Introduction
Lung transplantation is a therapeutic consideration for patients with most nonmalignant end-stage lung diseases. After an initial period of rapid growth from 1990 through 1995, activity has increased slowly to ~1700 transplants per year worldwide. The demand for transplantation exceeds the supply of donor organs, and the waiting time is often lengthy. Recognizing the window of opportunity for transplantation in the clinical course of various lung diseases is crucial because deaths while awaiting transplantation are not unusual. However, in appropriately selected recipients, transplantation prolongs survival and improves quality of life, but it is also associated with significant morbidity and mortality.
Indications
The indications for lung transplantation span the gamut of lung diseases (Table 260-1). The distribution reflects the prevalence and natural history of the diseases, and the most common indications are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), 1-antitrypsin deficiency emphysema, and primary pulmonary hypertension (PPH). "Others" in Table 260-1 comprise many less prevalent lung diseases.
Table 260-1 Indications for Adult Lung Transplantation (1995–2004)
Diagnosis Single Lung Transplantation (n = 6731) Bilateral Lung Transplantation (n = 6276) Total (n = 13,007)
Chronic obstructive pulmonary disease 3541 52.6% 1462 23.3% 5003 38.5%
Idiopathic pulmonary fibrosis 1618 24.0% 639 10.0% 2257 17.4%
Cystic fibrosis 151 2.2% 2002 31.9% 2153 16.6%
1-Antitrypsin deficiency emphysema
554 8.2% 571 9.1% 1125 8.6%
Primary pulmonary hypertension 79 1.2% 436 6.9% 515 4.0%
Sarcoidosis 157 2.3% 166 2.6% 323 2.5%
Bronchiectasis 45 0.7% 309 4.9% 354 2.7%
Eisenmenger's syndrome 13 0.2% 118 1.9% 131 1.0%
Lymphoangioleiomyomatosis 55 0.8% 83 1.3% 138 1.0%
Retransplantation 129 1.9% 104 1.7% 233 1.8%
Others 389 5.8% 386 6.2% 775 6.0%
Source: Adapted from Trulock et al.
Recipient Selection
Transplantation should be considered when other therapeutic options have been exhausted and when the patient's prognosis will be improved by the procedure. Survival rates after transplantation can be compared with predictive indices for the underlying disease, but each patient's clinical course must be integrated into the assessment, too. In any case, projected survival after transplantation should exceed life expectancy without the procedure. Quality of life is the primary motive for transplantation for many patients, and the prospect of an improved quality-adjusted survival is often attractive, even if the survival advantage itself might be marginal.
Disease-specific guidelines for referring patients for transplantation are summarized in Table 260-2, and these are intended to identify patients who may benefit from transplantation. Candidates for lung transplantation are thoroughly screened for any comorbidity that might adversely affect the outcome. Suitable candidates should have clinically and physiologically severe lung disease, but otherwise they must be in reasonably good health. The upper age limit is ~65 years at most centers.
Table 260-2 Disease-Specific Guidelines for Selecting Candidates for Lung Transplantation
COPD and 1-antitrypsin deficiency emphysema
FEV1 < 25% of predicted normal value (post-bronchodilator)
PaCO2 55 mmHg
Pulmonary arterial hypertension (mean pulmonary artery pressure > 25 mmHg)
Cystic fibrosis/bronchiectasis
FEV1 < 30% of predicted normal value
PaCO2 > 50 mmHg
PaO2 < 50 mmHg (on room air)
Pulmonary arterial hypertension
Adverse clinical course in spite of optimal medical management
Increasing hospitalizations
Recurrent, massive hemoptysis
Rapidly declining FEV1
Idiopathic pulmonary fibrosis
VC or TLC < 60–70% of predicted normal value
DLCO < 50–60% of predicted normal value
Pulmonary arterial hypertension
Hypoxemia (PaO2 < 60 mmHg or SpO2 < 90%) at rest or with activity (on room air)
Progressive disease in spite of drug therapy
Primary pulmonary hypertension
New York Heart Association functional class III or IV in spite of optimal drug therapy
Unfavorable hemodynamic profile
Right atrial pressure > 15 mmHg
Mean pulmonary artery pressure > 55 mmHg
Cardiac index < 2 (L/min)/m2
Abbreviations: VC, vital capacity; TLC, total lung capacity; FEV1, forced expiratory volume in 1 s; DLCO, diffusing capacity for carbon monoxide; PaO2 and PaCO2, partial pressure of oxygen and carbon dioxide, respectively, in arterial blood; SpO2, oxygen saturation by pulse oximetry.
