Host Response Changes and Their Association with Mortality in COVID-19 Patients with Lymphopenia.

Rationale: Lymphopenia in coronavirus disease (COVID-19) is associated with increased mortality. Objectives: To explore the association between lymphopenia, host response aberrations, and mortality in patients with lymphopenic COVID-19. Methods: We determined 43 plasma biomarkers reflective of four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, cytokine release, and chemokine release. We explored if decreased concentrations of lymphocyte-derived proteins in patients with lymphopenia were associated with an increase in mortality. We sought to identify host response phenotypes in patients with lymphopenia by cluster analysis of plasma biomarkers. Measurements and Main Results: A total of 439 general ward patients with COVID-19 were stratified by baseline lymphocyte counts: normal (>1.0 × 109/L; n = 167), mild lymphopenia (>0.5 to ⩽1.0 × 109/L; n = 194), and severe lymphopenia (⩽0.5 × 109/L; n = 78). Lymphopenia was associated with alterations in each host response domain. Lymphopenia was associated with increased mortality. Moreover, in patients with lymphopenia (n = 272), decreased concentrations of several lymphocyte-derived proteins (e.g., CCL5, IL-4, IL-13, IL-17A) were associated with an increase in mortality (at P < 0.01 or stronger significance levels). A cluster analysis revealed three host response phenotypes in patients with lymphopenia: "hyporesponsive" (23.2%), "hypercytokinemic" (36.4%), and "inflammatory-injurious" (40.4%), with substantially differing mortality rates of 9.5%, 5.1%, and 26.4%, respectively. A 10-biomarker model accurately predicted these host response phenotypes in an external cohort with similar mortality distribution. The inflammatory-injurious phenotype showed a remarkable combination of relatively high inflammation and organ damage markers with high antiinflammatory cytokine levels yet low proinflammatory cytokine levels. Conclusions: Lymphopenia in COVID-19 signifies a heterogenous group of patients with distinct host response features. Specific host responses contribute to lymphopenia-associated mortality in COVID-19, including reduced CCL5 levels.

Prospective evaluation of upper extremity access and total transfemoral approach during fenestrated and branched endovascular repair.

OBJECTIVE: Total transfemoral (TF) access has been increasingly used during fenestrated-branched endovascular aortic repair (FB-EVAR). However, it is unclear whether the potential decrease in the risk of cerebrovascular events is offset by increased procedural difficulties and other complications. The aim of this study was to compare outcomes of FB-EVAR using a TF vs upper extremity (UE) approach for target artery incorporation. METHODS: We analyzed the clinical data of consecutive patients enrolled in a prospective, nonrandomized clinical trial in two centers to investigate the use of FB-EVAR for treatment of complex abdominal aortic aneurysms (CAAA) and thoracoabdominal aortic aneurysms (TAAA) between 2013 and 2022. Patients were classified into TF or UE access group with a subset analysis of patients treated using designs with directional branches. End points were technical success, procedural metrics, 30-day cerebrovascular events defined as stroke or transient ischemic attack, and any major adverse events (MAEs). RESULTS: There were 541 patients (70% males; mean age, 74 ± 8 years) treated by FB-EVAR with 2107 renal-mesenteric TAs incorporated. TF was used in175 patients (32%) and UE in 366 patients (68%) including 146 (83%) TF and 314 (86%) UE access patients who had four or more TAs incorporated. The use of a TF approach increased from 8% between 2013 and 2017 to 31% between 2018 and 2020 and 96% between 2021 and 2022. Compared with UE access patients, TF access patients were more likely to have CAAAs (37% vs 24%; P = .002) as opposed to TAAAs. Technical success rate was 96% in both groups (P = .96). The use of the TF approach was associated with reduced fluoroscopy time and procedural time (each P < .05). The 30-day mortality rate was 0.6% for TF and 1.4% for UE (P = .67). There was no early cerebrovascular event in the TF group, but the incidence was 2.7% for UE patients (P = .035). The incidence of MAEs was also lower in the TF group (9% vs 18%; P = .006). Among 237 patients treated using devices with directional branches, there were no significant differences in outcomes except for a reduced procedural time for TF compared with UE access patients (P < .001). CONCLUSIONS: TF access was associated with a decreased incidence of early cerebrovascular events and MAEs compared with UE access for target artery incorporation. Procedural time was decreased in TF access patients irrespective of the type of stent graft design.

