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Angiopoietin 2 Is Associated with Vascular Necroptosis Induction in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome.

ABSTRACT: Vascular injury is a well-established, disease-modifying factor in acute respiratory distress syndrome (ARDS) pathogenesis. Recently, coronavirus disease 2019 (COVID-19)-induced injury to the vascular compartment has been linked to complement activation, microvascular thrombosis, and dysregulated immune responses. This study sought to assess whether aberrant vascular activation in this prothrombotic context was associated with the induction of necroptotic vascular cell death. To achieve this, proteomic analysis was performed on blood samples from COVID-19 subjects at distinct time points during ARDS pathogenesis (hospitalized at risk, N = 59; ARDS, N = 31; and recovery, N = 12). Assessment of circulating vascular markers in the at-risk cohort revealed a signature of low vascular protein abundance that tracked with low platelet levels and increased mortality. This signature was replicated in the ARDS cohort and correlated with increased plasma angiopoietin 2 levels. COVID-19 ARDS lung autopsy immunostaining confirmed a link between vascular injury (angiopoietin 2) and platelet-rich microthrombi (CD61) and induction of necrotic cell death [phosphorylated mixed lineage kinase domain-like (pMLKL)]. Among recovery subjects, the vascular signature identified patients with poor functional outcomes. Taken together, this vascular injury signature was associated with low platelet levels and increased mortality and can be used to identify ARDS patients most likely to benefit from vascular targeted therapies.

SUBMITTER: Price DR

PROVIDER: S-EPMC9027298 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Angiopoietin 2 Is Associated with Vascular Necroptosis Induction in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome.

Price David R DR Benedetti Elisa E Hoffman Katherine L KL Gomez-Escobar Luis L Alvarez-Mulett Sergio S Capili Allyson A Sarwath Hina H Parkhurst Christopher N CN Lafond Elyse E Weidman Karissa K Ravishankar Arjun A Cheong Jin Gyu JG Batra Richa R Büyüközkan Mustafa M Chetnik Kelsey K Easthausen Imaani I Schenck Edward J EJ Racanelli Alexandra C AC Outtz Reed Hasina H Laurence Jeffrey J Josefowicz Steven Z SZ Lief Lindsay L Choi Mary E ME Schmidt Frank F Borczuk Alain C AC Choi Augustine M K AMK Krumsiek Jan J Rafii Shahin S

The American journal of pathology 20220422 7

Vascular injury is a well-established, disease-modifying factor in acute respiratory distress syndrome (ARDS) pathogenesis. Recently, coronavirus disease 2019 (COVID-19)-induced injury to the vascular compartment has been linked to complement activation, microvascular thrombosis, and dysregulated immune responses. This study sought to assess whether aberrant vascular activation in this prothrombotic context was associated with the induction of necroptotic vascular cell death. To achieve this, pr ...[more]

