- Author: Bryan A Whitson, MD, PhD; Chief Editor: Mary C Mancini, MD, PhD, MMM more...
Lung transplantation is an accepted modality of treatment for advanced stage lung disease. Since the early 1990s, more than 25,000 lung transplants have been performed at centers around the world.
The agency for health care policy and research in the United States has concluded that "lung transplantation has evolved as a clinical procedure achieving a favorable risk-benefit ratio and acceptable 1- and 2-year survival rates." The International Society for Heart and Lung Transplantation continues to monitor lung transplantation and has an ongoing registry, which is reported annually.
For excellent patient education resources, visit eMedicineHealth's Lung Disease and Respiratory Health Center. Also, see eMedicineHealth's patient education articles Heart and Lung Transplant and Bronchoscopy.
History of the Procedure
Animal experimentation by various pioneers, including Demikhov and Metras, in 1940s and 1950s demonstrated that the procedure is feasible technically. Hardy performed the first human lung transplantation in 1963. The donation was essentially after cardiac death, and the recipient of the left lung transplant survived only 18 days. From 1963-1978, multiple attempts at lung transplantation failed because of rejection and problems with anastomotic bronchial and tracheal healing.
In the 1980s, the introduction of cyclosporin A, a powerful immunosuppressant, generated renewed interest in the area of organ transplantation, including lung transplantation. Alternative techniques for improving bronchial healing were devised. These techniques included refining the bronchial–pulmonary collateral circulation by limiting the length of the donor bronchus and revascularizing the bronchial circulation extrinsically by wrapping the anastomosis with omentum or a pericardial patch in early years.
The first successful single lung transplant was reported by Dr. Joel Cooper at the University of Toronto in 1986. In 1988, Dr. Alexander Patterson described the technique of en bloc double-lung transplantation. This particular en bloc technique was associated with tracheal anastomotic complications as a result of poor vascularity; as a result, bilateral sequential single-lung transplantation has become the standard of care for patients requiring bilateral lung replacement.
Dr. Denton Cooley and associates were the first to attempt heart-lung transplantation in 1968, when they did a transplant in a 2-year-old girl with an atrioventricular canal defect and pulmonary hypertension; the patient died 14 hours postoperatively. Canine studies were ongoing during the subsequent years, but it was not until the late 1970s that Reitz and colleagues at Stanford, using cyclosporin, achieved clinically acceptable results in primates. In 1981, the first successful heart-lung transplant was performed at Stanford in a 45-year-old woman who went on to do well for more than 5 years after the procedure.
Patients with advanced stage pulmonary disease have multiple causes of respiratory failure including chronic obstructive pulmonary disease (COPD), restrictive lung diseases including idiopathic pulmonary fibrosis (IPD), cystic fibrosis (CF), alpha1-antitrypsin disease, primary pulmonary hypertension, and various less common causes. Patients should be considered for lung transplantation when life expectancy is not predicted to exceed 24-36 months despite optimal and maximal medical management and they have class III and IV New York Heart Association (NYHA) symptoms. The patient must also have a stable nutritional status, be motivated for rehabilitation, and have an intact psychological support system.
Preoperative evaluation of specific diseases
The appropriate timing for referral to a transplant program is based on the patient's functional status and life expectancy. A symptomatic patient who is at least NYHA class III or whose life expectancy for 24-36 months is predicted at less than 50% should be referred for a transplant assessment. The natural history of the specific pulmonary diseases and the knowledge of survival outcome following transplant surgery help the patient and transplant team determine the appropriate timing for placing a patient on a waiting list. The chance of surviving the waiting period depends on the underlying disease and the system for allocation of donor organs. Waiting times are variable and based on many factors, such as height and blood group.
Chronic obstructive pulmonary disease
COPD is the most common indication for which lung transplantation is performed. In patients with COPD, survival has improved significantly with long-term oxygen therapy. Forced expiratory volume in 1 second (FEV1) of less than 30% predicted is associated with a 60-80% 2-year survival rate; therefore, lung transplantation should be offered to patients with emphysema who have an FEV1 substantially less than 30% predicted (ie, 20% of predicted).
