Lung transplantation: Disease-based choice of procedure

INTRODUCTION — Lung and heart-lung transplantation have been performed for most end-stage lung diseases. The different lung transplant procedures, the most common diseases that require lung transplant, and how the underlying lung disease affects the choice of procedure will be reviewed here.

An overview of lung transplantation, organizational process, outcomes, international guidelines for recipient selection, and indications for lung transplantation are presented separately. (See "Lung transplantation: An overview" and "Lung transplantation: General guidelines for recipient selection".)

OVERVIEW OF TYPES OF LUNG TRANSPLANT — Bilateral lung transplant (BLT) has been the most common type of lung transplantation reported to the International Society for Heart and Lung Transplantation Registry since 2001, when BLT procedures surpassed single lung transplantation (SLT) (figure 1) [1,2]. Combined heart-lung transplantation, which was once the most common procedure type, has been declining steadily in use since the 1990s [3]. In addition to these procedures, split lung bilateral lobar transplants and living donor lobar lung transplants were once occasionally performed but have largely fallen out of favor in recent years [4]. The reasons for choosing one procedure over another are reviewed here. An overview of the operative techniques is provided separately. (See "Lung transplantation: Procedure and postoperative management".)

According to the 2019 International Society for Heart and Lung Transplantation Registry report, the median survival for all adult recipients in the era between 2010 and 2017 was 6.7 years; bilateral lung recipients appear to have a better median survival than single lung recipients (7.8 versus 4.8 years, respectively for the years 1992 to 2017) [5]. However, it is unclear if this survival advantage is directly related to the type of operation or to the underlying recipient characteristics.

The general characteristics and advantages/disadvantages of the different types of lung transplantation are discussed in the following sections.

Bilateral lung transplantation — BLT is the procedure of choice for patients with advanced suppurative lung disease. For other patients, BLT is associated with improved long-term survival compared with SLT, although the survival curves do not diverge for the first several months [3]. In addition, BLT may allow greater use of marginal donor lungs that would otherwise be declined for single lung transplantation [6,7]. (See "Lung transplantation: Donor lung procurement and preservation" and "Lung transplantation: Procedure and postoperative management".)

Single lung transplantation — Compared with bilateral lung transplantation, SLT may extend the limited supply of donor organs to more patients. However, it provides less lung function as a buffer for late complications. As the operative procedure is shorter than bilateral transplantation, SLT may be preferable in older patients or those who would not tolerate the longer anesthesia time [8]. (See "Lung transplantation: Procedure and postoperative management".)

Split lung bilateral lobar transplantation — The principal advantage of split lung bilateral lobar transplantation is that it permits single lung transplantation from a donor with a large size discrepancy with the recipient, such as a small adult or child. With this procedure, a single left lung from a donor who is approximately 15 percent taller than the recipient is divided such that the left upper and lower lobes are implanted into the recipient's right and left hemithorax, respectively [9,10]. When appropriate, the remaining donor lung is given to another recipient. However, technical difficulties and appropriate donor-recipient size matching have limited the use of this procedure [11].

Living donor lobar lung transplantation — As with kidney and liver transplantation, living donor lobar lung transplantation was developed to increase organ availability and reduce long waiting times [12-16]. This procedure requires lung tissue from two donors. The right lower lobe retrieved from one donor is implanted into the recipient's right hemithorax, while the left lower lobe from another donor is placed in the recipient's left hemithorax. Because only one lobe is implanted in each hemithorax, this operation is limited to children and adults with small stature. As a result, the number of living donor lobar lung transplants performed annually peaked at 29 in 1999 in the United States and has diminished rapidly since the implementation of lung allocation systems that account for medical urgency (2005). In fact, no living donor lobar transplants were performed in the United States in 2014 or 2015 and only one was performed annually in 2011, 2012, and 2013 [17]. However, in countries where brain death is not recognized, this remains the only viable lung transplant procedure.

