A narrative review on the management of patients awaiting lung transplantation in Japan

Introduction

Background

Lung transplantation is an established procedure for patients with end-stage respiratory failure. However, the shortage of donor lungs is one of the most critical issues in lung transplantation, which is a particularly serious problem in Japan. Although the number of brain-dead donors and lung transplantations has increased since the revised Japanese transplantation law took effect in 2010 (1), the number of newly registered candidates for lung transplantation has increased at a pace far exceeding the number of donors. The average waiting time was more than 900 days, resulting in a nearly 50% mortality rate on the waiting list. Marginal or extended criteria lungs have sometimes been used, considering the recipient’s condition. However, lung transplantation in Japan shows favorable outcomes, with 5-year survival rate was 73.72% for cadaveric lung transplantation and 73.84% for living lung transplantation (2), which is getting better year by year (3-5) and also better than that reported by the International Society for Heart and Lung Transplantation registry.

Objective

Favorable outcomes of lung transplantation in Japan can be attributed to several factors, but there is no doubt that management during waiting periods is important. This article reviews the management of candidates listed for lung transplantation, especially in Japan. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1690/rc).

Methods

A literature search was conducted via PubMed in November 2022 using the following keywords: lung transplantation, waiting, management, recipient, and Japan from 2000 to 2022 (Table 1). Eleven papers were retrieved by search. We have also added the peer-reviewed paper from Japan which is related to the management of patients who are waiting on the list for lung transplantation selected by 2 authors. We may have missed some important literature. Peer-reviewed academic journal articles published in English including International Society for Heart and Lung Transplantation registry report were also included.

Results

Listing and de-listing candidates

An age limitation is enforced for recipients of lung transplantation in Japan, due to severe donor shortage. At the time of registration to be on the waiting list, the recipient must be under 60 for a single lung transplantation or under 55 for a bilateral lung transplantation. To save as many recipients as possible from one donor, single lung transplantation is a priority in Japan. Unless the candidates have pulmonary artery hypertension (PAH) or chronic respiratory infection, a single lung transplantation is usually the first option, and a bilateral lung transplantation is the second option. There is no priority system such as allocation system, based on severity or urgency in Japan. Once candidates are on the list, they must wait their turn. Due to the extremely long waiting time, earlier registration may be necessary in considering disease progression and age, rather than the timing of registration presented internationally (6). Once a recipient is enrolled, we may consider removing them from the waiting list if they no longer meet the eligibility criteria during the waiting time, such as when a vital organ remains irreversibly damaged, a malignancy which is difficult to treat, is diagnosed, rehabilitation is not possible after transplantation, or family members are not available.

Assessment of infections

Chronic infections or colonization with resistant organisms are sometimes a problem for lung transplantation and may be contraindications to lung transplantation. This problem is particularly important in patients with bronchiectasis, such as cystic fibrosis, which is uncommon in Japan, or diffuse panbronchiolitis (DPB) (7). Aspergillus species (8), nontuberculous mycobacteria (8), and multidrug-resistant bacteria, such as Burkholderia species or Pseudomonas aeruginosa, are sometimes cultured from these patients (9). These patients tend to have a more rapid decline in respiratory function during the waiting period (10). In addition to sinus surgery and nasal care for chronic rhinosinusitis, long-term macrolide antibiotic therapy has been shown to significantly improve the survival of patients with DPB (11).

Pulmonary complications after hematopoietic stem cell transplantation (HSCT)

HSCT is a highly invasive treatment for hematologic malignancies. Late-onset noninfectious pulmonary complications (LONIPCs) are life-threatening complications after HSCT. Five types LONIPICs were reported, including bronchiolitis obliterans (BOs), BOs with organizing pneumonia, diffuse alveolar damage, lymphocytic interstitial pneumonia, and non-classifiable pneumonia (12). Pleuroparenchymal fibroelastosis (PPFE) has been reported as an LONIPIs. Some patients with PPFE suffer from recurrent pneumothorax, which is resistant to treatment, leading to poor prognosis. Lung transplantation is not indicated for up to 2 years after the eradication of a hematological malignancy, and a disease-free interval of 5 years is ideal. In addition, there must be no severe damage to vital organs such as the liver and kidneys, and no uncontrollable graft versus host disease (GVHD). If the condition progresses too quickly to wait for a cadaveric lung transplant, living donor lung transplantation is considered according to the standards of each transplantation center. In fact, a report from Japan found that 17 patients received a cadaveric lung transplant while 45 patients received a living donor lung transplant (13).