Aneurysm sac shrinkage at 1 year after fenestrated-branched endovascular aortic repair of complex aortic aneurysms offers mid-term survival advantage.

OBJECTIVES: To investigate the impact of 1-year changes in aneurysm sac diameter on patient survival after fenestrated-branched endovascular aortic repair (FB-EVAR) of complex abdominal aortic aneurysms or thoracoabdominal aortic aneurysms. METHODS: We reviewed the clinical data of patients enrolled in a prospective nonrandomized study investigating FB-EVAR (2013-2022). Patients with sequential follow up computed tomography scans at baseline and 6 to 18 months after FB-EVAR were included in the analysis. Aneurysm sac diameter change was defined as the difference in maximum aortic diameter from baseline measurements obtained in centerline of flow. Patients were classified as those with sac shrinkage (≥5 mm) or failure to regress (<5 mm or expansion) according to sac diameter change. The primary end point was all-cause mortality. Secondary end points were aortic-related mortality (ARM), aortic aneurysm rupture (AAR), and aorta-related secondary intervention. RESULTS: There were 549 patients treated by FB-EVAR. Of these, 463 patients (71% male, mean age, 74 ± 8 years) with sequential computed tomography imaging were investigated. Aneurysm extent was thoracoabdominal aortic aneurysms in 328 patients (71%) and abdominal aortic aneurysms in 135 (29%). Sac shrinkage occurred in 270 patients (58%) and failure to regress in 193 patients (42%), including 19 patients (4%) with sac expansion at 1 year. Patients from both groups had similar cardiovascular risk factors, except for younger age among patients with sac shrinkage (73 ± 8 years vs 75 ± 8 years; P < .001). The median follow-up was 38 months (interquartile range, 18-51 months). The 5-year survival estimate was 69% ± 4.1% for the sac shrinkage group and 46% ± 6.2% for the failure to regress group. Survival estimates adjusted for confounders (age, chronic pulmonary obstructive disease, chronic kidney disease, congestive heart failure, and aneurysm extent) revealed a higher hazard of late mortality in patients with failure to regress (adjusted hazard ratio, 1.72; 95% confidence interval, 1.18-2.52; P = .005). The 5-year cumulative incidences of ARM (1.1% vs 3.1%; P = .30), AAR (0.6% vs 2.6%; P = .20), and aorta-related secondary intervention (17.0% ± 2.8% vs 19.0% ± 3.8%) were both comparable between the groups. CONCLUSIONS: Aneurysm sac shrinkage at 1 year is common after FB-EVAR and is associated with improved patient survival, whereas sac enlargement affects only a minority of patients. The low incidences of ARM and AAR indicate that failure to regress may serve as a surrogate marker for nonaortic-related death.

Effect of Family History of Aortic Disease on Outcomes of Fenestrated/Branched Endovascular Aneurysm Repair of Complex Aortic Aneurysms.

