Lung Transplantation: A Comprehensive Guide for Patients

Table of Contents

• Introduction: What is Lung Transplantation?
• Candidate Assessment and Selection
• Donor-Lung Selection and Utilization
• Lung Allocation Systems
• Surgical Approaches to Transplantation
• Post-Transplantation Care and Complications
• The Multidisciplinary Care Team
• Future Directions in Lung Transplantation
• Study Limitations
• Recommendations for Patients
• Source Information

Introduction: What is Lung Transplantation?

Lung transplantation has transformed over the past 60 years from an experimental procedure to an accepted standard treatment for life-threatening lung diseases. Suitable candidates can expect improved survival and quality of life, though they must manage challenges including primary graft dysfunction (early lung injury after transplant), chronic lung allograft dysfunction (CLAD, which is long-term scarring of the transplanted lungs), increased risk of opportunistic infections, cancer, and health issues related to chronic immunosuppression medication.

Despite growing worldwide demand, the number of lung transplants performed hasn't kept pace with need. This article reviews the current status of lung transplantation, recent developments, and future opportunities in delivering this challenging but potentially life-transforming therapy.

Candidate Assessment and Selection

Due to the scarcity of suitable donor lungs, transplantation centers must carefully select candidates most likely to benefit from transplantation. Traditionally, suitable candidates were defined as having:

• Greater than 50% estimated risk of dying from their lung disease within 2 years
• Greater than 80% likelihood of surviving 5 years after transplantation with adequate lung function

The most common conditions leading to lung transplantation include:

• Pulmonary fibrosis (scarring of lung tissue)
• Chronic obstructive pulmonary disease (COPD)
• Pulmonary vascular disease
• Cystic fibrosis

Patients are typically referred when they experience declining pulmonary function, reduced physical functioning, and disease progression despite maximal medical and surgical therapies. Early referral allows for better risk-benefit counseling and time to address potential barriers to successful transplantation outcomes.

A multidisciplinary team assesses the need for transplantation while evaluating risks associated with immunosuppression, including life-threatening infections. Essential screening includes:

• Extrapulmonary organ dysfunction
• Physical fitness
• Mental health
• Systemic immunity
• Cancer screening
• Specific assessments of coronary and cerebral arteries
• Kidney function
• Bone health
• Esophageal function
• Psychosocial capacity
• Social support systems

Selection criteria have evolved significantly. Where older age was once an absolute barrier, 34% of U.S. recipients were over 65 years in 2021, showing increased emphasis on physiological rather than chronological age. The 6-minute walk test is now often complemented by more formal assessments of frailty that focus on physical reserve and anticipated response to surgical stress.

Frailty has been associated with poor outcomes after lung transplantation and is often tied to body composition. Approaches to evaluating candidates have shifted from focusing solely on body-mass index (BMI) to more comprehensive assessments of adiposity and underlying muscle mass. Promising tools are being developed to quantify frailty, sarcopenia (muscle loss), and resilience to better predict recovery after transplantation.

Both body composition and frailty might be improved through preoperative pulmonary rehabilitation, potentially leading to better outcomes. Determining recoverability is particularly challenging for critically ill patients requiring mechanical ventilation or extracorporeal life support (advanced life support systems), though carefully selected patients in these situations can now achieve outcomes similar to those not requiring such support before transplantation.

Previously absolute contraindications are now assessed individually. The traditional 5-year cancer-free requirement before transplantation listing has been replaced with individualized assessments of recurrence risk. Similarly, systemic autoimmune diseases are no longer automatic barriers to transplantation, though disease-specific evaluations and treatments to reduce detrimental manifestations are recommended.

Some patients have circulating antibodies to specific HLA subclasses (proteins important for immune recognition), making them "sensitized" to certain donor organs. This leads to longer wait times, lower transplantation likelihood, and higher risk of acute organ rejection and CLAD. However, similar outcomes have been achieved using preoperative desensitization protocols including plasma exchange, intravenous immune globulin, and anti-B-cell therapies.

Donor-Lung Selection and Utilization

Organ donation remains an altruistic act, with consent and respect for donor autonomy being paramount ethical considerations. Donor lungs can sustain injuries from various causes including chest trauma, resuscitation maneuvers, aspiration, embolism, ventilator-associated injury or infection, or neurogenic injury, making many unsuitable for transplantation.

