Lung Transplantation

Animal experimentation by various pioneers, including Demikhov and Metras, in 1940s and 1950s demonstrated that the procedure is feasible technically. ^[12]  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. ^[13]  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 cyclosporine, 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. ^[14]  In 1988, Dr. Alexander Patterson described the technique of en bloc double-lung transplantation. ^[15]  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 performed a transplant in a 2-year-old girl with an atrioventricular canal defect and pulmonary hypertension; the patient died 14 hours postoperatively. ^[16]  Canine studies were ongoing during the subsequent years, but it was not until the late 1970s that Reitz and colleagues at Stanford, using cyclosporine, achieved clinically acceptable results in primates. ^[17]  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. ^[17]

Causes of respiratory failure in patients with advanced-stage pulmonary disease are as follows:

• Chronic obstructive pulmonary disease (COPD)
• Restrictive lung diseases (eg, idiopathic pulmonary fibrosis (IPD), cystic fibrosis (CF), alpha1-antitrypsin disease, primary pulmonary hypertension)
• Various less common causes

Patients should be considered for lung transplantation when they meet the following criteria:

• Life expectancy is not predicted to exceed 24-36 months despite optimal and maximal medical management
• Class III or IV New York Heart Association (NYHA) symptoms
• Stable nutritional status
• Motivated for rehabilitation
• Have an intact psychological support system

In 2021, 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 ^[18] :

• High (> 50%) risk of death from lung disease within 2 years if lung transplantation is not performed
• High (> 80%) likelihood of 5-year post-transplant survival from a general medical perspective provided that graft function remains adequate

Preoperative evaluation of specific diseases

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 ^[19] :

• 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 a BODE score 5-6, along with one or more of the following additional factors suggestive of increased risk of mortality ^[18] :

• Frequent acute exacerbations
• Increase in BODE score >1 over past 24 months
• Pulmonary artery to aorta diameter > 1 on CT scan
• Forced expiratory volume in 1 second (FEV₁) 20–25% predicted
• Clinical deterioration despite maximal treatment including medication; pulmonary rehabilitation; oxygen therapy; and, as appropriate, nocturnal noninvasive positive pressure ventilation
• Poor quality of life unacceptable to the patient
• For a patient who is a candidate for bronchoscopic or surgical lung volume reduction (LVR), simultaneous referral for both lung transplant and LVR evaluation is appropriate.

The ISHLT recommends listing COPD patients for transplantation when they meet one or more of the following criteria:

• BODE score 7-10
• Additional factors that may prompt listing include FEV₁< 20% predicted and presence of moderate to severe pulmonary hypertension
• History of severe exacerbations
• Chronic hypercapnia

Studies of whether lung volume reduction surgery (LVRS) for COPD affects the outcome of subsequent lung transplantation have yielded conflicting results. A review of the United Network for Organ Sharing database found a significantly increased risk of graft failure in patients with COPD who undergo LVRS before lung transplantation. ^[20] In contrast, a study from Switzerland concluded that previous LVRS does not negatively affect short-term and long-term outcomes of lung transplantation. ^[21]

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 ^[18] :

• Referral should be made at time of diagnosis, even if the patient is being started on therapy, for histopathologic usual interstitial pneumonia (UIP) or radiographic evidence of a probable or definite UIP pattern

• Any form of pulmonary fibrosis with forced vital capacity (FVC) of < 80% predicted or diffusion capacity of carbon monoxide (DLCO) < 40% predicted

• Any form of pulmonary fibrosis with one of the following in the past 2 years: Relative decline in FVC ≥ 10%, relative decline in DLCO ≥ 15%, or relative decline in FVC ≥ 5% in combination with worsening of respiratory symptoms or radiographic progression

• Supplemental oxygen requirement either at rest or on exertion

• For inflammatory ILDs, progression of disease (either on imaging or pulmonary function) despite treatment

• For patients with connective tissue disease or familial pulmonary fibrosis, early referral is recommended, as extrapulmonary manifestations may require special consideration.

