Vascular endotheliitis associated with infections: Its pathogenetic role and therapeutic implication.

Vascular endothelial cells are major participants in and regulators of immune responses and inflammation. Vascular endotheliitis is regarded as a host immune-inflammatory response of the endothelium forming the inner surface of blood vessels in association with a direct consequence of infectious pathogen invasion. Vascular endotheliitis and consequent endothelial dysfunction can be a principle determinant of microvascular failure, which would favor impaired perfusion, tissue hypoxia, and subsequent organ failure. Emerging evidence suggests the role of vascular endotheliitis in the pathogenesis of coronavirus disease 2019 (COVID-19) and its related complications. Thus, once initiated, vascular endotheliitis and resultant cytokine storm cause systemic hyperinflammation and a thrombotic phenomenon in COVID-19, leading to acute respiratory distress syndrome and widespread organ damage. Vascular endotheliitis also appears to be a contributory factor to vasculopathy and coagulopathy in sepsis that is defined as life-threatening organ dysfunction due to a dysregulated response of the host to infection. Therefore, protecting endothelial cells and reversing vascular endotheliitis may be a leading therapeutic goal for these diseases associated with vascular endotheliitis. In this review, we outline the etiological and pathogenic importance of vascular endotheliitis in infection-related inflammatory diseases, including COVID-19, and possible mechanisms leading to vascular endotheliitis. We also discuss pharmacological agents which may be now considered as potential endotheliitis-based treatment modalities for those diseases.

Vasculopathy in COVID-19.

COVID-19 is a primary respiratory illness that is frequently complicated by systemic involvement of the vasculature. Vascular involvement leads to an array of complications ranging from thrombosis to pulmonary edema secondary to loss of barrier function. This review will address the vasculopathy of COVID-19 with a focus on the role of the endothelium in orchestrating the systemic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The endothelial receptor systems and molecular pathways activated in the setting of COVID-19 and the consequences of these inflammatory and prothrombotic changes on endothelial cell function will be discussed. The sequelae of COVID-19 vascular involvement at the level of organ systems will also be addressed, with an emphasis on the pulmonary vasculature but with consideration of effects on other vascular beds. The dramatic changes in endothelial phenotypes associated with COVID-19 has enabled the identification of biomarkers that could help guide therapy and predict outcomes. Knowledge of vascular pathogenesis in COVID-19 has also informed therapeutic approaches that may control its systemic sequelae. Because our understanding of vascular response in COVID-19 continues to evolve, we will consider areas of controversy, such as the extent to which SARS-CoV-2 directly infects endothelium and the degree to which vascular responses to SARS-CoV-2 are unique or common to those of other viruses capable of causing severe respiratory disease. This conceptual framework describing how SARS-CoV-2 infection affects endothelial inflammation, prothrombotic transformation, and barrier dysfunction will provide a context for interpreting new information as it arises addressing the vascular complications of COVID-19.

Endothelial Dysfunction, Inflammation, and Oxidative Stress in COVID-19-Mechanisms and Therapeutic Targets.

The outbreak of the COVID-19 pandemic represents an ongoing healthcare emergency responsible for more than 3.4 million deaths worldwide. COVID-19 is the disease caused by SARS-CoV-2, a virus that targets not only the lungs but also the cardiovascular system. COVID-19 can manifest with a wide range of clinical manifestations, from mild symptoms to severe forms of the disease, characterized by respiratory failure due to severe alveolar damage. Several studies investigated the underlying mechanisms of the severe lung damage associated with SARS-CoV-2 infection and revealed that the respiratory failure associated with COVID-19 is the consequence not only of acute respiratory distress syndrome but also of macro- and microvascular involvement. New observations show that COVID-19 is an endothelial disease, and the consequent endotheliopathy is responsible for inflammation, cytokine storm, oxidative stress, and coagulopathy. In this review, we show the central role of endothelial dysfunction, inflammation, and oxidative stress in the COVID-19 pathogenesis and present the therapeutic targets deriving from this endotheliopathy.

From cellular function to global impact: the vascular perspective on COVID-19.

