Lung transplantation: An overview

INTRODUCTION — Over the past 40 years, lung transplantation has become a viable treatment option for patients with a variety of end-stage lung diseases. The first human lung transplant procedure was performed in 1963, and the recipient survived 18 days, ultimately succumbing to kidney failure and malnutrition [1]. Despite the outcome, this demonstrated that lung transplantation was technically feasible and that rejection could be averted with the available immunosuppressive agents, at least for a short time.

Over the ensuing 15 years, few lung transplant procedures were performed, and the majority of recipients died perioperatively because of bronchial anastomotic complications. However, in 1981, the first successful heart-lung transplantation was performed for idiopathic pulmonary arterial hypertension [2]. This was followed in 1983 by the first successful single lung transplantation for idiopathic pulmonary fibrosis [3] and in 1986 by the first double lung transplantation for emphysema [4]. These successes were attributed to improved surgical techniques and the advent of cyclosporine. Over the following several years, the number of lung transplant procedures performed rapidly increased, and the operation became an accepted treatment for end-stage lung disease.

An overview of lung transplantation, including a discussion of outcomes, is presented here. Lung transplantation indications, recipient selection, choice of procedure, post-operative management and complications are presented separately. (See "Lung transplantation: General guidelines for recipient selection" and "Lung transplantation: Disease-based choice of procedure" and "Lung transplantation: Procedure and postoperative management" and "Noninfectious complications following lung transplantation" and "Evaluation and treatment of acute cellular lung transplant rejection".)

ACTIVITY — There has been a steady growth in the number of lung transplant procedures performed annually since 2000, with approximately 4500 adult lung transplants reported annually since 2016 (figure 1) [5]. While part of this increase may be attributable to greater participation in the ISHLT Registry, the rapid rise in activity since 2005 suggests that the lung allocation system implemented in the US in 2005 has increased the number of transplants performed. In addition, the United States Organ Donation Breakthrough Collaborative, which began in 2003, increased organ donation and recovery by disseminating and implementing best practices across Collaborative hospitals [6].

A shortage of lung donors remains the major limiting factor to the number of transplants performed, despite a significant increase in the number of donors over the past decade [7]. Lung organ procurement rates from deceased donors have consistently been substantially lower than kidney, liver, and heart procurement rates. There is significant variability in organ donation and lung utilization across the world [8]; in the United States, lungs are retrieved from less than 30 percent [9] of all organ donors [8,10]. These disparities are likely due to the lung's vulnerability to potential complications that often arise before and after donor brain death such as thoracic trauma, aspiration, ventilator associated lung injury, pneumonia, and neurogenic pulmonary edema. Nonetheless, a portion of rejected donor lungs may have been suitable for transplantation [8]. Studies suggest that ex vivo lung perfusion and reconditioning may ameliorate lung injury in some cases and allow transplantation from donors previously deemed unsuitable [11,12]. Standard and extended criteria for donor lung selection and their impact on short and long-term outcomes are presented separately. (See "Lung transplantation: Donor lung procurement and preservation".)

In the early years, single lung transplantation was more frequent than bilateral transplantation. While the number of single lung transplants performed annually has remained stable, the number of bilateral transplants has consistently increased and surpassed the number of single lung procedures in 2002 (figure 1) [5]. The choice of procedure and recipient selection are presented separately. (See "Lung transplantation: General guidelines for recipient selection" and "Lung transplantation: Disease-based choice of procedure".)

The most common diseases that lead to lung transplant are interstitial lung disease (including idiopathic pulmonary fibrosis), chronic obstructive pulmonary disease, cystic fibrosis, alpha-1 antitrypsin deficiency, and idiopathic pulmonary hypertension (figure 2) [5]. (See "Lung transplantation: Disease-based choice of procedure".)

