Survival in Patients With Evidence of Pulmonary Thromboembolism on Ventilation‐Perfusion SPECT 12 Weeks After Double Lung Transplantation: A Retrospective Cohort Study
Introduction Double lung transplantation (DLTx) is an effective albeit high‐risk treatment for selected end‐stage pulmonary diseases. Currently, the median survival rate after DLTx is 6.5 years, which is the lowest among all solid organ transplantations . One risk following DLTx is thromboembolic complications such as pulmonary thromboembolism (PTE) . The etiology behind PTE in relation to DLTx is multifaceted with contributing factors such as impaired collateral bronchial circulation , older age, immobilization, postoperative pneumonia, antirejection treatment, and a possible postoperative hypercoagulable state . The reported prevalence of symptomatic PTE after DLTx varies widely, ranging from 1% to 15% , and increases to as much as 28% when applying routine postoperative imaging surveillance that includes asymptomatic patients  or postmortem data . Several studies have indicated that acute clinically suspected thromboembolic disease correlates with an elevated short‐term risk of all‐cause mortality after DLTx, but studies investigating the impact of asymptomatic (silent) PTE remain scarce . The conventional routine imaging protocol for establishing baseline airway and vascular function, including the screening of silent PTE following DLTx, has predominantly relied on planar ventilation‐perfusion (V̇‐Q̇) scintigraphy. The detection of PTE using this method has been associated with an elevated 6‐month mortality rate . However, ventilation‐perfusion single‐photon emission computed tomography (V̇‐Q̇ SPECT) now serves as the state‐of‐the‐art modality for PTE detection, as this technique enables the identification of smaller perfusion defects with enhanced specificity, sensitivity, and diagnostic accuracy, while also reducing the rate of nondiagnostic outcomes . Consequently, its diagnostic efficacy is comparable to that of computed tomography (CT) pulmonary angiography . Nevertheless, the prevalence of PTE following DLTx has not been evaluated using V̇‐Q̇ SPECT as a routine postoperative assessment in patients without clinical suspicion of PTE, and the prognostic significance of these findings in relation to all‐cause or graft‐related mortality remains inadequately investigated. This study therefore investigated the prevalence and prognostic impact of silent PTE diagnosed by V̇‐Q̇ SPECT 12 weeks after DLTx as a part of routine follow‐up. Furthermore, we investigated if any specific defects on the V̇‐Q̇ SPECT could inform prognosis further. We hypothesized that lung transplant recipients with silent PTE diagnosed by V̇‐Q̇ SPECT 12 weeks after DLTx would have higher all‐cause and graft‐related mortality when compared to those without.   Materials and Methods 2.1 Ethical Approval The study conformed to the standards set by the Declaration of Helsinki and was approved by the Danish Patient Safety Authority, the Danish Data Protection Agency (file no. 2012‐58‐0004), and the Danish Health Authority (file no. 3‐3013‐1129/1). In accordance with Danish legislation, additional approval was not required from the Regional Scientific Ethical Committee for this retrospective study, nor was additional informed consent from patients required, apart from that already provided for having lung function tests and V̇‐Q̇ SPECT performed as part of the clinical routine follow‐up. 2.2 Study Design and Setting This single‐center retrospective cohort study is reported according to the “Strengthening the Reporting of Observational Studies in Epidemiology” (STROBE) Statement: Guidelines for Reporting Observational Studies . We evaluated all patients who had undergone lung transplantation (LTx) at the Department of Cardiology, Section for LTx and Respiratory Medicine, Rigshospitalet, subsequently referred to the Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet for V̇‐Q̇ SPECT 12 weeks after transplant between 2012 and 2017. 2.3 Participants All available patients transplanted at Rigshospitalet with V̇‐Q̇ SPECT as a part of the clinical follow‐up between January 14, 2012, and December 11, 2017, were identified in our local database at the Department of Clinical Physiology and Nuclear Medicine at Rigshospitalet in Copenhagen, Denmark. Only DLTx patients with an available V̇‐Q̇ SPECT performed as a part of clinical control 12 weeks after DLTx were included. Single lung transplantation (SLTx) recipients, re‐transplantation, or recipients transplanted at other centers were excluded. 2.4 Variables 2.4.1 Clinical Data We evaluated patient electronic health records to assess clinical data. Information regarding recipient characteristics, drug use, comorbidities, postoperative complications, underlying lung disease, whether SLTx or DLTx were performed, and the date of V̇‐Q̇ SPECT, lung function, and DLTx were obtained. 