Since COVID-19 was declared a pandemic a year ago, our understanding of its effects on the vascular system has slowly evolved. At the cellular level, SARS-CoV-2 - the virus that causes COVID-19 - accesses the vascular endothelium through the angiotensin-converting enzyme 2 (ACE-2) receptor and induces proinflammatory and prothrombotic responses. At the clinical level, these pathways lead to thromboembolic events that affect the pulmonary, extracranial, mesenteric, and lower extremity vessels. At the population level, the presence of vascular risk factors predisposes individuals to more severe forms of COVID-19, whereas the absence of vascular risk factors does not spare patients with COVID-19 from unprecedented rates of stroke, pulmonary embolism and acute limb ischemia. Finally, at the community and global level, the fear of COVID-19, measures taken to limit the spread of SARS-CoV-2 and reallocation of limited hospital resources have led to delayed presentations of severe forms of ischemia, surgery cancellations and missed opportunities for limb salvage. The purpose of this narrative review is to present some of the data on COVID-19, from cellular mechanisms to clinical manifestations, and discuss its impact on the local and global surgical communities from a vascular perspective.

Depuis que la COVID-19 s'est vu donner le statut de pandémie il y a 1 an, notre connaissance des effets de cette maladie sur le système vasculaire a évolué. À l'échelle cellulaire, le SRAS-CoV-2 ­ le virus qui cause la COVID-19 ­ accède à l'endothélium vasculaire par le récepteur de l'enzyme de conversion de l'angiotensine-2 (ACE-2) et provoque des réponses proinflammatoires et prothrombotiques. À l'échelle clinique, ces réponses peuvent mener à une activité thromboembolique touchant les vaisseaux pulmonaires, extracrâniens, mésentériques et des membres inférieurs. À l'échelle populationnelle, la présence chez certaines personnes de facteurs de risque vasculaires les prédispose à une forme plus grave de la COVID-19, mais l'absence de ces facteurs n'empêche pas les patients atteints de la COVID-19 de présenter des taux sans précédent d'AVC, d'embolie pulmonaire et d'ischémie aiguë aux membres. Enfin, à l'échelle locale et mondiale, la peur entourant la COVID-19, les mesures prises pour en endiguer la propagation et le redéploiement des ressources limitées des hôpitaux ont mené au report de visites à l'hôpital pour des formes graves d'ischémie, à l'annulation de chirurgies et à des occasions manquées de préserver des membres. La présente revue non systématique a pour objectif de présenter une partie des données sur la COVID-19, de ses mécanismes cellulaires à ses manifestations cliniques, et de discuter des répercussions de la crise sur les communautés chirurgicales locales et mondiales, dans une optique vasculaire.

Efficacy of synthetic glucocorticoids in COVID-19 endothelites.

Since March 2020, the world has been fighting a global pandemic caused by a new coronavirus SARS-CoV-2 (COVID-19). SARS-CoV-2 is responsible for severe acute respiratory syndrome, an airway disease that can be severe and fatal in a percentage of cases. Patients with severe COVID-19 can develop extrapulmonary lesions, with renal, hepatic, cardiac, neurological, and tissue involvement that can cause further severe complications. On December 21, 2021, the European Medicines Agency (EMA) authorized the marketing of the first COVID-19 vaccine. However, several randomized trials are ongoing to find effective, safe, and widely available treatments. The most severe stages of COVID-19 infection are characterized by a multi-system inflammatory state induced by a cytokine storm causing multi-organ injury. Epidemiologic evidence has shown that glucocorticoids (GCs), particularly dexamethasone, are used in severe, hospitalized patients with COVID-19 with good therapeutic benefit. COVID-19 can also damage the endothelial system, causing microcirculatory disturbances and consequently leading to functional organ disorders. The combination of endothelial dysfunction with a generalized inflammatory state may contribute to the general pro-coagulative state described in patients with COVID-19 with increased risk of venous and arterial occlusions. The aim of this article is to describe the therapeutic utility of GCs in stabilizing the vascular endothelial barrier in COVID-19 infection. Indeed, we believe that the stabilization of the endothelial barrier and the anti-inflammatory effect of GCs could be the main effect underlying the therapeutic efficacy in COVID-19 patients.

