Lung Transplantation

Indications, Follow-Up Care and Long-Term Results

Background: Lung transplantation is the treatment of choice for end-stage nonmalignant lung disease. It has become a routine procedure through advances in donor lung preservation, extracorporeal membrane oxygenation, immunosuppression, intensive care medicine, and follow-up care.

Methods: This review is based on publications about lung transplantation that were retrieved by a selective literature search, and on the procedures and experience of two large-volume lung transplantation centers.

Results: The mean survival time after lung transplantation is six years, which is the shortest after the transplantation of any solid organ. Chronic graft dysfunction is present in 41% of patients at five years and is the main cause of death after lung transplantation, followed by infection and cancer.

Conclusion: Despite all the advances in lung transplantation, acute and—above all—chronic graft dysfunction still pose a major challenge for large-volume transplantation centers. Immunosuppression that is individually tailored to prevent both graft rejection and infection is important for these patients’ long-term survival. Xenotransplantation and so-called lung bioengineering may become available in the future as alternatives to allotransplantation.

Cite this as: Michel S, Schneider C, Ius F, Welte T, Gottlieb J, Kneidinger N: Lung transplantation—indications, follow-up care and long-term results. Dtsch Arztebl Int 2025; 122: 43–8. DOI: 10.3238/arztebl.m2024.0232

Lung diseases, alongside cardiovascular diseases, are among the leading causes of death in industrialized countries. For selected patients with end-stage non-malignant lung disease, the option of lung transplantation has been available since the early 1980s. It has become an established treatment approach in large centers as a result of research in the areas of organ preservation, bridging procedures to transplantation, and follow-up care. This article provides an overview of the current state of clinical lung transplantation.

Methods

A selective literature search was carried out in PubMed (1960–2024). The guidelines on lung transplantation of the International Society for Heart and Lung Transplantation (ISHLT) were taken into account.

Epidemiology

It is not possible to provide lung transplantation to an extent that would cover the demand for all patients in Germany with terminal lung disease. Transplantation centers are obliged to select the candidates referred to them based on the criteria of urgency and prospect of success set out in the German Transplant Act (Transplantationsgesetz).

In 2023, 20% of the patients on the waiting list for lung transplantation in Germany either died or were taken off the list (1). This happens when the general condition of the person in question is so poor that successful transplantation becomes unlikely, for example, due to multi-organ failure. In Germany, the number of new entries on the waiting list for lung transplantation is higher than the annual number of procedures carried out (Figure 1). This is due, at least in part, to the legal situation there. In Germany, the concept of “decision solution” applies, that is to say, a person is considered an organ donor when they have given their consent, while still alive, to donate their organs; if not, their next of kin decides. The number of organ donors per 1 million inhabitants in neighboring European countries where what is referred to as the “dissent solution” applies, such as Austria, is comparatively higher and waiting times correspondingly lower. With the “dissent solution,” everyone is considered an organ donor unless they dissented while still alive.

Figure 1

Lung transplantation in Germany in 2023

Candidate selection

Candidate selection poses one of the greatest challenges in transplantation medicine since it has a significant impact on the transplantation outcome. In accordance with the guidelines on lung transplantation pursuant to Section 16 (1) Nos. 2 and 5 of the German Transplant Act, organ transplantation may be medically indicated if diseases irreversibly progress or are caused by a genetic defect and endanger life or severely impair quality of life and can be successfully treated by transplantation (2).

In order to define the optimal timing for transplantation, a group of experts from the International Society for Heart and Lung Transplantation (ISHLT) recommends that the risk of death with and without transplantation be assessed in advance. Based on this, lung transplantation should be considered in adults with a high risk (>50%) of death from lung disease within 2 years and, at the same time, a high likelihood (>80%) of 5-year post-transplant survival (3). It is important that patients be referred to the transplantation center in a timely manner (Table 1).

Table 1

Indications and contraindications for lung transplantation

Prior to transplantation, extensive tests need to be carried out to assess the patient. In addition to instrument-based tests that serve to detect somatic comorbidities, the assessment of psychological/psychiatric and social factors plays an important role (Table 1).

Contraindications

Smoking is a contraindication for lung transplantation. Not only the use of harmful substances but also the dependence syndrome jeopardize long-term success. Abstinence from smoking, including nicotine replacement products and e-cigarettes, for at least 6 months must be documented by a laboratory test (cotinine test). Smoking cessation programs supervised by psychologists are established. Relapses following lung transplantation are the absolute exception. Other contraindications include:

• Malignant disease without a sufficient recurrence-free interval
• Respiratory failure with invasive ventilation or extracorporeal lung support without prior entry on the waiting list
• Colonization with certain treatment-resistant pathogens (for example, Mycobacterium abscessus, Burkholderia cenocepacia).