Source: Modified from International Guidelines for the Selection of Lung Transplant Candidates: Am J Respir Crit Care Med 158:335, 1998.
Typical exclusions include HIV infection, chronic hepatitis B antigenemia or chronic active hepatitis C infection, uncured malignancy, active cigarette smoking, drug or alcohol dependency or abuse, uncontrolled or untreatable pulmonary or extrapulmonary infection, irreversible physical deconditioning, chronic noncompliance with medical care, and significant disease of any vital organ other than the lungs. Other problems that might increase the risk of complications or might be aggravated by the posttransplantation medical regimen constitute relative contraindications. Some typical issues are ventilator-dependent respiratory failure, previous thoracic surgical procedures, osteoporosis, systemic hypertension, diabetes mellitus, obesity or cachexia, and psychosocial problems. Chronic infection with antibiotic-resistant Pseudomonas species, some Burkholderia species, Aspergillus species, or nontuberculous mycobacteria is a unique concern in some patients with CF or other diseases that have a component of bronchiectasis or chronic bronchitis. The potential impact of these and many other factors has to be judged in clinical context to determine an individual candidate's suitability for transplantation.
Waiting List and Organ Allocation
Organ allocation policies are influenced by ethical, medical, geographical, and political factors, and systems vary from country to country. Regardless of the system, potential recipients are placed on a waiting list and must be matched for blood group compatibility and, with some latitude, for lung size with an acceptable donor. In the United States a priority algorithm for allocating donor lungs was implemented in May 2005. Priority is determined by a lung allocation score that weighs both the patient's risk of death on the waiting list and the likelihood of survival after transplantation. Both the type and the severity of lung disease affect the allocation score; relevant parameters must be updated periodically but can be submitted whenever the patient's condition changes. However, this priority system does not diminish the importance of timely referral.
The impact of the priority allocation scheme on key outcome measures has not been analyzed yet; however, this information will be forthcoming and may lead to further refinement of the allocation system. Under the previous seniority system, the median time to transplantation was 1104 days for patients who initially registered on the national waiting list in 1998. Approximately 10% of the patients on the waiting list died before transplantation, but the death rate while waiting was much higher for patients with IPF, PPH, or CF than for those with COPD or 1-antitrypsin deficiency emphysema.
Transplant Procedure
Bilateral transplantation is mandatory for bronchiectasis because the risk of spillover infection from a remaining native lung precludes single lung transplantation. Heart-lung transplantation is obligatory for Eisenmenger's syndrome with complex anomalies that cannot be readily repaired in conjunction with lung transplantation and for concomitant end-stage lung and heart disease. However, cardiac replacement is not necessary for cor pulmonale because right ventricular function will recover when pulmonary vascular afterload is normalized by lung transplantation.
Either bilateral or single lung transplantation is an acceptable alternative for other diseases unless there is a special consideration. Bilateral transplantation provides more reserve lung function as a buffer against complications, and it has been increasingly utilized for many indications. In recipients with COPD and 1-antitrypsin deficiency emphysema, survival has been significantly better after bilateral transplantation, but there has not been a significant difference in survival between the two procedures for other diseases.
Living donor lobar transplantation has a limited role in adult lung transplantation. It has been performed predominantly in teenagers or young adults with CF. A right lower lobe is obtained from one living donor and a left lower lobe from another, and these lobes are implanted to replace the right and left lungs, respectively, in the recipient. Since a lobe must replace a whole lung, donor-recipient size considerations are crucial. The results have been comparable to those with transplantation from cadaveric donors. The usual morbidities associated with a lobectomy have been encountered in the donors, but no death has yet been reported. Because of ethical concerns, this approach is usually restricted to patients who are unlikely to survive the wait for a cadaveric donor.
Posttransplantation Management
Induction therapy with an antilymphocyte globulin or an interleukin 2 receptor antagonist is utilized by some centers, and a three-drug maintenance immunosuppressive regimen that includes a calcineurin inhibitor (cyclosporine or tacrolimus), a purine synthesis antagonist (azathioprine or mycophenolate mofetil), and prednisone is customary. Subsequently, other drugs such as sirolimus may be substituted in the maintenance regimen for various reasons. Prophylaxis for Pneumocystis jiroveci pneumonia is standard, and prophylaxis against cytomegalovirus (CMV) infection is prescribed in many protocols. The dose of cyclosporine or tacrolimus is adjusted by blood-level monitoring. Both are metabolized by the hepatic cytochrome P450 system, and interactions with medications that affect this pathway can significantly alter the clearance and blood levels of these key immunosuppressants.