Management of registered disease-specific treatment

Interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD) are the major registered respiratory diseases for lung transplantation in the world. However, lung transplantation is rarely performed in patients with other end-stage lung diseases, such as lymphangioleiomyomatosis (LAM) or PAH (14). In Japan, ILD, LAM, and COPD are common indications for single-lung transplantation, and PAH, ILD, and bronchiectasis are common indications for bilateral lung transplantation. Cystic fibrosis is a rare disease in Japan, and COPD is not a major indication due to the upper age limit, which is less than 55 years old for bilateral lung transplantation and 60 years old for single lung transplantation. Non-infectious pulmonary complications after HSCT are important cause of morbidity and mortality. Lung transplantation is one of the treatments option for selected HSCT recipients. To reduce the mortality rate of these patients on the waiting list, proper pre-transplantation management is very important.

ILD

ILD is a major indication for lung transplantation in Japan. Approximately one-third of ILD patients underwent cadaveric lung transplantation, whereas approximately 50% died while on the waiting list regardless of their specific diagnosis (15). This outcome is similar to the mortality rate of all Japanese candidates on the waiting list (16). Idiopathic PPFE and LONIPC with radiological PPFE has better survival on the wait list for lung transplantation than fibrotic ILD without radiological PPFE (17). A history of pneumothorax and a short 6-min walk distance were independent predictors of waitlist mortality in lung transplantation candidates with ILD. Recent advances in antifibrotic therapy may potentially reduce mortality in patients with ILD on the waiting list for lung transplantation (16).

LAM

LAM is a rare neoplastic disease characterized by the proliferation of abnormal smooth muscle-like cells, leading to cystic destruction of the lungs. Due to its rarity, LAM was a minor indication (0.9%) for lung transplantation in an international survey (18). However, it is one of the major indications (approximately 20%) in Japan. The prognosis after registration was similar to that after lung transplantation, which is 73.7% survival rate at 5 years, being favorable in LAM patients. Greater use of sirolimus is expected to improve the circumstances of pre-transplantation life in patients with advanced LAM (19).

PAH

PAH is a common indication for bilateral lung transplantation and the fourth leading cause of necessity for lung transplantation worldwide. Recent developments in PAH-specific drugs, such as prostacyclin, phosphodiesterase-5 inhibitors, endothelin receptor antagonists, soluble guanylate cyclase stimulators, and prostacyclin receptor agonists, have substantially improved the prognosis of PAH. Only about 10% of PAH patients died within 1 year after diagnosis of PAH. Even after registration for lung transplantation, patients receiving prostacyclin infusion soon after PAH diagnosis had a marked reduction in pulmonary artery pressure and long-term survival before lung transplantation (20). Nocturnal hypercapnia is prevalent among patients with advanced PAH who are waiting for lung transplantation and is associated with a percentage of total lung capacity (21).

Mechanical ventilation or extracorporeal membrane oxygenation (ECMO)

The lung allocation score (LAS) system was implemented in the United States in 2005. The number of patients who undergo lung transplantation while on mechanical ventilation or ECMO has increased. The purpose of the LAS system is to reduce waiting time and mortality and prioritize patients based on urgency (22). In contrast, the algorithm for donor lung allocation in Japan is based primarily on accrued time on the waiting list, which favors patients with slowly progressive diseases rather than rapidly progressive diseases (23). ECMO has been increasingly used as a bridge to lung transplantation since most patients undergo lung transplantation within a few weeks. However, the waiting time is longer in Japan owing to the severe shortage of donors. The indication of ECMO as a bridge to transplant is quite rare, and only a few cases have been reported (24).

Malignancy

Screening for malignancy is essential when considering the indications for lung transplantation. The risk of malignancy recurrence should be considered in patients with a history of cancer prior to registration. Although malignancy with a high risk of recurrence is a contraindication to transplantation, patients with a low risk of recurrence are candidates for lung transplantation. Pre-transplantation malignancy was associated with the risk of de novo malignancy after lung transplantation (25) but was not associated with an increased risk of mortality at 5 years (26). According to the Japanese national survey, de novo malignancy after lung transplantation was 10.1% and post-transplant lymphoproliferative disorder (PTLD) was the most common malignancy (27). PTLD occurred after both living-donor lobar lung transplantation and cadaveric lung transplantation (28). Among 40 cases undergoing lung transplantation after HSCT, 13 patients who had less than 5 years of disease-free interval experienced no recurrence (29). The waiting time is apparently longer than that in other countries, and periodic screening for malignancy might be important in Japan.