OBJECTIVE: The clinical significance of family history (FH) of aortic disease on the outcomes of fenestrated/branched endovascular aneurysm repair (FB-EVAR) has not been well described. This study aimed to assess how FH of aortic disease affects outcomes following FB-EVAR for complex aortic aneurysms (CAAs). METHODS: This study retrospectively reviewed the clinical data of consecutive patients enrolled in 10 ongoing, prospective, non-randomised, physician sponsored, investigational device exemption studies to evaluate FB-EVAR (2005 - 2022) in the United States Aortic Research Consortium database. Patients were stratified by presence or absence of FH of any aortic disease in any relative. Patients with confirmed genetically triggered aortic diseases were excluded. Primary outcomes were 30 day major adverse events (MAEs) and late survival. Secondary outcomes included late secondary interventions and aneurysm sac enlargement. RESULTS: During the study period, 2 901 patients underwent FB-EVAR. A total of 2 355 patients (81.2%) were included in the final analysis: 427 (18.1%) with and 1 928 (81.9%) without FH of aortic disease. Patient demographics, clinical characteristics, and aneurysm extent were similar between the groups. Patients with FH of aortic disease more frequently had prior open abdominal aortic repair, but less frequently had prior endovascular aneurysm repair (p < .050). There were no statistically significant differences in 30 day mortality (4% vs. 2%; p = .12) and MAEs for patients with or without FH of aortic disease (12% vs. 12%; p = .89). Three year survival estimates were 71% (95% confidence interval [CI] 0.67 - 0.78%) and 71% (95% CI 0.68 - 0.74%), respectively (p = .74). Freedom from secondary intervention and aneurysm sac enlargement were also not statistically significantly different between groups. CONCLUSION: A family history of aortic disease had no impact on 30 day and midterm outcomes of FB-EVAR of CAAs. In the absence of an identified genetically triggered aortic disease, treatment selection for CAAs should be based on clinical risk and patient anatomy rather than FH of aortic disease.

Midterm Outcomes and Aneurysm Sac Dynamics Following Fenestrated Endovascular Aneurysm Repair after Previous Endovascular Aneurysm Repair.

OBJECTIVE: Fenestrated endovascular aneurysm repair (FEVAR) is a feasible option for aortic repair after endovascular aneurysm repair (EVAR), due to improved peri-operative outcomes compared with open conversion. However, little is known regarding the durability of FEVAR as a treatment for failed EVAR. Since aneurysm sac evolution is an important marker for success after aneurysm repair, the aim of the study was to examine midterm outcomes and aneurysm sac dynamics of FEVAR after prior EVAR. METHODS: Patients undergoing FEVAR for complex abdominal aortic aneurysms from 2008 to 2021 at two hospitals in The Netherlands were included. Patients were categorised into primary FEVAR and FEVAR after EVAR. Outcomes included five year mortality rate, one year aneurysm sac dynamics (regression, stable, expansion), sac dynamics over time, and five year aortic related procedures. Analyses were done using Kaplan-Meier methods, multivariable Cox regression analysis, chi square tests, and linear mixed effect models. RESULTS: One hundred and ninety-six patients with FEVAR were identified, of whom 27% (n = 53) had had a prior EVAR. Patients with prior EVAR were significantly older (78 ± 6.7 years vs. 73 ± 5.9 years, p < .001). There were no significant differences in mortality rate. FEVAR after EVAR was associated with a higher risk of aortic related procedures within five years (hazard ratio [HR] 2.6; 95% confidence interval [CI] 1.1 - 6.5, p = .037). Sac dynamics were assessed in 154 patients with available imaging. Patients with a prior EVAR showed lower rates of sac regression and higher rates of sac expansion at one year compared with primary FEVAR (sac expansion 48%, n = 21/44, vs. 8%, n = 9/110, p < .001). Sac dynamics over time showed similar results, sac growth for FEVAR after EVAR, and sac shrinkage for primary FEVAR (p < .001). CONCLUSION: There were high rates of sac expansion and a need for more secondary procedures in FEVAR after EVAR than primary FEVAR patients, although this did not affect midterm survival. Future studies will have to assess whether FEVAR after EVAR is a valid intervention, and the underlying process that drives aneurysm sac growth following successful FEVAR after EVAR.

How We Would Treat Our Own Thoracoabdominal Aortic Aneurysm.

This manuscript is intended to provide a comprehensive review of the current state of knowledge on endovascular repair of thoracoabdominal aortic aneurysms (TAAAs). The management of these complex aneurysms requires an interdisciplinary and patient-specific approach in high-volume centers. An index case is used to discuss the diagnosis and treatment of a patient undergoing fenestrated-branched endovascular aneurysm repair for a TAAA.