Routine management is designed to monitor the allograft, to regulate immunosuppressive therapy, and to detect problems or complications expeditiously. The techniques include periodic contact with a transplant nurse coordinator, appointments with a physician, chest radiographs, blood tests, spirometry, and bronchoscopy. Lung function rapidly improves and then stabilizes by 3–6 months after transplantation. Subsequently, the coefficient of variation in spirometric measurements is small, and a sustained decline of 10–15% or more signals a potentially significant problem.
Outcomes
Survival
Major registries publish survival (Table 260-3) and other outcomes annually, and these reports are accessible via the Internet (www.ishlt.org; www.ustransplant.org).
Table 260-3 Recipient Survival, by Pretransplantation Diagnosis (1994–2003)
Survival Rate, %
Diagnosis n 3 Months 1 Year 3 Years 5 Years 10 Years
Chronic obstructive pulmonary disease 4888 90 81 63 48 19
1-Antitrypsin deficiency emphysema
1127 86 76 60 51 31
Cystic fibrosis 1934 88 81 65 54 32
Idiopathic pulmonary fibrosis 2058 81 69 54 42 15
Primary pulmonary hypertension 553 73 65 56 46 26
Source: Data from Trulock et al.
The main sources of perioperative mortality include technical complications of the operation, primary graft dysfunction, and infections. Acute rejection and CMV infection are common problems in the first year, but neither is usually fatal. Beyond the first year, chronic rejection and non-CMV infections cause the majority of deaths.
Function
Regardless of the disease, successful transplantation impressively restores cardiopulmonary function. After bilateral transplantation standard pulmonary function tests are typically normal; after single lung transplantation the remaining diseased lung typically contributes a mild abnormality. Formal exercise testing usually demonstrates some impairment in maximum work rate and maximum oxygen uptake, but few recipients report any limitation to activity.
Quality of Life
Both overall and health-related quality of life are enhanced. With multidimensional profiles, improvements extend across most domains and are sustained longitudinally unless chronic rejection or some other complication develops. Other problems that detract from quality of life include renal dysfunction and drug side effects.
Cost
The cost of transplantation depends on the health care system, other health care policies, and economic factors that vary from country to country. In the 1990s transplant hospitalization costs in the range of $160,000 were reported from two centers in the United States. At one of these centers, the average charge for posttransplantation care was ~$132,000 in the first year and $54,000 in subsequent years. The distribution of costs after lung transplantation was estimated by a center in the United Kingdom: 57% for routine care including medications, clinic appointments, and tests; 17% for rejection episodes; and 26% for infectious complications.
Complications
Lung transplantation can be complicated by a variety of problems. Aside from those that are unique to transplantation, side effects and toxicities of the immunosuppressive medications can cause new medical problems or aggravate preexisting conditions (Table 260-4).
Table 260-4 Major Potential Complications of Lung Transplantation and Posttransplantation Immunosuppression
Category Complication
Allograft Acute graft dysfunction; anastomotic dehiscence or stenosis; ischemic airway injury with bronchostenosis or bronchomalacia; rejection; infections
Thoracic Phrenic nerve injury—diaphragmatic dysfunction; recurrent laryngeal nerve injury—vocal cord dysfunction; cervical ganglia injury—Horner's syndrome; chylothorax; pneumothorax; pleural effusion
Cardiovascular Air embolism; postoperative pericarditis; venous thromboembolism; supraventricular dysrhythmias; systemic hypertension
Gastrointestinal Esophagitis (especially Candida species or CMV); gastroparesis; gastroesophageal reflux; C. difficile toxin diarrhea or pseudomembranous colitis
Hepatobiliary Hepatitis (especially CMV or drug-induced)
Renal Calcineurin inhibitor nephropathy; hemolytic-uremic syndrome (thrombotic microangiopathy)
Neurologic Tremors; seizures; reversible posterior leukoencephalopathy; headaches
Musculoskeletal Steroid myopathy; rhabdomyolysis (cyclosporine + HMG-CoA reductase inhibitor treatment); osteoporosis; avascular necrosis
Metabolic Obesity; diabetes mellitus; hyperlipidemia; idiopathic hyperammonemia
Hematologic Anemia; leukopenia; thrombocytopenia; thrombotic microangiopathy
Oncologic Lymphoproliferative disease and lymphoma; skin cancers; other malignancies
Graft Dysfunction
Primary graft dysfunction is an acute lung injury that is a manifestation of insults that are inherent in the transplantation process, and it has been referred to as reperfusion edema, reimplantation response, and ischemia-reperfusion injury. The principal clinical features are diffuse pulmonary infiltrates and hypoxemia within 72 h of transplantation, but the severity is variable. Pulmonary venous obstruction and hyperacute rejection can produce a similar pattern, and cardiogenic pulmonary edema and pneumonia must be excluded, too. The treatment is the conventional, supportive paradigm for acute lung injury, but inhaled nitric oxide and extracorporeal membrane oxygenation have been used successfully in severe cases. Most recipients recover, but severe primary graft dysfunction is a leading cause of early morbidity and mortality.