Continued deterioration despite optimal medical and surgical therapy that includes smoking cessation, maximal bronchodilator treatment, rehabilitation, long-term oxygen therapy, and endoscopic or surgical lung volume reduction where feasible, are additional indicators for referral for transplant assessment. Associated factors considered are hypoxemia and hypercapnia, weight loss, frequent hospitalizations, and repeated exacerbations.
The BODE index can be used to assess the need for transplantation in patients with COPD. It consists of the following :
B - Body mass index
O - Degree of airflow obstruction
D - Degree of dyspnea, as measured by the modified Medical Research Council dyspnea scale
E - Exercise capacity (E), which is measured with a 6-minute walk test
Patients with a BODE index of 5 or greater should be referred for transplant.
Restrictive lung diseases
The natural history of various interstitial diseases is quite variable. Idiopathic pulmonary fibrosis, of the usual interstitial variant (UIP), which is the second most frequent disease for which lung transplantation is performed, has a median survival of approximately 2.5 to 3.5 years from the time of diagnosis. Dismal survival rates of these patients on waiting lists indicate that these patients should have early referrals for transplantation evaluation.
Studies have shown that forced vital capacity of less than 60% is predictive of increased mortality. The diffusing capacity of lung for carbon monoxide (DLCO) is the other parameter that is helpful in predicting survival of patients with restrictive disease; a DLCO of less than 35-39% is associated with a higher risk of mortality.
Pulmonary arterial hypertension
The median survival for patients with primary pulmonary hypertension is 2.8 years. The indicators of poor survival are NYHA functional class III or IV, elevated mean right atrial pressure, elevated mean pulmonary arterial pressure and decreased cardiac index, and reduced diffusion. Mean pulmonary arterial pressure greater than 85 mm Hg is associated with a median survival of less than 12 months. A response to vasodilator therapy is associated with improved survival.
Present treatment of choice for NYHA class III and IV patients with pulmonary hypertension is long-term prostacyclin therapy, especially if they fail to demonstrate vasoreactivity during formal vasodilator trial. Prostacyclin has demonstrated improved survival, improved exercise capacity, and better quality of life.[11, 12] Transplantation is indicated only if the patient cannot tolerate or fails prostacyclin therapy. In patients who have developed severe right heart failure, the right heart pressures and functions return to near normal values following lung transplantation alone.
Cystic fibrosis and bronchiectasis
Cystic fibrosis is the third most common indication for which lung transplantation is performed. These patients develop a high risk of mortality when their FEV1 decreases to 30% or less. At this level of FEV, the mortality rate increases to 45% at 2 years. Other indicators of poor prognosis are weight loss, recurrent pneumothoraces, frequent hospitalization, and hemoptysis.
Liou and colleagues have validated a 5-year survivorship model for cystic fibrosis. This model identified the following eight characteristics, in addition to FEV1 as a percentage of predicted normal values, to accurately predict survival in patients with cystic fibrosis :
Weight-for-age z- score
Infection with Staphylococcus aureus
Infection with Burkholderia cepacia
Annual number of acute pulmonary exacerbations
The authors also have developed two worksheets, which help calculate weight-for-age z- score and 5-year predicted survival. This survivorship model has potential for use in investigating the effect of novel therapies and assignment of patients on lung transplantation waiting lists.
Guidelines for timing referrals
Patients should be referred for transplantation at a point in the course when they have less than a 50% chance of surviving 24-36 months and at such a time that transplantation is expected to confer a survival advantage. Poor quality of life is an additional consideration. The criteria vary according to the underlying disease.