Age limits have not proved to be a contraindication. Attention is increasingly paid to an individual’s biological age, that is to say, their physical aging status. As a result, some patients are deemed to be suitable candidates after reaching the age of 65 years.

Indications

The most frequent indication group comprises chronic obstructive pulmonary disease (COPD), including alpha-1 antitrypsin deficiency, various forms of interstitial lung disease, and cystic fibrosis (Table 1). Having said that, new pharmacological treatment options for cystic fibrosis have largely precluded the need for transplantation (4). Likewise for pulmonary arterial hypertension, there is now an effective drug in the form of sotatercept that is able to delay transplantation (5). Other indications for lung transplantation include bronchiectasis and, in highly selected cases, acute respiratory failure, for example, in COVID-19 (6, 7) (Table 1).

Once an evaluation has been completed, an interdisciplinary transplantation conference decides whether or not a patient is added to the waiting list. The aim here is to ensure that patients are allocated on a success-oriented basis, in addition to the individual benefits of transplantation. This concept is also used in the allocation system known as the lung allocation score (LAS), which has been in effect since 2011 and takes into account not only urgency but also the prospect of success. The LAS is calculated on the basis of current medical data and the underlying type of lung disease. Age, height, weight, and the primary disease are also taken into consideration, as are the severity of the lung function disorder and the ability to carry out everyday activities. Taken together, this information determines the urgency of lung transplantation and the prospects of success on a case-by-case basis. The introduction of the LAS has reduced mortality among patients on the waiting list (8).

Organ allocation is coordinated by the Eurotransplant Foundation, which has its headquarters in Leiden, the Netherlands, and is based on LAS, blood group, size, and regional factors.

Donor selection, donor criteria, and explantation

To assess the suitability of donor organs, a number of quality criteria are evaluated, such as the donor’s age, preexisting diseases, cause of death, and organ function. Size compatibility between donor and recipient are also assessed. Since a difference in size is associated with an unfavorable outcome, it is essential that the underlying lung disease, which may be accompanied by either shrinking (pulmonary fibrosis) or expansion of the thorax (lung emphysema), is also taken into account alongside body size in order to achieve a qualified match.

Due to the shortage of organs and as a result of the greater experience gained at large transplantation centers, the acceptance criteria for donor lungs have been extended without this having a negative impact on long-term outcomes following transplantation (9).

Donation after circulatory death (DCD) is now established for lung donation in many countries, given that it has achieved similar results following lung transplantation (10). This approach cannot be taken in Germany since, by law, brain death is the requirement for organ donation.

Lung retrieval is carried out as part of multi-organ removal at the donor hospital by the cardiothoracic team from the recipient center. Following median sternotomy, the pericardium and pleura are opened and the thoracic organs are directly inspected. Based on a consideration of all findings, including imaging and blood–gas analysis, the lungs are then either accepted for transplantation or rejected. The lungs are perfused with a dextran-containing preservation solution, retrieved, and packed on ice for transportation to the recipient center. Between 8 and 12 h are tolerable ischemic times (11).

Implantation techniques

Unilateral lung transplantation is generally possible in COPD or lung fibrosis, assuming the patient does not have high-grade pulmonary hypertension. The latter as well as colonization of the lungs by pathogenic micro-organisms (for example, in bronchiectasis) necessitate the transplantation of both lungs. Bilateral lung transplantation is associated with better long-term outcomes. Therefore, unilateral lung transplantations are mainly performed in patients of advanced age and with previous surgeries and comorbidities (coronary heart disease [CHD]), since there is less surgical trauma and convalescence is generally faster.

Bilateral lung transplantation is carried out either via bilateral anterolateral thoracotomy or transverse thoracosternotomy (clamshell incision). Double lung transplantation is performed sequentially, that is, first one side, then the other. Following resection of the diseased lungs, the donor lungs are implanted with three anastomoses: bronchus, left atrium (pulmonary veins), and pulmonary artery. The perioperative use of extracorporeal life support (ECLS) makes it possible to achieve 100% hemodynamic and pulmonary stability during the procedure. ECLS drains blood from the right atrium and returns it, oxygenated, to the aorta.