Commonalities Between COVID-19 and Radiation Injury.

As the multi-systemic components of COVID-19 emerge, parallel etiologies can be drawn between SARS-CoV-2 infection and radiation injuries. While some SARS-CoV-2-infected individuals present as asymptomatic, others exhibit mild symptoms that may include fever, cough, chills, and unusual symptoms like loss of taste and smell and reddening in the extremities (e.g., "COVID toes," suggestive of microvessel damage). Still others alarm healthcare providers with extreme and rapid onset of high-risk indicators of mortality that include acute respiratory distress syndrome (ARDS), multi-organ hypercoagulation, hypoxia and cardiovascular damage. Researchers are quickly refocusing their science to address this enigmatic virus that seems to unveil itself in new ways without discrimination. As investigators begin to identify early markers of disease, identification of common threads with other pathologies may provide some clues. Interestingly, years of research in the field of radiation biology documents the complex multiorgan nature of another disease state that occurs after exposure to high doses of radiation: the acute radiation syndrome (ARS). Inflammation is a key common player in COVID-19 and ARS, and drives the multi-system damage that dramatically alters biological homeostasis. Both conditions initiate a cytokine storm, with similar pro-inflammatory molecules increased and other anti-inflammatory molecules decreased. These changes manifest in a variety of ways, with a demonstrably higher health impact in patients having underlying medical conditions. The potentially dramatic human impact of ARS has guided the science that has identified many biomarkers of radiation exposure, established medical management strategies for ARS, and led to the development of medical countermeasures for use in the event of a radiation public health emergency. These efforts can now be leveraged to help elucidate mechanisms of action of COVID-19 injuries. Furthermore, this intersection between COVID-19 and ARS may point to approaches that could accelerate the discovery of treatments for both.

COVID-19: A double threat to takotsubo cardiomyopathy and spontaneous coronary artery dissection?

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic that has affected millions of individuals worldwide. Prior studies suggest that COVID-19 may be associated with an increased risk for various cardiovascular disorders, such as myocardial injury, arrhythmia, acute coronary syndrome, and venous thromboembolism. Early reports of non-COVID-19 patients have described the concurrence of takotsubo cardiomyopathy (TTC) and spontaneous coronary artery dissection (SCAD). However, the interplay between COVID-19, TTC and SCAD has not been well established. We herein propose two sets of two-hit hypotheses for the development of SCAD and TTC in the context of COVID-19. The first two-hit hypothesis explains the development of SCAD, in which TTC-associated formation of vulnerable coronary substrate serves as the first hit (predisposing factor), and COVID-19-associated inflammation and vascular disruption serves as the second hit (precipitating factor). The second two-hit hypothesis is proposed to explain the development of TTC, in which SCAD-associated formation of vulnerable myocardial substrate serves as the first hit, and COVID-19-associated sympathetic overactivity serves as the second hit. Under this conceptual framework, COVID-19 poses a double threat for the development of SCAD (among patients with underlying TTC) as well as TTC (among patients with underlying SCAD), thereby forming a reciprocal causation. This hypothesis provides a rationale for the joint assessment of TTC and SCAD in COVID-19 patients with pertinent cardiovascular manifestations.

Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation.

The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.

Endothelial dysfunction contributes to COVID-19-associated vascular inflammation and coagulopathy.

