ArticleLiterature Review

Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence

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The symptoms most commonly reported by patients affected by coronavirus disease (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g., high blood pressure, arterial and venous thromboembolism, kidney disease, neurologic disorders, and diabetes mellitus) indicate that the virus is targeting the endothelium, one of the largest organs in the human body. Herein, we report a systematic and comprehensive evaluation of both clinical and preclinical evidence supporting the hypothesis that the endothelium is a key target organ in COVID-19, providing a mechanistic rationale behind its systemic manifestations. Keywords: ACE2, acute kidney injury; blood pressure; catepsin; coronavirus; COVID; cytokine storm; endothelium; heparin; Kawasaki disease.
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... Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) has been spreading across the world since December 2019. Corona Virus Disease 2019 (COVID- 19), the disorder caused by SARS-CoV-2, can present as a highly heterogenous acute condition, ranging from patients with mild respiratory symptoms to severe or critical pneumonia [1,2]. In critical cases, a significant number of subjects experience organ dysfunction (acute cardiac and kidney injury), acute respiratory distress syndrome, and eventually death. ...
... SARS-CoV-2 infection also targets the endothelium [2] and, in case of severe infection, causes multi-organ failure, resulting in a hyper-inflammatory response and eventually acute thrombosis [11]. These mechanisms are initiated by the binding of SARS-CoV-2 to ACE2 receptors [13], followed by the entrance of SARS-COV-2 into host cells by cleavage of the S protein operated by the serine protease TMPRSS2, which generate the S1 and S2 subunits [13]. ...
... Multiple mechanisms might explain the association between hyperglycemia and worst outcomes, including cardiac damage, in patients with COVID-19 [36]. SARS-CoV-2 shows a higher tendency to colonize the epithelium of the upper airways in asymptomatic patients and patients with mild clinical manifestations [2,37]. However, ACE2 is a receptor ubiquitously expressed in humans, particularly in the endothelium and other target organs [37]. ...
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Background/aims: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-stranded single-stranded RNA virus, a member of the subgenus Sarbecovirus (beta-CoV lineage B) and responsible for the coronavirus disease 2019 (COVID-19). COVID-19 encompasses a large range of disease severity, from mild symptoms to severe forms with Intensive Care Unit admission and eventually death. The severe forms of COVID-19 are usually observed in high-risk patients, such as those with type two diabetes mellitus. Here, we review the available evidence linking acute and chronic hyperglycemia to COVID-19 outcomes, describing also the putative mediators of such interactions. Findings/conclusions: Acute hyperglycemia at hospital admission represents a risk factor for poor COVID-19 prognosis in patients with and without diabetes. Acute and chronic glycemic control are both emerging as major determinants of vaccination efficacy, disease severity and mortality rate in COVID-19 patients. Mechanistically, it has been proposed that hyperglycemia might be a disease-modifier for COVID-19 through multiple mechanisms: (a) induction of glycation and oligomerization of ACE2, the main receptor of SARS-CoV-2; (b) increased expression of the serine protease TMPRSS2, responsible for S protein priming; (c) impairment of the function of innate and adaptive immunity despite the induction of higher pro-inflammatory responses, both local and systemic. Consistently, managing acute hyperglycemia through insulin infusion has been suggested to improve clinical outcomes, while implementing chronic glycemic control positively affects immune response following vaccination. Although more research is warranted to better disentangle the relationship between hyperglycemia and COVID-19, it might be worth considering glycemic control as a potential route to optimize disease prevention and management.
... As expected, COVID-19, the kidneys and the CV system are linked in a bidirectional way. On one hand, both CVD and renal disease represent a risk amplifier for morbi-mortality in the COVID-19 setting [12,13]; on the other hand COVID-19 can exacerbate associated CVD and determine de novo cardiac complications (acute myocardial injury, stress cardiomyopathy, myocarditis, pericarditis, arrhythmias, heart failure and cardiogenic shock) [3,12]. Furthermore, myocardial injury is also an important prognostic factor for the disease severity [14], as well as in-hospital and long-term mortality [14,15]. ...
... The underlying mechanisms of these manifestations and long-term complications are not completely understood, but emerging data emphasize the endothelium, as a central pillar in the long COVID conundrum, with implications in inflammation, the pro-thrombotic phenotype and disseminated intravascular coagulation [26]. Endothelial dysfunction (ED) refers to a systemic condition in which the endothelium loses its physiological properties, including the tendency to promote vasodilation, fibrinolysis, and anti-aggregation [13]. ...
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Background The coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produced a pandemic since March 2020 by affecting more than 243 million people with more than 5 million deaths globally. SARS-CoV-2 infection is produced by binding to angiotensin-converting enzyme, which among other sites is highly expressed in the endothelial cells of the blood vessels, pericytes and the heart, as well as in renal podocytes and proximal tubular epithelial cells. SARS-CoV-2 and cardiovascular disease (CVD) are interconnected by risk factors association with an increased incidence of the disease and by determining de novo cardiac complications. At the same time, COVID-19 disease can lead to acute kidney injury directly, or due to sepsis, multi-organ failure and shock. Therefore, the pre-existence of both CVD and chronic kidney disease (CKD) is linked with a higher risk of severe disease and worse prognosis. Methods The main aim of this study is to assess the CV risk in a CKD (stage 3 to 5), dialysis and kidney transplanted population, following SARS-CoV-2 infection, with focus on the endothelial dysfunction as compared to a control group of matched patients. By using clinical evaluation, flow-mediated dilatation, carotid-femoral pulse wave velocity, intima-media thickness, echocardiographic parameters, lung ultrasound, bioimpedance spectroscopy and a series of novel biomarkers, the investigators will determine the long-term impact of this disease on CV and renal outcomes. Discussion This study will address the challenges and implications in long-term CV sequeale of COVID-19 and focus on a better understanding of the underlying mechanisms and possible therapeutic options. Trial registration Patient enrolment in the trial started in January 2021 and is expected to finish at the end of 2022. The study can be found on ClinicalTrials.gov database with NCT05125913 identifier. Registered on 18 November 2021 - Retrospectively registered.
... However, ACE-2 is also expressed by endothelial cells elsewhere. In fact, various complications seen in Covid-19 like hypertension, thrombosis, pulmonary embolism, acute kidney injury, and brain stroke indicate that endothelium is the prime target for the virus [17]. This is because, in physiology, endothelium has an important role in promoting vasodilation, fibrinolysis, and anti-aggregation. ...
... p > 0.05) between the two groups. Median CT score was 17 (14.25-19.75) in the IVIG group and 18 (15)(16)(17)(18)(19)(20) in the Non-IVIG group (p > 0.05). Median APACHE II score was 9 (6)(7)(8)(9)(10)(11)(12) in the IVIG group and 10 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) Table 1. ...
Article
Background Various immunomodulatory therapies have been explored to manage the dysregulated immune response seen in severe COVID-19 infection. The objective of this study was to evaluate the efficacy of intravenous immunoglobulin (IVIG) in severe and critical COVID-19 disease. Methods This retrospective study included 535 patients with severe and critical COVID-19 admitted to the intensive care unit (ICU) of a tertiary care hospital, from May 2020 to December 2020. Primary outcome was the percentage of patients requiring mechanical ventilation. Secondary outcomes were a) in-hospital mortality, b) 28-day mortality, c) ICU-length of stay (ICU-LOS), d) days to discontinuation of supplemental oxygen, and e) days to COVID-PCR negativity. Logistic regression and linear regression were performed using the adjusted and unadjusted analyses. Results We analyzed a total of 535 patients out of which 255 (47.7%) received IVIG along with standard treatment and 280 (52.3%) received only standard treatment. Two groups were similar in terms of COVID-19 severity, APACHE II score, oxygen requirements, and initial management. The requirement of invasive ventilation was significantly less in the IVIG group compared to the Non-IVIG group (32.2% vs 40.4%, p<0.05). In-hospital mortality, 28-day mortality, and ICU-LOS were also significantly less in the IVIG group (all p<0.05). Subgroup analysis within the IVIG group showed that early administration of IVIG (≤ 7 days from ICU admission), old age (≥ 65 years), and obesity were associated with better outcomes (need for mechanical ventilation and in-hospital mortality) (all p<0.05). IVIG administration in patients with chronic respiratory disease was associated with a reduced requirement for mechanical ventilation (p<0.05), but there was an insignificant improvement in mortality. Conclusion High-dose IVIG improves outcomes in severe and critical COVID-19 patients. The study also underscores the importance of timing and patient selection when administering IVIG.
... Our investigation was based on a robust rationale, i.e. targeting endothelial dysfunction in Long-COVID. Indeed, endothelial cell infection with consecutive inflammatory cell recruitment and endothelial dysfunction could explain the impaired microcirculation observed across vascular beds in COVID-19, triggering vasoconstriction, ischemia, and a pro-coagulant state[92][93][94][95] . Consistent with our view, several investigators had proposed that endotheliitis could be a critical mechanism underlying systemic impaired microcirculatory function observed in different vascular beds in patients experiencing Long-COVID symtoms92,96 .Of note, a recent clinical study has demonstrated that COVID-19 patients develop endothelial dysfunction, which remains significantly impaired compared to healthy controls subjects at a 6month follow-up97 , implicating that endothelial dysfunction is a main player in both acute COVID-19 and Long-COVID. ...