Heart-lung transplantation — Heart-lung transplantation is reserved for select patients with Eisenmenger syndrome, surgically uncorrectable congenital defects, and severe and potentially irreversible right heart failure due to pulmonary hypertension of any etiology. The latter indication has proved problematic as severe right ventricular dysfunction may reverse after isolated lung transplantation, once pulmonary pressures normalize, suggesting that heart-lung transplantation is not always necessary in such patients [18-22]. However, predicting whether heart function can recover after lung transplantation alone can be difficult. The annual volume of combined heart-lung transplantation has decreased over the past 25 years in the United States, unlike the volume of isolated lung or heart transplants. In fact, 71 heart-lung transplants were performed in 1994 and only 45 were performed in 2021 [23,24]. This is in part related to challenges in allocation policies for combined heart-lung blocks. Nonetheless, this trend mirrors the annual volume of heart-lung transplants reported to the ISHLT Registry report [25]. (See "Heart-lung transplantation in adults" and "Heart transplantation in adults: Indications and contraindications" and "Pulmonary hypertension in adults with congenital heart disease: Disease-specific management", section on 'Transplantation'.)

DISEASE-BASED CONSIDERATIONS — The underlying lung disease is an important factor in deciding which lung transplant procedure to perform [26]. The majority of lung transplants are bilateral, although variability occurs based on allograft availability, disease-specific concerns, and transplant center.

Interstitial lung disease — End-stage interstitial lung disease (ILD) accounts for about 40 percent of lung transplants [5,27]. Among ILDs, idiopathic pulmonary fibrosis (IPF) most commonly requires lung transplantation; nonspecific interstitial pneumonia (NSIP) is the next most common [28-30]. Discussions of the indications for and timing of transplant for IPF and NSIP are presented separately. (See "Idiopathic interstitial pneumonias: Classification and pathology" and "Treatment of idiopathic pulmonary fibrosis", section on 'Lung transplantation' and "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Lung transplantation' and "Lung transplantation: General guidelines for recipient selection".)

Single lung transplantation (SLT) was the standard procedure for patients with IPF for many years and survival statistics were comparable to other indications for lung transplantation (figure 2) [31-34]. However, a growing percentage of patients are now undergoing bilateral lung transplantation (BLT) [25,35,36]. For example, between 1995 and 2018, BLT procedures accounted for more than 50 percent of adult lung transplants for idiopathic interstitial pneumonia (IIP) [37]. The reasons for this shift in practice are unclear, although improved surgical technique, as well as better lung function and longer survival for BLT recipients are likely contributors [35].

The survival outcomes of BLT compared with SLT for patients with IIP are described in the 2019 ISHLT Registry Report analysis of 15,531 transplants performed between 1992 and 2017 [37]. SLT was associated with a survival benefit in the short term (up to one year), while BLT was associated with a survival benefit in the long term. However, this univariate analysis does not account for other potential risk factors (eg, age, lung allocation score) that might influence survival among SLT and BLT recipients. A separate analysis of lung transplant outcomes between 2005 and 2012 in the United States found that BLT for IPF was associated with better graft survival than SLT (62 months, interquartile range [IQR] 21.4 to 91.3, versus 50 months, IQR 17 to 87.5, respectively, p<0.001) [38]. Furthermore, in a propensity matched analysis of the UNOS database, BLT was associated with a survival advantage over SLT among patients who were 65 years of age or older, and this survival advantage was detectable by one year after transplantation [39].

Despite superior survival with BLT, the limited availability of lungs for transplantation makes it more difficult to obtain a BLT than SLT. Among 1339 patients with IPF listed for lung transplantation between May 2005 and June 2009, those listed for BLT only, compared with SLT only or either SLT or BLT, were slightly more likely to die on the waiting list and less likely to receive a transplant [40]. Thus, the choice of procedure requires careful consideration of the patient’s anticipated survival pre and post-transplant.

Patients with nonspecific interstitial pneumonia (NSIP) generally have a better prognosis and better response to medical therapy than those with IPF [27,28]. Nonetheless, some patients with NSIP, especially those with the fibrotic variant, have a progressive decline in lung function, and eventually become candidates for transplantation. The choice between SLT and BLT for NSIP follows the experience with IPF described above.

Living donor lobar lung transplantation has been suggested as an alternative procedure for patients with end-stage IPF who are not expected to survive the waiting time for deceased donor transplantation [41]. However, experience with the current UNOS lung organ allocation system suggests that the waiting time for a deceased donor lung for a patient with end-stage IPF should be short and that living donor transplantation is not necessary in areas with similar allocation systems.

