Lung Transplantation In Japan Research Articles

Patient selection, surgery and perioperative management in lung transplantation in Japan.

Lung transplantation (LT) is the final treatment option for end-stage respiratory diseases. The current prognosis of LT recipients in Japan is good, however, the reason for the good prognosis is unclear. In Japan, the waiting time for cadaveric LT is long, which is approximately 900 days on average. A long waiting time affects several aspects of LT. The diseases progress while they await LT in most patients are waiting for LT. Along with the disease progression of the disease, secondary pulmonary hypertension can newly emerge. Some patients suffer from refractory secondary pneumothorax and may receive pleurodesis. Transplant operations can become more difficult, and postoperative management becomes more complicated owing to the disease progression. Thoracic surgeons in Japan have managed the tough difficult situation of LT patients with LT. Possible explanations for how we to maintain a better prognosis in such a situation include sophisticated surgical techniques and ideas, and vigorous postoperative management by thoracic surgeons. Thoracic surgeons are vigorously involved both in operations and in postoperative management in the intensive care unit with or without intensivists in Japan. On the other hand, the long waiting time in Japan and allocation rules with age restriction without considering the severity of patients may have resulted in the selection of recipients to include relatively young recipients, fewer patients with interstitial lung disease and fewer recipients with extracorporeal membrane oxygenation (ECMO) as a bridge to LT. These recipients' characteristics possibly may have affected the prognosis of LT patients with LT in Japan. There is a chance that a future increase in the number of cadaveric donors in Japan may result in a prognosis close that is similar to the international average if the current waiting time in Japan decreases. We review patient selection, surgery and perioperative management in LT in Japan to address the question of why the current prognosis of LT recipients in Japan is good.

The effect of infectious diseases on lung transplantation in Japan.

Lung transplantation in Japan is an increasingly accessible treatment option for end-stage lung disease; however, the lack of donor organs is a persisting challenge. Five- and 10-year survival rates of lung transplant recipients in Japan are comparable, if not superior, to international standards. The outcomes of lung transplantation in Japan are likely affected by multiple factors. Infectious disease complications are a significant burden to transplant recipients and account for approximately 30% of recipient mortality in Japan, presenting a major challenge in peri-transplant management. Herein, we explore the current status of infectious disease epidemiology, available evidence surrounding infectious diseases in lung transplantation, and potentially influential factors pertinent to lung transplantation outcomes in Japan. Although infection remains the major cause of morbidity and mortality associated with lung transplantation in Japan, there is limited data and evidence. Despite some uncertainties, publicly available data suggests a low rate of antimicrobial resistance in Gram-negative bacteria and a distinct set of endemic pathogens that recipients may encounter. As a countermeasure against the burden of infectious diseases, 8 out of 10 transplant centers in Japan have a dedicated infectious diseases department. Despite these efforts, specific surveillance, prevention, and management are indispensable to improving post-transplantation infectious disease management. We accordingly lay out potential areas for improving infectious disease-related outcomes among lung transplant recipients in Japan.

Effects of case volume on short- and long-term outcomes following cadaveric lung transplantation in Japan.

Despite the low number of lung transplantations (LTs) in Japan, 10 LT facilities are accredited and good outcomes have been reported. A database review was conducted to clarify the impact of case volume at LT facilities in Japan on short- and long-term outcomes. All cadaveric LT cases treated between 2000 and 2021 in Japan were analyzed using the database of the Japanese Society of Lung and Heart-Lung Transplantation (JSLHT). The nine institutions represented were categorized into the low-volume (LV; <80 cumulative LT cases, <8 LTs/year, n=5) and high-volume (HV; ≥80 cumulative LT cases, ≥8 LTs/year, n=4) centers. Ninety-day and 1-year mortality, as well as 5- and 10-year survival data were evaluated. A total of 658 cadaveric LTs were performed at the nine institutions. The 90-day rates of mortality at the HV and LV centers were 3.5% and 3.9%, respectively (P=0.801), while the 1-year mortality rates were 9.2% and 11.5%, respectively (P=0.199). Additionally, log-rank analysis of Kaplan-Meier curves showing case volume did not reveal a significant difference in long-term survival between the HV and LV centers (P=0.272), though the LV centers had wide differences for long-term outcomes (P=0.030). Case volume did not have effects on short- or long-term outcomes following LT in Japan, while there were large variations in long-term outcomes among the LV centers compared to those of the HV centers.

