treatment of several different types of cancers. Accordingly, these agents may have a potential role in treating PTLD. Extreme caution is warranted if mTOR inhibitors are used early after transplantation, because bronchial dehiscence can be a serious complication.

Pitfalls of Immunosuppressive Therapy

Common complications from the chronic use of immunosuppressive drugs vary, depending on the specific agent and the recipient’s predisposing characteristics (Table 75-13). Toxicities may be severe and irreversible, as is evident in cases of posttransplantation malignancy. Frequent checks for metabolic derangements and end-organ toxicity are critical. Unfortunately, serum drug levels do not correlate with the dosage of administered drugs and are not predictive of the potential toxic effects, because these factors vary from person to person.

Reaching and maintaining an adequate level of immunosuppression are difficult, leading some researchers to consider case-by-case analysis for specific genetic polymorphisms that affect drug metabolism to tailor specific treatments to the individual patient. Adjunctive testing of immune activity by the measurement of adenosine triphosphate (ATP) levels may be a more accurate way to adjust dosing. These basic issues warrant further investigation, because they are likely to affect the future of immunosuppressive management.

A current trend is for the use of tacrolimus, MMF, and sirolimus (Figure 75-22). A recent study comparing azathioprine and MMF in lung transplant recipients failed to show a significant difference in prevention of BOS. Although there are multiple reasons why a difference was not observed, there is still no definitive evidence to suggest superior outcomes with these newer drugs.

Figure 75-22 Adult lung recipients’ maintenance immunosuppression drug combinations at time of follow-up (data for follow-up evaluations performed between January 2002 and June 2005). Conventional combinations analysis was limited to patients receiving prednisone. AZA, azathioprine; Cy, cyclosporine; MMF, mycophenolate mofetil; Rapa, rapamycin; Tac, tacrolimus.

Medical Complications in Lung Transplant Survivors

Lung transplant survivors are at risk for multiple medical complications related to their predisposing illness and toxicities resulting from chronic immunosuppression. The aim of long-term care in the transplant recipient revolves around prevention and early detection of commonly described posttransplantation medical illnesses.

Malignancy

Posttransplantation malignancy (Figure 75-23) frequently is seen after solid organ transplantation. The calcineurin inhibitors and azathioprine have been associated with a higher risk of cancer. Currently, a 10% incidence of tumor development is reported in 5-year survivors, with lymphoid and skin cancers accounting for a majority. Newer immunosuppressive agents, such as the mTOR inhibitors, seem to have antineoplastic properties; evidence that these agents lead to lower cancer risk or decreased mortality is lacking, however.

Figure 75-23 Freedom from malignancy for adult lung recipients (data for follow-up evaluations performed between April 1994 and June 2005).

Other Medical Complications after Transplantation

Acute and chronic nephrotoxicity is well described with use of the calcineurin inhibitors and is characterized by hyalinosis of afferent arterioles, vacuolization of proximal tubules, and focal areas of interstitial and glomerular fibrosis (Figure 75-24). Although renal dysfunction is rather common in 1-year survivors, renal failure requiring dialysis remains rare. Use of calcineurin inhibitors as well as corticosteroids also can lead to diabetes mellitus, hypertension, and dyslipidemia (Table 75-14).

Figure 75-24 Adult lung recipients’ functional status of surviving recipients (data for follow-up evaluations performed between April 1994 and June 2005).

Table 75-14 Post–Lung Transplantation Morbidity in Adults