Chronic obstructive pulmonary disease — Historically, chronic obstructive pulmonary disease (COPD) was the most common indication for lung transplantation in the US, but interstitial lung disease (ILD) has surpassed COPD as the leading indication in recent years, accounting for approximately 50 percent of all lung transplants (OPTN/SRTR Annual Data Report). A similar trend is seen internationally in the International Society for Heart and Lung Transplantation (ISHLT) Registry Report [42,43]. The specific indications for lung transplantation in COPD are reviewed separately. (See "Stable COPD: Overview of management", section on 'Nonpharmacologic therapy' and "Lung transplantation: General guidelines for recipient selection", section on 'Chronic obstructive pulmonary disease (COPD)'.)

The two principal transplant options for those with end-stage COPD are SLT and BLT [8,44-49]. The choice between these options is center and availability specific, but the majority of patients with COPD undergo BLT. Based on ISHLT registry data, in 2017, approximately 80 percent of transplants for COPD were BLT [37]. By comparison, 50 percent of transplants for COPD in 2005 were BLT [37]. In a separate analysis, among patients with emphysema due to alpha-1 antitrypsin deficiency, 88 percent received a BLT and 12 percent an SLT in 2014 [25].

A factor favoring the bilateral procedure is the slightly superior actuarial survival in BLT recipients with COPD (figure 3) [50,51]. This trend toward improved long-term survival following bilateral transplantation is primarily seen in patients under age 60 [52-54]. A retrospective analysis of 9883 recipients with COPD demonstrated that, among those younger than 60, BLT offered a survival advantage over SLT [53]. In contrast, among those older than 60, the survival benefit of BLT over SLT was no longer apparent. Similarly, one-year survival was nearly equivalent after BLT and SLT in patients over age 60 in the ISHLT registry, but further survival to five years among those living for one year favored BLT recipients [43]. A possible explanation for this is that SLT is a simpler, shorter operation with a lower perioperative complication rate than BLT in older patients with emphysema [8].

In a separate analysis that adjusted for treatment selection bias, age, sex, body mass index, diabetes, renal insufficiency, and other co-morbid factors, there was no significant survival benefit at five years associated with BLT over SLT for COPD, although there was a significant survival benefit at five years associated with BLT for ILD [38]. COPD results in significant hyperinflation of the thoracic cavity, and this allows the implantation of an oversized single allograft, which may mitigate some of the benefits of BLT over SLT. Further study is needed to determine the optimal procedure in patients with COPD.

There are a few additional differences between SLT and BLT that may provide a survival benefit with BLT:

●Following SLT, a few patients develop severe hyperinflation of the remaining native lung such that it crosses the mediastinum and compresses the transplanted lung. When this occurs, lung volume reduction surgery of the native lung is sometimes needed [55].

●The leading cause of death among lung transplant recipients over the long term is chronic rejection. Among those who develop this complication, BLT recipients survive longer than patients who have received a SLT [50,56]. BLT provides additional lung reserve that may compensate for the loss of lung function resulting from chronic rejection, although the mechanism underlying this observation is unclear [57]. In addition, SLT may be associated with an increased risk of chronic rejection. (See "Lung transplantation: An overview" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

●Another frequent cause of death following lung transplantation is malignancy. In the ISHLT registry, among those with an underlying diagnosis of COPD, freedom from new-onset nonskin malignancy in double versus single lung transplants was 94 versus 88 percent at five years, 86 versus 75 percent at ten years, and 76 versus 66 percent at fifteen years, respectively [43]. The difference between double versus single lung transplantation was driven entirely by new-onset lung cancer in the retained native lung; all other nonskin malignancies occurred at similar frequencies.

Pulmonary function testing provides an indirect measure of quality of life after the different lung transplant procedures. Among patients with COPD who undergo lung transplantation, BLT is associated with a greater improvement in spirometry compared with SLT; however, this does not translate into a significant difference in exercise capacity (eg, six-minute walk test, cardiopulmonary exercise test) between BLT and SLT [44,58,59]. (See "Physiologic changes following lung transplantation", section on 'COPD/emphysema'.)