2.4.2 V̇‐Q̇ SPECT Since 2012, all lung transplant recipients at our institution have undergone V̇‐Q̇ SPECT scans as part of a routine surveillance follow‐up 12 weeks after transplantation to establish a baseline assessment of graft function. None of the patients received the V̇‐Q̇ SPECT scan based on symptoms as the scan was only performed as a part of routine follow‐up in asymptomatic stable patients. The detailed protocol for the V̇‐Q̇ SPECT scans has been described elsewhere . Per the EANM guidelines, a V̇‐Q̇ SPECT scan was interpreted as positive for PTE with either the presence of one or more segmental perfusion mismatches or at least two subsegmental mismatches in keeping with pulmonary vascular anatomy (wedge‐shaped defects with base projecting to lung periphery) . 2.4.3 Lung Function Testing All lung function tests were performed at the Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet in accordance with consensus guidelines and established quality criteria for clinical use  as described elsewhere . The following data were obtained while blinded to PTE findings on V̇‐Q̇ SPECT: forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), the FEV 1 /FVC‐ratio, total lung capacity (TLC), residual volume (RV), and diffusing capacity for carbon monoxide corrected for hemoglobin (D LCOc ). 2.4.4 Mortality To assess all‐cause mortality and graft‐related mortality, the date of death was obtained from the electronic health records. The specific underlying causes of death were obtained through the use of the Classification of Death Causes after Transplantation (CLASS) method, which involves assessment of death causes through a review process including transplant specialists and has previously proven to reduce the uncertainty of the actual cause of death in this specialized patient population . The death causes have previously been validated  and this study includes deaths caused by complications related to the transplanted graft, such as graft failure (primary non‐function and non‐specific) graft rejection (acute and chronic), infections leading to graft failure, and graft‐versus‐host‐disease (acute and chronic). These complications have collectively been categorized as graft‐related deaths. See Table for the full list of possible causes of death. 2.4.5 Outcomes The primary outcome was all‐cause mortality, and the secondary outcome was graft‐related mortality. Time at risk began from the date of the V̇‐Q̇ SPECT scan and continued until the outcome occurred or the end of follow‐up (June 16, 2024). 2.5 Data Sources Results of V̇‐Q̇ SPECT were extracted from the Department's radiology information and picture archiving system (Sectra AB, Linköping, Sweden). Lung function data were extracted from a local database (DatGen, version 0.6b) at the Department of Clinical Physiology and Nuclear Medicine at Rigshospitalet in Copenhagen connected to the Department's lung function system (Jaeger MasterScreen PFT pro, CareFusion, Höchberg, Germany). Patient demographic and clinical data were extracted from electronic health records (Epic, Verona, WI, USA). Specific causes of death were extracted from the data repository at the Centre of Excellence for Personalized Medicine of Infectious Complications in Immune Deficiency (PERSIMUNE), Rigshospitalet, University of Copenhagen, Centre of Excellence for Health, Immunity and Infections (CHIP). 2.6 Potential Sources of Bias The risk of selection bias in this study is anticipated to be low, as all patients undergoing DLTx referred to the Department of Cardiology, Section for LTx and Respiratory Medicine, were assessed for eligibility during the study period, and the majority were included. This department serves all patients from Denmark, Greenland, and the Faroe Islands. Furthermore, the lung function testing procedures used were consistent and validated, minimizing measurement bias. The causes of death were also obtained from a previously validated database . All V̇‐Q̇ SPECT scans were read by the same board‐certified specialist (R.M.G.B) in clinical physiology and nuclear medicine. However, we excluded patients who did not have a V̇‐Q̇ SPECT 12 weeks after DLTx, and these patients could represent a subset with more severe health conditions or complications that prevented follow‐up. 2.7 Study Size No formal a priori statistical power calculation was conducted before the study, and the sample size was based on available data during the defined study period. 