... Indeed, endothelial cell infection with consecutive inflammatory cell recruitment and endothelial dysfunction could explain the impaired microcirculation observed across vascular beds in COVID-19, triggering vasoconstriction, ischemia, and a pro-coagulant state[92][93][94][95] . Consistent with our view, several investigators had proposed that endotheliitis could be a critical mechanism underlying systemic impaired microcirculatory function observed in different vascular beds in patients experiencing Long-COVID symtoms92,96 .Of note, a recent clinical study has demonstrated that COVID-19 patients develop endothelial dysfunction, which remains significantly impaired compared to healthy controls subjects at a 6month follow-up97 , implicating that endothelial dysfunction is a main player in both acute COVID-19 and Long-COVID. Interestingly, increased numbers of circulating endothelial cells, a biomarker of vascular injury 98 , most likely detached from the vessel wall due to pathological insults, were found to significantly correlate with the severity of COVID-19 outcome 99 . ...
Article
Introduction: Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms. Methods: We designed a survey (LINCOLN: L-Arginine and Vitamin C improves Long-COVID), assessing several symptoms that have been associated with Long-COVID to be administered nationwide to COVID-19 survivors; the survey also included effort perception, measured using the Borg scale. Patients receiving the survey were divided in two groups, with a 2:1 ratio: the first group included patients that received L-Arginine + Vitamin C, whereas the second group received a multivitamin combination (alternative treatment). Results: 1390 successfully completed the survey. Following a 30-day treatment in both groups, the survey revealed that patients in the L-Arginine + Vitamin C treatment arm had significantly lower scores compared to patients who had received the multivitamin combination. There were no other significant differences between the two groups. When examining effort perception, we observed a significantly lower value (p < 0.0001) in patients receiving L-Arginine + Vitamin C compared to the alternative-treatment arm. Conclusions: Taken together, our surveys indicates that the supplementation with L-Arginine + Vitamin C has beneficial effects in Long-COVID, in terms of attenuating its typical symptoms and improving effort perception.
... In particular, SARS-CoV-2 uses ACE2 as the input receptor and the cell protease of TMPRSS2 for the S protein primer [70]. Cross surveys on ACE2 and the TMPRSS2-positive cells on human tissue found these proteins the expression in the nasal goblet and the ciliated epithelial cells and also oligodendrocytes [71]. Co-expression of ACE2/TMPRSS2 in oligodendrocytes can be one method of CNS proliferation or infiltration. ...
... The significance and implications of genetic differences are still unclear. Coronaviruses may be cross into CNS through the BBB that is compromised by inflammatory mediators, endotheliitis or endothelins injury, transmigration of virus-carrying macrophages, or direct endothelial cells infection themselves [71,75,81]. ...
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Some of the recent researches show that air pollutants such as particulate matter (PM), including fine particles (PM<2.5μm, PM2.5) and very fine particles (PM <0.1μm, PM 0.1) can reach the brain and affect CNS health. Neurological complications with Coronavirus Disease 2019 (COVID-19) have been observed. The aim of this review the relationship between air pollutants exposure and COVID-19 was focused on the role of airborne aerosol particles in the prevalence of the disease, as well as the neurological effects of COVID-19. It is not yet clear how the virus is transmitted from one sick person to another and why it is so transmissible. Viruses can be probably transmitted through speech and exhalation aerosols. Findings show that SARS-CoV-2 aerosol transmission is possible. Spike (S) proteins of SARS-CoV-2 determine tissue tropism using an angiotensin-converting enzyme receptor type2 (ACE-2) to bind to the cells. ACE-2 receptor is found in the tissues of the nervous system. Neurological disorders that occur with COVID-19 can have many pathophysiological backgrounds. Some are the result of a direct viral attack on tissues of the nervous system, others appear to be an autoimmune process post-viral, and still others appear to be the result of systemic and metabolic complications associated with critical illness.
... The potential role of the endothelium as a key determinant of vascular dysfunction in COVID-19 has been elaborated upon by a number of publications. 69,76,77 Like the lung epithelium, microvascular endothelial cells (representing approximately one-third of lung cells) 78 are susceptible to COVID-19 viral infection, presumably because of their expression of ACE2. 68 As summarized in Figure 2, 15,55,58,61,64,66,73,79-108 dysregulation of many of the above-cited pathways and cascades converge on the vascular endothelium, acting as a common pathway to promote severe COVID-19 vasculopathy. ...
... For example, patients with type 2 diabetes, metabolic syndrome, cardiovascular disease, or kidney disease-all of which share endothelial dysfunction-are at enhanced risk of increased morbidity in the setting of COVID-19, as summarized in depth in recent reviews. 68,69 Consequently, therapeutic strategies that target the endothelium, the coagulation cascade, and the platelet-endothelium interaction process that triggers microvascular thrombosis are of central importance in defining the treatment strategy for managing such individuals. ...
Article
The coronavirus disease 2019 (COVID-19) pandemic, causing considerable mortality and morbidity worldwide, has fully engaged the biomedical community in attempts to elucidate the pathophysiology of COVID-19 and develop robust therapeutic strategies. To this end, the predominant research focus has been on the adaptive immune response to COVID-19 infections stimulated by mRNA and protein vaccines and on the duration and persistence of immune protection. In contrast, the role of the innate immune response to the viral challenge has been underrepresented. This overview focuses on the innate immune response to COVID-19 infection, with an emphasis on the roles of extracellular proteases in the tissue microenvironment. Proteinase-mediated signaling caused by enzymes in the extracellular microenvironment occurs upstream of the increased production of inflammatory cytokines that mediate COVID-19 pathology. These enzymes include the coagulation cascade, kinin-generating plasma kallikrein, and the complement system, as well as angiotensin-generating proteinases of the renin–angiotensin system. Furthermore, in the context of several articles in this Supplement elucidating and detailing the trajectory of diverse profibrotic pathways, we extrapolate these insights to explore how fibrosis and profibrotic pathways participate importantly in the pathogenesis of COVID-19. We propose that the lessons garnered from understanding the roles of microenvironment proteinases in triggering the innate immune response to COVID-19 pathology will identify potential therapeutic targets and inform approaches to the clinical management of COVID-19. Furthermore, the information may also provide a template for understanding the determinants of COVID-19–induced tissue fibrosis that may follow resolution of acute infection (so-called “long COVID”), which represents a major new challenge to our healthcare systems.
... Coronavirus disease 2019 (COVID- 19) primarily results in a respiratory disease (Severe Acute Respiratory Distress Syndrome-ARDS); through endothelial damage [1], it may also result in multi-organ involvement, including the cardiovascular (CV) system [2]. Indeed, Biomedicines 2022, 10,1940 2 of 12 patients with CV risk factors (diabetes mellitus, arterial hypertension, obesity) and those with established CV disease represent a vulnerable population in which COVID-19 results in increased morbidity and mortality [3]. ...
... Similarly, the virus interacts with the extracellular matrix metalloproteinase inducer (a transmembrane glycoprotein), leading to the upregulation of the expression of several cytokines and promoting oxidative stress [35]. Finally, the specific role of SARS-CoV-2 in determining endothelial dysfunction has been characterized well [1]. ...
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(1) Background: Among the different cardiovascular (CV) manifestations of the coronavirus disease 2019 (COVID-19), arrhythmia and atrial fibrillation (AF) in particular have recently received special attention. The aims of our study were to estimate the incidence of AF in patients hospitalized for COVID-19, and to evaluate its role as a possible predictor of in-hospital all-cause mortality. (2) Methods: We enrolled 3435 people with SARS-CoV2 infection admitted to three hospitals in Northern Italy from February 2020 to May 2021. We collected data on their clinical history, laboratory tests, pharmacological treatment and intensive care unit (ICU) admission. Incident AF and all-cause in-hospital mortality were considered as outcomes. (3) Results: 145 (4.2%) patients developed AF during hospitalization, with a median time since admission of 3 days (I-III quartile: 0, 12). Patients with incident AF were admitted more frequently to the ICU (39.3 vs. 12.4%, p < 0.001), and more frequently died (37.2 vs. 16.9%, p < 0.001). In the Cox regression model, the significant determinants of incident AF were age (HR: 1.041; 95% CI: 1.022, 1.060 per year), a history of AF (HR: 2.720; 95% CI: 1.508, 4.907), lymphocyte count (HR: 0.584; 95% CI: 0.384, 0.888 per 103/µL), estimated glomerular filtration rate (eGFR, HR: 0.988; 95% CI: 0.980, 0.996 per mL/min) and ICU admission (HR: 5.311; 95% CI: 3.397, 8.302). Incident AF was a predictor of all-cause mortality (HR: 1.405; 95% CI: 1.027, 1.992) along with age (HR: 1.057; 95% CI: 1.047, 1.067), male gender (HR: 1.315; 95% CI: 1.064; 1.626), dementia (HR: 1.373; 95% CI: 1.045, 1.803), lower platelet (HR: 0.997; 95% CI: 0.996, 0.998 per 103/µL) and lymphocyte counts (HR: 0.843; 95% CI: 0.725, 0.982 per 103/µL), C-Reactive protein values (HR: 1.004; 95% CI: 1.003, 1.005 per mg/L), eGFR (HR: 0.990; 95% CI: 0.986, 0.994 per mL/min), and ICU admission (HR: 1.759; 95% CI: 1.292, 2.395). (4) Conclusions: Incident AF is a common complication in COVID-19 patients during hospitalization, and its occurrence strongly predicts in-hospital mortality.
... This socalled "cytokine storm" promotes thrombosis through multiple mechanisms, including activation of monocytes, neutrophils, and endothelium, finally inducing vascular injury (Abou-Ismail, Diamond et al. 2020). In this scenario, endothelial dysfunction is a leading actor, as suggested by several reports (Evans, Rainger et al. 2020 receptor, transmembrane serine protease 2 (TMPRSS2), and extracellular matrix metalloproteinase inducer (CD147); cathepsin B and L also participate in virus entry (Sardu, Gambardella et al. 2020). ...