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

The number of lung transplantations performed in Japan is increasing, and post-transplant outcomes are relatively favorable. A major concern is the extremely long waiting time and the high mortality rate on the waitlist. The management of patients before transplantation is very important and essential for further improvement of outcomes. In this review, we summarize the management of patients awaiting lung transplantation in Japan. A literature search was conducted via PubMed in November 2022 using the following keywords: lung transplantation, waiting, management, recipient, and Japan. Peer-reviewed academic journal articles published in English were also included. A growing number of studies have evaluated the management of pre-transplant patients. This includes infection control, vaccination, respiratory disease-specific treatment, malignancy, nutrition, rehabilitation, psychosocial assessment, and health-related quality of life (HRQOL) for patients on the waitlist. Each is important, and various evaluation methods and strategies to improve outcomes have been reported. Proper and multifaceted management of pretransplant patients is extremely important to reduce the mortality of candidates for lung transplantation. Integrated management is crucial to the success and survival of lung transplant recipients.

Roles of respirologists in lung transplantation in Japan: narrative review.

Lung transplantation (LTx) in Japan has taken steps toward increasing the number of donors and recipients and is at the maturity stage of development, at which point pulmonologists (hereinafter referred to as "respirologists") become involved in transplant practice. Because of severe donor shortage and limited number of LTx surgeries, most of transplant process from candidacy evaluation to post-operative management has been handled only by thoracic surgeons, which takes away opportunities from respirologists to manage LTx recipients. Given the growth of both LTx and the number of patients with complex problems, cooperation with respirologists in transplant practice is urgently needed to achieve transplant success in Japan. Authors summarized current transplant circumstance in Japan from the transplant physician's standpoint. A systematic search through PubMed database and Google Scholar was performed by terms of "respirologists", "pulmonologist", "lung transplant" or "Japan" from 2000 and 2022. Thoracic surgeons working at each transplant center were asked to complete a questionnaire on physicians' intervention to LTx. The roles of respirologists in LTx differ with facility size and function, depending on whether they are working at a non-transplant center with other respirologists or at a transplant center with transplant physicians. LTx centers are currently devoted to educating respirologists who work at non-transplant or low-volume transplant centers in order for them to deal with patients before and after transplantation. Joint efforts and training of outstanding personnel who can take care of recipients are required, this being the greatest issue for the success of transplantation in Japan.

Long-term management and outcome of lung transplantation in Japan.

The long-term survival after lung transplantation (LT) is favorable in Japan. However, long-term survivors after LT are subject to late complications, including chronic lung allograft dysfunction (CLAD), malignancy, infection, and chronic kidney disease (CKD) because of the need for lifelong immunosuppression. The rates of single cadaveric LT (CLT) and living-donor lobar LT (LDLLT) are higher than that of bilateral CLT in Japan. Here, we will describe the management of late complications and long-term outcome after LT in Japan. Attention should be paid to not only the phenotype of CLAD but also the difference in CLAD after CLT and after LDLLT as well as the timing of lung re-transplantation for advanced CLAD, especially after single CLT. Since post-transplant lymphoproliferative disorder is the most common malignancy after LT, infection monitoring for infection-related malignancies and appropriate screening are keys to the early diagnosis and treatment of malignancy after LT. The long-term management of infection after LT is also important, especially with regard to community-acquired pathogens, Aspergillus, and cytomegalovirus. When providing long-term care after LT, physicians should be aware of CKD and the timing of renal replacement therapy in cases with severe CKD. The widespread use of computed tomography and dialysis in Japan are beneficial for long-term survivors of LT. The similar survival outcomes of single CLT and LDLLT, compared with bilateral CLT, might contribute to improved long-term survival in Japan. Pulmonologists are encouraged to become further involved in long-term management after LT in Japan.