Age-related changes in plasma biomarkers and their association with mortality in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19. METHODS: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort. RESULTS: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively). CONCLUSIONS: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19.

Changes in renal-mesenteric duplex ultrasound velocities after fenestrated and branched endovascular aortic aneurysm repair.

OBJECTIVE: Stenting of renal and mesenteric vessels may result in changes in velocity measurements due to arterial compliance, potentially giving rise to confusion about the presence of stenosis during follow-up. The aim of our study was to compare preoperative and postoperative changes in peak systolic velocity (PSV, cm/s) after placement of the celiac axis (CA), superior mesenteric artery (SMA) and renal artery (RAs) bridging stent grafts during fenestrated-branched endovascular aortic repair (FB-EVAR) for treatment of complex abdominal aortic aneurysms (AAA) and thoracoabdominal aortic aneurysms. METHODS: Patients were enrolled in a prospective, nonrandomized single-center study to evaluate FB-EVAR for treatment of complex AAA and thoracoabdominal aortic aneurysms between 2013 and 2020. Duplex ultrasound examination of renal-mesenteric vessels were obtained prospectively preoperatively and at 6 to 8 weeks after the procedure. Duplex ultrasound examination was performed by a single vascular laboratory team using a predefined protocol including PSV measurements obtained with <60° angles. All renal-mesenteric vessels incorporated by bridging stent grafts using fenestrations or directional branches were analyzed. Target vessels with significant stenosis in the preoperative exam were excluded from the analysis. The end point was variations in PSV poststent placement at the origin, proximal, and mid segments of the target vessels for fenestrations and branches. RESULTS: There were 419 patients (292 male; mean age, 74 ± 8 years) treated by FB-EVAR with 1411 renal-mesenteric targeted vessels, including 260 CAs, 409 SMAs, and 742 RAs. No significant variances in the mean PSVs of all segments of the CA, SMA, and RAs at 6 to 8 weeks after surgery were found as compared with the preoperative values (CA, 135 cm/s vs 141 cm/s [P = .06]; SMA, 128 cm/s vs 125 cm/s [P = .62]; RAs, 90 cm/s vs 83 cm/s [P = .65]). Compared with baseline preoperative values, the PSV of the targeted vessels showed no significant differences in the origin and proximal segment of all vessels. However, the PSV increased significantly in the mid segment of all target vessels after stent placement. CONCLUSIONS: Stent placement in nonstenotic renal and mesenteric vessels during FB-EVAR is not associated with a significant increase in PSVs at the origin and proximal segments of the target vessels. Although there is a modest but significant increase in velocity measurements in the mid segment of the stented vessel, this difference is not clinically significant. Furthermore, PSVs in stented renal and mesenteric arteries were well below the threshold for significant stenosis in native vessels. These values provide a baseline or benchmark for expected PSVs after renal-mesenteric stenting during FB-EVAR.

Technical pitfalls and proposed modifications of instructions for use for endovascular aortic aneurysm repair using the Gore Excluder conformable device in angulated and short landing zones.

We describe a case of an abdominal aortic aneurysm (AAA) and angulated proximal neck treated with a Gore Excluder conformable endoprosthesis and show relevant technical pitfalls in the deployment of the graft main body. An 82-year-old man presented with a 71-mm asymptomatic AAA with an angulated infrarenal proximal neck (75°) and was referred to our unit. The patient was treated with a 26-mm Gore Excluder conformable device, which was deployed slightly above the renal arteries after precatheterization of the lowest renal artery. The graft was then repositioned with support of the introducer sheath and a stiff guide wire. The proximal sealing zone was ballooned before the endograft delivery system was retrieved to avoid distal migration. Technical success was achieved. The patient was discharged with no complications. No type Ia endoleak was present on the 6-month computed tomography scan. Endovascular treatment of an AAA with a severe angulated proximal neck can be effective with a conformable stent graft if technical measures are used during deployment of the main body to optimize the seal.