... ,Libby and Lüscher 2020, Sardu, Gambardella et al. 2020, Gambardella and Santulli 2021, Okada, Yoshida et al. 2021). SARS-CoV-2 accesses host cells via the binding of its spike glycoprotein to angiotensin-converting enzyme 2 (ACE2), sialic acid ...
Article
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to be a global challenge due to resulting morbidity and mortality. Cardiovascular (CV) involvement is a crucial complication in COVID-19, and no strategies are available to prevent or specifically address CV events in COVID patients. The identification of molecular partners contributing to CV manifestations in COVID-19 patients is crucial for providing early biomarkers, prognostic predictors and new therapeutic targets. The current report will focus on the role of miRNAs in CV complications associated with COVID-19. Indeed, miRNAs have been proposed as valuable biomarkers and predictors of both cardiac and vascular damage occurring in SARS-CoV-2 infection. Significance Statement It is essential to identify the molecular mediators of COVID-19 cardiovascular (CV) complications. This report focused on the role of miRNAs in CV complications associated with COVID-19, discussing their potential use as biomarkers, prognostic predictors, and therapeutic targets.
... To investigate the consequences of this combination on the composition of fibrin degradation products, we performed SDS-gel electrophoresis and Western blotting for the Ddimer epitope, finding reduced fractions of the final fibrin degradation product D-dimer in COVID-19+ patients with low PAP. There is increasing evidence suggesting that endothelial cell injury may play a key role in the COVID-19 associated coagulopathy [31,32]. A massive elevation of VWF, a factor that is released upon endothelial cell activation, has been reported by several studies [9,12,[17][18][19]33]. ...
Article
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In this single-center cohort study, we applied a panel of laboratory markers to characterize hemostatic function in 217 consecutive patients that underwent testing for COVID-19 as they were admitted to Linköping University Hospital between April and June 2020. In the 96 patients that tested positive for SARS-CoV-2 (COVID-19+), the cumulative incidences of death and venous thromboembolism were 24.0% and 19.8% as compared to 12.4% (p = 0.031) and 11.6% (p = 0.13) in the 121 patients that tested negative (COVID-19−). In COVID-19+ patients, we found pronounced increases in plasma levels of von Willebrand factor (vWF) and fibrinogen. Excess mortality was observed in COVID-19+ patients with the following aberrations in hemostatic markers: high D-dimer, low antithrombin or low plasmin-antiplasmin complex (PAP) formation, with Odds Ratios (OR) for death of 4.7 (95% confidence interval (CI95) 1.7–12.9; p = 0.003) for D-dimer >0.5 mg/L, 5.9 (CI95 1.8–19.7; p = 0.004) for antithrombin (AT) ˂0.85 kIU/l and 4.9 (CI95 1.3–18.3; p = 0.019) for PAP < 1000 μg/L. Compounding increases in mortality was observed in COVID-19+ patients with combined defects in markers of fibrinolysis and coagulation, with ORs for death of 15.7 (CI95 4.3–57; p < 0.001) for patients with PAP <1000 μg/L and D-dimer >0.5 mg/L and 15.5 (CI95 2.8–87, p = 0.002) for patients with PAP <1000 μg/L and AT ˂0.85 kIU/L. We observed an elevated fraction of incompletely degraded D-dimer fragments in COVID-19+ patients with low PAP, indicating impaired fibrinolytic breakdown of cross-linked fibrin.
... 19,20 From this perspective, clinical data and autopsy studies revealing endotheliitis and thrombosis have raised the possibility that endothelial dysfunction, particularly alterations in vascular integrity and coagulative capacity, could be a driver of clinical outcomes. 21,22 Thrombosis, fluid extravasation, and microangiopathy observed in the small vessels and capillaries of the lungs directly support the notion that an intense vascular reaction takes place in those with severe disease. 23,24 Indeed, substantial evidence has demonstrated that the endothelium is dysregulated in COVID-19 infection, 25,26 and this has led to early investigation into supportive therapeutics, and the proposal that new therapeutics should prioritize endothelial stabilization. ...
Article
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Background Endothelial cell (EC) activation, endotheliitis, vascular permeability, and thrombosis have been observed in patients with severe coronavirus disease 2019 (COVID-19), indicating that the vasculature is affected during the acute stages of SARS-CoV-2 infection. It remains unknown whether circulating vascular markers are sufficient to predict clinical outcomes, are unique to COVID-19, and if vascular permeability can be therapeutically targeted. Methods Prospectively evaluating the prevalence of circulating inflammatory, cardiac, and EC activation markers as well as developing a microRNA atlas in 241 unvaccinated patients with suspected SARS-CoV-2 infection allowed for prognostic value assessment using a Random Forest model machine learning approach. Subsequent ex vivo experiments assessed EC permeability responses to patient plasma and were used to uncover modulated gene regulatory networks from which rational therapeutic design was inferred. Findings Multiple inflammatory and EC activation biomarkers were associated with mortality in COVID-19 patients and in severity-matched SARS-CoV-2-negative patients, while dysregulation of specific microRNAs at presentation was specific for poor COVID-19-related outcomes and revealed disease-relevant pathways. Integrating the datasets using a machine learning approach further enhanced clinical risk prediction for in-hospital mortality. Exposure of ECs to COVID-19 patient plasma resulted in severity-specific gene expression responses and EC barrier dysfunction, which was ameliorated using angiopoietin-1 mimetic or recombinant Slit2-N. Interpretation Integration of multi-omics data identified microRNA and vascular biomarkers prognostic of in-hospital mortality in COVID-19 patients and revealed that vascular stabilizing therapies should be explored as a treatment for endothelial dysfunction in COVID-19, and other severe diseases where endothelial dysfunction has a central role in pathogenesis. Funding Information This work was directly supported by grant funding from the Ted Rogers Center for Heart Research, Toronto, Ontario, Canada and the Peter Munk Cardiac Center, Toronto, Ontario, Canada.
... Another potential mechanism for cardiopulmonary symptoms in PASC that was not investigated is endothelial or microvascular dysfunction (40)(41)(42). Endothelial cells express SARS-CoV-2 targets for cell entry, angiotensin-converting enzyme 2 (ACE2) receptor, and transmembrane serine protease 2 (TMPRSS2), allowing for direct viral infection of endothelial cells (43). Microvascular dysfunction and thromboembolism have been implicated in the pathology of acute COVID-19 (41,42), with autopsy studies demonstrating endotheliitis (44). ...
Article
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Shortness of breath, chest pain, and palpitations occur as post-acute sequelae of COVID-19 (PASC), but whether symptoms are associated with echocardiographic abnormalities, cardiac biomarkers, or markers of systemic inflammation remains unknown. In a cross-sectional analysis, we assessed symptoms, performed echocardiograms, and measured biomarkers among adults >8 weeks after confirmed SARS-CoV-2 infection. We modeled associations between symptoms and baseline characteristics, echocardiographic findings, and biomarkers using logistic regression. We enrolled 102 participants at a median 7.2 months (IQR 4.1-9.1) following COVID-19 onset; 47 individuals reported dyspnea, chest pain, or palpitations. Median age was 52 years (range 24-86) and 41% were women. Female sex, hospitalization, IgG antibody to SARS-CoV-2 receptor binding domain and C-reactive protein were associated with symptoms. Regarding echocardiographic findings, 4/47 (9%) with symptoms had pericardial effusions compared to 0/55 without symptoms (p=0.038); those with effusions had a median 4 symptoms compared to 1 without (p<0.001). There was no strong evidence for a relationship between symptoms and echocardiographic functional parameters or other biomarkers. Among adults >8 weeks after SARS-CoV-2 infection, SARS-CoV-2 RBD antibodies, markers of inflammation and, possibly, pericardial effusions are associated with cardiopulmonary symptoms. Investigation into inflammation as a mechanism underlying PASC is warranted.
... However, it remains unclear whether SARS-CoV-2 can directly infect the endothelium [5,6]. The major clinical events usually observed in COVID-19 patients, such thrombosis and cerebrovascular disorders, indicate that the virus is targeting the endothelium [7]. The pathological steps from SARS-CoV-2 infection and the COVID-19 disease can be divided into three phases: (i) an asymptomatic phase; (ii) a non-severe symptomatic phase with upper airway involvement; and (iii) a severe disease with hypoxia, cellular infiltrates in the lung, and progression to acute respiratory distress syndrome (ARDS). ...
Article
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In the novel pandemic of Coronavirus Disease 2019, high levels of pro-inflammatory cytokines lead to endothelial activation and dysfunction, promoting a pro-coagulative state, thrombotic events, and microvasculature injuries. The aim of the present work was to investigate the effect of SARS-CoV-2 on pro-inflammatory cytokines, tissue factor, and chemokine release, with Human Microvascular Endothelial Cells (HMEC-1). ACE2 receptor expression was evaluated by western blot analysis. SARS-CoV-2 infection was assessed by one-step RT-PCR until 7 days post-infection (p.i.), and by Transmission Electron Microscopy (TEM). IL-6, TNF-α, IL-8, IFN-α, and hTF mRNA expression levels were detected by RT-PCR, while cytokine release was evaluated by ELISA. HMEC-1 expressed ACE2 receptor and SARS-CoV-2 infection showed a constant viral load. TEM analysis showed virions localized in the cytoplasm. Expression of IL-6 at 24 h and IFN-α mRNA at 24 h and 48 h p.i. was higher in infected than uninfected HMEC-1 (p < 0.05). IL-6 levels were significantly higher in supernatants from infected HMEC-1 (p < 0.001) at 24 h, 48 h, and 72 h p.i., while IL-8 levels were significantly lower at 24 h p.i. (p < 0.001). These data indicate that in vitro microvascular endothelial cells are susceptible to SARS-CoV-2 infection but slightly contribute to viral amplification. However, SARS-CoV-2 infection might trigger the increase of pro-inflammatory mediators.
