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Influence of Pulmonary Hypertension on Intrahospital Mortality in Lung Transplantation for Interstitial Lung Disease
Influence of Pulmonary Hypertension on Intrahospital Mortality in Lung Transplantation for Interstitial Lung Disease M. Corral-Blanco*, V.C. Prudencio-Ribera, M.E. Jarrín-Estupiñán, R. Alonso-Moralejo, V. Pérez-González, J.C. Meneses-Pardo, A. Hermira-Anchuelo, and A. De Pablo-Gafas Lung Transplantation Unit, 12 de Octubre University Hospital, Madrid, Spain
ABSTRACT Background. Pulmonary hypertension (PH) is a comorbidity associated with interstitial lung disease (ILD). The purpose of this study was to evaluate the influence of PH on intrahospital mortality in lung transplantation (LT) for ILD. Methods. We conducted a retrospective cohort study of 66 patients who underwent LT for ILD at the 12 de Octubre University Hospital (Madrid, Spain) from October 2008 to June 2014. PH was defined as mean pulmonary arterial pressure (mPAP) 25 mmHg on right-sided heart catheterization and intrahospital mortality as any death taken place after the transplantation of patients not being discharged. Results. We retrospectively analyzed data of 66 patients; they were stratified by the presence or absence of PH before LT. Twenty-seven patients (41%) had PH. The PH group had a lower diffusing capacity of carbon monoxide (DLCO), carbon monoxide transfer coefficient (KCO), and 6-minute walk distance test (6MWT) and a higher total lung capacity (TLC), modified medical research council dyspnea scale (mMRC), and lung allocation score (LAS) than the non-PH group. Patients with PH more often underwent double lung transplantation (DLT; 59%) than single lung transplantation (SLT). Intrahospital mortality was 13% (9/66). No significant differences were observed in KaplanMeier survival curves for the PH and non-PH groups with a median survival time of 46 days versus 33 days (IQR 26e74; log-rank P ¼ .056); however, the postoperative length of stay in the hospital was greater in the PH group. Conclusions. In our cohort, pulmonary hypertension was not related to early mortality in lung transplantation recipients for interstitial lung diseases.
P
ULMONARY hypertension (PH), defined as a mean pulmonary artery pressure (mPAP) greater than 25 mmHg, is a comorbidity associated with interstitial lung disease (ILD). Identification of PH is vital owing to worse prognoses and is associated with poorer functional capacity and higher mortality [1,2]. The effect of PH in the postelung transplantation course is not well defined, with studies showing a significantly higher risk for 90-day postoperative death [3], whereas others did not find a significant risk of death after Lung Transplantation (LT) [4,5]. The purpose of this study was to evaluate the influence of PH on intrahospital mortality in LT for ILD. 0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.10.018
380
MATERIALS AND METHODS We conducted an observational and retrospective cohort study of 66 patients who underwent LT for ILD at the 12 de Octubre University Hospital (Madrid, Spain) from October 2008 to June 2014. One patient with retransplantation was previously excluded from the analysis. We defined intrahospital mortality as any death that takes place after the transplantation of patients not being discharged, regardless of the length of admission. The mPAP obtained were those
*Address correspondence to Dr Marta Corral Blanco, Hospital 12 de Octubre, Madrid, Spain. E-mail: m.corralblanco@gmail. com ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 380e382 (2019)
PULMONARY HYPERTENSION & INTRAHOSPITAL MORTALITY
381
Table 1. Recipient, Surgical, and Postoperative Data of Patients With (n [ 27) and Without (n [ 39) Pulmonary Hypertension (PH) Recipient Data
Age (y), median (IQR) Male sex, No. (%) FVC (%), median (IQR) TLC (%), median (IQR) DLCO (%), mean (SD) KCO (%), median (IQR) 6MWT (m), mean (SD) mPAP (mmHg), median (IQR) mMRC scale 2 No. (%) 3 No. (%) 4 No. (%) LAS, median (IQR) Surgical Data Single LT, No. (%) Double LT, No. (%) ECC, No (%) Ischemic time 1st (min), median (IQR) Ischemic time 2nd (min), median (IQR) Postoperative Data RU stay (d), median (IQR) Mechanic ventilation (d), median (IQR) Cardiac output < 2.2, No. (%) Acute kidney injury, No. (%) Pulmonary graft dysfunction, No. (%) Postoperative stay in the hospital (d) No. (%)