In children, living-donor lung transplantation is an option whereby two relatives each donate one lower lobe for implantation (12). However, only a handful of centers worldwide (primarily in Japan) offer this highly complex intervention. Living-donor transplantation has immunological advantages when carried out between relatives. Moreover, it eliminates the negative effects of brain death on the donor organ (inflammation), and the ischemic times of the donor organ are usually short due to the fact that donor and recipient are in the same hospital. As a result, living-donor lung transplantation has very good results in Japan (5-year survival of 74.1% [12]). Alternatively, in individual cases, there is the option in children to accept a larger organ and perform an atypical or anatomical lobectomy in order to reduce the waiting time for a suitable organ. The 5-year survival rate in Europe following pediatric lung transplantation is 52% (13). On average, the children need to undergo retransplantion after this period.

The combined heart–lung transplantation that was frequently performed in the past for pulmonary hypertension is indicated today only in complex, difficult-to-correct heart defects and Eisenmenger syndrome, for example, pulmonary atresia with ventricular septal defect (VSD) and multifocal lung perfusion (14). Eisenmenger syndrome involves pulmonary vascular changes that cause pulmonary hypertension and, as a result, lead to a right-to-left shunt reversal. It is the long-term sequela of an untreated left-to-right shunt. For idiopathic pulmonary hypertension, only double lung transplantations are performed today, since the right heart has high regenerative potential and right heart dilatation can recede.

The abovementioned procedures last between 3 and 10 h, depending on whether:

• A single or double lung/heart–lung transplantation is performed
• Surgery is performed with or without the use of ECLS/ECMO
• The recipient has been previously operated and adhesions are present or not.

Bridging procedures

In patients with severe respiratory failure, preoperative venovenous extracorporeal membrane oxygenation (ECMO) may be indicated to treat hypoxia and/or hypercapnia. Ideally, this is carried out as “awake ECMO” so as to avoid the negative effects of invasive ventilation and analgosedation and enable patients to receive physiotherapy. The latter serves to improve patients’ physical condition prior to transplantation.

Venovenous ECMO can sometimes continue for months without complications, whereas venoarterial ECMO is often fraught with complications after only 2 weeks (bleeding, thromboembolism).

In the case of pulmonary arterial hypertension, venoarterial ECLS—for example, via femoral vessel cannulation—can be considered in order to prevent right heart failure.

Postoperative intensive care

The greatest postoperative problem is primary graft dysfunction (PGD). This is often caused by reperfusion edema and treated with negative fluid balance, inhaled nitric oxide (NO), and ventilatory support. The proactive use of intra- and postoperative ECMO, by regulating blood flow, allows the transplanted graft to gently adapt to the new conditions. For 75% of patients, the hospital length of stay is up to 25 days (15).

Follow-up care

Immunosuppressive therapy following lung transplantation comprises a calcineurin inhibitor, a purine synthesis antagonist, and prednisolone. This combination is intended to prevent acute and chronic cellular and humoral responses against the transplanted graft. With regard to calcineurin inhibitors, tacrolimus has proven superior to cyclosporine in terms of the occurrence of chronic rejection: In a randomized controlled study with 249 patients, 39% in the cyclosporine group but only 13% in the tacrolimus group developed chronic graft dysfunction at 3 years following lung transplantation (16). As yet, none of the available combination partners has been shown to be superior. Mycophenolate mofetil is the drug most commonly used here, followed by azathioprine and one of the available mTOR inhibitors (for example, everolimus) (17). Particularly immunocompetent patients (children and adolescents) or sensitized individuals (HLA antibodies) receive induction therapy (for example, with antithymocyte globulin, basiliximab, or alemtuzumab). This offers better protection against rejection, but carries a somewhat higher risk for infections as the cause of death (30% for alemtuzumab versus 22% when no induction therapy is given) (18).

Calcineurin inhibitors are dosed according to trough levels. A starting dose for orientation (although extremely variable from person to person) is 0.1 mg/kg body weight/day. Target levels are overall higher compared to other solid organ transplantations (target level in the 1st year: 10–15 ng/mL) since the lungs are considered to be a particularly immunocompetent organ. The more intensive immunosuppression is therefore associated with a higher rate of adverse effects and long-term sequelae. The increased risk for opportunistic infectious diseases and protracted courses of pathogen infection are often associated with early morbidity and mortality. Infection prevention includes consistent active immunizations before and after transplantation, hygiene measures, and universal antimicrobial prophylaxis against Pneumocystis jirovecii pneumonia as well as cytomegalovirus (CMV) and fungal infections.