... The elevation of proinflammatory cytokines and chemokines during COVID-19 infection inhibits anticoagulation pathways, consequently promoting thrombin formation [53]. Recently, high levels of Ang II were detected in COVID-19 patients, possibly contributing to the thrombosis seen in these patients [46,54]. ...
Article
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The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2), causes its down-regulation, which subsequently leads to the dysregulation of the renin-angiotensin system (RAS) in favor of the ACE-angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis. AT1R has a major role in RAS by being involved in several physiological events including blood pressure control and electrolyte balance. Following SARS-CoV-2 infection, pathogenic episodes generated by the vasoconstriction, proinflammatory, profibrotic, and prooxidative consequences of the Ang II-AT1R axis activation are accompanied by a hyperinflammatory state (cytokine storm) and an acute respiratory distress syndrome (ARDS). AT1R, a member of the G protein-coupled receptor (GPCR) family, modulates Ang II deleterious effects through the activation of multiple downstream signaling pathways, among which are MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases (PDGF, EGFR, insulin receptor), and nonreceptor tyrosine kinases (Src, JAK/STAT, focal adhesion kinase (FAK)), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. COVID-19 is well known for generating respiratory symptoms, but because ACE2 is expressed in various body tissues, several extrapulmonary pathologies are also manifested, including neurologic disorders, vasculature and myocardial complications, kidney injury, gastrointestinal symptoms, hepatic injury, hyperglycemia, and dermatologic complications. Therefore, the development of drugs based on RAS blockers, such as angiotensin II receptor blockers (ARBs), that inhibit the damaging axis of the RAS cascade may become one of the most promising approaches for the treatment of COVID-19 in the near future. We herein review the general features of AT1R, with a special focus on the receptor-mediated activation of the different downstream signaling pathways leading to specific cellular responses. In addition, we provide the latest insights into the roles of AT1R in COVID-19 outcomes in different systems of the human body, as well as the role of ARBs as tentative pharmacological agents to treat COVID-19.
... Patients often present with abnormal coagulation lab values including D-dimer and activated partial thromboplastin time (aPTT) [8]. This hypercoagulability is likely caused by the direct action of the virus on vascular endothelium and platelets, among other tissues, and is potentiated by indirect immune activation [9,10]. Venous thromboembolism, for example, is estimated to affect 25% of COVID-19 patients in the ICU, often despite prophylactic anticoagulation therapy [11]. ...
Article
Background As of December 2021, the coronavirus disease 2019 (COVID-19) pandemic has resulted in the deaths of over 5 million people. It is known that infection with this virus causes a state of hypercoagulability. Because of this, there has been considerable debate on whether or not patients should be placed on anticoagulation prophylaxis/therapy. The goal of our project was to shed light on this topic by examining the effects of preexisting anticoagulation therapy in COVID-19 patients on disease severity (measured by blood clot readmissions, transfusion counts, and length of hospital stay). In this retrospective cohort study, we conducted an analysis based on data from 30,076 COVID-19-positive patients' electronic medical records. Materials and methods This is a retrospective cohort study. Patients included in this study were identified from the HCA Healthcare corporate database. Registry data was sourced from HCA East Florida hospitals. All patients included in this study were COVID-19 positive via polymerase chain reaction (PCR) or rapid antigen testing on admission and over age 18. A total of 30,076 patients were included in this study with hospital admission dates from March 1, 2020 to June 30, 2021. The analysis examined the relationship between age, sex, blood clot history, and most importantly current anticoagulation status on COVID-19 disease severity (through blood clot readmissions, length of stay, and transfusion count). Blood clot readmissions were analyzed with a logistic regression model while the length of hospital stay and transfusion count were analyzed with a linear regression model. Results Our analysis revealed that the odds of experiencing a blood clot readmission is 2.017 times more likely in patients already on anticoagulation therapy compared to those who were not (p = 0.0024). We also found that patients on anticoagulation therapy had a hospital stay of 6.90 days longer on average than patients not on anticoagulation therapy (p < 0.0001). Finally, patients on anticoagulation therapy had, on average, 0.20 more blood transfusions than patients not on anticoagulation therapy (p < 0.001). Conclusion While these findings may be affected by the underlying conditions of those on preexisting anticoagulation therapy, they provide valuable insight into the debate on whether COVID-19-positive patients should be anticoagulated on admission to a hospital.
... Arg ale může být efektivní a finančně nenáročnou formou terapie u oslabené či nemocné populace s endoteliální dysfunkcí (ateroskleróza, hypertenze, diabetes mellitus, trombóza apod.) . V kontextu onemocnění COVID-19 se v odborných textech zmiňuje, že právě endoteliální dysfunkce a nízká dostupnost NO z endogenních zdrojů může být jednou z možných příčin těžkého průběhu onemocnění (Kidde et al., 2021;Sardu et al., 2020). ...
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Dietary nitrates (DN) are scientifically proven ergogenic substances. Their benefits are described in physical performance of medium to maximum intensity lasting 6-30 minutes. The increased availability of DN supports the production of nitric oxide (NO) and, therefore, muscle work, which can positively affect exercise economy and physical per-formance. Improvement is more often seen after long-term use with a higher degree of effectiveness in a less-trained population. We carried out a double-blind cross-over placebo-controlled study focusing on the effects of acute and chronic beetroot juice concentrate intake (400-800 mg of DN per dose) on endurance performance in 19 young men (10 recreationally trained and 9 trained). On the 1., 7. and 8. day of DN use, the group underwent physical testing, blood sampling and additional measurements. We observed increased NO availability via increased plasma nitrate values (p < 0.05). However, blood pressure (BP), oxygen consumption during the tests, exercise tolerance, RPE and biochemical response remained unchanged despite the high availability of NO (p > 0.05). Group’s VO2max over 45 ml/kg/min, which according to current knowledge, may have limited the ergogenic effect of DN. Future re-search should focus on even less-trained or weakened populations, where DN can serve as a nutritional training aid or a treatment aid. It can also be used in other sports disciplines requiring a higher involve-ment of type II muscle fibres.
... The frequency of thrombosis has been increased in the course of COVID-19 disease 3 . Thrombosis in COVID-19 disease may be due to hyperinflammatory response, hypoxic injury, endothelial dysfunction, hypercoagulability and/or increased platelet activity 4,8 . Even in the early stages of COVID-19 disease, viral inclusion bodies can cause organ damage by causing apoptosis, inflammatory cell infiltration and microvascular thrombosis in endothelial cells. ...
... Although COVID-19 typically gains infectious penetration in the respiratory epithelium [1][2][3], vascular damage is frequently observed in lungs and other organ systems of COVID-19 patients, with morbidities such as intravascular clotting, microvascular occlusion and peripheral ischemia [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Histological studies from COVID-19 patients have found extensively damaged endothelium of pulmonary capillaries adjoining relatively intact alveoli [18,19], corresponding to hypoxemia with normal breathing mechanics observed in patients with this viral disease [10,[16][17][18]20,21]. ...
Article
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Rouleaux (stacked clumps) of red blood cells (RBCs) observed in the blood of COVID-19 patients in three studies call attention to the properties of several enveloped virus strains dating back to seminal findings of the 1940s. For COVID-19, key such properties are: (1) SARS-CoV-2 binds to RBCs in vitro and also in the blood of COVID-19 patients; (2) although ACE2 is its target for viral fusion and replication, SARS-CoV-2 initially attaches to sialic acid (SA) terminal moieties on host cell membranes via glycans on its spike protein; (3) certain enveloped viruses express hemagglutinin esterase (HE), an enzyme that releases these glycan-mediated bindings to host cells, which is expressed among betacoronaviruses in the common cold strains but not the virulent strains, SARS-CoV, SARS-CoV-2 and MERS. The arrangement and chemical composition of the glycans at the 22 N-glycosylation sites of SARS-CoV-2 spike protein and those at the sialoglycoprotein coating of RBCs allow exploration of specifics as to how virally induced RBC clumping may form. The in vitro and clinical testing of these possibilities can be sharpened by the incorporation of an existing anti-COVID-19 therapeutic that has been found in silico to competitively bind to multiple glycans on SARS-CoV-2 spike protein.
... Патогенез асептического некроза, вызванного инфекцией COVID-19 В настоящее время в патогенезе асептического некроза, вызванного COVID-19, обсуждается роль самого вируса и терапии глюкокортикоидами. Что касается возможной связи вируса SARS-CoV-2 с развитием асептического некроза, то к настоящему времени выявлено, что при COVID-19 вирус SARS-CoV-2 непосредственно проникает в клетки эндотелия сосудов через ангиотензинпревращающий фермент-2 (АСЕ2), который экспрессируется эндотелиальными клетками не только в легких, но и во многих других органах и тканях, что приводит к поражению сосудов через развитие коагулопатии и обширного воспалительного синдрома [8]. R. Escher с соавторами наблюдали пациента с инфекцией COVID-19, у которого отмечалось значительное повышение фактора фон Виллебранда, что, по их предположению, подтверждало разрушение эндотелия сосудов [9]. ...
