Lung Transplant: Purpose, Procedure, and Risks

Lung transplantation is an accepted modality of treatment for advanced stage lung disease. Since 1988, nearly 40,000 lung transplants and over 1200 heart/lung transplantations have been performed in the Unites States, representing approximately 5% of all organ transplants. 

Lung Transplant

Indications

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 :

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 :

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:

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.

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 

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 :

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 :

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 :

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 :

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.  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  :

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 :

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

Contraindications

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  :

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:

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. 

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.  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.

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. ^[24] 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.