ORGANIZATIONS — Transplant organizations and organ allocation policies are influenced by medical, ethical, geographical, and political factors and systems vary from country to country. In the United States, there are three main components of the transplant system: the United Network for Organ Sharing (UNOS), the organ procurement organizations (OPOs), and the transplant centers. Their different responsibilities are reviewed here.

United Network for Organ Sharing — UNOS is a private, non-profit organization that operates the Organ Procurement and Transplantation Network (OPTN) under a contract with the US Department of Health and Human Services. UNOS develops policies that govern the transplant system with the goal of maximizing the efficient and equitable use of organs. In addition, UNOS maintains data pertaining to the waiting list, organ matching, and transplants. All OPOs and transplant centers must be members of UNOS.

Organ procurement organizations — OPOs are private, non-profit organizations that recover organs within their geographical territory and allocate them based on UNOS guidelines.

Lung transplant centers — Transplant centers are the focal point of the transplant system for patients and clinicians. In the United States, many health plans have preferred provider provisions for lung transplantation, and Medicare will only cover the procedure at approved centers.

LUNG ALLOCATION — Since March 2023, the order of patients on the waiting list for lung transplantation has been based on a lung Composite Allocation Score (CAS), which was developed to further improve waitlist mortality and provide more lung transplants to the most medically urgent candidates [13].

The adoption of CAS is part of a new policy that utilizes an approach known as continuous distribution, in which all of the factors used for organ matching are included in a single, weighted score calculated for each lung transplant candidate and lung offer. Under the previous lung allocation system, a set of different matching classifications (eg, candidate urgency, donor compatibility, and distance between donor and transplant hospitals) were determined individually and then applied sequentially to determine lung offers.

The CAS has a theoretical maximum score of 100 points, and has the following individual components (table 1):

●Candidate medical urgency (ie, expected waitlist survival, maximum 25 points)

●Likelihood of recipient survival over five years post-transplant (maximum 25 points)

●Potential biological challenges in matching, such as the candidate’s blood type, height, or allosensitization (maximum 15 points)

●Whether the candidate was younger than age 18 years when listed for a transplant (20 points)

●Whether the candidate was a prior living organ donor (5 points)

●Placement efficiency (based on logistics of preserving and transporting the lungs between donor and transplant hospitals, maximum 10 points)

The CAS is different for every offer due to the placement efficiency component. The CAS replaces the previous Lung Allocation Score (LAS) for patients 12 years of age and older. An approximate CAS calculator is available on the Organ Procurement and Transplantation Network (OPTN) website. For patients under the age of 12 years, the current pediatric priority scores are incorporated into the CAS medical urgency formula in addition to the "patient access" points for candidates younger than age 18 years.

The Scientific Registry of Transplant Recipients performed two rounds of simulation modeling to assess potential effects of these changes on transplant allocation and outcomes [14,15]. The results of these analyses indicated that compared to LAS, CAS should decrease waitlist deaths, reduce median distance lungs are transported, lessen variability across OPTN regions, and increase lung allocation to the following groups: pediatric patients; urgent adult patients (LAS >60); adult patients with reduced height (<158 cm); patients with type O blood; and patients with the best predicted post-transplant outcomes. The actual impact of this change on lung allocation and transplant outcomes remains to be seen.

REFERRAL FOR TRANSPLANT EVALUATION — Patients with untreatable, advanced stage lung disease are referred to regional transplant centers for evaluation. Transplant centers typically screen the medical records of referred patients before an on-site evaluation is scheduled. The transplant centers thoroughly evaluate patients to determine the appropriateness of placing them on the transplant waiting list and to collect the information from which the CAS is derived. The patient is registered with UNOS, and the patient's profile is updated at intervals of at least every six months or more often if there is a change in the patient’s clinical status.

●When donor organs become available, the procuring organization contacts UNOS' national transplant communications center, UNet, by telephone or internet access. The UNet computer system runs donor/recipient matches based on blood type, size of the organ, and distance between the donor and recipient.