One-year change in the health status predicts the subsequent hospitalization and mortality in patients waitlisted for lung transplantation in Japan

BackgroundPoor health-related quality of life (HRQL) at the registration for lung transplantation is related to waitlist mortality. We investigated the relationship between 1-year change in HRQL and subsequent outcomes in patients waitlisted for lung transplantation. MethodsIn a 5-year longitudinal study, we analyzed the factors related to waitlist mortality in 197 lung transplant patients registered on the Japan Organ Transplant Network. HRQL was assessed using St. George's Respiratory Questionnaire (SGRQ), and factors related to changes in SGRQ scores were evaluated after 1 year. We assessed the relationship between the 1-year change in SGRQ score and subsequent mortality or hospitalization. ResultsAmong 197 patients, 108 remained waitlisted during the first-year assessment. During the median follow-up period of 469 d, 28 patients died, and 54 underwent lung transplantation. Univariate Cox proportional hazards analysis revealed that the changes in all components and total score of the SGRQ after 1 year were associated with waitlist mortality (p < 0.05). Stepwise multivariate analysis revealed that the 1-year changes in SGRQ scores were significantly related to waitlist mortality. Forty-three patients with worsened HRQL after 1 year had higher likelihoods of hospitalization (p = 0.038) and mortality (p = 0.026) after 1 and 4 years of follow-up, respectively, than 61 patients without worsened HRQL. ConclusionsPatients with worsened health status during the first year after registration had higher likelihoods of hospitalization and mortality after 1 and 4 years of follow-up, respectively, than those without worsened HRQL. Strategies to improve health status while waiting are needed to reduce waitlist hospitalization or mortality.

(78) Indication and Long-Term Outcome of Pediatric Lung Transplantation in Japan; A Multicenter, Retrospective Study

(78) Indication and Long-Term Outcome of Pediatric Lung Transplantation in Japan; A Multicenter, Retrospective Study

Current status of inhaled nitric oxide therapy for lung transplantation in Japan: A nationwide survey

Current status of inhaled nitric oxide therapy for lung transplantation in Japan: A nationwide survey

Current status of inhaled nitric oxide therapy for lung transplantation in Japan: a nationwide survey.

Currently, inhaled nitric oxide (NO) therapy for lung transplantation is not covered by public health insurance in Japan. In this study, we evaluated the perioperative use and safety of inhaled NO therapy for lung transplantation. Data regarding the duration of treatment and adverse events of inhaled NO therapy were collected for all lung transplantations performed from January 1, 2015, to December 31, 2019, at nine lung transplant facilities in Japan. During the study period, lung transplants were performed in 357 patients, among whom inhaled NO therapy was administered to 349 patients (98%). The median initial and median maximum inhaled NO doses were 10 and 20ppm, respectively. Inhaled NO therapy was introduced during surgery and continued postoperatively in 313 patients (90%) for a median of 4days. Significant improvements in oxygenation and decreases in pulmonary arterial pressure were observed in patients receiving inhaled NO therapy. Side effects of inhaled NO therapy, such as methemoglobinemia, were observed in 15 patients (4%), with a significant incidence in patients aged < 18years. Inhaled NO therapy was performed in almost all patients who underwent lung transplantation in Japan and showed reasonable efficacy. Therefore, public health insurance coverage for inhaled NO therapy during lung transplantation is recommended.

