To our knowledge, this is the first study based on a Japanese transplant center to report the survival time after listing for LTX and the waitlist mortality in each disease category. Waiting time for listed LTX candidates is a common worldwide issue, especially in low-volume centers or regions with an imbalance between organ supply and transplant demand. The median waiting time in our center was 573 days, which was considerably longer than that in other countries[8]; moreover, over one-third of the LTX candidates died after listing. Until December 2018, 668 LTX procedures, including 447 cadaveric-donor and 221 living-donor cases, were performed in Japan, with 18.0% (120/668) of these cases being conducted in TUH [7]. This indicates that all Japanese LTX centers have long waiting times probably due to severe donor shortage (0.61 donations per million) [9]. To alleviate the lack of donated lungs, transplant centers in Japan adopted several policies, including rigorous age limits for listing (under age 55 and 60 for a bilateral and single LTX, respectively); performing single rather than bilateral LTX to maximize LTX opportunities through donor sharing; and providing living-donor transplants for LTX candidates too sick to await cadaveric lungs and with two immediate family members eligible for donating, which accounts for 33.1% (221/668) of all LTX procedures in Japan. As increasing the number of donors could address the long waiting time, close collaboration between all transplant centers and the Japanese government is needed. However, more time is required to address this issue.
Generally, ILD (termed as Fibrosis in this paper) has a poor prognosis; moreover, IPF has a worse prognosis even after listing for LTX [10,11,12,13,14]. At our transplant center, 50.9% and 61.4% of the patients with ILD and IPF, respectively, died while on the waiting list. The consensus from the international society of heart and lung transplantation (ISHLT) proposed listing patients with ILD for LTX after confirming a ≥ 10% drop in FVC or > 50 m decline in 6-min walk test over 6 months [15]. These criteria may be suitable for candidate selection in North America but not for regions with a short donor supply. FVC is routinely measured in respiratory clinics and is among the reliable indicators for assessing disease progression in ILD [16]. Therefore, we validated the probability of waitlist mortality and survival time based on FVC at the time of listing (Fig. 3B and 3C); however, it could not predict them. Therefore, there is a need for studies on credible variables or variable combinations for informing the listing of patients with ILD, especially IPF. Regarding other LTX centers in Japan, a study conducted in Kyoto by Ikezoe et al. reported that shorter 6MWD and lower BMI were independent prognostic factors in candidates with ILD (n = 77) [12]. Moreover, a study conducted in Fukuoka by Miyahara et al. reported that a history of pneumothorax and short 6MWD affected waitlist mortality in patients with ILD [13]. In our study, multivariate Cox analysis revealed that greater age, male sex, and higher RVP were significantly associated with waitlist mortality in Fibrosis. Future studies should assess whether these variables can be used to predict survivors with ILD.
To identify risk factors or outcomes in LTX candidates with similar pathophysiology, it would be useful to categorize pulmonary diseases into smaller groups. Pulmonary disease has been classified as A (obstructive disease), B (vascular disease), C (cystic fibrosis), and D (restrictive disease) in the United States, which has improved allocation equity and quality according to the Organ Procurement and Transplantation Network [3, 17]. Since the prevalence of diseases in Japan differs from that in other countries, as well as the little genetic diversity or age limit for listing, we categorized pulmonary diseases based on the transplant circumstance (Additional file 1). Generally, single LTX is primarily considered for the Obstructive and Fibrosis disease categories, as clinically appropriate, while bilateral LTX is inevitably selected for the Vascular and Suppurative disease categories. The Obstructive disease category was mostly comprised of lymphangioleiomyomatosis (LAM). Compared with the ISLHT registry report, there were fewer cases of chronic obstructive pulmonary disease listed in the Obstructive category due to the strict age limit (Fig. 4). Further, bronchiectasis was categorized into the Suppurative, rather than the Obstructive, category since cystic fibrosis is extremely rare in Japan [18, 19]. Compared with other countries, Japan has more cases of pulmonary complications after hematopoietic stem cell transplantation listed for LTX [7, 20]. Since graft-versus-host disease presents with various lung injury phenotypes, including obstructive, restrictive, and mixed [21, 22], it could not simply be categorized into the Obstructive or Fibrosis category. Notably, this phenotypical diversity has been observed in chronic lung allograft dysfunction [23], which could be considered as a host-versus-graft disease from a pathogenesis perspective. To elucidate the risk factors or outcomes in those populations, the Allogeneic category was independently set up and analyzed. There is a need for large-scale studies to determine how to best group LTX indications and to practically assess risk factors for waitlist mortality.
This study has several limitations. First, this was a single-center retrospective study; therefore, our findings do not fully represent the current transplant circumstance in Japan. Some of the patients were listed a decade ago, with the LTX indications having changed over time. Currently, LAM is not often listed while IPF has become increasingly listed and is the most common indication for LTX. Therefore, there is a need for routine reports from the registry organization or academic societies regarding outcomes based on the pulmonary disease listed for LTX. Moreover, there is a need for a prospective study including all transplant centers in Japan to identify risk factors for waitlist mortality in each disease category or specific disease. The timing of referral or listing for LTX should be configured based on the probability of the mortality from the perspective of the waiting time in each region or country. Although our findings are too preliminary to conclude the optimal timing for listing patients with IPF or even the disease category, they could facilitate future multicenter trials.