Article
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Background. Aseptic bone necrosis (osteonecrosis), as a consequence of the ongoing coronavirus disease-2019 (COVID-19) pandemic, is increasingly becoming the cause of severe pain syndrome in the hip, knee, and shoulder joints with disruption of their function. The discussion of the pathogenesis of post-COVID-19 osteonecrosis, possibility of its diagnosis, and treatment at early stages continue. As COVID-19 affects young and able-bodied people, the diagnosis and treatment of this form of aseptic necrosis at early stages have great social and economic importance. Methods. The literature search was conducted in the databases of eLIBRARY, PubMed, and Scopus. The search depth was 10 years. Selected publications were related to the early diagnosis and treatment of aseptic necrosis following COVID-19. Results. The form of osteonecrosis that developed after COVID-19 should now be classified according to ICD-10 as M87.3 (another secondary osteonecrosis). The review provides data on the possible mechanisms of osteonecrosis development in patients who had COVID-19, explains the role of MRI for the early detection of the pathology, provides the results of treatment that can influence both pathogenesis mechanisms, and leads to disease regression if treatment was initiated at an early stage. Conclusions. Improving the doctors awareness about the pathogenesis, diagnostic methods, and treatment of early disease stages will reduce the risk of developing an advanced stage of aseptic necrosis post-COVID-19, slow down the progression of the pathology, and delay or even prevent the need for joint replacement. Our concern is based on the continuation of the pandemic, the observed fact of the dramatic increase in the frequency of aseptic necrosis post-COVID-19, and the number of total arthroplasties in young and middle-aged people for aseptic necrosis of the femoral head.
... The suspected downregulation of ACE-2 by the virus may lead to the pulmonary, circulatory, and other complications seen in severe COVID infection [110]. Comorbidities, which seem to exacerbate COVID symptoms, such as obesity and hypertension, involve underlying endothelial damage and dysfunction [111]. Endothelial dysfunction is a systemic condition in which the endothelium no longer promotes vasodilation, fibrinolysis, and anti-aggregation. ...
Article
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Neuropathic pain is defined as a painful condition caused by neurological lesions or diseases. Sometimes, neurological disorders may also be associated with neuropathic pain, which can be challenging to manage. For example, multiple sclerosis (MS) may cause chronic centralized painful symptoms due to nerve damage. Other chronic neuropathic pain syndromes may occur in the form of post-stroke pain, spinal cord injury pain, and other central pain syndromes. Chronic neuropathic pain is associated with dysfunction, disability, depression, disturbed sleep, and reduced quality of life. Early diagnosis may help improve outcomes, and pain control can be an important factor in restoring function. There are more than 100 different types of peripheral neuropathy and those involving sensory neurons can provoke painful symptoms. Accurate diagnosis of peripheral neuropathy is essential for pain control. Further examples are represented by gluten neuropathy, which is an extraintestinal manifestation of gluten sensitivity and presents as a form of peripheral neuropathy; in these unusual cases, neuropathy may be managed with diet. Neuropathic pain has been linked to CoronaVirus Disease (COVID) infection both during acute infection and as a post-viral syndrome known as long COVID. In this last case, neuropathic pain relates to the host's response to the virus. However, neuropathic pain may occur after any critical illness and has been observed as part of a syndrome following intensive care unit hospitalization.
... Second, the endothelium is the main effector contributing to the inflammatory process and thrombosis. SARS-CoV-2 may cause endothelial dysfunction directly through EC infection, or indirectly through the sustained and exaggerated activation of endothelial cells through a massive pro-inflammatory cytokine release secondary to viral infection [45]. ...
Article
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Background: Presently, a number of specific observations have been performed on microcirculatory function in a coronavirus disease-19 (COVID-19) setting. We hypothesized that, in the critically ill, endothelial dysfunction secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the subsequent inflammation and coagulopathy may lead to microcirculatory alterations, further exacerbated by the hypoxemic state. A dysfunctional microcirculation may represent the hidden motor underlying the development of COVID-19's clinical manifestations. Methods: A single center, prospective, observational study. We analyzed bedside sublingual microcirculation in twenty-four consecutive COVID-19-associated acute respiratory distress syndrome (ARDS) patients mechanically ventilated in an Intensive Care Unit (ICU), together with macro-hemodynamics, clinical parameters, echocardiography, and laboratory data at a single time-point after ICU admission. All participants were recruited between March and May 2020. Results: The microcirculatory pattern was characterized by increased values of total vessel density and perfused vessel density, a reduced value of proportion of perfused vessels and microvascular flow index, and high values of heterogeneity index. The duration of mechanical ventilation before microcirculation assessment was inversely associated with the proportion of perfused vessels (p = 0.023). Within the macro-hemodynamic parameters, the right ventricle end-diastolic diameter was inversely associated with proportion of perfused vessels and microvascular flow index (p = 0.039 and 0.014, respectively) and directly associated with the heterogeneity index (p = 0.033). Conclusions: In COVID-19-associated ARDS patients, the microcirculation showed impaired quality of flow parameters coupled with a high vessel density.
... [4] In severe COVID-19 cases, the endothelium is an essential target, and mediators mainly cause the adverse effects. [5][6][7][8] These effectors drive the endothelial disease responsible for coagulopathy, and the other complications. [9] In order to contain the COVID-19 infection contagion, many restrictive measures have been adopted by the Italian government, starting from the isolation of the population within their own homes. ...
Article
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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is experiencing pandemic diffusion. The experience of an Italian private health care structure was reviewed. We retrospectively collected data about services provided in a single medium complexity private health care structure. Furthermore, we classified specialties within 4 categories, based on the performance of urgent non-deferrable services and possible provision of services without a necessary contact with the patient. The structure canceled/postponed almost every deferrable service, providing only 3% of services that could be performed without direct contact with patients. Regarding non-deferrable services requiring the presence of the patient, about 42% of booked services have been autonomously canceled/postponed by patients for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) fear. The administrative services have been remotely performed by smart working as far as possible. Private health care structures may safely continue to provide non-deferrable services while respecting the restrictive measures imposed by the government, encouraging telehealth and smart working modalities.
... patients with ARDS showed 10-to 60-fold higher levels of interleukin-1β and interleukin-6 than patients with moderate cases. [34][35][36] Excessive inflammatory responses may therefore partly explain the association between high BPV and adverse outcomes in COVID-19 patients with hypertension. We also found the correlations of BNP and hs-TnI with BPV, perhaps implying the detrimental role of cardiac dysfunction and myocardial injury on BP stability. ...
Article
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Hypertension is the most common comorbidity in patients with coronavirus disease 2019 (COVID‐19) and increases in‐hospital mortality. Day‐by‐day blood pressure (BP) variability (BPV) is associated with clinical outcomes in hypertensive patients. However, little information is available on the association of BPV with the outcomes of COVID‐19 patients with hypertension. This study aimed to demonstrate whether day‐by‐day in‐hospital BPV had prognostic significance in these patients. The authors included 702 COVID‐19 patients with hypertension from Huoshenshan Hospital (Wuhan, China), who underwent valid in‐hospital BP measurements on at least seven consecutive days. Day‐by‐day BPV was assessed by standard deviation (SD), coefficient of variation (CV), and variation independent of mean (VIM). Overall, patients with severe COVID‐19 and non‐survivors had higher BPV than moderate cases and survivors, respectively. Additionally, higher BPV was correlated with greater age and higher levels of C‐reactive protein, procalcitonin, high‐sensitive cardiac troponin I, and B‐type natriuretic peptide. In multivariable Cox regression, SD of systolic BP (SBP) was predictive of mortality [hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.05–1.30] as well as acute respiratory distress syndrome (ARDS) (HR 1.09, 95% CI 1.01–1.16). Similar trends were observed for CV and VIM of SBP, but not indices of diastolic BP variability. The authors demonstrated that day‐by‐day in‐hospital SBP variability can independently predict mortality and ARDS in COVID‐19 patients with hypertension. And high BPV might be correlated with severe inflammation and myocardial injury. Further studies are needed to clarify whether early reduction of BPV will improve the prognosis of these patients.
... As proof of this, investigators have identified thrombotic and microvascular complications as the potent cause of deaths in patients with complicated COVID-19 [28,62,63]. Arterial and venous thromboembolism, kidney disease, and neurological disorders are mandatory among the pathological events responsible for the onset of severe symptoms in COVID-19 patients requiring hospitalization [64,65] (Figure 4). This suggests a leading role of SARS-CoV-2 in activating the vascular system in a consistent process, which is potentially responsible for the multi-organ involvement of the infection and the consequential multi-organ failure. ...
Article
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One of the hallmarks of the SARS-CoV-2 infection has been the inflammatory process that played a role in its pathogenesis, resulting in mortality within susceptible individuals. This uncontrolled inflammatory process leads to severe systemic symptoms via multiple pathways; however, the role of endothelial dysfunction and thrombosis have not been truly explored. This review aims to highlight the pathogenic mechanisms of these inflammatory triggers leading to thrombogenic complications. There are direct and indirect pathogenic pathways of the infection that are examined in detail. We also describe the case of carotid artery thrombosis in a patient following SARS-CoV-2 infection while reviewing the literature on the role of ACE2, the endothelium, and the different mechanisms by which SARS-CoV-2 may manifest both acutely and chronically. We also highlight differences from the other coronaviruses that have made this infection a pandemic with similarities to the influenza virus.
... Hypertension is considered a major risk factor for poor prognosis and death. The exact incidence of new diagnosed hypertension after COVID-19 is unknown, due to lack of data (28). ...