Patient-reported dyspnea and health predict waitlist mortality in patients waiting for lung transplantation in Japan

BackgroundWaitlist mortality due to donor shortage for lung transplantation is a serious problem worldwide. Currently, the selection of recipients in Japan is mainly based on the registration order. Hence, scientific evidence for risk stratification regarding waitlist mortality is urgently needed. We hypothesized that patient-reported dyspnea and health would predict mortality in patients waitlisted for lung transplantation.MethodsWe analyzed factors related to waitlist mortality using data of 203 patients who were registered as candidates for lung transplantation from deceased donors. Dyspnea was evaluated using the modified Medical Research Council (mMRC) dyspnea scale, and the health status was determined with St. George’s Respiratory Questionnaire (SGRQ).ResultsAmong 197 patients who met the inclusion criteria, the main underlying disease was interstitial lung disease (99 patients). During the median follow-up period of 572 days, 72 patients died and 96 received lung transplantation (69 from deceased donors). Univariable competing risk analyses revealed that both mMRC dyspnea and SGRQ Total score were significantly associated with waitlist mortality (p = 0.003 and p < 0.001, respectively) as well as age, interstitial lung disease, arterial partial pressure of carbon dioxide, and forced vital capacity. Multivariable competing risk analyses revealed that the mMRC and SGRQ score were associated with waitlist mortality in addition to age and interstitial lung disease.ConclusionsBoth mMRC dyspnea and SGRQ score were significantly associated with waitlist mortality, in addition to other clinical variables such as patients’ background, underlying disease, and pulmonary function. Patient-reported dyspnea and health may be measured through multi-dimensional analysis (including subjective perceptions) and for risk stratification regarding waitlist mortality.

Current status of lung transplantation in Japan—report from Japanese lung transplant registry

Current status of lung transplantation in Japan—report from Japanese lung transplant registry

Ex vivo lung perfusion in lung transplantation.

Lung transplantation is an established life-saving intervention for patients with end-stage lung diseases. The success of lung transplantation mainly depends on the quality and function of the implanted donor lungs, which are frequently subject to brain-death-induced lung injuries and intensive care unit (ICU)-related complications before transplantation. Recent innovations, particularly the development of ex vivo lung perfusion (EVLP), in which donor lungs are ventilated and perfused under normothermic conditions outside the body, have allowed clinicians to more accurately assess the donor lung function prior to transplantation. Therefore, EVLP has been successfully translated into clinical practice with the expansion of the donor lung pool, leading to favorable post-transplant outcomes in a growing number of transplant centers worldwide. The EVLP system and techniques, following the Toronto protocol, have recently been applied for the assessment of extended criteria brain-death donors in clinical lung transplantation in Japan. The advancement of EVLP from organ assessment to organ treatment will be the next challenging stage not only to expand donor lung pool, but also to improve graft survival and long-term outcomes after transplantation.

A growing demand for transplant physicians for lung transplantation in Japan

A growing demand for transplant physicians for lung transplantation in Japan

Current situation of lung transplantation in Japan

: The first lung transplantation (LTx) from a neurologically dead donor (NDD) was performed in 2000 in Japan. This was 2 years after the first LTx from living donors. A total of 250 patients underwent bilateral and 276 patients underwent unilateral LTx procedures from NDDs from then to 2019. The number of LTx s has been increasing since revision of the Japanese organ transplantation law in 2010. However, the shortage of donors and the long waiting time (>2 years) remain problematic. Donation after cardiac death is impractical because controlled death is not permitted in Japan. We challenge the donor shortage with the use of a medical consultant system in which medical consultants give suggestions to the intensivists who care for possible donors, aggressive use of marginal donors such as older donors, smokers, suicidal hanging donors, donors who have contralateral pneumonia, and donors with a long intubation time, preoperative extracorporeal membrane oxygenation support, and living-donor LTx. In total, 234 cases of living-donor LTx were performed. Despite the aggressive use of marginal donors, outcomes in Japan are comparable with international outcomes. Careful assessment of marginal donors and meticulous management of possible donors are important key factors in rescuing as many patients as possible in the currently difficult situation of LTx in Japan.

Sleep quality and its association with health-related quality of life of patients on lung transplantation waitlist in Japan.