PH Group
61 (52e64) 21 (77.8%) 50 (45e56) 57.5 (48.8e70.3) 24.6 7.2 40.5 (36.3e50.8) 256 95 30 (28e35) 1 12 14 41.43
(3.7%) (44.4%) (51.9%) (40.50e46.97)
Non-PH Group
60 (55e64) 25 (64.1%) 47 (40e56) 51.5 (41.8e59.0) 31.2 7.8 65.0 (54.0e77.0) 335 125 19 (16e21) 5 25 9 38.97
(12.8%) (64.1%) (23.1%) (35.50e41.87)
P
.633 .235 .368 .031 .002 <.001 .012 <.001
.042 .006
11 16 14 295 445
(40.7%) (59.3%) (51.9%) (255e360) (384e525)
26 13 11 290 425
(66.7%) (33.3%) (28.2%) (260e330) (385e480)
.037 .052 .667 .775
7 3 6 5 7 30
(6e17) (2e6) (28.6%) (20.0%) (25.9%) (22.8e48.8)
6 3 6 10 10 24
(4e26) (1e24) (17.6%) (26.3%) (25.6%) (19.5e34.0)
.334 .894 .341 .565 .979 .030
Abbreviations: IQR, interquartile range; FVC, forced vital capacity; TLC, total lung capacity; DLCO, diffusing capacity of carbon monoxide; SD, standard deviation; KCO, carbon monoxide transfer coefficient; 6MWT, 6-minute walk distance test; mPAP, mean pulmonary arterial pressure; mMRC, modified medical research council dyspnea scale; LAS, lung allocation score; LT, lung transplant; ECC, extracorporeal circulation; RU, recovery unit.
reported from the right heart catheterization at the time of listing for lung transplantation. The following information was also gathered in patients with and without PH: donor and recipient variables, surgical data, and postoperative period in our Recovery Unit data.
Statistical Analysis Quantitative variables were measured as mean and standard deviation (SD) or medians and Interquartile Range (IQR; 25th75th percentile), and they were analyzed using the Student t or Mann-Whitney U tests, giving their normal distribution or not, as assessed by the Kolmogorov-Smirnov test. Qualitative variables were measured as frequencies and percentages, and they were analyzed using c2 or Fisher exact tests. Kaplan-Meier estimation and log-rank testing were used to assess patient survival. All tests of significance were two-tailed, and P values of .05 or less were considered statistically significant.
RESULTS
We retrospectively analyzed data of 66 patients; they were stratified by the presence or absence of PH before LT. Twenty-seven patients (41%) had PH (41% had mPAP <30 mmHg, 33% mPAP 30 to 34 mmHg, and 26% mPAP 35 mmHg). Median recipient age was 61 years (IQR, 53e63), with a predominance of men in both groups. Patients over 60 with PH had values of mPAP <30 mmHg.
Recipient, surgical, and postoperative data are shown in Table 1. The PH group had a lower diffusing capacity of carbon monoxide (DLCO), carbon monoxide transfer coefficient (KCO), and 6-minute walk distance test (6MWT) and a higher total lung capacity (TLC), modified medical research council dyspnea scale (mMRC), and lung allocation score (LAS) than the non-PH group. We did not find any difference in donor characteristics (age, mechanical ventilation hours, PaO2/FiO2). Among all LT, a double lung transplant (DLT) was performed in 29 cases and a single lung transplant (SLT) in 37 cases. Patients with PH more often received a DLT (59%) than SLT. Patients with HP who underwent SLT had values of mPAP <30 mmHg. Intrahospital mortality was of 13% (9/66), with a median survival time of 34 days (IQR 28e66). The causes of death in non-HP group were: 1 case of surgical complication, 1 fungal infection, 1 bacterial infection, 1 acute rejection, 1 primary graft dysfunction, and 3 cases of acute respiratory distress syndrome; in the HP group, there was 1 case of gastrointestinal perforation. No significant differences were observed in Kaplan-Meier survival curves for PH and non-PH group with a median survival time of 46 days versus 33 days (IQR 26e74; P ¼ .056 by log-rank test statistic) (Fig 1); however, the postoperative length of stay in the hospital was greater in the PH groupd30 days (IQR 23e49) versus 24 days (IQR 19e34; P ¼ .03).