Criteria for referral in patients with COPD and alpha1-antitrypsin deficiency emphysema are as follows:
BODE index >5
Postbronchodilator FEV 1 < 25% predicted
Resting hypoxemia (ie, PaO 2 < 55-60 mm Hg)
Hypercapnia (PaCO 2 >50 mm Hg)
Clinical course marked by rapid rate of decline in FEV 1 or life-threatening exacerbations
Criteria for referral in patients with cystic fibrosis are as follows:
Postbronchodilator FEV 1 < 30% predicted
Resting hypoxemia, ie, PaO 2 < 55 mm Hg
Clinical course - Increasing frequency and severity of exacerbations (ICU stays)
Development of pulmonary hypertension
Criteria for referral in patients with idiopathic pulmonary fibrosis are as follows:
DLCO < 39% predicted
A 10% or greater decrement in forced vital capacity (FVC) during 6 months' follow-up
FVC < 60-65% predicted
Decrease in oxygen saturations < 88% during 6-minute walk test
Criteria for referral in patients with pulmonary arterial hypertension are as follows:
NYHA functional class III or IV on maximal medical therapy
Mean right atrial pressure >15 mm Hg
Mean pulmonary arterial pressure >50 mm Hg
Cardiac index < 2.0 L/min/m 2
Failure of therapy with long-term vasodilator therapy
Declining 6-minute walk test results
Lung transplantation for advanced stage lung disease is a complex therapy with significant risk of perioperative morbility and mortality. Therefore, each patient needs to be evaluated individually, considering absolute and relative contraindications. The absolute contraindications are as follows:
Malignancy in the last 2 years, with the exception of cutaneous squamous and basal cell tumors (a 5-y disease-free interval is prudent)
Untreatable advanced dysfunction of another major organ system
Current cigarette smoking
Poor nutritional status
Poor rehabilitation potential
Significant psychosocial problems, substance abuse, or history of medical noncompliance
The lung transplant team evaluates each referral in view of potential risks and benefits to the patient and the ability and experience of the individuals at the transplant center. The following are some of the issues related to contraindications:
Extrapulmonary organ dysfunction
Severe symptomatic osteoporosis is a risk factor for posttransplant complications. It is a relative contraindication.
Based on past experience, advanced age is associated with higher mortality rates. Recent pooled data have shown no statistical difference between patients younger than 65 years and patients older than 65 years, although a trend toward lower survival for recipients older than 65 years was present. Most centers have an age cut-off of 50 years for heart-lung transplantation, 60 years for bilateral sequential lung transplantation, and 65 years for single-lung transplantation (SLT).
The limited data suggest that patients who are dependent on a ventilator prior to the transplant have higher mortality rates but may be candidates for lung transplantation.[15, 16] Singer et al found that ventilator dependence was associated with decreased overall survival; risk of death was highest in the first 6 months posttransplant. A prolonged wait while the patient is on a mechanical ventilator may lead to various complications such as infections, cardiovascular deconditioning, and muscle atrophy, all of which further compromise the outcome of the transplant.
In the past, corticosteroid treatment was considered a contraindication to transplantation because of concerns about anastomotic dehiscence. Low-dose steroid therapy (ie, < 20 mg/d) is acceptable in a transplant candidate.
Individuals who currently smoke, abuse drugs, or drink alcohol heavily are not candidates for transplantation. Patients with other psychosocial issues, such as poor compliance and psychiatric disorders that may complicate posttransplant therapy, are not considered good candidates.
In patients with cystic fibrosis, infection with B cepacia is associated with significant mortality rates because this organism is resistant to all antibiotics. Some centers do not offer transplants to patients infected with B cepacia. Also, patients who have active tuberculosis infection are not candidates for transplantation. Nontuberculous mycobacterial colonization is not a contraindication. Aspergillus fumigatus colonization of a patient with cystic fibrosis is only a relative contraindication. These patients are treated with itraconazole prior to transplant in an attempt to eradicate colonization with this fungus.
Patients who have cachexia (BMI < 16) likely have poor nutritional status and would have a poor outcome following transplantation. Obesity (BMI >30) also may be a concern because of postoperative atelectasis and pneumonia.
Extrapulmonary organ dysfunction
Patients with a significant heart, liver, or kidney disease are not transplant candidates. The immunosuppressive drugs are nephrotoxic, and a creatinine clearance of less than 50 mL/min is a risk factor for subsequent development of renal failure. Significant coronary artery disease predisposes a patient to myocardial infarction in the perioperative period.
A patient with severe left ventricular systolic or diastolic dysfunction is not a candidate for lung transplantation. The presence of significant liver disease, as indicated by a total bilirubin level of greater than 2 mg/dL, is associated with an unfavorable outcome following transplant.
Although the practices of individual transplant centers may vary, patients with systemic connective tissue diseases do not necessarily have unfavorable outcomes if their disease is quiescent. These patients may be considered as transplant candidates on an individual basis.
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