Symptomatic human immunodeficiency virus infection is associated with advanced presentation and perioperative mortality in patients undergoing surgery for peripheral arterial disease.

OBJECTIVE: Prior studies have demonstrated an increased risk of developing cardiovascular and peripheral arterial disease (PAD) in patients with human immunodeficiency virus (HIV). However, the effect of chronic HIV infection in patients with preexisting PAD and requiring vascular intervention is unclear. In the present study, we assessed the differences in clinical presentation and perioperative outcomes for patients with PAD who had undergone revascularization or amputation with and without HIV infection. METHODS: International Classification of Diseases, 9th and 10th Revisions, Clinical Modification, codes were used to identify patients with a prior diagnosis of PAD who had undergone lower extremity revascularization or amputation in the National Inpatient Sample (2003-2017). From this group, the patients were divided for analysis into those with and without HIV infection. Of the patients with HIV infection (PWHs), we identified additional subsets of patients: those with any prior or current diagnosis of an HIV-related illness, including acquired immunodeficiency syndrome, designated as symptomatic HIV, and those without such a diagnosis, designated as asymptomatic HIV infection. Propensity score matching was performed to create matched cohorts. Population-based comparative analyses were performed of the clinical characteristics of the HIV-infected and HIV-uninfected groups. Univariate and multivariate logistic regression analyses of the perioperative in-hospital outcomes were performed on the matched cohorts. RESULTS: A total of 224,912 patients aged 18 to 85 years were identified who had been admitted with an established diagnosis of PAD and had undergone a lower extremity procedure. Of these patients, 1264 (0.56%) also had a diagnosis of HIV infection. Symptomatic PWHs were more likely to present with critical limb ischemia than were the HIV-uninfected patients or asymptomatic PWHs (66.2% vs 46.3% and 43.6%; P < .01). However, both asymptomatic and symptomatic PWHs were more likely to have required minor (7.5% and 6.7% vs 2.6%; P < .01) and major (12.9% and 27.4% vs 7.0%; P < .01) amputations than were matched HIV-uninfected controls. Although adjusted multivariate logistic regression analysis demonstrated symptomatic HIV infection to be a significant, independent predictor of in-hospital mortality (odds ratio, 2.46; 95% confidence interval, 1.37-4.40; P = .003), the perioperative mortality for the asymptomatic PWH was comparable to that of matched HIV-uninfected controls. CONCLUSIONS: Symptomatic PWHs, including patients living with acquired immunodeficiency syndrome, who had required a PAD-related procedure had presented with more advanced vascular disease and were most at risk of early perioperative mortality. However, the presentation and mortality between asymptomatic PWHs with well-controlled disease and HIV-uninfected patients were comparable. All PWHs with PAD were more likely to undergo lower extremity amputations than were HIV-uninfected matched controls. Asymptomatic, well-controlled HIV infection should not be a contraindication to elective PAD-related procedures because the mortality was similar to that of HIV-uninfected controls. However, the limb salvage rates might be lower for all PWHs with PAD, regardless of HIV disease severity. Taken together, these findings can improve perioperative risk stratification and surgical management of PAD in this high-risk population.

Hospital-based delays to revascularization increase risk of postoperative mortality and short bowel syndrome in acute mesenteric ischemia.