Article
Since WHO declared COVID-19 a pandemic, globally more than 212 milion people were infected and approximately 4.4 milion died (25 August 2021). As the pandemic evolved, it became clear that there are many more things to research and discover about the SARS-CoV-2 infection. Besides the fact that SARS-CoV-2 primarily affects the respiratory system, more and more articles indicate a systemic involvement which could be responsible for long term consequences. The aim of this review was to evaluate the long- term signs and symptoms of COVID-19 infection. We looked for information regarding the prevalence and persistence of symptoms associated with COVID-19 infection and the persistence of organ dysfunction beyond the acute phase. We also searched data regarding the impact of the infection on the quality of life, physical, mental and psychosocial function. Recent studies have shown that some symptoms can persist a long time after the acute episode of COVID-19. Furthermore, organ sequalae can be present after the acute episode. The most common symptoms of “long COVID” are: fatigue and shortness of breath, lack of taste/smell, cough, myalgia and arthralgia, headache. Also, cardiac abnormalities, cognitive impairment, insomnia, anxiety and concentration issues can be present.
... The susceptibility of SARS-CoV2 infection is higher in any cells expressing ACE2, such as the small intestine, testis, kidneys, heart, thyroid and adipose tissue. (Li MY et al., 2020)ACE2 receptor is expressed in endothelial cells throughout our body therefore, endothelial dysfunction appears to be consistent with systemic manifestations observed in COVID-19 patients, such as hypertension, thrombosis, kidney injury, and diabetes (Sardu et al, 2020). Moreover, the inflammatory response plays a critical role in increasing the severity of COVID-19 . ...
Article
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Endocrine dysfunction in COVID-19 plays a role in clinical issues related to different disorders, including, hypogonadism, anxiety, stress and depression. Hypogonadism as an essential determinant for COVID-19-related pathogenesis which regulates the link between the brain and testes. In Indonesia, there is no studying about FSH and LH in COVID-19 survivors. Research design was cross sectional. We conducted this study at the Department of Biomedical Science Faculty of Medicine,, Universitas Airlangga Surabaya, Indonesia. A total of 34 male participants that recovery from COVID-19 enrolled, only 18 participants meet the criteria included. We conducted anamnesis, physical examination including height, weight, waist circumference and we analyzed hormone by using immunoflouroscene analyzer VIDAS and the ELFA method. Normal levels of FSH and LH were 1-8 IU / L and LH 2–10 IU / L, respectively. The mean age of COVID-19 survivors was 36.56 ± 5.69 while the mean marriage duration was 9.56 ± 6.17. The majority of participants had comorbid obesity class I of 6/18 (28.57%) with a mean waist circumference was 91.00 ± 11.68. Mild type COVID-19 was the most frequent 9/18 (50.0%). There were 3/18 (16.7%) pneumonia confirmed COVID-19, but only 2/3 pneumonia confirmed COVID-19 that had elevated FSH and LH levels.
... Several studies report acute kidney injury (AKI) among hospitalised patients with COVID-19 while less data are obtained exclusively in intensive care unit (ICU) patients. [2][3][4][5][6][7][8][9][10] To our knowledge, previous studies are not based on all ICU admissions within a large population. Furthermore, there is a call from the consensus report on COVID-19 associated AKI published by the 25th Acute Dialysis Quality Initiative (ADQI) Workgroup that studies should 'incorporate the information about the proportion of different comorbidities in patients with and without AKI, including potential risk factors for the development of AKI'. ...
Article
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Objectives Acute kidney injury (AKI) is a frequent complication among critical ill patients with COVID-19, but the actual incidence is unknown as AKI-incidence varies from 25% to 89% in intensive care unit (ICU) populations. We aimed to describe the prevalence and risk factors of AKI in patients with COVID-19 admitted to ICU in Norway. Design Nation-wide observational study with data sampled from the Norwegian Intensive Care and Pandemic Registry (NIPaR) for the period between 10 March until 31 December 2020. Setting ICU patients with COVID-19 in Norway. NIPaR collects data on intensive care stays covering more than 90% of Norwegian ICU and 98% of ICU stays. Participants Adult patients with COVID-19 admitted to Norwegian ICU were included in the study. Patients with chronic kidney disease (CKD) were excluded in order to avoid bias from CKD on the incidence of AKI. Primary and secondary outcome measures Primary outcome was AKI at ICU admission as defined by renal Simplified Acute Physiology Score in NIPaR. Secondary outcome measures included survival at 30 and 90 days after admission to hospital. Results A total number of 361 patients with COVID-19 were included in the analysis. AKI was present in 32.0% of the patients at ICU admission. The risk for AKI at ICU admission was related to acute circulatory failure at admission to hospital. Survival for the study population at 30 and 90 days was 82.5% and 77.6%, respectively. Cancer was a predictor of 30-day mortality. Age, acute circulatory failure at hospital admission and AKI at ICU admission were predictors of both 30-day and 90-day mortality. Conclusions A high number of patients with COVID-19 had AKI at ICU admission. The study indicates that AKI at ICU admission was related to acute circulatory failure at hospital admission. Age, acute circulatory failure at hospital admission and AKI at ICU admission were associated with mortality.
... In severe malaria, there is generally a decline in red blood cell, haemoglobin, and platelet counts due to sequestration of infected red blood cells caused by the activation of endothelial activation markers and surface adhesion molecules. However, ours was not a case of severe malaria, but rather a case of malaria complicated by MIS-C in fact even SARS-CoV-2 infection is associated with a cytokine cascade and endothelial activation [12][13][14]. ...
Article
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Background: The ongoing Coronavirus Disease 2019 (COVID-19) epidemic represents an unprecedented global health challenge. Many COVID-19 symptoms are similar to symptoms that can occur in other infections. Malaria should always be considered in patients with SARS-CoV-2 infection returning from endemic areas. Case presentation: We present the first case of multisystem inflammatory syndrome (MIS-C) and Plasmodium vivax-falciparum and SARS-CoV2 coinfection in children. Despite clearance of parassitaemia and a negative COVID-19 nasopharyngeal PCR, the patient's clinical conditions worsened. The World Health Organization (WHO) criteria were used to make the diagnosis of MIS-C. Treatment with intravenous immunoglobulins and methylprednisolone was effective. Conclusions: This case emphasizes the importance of considering malaria diagnosis in patients returning from endemic areas, even in the COVID 19 era. Malaria and SARS-CoV2 co-infection may increase the risk of MIS-C, for which early detection is critical for proper management.
... 18 Resistensi insulin juga berkaitan dengan terjadinya peradangan sistemik serta disfungsi vaskular, yang pada akhirnya mengakibatkan perburukan prognosis pasien COVID-19. 22 Dalam penelitian ini, pada kelompok yang mengalami prolonged LOS, TG ditemukan signifikan lebih tinggi dibandingkan pada kelompok non-prolonged LOS. Kadar HDL juga ditemukan lebih rendah, namun temuan ini tidak signifikan secara statistik. ...
Article
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Introduction: Atherogenic index of plasma (AIP) is a logarithmic calculation of the ratio of triglycerides to HDL cholesterol as a marker of lipid profile abnormalities. In COVID-19 patients with comorbid type 2 diabetes mellitus (T2DM), higher AIP tend to worsen the patient conditions. This study aims to assess the correlation between AIP and length of stay (LOS) in COVID-19 patients with T2DM. Methods: An analytical observational study with a cross-sectional approach was conducted among COVID-19 patients with comorbid T2DM. Data were collected from online medical records of confirmed COVID-19 patients with comorbid T2DM who were treated at Sanglah Hospital Denpasar during the period August 1-December 31, 2021. Patients who were <18 years old and did not have lipid profile data during treatment, were excluded from this study. Results: There were 83 data samples that met the study criteria. The median age of the patients was 64 (23- 91) years, the majority were male (59%; n=49), and 30 patients died during treatment (36.1%). The median LOS for all patients was 10 (1-26) days. Patients with prolonged LOS (≥10 days) had higher triglyceride levels (171.8 vs. 120 mg/dL; p<0.001) and AIP values (0.442 vs. 0.286; p=0.02). There was a strong relationship between AIP and LOS values in COVID-19 patients with T2DM (r=0.632; p<0.001). The AIP value can well-discriminated in prolonged LOS conditions (AUC=0.883; 95%CI 0.792-0.974) with the optimal cut-off value of 0.3045 (sensitivity 75.9% and specificity 83.3%). Conclusion: AIP is correlated with prolonged LOS in COVID-19 patients with T2DM. Holistic management of COVID-19 patients with T2DM is urgently needed, including lipid profile control. Keywords: Atherogenic Index of Plasma, COVID-19, length of stay, type 2 diabetes mellitus
... 7,8 The endothelial cell (EC) expressing the angiotensinconverting enzyme type 2 (ACE2), is a target of SARS-CoV-2. 9 Consistently, COVID-19 has been proposed to be an endothelial disease, 10 where a vascular inflammation would promote oxidative stress and thrombus formation. 11 It has previously been proposed that an early EC dysfunction in COVID-19 may induce a pro-oxidant status. ...
Article
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COVID‐19 has been proposed to be an endothelial disease, as endothelial damage and oxidative stress contribute to its systemic inflammatory and thrombotic events. Polyphenols, natural antioxidant compounds appear as promising agents to prevent and treat COVID‐19. Polyphenols bind and inhibit the F1Fo‐ATP synthase rotary catalysis. An early target of polyphenols may be the ectopic F1Fo‐ATP synthase expressed on the endothelial plasma membrane. Among the pleiotropic beneficial action of polyphenols in COVID‐19, modulation of the ecto‐F1Fo‐ATP synthase, lowering the oxidative stress produced by the electron transfer chain coupled to it, would not be negligible.