●UNOS then communicates the ranked match results to the OPOs to contact the transplant centers of the highest ranked patient. Once the organ is accepted, the OPO arranges transportation and the transplant surgery is scheduled.

Specifics of donor and recipient lung evaluation, selection, and management are discussed separately. (See "Lung transplantation: General guidelines for recipient selection" and "Lung transplantation: Deceased donor evaluation".)

The type of transplant procedure and postoperative management are also discussed separately. (See "Lung transplantation: Disease-based choice of procedure" and "Lung transplantation: Procedure and postoperative management".)

OUTCOMES — Outcome after lung transplantation can be assessed based on several different metrics: survival, quality of life, physiologic changes, and cost benefit [5,16]. Survival is perhaps the most straightforward assessment of outcome, and large registries can easily generate actuarial survival estimates based on multi-center and international data. However, other endpoints such as quality of life offer important insights into the benefits of lung transplantation.

Survival — The International Society for Heart and Lung Transplantation (ISHLT) has maintained a registry that has accrued data on more than 64,000 recipients from over a hundred transplant centers worldwide. The Registry has generated survival estimates from these data annually that have become a benchmark for the field [5].

According to the ISHLT registry report, the median survival for adult recipients since 2010 is 6.7 years, but bilateral lung recipients appear to have a better median survival than single lung recipients (7.8 versus 4.8 years, respectively; for a figure showing updated information, please see the International Society for Heart and Lung Transplantation 2019 slide set "Overall Lung and Adult Lung Transplantation Statistics," slide titled Adult Lung Transplantation Kaplan-Meier Survival by Procedure Type at: ISHLT Registry) [17].

However, it is unclear if this survival advantage is directly related to the choice of operation or to the underlying recipient characteristics that influence this choice. A study that evaluated the impact of recipient age and operation performed on the survival of recipients with pulmonary fibrosis, found that single lung recipients younger than 60 years of age had a survival advantage over bilateral recipients in the same age group [18].

The impact of underlying diagnosis on survival after transplantation has been evaluated extensively (figure 3) [5,19,20]. The underlying diagnosis is often linked to age. In addition, certain diagnoses carry higher risks of operative complications and primary graft dysfunction. Nonetheless, recipients with COPD have the best one-year survival, but a lower ten-year survival compared to those with cystic fibrosis (CF), idiopathic pulmonary arterial hypertension, and alpha-1 antitrypsin deficiency [5]. Recipients with IPAH have the lowest one-year survival, but their ten-year survival approaches those with CF. Lastly, those with idiopathic interstitial pneumonia or COPD have a lower ten-year survival compared to others.

The Registry has also reported that one-year survival between the years 2010 and 2017 was significantly better than the two previous eras (1992 to 2001 and 2002 to 2009; For a figure showing updated information, please see the International Society for Heart and Lung Transplantation 2019 slide set "Overall Lung and Adult Lung Transplantation Statistics," slide titled Adult Lung Transplantation Kaplan-Meier Survival by Era [Transplants: January 1992 to June 2017] at: ISHLT Registry). However, the five-year survival of patients alive at one-year post-transplant was not different between the 2002 to 2007 and 2008 to 2013 eras, suggesting that management strategies have been more effective at reducing early complications than later ones, possibly due to refinements in surgical techniques and postoperative care [5]. In contrast, survival beyond the first year is primarily affected by chronic rejection and infections [21,22].

Causes of death — Primary graft dysfunction (PGD), a form of acute lung injury, which occurs in the early hours to days after transplant, is the leading cause of death in the first 30 days after transplantation, accounting for more than 20 percent of deaths [5,23]. The incidence of PGD has varied depending on the definition used [24]. (See "Primary lung graft dysfunction".)