PMID: 35469796

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Project description:ObjectivesTo characterize the incidence and characteristics of propofol-associated hypertriglyceridemia in coronavirus disease 2019 versus noncoronavirus disease 2019 acute respiratory distress syndrome.DesignSingle-center prospective, observational cohort study.SettingMedical ICU and regional infectious containment unit.PatientsPatients with acute respiratory distress syndrome admitted from April 7, 2020, to May 15, 2020, requiring continuous propofol administration.InterventionsNone.Measurements and main resultsOf 50 patients enrolled, 54% had coronavirus disease 2019 acute respiratory distress syndrome. Median Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were 35.5 (interquartile range, 30.2-41) and 8 (interquartile range, 6-9). Pao2/Fio2 ratio was 130.5 (interquartile range, 94.5-193.8). Patients with coronavirus disease 2019-associated acute respiratory distress syndrome experienced a higher rate of hypertriglyceridemia (triglyceride ≥ 500 mg/dL) than noncoronavirus disease 2019-associated acute respiratory distress syndrome (9 [33.3%] vs 1 [4.3%]; p = 0.014). Those with coronavirus disease 2019, compared with those without, received more propofol prior to becoming hypertriglyceridemic (median, 5,436.0 mg [interquartile range, 3,405.5-6,845.5 mg] vs 4,229.0 mg [interquartile range, 2,083.4-4,972.1 mg]; p = 0.027). After adjustment for propofol dose with logistic regression (odds ratio, 5.97; 95% CI, 1.16-59.57; p = 0.031) and propensity score matching (odds ratio, 8.64; 95% CI, 1.27-149.12; p = 0.025), there remained a significant difference in the development of hypertriglyceridemia between coronavirus disease 2019-associated acute respiratory distress syndrome and noncoronavirus disease 2019-associated acute respiratory distress syndrome. There was no difference between groups in time to hypertriglyceridemia (p = 0.063). Serum lipase was not different between those who did or did not develop hypertriglyceridemia (p = 0.545). No patients experienced signs or symptoms of pancreatitis.ConclusionsPatients with coronavirus disease 2019 acute respiratory distress syndrome experienced a higher rate of propofol-associated hypertriglyceridemia than noncoronavirus disease 2019 acute respiratory distress syndrome patients, even after accounting for differences in propofol administration.

Project description:ObjectivesMicrovascular thrombosis contributes to acute respiratory distress syndrome pathophysiology and has been demonstrated in coronavirus disease 2019-associated acute respiratory distress syndrome. Clinical laboratory measurements of coagulation and disseminated intravascular coagulation, such as coagulation factor function, platelet count, and fibrinogen, may not fully reflect the extent of microvascular thrombosis present in these patients. We investigated thromboelastography in patients with coronavirus disease 2019-associated acute respiratory distress syndrome with the objective of characterizing suspected coagulopathy and impaired fibrinolysis.DesignRetrospective observational cohort study.SettingSingle-center academic medical center.PatientsTen patients with polymerase chain reaction-confirmed coronavirus disease 2019 disease complicated by acute respiratory distress syndrome.InterventionsMeasurement of thromboelastography (n = 10) and thrombolysis with alteplase (n = 4).Measurements and main resultsHypercoagulability and decreased or absent fibrinolysis were demonstrated by thromboelastography. Thrombocytopenia and hypofibrinogenemia were not observed, while seven of 10 patients had elevated d-dimer values. For patients who received thrombolytic therapy, repeat thromboelastography demonstrated improvements in coagulation index and lysis at 30 minutes reflecting reduced hypercoagulability and increased fibrinolysis. One major bleeding complication was detected following thrombolysis. Eight of 10 patients survived and were successfully extubated, and six of 10 have since been discharged.ConclusionsIn coronavirus disease 2019 patients with acute respiratory distress syndrome in whom thromboelastography was performed, hypercoagulability and impaired fibrinolysis were observed. In the context of autopsy studies demonstrating pulmonary microvascular thromboses in coronavirus disease 2019 patients, noninvasive detection of hypercoagulability and deficient fibrinolysis in coronavirus disease 2019 acute respiratory distress syndrome using thromboelastography could improve understanding and management of coronavirus disease 2019.

