Lung Transplantation

Animal experimentation by various pioneers, including Demikhov and Metras, in 1940s and 1950s demonstrated that the procedure is feasible technically. ^[10]  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. ^[11]  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. ^[12]  In 1988, Dr. Alexander Patterson described the technique of en bloc double-lung transplantation. ^[13]  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. ^[14]  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. ^[15]  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. ^[15]

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 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 ^[16] :

• High (> 50%) risk of death from lung disease within 2 years if lung transplantation is not performed
• High (> 80%) likelihood of surviving at least 90 days after lung transplantation
• 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 ^[17] :

• 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 ^[16] :

• 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 (FEV ₁) < 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.

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. ^[18] In contrast, a study from Switzerland concluded that previous LVRS does not negatively affect short-term and long-term outcomes of lung transplantation. ^[19]

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 ^[16] :

• 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 ^[16] :

• 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 < 250 m on 6-minute-walk test or > 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 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 ^[20] :

• 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 ^[16] :

• FEV₁ that has fallen to 30% or a rapidly falling FEV₁ in a patient with advanced disease 

• 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 ^[16] :

• Chronic respiratory failure, with hypoxia alone (PaO ₂< 60 mm Hg) or with hypercapnia (PaCO ₂ > 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. ^{[21, 22]} 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 ^[16] :

• 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 ^[16] :

• NYHA functional class III or IV despite a trial of at least 3 months of combination therapy including prostanoids
• Cardiac index < 2 L/min/m ²
• 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

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 ^[23] :

• 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 ^[23] and Schaheen et al ^[24] have published recommendations for the evaluation of COVID-19 patients for lung transplantation. ^[23]

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, the absolute contraindications are as follows ^[16] :

• 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)

• History of repeated or prolonged episodes of non-adherence to medical therapy that are perceived to increase the risk of non-adherence after transplantation

• 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.

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.

Relative contraindications include the following ^[16] :

• Older age
• Class I obesity (BMI 30.0–34.9 kg/m ²)
• Progressive or severe malnutrition
• Severe, symptomatic osteoporosis
• Prior chest surgery with lung resection
• Infection with highly resistant or virulent bacteria, fungi, and certain strains of mycobacteria (eg, chronic extrapulmonary infection expected to worsen after transplantation)

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. ^[16]

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). ^[10]

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. ^{[25, 26]} Singer et al found that ventilator dependence was associated with decreased overall survival; risk of death was highest in the first 6 months posttransplant. ^[27] 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. ^[28] 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 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 < 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 78% and 5-year survival rate of 51% following lung transplantation. ^[3]  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 pre-transplant diagnosis shows that after 1 year, patients with chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) had the worst long-term survival. ^[3]  In general, bilateral procedures have 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. ^[29]

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. ^[30]

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.