Airway Complications
The bronchial blood supply to the donor lung is disrupted, and bronchial revascularization is not widely practiced. Consequently, when the lung is implanted in the recipient, the bronchus is dependent on retrograde bronchial blood flow through the pulmonary circulation and is vulnerable to ischemia.
The prevalence of major airway complications—dehiscence, stenosis, and bronchomalacia—has ranged from 4–20%, but the associated mortality has been very low. Bronchoscopic debridement or dilatation is sufficient in many cases, but stent placement is often necessary if a stricture or bronchomalacia evolves.
Acute Rejection
This is an immunologic response to alloantigen recognition, and it is characterized by arteriolar and bronchiolar lymphocytic inflammation. With current immunosuppressive regimens, ~50% recipients have at least one episode of acute rejection in the first year. Acute rejection can be clinically silent, or it can be manifested by nonspecific symptoms or signs that may include cough, low-grade fever, dyspnea, hypoxemia, inspiratory crackles, interstitial infiltrates, and declining lung function; however, clinical impression is not reliable. The diagnosis should be confirmed by transbronchial biopsy, and a standardized pathologic classification scheme for rejection is used to grade the biopsies. Treatment usually includes a short course of high-dose steroid therapy and adjustment of the maintenance immunosuppressive regimen, but more intensive therapy may be necessary for persistent or recurrent episodes.
Chronic Rejection
This complication is the main impediment to better medium-term survival rates, and it is the source of substantial morbidity because of its impact on lung function and quality of life. The pathogenesis is still a conundrum, but both alloimmune inflammatory and nonalloimmune fibroproliferative mechanisms are probably important.
Clinically, chronic rejection is a form of graft dysfunction that is synonymous with bronchiolitis obliterans syndrome (BOS). BOS is characterized physiologically by airflow limitation and pathologically by bronchiolitis obliterans. Transbronchial biopsies are relatively insensitive for detecting bronchiolitis obliterans, and the diagnosis of BOS is usually based on a sustained decrement (20%) in the FEV1. A smaller decline in FEV1 (10%) or a decrease in the FEF25–75% may presage BOS.
The prevalence of BOS approaches 50% by 5 years after transplantation. Both antecedent acute rejection and lymphocytic bronchiolitis are risk factors for subsequent BOS, and CMV pneumonitis has been implicated inconsistently. BOS is usually treated with augmented immunosuppression. While immunosuppressive therapy may stabilize lung function, the overall results of treatment have been disappointing, probably because the fibroproliferative process is already well established. Retransplantation may be an option in ambulatory recipients without other complications, but in many cases the risk is prohibitive.
Infection
The lung allograft is especially susceptible to infection, and infection has been one of the leading causes of death. In addition to a blunted immune response from the immunosuppressive drugs, other normal defenses are breached; the cough reflex is diminished, and mucociliary clearance is impaired in the transplanted lung. The spectrum of infections includes both opportunistic and nonopportunistic pathogens.
Bacterial bronchitis or pneumonia can occur at any time but are almost universal in the postoperative period. Later, episodes of bronchitis are quite common, especially in recipients with BOS, and Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus is often the culprit.
CMV is the most frequent viral infection. Although gastroenteritis, colitis, and hepatitis can occur, CMV viremia and CMV pneumonia are the main illnesses. Most episodes occur in the first 6 months, and treatment with ganciclovir is effective unless resistance develops with repeated exposure. Other community-acquired viruses such as influenza, parainfluenza, and respiratory syncytial virus also contribute to respiratory complications. Aspergillus species have been the most problematic fungal infection.
Other Complications
Other potential complications are summarized in Table 260-4, and many of these are related to side effects or toxicities of the immunosuppressive drugs. Management of most of these general medical problems is guided by standard practices for the condition, but the complex milieu of transplantation dictates close collaboration and good communication among health care providers.
Acknowledgment
Dr. G. Alexander Patterson and Dr. Joel D. Cooper were co-authors of this chapter in the 16th edition. Some of the materials have been carried over into this edition.
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