Poor quality of sleep is a common feature in patients with various lung diseases and affects their health-related quality of life (HRQL). We evaluated sleep quality and HRQL in patients on the waitlist for lung transplantation in Japan. In this prospective study, patient-reported and physiological data were collected from patients newly registered on the waitlist for lung transplantation in Japan. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI) and HRQL using the St. George's Respiratory Questionnaire (SGRQ). The frequency of poor sleep quality, correlations between sleep quality and various clinical parameters, and predictive factors of sleep quality were examined. Of 193 patients, the three most-frequent indications for lung transplantation were interstitial pneumonia (n = 96), pulmonary complications of hematopoietic stem cell transplantation (n = 25), and pulmonary hypertension (n = 17). Poor sleep quality (PSQI > 5) was observed in 102 patients (53%) and was significantly associated with worse Hospital Anxiety and Depression Score (HADS), worse SGRQ score, worse modified Medical Research Council Dyspnea score, and shorter 6-min walk distance. However, it was not associated with sex, pulmonary function, interstitial pneumonia, or arterial blood gas. Stepwise multiple regression analysis indicated that poor sleep quality was explained significantly by HADS anxiety (23%) and SGRQ Symptoms (10%). Poor sleep quality was found to be common among patients on the lung transplantation waitlist in Japan. The two most significant factors responsible for impaired sleep quality were anxiety and respiratory symptoms. Additional care should be taken to ensuring a better quality of sleep for such patients.

Malignancy after Lung Transplantation in Japan

Malignancy is one of the leading causes of death after organ transplantation. We conducted a national survey of malignancy after lung transplantation among all lung transplant centers in Japan. All recipients who underwent lung transplantation since October 1998 until December 2017 in Japan were retrospectively reviewed. Malignant diseases developed in 41 (6.9%) of 596 lung transplant recipients in 388 brain-dead donor lung transplantation and 208 living donor lobar lung transplantation. Except recurrence of the original malignant diseases (n=4/596, 0.7%) and possible progression after transplantation in cancer-baring recipients (n=5/596, 0.8%), de novo malignancy occurred in 33 patients (5.5%). The most common de novo malignancy was lymphoproliferative disorder (n=16/34, 46%). Compared with the ISHLT registry, we observed far fewer skin cancer (n=1). In terms of the underlying disease for lung transplantation, interstitial pneumonitis (n=13/33, 39%) and lung complication after hematopoietic stem cell transplantation (n=10/33, 30%) were common, suggesting that long-term immunosuppression before and after transplantation has a negative impact on occurrence of de novo malignancy. The average time of occurrence after transplantation was 39 (±38) months. Death due to malignancy occurred in 11/33 (33%). The overall 5-year survival of patients with malignancies after lung transplantation was 49%. In Japan, the most common malignancy after lung transplantation was posttransplant lymphoproliferative disorder. Long-term immunosuppression before and after transplantation can have a negative impact on occurrence of de novo malignancy after lung transplantation.