OBJECTIVE: Acute mesenteric ischemia (AMI) is a surgical emergency for which delays in treatment have been closely associated with high morbidity and mortality. Although the duration of ischemia as a determinant of outcomes for AMI is well known, the objective of this study was to identify hospital-based determinants of delayed revascularization and their effects on postoperative morbidity and mortality in AMI. METHODS: All patients who underwent any surgery for AMI from a multi-center hospital system between 2010 and 2020 were divided into two groups based on timeliness of mesenteric revascularization after presentation. Early revascularization (ER) was defined as having both vascular consultation ≤12 hours of presentation and vascular surgery performed at the patient's initial operation. Delayed revascularization (DR) was defined as having either delays to vascular consultation or vascular surgery. A retrospective review of demographic and postoperative data was performed. The effect of DR on major postoperative outcomes, including 30-day and 2-year mortality, total length of bowel resection, and development of short bowel syndrome, were analyzed. Effects of delayed vascular consultation alone, delayed vascular surgery alone, no revascularization during admission, and admitting service on outcomes were also examined on subgroup analyses. RESULTS: A total of 212 patients were analyzed. Ninety-nine patients received ER, whereas the remaining 113 patients experienced a DR after hospital presentation. Among the DR group, 55 patients (25.9%) had delayed vascular consultation, whereas vascular surgery was deferred until after the initial operation in 37 patients (17.4%). Fifty-one patients (24.0%) were never revascularized during admission. DR was a significant predictor of 30-day (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.4-4.9; P = .03) and 2-year mortality (hazard ratio, 1.55, 95% CI, 1.0-2.3; P = .04). DR was also independently associated with increased bowel resection length (OR, 7.47; P < .01) and postoperative short bowel syndrome (OR, 2.4; P = .03) on multivariate analyses. When examined separately on subgroup analysis, both delayed vascular consultation (OR, 3.38; P = .03) and vascular surgery (OR, 4.31; P < .01) independently increased risk of 30-day mortality. Hospital discharge after AMI without mesenteric revascularization was associated with increased risk of short bowel syndrome (OR, 2.94; P < .01) and late mortality (hazard ratio, 1.60; P = .04). CONCLUSIONS: Delayed vascular consultation and vascular surgery are both significant hospital-based determinants of postoperative mortality and short bowel syndrome in patients with AMI. Timing-based management protocols that emphasize routine evaluation by a vascular surgeon and early, definitive mesenteric revascularization should be established and widely adopted for all patients with clinically suspected AMI at presentation.

Contemporary management of acute and chronic mesenteric ischemia: 10-year experience from a multihospital healthcare system.

OBJECTIVE: Endovascular and hybrid methods have been increasingly used to treat mesenteric ischemia. However, the long-term outcomes and risk of symptom recurrence remain unknown. The objective of the present study was to define the predictors of postoperative morbidity, mortality, and patency loss for acute mesenteric ischemia (AMI) and chronic mesenteric ischemia (CMI). METHODS: The inpatient and follow-up records for all patients who had undergone revascularization for AMI and CMI from 2010 to 2020 at a multicenter hospital system were reviewed. Patency and mortality were evaluated with Cox regression, visualized with Kaplan-Meier curves, and compared using log-rank testing. Patency was further evaluated using Fine-Gray regression with death as a competing risk. The postoperative major adverse events (MAE) and 30-day mortality were evaluated with logistic regression. RESULTS: A total of 407 patients were included, 148 with AMI and 259 with CMI. For the AMI group, the 30-day mortality was 31%. Open surgery was associated with lower rates of bowel resection (odds ratio [OR], 0.23; 95% confidence interval [CI], 0.13-0.61). The etiology of AMI also did not change the outcomes (OR, 1.30; 95% CI, 0.77-2.19). Adjusted analyses indicated that a history of diabetes (OR, 2.77; 95% CI, 1.37-5.61) and sepsis on presentation (OR, 2.32; 95% CI, 1.18-4.58) were independently associated with an increased risk of 30-day MAE. In the CMI group, open surgery and chronic kidney disease were associated with a higher incidence of MAE (OR, 3.03; 95% CI, 1.14-8.05; OR, 2.37; 95% CI, 1.31-4.31). In contrast, chronic kidney disease (OR, 3.02; 95% CI, 1.10-8.37) and inpatient status before revascularization (OR, 2.78; 95% CI, 1.01-7.61) were associated with increased 30-day mortality. For the CMI group, the endovascular cohort had experienced greater rates of symptom recurrence (29% vs 13%) with a faster onset (endovascular, 64 days; vs bypass, 338 days). CONCLUSIONS: AMI remains a morbid disease despite the evolving revascularization techniques. An open approach should remain the reference standard because it reduces the likelihood of bowel resection. For CMI, endovascular interventions have improved the postoperative morbidity but have also resulted in early symptom recurrence and reintervention. An endovascular-first approach should be the standard of care for CMI with close surveillance.

Donor-derived regulatory dendritic cell infusion results in host cell cross-dressing and T cell subset changes in prospective living donor liver transplant recipients.