2.8 Statistical Methods Normally distributed continued variables are reported as mean (SD) and non‐normal distributed data as median [25 th –75 th percentile]. Categorical variables are summarized as frequencies and percentages. After examining normality plots and skewness statistics, we evaluated between‐group differences in numerical data by a student's t ‐test for normally distributed data and the Mann–Whitney U test for non‐normally distributed data. For categorical data, Chi‐square and Fisher's Exact Test were used as appropriate, depending on the degrees of freedom. In all survival analyses, time at risk began the day of V̇‐Q̇ SPECT. Follow‐up was truncated on June 16, 2024. At this time point, patients could be either censored or dead (all‐causes or graft‐related). Cumulative incidence curves were used to compare differences in all‐cause and graft‐related mortality between patients with PTE and those without PTE. The cumulative incidence of all‐cause mortality was estimated by calculating 1 minus the Kaplan‐Meier estimate with the log‐rank test used to compare differences between groups. For graft‐related mortality, Aalen‐Johansen cumulative incidence functions were calculated and illustrated, considering all‐cause mortality as a competing risk when evaluating graft‐related mortality. Gray's test was then applied to compare differences between groups. A multivariable Cox regression analysis was performed to investigate the independent association of PTE with survival time outcomes after adjusting for age, sex, body mass index, Hb, previous lung disease, postoperative complications, and postoperative anticoagulation treatment to account for possible confounders of all‐cause and graft‐related mortality. The covariates were a priori chosen based on their clinical importance and potential role as confounders in the relationship between PTE and survival outcome. Model assumptions were tested with the cumulative martingale residuals test and proportionality assumption by a visual inspection of the cumulative hazards on log scale. Moreover, we tested the proportional hazards assumption of the Cox proportional hazards model using Schoenfeld residuals to test if the hazard ratios remain constant over time. The proportional hazards assumption was not violated. Therefore, no further model adjustments were required. Results are presented as hazard ratio estimates per unit decrease unless otherwise explicitly stated and with 95% CI (lower limit [LL], upper limit [UL]). All statistical analyses were conducted using R statistical software version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria) within RStudio (version 1.4.1717). A two‐tailed p < 0.05 was considered statistically significant.   Ethical Approval The study conformed to the standards set by the Declaration of Helsinki and was approved by the Danish Patient Safety Authority, the Danish Data Protection Agency (file no. 2012‐58‐0004), and the Danish Health Authority (file no. 3‐3013‐1129/1). In accordance with Danish legislation, additional approval was not required from the Regional Scientific Ethical Committee for this retrospective study, nor was additional informed consent from patients required, apart from that already provided for having lung function tests and V̇‐Q̇ SPECT performed as part of the clinical routine follow‐up.   Study Design and Setting This single‐center retrospective cohort study is reported according to the “Strengthening the Reporting of Observational Studies in Epidemiology” (STROBE) Statement: Guidelines for Reporting Observational Studies . We evaluated all patients who had undergone lung transplantation (LTx) at the Department of Cardiology, Section for LTx and Respiratory Medicine, Rigshospitalet, subsequently referred to the Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet for V̇‐Q̇ SPECT 12 weeks after transplant between 2012 and 2017.   Participants All available patients transplanted at Rigshospitalet with V̇‐Q̇ SPECT as a part of the clinical follow‐up between January 14, 2012, and December 11, 2017, were identified in our local database at the Department of Clinical Physiology and Nuclear Medicine at Rigshospitalet in Copenhagen, Denmark. Only DLTx patients with an available V̇‐Q̇ SPECT performed as a part of clinical control 12 weeks after DLTx were included. Single lung transplantation (SLTx) recipients, re‐transplantation, or recipients transplanted at other centers were excluded.   Variables 2.4.1 Clinical Data We evaluated patient electronic health records to assess clinical data. Information regarding recipient characteristics, drug use, comorbidities, postoperative complications, underlying lung disease, whether SLTx or DLTx were performed, and the date of V̇‐Q̇ SPECT, lung function, and DLTx were obtained. 2.4.2 V̇‐Q̇ SPECT Since 2012, all lung transplant recipients at our institution have undergone V̇‐Q̇ SPECT scans as part of a routine surveillance follow‐up 12 weeks after transplantation to establish a baseline assessment of graft function. None of the patients received the V̇‐Q̇ SPECT scan based on symptoms as the scan was only performed as a part of routine follow‐up in asymptomatic stable patients. The detailed protocol for the V̇‐Q̇ SPECT scans has been described elsewhere . Per the EANM guidelines, a V̇‐Q̇ SPECT scan was interpreted as positive for PTE with either the presence of one or more segmental perfusion mismatches or at least two subsegmental mismatches in keeping with pulmonary vascular anatomy (wedge‐shaped defects with base projecting to lung periphery) . 