One long-term consequence—and meanwhile the most common cause of death after chronic rejection—is the occurrence of cancers (lymphomas, skin tumors), which are difficult to treat in the transplantation context. Other side effects such as the increased risk for thromboembolic events, arterial hypertension, hypercholesterinemia, and polyneuropathy highlight the need for an interdisciplinary treatment approach in this patient collective.

In addition to the monitoring of immunosuppressive therapy, the surveillance of graft function also plays a crucial role. Following lung transplantation, regular lung function tests, imaging (primarily computed tomography) as well as the analysis of cells and tissue taken during bronchoscopy are performed. Spirometric determination of forced expiratory volume per second also plays and important role. The additional use of body plethysmography enables the early and reliable diagnosis of restrictive or complex ventilation disorders (Figure 2). In order to likewise detect occult cellular and humoral transplant rejection, structured surveillance bronchoscopy has become established, affecting clinical decision-making in 20% of cases (19). In addition to monitoring organ function, follow-up care should also take extrapulmonary aspects into consideration in a structured manner (Box).

Box

Elements of multimodal follow-up care after lung transplantation

Figure 2

Lung function following transplantation

Long-term results and quality of life

Survival following lung transplantation is well studied in Germany thanks to the federal quality assurance carried out for up to 3 years following transplantation (20). In 2019, the 3-year survival rate was 73%; at the two largest German lung transplantation centers (Hannover Medical School [MHH] and the Ludwig Maximilian University of Munich [LMU]), 1-year survival is 92% (MHH) and 91% (LMU), respectively, and 5-year survival 72% (MHH) and 73% (LMU), respectively. Data from the ISHLT registry show a median survival time following lung transplantation, depending on age, of between 4.8 (in over-60-year-olds) and 7 years (21). The main causes of death following lung transplantation include, in descending order, chronic graft failure, infections, cancer, and cardiovascular disease. Chronic lung allograft dysfunction (CLAD) is characterized by a progressive, usually obstructive ventilation disorder with a steady decline in forced expiratory volume in 1 s (FEV₁) and subsequent respiratory failure (Figure 2). Comorbidities (kidney failure, diabetes mellitus, and osteoporosis) are also very common, particularly in the long term (Table 2).

Table 2

Cumulative frequencies of morbidities following lung transplantation in adults, according to the ISHLT

Quality of life significantly improves in the vast majority of patients following lung transplantation. Data prospectively collected in patient surveys at individual centers in the USA (22) and Canada (23) describe quality of life that is, on average, comparable to the respective national reference dataset for up to 5 years post-transplantation. Thereafter, it is comorbidities in particular that impair quality of life. Approximately 40% of lung transplant patients are in employment; among young transplant patients (mean of 29 years) with cystic fibrosis in Switzerland, the percentage at 1 year post-transplantation was between 64 and 75% (24).

Outlook

Future developments will aim to improve candidate selection while taking into account new insights, such as genetic changes and anthropometric factors. In order to reduce waitlist mortality, the medium-term goal, in addition to better risk stratification, is to expand the donor pool through the acceptance of marginal organs.

The tailoring of immunosuppression is also challenging; it influences the main causes of death associated with too little or too much immunosuppressive therapy. Increased immunosuppression can prevent chronic rejection to only a certain extent. The goal is to achieve the lowest possible level necessary to preserve graft function in order to minimize the burden of side effects and long-term sequelae. The determination of torque teno virus (TTV) in peripheral blood is suitable for the management of immunosuppressive therapy. This non-pathogenic virus is found in all immunocompromised patients, and viral load serves as a marker for the level of immunosuppression (25).

Other promising tools for the detection of graft dysfunction include new methods to monitor graft function by measuring donor-derived cell-free DNA (dd cfDNA) in serum (26).

In the long term, one of the major goals is the use of alternative lung replacement approaches. Here, advances are being made in xenotransplantation (27), as well as in the bioengineering of functional, transplantable organs.

Conflict of interest statement

JG is on the DSMB of the ScanCLAD study.

The remaining authors declare that no conflict of interest exists.

Manuscript received on 21 March 2024, revised version accepted on 28 October 2024.

Translated from the original German by Christine Rye.

Corresponding author
Prof. Dr. med. Sebastian Michel

Herzchirurgische Klinik, LMU Klinikum

Marchioninistrasse 15, 81377 München, Germany

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