Regulatory dendritic cells (DCreg) promote transplant tolerance following their adoptive transfer in experimental animals. We investigated the feasibility, safety, fate, and impact on host T cells of donor monocyte-derived DCreg infused into prospective, living donor liver transplant patients, 7 days before transplantation. The DCreg expressed a tolerogenic gene transcriptional profile, high cell surface programed death ligand-1 (PD-L1):CD86 ratios, high IL-10/no IL-12 productivity and poor ability to stimulate allogeneic T cell proliferation. Target DCreg doses (range 2.5-10 × 106 cells/kg) were achieved in all but 1 of 15 recipients, with no infusion reactions. Following DCreg infusion, transiently elevated levels of donor HLA and immunoregulatory PD-L1, CD39, and CD73 were detected in circulating small extracellular vesicles. At the same time, flow and advanced image stream analysis revealed intact DCreg and "cross-dressing" of host DCs in blood and lymph nodes. PD-L1 co-localization with donor HLA was observed at higher levels than with recipient HLA. Between DCreg infusion and transplantation, T-bethi Eomeshi memory CD8+ T cells decreased, whereas regulatory (CD25hi CD127- Foxp3+ ): T-bethi Eomeshi CD8+ T cell ratios increased. Thus, donor-derived DCreg infusion may induce systemic changes in host antigen-presenting cells and T cells potentially conducive to modulated anti-donor immune reactivity at the time of transplant.

Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus.

Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination.

Donor-derived regulatory dendritic cell infusion modulates effector CD8+ T cell and NK cell responses after liver transplantation.

Immune cell-based therapies are promising strategies to facilitate immunosuppression withdrawal after organ transplantation. Regulatory dendritic cells (DCreg) are innate immune cells that down-regulate alloimmune responses in preclinical models. Here, we performed clinical monitoring and comprehensive assessment of peripheral and allograft tissue immune cell populations in DCreg-infused live-donor liver transplant (LDLT) recipients up to 12 months (M) after transplant. Thirteen patients were given a single infusion of donor-derived DCreg 1 week before transplant (STUDY) and were compared with 40 propensity-matched standard-of-care (SOC) patients. Donor-derived DCreg infusion was well tolerated in all STUDY patients. There were no differences in postoperative complications or biopsy-confirmed acute rejection compared with SOC patients up to 12M. DCreg administration was associated with lower frequencies of effector T-bet+Eomes+CD8+ T cells and CD16bright natural killer (NK) cells and an increase in putative tolerogenic CD141+CD163+ DCs compared with SOC at 12M. Antidonor proliferative capacity of interferon-γ+ (IFN-γ+) CD4+ and CD8+ T cells was lower compared with antithird party responses in STUDY participants, but not in SOC patients, at 12M. In addition, lower circulating concentrations of interleukin-12p40 (IL-12p40), IFN-γ, and CXCL10 were detected in STUDY participants compared with SOC patients at 12M. Analysis of 12M allograft biopsies revealed lower frequencies of graft-infiltrating CD8+ T cells, as well as attenuation of cytolytic TH1 effector genes and pathways among intragraft CD8+ T cells and NK cells, in DCreg-infused patients. These reductions may be conducive to reduced dependence on immunosuppressive drug therapy or immunosuppression withdrawal.

Intravascular ultrasound evaluation during iliofemoral venous stenting is associated with improved midterm patency outcomes.