Cystic fibrosis — In the United States, cystic fibrosis (CF) is the foremost cause of end-stage obstructive lung disease during the first three decades of life; it is the third most common indication for lung transplantation [1,60,61]. The indications for lung transplantation in cystic fibrosis are discussed separately. (See "Cystic fibrosis: Management of advanced lung disease", section on 'Lung transplant evaluation' and "Lung transplantation: General guidelines for recipient selection", section on 'Cystic fibrosis and bronchiectasis'.)

BLT is the procedure of choice for most adults with CF [62]. Because of the risk of spillover infection, removal of both lungs is mandatory for lung transplantation for CF and is generally advised for other forms of generalized bronchiectasis although data are lacking [63].

Living donor lobar lung transplantation (LDLT) is an alternative that circumvents the shortage of deceased donors [12,13]. This approach is rarely used now that waiting list times have decreased since development of lung allocation systems that account for medical urgency (see "Lung transplantation: An overview", section on 'Lung allocation'). LDLT is especially suited for children and young adults with CF who are small in size and would attain sufficient lung function from two adult donor lobes [64]. Long-term survival results with this procedure have been comparable to transplantation from deceased donors [65]. Additionally, donor lobectomy has been associated with relatively low morbidity and no mortality [66].

SLT with a contralateral pneumonectomy has been employed in few special circumstances (eg, skeletal asymmetry), but this has not been the standard approach [67,68]. Lung transplantation has been successfully combined with simultaneous liver transplantation in a few patients with cirrhosis [69].

Pulmonary arterial hypertension — Pulmonary arterial hypertension (PAH) accounts for less than 5 percent of lung transplants [1]. Overall, patients with PAH have the highest 30-day mortality following lung transplantation (figure 2) [70]. The specific indications for lung transplantation in PAH are reviewed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Lung transplantation' and "Lung transplantation: General guidelines for recipient selection".)

While the majority of patients undergo BLT, both SLT and BLT have been performed successfully for PAH [25,71]. Based on analysis of databases, survival comparisons favor BLT after the first year [25,72].

An additional factor that has favored BLT is that SLT for PAH is a difficult procedure. Ventilation is evenly divided between the allograft and the native lung while perfusion is almost entirely directed to the allograft (due to the high pulmonary vascular resistance in the native lung). Any complication in the allograft (eg, pneumonia, primary graft dysfunction, rejection) can result in severe ventilation-perfusion mismatch and hypoxemia [73].

Heart-lung transplantation was originally the standard procedure for patients with PAH. However, it was replaced by isolated lung transplantation in most centers in the 1990s. This is because right ventricular dysfunction recovers quickly with the rapid reduction in pulmonary vascular resistance after lung transplantation, making heart transplantation unnecessary [74-76].

Eisenmenger syndrome — Eisenmenger syndrome may result from atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA), or multiple cardiac anomalies [77]. Both heart-lung transplantation and lung transplantation with intracardiac repair are performed for patients with Eisenmenger syndrome [77]. The choice is based on whether the cardiac defect is amenable to surgical repair (eg, ASD, PDA). Otherwise, HLT is generally preferred for patients with Eisenmenger syndrome due to VSD or other anomalies that are combined with severe left ventricular failure, when they meet criteria for transplantation. Indications for transplantation are discussed separately [53,77-80]. (See "Heart-lung transplantation in adults" and "Pulmonary hypertension in adults with congenital heart disease: Disease-specific management", section on 'Transplantation'.)

The optimal therapeutic choice in those with Eisenmenger syndrome is based principally upon the underlying heart disorder. Data in support of specific options are derived entirely from retrospective reviews of relatively small numbers of patients. In one of the larger retrospective reviews, the outcomes after lung and heart-lung transplantation were reported for 605 patients with Eisenmenger syndrome [77]. Causes of the syndrome included ASD (171 patients), VSD (164), multiple congenital anomalies (68) and PDA (32). Procedures included HLT, BLT, and SLT in 430, 106 and 69 transplants, respectively. The following results were reported:

●Among those with VSD, there was improved survival following HLT compared with BLT and SLT. This seemed related to early postoperative ventricular failure in the lung transplant group.

