Among 203 patients enrolled, 6 patients were excluded, of which 4 were unavailable for follow-up and 2 were transferred to other hospitals just after registration. Therefore, 197 patients (102 males) who met the inclusion criteria were analyzed, and their baseline characteristics are presented in Table 1. The study population had a median age of 47 (38-54) years and low body mass index (BMI) of 19.0 (16.7-21.7) kg/m2. The primary underlying diseases were IP (99 patients, 50.3%), BO (21 patients, 10.7%), pulmonary hypertension (15 patients, 7.6%), LAM (15 patients, 7.6%), COPD (12 patients, 6.1%), bronchiectasis (11 patients, 5.6%), and lung injury after hematopoietic stem cell transplantation (10 patients, 5.1%). Long-term oxygen therapy (LTOT) was prescribed for 174 patients and noninvasive ventilation (NIV) was used for 11 patients. FVC and FEV1 values were low at 46.4 (36.1-61.6) %predicted and 40.8 (24.5-55.8) %predicted, respectively.
Prospective Survival Study
During the median follow-up period of 572 days (range: 1–1987 days), 96 patients (48.7%) received lung transplantation. Among them, 27 patients underwent living-donor lung lobar transplantation because they could not wait for a deceased donor. Regarding 69 patients who underwent lung transplantation from a deceased donor, the median time from registration to lung transplantation was 752 days (range: 38–1979 days). Of note, 72 patients on the waitlist (36.5%) expired: 49 had IP, and 23 had other respiratory diseases. With regard to the cause of death, 70 (97.2%) patients died because of worsening of the original respiratory diseases, 1 patient died because of pneumonia, and 1 patient died because of pulmonary hemorrhage.
Univariable competing risk regressions with the Fine-Gray model were performed to investigate the relationships between clinical measurements and waitlist mortality (Table 2). Higher age, IP, higher arterial carbon dioxide pressure (PaCO2), and lower FVC were significantly related to waitlist mortality (p<0.05). Regarding patient-reported measures, mMRC dyspnea was significantly related to waitlist mortality (HR=1.46, 95% CI=1.13-1.87, p=0.003). For patients classified according to the median mMRC (3), cumulative incidence curves between lower and higher mMRC score groups (score 0-2, n=79; score 3 or 4, n=115; missing, n=3) are presented (p=0.011) (Figure 1). Regarding HRQL, Symptoms, Activities, Impacts, and Total scores of the SGRQ had strong associations with waitlist mortality (HR=1.02, 95% CI=1.01-1.04, p=0.0014; HR=1.03, 95% CI=1.01-1.05, p=0.002; HR=1.03, 95% CI=1.02-1.04, p<0.001; and HR=1.04, 95% CI=1.02-1.05, p<0.001, respectively). For patients classified according to the median SGRQ Total (67.3), cumulative incidence curves between higher and lower SGRQ Total groups (n=97 and n=98, respectively; missing, n=2) are presented (p<0.001) (Figure 2). HADS anxiety and depression also had weak but significant relationship with waitlist mortality (HR=1.07, 95% CI=1.02-1.13, p=0.013; and HR=1.05, 95% CI=1.01-1.10, p=0.024). Other variables such as gender, BMI, smoking history, comorbidities, LTOT, FEV1, and 6-minute walk distance were not significant (p>0.05).
Multivariable competing risk regression with the Fine–Gray model was performed using age, IP, PaCO2, FVC (%predicted), and mMRC (Model I: dyspnea) or SGRQ Total (Model II: HRQL) or HADS (Model III: psychological status) as explanatory variables, all of which were significant factors in the univariable analyses (Table 3). We divided them into these three groups because SGRQ Total includes the evaluation of dyspnea and psychological status. In Model I, age, IP, FVC, and mMRC dyspnea were significantly related to waitlist mortality (HR=1.04, p=0.007; HR=2.41, p=0.002; HR=0.98, p=0.016; and HR=1.36, p=0.037, respectively). In Model II, age, IP, and SGRQ Total were significantly related to waitlist mortality (HR=1.03, p=0.010; HR=2.24, p=0.003; and HR=1.03, p=0.0014, respectively). In Model III, age, IP and FVC were significant factors related to waitlist mortality, and HADS was not. We also analyzed the data excluding patients who underwent living-donor lobar lung transplantation after registration in this study. We found that the SGRQ total and mMRC dyspnea remained significantly related to waitlist mortality after multivariable analysis (Additional file 1: Table S1).
Finally, we analyzed data regarding the LAS. It ranged from 32.6 to 71.2 with a median score of 40.1. LAS was significantly but weakly related to mMRC (Spearman’s rank correlation coefficient (Rs)= 0.27, p<0.001), SGRQ Total (Rs=0.36, p<0.001), and HADS anxiety (Rs=0.17, p=0.030) and depression (Rs=0.22, p=0.004). Scatter plots between the LAS, mMRC, and SGRQ are shown in Additional file 2 and 3 (Figure S1 and Figure S2). Univariable competing risk analysis revealed that the LAS was significantly related to waitlist mortality (HR=1.04; 95% CI=1.01–1.07, p=0.004). Cumulative incidence curves for the groups with lower versus higher LAS are presented (n=87 and n=86, respectively) (p=0.025) (Additional file 4: Figure S3). We subsequently analyzed whether its significant relationship with waitlist mortality was independent of patient-reported measures. Therefore, multivariable competing risk analysis was performed to investigate the relationships with waitlist mortality between the LAS and (a) Model I: mMRC score (dyspnea), (b) Model II: SGRQ Total (HRQL), and (c) Model III: HADS anxiety and depression (psychological status). In Model III, only the LAS was significant (p=0.012); in Model I, both the LAS and the mMRC were significantly related with waitlist mortality (p=0.039 and 0.038, respectively); and in Model II, the SGRQ was significant (p<0.001) but the LAS was not (p=0.11) (Additional file 5: Table S2).