Project description:ObjectivesPatients with coronavirus disease 2019 acute respiratory distress syndrome appear to present with at least two distinct phenotypes: severe hypoxemia with relatively well-preserved lung compliance and lung gas volumes (type 1) and a more conventional acute respiratory distress syndrome phenotype, displaying the typical characteristics of the "baby lung" (type 2). We aimed to test plausible hypotheses regarding the pathophysiologic mechanisms underlying coronavirus disease 2019 acute respiratory distress syndrome and to evaluate the resulting implications for ventilatory management.DesignWe adapted a high-fidelity computational simulator, previously validated in several studies of acute respiratory distress syndrome, to: 1) develop quantitative insights into the key pathophysiologic differences between the coronavirus disease 2019 acute respiratory distress syndrome and the conventional acute respiratory distress syndrome and 2) assess the impact of different positive end-expiratory pressure, Fio2, and tidal volume settings.SettingInterdisciplinary Collaboration in Systems Medicine Research Network.SubjectsThe simulator was calibrated to represent coronavirus disease 2019 acute respiratory distress syndrome patients with both normal and elevated body mass indices undergoing invasive mechanical ventilation.InterventionsNone.Measurements and main resultsAn acute respiratory distress syndrome model implementing disruption of hypoxic pulmonary vasoconstriction and vasodilation leading to hyperperfusion of collapsed lung regions failed to replicate clinical data on type 1 coronavirus disease 2019 acute respiratory distress syndrome patients. Adding mechanisms to reflect disruption of alveolar gas-exchange due to the effects of pneumonitis and heightened vascular resistance due to the emergence of microthrombi produced levels of ventilation perfusion mismatch and hypoxemia consistent with data from type 1 coronavirus disease 2019 acute respiratory distress syndrome patients, while preserving close-to-normal lung compliance and gas volumes. Atypical responses to positive end-expiratory pressure increments between 5 and 15 cm H2O were observed for this type 1 coronavirus disease 2019 acute respiratory distress syndrome model across a range of measures: increasing positive end-expiratory pressure resulted in reduced lung compliance and no improvement in oxygenation, whereas mechanical power, driving pressure, and plateau pressure all increased. Fio2 settings based on acute respiratory distress syndrome network protocols at different positive end-expiratory pressure levels were insufficient to achieve adequate oxygenation. Incrementing tidal volumes from 5 to 10 mL/kg produced similar increases in multiple indicators of ventilator-induced lung injury in the type 1 coronavirus disease 2019 acute respiratory distress syndrome model to those seen in a conventional acute respiratory distress syndrome model.ConclusionsOur model suggests that use of standard positive end-expiratory pressure/Fio2 tables, higher positive end-expiratory pressure strategies, and higher tidal volumes may all be potentially deleterious in type 1 coronavirus disease 2019 acute respiratory distress syndrome patients, and that a highly personalized approach to treatment is advisable.

Project description:BackgroundDuring the coronavirus disease 2019 (COVID-19) pandemic, lung ultrasonography (US) has been gaining importance in pediatric intensive care and emergency settings for the screening, diagnosis, and monitoring of pulmonary pathology.PurposeTo describe the pattern of lung US changes in patients with COVID-19 pneumonia and its potential role in monitoring ventilated patients.MethodsThis prospective observational study included children aged 1 month to 12 years with a confirmed diagnosis of COVID-19. Lung US was performed using a high-frequency linear probe (5-12 MHz) in all children with moderate/severe respiratory symptoms within 24 hours of admission and then daily until the patient required oxygen therapy. Lung involvement severity was assessed using lung US scores, while lung aeration improvement or deterioration was measured using lung ultrasound reaeration scores (LUSReS).ResultsOf 85 children with moderate to severe disease, 54 with pulmonary disease were included. Of them, 50 (92.5%) had an interstitial pattern, followed by pleural line abnormalities in 44 (81.5%), reduced or absent lung sliding in 31 (57.4%), and consolidation in 28 (51.8%). A significantly higher lung US score (median, 18; interquartile range [IQR], 11-22) was observed in ventilated versus nonventilated patients (median, 9; IQR, 6-11). LUSReS improvement after positive end-expiratory pressure titration was positively correlated with improved dynamic lung compliance and oxygenation indices and negatively correlated with the requirement for driving pressure. Successful weaning could be predicted with 100% specificity if loss of LUSReS ≤ 5.ConclusionInterstitial syndrome, fragmented pleural line, and subpleural microconsolidation were the most prevalent lung US findings in children with COVID-19 pneumonia. Thus, lung US may have the ability to monitor changes in lung aeration caused by mechanical ventilation and predict its successful weaning in children with COVID-19.

Dataset Information

Angiopoietin 2 Is Associated with Vascular Necroptosis Induction in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome.

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Angiopoietin 2 Is Associated with Vascular Necroptosis Induction in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome.

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