2.4.3 Lung Function Testing All lung function tests were performed at the Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet in accordance with consensus guidelines and established quality criteria for clinical use  as described elsewhere . The following data were obtained while blinded to PTE findings on V̇‐Q̇ SPECT: forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), the FEV 1 /FVC‐ratio, total lung capacity (TLC), residual volume (RV), and diffusing capacity for carbon monoxide corrected for hemoglobin (D LCOc ). 2.4.4 Mortality To assess all‐cause mortality and graft‐related mortality, the date of death was obtained from the electronic health records. The specific underlying causes of death were obtained through the use of the Classification of Death Causes after Transplantation (CLASS) method, which involves assessment of death causes through a review process including transplant specialists and has previously proven to reduce the uncertainty of the actual cause of death in this specialized patient population . The death causes have previously been validated  and this study includes deaths caused by complications related to the transplanted graft, such as graft failure (primary non‐function and non‐specific) graft rejection (acute and chronic), infections leading to graft failure, and graft‐versus‐host‐disease (acute and chronic). These complications have collectively been categorized as graft‐related deaths. See Table for the full list of possible causes of death. 2.4.5 Outcomes The primary outcome was all‐cause mortality, and the secondary outcome was graft‐related mortality. Time at risk began from the date of the V̇‐Q̇ SPECT scan and continued until the outcome occurred or the end of follow‐up (June 16, 2024).   Clinical Data We evaluated patient electronic health records to assess clinical data. Information regarding recipient characteristics, drug use, comorbidities, postoperative complications, underlying lung disease, whether SLTx or DLTx were performed, and the date of V̇‐Q̇ SPECT, lung function, and DLTx were obtained.   V̇‐Q̇ SPECT Since 2012, all lung transplant recipients at our institution have undergone V̇‐Q̇ SPECT scans as part of a routine surveillance follow‐up 12 weeks after transplantation to establish a baseline assessment of graft function. None of the patients received the V̇‐Q̇ SPECT scan based on symptoms as the scan was only performed as a part of routine follow‐up in asymptomatic stable patients. The detailed protocol for the V̇‐Q̇ SPECT scans has been described elsewhere . Per the EANM guidelines, a V̇‐Q̇ SPECT scan was interpreted as positive for PTE with either the presence of one or more segmental perfusion mismatches or at least two subsegmental mismatches in keeping with pulmonary vascular anatomy (wedge‐shaped defects with base projecting to lung periphery) .   Lung Function Testing All lung function tests were performed at the Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet in accordance with consensus guidelines and established quality criteria for clinical use  as described elsewhere . The following data were obtained while blinded to PTE findings on V̇‐Q̇ SPECT: forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), the FEV 1 /FVC‐ratio, total lung capacity (TLC), residual volume (RV), and diffusing capacity for carbon monoxide corrected for hemoglobin (D LCOc ).   Mortality To assess all‐cause mortality and graft‐related mortality, the date of death was obtained from the electronic health records. The specific underlying causes of death were obtained through the use of the Classification of Death Causes after Transplantation (CLASS) method, which involves assessment of death causes through a review process including transplant specialists and has previously proven to reduce the uncertainty of the actual cause of death in this specialized patient population . The death causes have previously been validated  and this study includes deaths caused by complications related to the transplanted graft, such as graft failure (primary non‐function and non‐specific) graft rejection (acute and chronic), infections leading to graft failure, and graft‐versus‐host‐disease (acute and chronic). These complications have collectively been categorized as graft‐related deaths. See Table for the full list of possible causes of death.   Outcomes The primary outcome was all‐cause mortality, and the secondary outcome was graft‐related mortality. Time at risk began from the date of the V̇‐Q̇ SPECT scan and continued until the outcome occurred or the end of follow‐up (June 16, 2024).   