Lung Transplantation
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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. [1]
For patient education information, see Lung Disease and Respiratory Health Center, as well as Heart and Lung Transplant and Bronchoscopy.
Animal experimentation by various pioneers, including Demikhov and Metras, in 1940s and 1950s demonstrated that the procedure is feasible technically. [2] 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. [3] 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. [4] In 1988, Dr. Alexander Patterson described the technique of en bloc double-lung transplantation. [5] 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. [6] 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. [7] 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. [7]
Causes of respiratory failure in patients with advanced-stage pulmonary disease are as follows:
Patients should be considered for lung transplantation when they meet the following criteria:
In 2014, the International Society for Heart and Lung Transplantation (ISHLT) released an updated consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation. The statement concluded that lung transplantation should be considered for adults with chronic, end-stage lung disease who meet all the following general criteria [8] :
The appropriate timing for referral to a transplant program and placement on the transplantation waiting list is based on the patient’s functional status and life expectancy. Criteria for referral and listing vary with the specific underlying pulmonary diseases.
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
Chronic obstructive pulmonary disease (COPD) is the most common indication for which lung transplantation is performed. The BODE index can be used to assess the need for transplantation in patients with COPD. It consists of the following [9] :
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
The ISHLT criteria for timing of referral for lung transplantation in patients with COPD are as follows [8] :
Disease is progressive, despite treatment including medication, pulmonary rehabilitation, and oxygen therapy.
Patient is not a candidate for endoscopic or surgical lung volume reduction surgery (LVRS); simultaneous referral of patients with COPD for both lung transplant and LVRS evaluation is appropriate.
BODE index >5
Partial pressure of carbon dioxide (PaCO2 >50 mm Hg and/or partial pressure of oxygen (PaO2) <60 mm Hg
FEV1 <25% predicted.
The ISHLT recommends listing COPD patients for transplantation when they meet one or more of the following criteria:
BODE index ≥7
Forced expiratory volume in 1 second (FEV1) <15% to 20% of predicted
Three or more severe exacerbations during the preceding year.
One severe exacerbation with acute hypercapnic respiratory failure.
Moderate to severe pulmonary hypertension.
Interstitial lung diseases
The natural history of various interstitial diseases is quite variable. Idiopathic pulmonary fibrosis, of the usual interstitial variant, 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.
ISHLT criteria for timing of referral in patients with interstitial lung disease are as follows [8] :
Evidence of usual interstitial pneumonitis or fibrosing nonspecific interstitial pneumonitis, regardless of lung function
Forced vital capacity (FVC) <80% predicted or diffusing capacity of lung for carbon monoxide (DLCO) <40% predicted
Any dyspnea or functional limitation attributable to lung disease
Any oxygen requirement, even if only during exertion
For inflammatory interstitial lung disease (ILD), failure to improve dyspnea, oxygen requirement, and/or lung function after a clinically indicated trial of medical therapy
ISHLT criteria for timing of listing for transplantation in patients with interstitial lung disease are as follows [8] :
Decline in FVC ≥10% during 6 months of follow-up
Decline in DLCO ≥15% during 6 months of follow-up
Desaturation to <88% or distance 50 m decline in 6-minute-walk distance over a 6-month period
Pulmonary hypertension on right heart catheterization or 2-dimensional echocardiography
Hospitalization because of respiratory decline, pneumothorax, or acute exacerbation
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 [10] :
Age
Gender
Weight-for-age z- score
Pancreatic insufficiency
Diabetes mellitus
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.
ISHLT criteria for timing of referral in patients with cystic fibrosis are as follows [8] :
FEV1 that has fallen to 30% or a patient with advanced disease with a rapidly falling FEV1
A 6-minute walk distance <400 m
Development of pulmonary hypertension in the absence of a hypoxic exacerbation (as defined by PAP >35 mm Hg on echocardiography or mean PAP >25 mm Hg measured by right heart catheterization)
Clinical decline
Clinical decline may be characterized by increasing frequency of exacerbations associated with any of the following:
An episode of acute respiratory failure requiring non-invasive ventilation.