A grading system for PGD incorporates the PaO₂/FiO₂ ratio and chest radiograph findings [24]:

●PGD grade 0: PaO₂/FiO₂ >300 and no pulmonary edema on chest radiograph

●PGD grade 1: PaO₂/FiO₂ >300 and pulmonary edema on chest radiograph

●PGD grade 2: PaO₂/FiO₂ = 200 to 300 and pulmonary edema on chest radiograph

●PGD grade 3: PaO₂/FiO₂ <200 and pulmonary edema on chest radiograph

The effect of PGD on survival is discussed separately. (See "Primary lung graft dysfunction", section on 'Survival'.)

Chronic lung allograft dysfunction (CLAD), which manifests as BOS or restrictive allograft syndrome (RAS), is the leading cause of mortality after the first year, accounting for 20 to 30 percent of deaths [5]. This remains the primary obstacle to better long-term outcomes after lung transplantation. The incidence of BOS approaches 50 percent within five years of transplantation [5]. Survival three years after the onset of BOS is only 50 percent, and drops to 30 to 40 percent at five years. Superimposed infections and malignancies due to immunosuppressive therapy often further complicate the course. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome" and "Chronic lung allograft dysfunction: Restrictive allograft syndrome".)

Infectious complications remain a leading cause of death at all time points after lung transplantation, accounting for 35 percent of deaths in the first year and 20 percent of deaths thereafter [5]. Bacterial bronchitis and pneumonia are most common, but fungi, cytomegalovirus, community acquired respiratory viruses, and mycobacteria all contribute to the overall burden [25-28]. (See "Bacterial infections following lung transplantation" and "Prevention of cytomegalovirus infection in lung transplant recipients".)

Malignancy accounts for a small percentage of mortality in the first year after transplantation; beyond the first year, 7 to 10 percent of all deaths are due to cancer. Nonmelanoma skin cancer is the most prevalent malignancy overall, but posttransplant lymphoproliferative disease (PTLD) is the most common malignancy in the first year after transplant and second most common overall [5]. Other malignancies include colon and breast cancer. A study from Israel found an increased incidence of Kaposi's sarcoma and transitional cell carcinoma of the bladder (4 percent each) in addition to non-melanotic skin cancer and PTLD [29]. (See "Noninfectious complications following lung transplantation", section on 'Malignancy'.)

Quality of life — After the postoperative recovery, most recipients are able to resume an unencumbered lifestyle. Over 80 percent report no activity limitations and almost 40 percent of five-year survivors are working at least part-time [5]. Furthermore, multiple studies have documented that lung transplantation confers significant benefits in health-related quality of life [30,31]. One study showed comparable health-related quality of life results between lung transplant recipients and a normative sample of healthy people, with the exception of the social functioning domain [32].

Postoperative complications hamper this improvement in quality of life. One study showed that PGD grade 3 attenuated the improvement in health-related quality of life and that this was related to the duration of mechanical ventilation [33]. Likewise, postoperative delirium is associated with attenuated improvement in health-related quality of life [34]. Recipients who have developed BOS report more physical restrictions and depressive and anxiety symptoms than those who have not and have decrements in health-related quality of life compared to their pre-BOS evaluation [32,35,36]. A study that validated a lung transplant quality of life survey demonstrated that recipients with severe CLAD reported significantly worse health-related quality of life than those without CLAD [37]. Similarly, infections and episodes of acute rejection have a negative impact on health-related quality of life [32]. Nonetheless, even if the survival advantage itself is modest, the prospect of improving quality of life and quality-adjusted survival is often the motivation for transplantation for many recipients.

Retransplantation — Retransplantation among lung transplant recipients is infrequent and accounts for approximately 4 percent of lung transplant procedures [5]. Survival after first retransplant operation is 75 percent at 1 year, 36 percent at 5 years, and 21 percent at 10 years [38]. (See "Lung transplantation: Procedure and postoperative management", section on 'Retransplantation'.)

Cost and cost-effectiveness — Lung transplantation is an expensive treatment with perhaps only modest improvements in quality-adjusted survival. Nonetheless, there is no social consensus on the monetary value of a quality-adjusted life year gained through lung transplantation or any other treatment.