OBJECTIVE: Intravascular ultrasound (IVUS) examination is increasingly used in the treatment of iliofemoral venous disease and provides more sensitive and specific detection of stenotic lesions when compared with traditional multiplanar venography alone. Correlations with deep venous stent patency, however, have not yet been investigated. The objective of the study was to evaluate the impact of the use of IVUS examination in addition to multiplanar venography on iliofemoral venous patency. METHODS: Consecutive patients who underwent stenting for symptomatic thrombotic or nonthrombotic iliofemoral venous lesions (NIVLs) between 2014 and 2020 at a single institution were identified and divided into two groups based on whether IVUS examination was used before stent deployment in addition to multiplanar venography compared with venography alone. A retrospective review of demographic, operative, and follow-up data was performed. Thirty-day and 2-year stent patency were measured as primary end points. χ2 analysis, logistic regression models, and Kaplan-Meier survival analysis were used to determine outcomes. Technical details and outcomes were additionally examined among patients treated for acute deep venous thrombosis, post-thrombotic syndrome, or NIVLs separately on subgroup analysis. RESULTS: We identified 150 patients (173 limbs, 23 bilateral) who underwent iliofemoral stenting during the study period at our institution (mean age: 48.8 ± 16.8 years, 61% female). Adjunctive IVUS utilization before stent deployment was reported in 69 of 173 (39.9%) treated limbs. IVUS examination was more likely to be used in patients who underwent stenting for NIVLs compared with thrombotic disease (41.0% vs 11.2%, P < .01). There was no difference in the number of stents deployed between IVUS and non-IVUS cohorts. However, IVUS examination was associated with the increased total length of the stent deployed (126 ± 56 vs 112 ± 48 mm, P = .04) and a higher rate of infrainguinal stent extension (17.4% vs 6.7%, P = .03). In addition, mean stent diameter was significantly higher when IVUS examination was performed before stent placement (16.3 ± 3.7 vs 15.2 ± 1.9 mm, P < .01). Both 30-day (98.5% vs 89.4%, P = .02) and 2-year (90.3% vs 78.7%, P = .03) primary patency were significantly higher in the IVUS cohort. Adjunctive IVUS use was found to significantly protect against stent reintervention at 2 years on adjusted Cox regression analysis (hazard ratio: 0.22, 95% confidence interval: 0.07-0.71, P = .01). CONCLUSIONS: Adjunctive IVUS utilization is associated with differences in stent diameter and length selections as well as landing segments in the treatment of thrombotic and nonthrombotic iliofemoral venous disease. IVUS examination before stent deployment significantly protects against 30-day and 2-year stent reintervention when compared with the use of multiplanar venography alone. These data provide stronger evidence for routine IVUS use in addition to venography before iliofemoral venous stenting.

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection.

Liver allograft recipients are more likely to develop transplantation tolerance than those that receive other types of organ graft. Experimental studies suggest that immune cells and other non-parenchymal cells in the unique liver microenvironment play critical roles in promoting liver tolerogenicity. Of these, liver interstitial dendritic cells (DCs) are heterogeneous, innate immune cells that appear to play pivotal roles in the instigation, integration and regulation of inflammatory responses after liver transplantation. Interstitial liver DCs (recruited in situ or derived from circulating precursors) have been implicated in regulation of both ischemia/reperfusion injury (IRI) and anti-donor immunity. Thus, livers transplanted from mice constitutively lacking DCs into syngeneic, wild-type recipients, display increased tissue injury, indicating a protective role of liver-resident donor DCs against transplant IRI. Also, donor DC depletion before transplant prevents mouse spontaneous liver allograft tolerance across major histocompatibility complex (MHC) barriers. On the other hand, mouse liver graft-infiltrating host DCs that acquire donor MHC antigen via "cross-dressing", regulate anti-donor T cell reactivity in association with exhaustion of graft-infiltrating T cells and promote allograft tolerance. In an early phase clinical trial, infusion of donor-derived regulatory DCs (DCreg) before living donor liver transplantation can induce alterations in host T cell populations that may be conducive to attenuation of anti-donor immune reactivity. We discuss the role of DCs in regulation of warm and liver transplant IRI and the induction of liver allograft tolerance. We also address design of cell therapies using DCreg to reduce the immunosuppressive drug burden and promote clinical liver allograft tolerance.

Detection and Monitoring of Regulatory Immune Cells Following Their Adoptive Transfer in Organ Transplantation.

Application of cell-based immunotherapy in organ transplantation to minimize the burden of immunosuppressive medication and promote allograft tolerance has expanded significantly over the past decade. Adoptively transferred regulatory immune cells prolong allograft survival and transplant tolerance in pre-clinical models. Many cell products are currently under investigation in early phase human clinical trials designed to assess feasibility and safety. Despite rapid advances in manufacturing practices, defining the appropriate protocol that will optimize in vivo conditions for tolerance induction remains a major challenge and depends heavily on understanding the fate, biodistribution, functional stability and longevity of the cell product after administration. This review focuses on in vivo detection and monitoring of various regulatory immune cell types administered for allograft tolerance induction in both pre-clinical animal models and early human clinical trials. We discuss the current status of various non-invasive methods for tracking regulatory cell products in the context of organ transplantation and implications for enhanced understanding of the therapeutic potential of cell-based therapy in the broad context of control of immune-mediated inflammatory disorders.