The International Society for Heart and Lung Transplantation (ISHLT) has defined generally acceptable donor criteria, though these vary among transplantation centers. Very few donors meet "ideal" criteria, but donor-lung utilization continues to increase through:

• Use of extended-criteria donors (those not meeting standard ideal criteria)
• Careful evaluation
• Active donor care
• Ex vivo assessment (evaluating lungs outside the body)

Donor history of active cigarette smoking is a risk factor for primary graft dysfunction in recipients, though the increased risk of death is limited and must be balanced against the mortality risk of longer wait times for lungs from never-smokers.

The use of carefully selected lungs from older donors (>70 years) with no other risk factors has shown similar survival and allograft function outcomes compared to younger donors. The use of lungs from controlled donation after circulatory death (DCD) has risen to 30-40% in some countries, with similar rates of acute organ rejection, CLAD, and survival.

Transplantation of organs from donors infected with transmissible viruses has become more feasible. Direct-acting antiviral agents against hepatitis C virus (HCV) have enabled safe transplantation of HCV-positive donor lungs into HCV-negative recipients. Similarly, HIV-positive donor lungs can be transplanted into HIV-positive recipients, and HBV-positive donor lungs can be transplanted into vaccinated recipients with existing immunity.

Transplanting lungs from donors with active or past SARS-CoV-2 infection has been reported, though more evidence is needed to determine safety. Evaluation of lung quality can be challenging during multi-organ procurement, but ex vivo lung perfusion systems allow more detailed functional assessment and potential reconditioning before transplantation.

These systems provide a platform for administering specific biologic treatments to repair injured donor lungs. Two randomized trials showed that normothermic ex vivo lung perfusion (keeping lungs at body temperature outside the body) for standard-criteria donor lungs is safe and allows extended preservation times.

New preservation techniques include maintaining donor lungs at elevated hypothermic temperatures (6-10°C) rather than 0-4°C on ice, which has shown better mitochondrial health, less injury, and improved pulmonary function. Promising outcomes have been reported with longer overnight preservation for semi-elective daytime transplantation.

A large noninferiority safety trial comparing preservation at 10°C with standard cold storage is underway. There is growing use of multiorgan donor-care centers to facilitate timely organ recovery and organ-repair centers to improve organ function before transplantation.

Lung Allocation Systems

In 2005, the United States transitioned from a wait-time-based allocation system to an urgency-weighted lung allocation score involving a ratio of estimated 1-year survival with versus without lung transplantation. Other nations adopted similar approaches to reduce wait-list mortality and increase transplantation activity.

In March 2023, the United States adopted a new composite allocation score prioritizing five domains:

1. Medical urgency (based on expectation of surviving 1 year without transplant)
2. Post-transplantation outcomes (based on 5-year survival)
3. Biologic disadvantages (based on blood type, height, and sensitization)
4. Patient access (based on pediatric status and living-organ donation history)
5. Transplantation efficiency (based on travel distance, cost, and transportation efficiency)

Current practice doesn't formally quantify donor organ-associated risks of poor outcomes, representing an opportunity for future refinement.

Surgical Approaches to Transplantation

Bilateral, sequential lung transplantation is the most common procedure for all disease indications. Single-lung transplantation has decreased over time but remains a valuable option with similar outcomes and fewer postoperative complications, especially in older patients.

Debate continues regarding the benefit of bilateral versus single-lung transplantation, with data limited by selection and indication bias in observational studies. Heart-lung transplantation has also decreased over time and is reserved for patients with both end-stage heart and lung failure whose cardiac condition cannot be corrected by bilateral lung transplantation with concomitant cardiac repair.

Surgical approaches vary among centers according to preference and experience. Bilateral thoracotomy with transverse sternotomy ("clamshell" incision) facilitates good exposure but may be associated with increased pain and delayed recovery. Alternative approaches include bilateral anterior thoracotomy without sternotomy or posterolateral thoracotomy for single-lung transplantation.