Increasing antibiotic resistance and poor clinical recovery from exacerbations.
Worsening nutritional status despite supplementation.
Pneumothorax.
Life-threatening hemoptysis despite bronchial embolization.
ISHLT criteria for timing of listing for transplantation in patients with cystic fibrosis are as follows [8] :
Chronic respiratory failure, with hypoxia alone (PaO22</sub> >50 mm Hg)
Long-term non-invasive ventilation therapy
Pulmonary hypertension
Frequent hospitalization
Rapid lung function decline
World Health Organization functional class IV
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.
ISHLT criteria for referral for transplantation in patients with pulmonary hypertension are as follows [8] :
NYHA functional class III or IV symptoms during escalating therapy
Rapidly progressive disease (assuming weight and rehabilitation concerns not present)
Use of parenteral targeted pulmonary arterial hypertension (PAH) therapy regardless of symptoms or NYHA Functional Class
Known or suspected pulmonary veno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis
ISHLT criteria for listing for transplantation in patients with pulmonary hypertension are as follows [8] :
NYHA functional class III or IV despite a trial of at least 3 months of combination therapy including prostanoids
Cardiac index 2</sup>
Mean right atrial pressure >15 mm Hg
6-minute walk test <350 m
Development of significant hemoptysis, pericardial effusion, or signs of progressive right heart failure
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.
According to the International Society for Heart and Lung Transplantation, the absolute contraindications are as follows [8] :
Malignancy in the last 2 years, with the exception of non-melanoma localized skin cancer that has been treated appropriately (a 5-y disease-free interval is prudent)
Untreatable advanced dysfunction of another major organ system unless combined organ transplantation can be performed
Atherosclerotic disease with suspected or confirmed end-organ ischemia or dysfunction and/or coronary artery disease not amenable to revascularization
Acute medical instability such as acute sepsis, myocardial infarction, and liver failure
Uncorrectable bleeding diathesis
Chronic infection with highly virulent and/or resistant microbes that are poorly controlled pre-transplant
Active Mycobacterium tuberculosis infection
Significant chest wall or spinal deformity expected to cause severe restriction after transplantation
Class II-III obesity (body mass index ≥35.0 kg/m2)
Psychiatric conditions associated with the inability to cooperate with the medical/allied health care team and/or adhere with complex medical therapy
Absence of an adequate or reliable social support system
Severely limited functional status with poor rehabilitation potential
Substance abuse or dependence; meaningful and/or long-term participation in therapy should be required before offering lung transplantation; serial blood and urine testing can be used to verify abstinence from substances of concern
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.
Adults older than 75 years are unlikely to be candidates for lung transplantation in most cases. Although age by itself should not be considered a contraindication to transplant, increasing age generally is associated with comorbid conditions that are either absolute or relative contraindications.
Relative contraindications include the following [8] :
Age
Adults older than 75 years are unlikely to be candidates for lung transplantation in most cases. Although age by itself should not be considered a contraindication to transplant, increasing age generally is associated with comorbid conditions that are either absolute or relative contraindications. [8]
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).{ref8
Atherosclerosis
Lung transplantation is relatively contraindicated in patients with atherosclerotic disease who are at risk for end-organ disease after transplantation. However, some patients with coronary artery disease will be candidates for percutaneous coronary intervention or coronary artery bypass grafting (CABG) preoperatively or, in some instances, combined lung transplant and CABG.
Infection
Lung transplantation can be considered in patients infected with hepatitis B and/or C who are stable on appropriate therapy without significant clinical, radiologic, or biochemical signs of cirrhosis or portal hypertension. Lung transplantation in candidates with hepatitis B and/or C should be performed in centers with experienced hepatology units.
Lung transplantation can be considered in HIV-infected patients with undetectable HIV RNA who are compliant on combined antiretroviral therapy. The most suitable candidates should have no current acquired immunodeficiency syndrome (AIDS)–defining illness. Lung transplantation in HIV-positive candidates should be performed in centers with expertise in the care of HIV-positive patients.