Great attention has been paid to endothelial dysfunction (ED) in coronavirus disease 2019 (COVID-19). There is growing evidence to suggest that the angiotensin converting enzyme 2 receptor (ACE2 receptor) is expressed on endothelial cells (ECs) in the lung, heart, kidney, and intestine, particularly in systemic vessels (small and large arteries, veins, venules, and capillaries). Upon viral infection of ECs by severe acute respiratory syndrome coronarvirus 2 (SARS-CoV-2), ECs become activated and dysfunctional. As a result of endothelial activation and ED, the levels of pro-inflammatory cytokines (interleukin -1, interleukin-6 (IL-6), and tumor necrosis factor-α), chemokines (monocyte chemoattractant protein-1), von Willebrand factor (vWF) antigen, vWF activity, and factor VIII are elevated. Higher levels of acute phase reactants (IL-6, C-reactive protein, and D-dimer) are also associated with SARS-CoV-2 infection. Therefore, it is reasonable to assume that ED contributes to COVID-19-associated vascular inflammation, particularly endotheliitis, in the lung, heart, and kidney, as well as COVID-19-associated coagulopathy, particularly pulmonary fibrinous microthrombi in the alveolar capillaries. Here we present an update on ED-relevant vasculopathy in COVID-19. Further research for ED in COVID-19 patients is warranted to understand therapeutic opportunities.

Nailfold capillaroscopy findings in patients with coronavirus disease 2019: Broadening the spectrum of COVID-19 microvascular involvement.

OBJECTIVE: Increasing evidence points to endothelial dysfunction as a key pathophysiological factor in coronavirus disease-2019 (COVID-19). No specific methods have been identified to predict, detect and quantify the microvascular alterations during COVID-19. Our aim was to assess microvasculature through nailfold videocapillaroscopy (NVC) in COVID-19 patients. METHODS: We performed NVC in patients with a confirmed diagnosis of COVID-19 pneumonia. Elementary alterations were reported for each finger according to a semi-quantitative score. Capillary density, number of enlarged and giant capillaries, number of micro-hemorrhages and micro-thrombosis (NEMO score) were registered. RESULTS: We enrolled 82 patients (mean age 58.8 ± 13.2 years, male 68.3%) of whom 28 during the hospitalization and 54 after recovery and hospital discharge. At NVC examination we found abnormalities classifiable as non-specific pattern in 53 patients (64.6%). Common abnormalities were pericapillary edema (80.5%), enlarged capillaries (61.0%), sludge flow (53.7%), meandering capillaries and reduced capillary density (50.0%). No pictures suggestive of scleroderma pattern have been observed. Acute COVID-19 patients, compared to recovered patients, showed a higher prevalence of hemosiderin deposits as a result of micro-hemorrhages (P = .027) and micro-thrombosis (P < .016), sludge flow (P = .001), and pericapillary edema (P < .001), while recovered patients showed a higher prevalence of enlarged capillaries (P < .001), loss of capillaries (P = .002), meandering capillaries (P < .001), and empty dermal papillae (P = .006). CONCLUSION: COVID-19 patients present microvascular abnormalities at NVC. Currently ill and recovered subjects are characterized by a different distribution of elementary capillaroscopic alterations, resembling acute and post-acute microvascular damage. Further studies are needed to assess the clinical relevance of NVC in COVID-19.

Linking ACE2 and angiotensin II to pulmonary immunovascular dysregulation in SARS-CoV-2 infection.

Angiotensin-converting enzyme 2 (ACE2) is the receptor of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic. ACE2 has been shown to be down-regulated during coronaviral infection, with implications for circulatory homeostasis. In COVID-19, pulmonary vascular dysregulation has been observed resulting in ventilation perfusion mismatches in lung tissue, causing profound hypoxemia. Despite the loss of ACE2 and raised circulating vasoconstrictor angiotensin II (AngII), COVID-19 patients experience a vasodilative vasculopathy. This article discusses the interplay between the immune system and pulmonary vasculature and how SARS-CoV-2-mediated ACE2 disruption and AngII may contribute to the novel vascular pathophysiology of COVID-19.

Pulmonary Angiopathy in Severe COVID-19: Physiologic, Imaging, and Hematologic Observations.