382
CORRAL-BLANCO, PRUDENCIO-RIBERA, JARRÍN-ESTUPIÑÁN ET AL
Fig 1. Kaplan-Meier survival curves for PH and non-PH group.
DISCUSSION
The family of interstitial lung diseases is characterized by cellular proliferation, interstitial inflammation, fibrosis, or a combination of such findings. The majority of patients with interstitial fibrosis ultimately receive a diagnosis of chronic hypersensitivity pneumonitis, pulmonary sarcoidosis, an underlying autoimmune disease, or an idiopathic interstitial pneumonia. The most common idiopathic interstitial pneumonia is idiopathic pulmonary fibrosis (IPF), a chronic, progressive, fibrotic interstitial lung disease of unknown cause [6]. In our cohort, among the 67 patients who underwent LT during the study period, 51 had IPF, 6 nonspecific interstitial pneumonia (NSIP), and 10 other ILD. ILD, and above all IPF, have the worst prognoses among the diseases treated with LT, with a median survival of 2e3 years from diagnosis and a 5-year survival rate of 20%-30% [7]. End-stage lung disease can be complicated by the presence of PH. In the literature, the prevalence of PH in IPF patients ranges from 8% to 21%, but higher percentages (30% to 50%) are found in advanced and end-stage cases [8]. In our experience, the prevalence of PH in ILD patients was 41%, in line with the current data [9]. The effect of PH in the largest observational studies is not clear. Whelan et al compared the survival of lung-transplant recipients with IPF and PH and found a significantly higher risk for 90-day postoperative death in recipients with HP [3].
Hayes et al found there was no significant difference in survival for an mPAP above or below 25 mmHg [4]. In addition, the decision to perform SLT in patients with HP and is controversial. Villavivencio et al found that when a DLT is performed, the mPAP does not affect survival and an mPAP greater than 25 does not affect survival when a SLT is performed. However, an mPAP greater than 30 was associated with shorter survival, and the effect was even more detrimental when the mPAP was greater than 40 when an SLT is performed [10]. In our experience, intrahospital mortality did not differ between patients with or without PH; however, the postoperative length of stay in the hospital was greater in the PH group. In our series, SLT was performed in 11 cases in the PH-group (all patients had values of mPAP <30 mmHg), and no significant association was found to intrahospital mortality. The main limitation for the study was the small sample size and the retrospective design. Furthermore, ILD can represent a heterogeneous group of diseases with different prognoses. A larger multicenter study is needed to further confirm the results of our study. REFERENCES [1] Fitton TP, Kosowski TR, Barreiro CJ, Chan V, Patel ND, Borja MC, et al. Impact of secondary pulmonary hypertension on lung transplant outcome. J Heart Lung Transplant 2005;24:1254e9. [2] Kimura M, Taniguchi H, Kondoh Y, et al. Pulmonary hypertension as a prognostic indicator at the initial evaluation in idiopathic pulmonary fibrosis. Respiration 2013;85:456e63. [3] Whelan TP, Dunitz JM, Kelly RF, et al. Effect of preoperative pulmonary artery pressure on early survival after lung transplantation for idiopathic pulmonary fibrosis. J Heart Lung Transplant 2005;24:1269e74. [4] Hayes Jr D, Higgins RS, Black SM, et al. Effect of pulmonary hypertension on survival in patients with idiopathic pulmonary fibrosis after lung transplantation: an analysis of the United Network of Organ Sharing registry. J Heart Lung Transplant 2015;34:430e7. [5] Omari MK, Smith SA, Jacobsen G, Kaza V. Effect of pulmonary hypertension in patients with end-stage lung disease on posttransplantation outcomes. Transplant Proc 2011;43:1881e6. [6] Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med 2018;378:1811e23. [7] Raghu G. IPF: guidelines for diagnosis and clinical management have advanced from consensus-based in 2000 to evidence based in 2011. Eur Respir J 2011;37:743e6. [8] Seeger W, Adir Y, Barberà JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol 2013;62:D109e16. [9] Shorr AF, Wainright JL, Cors CS, Lettieri CJ, Nathan SD. Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant. Eur Respir J 2007;30:715e21. [10] Villavicencio MA, Axtell AL, Osho A, Astor T, Roy N, Melnitchouk S, et al. Single-versus double-lung transplantation in pulmonary fibrosis: impact of age and pulmonary hypertension. Ann Thorac Surg 2018;106:856e63.