●Survival following BLT or SLT for ASD or PDA is not as good as HLT for VSD or multiple cardiac anomalies. This suggests some technical difficulties arise when BLT/SLT are combined with cardiac repair, compared with the relatively more straightforward procedure of HLT.

In patients with cardiac anomalies that can be surgically repaired (eg, ASD, PDA), the scarcity of heart-lung blocks makes it preferable to combine lung transplantation with intraoperative cardiac repair, unless the combined procedure would require prolonged time on cardiopulmonary bypass [81]. If the cardiac repair is more complicated than ASD or PDA repair, HLT is generally preferred.

Pulmonary hypertension due to underlying lung parenchymal disease — Patients with end-stage lung disease often develop pulmonary hypertension (PH). Heart-lung transplant is generally not needed unless both left and right heart failure are present. Data are conflicting as to whether PH should affect the choice of SLT versus BLT. In a retrospective review that compared outcomes among 104 patients with normal mean pulmonary artery pressure (PAM), mildly elevated PAM, and high PAM, no differences in survival were noted between types of procedure (SLT or BLT) or between levels of PAM [80]. Similarly, in a retrospective review of 318 patients undergoing SLT, mild or severe secondary PH did not impact the length of postoperative mechanical ventilation, severity of primary graft dysfunction, or survival [82]. In contrast, among patients undergoing transplant for idiopathic pulmonary fibrosis, PH was an independent risk factor for early mortality after SLT [83].

RETRANSPLANTATION — Because outcomes after lung transplantation remain disappointing and graft failure is the leading cause of death, retransplantation can be considered in carefully selected patients. However, survival remains significantly worse after retransplantation than after primary transplantation, although survival after retransplantation has improved over time [25,84]. In the 2018 ISHLT Registry, the median survival after retransplantation was 3.1 years compared with 6.2 years after primary transplantation [42,85].

Retransplantation is technically more difficult because of thoracic adhesions due to primary transplantation. Because of these technical challenges, single lung transplantation is sometimes the only feasible retransplant procedure. However, based on outcomes data after retransplantation from the UNOS Registry, single lung transplantation was associated with an increased risk of death compared with bilateral lung transplantation in a multivariate analysis [84].

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".)

SUMMARY AND RECOMMENDATIONS

●Bilateral lung transplantation (BLT) is now the most common lung transplant procedure, followed by single lung transplantation (SLT) (figure 1). In contrast, heart-lung transplantation has become an uncommon procedure. (See 'Overview of types of lung transplant' above.)

●In general, BLT is necessary only for bronchiectasis (eg, cystic fibrosis), but it is often performed for other indications because of the perceived better long-term outcomes. (See 'Bilateral lung transplantation' above.)

●SLT extends the limited supply of donor organs to more patients, but it provides less lung function as a buffer for late complications than BLT and may not be appropriate when using marginal organ donors. (See 'Single lung transplantation' above.)

●Living lobar lung transplantation in which each of two donors provides a lobe was developed to increase organ availability and reduce long waiting times, but this has become an uncommon procedure in recent years because of changes in the allocation system. (See 'Living donor lobar lung transplantation' above.)

●Both SLT and BLT are performed for COPD and alpha-1 antitrypsin deficiency. Further study is needed to determine which of these procedures is optimal in patients with COPD. (See 'Chronic obstructive pulmonary disease' above.)

●Idiopathic pulmonary fibrosis is the most common interstitial lung disease that requires lung transplantation. SLT is associated with better short term survival, but BLT is associated with better long term survival. (See 'Interstitial lung disease' above.)

●Removal of both lungs is mandatory in lung transplantation for patients with end-stage cystic fibrosis, because of the risk of spillover infection. Therefore, BLT is the procedure of choice. (See 'Cystic fibrosis' above.)

●In patients with pulmonary arterial hypertension (PAH) who require lung transplantation, we favor BLT over SLT. A few patients with concomitant left heart failure will need HLT. (See 'Pulmonary arterial hypertension' above.)

●Heart-lung transplantation should be reserved for patients with concomitant lung and heart disease who cannot be treated by lung transplantation alone (eg, Eisenmenger in a patient with a surgically uncorrectable cardiac anomaly). (See 'Heart-lung transplantation' above.)