Nutrition

The nutritional status of patients on the waiting list is related to post-transplant survival. Several studies have identified obesity (30), low body mass index (31) and low serum albumin concentration (32) as significant risk factors for mortality after lung transplantation. Immunosuppressive therapy after lung transplantation can exacerbate the pre-existing risk of infection in patients with malnutrition. Physicians in charge need to optimize the nutritional status of these patients with lifestyle changes, appropriate steroid tapering, nutritional counseling, and dietary modifications (14).

Rehabilitation

Although respiratory function can improve after lung transplantation, which takes up to 6 months (33), exercise capacity may not return to normal after 18 months (34). This might be associated with the negative effect of chronic underlying diseases, mostly musculoskeletal and cardiopulmonary function. Pre-transplant rehabilitation could contribute to improving muscle strength, enhancing exercise capacity, and reducing dyspnea. This would positively influence the candidate’s health-related quality of life (HRQOL) (35). Pre-transplant rehabilitative interventions mainly focus on motor and breathing exercises (36) and have been integrated into an education program. Lung transplant candidates should be encouraged to attend pre-transplant rehabilitation to preserve and improve their HRQOL (37).

Psychosocial assessment

Lung transplant candidates are screened for psychological problems that may cause poor adherence to the management of lung transplants, such as medication or rehabilitation. Patients with end-stage respiratory diseases tend to experience more depression or anxiety over their lifetime (38). Lung transplant candidates could become more fearful of death during the waiting time and tend to be emotionally unstable (39). Even if transplantation is successful, anxiety and fear of problems, such as rejection or infection, will follow. Therefore, psychiatric and psychosocial aspects, as well as family support, are extremely important throughout the pre- and post-transplant periods.

Quality of life

The ultimate goal of lung transplantation is not only to improve survival but also to improve functional outcomes. Improving the HQROL of end-stage lung disease is an important aspect of the physical, psychological, and social limitations due to severe respiratory disease. Poor sleep quality due to anxiety and respiratory symptom was common among candidates who were on the waitlist in Japan (40). Since it is the most appropriate evaluation or questionnaire to assess HQROL, some studies have been reported. Both modified Medical Research Council dyspnea and St. George’s Respiratory Questionnaire scores were significantly associated with waitlist mortality (41). Another study showed that the Maugeri Respiratory Failure Questionnaire-26 and the Severe Respiratory Insufficiency Questionnaire were effective and useful measures of HRQOL (42). These parameters can be utilized to improve the allocation system or waiting period mortality in the future.

Inactive system

The Japanese organ-transplant registration system allows recipients to self-determine whether they want to have an “inactive status”, i.e., temporary removal from the waiting list for lung transplantation; when they prefer restoration to an “active status”, they can resume their position on the waiting list where they were originally registered. Common reasons for an inactive status are the stable conditions of recipients with medical care, and the clinical features of LAM patients with a history of inactive status have also been reported (19). Currently the outcome of treatment for PAH has improved, there are many patients of PAH with inactive status. The patients of PAH had higher mortality risk in the first 3 months after lung transplantation than other major diagnoses (18), they need to think about the timing of lung transplantation or optimal drug therapy (43).