ABSTRACT Background. Pulmonary hypertension (PH) is a comorbidity associated with interstitial lung disease (ILD). The purpose of this study was to evaluate the influence of PH on intrahospital mortality in lung transplantation (LT) for ILD. Methods. We conducted a retrospective cohort study of 66 patients who underwent LT for ILD at the 12 de Octubre University Hospital (Madrid, Spain) from October 2008 to June 2014. PH was defined as mean pulmonary arterial pressure (mPAP) 25 mmHg on right-sided heart catheterization and intrahospital mortality as any death taken place after the transplantation of patients not being discharged. Results. We retrospectively analyzed data of 66 patients; they were stratified by the presence or absence of PH before LT. Twenty-seven patients (41%) had PH. The PH group had a lower diffusing capacity of carbon monoxide (DLCO), carbon monoxide transfer coefficient (KCO), and 6-minute walk distance test (6MWT) and a higher total lung capacity (TLC), modified medical research council dyspnea scale (mMRC), and lung allocation score (LAS) than the non-PH group. Patients with PH more often underwent double lung transplantation (DLT; 59%) than single lung transplantation (SLT). Intrahospital mortality was 13% (9/66). No significant differences were observed in KaplanMeier survival curves for the PH and non-PH groups with a median survival time of 46 days versus 33 days (IQR 26e74; log-rank P ¼ .056); however, the postoperative length of stay in the hospital was greater in the PH group. Conclusions. In our cohort, pulmonary hypertension was not related to early mortality in lung transplantation recipients for interstitial lung diseases.
P
ULMONARY hypertension (PH), defined as a mean pulmonary artery pressure (mPAP) greater than 25 mmHg, is a comorbidity associated with interstitial lung disease (ILD). Identification of PH is vital owing to worse prognoses and is associated with poorer functional capacity and higher mortality [1,2]. The effect of PH in the postelung transplantation course is not well defined, with studies showing a significantly higher risk for 90-day postoperative death [3], whereas others did not find a significant risk of death after Lung Transplantation (LT) [4,5]. The purpose of this study was to evaluate the influence of PH on intrahospital mortality in LT for ILD. 0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.10.018
380
MATERIALS AND METHODS We conducted an observational and retrospective cohort study of 66 patients who underwent LT for ILD at the 12 de Octubre University Hospital (Madrid, Spain) from October 2008 to June 2014. One patient with retransplantation was previously excluded from the analysis. We defined intrahospital mortality as any death that takes place after the transplantation of patients not being discharged, regardless of the length of admission. The mPAP obtained were those
*Address correspondence to Dr Marta Corral Blanco, Hospital 12 de Octubre, Madrid, Spain. E-mail: m.corralblanco@gmail. com ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 380e382 (2019)
PULMONARY HYPERTENSION & INTRAHOSPITAL MORTALITY
381
Table 1. Recipient, Surgical, and Postoperative Data of Patients With (n [ 27) and Without (n [ 39) Pulmonary Hypertension (PH) Recipient Data
Age (y), median (IQR) Male sex, No. (%) FVC (%), median (IQR) TLC (%), median (IQR) DLCO (%), mean (SD) KCO (%), median (IQR) 6MWT (m), mean (SD) mPAP (mmHg), median (IQR) mMRC scale 2 No. (%) 3 No. (%) 4 No. (%) LAS, median (IQR) Surgical Data Single LT, No. (%) Double LT, No. (%) ECC, No (%) Ischemic time 1st (min), median (IQR) Ischemic time 2nd (min), median (IQR) Postoperative Data RU stay (d), median (IQR) Mechanic ventilation (d), median (IQR) Cardiac output < 2.2, No. (%) Acute kidney injury, No. (%) Pulmonary graft dysfunction, No. (%) Postoperative stay in the hospital (d) No. (%)
PH Group