Data Sources Results of V̇‐Q̇ SPECT were extracted from the Department's radiology information and picture archiving system (Sectra AB, Linköping, Sweden). Lung function data were extracted from a local database (DatGen, version 0.6b) at the Department of Clinical Physiology and Nuclear Medicine at Rigshospitalet in Copenhagen connected to the Department's lung function system (Jaeger MasterScreen PFT pro, CareFusion, Höchberg, Germany). Patient demographic and clinical data were extracted from electronic health records (Epic, Verona, WI, USA). Specific causes of death were extracted from the data repository at the Centre of Excellence for Personalized Medicine of Infectious Complications in Immune Deficiency (PERSIMUNE), Rigshospitalet, University of Copenhagen, Centre of Excellence for Health, Immunity and Infections (CHIP).   Potential Sources of Bias The risk of selection bias in this study is anticipated to be low, as all patients undergoing DLTx referred to the Department of Cardiology, Section for LTx and Respiratory Medicine, were assessed for eligibility during the study period, and the majority were included. This department serves all patients from Denmark, Greenland, and the Faroe Islands. Furthermore, the lung function testing procedures used were consistent and validated, minimizing measurement bias. The causes of death were also obtained from a previously validated database . All V̇‐Q̇ SPECT scans were read by the same board‐certified specialist (R.M.G.B) in clinical physiology and nuclear medicine. However, we excluded patients who did not have a V̇‐Q̇ SPECT 12 weeks after DLTx, and these patients could represent a subset with more severe health conditions or complications that prevented follow‐up.   Study Size No formal a priori statistical power calculation was conducted before the study, and the sample size was based on available data during the defined study period.   Statistical Methods Normally distributed continued variables are reported as mean (SD) and non‐normal distributed data as median [25 th –75 th percentile]. Categorical variables are summarized as frequencies and percentages. After examining normality plots and skewness statistics, we evaluated between‐group differences in numerical data by a student's t ‐test for normally distributed data and the Mann–Whitney U test for non‐normally distributed data. For categorical data, Chi‐square and Fisher's Exact Test were used as appropriate, depending on the degrees of freedom. In all survival analyses, time at risk began the day of V̇‐Q̇ SPECT. Follow‐up was truncated on June 16, 2024. At this time point, patients could be either censored or dead (all‐causes or graft‐related). Cumulative incidence curves were used to compare differences in all‐cause and graft‐related mortality between patients with PTE and those without PTE. The cumulative incidence of all‐cause mortality was estimated by calculating 1 minus the Kaplan‐Meier estimate with the log‐rank test used to compare differences between groups. For graft‐related mortality, Aalen‐Johansen cumulative incidence functions were calculated and illustrated, considering all‐cause mortality as a competing risk when evaluating graft‐related mortality. Gray's test was then applied to compare differences between groups. A multivariable Cox regression analysis was performed to investigate the independent association of PTE with survival time outcomes after adjusting for age, sex, body mass index, Hb, previous lung disease, postoperative complications, and postoperative anticoagulation treatment to account for possible confounders of all‐cause and graft‐related mortality. The covariates were a priori chosen based on their clinical importance and potential role as confounders in the relationship between PTE and survival outcome. Model assumptions were tested with the cumulative martingale residuals test and proportionality assumption by a visual inspection of the cumulative hazards on log scale. Moreover, we tested the proportional hazards assumption of the Cox proportional hazards model using Schoenfeld residuals to test if the hazard ratios remain constant over time. The proportional hazards assumption was not violated. Therefore, no further model adjustments were required. Results are presented as hazard ratio estimates per unit decrease unless otherwise explicitly stated and with 95% CI (lower limit [LL], upper limit [UL]). All statistical analyses were conducted using R statistical software version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria) within RStudio (version 1.4.1717). A two‐tailed p < 0.05 was considered statistically significant.   