Conclusions

The survival outcome of lung transplantation in Japan is favorable, but major concerns are the long waiting time and high mortality rate during the waiting period. Pre-transplant management of candidates is important to improve transplant outcomes by increasing the probability of patients reaching transplantation. It is important to provide proper and multifaceted support by various professionals to reduce mortality while patients are on the waiting list.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Masaaki Sato) for the series “Why is the Outcome Good? Secrets of Lung Transplantation in Japan” published in Journal of Thoracic Disease. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1690/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1690/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1690/coif). The special series “Why is the Outcome Good? Secrets of Lung Transplantation in Japan” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Egawa H, Tanabe K, Fukushima N, et al. Current status of organ transplantation in Japan. Am J Transplant 2012;12:523-30. [Crossref] [PubMed]
2. The Japanese Society of lung and heart-lung transplantation in 2022. Available online: http://www2.idac.tohoku.ac.jp/dep/surg/shinpai/pg185.html
3. Bando T, Date H, Minami M, et al. First registry report: lung transplantation in Japan: The Japanese Society of Lung and Heart-Lung Transplantation. Gen Thorac Cardiovasc Surg 2008;56:17-21. [Crossref] [PubMed]
4. Oto T, Okada Y, Bando T, et al. Registry of the Japanese society of lung and heart-lung transplantation: the official Japanese lung transplantation report 2012. Gen Thorac Cardiovasc Surg 2013;61:208-11. [Crossref] [PubMed]
5. Sato M, Okada Y, Oto T, et al. Registry of the Japanese Society of Lung and Heart-Lung Transplantation: official Japanese lung transplantation report, 2014. Gen Thorac Cardiovasc Surg 2014;62:594-601. [Crossref] [PubMed]
6. Leard LE, Holm AM, Valapour M, et al. Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2021;40:1349-79. [Crossref] [PubMed]
7. Chen F, Hasegawa S, Bando T, et al. Recurrence of bilateral diffuse bronchiectasis after bilateral lung transplantation. Respirology 2006;11:666-8. [Crossref] [PubMed]
8. Tachibana K, Okada Y, Matsuda Y, et al. Nontuberculous mycobacterial and Aspergillus infections among cadaveric lung transplant recipients in Japan. Respir Investig 2018;56:243-8. [Crossref] [PubMed]
9. Chalermskulrat W, Sood N, Neuringer IP, et al. Non-tuberculous mycobacteria in end stage cystic fibrosis: implications for lung transplantation. Thorax 2006;61:507-13. [Crossref] [PubMed]
10. Lechtzin N, John M, Irizarry R, et al. Outcomes of adults with cystic fibrosis infected with antibiotic-resistant Pseudomonas aeruginosa. Respiration 2006;73:27-33. [Crossref] [PubMed]
11. Sugimoto S, Miyoshi K, Yamane M, et al. Lung transplantation for diffuse panbronchiolitis: 5 cases from a single centre. Interact Cardiovasc Thorac Surg 2016;22:679-81. [Crossref] [PubMed]
12. Palmas A, Tefferi A, Myers JL, et al. Late-onset noninfectious pulmonary complications after allogeneic bone marrow transplantation. Br J Haematol 1998;100:680-7. [Crossref] [PubMed]
13. Chen-Yoshikawa TF, Sugimoto S, Shiraishi T, et al. Prognostic Factors in Lung Transplantation After Hematopoietic Stem Cell Transplantation. Transplantation 2018;102:154-61. [Crossref] [PubMed]
14. Adegunsoye A, Strek ME, Garrity E, et al. Comprehensive Care of the Lung Transplant Patient. Chest 2017;152:150-64. [Crossref] [PubMed]
15. Ikezoe K, Handa T, Tanizawa K, et al. Prognostic factors and outcomes in Japanese lung transplant candidates with interstitial lung disease. PLoS One 2017;12:e0183171. [Crossref] [PubMed]
16. Nagata S, Ohsumi A, Handa T, et al. Assessment of listing criteria for lung transplant candidates with interstitial lung disease. Gen Thorac Cardiovasc Surg 2023;71:20-6. [Crossref] [PubMed]
17. Tanizawa K, Handa T, Kubo T, et al. Clinical significance of radiological pleuroparenchymal fibroelastosis pattern in interstitial lung disease patients registered for lung transplantation: a retrospective cohort study. Respir Res 2018;19:162. [Crossref] [PubMed]
18. Khush KK, Cherikh WS, Chambers DC, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult heart transplantation report - 2019; focus theme: Donor and recipient size match. J Heart Lung Transplant 2019;38:1056-66. [Crossref] [PubMed]
19. Ando K, Okada Y, Akiba M, et al. Lung Transplantation for Lymphangioleiomyomatosis in Japan. PLoS One 2016;11:e0146749. [Crossref] [PubMed]