ISHLT criteria for timing of listing for transplantation in patients with interstitial lung disease are as follows ^[18] :

• Any form of pulmonary fibrosis with one of the following in the past 6 months despite appropriate treatment: Absolute decline in FVC > 10%, absolute decline in DLCO > 10%, or absolute decline in FVC > 5% with radiographic progression

• Desaturation to < 88% on 6-minute-walk test or > 50 m decline in 6-minute-walk distance in the past 6 months

• Pulmonary hypertension on right heart catheterization or 2-dimensional echocardiography (in the absence of diastolic dysfunction)

• 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 FEV₁, 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 ^[22] :

• 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.

The ISHLT recommends referral for lung transplantation in adult patients with cystic fibrosis who have an FEV1 < 30% predicted and pediatric patients with FEV1 < 40% predicted despite optimal medical management, including a trial of elexacaftor/tezacaftor/vacaftor if eligible. ^[18] In addition, the ISHLT recommends referral for patients with FEV₁< 40% predicted in adults (or < 50% predicted in children) who meet any of the following criteria: 

• 6-minute walk distance < 400 meters
• P_aCO₂ > 50 mmHg
• Hypoxemia at rest or with exertion
• Pulmonary hypertension (PA systolic pressure > 50 mm Hg on echocardiogram or evidence of right ventricular dysfunction)
• Worsening nutritional status despite supplementation
• Two exacerbations per year requiring intravenous antibiotics
• Massive hemoptysis (> 240 mL) requiring bronchial artery embolization
• Pneumothorax
• FEV₁< 50% predicted and rapidly declining based on pulmonary function testing or progressive symptoms
• Any exacerbation requiring positive pressure ventilation

ISHLT criteria for timing of listing for transplantation in patients with cystic fibrosis are as follows ^[18] :

• FEV₁< 25% predicted
• Rapid decline in lung function or progressive symptoms (> 30% relative decline in FEV₁ over 12 months)
• Frequent hospitalization, particularly if > 28 days hospitalized in the preceding year
• Any exacerbation requiring mechanical ventilation
• Chronic respiratory failure with hypoxemia or hypercapnia, particularly for those with increasing oxygen requirements or needing long-term noninvasive ventilation therapy
• Pulmonary hypertension (pulmonary artery systolic pressure > 50 mmHg on echocardiogram or evidence of right ventricular dysfunction)
• Worsening nutritional status particularly with body mass index (BMI) < 18 kg/m² despite nutritional interventions
• Recurrent massive hemoptysis despite bronchial artery embolization
• World Health Organization functional class IV

The ISHLT recommends considering a lower threshold for both lung transplant referral and listing in females and in patients with short stature; diabetes; or increasing antibiotic resistance, including infection with Burkholderia cepacia complex or nontuberculous mycobacteria. ^[18]

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. ^{[23, 24]} 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 artery hypertension (PAH) are as follows ^[18] :

• European Society of Cardiology/European Respiratory Society (ESC/ERS) intermediate or high risk score or REVEAL risk score ≥8 despite appropriate PAH therapy
• Significant right ventricular dysfunction despite appropriate PAH therapy
• Need for intravenous or subcutaneous prostacyclin therapy
• Progressive disease despite appropriate therapy or recent hospitalization for worsening of PAH 
• Known or suspected high-risk variants such as pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (PVOD/PCH), scleroderma, large and progressive pulmonary artery aneurysms
• Signs of secondary liver or kidney dysfunction due to PAH 
• Potentially life-threatening complications such as recurrent hemoptysis

ISHLT criteria for listing for transplantation in patients with PAH are as follows ^[18] :

• ESC/ERS high risk or REVEAL risk score >10 on appropriate PAH therapy, including IV or SC prostacyclin analogues
• Progressive hypoxemia, especially in patients with PVOD or PCH 
• Progressive, but not end-stage, liver or kidney dysfunction due to PAH 
• Life-threatening hemoptysis