... as well as increased pressure due to increased coronary blood flow, can accelerate plaque rupture, leading to acute myocardial infarction. The prothrombotic environment during systemic inflammation exacerbates the situation increasing the risks of thrombosis[29] • Various antiviral drugs, corticosteroids, and other treatments used in the treatment of COVID-19 can also have a detrimental effect on the cardiovascular system[30] • Electrolyte imbalance can occur in any critical systemic disease and cause arrhythmia, especially in patients with pre-existing cardiac disease. ...
Article
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BACKGROUND: Coronavirus disease 2019 (COVID-19) causes a hypercoagulable state with a high incidence of thrombotic complications. Patients with a history of myocardial revascularization have more severe complications due to COVID-19. Coronary stent thrombosis has become significantly more common during the COVID-19 pandemic. AIM: The aim of our study is to analyze scientific information on the risks of stent thrombosis in patients who underwent COVID-19. METHODS: A search was made for scientific publications in evidence-based medicine databases and web resources: PubMed, MEDLINE, UpToDate, TripDatabase, ResearchGate, and Google Scholar. Inclusion criteria were: (1) Observational studies or case series involving patients with a confirmed diagnosis of COVID-19 and myocardial infarction requiring myocardial revascularization; (2) the division of the population into survivors and non-survivors; and (3) data on the presence of the previous myocardial revascularization. Exclusion criteria: Case description and editorials/bulletins. In all articles selected for further analysis, 49 sources were considered that met the inclusion criteria and excluded duplication or repetition of information. RESULTS: Coronavirus infection has contributed to the change in the course of myocardial infarction in patients undergoing myocardial revascularization. The incidence of stent thrombosis has a positive correlation with the severity of the coronavirus infection. The previous myocardial revascularization procedures significantly increase the risk of mortality in patients with coronavirus infection. This is especially actual for elderly patients. CONCLUSION: One of the most vulnerable groups is elderly patients who have undergone myocardial revascularization after myocardial infarction in the past and have concomitant diseases. An analysis of scientific publications has shown that further larger-scale clinical studies are needed to confirm the hypothesis about the negative impact of coronavirus infection on stent thrombosis in patients who have undergone COVID-19.
... Virus phagocytosed by macrophages and those that are free could target the different sites where ACE2 is expressed [83]. This would explain how SARS-CoV-2 virus can cause multiple clinical manifestations such as respiratory, gastrointestinal, cardiovascular and renal problems observed in critically ill patients [84,85]. The difference of ACE2 expression levels in some organs is variable with respect to the vulnerability of SAR-CoV 2 infection. ...
Article
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SARS-CoV-2 virus has become a global health problem that has caused millions of deaths worldwide. The infection can present with multiple clinical features ranging from asymptomatic or mildly symptomatic patients to patients with severe or critical illness that can even lead to death. Although the immune system plays an important role in pathogen control, SARS-CoV-2 can drive dysregulation of this response and trigger severe immunopathology. Exploring the mechanisms of the immune response involved in host defense against SARS-CoV-2 allows us to understand its immunopathogenesis and possibly detect features that can be used as potential therapies to eliminate the virus. The main objective of this review on SARS-CoV-2 is to highlight the interaction between the virus and the immune response. We explore the function and action of the immune system, the expression of molecules at the site of infection that cause hyperinflammation and hypercoagulation disorders, the factors leading to the development of pneumonia and subsequent severe acute respiratory distress syndrome which is the leading cause of death in patients with COVID-19.
... A dysregulated host immune response is central to COVID-19 pathology and inflammatory symptoms such as hypercoagulability that are common especially in severe cases. 1,2 However, the course of the disease varies from asymptomatic courses to life-threatening pneumonia with respiratory failure. Overall infection fatality rates of COVID- 19 in Germany have been estimated to range from 0.2% to 3.5%, with a large degree of variation over the course of the pandemic and between age groups. ...
Article
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Introduction: Patients with hematologic disease are at high risk of morbidity and mortality from COVID-19 due to disease-inherent and therapy-related immunodeficiency. Whether infection with the SARS-CoV2 omicron variant leads to attenuated disease severity in these patients is currently unknown. Methods: We assessed clinical and laboratory parameters in 61 patients with underlying hematologic conditions with a SARS-CoV2 omicron variant infection confirmed by nucleic acid amplification testing. Results: Fifty patients reported symptoms of COVID-19, most commonly fatigue (37 patients, 60.66%) and cough (32 patients, 52.46%). 39.34% of patients reported fever. Dyspnea was reported by 10 patients and 7 patients (11.48%) required oxygen therapy. Anosmia and ageusia were relatively rare, occurring in less than 10% of patients. Severity of SARS-CoV2 infection could be assessed in 60 patients. Five cases of critical illness leading to ICU admission occurred during the observation period. Overall mortality was 9.84% in this patient cohort, with heterogeneous causes of death. The majority of omicron-infected hematologic patients experienced mild symptoms or remained asymptomatic. Discussion: In this study, symptoms of COVID-19 tended to be milder than described for previous SARS-CoV2 variants. However, the extent to which attenuated severity of omicron-variant SARS-CoV2 infection is caused by altered viral pathogenicity or pre-existing host immunity cannot be inferred from our data and should be investigated in larger prospective studies.
... In addition to age, pre-existing hypertension, diabetes, and obesity are major risk factors for severe COVID- 19 and increased mortality (9)(10)(11). Black and Hispanic patients have been disproportionately affected by COVID-19 and have increased mortality. ...
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... Teuwen et al. suggested that endothelial cells are pivotal contributors to the initiation and development of COVID-19 severity [42]. Therefore, endothelial dysfunction, one of the important determinant factors, is responsible for clinical manifestations observed in COVID-19 patients such as hypertension, diabetes mellitus, kidney disease, neurologic disorders, cerebrovascular events and thrombosis [43][44][45][46]. In addition, endothelial cells have played a central role in the pathogenesis of ARDS and multiple organ damage in patients with COVID-19 [47]. ...
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Background: The coronavirus disease-2019 (COVID-19) pandemic has caused important health, economic, social, and cultural problems worldwide. Recent findings demonstrate an excessive cytokine release during the disease development, especially in the seriously life-threatening form of COVID-19. Among other chemokines and cytokines that are released in high amounts at the infection site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), midkine (MK), which is a potent pro-inflammatory growth factor/ cytokine, can be also overexpressed and contribute to the pathophysiological process in patients infected with SARS-CoV-2. Materials and method: Serum was collected from 87 intensive care unit (ICU) patients that are COVID-19 positive and 50 healthy volunteers in the control group with a negative PCR test and without disease symptoms. Circulating MK concentration was measured by enzyme-linked immunosorbent assay (ELISA). Results: COVID-19 patients had a significantly higher serum MK concentration compared to non-COVID-19 control subjects (1892.8 ± 1615.8 pg/mL versus 680.7 ± 907.6 pg/mL, respectively; P < 0.001). The cut-off MK concentration was 716.7 pg/ mL, with the sensitivity and specificity of 75.9 % and 76.0 %, respectively. The area under the receiver operating characteristic (ROC) curve of MK was = 0.827. Our findings showed that circulating MK levels are significantly increased in SARS-CoV-2 infected patients. Conclusion: We suggest that MK is involved in the pathogenesis of COVID-19 and may be a part of hypercytokinaemia. Therefore, MK may serve as a supporting biomarker in the diagnosis of COVID-19, and blocking MK actions or its targets may attenuate the inflammatory process and the severity of the disease.
... As our meta-analysis focused specifically on the prevaccination phase of the pandemic, we are unable to comment on the association between DM, HTN, IHD and myocardial injury with biomarkers of disease severity including coagulation indicators such as fibrinogen degradation products, prothrombin time, D-dimer and platelets, as these were infrequently reported in earlier studies included. Indeed, the pro-coagulation state in COVID-19 disease is now well-recognized and biomarkers such as D-dimer are used to guide routine use of anticoagulants in COVID-19 patients (35). Whilst findings from the REMAP-CAP trial have not shown a protective effect of antiplatelets in patients with critically-ill patients with COVID-19, it would be interesting to further stratify whether empirical antiplatelet and anticoagulant therapy in patients with different risk profiles (e.g., DM vs. non-DM) will improve overall outcomes (36). ...
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Background: More than 80% of individuals in low and middle-income countries (LMICs) are unvaccinated against coronavirus disease 2019 (COVID-19). In contrast, the greatest burden of cardiovascular disease is seen in LMIC populations. Hypertension (HTN), diabetes mellitus (DM), ischaemic heart disease (IHD) and myocardial injury have been variably associated with adverse COVID-19 outcomes. A systematic comparison of their impact on specific COVID-19 outcomes is lacking. We quantified the impact of DM, HTN, IHD and myocardial injury on six adverse COVID-19 outcomes: death, acute respiratory distress syndrome (ARDS), invasive mechanical ventilation (IMV), admission to intensive care (ITUadm), acute kidney injury (AKI) and severe COVID-19 disease (SCov), in an unvaccinated population. Methodology: We included studies published between 1st December 2019 and 16th July 2020 with extractable data on patients ≥18 years of age with suspected or confirmed SARS-CoV-2 infection. Odds ratios (OR) for the association between DM, HTN, IHD and myocardial injury with each of six COVID-19 outcomes were measured. Results: We included 110 studies comprising 48,809 COVID-19 patients. Myocardial injury had the strongest association for all six adverse COVID-19 outcomes [death: OR 8.85 95% CI (8.08-9.68), ARDS: 5.70 (4.48-7.24), IMV: 3.42 (2.92-4.01), ITUadm: 4.85 (3.94-6.05), AKI: 10.49 (6.55-16.78), SCov: 5.10 (4.26-6.05)]. HTN and DM were also significantly associated with death, ARDS, ITUadm, AKI and SCov. There was substantial heterogeneity in the results, partly explained by differences in age, gender, geographical region and recruitment period. Conclusion: COVID-19 patients with myocardial injury are at substantially greater risk of death, severe disease and other adverse outcomes. Weaker, yet significant associations are present in patients with HTN, DM and IHD. Quantifying these associations is important for risk stratification, resource allocation and urgency in vaccinating these populations. Systematic review registration: https://www.crd.york.ac.uk/prospero/, registration no: CRD42020201435 and CRD42020201443.