Results 3.1 Patient Characteristics A flow chart depicting selection of study participants is given in Figure . A total of 130 DLTx patients were included in this study during the period 2012–2017. Of those, 32 patients (24.6%) had evidence of PTE on V̇‐Q̇ SPECT measured 12 weeks after DLTx. There were no significant differences between the groups regarding baseline characteristics, underlying lung disease, cause of death, pretransplant use of anticoagulation therapy, or posttransplantation risk factors ( Table ). Moreover, there were no detectable differences between those with and without PTE regarding postoperative complications such as diaphragmatic paralysis or bronchial, pleural, kidney, and abdominal complications. Both groups received similar standard prophylactic anticoagulants (low molecular weight heparin) given subcutaneously once daily (enoxaparin) in the immediate postoperative period, which was tapered over the following weeks during hospitalization if no specific indications were present ( Table ). No patients underwent fibrinolytic therapy either before or after V̇‐Q̇ SPECT. Of note, 2 patients (6.3%) in the PTE group received anticoagulation therapy for other reasons prior to DLTx, while it was 5 patients (4.1%) in those without PTE. Of the 32 patients with PTE, 5 (15.6%) received therapeutic anticoagulation based on individual risk profile as reassessment of the patients revealed clinical signs and/or symptoms consistent with PTE prompting concurrent CT pulmonary angiography for further evaluation. The other 27 (84.4%) patients with PTE were managed conservatively, as reassessment did not indicate the need for further investigations. 3.2 PTE and Lung Function V̇‐Q̇ SPECT evidence of PTE at the 12‐week mark was not associated with a detectable difference in lung function metrics such as FEV 1 , FVC, TLC, RV, and D LCOc measured 6 months after DLTx ( Table ). 3.3 PTE and Mortality For all included patients, the median survival was 9.8 years, and the median follow‐up time was 6.9 years. In the total study population, 57 patients died. Of those with PTE, 11 patients (34.5%) died versus 46 patients (46.9%) in those without PTE. Moreover, of those who died, 8 (72.7%) with PTE were due to graft‐related reasons and in those without PTE, 24 (52.2%) were due to graft‐related reasons. PTE was not associated with an increased hazard ratio for all‐cause mortality (HR = 0.723; 95% CI: 0.371–1.410; p = 0.341) nor for graft‐related mortality (HR = 0.953; 95% CI: 0.420–2.162; p = 0.910) in the multivariable Cox regression analysis. As illustrated by the cumulative incidence curves, there was no difference in survival between the groups when using either all‐cause mortality (log‐rank, p = 0.30) ( Figure ) or when assessing the cumulative incidence curve for graft‐related mortality (Gray's test, p = 0.99) ( Figure ). 3.4 Other V̇‐Q̇ SPECT Defects and Mortality Including all DLTx‐patients, the presence of a segmental inversely mismatched defect was the only V̇‐Q̇ SPECT parameter that was associated with an increased hazard of all‐cause mortality (HR = 1.178; 95% CI: 1.021–1.360; p = 0.025) ( Table ). No defect pattern on V̇‐Q̇ SPECT was associated with increased HRs for graft‐related mortality in the multivariable Cox regression ( Table ). There were no detectable interactions between the PTE group and the assessed V̇‐Q̇ SPECT defect patterns on all‐cause mortality or graft‐related mortality (all p > 0.05 for interaction). Of note, radiological signs of lung infarction were observed in 1 patient with PTE (3.1%) and 2 patients without PTE (2.0%).   Patient Characteristics A flow chart depicting selection of study participants is given in Figure . A total of 130 DLTx patients were included in this study during the period 2012–2017. Of those, 32 patients (24.6%) had evidence of PTE on V̇‐Q̇ SPECT measured 12 weeks after DLTx. There were no significant differences between the groups regarding baseline characteristics, underlying lung disease, cause of death, pretransplant use of anticoagulation therapy, or posttransplantation risk factors ( Table ). Moreover, there were no detectable differences between those with and without PTE regarding postoperative complications such as diaphragmatic paralysis or bronchial, pleural, kidney, and abdominal complications. Both groups received similar standard prophylactic anticoagulants (low molecular weight heparin) given subcutaneously once daily (enoxaparin) in the immediate postoperative period, which was tapered over the following weeks during hospitalization if no specific indications were present ( Table ). No patients underwent fibrinolytic therapy either before or after V̇‐Q̇ SPECT. Of note, 2 patients (6.3%) in the PTE group received anticoagulation therapy for other reasons prior to DLTx, while it was 5 patients (4.1%) in those without PTE. Of the 32 patients with PTE, 5 (15.6%) received therapeutic anticoagulation based on individual risk profile as reassessment of the patients revealed clinical signs and/or symptoms consistent with PTE prompting concurrent CT pulmonary angiography for further evaluation. The other 27 (84.4%) patients with PTE were managed conservatively, as reassessment did not indicate the need for further investigations.   