COVID-19

Since the onset of the COVID-19 pandemic, millions of people have suffered acute lung injury, in the form of COVID-related acute respiratory distress syndrome (CARDS) or post-COVID pulmonary fibrosis. Lung transplantation has been used successfully for both CARDS and post-COVID fibrosis in a limited number of patients. However, assessment of these patients for lung transplantation is challenging, for the following reasons ^[25] :

• In patients with severe CARDS, inability to conduct proper psychosocial evaluation and pretransplantation education, marked deconditioning from critical illness, and infectious concerns regarding viral reactivation
• In patients with post-COVID fibrosis, limited knowledge about the natural history of recovery after COVID-19 infection
• The need to wait long enough to ensure that patients are not likely to recover from their illness, or too late, but not wait so long that the patient develops complications or severe deconditioning that precludes transplantation

King et al ^[25] and Schaheen et al ^[26] have published recommendations for the evaluation of COVID-19 patients for lung transplantation. ^[25]

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.

Absolute contraindications

According to the International Society for Heart and Lung Transplantation (ISHLT), the absolute contraindications are as follows ^[18] :

• Lack of patient willingness or acceptance of transplant

• Malignancy with high risk of recurrence or cancer-related death

• Glomerular filtration rate (GFR) < 40 mL/min/1.73 m² unless the patient is being considered for multi-organ transplant

• Acute coronary syndrome or myocardial infarction within 30 days (excluding demand ischemia)

• Stroke within 30 days

• Liver cirrhosis with portal hypertension or synthetic dysfunction unless the patient is being considered for multi-organ transplant

• Acute liver failure

• Acute kidney failure with rising creatinine or on dialysis and low likelihood of recovery

• Septic shock

• Active extrapulmonary or disseminated infection

• Active tuberculosis

• HIV infection with detectable viral load 

• Limited functional status (eg, non-ambulatory) with poor potential for post-transplant rehabilitation

• Progressive cognitive impairment

• Repeated episodes of non-adherence without evidence of improvement (note that for pediatric patients this is not an absolute contraindication; ongoing assessment of non-adherence should occur as they progress through different developmental stages) 

• Active substance use or dependenc,e including current tobacco use, vaping, marijuana smoking, or IV drug use

• Other severe uncontrolled medical condition expected to limit survival after transplantation

Extrapulmonary organ dysfunction

Patients with a significant heart, liver, or kidney disease are not transplant candidates. Note the following:

• 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.
• The immunosuppressive drugs are nephrotoxic, and a creatinine clearance of less than 50 mL/min is a risk factor for subsequent development of acute kidney injury.

Relative contraindications

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.

The ISHLT lists the following as relative contraindications associated with high or substantially increased risk, and notes that the presence of more than one may multiply risk ^[18] :

• Age over 70 years
• Severe coronary artery disease that requires coronary artery bypass grafting at transplant
• Left ventricular ejection fraction < 40% 
• Significant cerebrovascular disease 
• Severe esophageal dysmotility 
• Untreatable hematologic disorders including bleeding diathesis, thrombophilia, or severe bone marrow dysfunction 
• BMI ≥35 kg/m² or < 16 kg/m² 
• Limited functional status with potential for post-transplant rehabilitation
• Psychiatric, psychological, or cognitive conditions with potential to interfere with medical adherence without sufficient support systems 
• Unreliable support system or caregiving plan 
• Lack of understanding of disease and/or transplant despite teaching 
• Infection with Mycobacterium abscessus, Lomentospora prolificans, Burkholderia cenocepacia, orB gladioli 
• Hepatitis B or C with detectable viral load and liver fibrosis  
• Chest wall or spinal deformity expected to cause restriction after transplant 
• Extracorporeal life supportt
• Retransplant < 1 year following initial lung transplant 
• Retransplant for restrictive chronic lung allograft dysfunction (CLAD
• Retransplant for antibody-mediated rejection as etiology for CLAD