61 (52e64) 21 (77.8%) 50 (45e56) 57.5 (48.8e70.3) 24.6 7.2 40.5 (36.3e50.8) 256 95 30 (28e35) 1 12 14 41.43
(3.7%) (44.4%) (51.9%) (40.50e46.97)
Non-PH Group
60 (55e64) 25 (64.1%) 47 (40e56) 51.5 (41.8e59.0) 31.2 7.8 65.0 (54.0e77.0) 335 125 19 (16e21) 5 25 9 38.97
(12.8%) (64.1%) (23.1%) (35.50e41.87)
P
.633 .235 .368 .031 .002 <.001 .012 <.001
.042 .006
11 16 14 295 445
(40.7%) (59.3%) (51.9%) (255e360) (384e525)
26 13 11 290 425
(66.7%) (33.3%) (28.2%) (260e330) (385e480)
.037 .052 .667 .775
7 3 6 5 7 30
(6e17) (2e6) (28.6%) (20.0%) (25.9%) (22.8e48.8)
6 3 6 10 10 24
(4e26) (1e24) (17.6%) (26.3%) (25.6%) (19.5e34.0)
.334 .894 .341 .565 .979 .030
Abbreviations: IQR, interquartile range; FVC, forced vital capacity; TLC, total lung capacity; DLCO, diffusing capacity of carbon monoxide; SD, standard deviation; KCO, carbon monoxide transfer coefficient; 6MWT, 6-minute walk distance test; mPAP, mean pulmonary arterial pressure; mMRC, modified medical research council dyspnea scale; LAS, lung allocation score; LT, lung transplant; ECC, extracorporeal circulation; RU, recovery unit.
reported from the right heart catheterization at the time of listing for lung transplantation. The following information was also gathered in patients with and without PH: donor and recipient variables, surgical data, and postoperative period in our Recovery Unit data.
Statistical Analysis Quantitative variables were measured as mean and standard deviation (SD) or medians and Interquartile Range (IQR; 25th75th percentile), and they were analyzed using the Student t or Mann-Whitney U tests, giving their normal distribution or not, as assessed by the Kolmogorov-Smirnov test. Qualitative variables were measured as frequencies and percentages, and they were analyzed using c2 or Fisher exact tests. Kaplan-Meier estimation and log-rank testing were used to assess patient survival. All tests of significance were two-tailed, and P values of .05 or less were considered statistically significant.
RESULTS
We retrospectively analyzed data of 66 patients; they were stratified by the presence or absence of PH before LT. Twenty-seven patients (41%) had PH (41% had mPAP <30 mmHg, 33% mPAP 30 to 34 mmHg, and 26% mPAP 35 mmHg). Median recipient age was 61 years (IQR, 53e63), with a predominance of men in both groups. Patients over 60 with PH had values of mPAP <30 mmHg.
Recipient, surgical, and postoperative data are shown in Table 1. The PH group had a lower diffusing capacity of carbon monoxide (DLCO), carbon monoxide transfer coefficient (KCO), and 6-minute walk distance test (6MWT) and a higher total lung capacity (TLC), modified medical research council dyspnea scale (mMRC), and lung allocation score (LAS) than the non-PH group. We did not find any difference in donor characteristics (age, mechanical ventilation hours, PaO2/FiO2). Among all LT, a double lung transplant (DLT) was performed in 29 cases and a single lung transplant (SLT) in 37 cases. Patients with PH more often received a DLT (59%) than SLT. Patients with HP who underwent SLT had values of mPAP <30 mmHg. Intrahospital mortality was of 13% (9/66), with a median survival time of 34 days (IQR 28e66). The causes of death in non-HP group were: 1 case of surgical complication, 1 fungal infection, 1 bacterial infection, 1 acute rejection, 1 primary graft dysfunction, and 3 cases of acute respiratory distress syndrome; in the HP group, there was 1 case of gastrointestinal perforation. No significant differences were observed in Kaplan-Meier survival curves for PH and non-PH group with a median survival time of 46 days versus 33 days (IQR 26e74; P ¼ .056 by log-rank test statistic) (Fig 1); however, the postoperative length of stay in the hospital was greater in the PH groupd30 days (IQR 23e49) versus 24 days (IQR 19e34; P ¼ .03).
382
CORRAL-BLANCO, PRUDENCIO-RIBERA, JARRÍN-ESTUPIÑÁN ET AL
Fig 1. Kaplan-Meier survival curves for PH and non-PH group.