PTE and Lung Function V̇‐Q̇ SPECT evidence of PTE at the 12‐week mark was not associated with a detectable difference in lung function metrics such as FEV 1 , FVC, TLC, RV, and D LCOc measured 6 months after DLTx ( Table ).   PTE and Mortality For all included patients, the median survival was 9.8 years, and the median follow‐up time was 6.9 years. In the total study population, 57 patients died. Of those with PTE, 11 patients (34.5%) died versus 46 patients (46.9%) in those without PTE. Moreover, of those who died, 8 (72.7%) with PTE were due to graft‐related reasons and in those without PTE, 24 (52.2%) were due to graft‐related reasons. PTE was not associated with an increased hazard ratio for all‐cause mortality (HR = 0.723; 95% CI: 0.371–1.410; p = 0.341) nor for graft‐related mortality (HR = 0.953; 95% CI: 0.420–2.162; p = 0.910) in the multivariable Cox regression analysis. As illustrated by the cumulative incidence curves, there was no difference in survival between the groups when using either all‐cause mortality (log‐rank, p = 0.30) ( Figure ) or when assessing the cumulative incidence curve for graft‐related mortality (Gray's test, p = 0.99) ( Figure ).   Other V̇‐Q̇ SPECT Defects and Mortality Including all DLTx‐patients, the presence of a segmental inversely mismatched defect was the only V̇‐Q̇ SPECT parameter that was associated with an increased hazard of all‐cause mortality (HR = 1.178; 95% CI: 1.021–1.360; p = 0.025) ( Table ). No defect pattern on V̇‐Q̇ SPECT was associated with increased HRs for graft‐related mortality in the multivariable Cox regression ( Table ). There were no detectable interactions between the PTE group and the assessed V̇‐Q̇ SPECT defect patterns on all‐cause mortality or graft‐related mortality (all p > 0.05 for interaction). Of note, radiological signs of lung infarction were observed in 1 patient with PTE (3.1%) and 2 patients without PTE (2.0%).   Discussion To our knowledge, this is the first study investigating both all‐cause and graft‐related mortality in DLTx patients with clinically silent PTE diagnosed by V̇‐Q̇ SPECT as a modality. Approximately 25% of the DLTx patients showed evidence of PTE on V̇‐Q̇ SPECT 12 weeks after DLTx, despite the absence of clinical suspicion for PTE in any of the patients. As opposed to our study hypothesis, this was not associated with a detectable increase in risk of all‐cause or graft‐related mortality, nor did it impact cumulative incidence rates over a 1–5‐year follow‐up period. This was the case independently of therapeutic anticoagulation in patients with PTE. Most studies have investigated the presence of clinically suspected thromboembolic disease , demonstrating an increased hazard of mortality by up to 70% . In contrast, studies focusing specifically on PTE and mortality in lung transplant recipients remains more limited and primarily concentrate on cases of acute PTE , wherein clinical suspicion led to subsequent imaging. Overall, acute clinically suspected PTE following DLTx seems to impact survival negatively . This was also confirmed by a recent study  involving 928 lung transplant recipients, demonstrating an 80% increased hazard of all‐cause mortality and graft failure associated with PTE and another large registry‐based study found the odds of in‐hospital death in lung transplant recipients with PTE was thrice as high as compared to those without any VTE . These studies differ fundamentally from the present study, in which imaging was routinely performed and as such restricted to asymptomatic patients. Furthermore, our previous findings, namely that clinically silent PTE diagnosed by planar V̇‐Q̇ scintigraphy was evident in 28% of DLTx patients 12 weeks after transplantation and that the presence of PTE was associated with a five‐fold higher risk of 6‐month all‐cause mortality , was not reproduced here. Others have reported a somewhat lower prevalence of 9% for PTE diagnosed 12 weeks after DLTx by planar V̇‐Q̇ scintigraphy, and like in the present study, no effect of PTE on 1‐year survival and overall survival was found . The discrepancy from our previous study and the findings in patients with symptomatic PTE may be attributed to the choice of imaging modality, as V̇‐Q̇ SPECT has demonstrated higher sensitivity and specificity for diagnosing PTE compared to planar V̇‐Q̇ scintigraphy . However more importantly, our cohort, which included patients from 2012 to 2017, may differ significantly from the study by Kristensen , which included patients from 2007 to 2011, and this may partly explain the difference, as more recent transplant eras independently favor 1‐ and 5‐year survival . This improved overall survival, as a result of improved outcomes following advances in lung transplant management , certainly limits power to detect differences in adverse prognostic outcomes in the current study as compared to the study by Kristensen . The risk of developing PTE is highest in the first month after LTx  and PTE may thus contribute more to mortality