The ISHLT lists the following as relative contraindications with unfavorable implications for short and/or long-term outcomes after lung transplant, and notes that the presence of multiple factors may increase risk ^[18] :

• Age 65–70 years
• GFR rate 40-60 mL/min/1.73m² 
• Mild to moderate coronary artery disease
• Severe coronary artery disease that can be revascularized via percutaneous coronary intervention prior to transplant 
• Prior coronary artery bypass grafting 
• Left ventricular ejection fraction 40–50%
• Peripheral vascular disease  
• Connective tissue diseases (scleroderma, lupus, inflammatory myopathies) 
• Severe gastroesophageal reflux disease 
• Esophageal dysmotility 
• Thrombocytopenia, leukopenia, or anemia with high likelihood of persistence after transplant 
• Osteoporosis 
• BMI 30-34.9 kg/m² or 16–17 kg/m²
• Frailty 
• Hypoalbuminemia 
• Poorly controlled insulin-dependent diabetes
•  Edible marijuana use 
• Scedosporium apiospermum infection 
• HIV infection with undetectable viral load 
• Previous thoracic surgery 
• Prior pleurodesis 
• Mechanical ventilation 
• Retransplant > 1 year for obstructive CLAD

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. ^[18]

Pooled data have shown no statistically significant 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). ^[12]

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) prior to transplantation 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. ^{[27, 28]} Singer et al found that ventilator dependence was associated with decreased overall survival; risk of death was highest in the first 6 months posttransplant. ^[29] 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. ^[30] Low-dose steroid therapy (ie, < 20 mg/d) is acceptable in a transplant candidate.

Infection

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 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 < 16 kg/m²) 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:

• Diabetes mellitus
• Systemic hypertension
• Epilepsy
• Central venous obstruction
• Peptic ulcer disease
• Gastroesophageal reflux

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.

The International Society for Heart and Lung Transplantation Registry reports a 1-year survival rate of 81-92% and 5-year survival rate of 53-62% following initial lung transplantation, with rates varying by pretransplant diagnosis. ^[7]  Mortality is highest in the first year, and attrition was consistent across the subsequent time periods. In the first 30 days, graft failure, non-cytomegalovirus (CMV) infections, cardiovascular complications, and technical problems account for most of the mortality. After the first year, bronchiolitis obliterans syndrome (BOS) and non-CMV infections were the predominant causes of death. By 5 years, malignancies and cardiovascular causes account for almost 17% of reported causes of death.

Overall survival according to pretransplant diagnosis shows that patients with cystic fibrosis had the best 1-year and 5-year survival, while those with chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) had the worst survival. ^[7]  In general, bilateral procedures yield better survival in each diagnosis category, especially in patients with COPD. Survival according to pretransplant CMV serologic status was most influenced by the CMV status of the donor. Survival during the first 5 years after transplantation was significantly better among recipients of a transplant from a donor who was CMV-seronegative.

Early diffuse alveolar damage may be associated with bronchiolitis obliterans syndrome and early mortality. Late diffuse alveolar damage may increase the risk of restrictive allograft syndrome. ^[31]

One study compared survival in patients with and without the supranormal expiratory and normal inspiratory flow rates (SUPRA pattern). The study found improved survival in patients with the SUPRA pattern and suggests potential therapeutic approaches to improve outcomes in patients who have undergone bilateral lung and heart-lung transplant. ^[32]

Whether lung transplantation truly increases survival over the natural history of the underlying disease remains difficult to ascertain in the absence of randomized trials. A survival advantage has been reported for patients with cystic fibrosis and pulmonary fibrosis who have received transplants, but this advantage has not been demonstrated for patients with emphysema.

Patients are referred for transplantation at a point in the course of their disease at which death is considered likely within 2-3 years. Therefore, transplantation would be expected to confer a survival advantage. Severe dyspnea and poor quality of life can be additional considerations for lung transplantation.