20. Akagi S, Matsubara H, Nakamura K, et al. Marked Reduction of Pulmonary Artery Pressure After Registration for Lung Transplantation Is Associated With Long-Term Survival in Patients With Pulmonary Arterial Hypertension - Cohort Study. Circ J 2020;84:245-51. [Crossref] [PubMed]
21. Nakatsuka Y, Chen-Yoshikawa T, Kinoshita H, et al. Nocturnal hypercapnia with daytime normocapnia in patients with advanced pulmonary arterial hypertension awaiting lung transplantation. PLoS One 2020;15:e0227775. [Crossref] [PubMed]
22. McShane PJ, Garrity ER Jr. Impact of the lung allocation score. Semin Respir Crit Care Med 2013;34:275-80. [Crossref] [PubMed]
23. Date H. Current status and problems of lung transplantation in Japan. J Thorac Dis 2016;8:S631-6. [Crossref] [PubMed]
24. Yoshiyasu N, Sato M, Anraku M, et al. Lung transplant after long-term veno-venous extracorporeal membrane oxygenation: a case report. J Cardiothorac Surg 2021;16:246. [Crossref] [PubMed]
25. Sekowski V, Jackson K, Halloran K, et al. Pre-transplant malignancy is associated with increased risk of de novo malignancy post-lung transplantation. Respir Med 2022;197:106855. Erratum in: Respir Med 2022;200:106914. [Crossref] [PubMed]
26. Beaty CA, George TJ, Kilic A, et al. Pre-transplant malignancy: an analysis of outcomes after thoracic organ transplantation. J Heart Lung Transplant 2013;32:202-11. [Crossref] [PubMed]
27. Miyazaki T, Oto T, Okumura M, et al. De novo malignancy after lung transplantation in Japan. Gen Thorac Cardiovasc Surg 2016;64:543-8. [Crossref] [PubMed]
28. Tanaka S, Chen-Yoshikawa TF, Yamada T, et al. Malignancies after living-donor and cadaveric lung transplantations in Japanese patients. Surg Today 2016;46:1415-9. [Crossref] [PubMed]
29. Noguchi M, Chen-Yoshikawa TF, Arai Y, et al. Expanded indications for lung transplantation for pulmonary complications after hematopoietic stem cell transplantation. J Thorac Cardiovasc Surg 2022;163:1549-57.e4. [Crossref] [PubMed]
30. Allen JG, Arnaoutakis GJ, Weiss ES, et al. The impact of recipient body mass index on survival after lung transplantation. J Heart Lung Transplant 2010;29:1026-33. [Crossref] [PubMed]
31. Komatsu T, Chen-Yoshikawa TF, Oshima A, et al. Severe underweight decreases the survival rate in adult lung transplantation. Surg Today 2017;47:1243-8. [Crossref] [PubMed]
32. Oshima A, Nishimura A, Chen-Yoshikawa TF, et al. Nutrition-related factors associated with waiting list mortality in patients with interstitial lung disease: A retrospective cohort study. Clin Transplant 2019;33:e13566. [Crossref] [PubMed]
33. van Adrichem EJ, Reinsma GD, van den Berg S, et al. Predicting 6-minute walking distance in recipients of lung transplantation: longitudinal study of 108 patients. Phys Ther 2015;95:720-9. [Crossref] [PubMed]
34. Ambrosino N, Bruschi C, Callegari G, et al. Time course of exercise capacity, skeletal and respiratory muscle performance after heart-lung transplantation. Eur Respir J 1996;9:1508-14. [Crossref] [PubMed]
35. Pehlivan E, Balcı A, Kılıç L, et al. Preoperative Pulmonary Rehabilitation for Lung Transplant: Effects on Pulmonary Function, Exercise Capacity, and Quality of Life; First Results in Turkey. Exp Clin Transplant 2018;16:455-60. [Crossref] [PubMed]
36. Sato T, Sato S, Oshima Y, et al. Impact of inspiratory muscle strength on exercise capacity after lung transplantation. Physiother Res Int 2022;27:e1951. [Crossref] [PubMed]
37. Polastri M, Dell'Amore A, Eden A, et al. Does Preoperative Rehabilitation Influence the Quality of Life in Patients Who Are Candidates for Lung Transplant? Exp Clin Transplant 2022;20:543-8. [Crossref] [PubMed]
38. Woodman CL, Geist LJ, Vance S, et al. Psychiatric disorders and survival after lung transplantation. Psychosomatics 1999;40:293-7. [Crossref] [PubMed]
39. Parekh PI, Blumenthal JA, Babyak MA, et al. Psychiatric disorder and quality of life in patients awaiting lung transplantation. Chest 2003;124:1682-8. [Crossref] [PubMed]
40. Tokuno J, Oga T, Chen-Yoshikawa TF, et al. Sleep quality and its association with health-related quality of life of patients on lung transplantation waitlist in Japan. Sleep Breath 2021;25:219-25. [Crossref] [PubMed]
41. Ikeda M, Oga T, Chen-Yoshikawa TF, et al. Patient-reported dyspnea and health predict waitlist mortality in patients waiting for lung transplantation in Japan. Respir Res 2021;22:116. [Crossref] [PubMed]
42. Tokuno J, Chen-Yoshikawa TF, Oga T, et al. Analysis of Optimal Health-Related Quality of Life Measures in Patients Waitlisted for Lung Transplantation. Can Respir J 2020;2020:4912920. [Crossref] [PubMed]
43. Maki H. Should Patients Choose Lung Transplantation or Optimal Drug Therapy? - The Clinical Situation in the Treatment of Pulmonary Arterial Hypertension in Japan. Circ J 2020;84:158-60. [Crossref] [PubMed]