Lung transplantation can be considered in patients infected with Burkholderia cenocepacia, Burkholderia gladioli, and multi-drug–resistant Mycobacterium abscessus if the infection is sufficiently treated preoperatively and there is a reasonable expectation for adequate control postoperatively. To be considered suitable transplant candidates, these patients should be evaluated by centers with significant experience managing these infections in the transplant setting, and patients should be made aware of the increased risk of transplant because of these infections.
Ventilator dependence
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. [13, 14] Singer et al found that ventilator dependence was associated with decreased overall survival; risk of death was highest in the first 6 months posttransplant. [15] 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.
Psychosocial issues
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.
Corticosteroid therapy
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.
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.
Body weight
Patients who have cachexia (BMI 2</sup>) likely have poor nutritional status and would have a poor outcome following transplantation. Obesity (BMI >30) is a concern because of postoperative atelectasis and pneumonia.
Other comorbid conditions
Other medical conditions that have not resulted in end-stage organ damage should be optimally treated before transplantation. Examples include the following:
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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Bryan A Whitson, MD, PhD Assistant Professor of Cardiac Surgery, Division of Cardiac Surgery, Department of Surgery, Lead Surgeon, Lung Transplant Program, Co‐Director, Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Laboratory, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center
Bryan A Whitson, MD, PhD is a member of the following medical societies: American College of Surgeons, American Society for Artificial Internal Organs, American Society of Transplant Surgeons, Association for Academic Surgery, International Society for Heart and Lung Transplantation, Society of Thoracic Surgeons, International Society for Minimally Invasive Cardiothoracic Surgery
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Shreekanth V Karwande, MBBS Chair, Professor, Department of Surgery, Division of Cardiothoracic Surgery, University of Utah School of Medicine and Medical Center
Shreekanth V Karwande, MBBS is a member of the following medical societies: American Association for Thoracic Surgery, American College of Chest Physicians, American College of Surgeons, American Heart Association, Society of Critical Care Medicine, Society of Thoracic Surgeons, Western Thoracic Surgical Association
Disclosure: Nothing to disclose.
Mary C Mancini, MD, PhD, MMM Surgeon-in-Chief and Director of Cardiothoracic Surgery, Christus Highland
Mary C Mancini, MD, PhD, MMM is a member of the following medical societies: American Association for Thoracic Surgery, American College of Surgeons, American Surgical Association, Phi Beta Kappa, Society of Thoracic Surgeons
Disclosure: Nothing to disclose.
Jeffrey C Milliken, MD Chief, Division of Cardiothoracic Surgery, University of California at Irvine Medical Center; Clinical Professor, Department of Surgery, University of California, Irvine, School of Medicine
Jeffrey C Milliken, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Thoracic Surgery, American College of Cardiology, American College of Chest Physicians, American College of Surgeons, American Heart Association, American Society for Artificial Internal Organs, California Medical Association, International Society for Heart and Lung Transplantation, Phi Beta Kappa, Society of Thoracic Surgeons, SWOG, Western Surgical Association
Disclosure: Nothing to disclose.
Susan D Moffatt-Bruce, MD, PhD, FRCS(C), FACS Chief Quality and Patient Safety Officer, Deputy Director, Comprehensive Transplant Center, Ohio State University Wexner Medical Center; Associate Dean of Clinical Affairs, Quality and Patient Safety, Associate Professor of Surgery, Department of Surgery, Ohio State University College of Medicine
Susan D Moffatt-Bruce, MD, PhD, FRCS(C), FACS is a member of the following medical societies: Alpha Omega Alpha, American College of Surgeons, American Society of Transplant Surgeons, American Society of Transplantation, American Thoracic Society, Central Surgical Association, International Society for Heart and Lung Transplantation, Ohio State Medical Association, Royal College of Physicians and Surgeons of Canada, SocietyofThoracic Surgeons, Transplantation Society, and Western Thoracic Surgical Association
Disclosure: Nothing to disclose.
Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital
Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association
Disclosure: Nothing to disclose.
Helmut Unruh, MD Director, Manitoba Lung Transplant Program; Head, Section of Thoracic Surgery, Director of Research, Department of Surgery, University of Manitoba Faculty of Medicine, Canada
Disclosure: Nothing to disclose.
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