A relatively small number of studies have examined the cost and the cost-effectiveness of lung transplantation [39,40]. As examples:

●In a study of lung transplantations performed at one center between May 2005 and June 2009, median charges for the transplantation admission were USD $153,995 for patients with lung allocation scores (LAS) in the three lower quartiles, compared with USD $276,668 for those with LAS scores in the highest quartile [39]. However, no difference between the LAS quartiles was noted in the charges for the first year, when the transplantation admission charges were excluded.

●In a study that examined the index hospitalization charges of patients who required extracorporeal membrane oxygenation (ECMO) between 2000 and 2011, median charges for lung transplant recipients who required ECMO were USD $780,391 compared with USD $324,279 for those who did not [40].

●Cost during the index hospitalization is the main contributor to total cost [41], and this cost varies based on the underlying lung disease. Between 2013 and 2019 in the United States, cost was highest for patients with pulmonary vascular disease (mean USD $639,141) and lowest for those with obstructive lung disease (mean USD $354,429). Not surprisingly, the use of extracorporeal membrane oxygenation, mechanical ventilation, and complications were associated with higher cost during the index hospitalization.

Wage effects are not included in the cost-effectiveness analysis in most studies, and if recipients returned to work, this would be an obvious asset. Employment after lung transplantation varies; this is in part dependent on whether the recipient was already at or past retirement age. In an analysis of the ISHLT registry, approximately 13 percent of lung recipients were working at one year after transplant and 18 percent after 5 years [5].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lung transplantation".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient education: Lung transplant (The Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Lymphangioleiomyomatosis (LAM)".)

SUMMARY AND RECOMMENDATIONS

●Frequency of lung transplantation – The number of lung transplants performed each year has grown steadily since 1985, although further increases in this number appear to be limited by organ availability. The proportion of bilateral lung transplants has increased and surpassed that of single lung transplants (figure 1). (See 'Activity' above.)

●Recipient characteristics – The most common diseases that lead to lung transplant are interstitial lung disease (ILD), chronic obstructive pulmonary disease (COPD), cystic fibrosis, alpha-1 antitrypsin deficiency, and idiopathic pulmonary arterial hypertension (IPAH) (figure 2). (See 'Activity' above.)

●Recipient evaluation and lung allocation in the United States

•Responsible organizations – Responsibility for recipient evaluation, waiting list management, and matching of donor organs with recipients is shared by three organizations: United Network for Organ Sharing (UNOS), Organ Procurement Organizations (OPOs), and lung transplant centers. (See 'Organizations' above.)

•Lung allocation score – Lung allocation to patients on the waiting list has been based on a Lung "Composite Allocation Score" since March 2023 (table 1). This score includes a measure of urgency of need for transplant, a post-transplant likelihood of survival measure, a biologic compatibility measure, and a placement efficiency measure. (See 'Lung allocation' above.)

●Outcomes

•Survival – According to the ISHLT registry report, the median survival for adult recipients since 2010 is 6.7 years, but this varies by age of recipient and by the recipient’s pretransplant pulmonary disease.

The first-year mortality is lowest for recipients listed for COPD and highest for those transplanted for IPAH. In contrast, mortality at 10 years is highest for COPD and idiopathic interstitial pneumonia and lowest for cystic fibrosis and alpha-1 antitrypsin (figure 3). (See 'Outcomes' above.)

•Causes of morbidity and mortality post-transplant – Primary graft dysfunction (PGD) and infections are the major causes of death in the first year following transplantation; chronic graft dysfunction due to bronchiolitis obliterans syndrome is the major cause of death after the first year. (See 'Outcomes' above and "Primary lung graft dysfunction" and "Infection in the solid organ transplant recipient".)

•Cost and cost-effectiveness – Lung transplantation is an expensive treatment that provides only modest gains in quality adjusted life years. (See 'Outcomes' above.)