in the early postoperative period, potentially not be captivated in our study, as all included patients survived the first 12 weeks postoperatively. This notion is supported from a previous postmortem study, in which a higher incidence of clinically silent PTE was observed in patients who died within the first month following transplantation . As PTE impacts the alveolar‐capillary barrier by reducing the number of capillaries available for gas exchange, it could consequently be anticipated that individuals with silent PTE would exhibit lower D LCOc values . This would also align with previous studies demonstrating reduced D LCOc in patients with acute PTE . However, our findings did not reveal an effect of silent PTE on D LCOc or any other lung function metric. Silent PTE may therefore not substantially impair pulmonary circulation, and this could serve as a partly explanation to the lack of influence on mortality. The median survival time in our cohort was 9.8 years, exceeding the previously overall reported 6.5 years and the 8.7 years for those who survived the first year posttransplantation . Moreover, the higher overall survival may be attributable to excluding patients who were unable to undergo the V̇‐Q̇ SPECT scan after 12 weeks, and as such reflects a form of conditional survival, which could potentially obscure the impact of PTE on overall mortality. Additionally, the diagnosis of PTE could only be done 12 weeks after DLTx, which may cause an underrepresentation of individuals with both symptomatic and silent PTE before and after the 12‐week mark. Given that most posttransplantation deaths due to PTE occur within the first 30 days, this might skew the actual impact of PTE on mortality. As the patients in our cohort are asymptomatic, our findings of PTE pose a challenge in determining the origin of the clots. It is plausible that the detected PTE may be donor‐derived, as recipient‐derived clots would typically be expected to cause symptoms and/or clinical signs . Based on our findings, we recommend reassessment when PTE is identified on V̇‐Q̇ SPECT. However, in the absence of clinical symptoms, conservative management appears to be a safe approach. The single‐center nature of the study may limit the generalizability of the findings to other transplantation centers with different surgical procedures, postoperative management, and imaging surveillance protocols. Some clinical variables, including detailed donor information and certain comorbidities, were not incorporated into our analysis. This restricts our ability to identify other potentially significant prognostic factors associated with survival. Furthermore, our analytical methods did not permit the investigation of underlying pathophysiological mechanisms responsible for the observed outcomes. The inclusion of DLTx patients from 2012 to 2017 covers a timeframe that may not be directly comparable with other studies. Moreover, full lung function testing was first performed 6 months after DLTx, whereas V̇‐Q̇ SPECT scans were performed 12 weeks posttransplant. This timing discrepancy may obscure the relationship between V̇‐Q̇ SPECT findings and lung function, as changes in graft function could occur between the two assessments. Lastly, it is also important to note, that this study's findings do not apply to patients with any clinical suspicion of acute PTE or where a V̇‐Q̇ SPECT scan is ordered following clinical indication.   Conclusions In this study, we observed that around one‐quarter of DLTx recipients had clinically silent PTE as detected on V̇‐Q̇ SPECT performed routinely 12 weeks posttransplantation. However, this was not associated with increased all‐cause mortality, graft‐related mortality, or reduced lung function metrics measured at 6‐month follow‐up.   Milan Mohammad: data collection, data analysis, data interpretation, figures, first draft, revisions. Anna W. Kristensen: data collection, data interpretation, revisions. Jacob P. Hartmann: data analysis, data interpretation, figures, revisions. Neval E. Wareham: data collection, data interpretation, revisions. Sana N. Buttar: data collection, data interpretation, revisions. Anders M. Greve: data analysis, data interpretation, revisions. Thomas K. Lund: data interpretation, revisions. Kristine Jensen: data interpretation, revisions. Hans H. L. Schultz: data interpretation, revisions. Michael Perch: data collection, data interpretation, revisions. Ronan M. G. Berg: conception, design, data collection, data interpretation, revisions, supervision. Jann Mortensen: conception, design, data interpretation, revisions, supervision. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Ronan M. G. Berg is the guarantor of this work and accepts full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish.   The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.   The authors declare no conflicts of interest.   Supporting Information   