DISCUSSION
The family of interstitial lung diseases is characterized by cellular proliferation, interstitial inflammation, fibrosis, or a combination of such findings. The majority of patients with interstitial fibrosis ultimately receive a diagnosis of chronic hypersensitivity pneumonitis, pulmonary sarcoidosis, an underlying autoimmune disease, or an idiopathic interstitial pneumonia. The most common idiopathic interstitial pneumonia is idiopathic pulmonary fibrosis (IPF), a chronic, progressive, fibrotic interstitial lung disease of unknown cause [6]. In our cohort, among the 67 patients who underwent LT during the study period, 51 had IPF, 6 nonspecific interstitial pneumonia (NSIP), and 10 other ILD. ILD, and above all IPF, have the worst prognoses among the diseases treated with LT, with a median survival of 2e3 years from diagnosis and a 5-year survival rate of 20%-30% [7]. End-stage lung disease can be complicated by the presence of PH. In the literature, the prevalence of PH in IPF patients ranges from 8% to 21%, but higher percentages (30% to 50%) are found in advanced and end-stage cases [8]. In our experience, the prevalence of PH in ILD patients was 41%, in line with the current data [9]. The effect of PH in the largest observational studies is not clear. Whelan et al compared the survival of lung-transplant recipients with IPF and PH and found a significantly higher risk for 90-day postoperative death in recipients with HP [3].
Hayes et al found there was no significant difference in survival for an mPAP above or below 25 mmHg [4]. In addition, the decision to perform SLT in patients with HP and is controversial. Villavivencio et al found that when a DLT is performed, the mPAP does not affect survival and an mPAP greater than 25 does not affect survival when a SLT is performed. However, an mPAP greater than 30 was associated with shorter survival, and the effect was even more detrimental when the mPAP was greater than 40 when an SLT is performed [10]. In our experience, intrahospital mortality did not differ between patients with or without PH; however, the postoperative length of stay in the hospital was greater in the PH group. In our series, SLT was performed in 11 cases in the PH-group (all patients had values of mPAP <30 mmHg), and no significant association was found to intrahospital mortality. The main limitation for the study was the small sample size and the retrospective design. Furthermore, ILD can represent a heterogeneous group of diseases with different prognoses. A larger multicenter study is needed to further confirm the results of our study. REFERENCES [1] Fitton TP, Kosowski TR, Barreiro CJ, Chan V, Patel ND, Borja MC, et al. Impact of secondary pulmonary hypertension on lung transplant outcome. J Heart Lung Transplant 2005;24:1254e9. [2] Kimura M, Taniguchi H, Kondoh Y, et al. Pulmonary hypertension as a prognostic indicator at the initial evaluation in idiopathic pulmonary fibrosis. Respiration 2013;85:456e63. [3] Whelan TP, Dunitz JM, Kelly RF, et al. Effect of preoperative pulmonary artery pressure on early survival after lung transplantation for idiopathic pulmonary fibrosis. J Heart Lung Transplant 2005;24:1269e74. [4] Hayes Jr D, Higgins RS, Black SM, et al. Effect of pulmonary hypertension on survival in patients with idiopathic pulmonary fibrosis after lung transplantation: an analysis of the United Network of Organ Sharing registry. J Heart Lung Transplant 2015;34:430e7. [5] Omari MK, Smith SA, Jacobsen G, Kaza V. Effect of pulmonary hypertension in patients with end-stage lung disease on posttransplantation outcomes. Transplant Proc 2011;43:1881e6. [6] Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med 2018;378:1811e23. [7] Raghu G. IPF: guidelines for diagnosis and clinical management have advanced from consensus-based in 2000 to evidence based in 2011. Eur Respir J 2011;37:743e6. [8] Seeger W, Adir Y, Barberà JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol 2013;62:D109e16. [9] Shorr AF, Wainright JL, Cors CS, Lettieri CJ, Nathan SD. Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant. Eur Respir J 2007;30:715e21. [10] Villavicencio MA, Axtell AL, Osho A, Astor T, Roy N, Melnitchouk S, et al. Single-versus double-lung transplantation in pulmonary fibrosis: impact of age and pulmonary hypertension. Ann Thorac Surg 2018;106:856e63.