Analysis of the Change in Sleep Quality in Lung Transplant Recipients

We previously reported that sleep quality is impaired in waitlisted patients for lung transplantation in Japan, and that respiratory symptoms and psychological status were main contributive factors to sleep quality. However, it is unknown whether sleep quality would improve after lung transplantation or not. Then we aim to assess changes in sleep quality and other patient reported measures including health related quality of life (HRQL) after lung transplantation. In this multicentric study, we prospectively collected patient-reported data of 56 lung transplant recipients. We assessed sleep quality using the Pittsburgh Sleep Quality Index (PSQI), HRQL using the St. George's Respiratory Questionnaire (SGRQ), psychological status using Hospital Anxiety and Depression Scale (HADS) and dyspnea using modified Medical Research Council Dyspnea Scale (mMRC). We then examined the changes in sleep quality, HRQL, psychological status and dyspnea within about one year after lung transplantation. We also assessed PSQI subscale scores to examine the details of changes in sleep quality. Interstitial pneumonia (n=24), pulmonary complication after post hematopoietic stem cell transplantation (n=8), chronic obstructive pulmonary disease (n=7) and lymphangioleiomyomatosis (n=7) were the four most frequent indications. HRQL, psychological status and dyspnea significantly improved after lung transplantation (p< 0.0001). The PSQI score neither significantly change from 6.7 ± 3.6 to 7.1 ± 3.8 (p = 0.38), nor the percentage of the patients with poor sleep quality (PSQI > 5) changed significantly from 51.7% (at baseline) to 62.5% (after lung transplantation) (p = 0.25). In PSQI subscales, sleep medication worsened significantly (p= 0.04) after lung transplantation. While lung transplantation had positive impacts on HRQL, psychological status and dyspnea, sleep quality remained unchanged. Sleep quality should be followed separately from those patient-reported measures not to miss its worsening.

Current status and problems of lung transplantation in Japan.

Lung transplantation has been performed worldwide and recognized as an effective treatment for patients with various end-stage lung diseases. Shortage of lung donors is one of the main obstacles in most of the countries, especially in Japan. Every effort has been made to promote organ donation during the past 20 years. In 2010, Japanese transplant low was revised so that the family of the brain dead donors can make a decision for organ donation. Since then, the number of cadaveric lung donor has increased by 5-fold. However, the average waiting time is still more than 800 days resulting in considerable number of deaths on the waiting list. Lung transplantation in the use of donation after cardiac death (DCD) has now been increasingly performed in Europe, Australia and North America with promising results. However, controlled death is not permitted in Japan making it difficult to accept this strategy. Use of marginal donors is one of the strategies for organ shortage. In Japan, the rate of lung usage is now well over 60% because of careful donor management by medical consultants and aggressive use of marginal donors. Living-donor lobar lung transplantation (LDLLT) has been developed to offset the mismatch between supply and demand for those patients awaiting cadaveric lung transplantation (CLT) and it is often the most realistic option for very ill patients. Between 1998 and 2015, lung transplantation has been performed in 464 patients (55 children, 419 adults) at 9 lung transplant centers in Japan. CLT was performed in 283 patients (61%) and LDLLT was performed in 181 patients (39%). The 5-year survival was 72.3% and 71.6%, respectively. Of note, only seven children received CLT. In conclusion, lung transplantation in Japan has grown significantly with excellent results but the shortage of cadaveric lung donor remains to be an important unsolved problem. LDLLT is often the only realistic option for very ill patients especially for children.

De novo malignancy after lung transplantation in Japan.

Lung transplant recipients have an increased de novo cancer risk due to long-term immunosuppression and several oncogenic viral infections. In Japan, to date, there have been no national surveys of the incidence of de novo malignancy after lung transplantation. This national survey was conducted by the Japanese Society for Transplantation. The questionnaire was distributed to lung transplant institutions, asking about several clinical factors related to de novo malignancy patients transplanted from 2001 to 2010. 179 cases of lung transplantation were performed by seven institutions in Japan between 2001 and 2010. De novo malignancies occurred in 18 patients (10.1%). The most common malignancy was a lymphoproliferative malignancy (12 cases, including 1 double de novo cancer after tongue cancer), followed by cervical cancer (4 cases), breast cancer (2 cases), and tongue cancer (1 case). The mean time of occurrence after transplantation was 37.8 (range 4-148) months. Reduction and/or withdrawal of immunosuppression for the treatment of malignancy was seen in 14 cases. Death due to cancer occurred in 6 cases. The overall 5-year survival of 18 patients was 58.9%. The 5-year survival of post-transplant lymphoproliferative disorder was not significantly different from that of other malignancies (47.6 and 62.5%, respectively; p=0.33). This is the first national survey of the incidence of de novo malignancy after lung transplantation in Japan. The incidence was 10.1% and post-transplant lymphoproliferative disorder was the most common malignancy.