Post-Transplantation Care and Complications

After transplantation, patients require lifelong immunosuppression to prevent rejection, which creates a balance between protecting the new lungs and managing medication side effects. Common complications include:

Primary Graft Dysfunction (PGD): This is the major cause of early complications and death, occurring in the first 72 hours after transplantation. It represents a form of acute lung injury with various grades of severity.

Chronic Lung Allograft Dysfunction (CLAD): This remains the main obstacle to long-term survival, affecting approximately 50% of patients by 5 years after transplantation. CLAD involves progressive scarring and decline in lung function.

Infections: Immunosuppressed patients have increased risk of opportunistic infections, requiring careful monitoring and preventive strategies.

Cancer: Immunosuppression increases cancer risk, particularly skin cancers and lymphoproliferative disorders, requiring regular screening.

Other complications: These include kidney dysfunction, bone disease, diabetes, and cardiovascular issues related to immunosuppressive medications.

Careful monitoring and management of immunosuppression levels is crucial to balance rejection prevention with side effect minimization.

The Multidisciplinary Care Team

Lung transplantation requires a comprehensive team approach throughout the process. The multidisciplinary team includes:

• Transplantation pulmonologists
• Transplantation surgeons
• Transplantation coordinators
• Pharmacists
• Nutritionists
• Pulmonary rehabilitation specialists
• Physical therapists
• Social workers
• Critical care specialists
• Endocrinologists
• Immunologists
• Infectious disease specialists
• Gastroenterologists
• Psychiatrists
• Financial coordinators

This team supports patients through evaluation, pretransplantation care, immediate post-transplantation care, and long-term management, focusing on improving function and quality of life.

Future Directions in Lung Transplantation

Research continues to address the major challenges in lung transplantation. Key areas of focus include:

CLAD Prevention and Treatment: Further research into CLAD mechanisms and multicenter clinical trials of preventive and therapeutic strategies are urgently needed.

Organ Preservation: Emerging technologies enabling ex situ and in situ assessments show potential for extending preservation time while reducing PGD risk.

Immunosuppression Optimization: Developing better strategies to balance the protective and adverse effects of long-term immunosuppression.

Expanding Donor Pool: Continued refinement of criteria for extended-criteria donors and improved organ repair techniques.

Allocation Systems: Further refinement of allocation algorithms to improve efficiency and equity.

Study Limitations

This review article summarizes current knowledge but has several limitations. As a review rather than original research, it depends on available published studies which may have their own limitations. Much of the data comes from observational studies rather than randomized controlled trials, limiting definitive conclusions about cause and effect.

The field continues to evolve rapidly, and some recommendations may change as new evidence emerges. Practices vary among transplantation centers, and not all approaches described may be available at every institution. Long-term data on newer techniques and approaches remain limited.

Recommendations for Patients

For patients considering or undergoing lung transplantation:

1. Seek early referral: Discuss transplantation with your pulmonologist early in your disease course, even if you're not immediately eligible.
2. Participate in rehabilitation: Preoperative pulmonary rehabilitation can improve your physical condition and potentially enhance outcomes.
3. Build your support system: Ensure you have adequate caregiver support and social resources before proceeding with transplantation.
4. Address modifiable risk factors: Work with your healthcare team to optimize conditions like nutrition, diabetes control, and other health issues before transplantation.
5. Understand the commitment: Recognize that transplantation requires lifelong medication, monitoring, and lifestyle adjustments.
6. Choose an experienced center: Select a transplantation program with extensive experience and comprehensive multidisciplinary support.
7. Maintain realistic expectations: While transplantation can significantly improve quality of life and survival, it is not a cure and involves ongoing challenges.

Source Information

Original Article Title: Lung Transplantation
Authors: Jason D. Christie, M.D., Dirk Van Raemdonck, M.D., Ph.D., and Andrew J. Fisher, Ph.D., B.M., B.S.
Publication: The New England Journal of Medicine, November 14, 2024
DOI: 10.1056/NEJMra2401039

This patient-friendly article is based on peer-reviewed research from the Division of Pulmonary Allergy and Critical Care Medicine at the University of Pennsylvania Perelman School of Medicine, the Department of Thoracic Surgery at University Hospitals Leuven, and the Department of Transplantation and Regenerative Medicine at Newcastle University.