Rationale: Clinical and epidemiologic data in coronavirus disease (COVID-19) have accrued rapidly since the outbreak, but few address the underlying pathophysiology.Objectives: To ascertain the physiologic, hematologic, and imaging basis of lung injury in severe COVID-19 pneumonia.Methods: Clinical, physiologic, and laboratory data were collated. Radiologic (computed tomography (CT) pulmonary angiography [n = 39] and dual-energy CT [DECT, n = 20]) studies were evaluated: observers quantified CT patterns (including the extent of abnormal lung and the presence and extent of dilated peripheral vessels) and perfusion defects on DECT. Coagulation status was assessed using thromboelastography.Measurements and Results: In 39 consecutive patients (male:female, 32:7; mean age, 53 ± 10 yr [range, 29-79 yr]; Black and minority ethnic, n = 25 [64%]), there was a significant vascular perfusion abnormality and increased physiologic dead space (dynamic compliance, 33.7 ± 14.7 ml/cm H2O; Murray lung injury score, 3.14 ± 0.53; mean ventilatory ratios, 2.6 ± 0.8) with evidence of hypercoagulability and fibrinolytic "shutdown". The mean CT extent (±SD) of normally aerated lung, ground-glass opacification, and dense parenchymal opacification were 23.5 ± 16.7%, 36.3 ± 24.7%, and 42.7 ± 27.1%, respectively. Dilated peripheral vessels were present in 21/33 (63.6%) patients with at least two assessable lobes (including 10/21 [47.6%] with no evidence of acute pulmonary emboli). Perfusion defects on DECT (assessable in 18/20 [90%]) were present in all patients (wedge-shaped, n = 3; mottled, n = 9; mixed pattern, n = 6).Conclusions: Physiologic, hematologic, and imaging data show not only the presence of a hypercoagulable phenotype in severe COVID-19 pneumonia but also markedly impaired pulmonary perfusion likely caused by pulmonary angiopathy and thrombosis.

Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study.

BACKGROUND: An important feature of severe acute respiratory syndrome coronavirus 2 pathogenesis is COVID-19-associated coagulopathy, characterised by increased thrombotic and microvascular complications. Previous studies have suggested a role for endothelial cell injury in COVID-19-associated coagulopathy. To determine whether endotheliopathy is involved in COVID-19-associated coagulopathy pathogenesis, we assessed markers of endothelial cell and platelet activation in critically and non-critically ill patients admitted to the hospital with COVID-19. METHODS: In this single-centre cross-sectional study, hospitalised adult (≥18 years) patients with laboratory-confirmed COVID-19 were identified in the medical intensive care unit (ICU) or a specialised non-ICU COVID-19 floor in our hospital. Asymptomatic, non-hospitalised controls were recruited as a comparator group for biomarkers that did not have a reference range. We assessed markers of endothelial cell and platelet activation, including von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand, as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes. We compared the level of each marker in ICU patients, non-ICU patients, and controls, where applicable. We assessed correlations between these laboratory results with clinical outcomes, including hospital discharge and mortality. Kaplan-Meier analysis was used to further explore the association between biochemical markers and survival. FINDINGS: 68 patients with COVID-19 were included in the study from April 13 to April 24, 2020, including 48 ICU and 20 non-ICU patients, as well as 13 non-hospitalised, asymptomatic controls. Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen (mean 565% [SD 199] in ICU patients vs 278% [133] in non-ICU patients; p<0·0001) and soluble P-selectin (15·9 ng/mL [4·8] vs 11·2 ng/mL [3·1]; p=0·0014). VWF antigen concentrations were also elevated above the normal range in 16 (80%) of 20 non-ICU patients. We found mortality to be significantly correlated with VWF antigen (r = 0·38; p=0·0022) and soluble thrombomodulin (r = 0·38; p=0·0078) among all patients. In all patients, soluble thrombomodulin concentrations greater than 3·26 ng/mL were associated with lower rates of hospital discharge (22 [88%] of 25 patients with low concentrations vs 13 [52%] of 25 patients with high concentrations; p=0·0050) and lower likelihood of survival on Kaplan-Meier analysis (hazard ratio 5·9, 95% CI 1·9-18·4; p=0·0087). INTERPRETATION: Our findings show that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death. Early identification of endotheliopathy and strategies to mitigate its progression might improve outcomes in COVID-19. FUNDING: This work was supported by a gift donation from Jack Levin to the Benign Hematology programme at Yale, and the National Institutes of Health.