... 7 These findings may help explain localized endothelial injury and thrombosis with SARS-CoV-2 infection that leads to stroke-especially in young patients without typical stroke risk factors-but also why patients with co-morbidities that have preexisting vascular dysfunction such as diabetes and hypertension fair worse with COVID-19 infection. 8 Activation of the inflammatory cascade ("cytokine storm") that exacerbates endothelial dysfunction and bloodbrain barrier permeability represents another means by which SARS-CoV-2 adversely impacts the cerebrovasculature that may be involved in COVID-19 stroke pathophysiology. 9 ...
... Coronavirus has become a pandemic disease in the world. The COVID-19 virus has much adverse impact on human bodies resulting in pneumonia, kidney dysfunction, hypertension, thrombosis, cardiovascular diseases, and diabetes [2], [20], [21]. ...
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ABSTRACT— COVID-19 diseases due to the SARS-Cov-2 virus have become a global infectious disease. It is, therefore, crucial to investigate biomarkers that are involved in the pathogenicity and severity of the disease. This study aimed to investigate some immune-inflammatory and pathological biomarkers s during COVID-19 diseases. After providing written consent, 5 ml blood samples were drawn from 121 COVID-19 patients confirmed by Real Time Polymerase Chain Reaction (RT-PCR), including 77 Male and 44 Female COVID-19 cases with 52.64 years of mean age. Clinical analysis was performed including White blood cells (WBC), Lymphocytes (Lymph), D-dimer, Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), Ferritin, creatinine, urea and blood glucose were analysed after adjusting for sex, presence of comorbidity, weight and smoking status. Elevation of some clinical parameters was elevated in severe COVI D-19 patients compared to mild patients, also female COVID-19 patients had higher WBC and ferritin level compared to male patients. It can be concluded that some clinical biomarkers in COVID-19 patients, such as WBC, lymph percent, D-Dimer, Ferritin, ESR, CRP urea, and creatinine, are distinct predictive indicators for severe male COVID-19 patients, which are more frequent than opposite-sex gender. KEYWORDS: COVID-19 disease, immuno-inflammatory markers, pathogenicity, severe and non-sever patients
... Typical clinical symptoms of SARS-CoV-2 infection includes acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), multiple organ failure (MOF), and disseminated intravascular coagulation (DIC) [2,4,5]. Some other clinical events usually observed in COVID-19 patients, including high blood pressure, thrombosis kidney disease, pulmonary embolism, Kawasaki disease, cerebrovascular and neurologic disorders, mesenteric ischemia, and cutaneous vasculitis, all indicating that the virus impairs vascular endothelial function [6,7]. Clinical markers for indicating the activation of coagulation and fibrinolysis, including d-dimer and Von Willebrand factor (VWF), were significantly elevated in COVID-19 patients and were predictive of poor outcome, further supporting the hypothesis of SARS-CoV-2-induced endothelial damage [8,9]. ...
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COVID-19 is a highly infectious respiratory disease caused by a new coronavirus known as SARS-CoV-2. COVID-19 is characterized by progressive respiratory failure resulting from diffuse alveolar damage, inflammatory infiltrates, endotheliitis, and pulmonary and systemic coagulopathy forming obstructive microthrombi with multi-organ dysfunction, indicating that endothelial cells (ECs) play a central role in the pathogenesis of COVID-19. The glycocalyx is defined as a complex gel-like layer of glycosylated lipid–protein mixtures, which surrounds all living cells and acts as a buffer between the cell and the extracellular matrix. The endothelial glycocalyx layer (EGL) plays an important role in vascular homeostasis via regulating vascular permeability, cell adhesion, mechanosensing for hemodynamic shear stresses, and antithrombotic and anti-inflammatory functions. Here, we review the new findings that described EGL damage in ARDS, coagulopathy, and the multisystem inflammatory disease associated with COVID-19. Mechanistically, the inflammatory mediators, reactive oxygen species (ROS), matrix metalloproteases (MMPs), the glycocalyx fragments, and the viral proteins may contribute to endothelial glycocalyx damage in COVID-19. In addition, the potential therapeutic strategies targeting the EGL for the treatment of severe COVID-19 are summarized and discussed.
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Throughout 2021, the scientific and medical communities were concentrated on dealing with the acute morbidity and mortality induced by the COVID-19 pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We reviewed the present data for adverse effects of COVID-19 on the different parts of the male urogenital system during the dynamic situation of the COVID-19 pandemic. With the approval of COVID-19 vaccinations, there is a ray of hope at the end of this dark tunnel and a chance to look ahead for the management of long-term consequences in males with urogenital illnesses. A multidisciplinary investigation of these cases could provide information for establishing and optimizing treatment protocols. Teaser: COVID-19 is more severe and lethal in male patients, probably due to gender-specific alterations in ACE2 receptor expression. Furthermore, COVID-19 has adverse effects on the reproductive system, sexual and bladder functions, and prostate pathologies.
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Проблема COVID-19 на сьогодні є найбільш невирішеною. Хвороба маніфестує симптомами ураження легеневої системи з подальшим ушкодженням інших систем і органів. Враховуючи, що серцево-судинні захворювання залишаються головною причиною смертності у всьому світі, вкрай необхідним є вивчення особливостей перебігу COVID-19 на тлі існуючої серцево-судинної патології. В статті проаналізовані існуючі дані мета-аналізів щодо особливостей перебігу COVID-19 на фоні існуючої серцево-судинної патології.
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Identifying signaling pathways and molecules involved in SARS-CoV-2 pathogenesis is pivotal for developing new effective therapeutic or preventive strategies for COVID-19. Pannexins (PANX) are ATP-release channels in the plasma membrane essential in many physiological and immune responses. Activation of pannexin channels and downstream purinergic receptors play dual roles in viral infection, either by facilitating viral replication and infection or inducing host antiviral defense. The current review provides a hypothesis demonstrating the possible contribution of the PANX1 channel and purinergic receptors in SARS-CoV-2 pathogenesis and mechanism of action. Moreover, we discuss whether targeting these signaling pathways may provide promising preventative therapies and treatments for patients with progressive COVID-19 resulting from excessive pro-inflammatory cytokines and chemokines production. Several inhibitors of this pathway have been developed for the treatment of other viral infections and pathological consequences. Specific PANX1 inhibitors could be potentially included as part of the COVID-19 treatment regimen if, in future, studies demonstrate the role of PANX1 in COVID-19 pathogenesis. Of note, any ATP therapeutic modulation for COVID-19 should be carefully designed and monitored because of the complex role of extracellular ATP in cellular physiology.
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Introduction : Despite the improvement in COVID-19 therapeutic management the mortality of mechanically ventilated COVID-19 patients remains high. In this study, we determined risk factors of mortality in these cases. Methods : This retrospective study examined clinical and paraclinical data of COVID-19 patients mechanically ventilated at the time of hospitalization to ICU admission until death or discharge from hospital between April and September in 2021 in three COVID-19 referral hospitals. Results : One hundred twenty-five patients (60% male, mean age 62 ± 15.18, range 17 to 97 years old) were recruited to this study. 51(40%) survived and 74 (60%) didn’t survive. At the time of hospital admission, the vital signs were not significantly different between the survivors and non-survivors groups, also diarrhea was not reported in non-survivors, but reported in 9.5% of survivors (P = 0.02). The mean age of 74 non-survivors was higher than 51 survivors (65.1 ± 14.17 vs 56.9 ± 15.41, P = 0.003). The intubation time since the patients were admitted to hospitals was not significantly different between the two groups (3.38 ± 2.88 days vs 4.16 ± 3.42 days, P = 0.34). The mean LDH and D-dimer at the time of ICU admission were significantly higher in the non-survivors group (863 ± 449 vs 613 ± 326, P = 0.01; 4081 ± 3342 vs 542 ± 634, P = 0.009; respectively). However, the mean CRP was not significantly different between the two groups (76 ± 66.4, 54 ± 84.3; P = 0.1). Mean APACHE-II score was higher in the non-survivors than the survivors (15 vs 13; P = 0.01). Use of remdesivir, interfrone beta-1a, and low dose corticosteroids were significantly higher in the survivors group (P = 0.009, P = 0.001, P = 0.000). Conclusion : Success of weaning and hospital discharge among mechanically ventilated COVID-19 patients are probably higher in younger patients with lower D-dimmer and LDH levels that received low dose corticosteroids during treatment.
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The foremost challenge in countering infectious diseases is the shortage of effective therapeutics. The emergence of coronavirus disease (COVID-19) outbreak has posed a great menace to the public health system globally, prompting unprecedented endeavors to contain the virus. Many countries have organized research programs for therapeutics and management development. However, the longstanding process has forced authorities to implement widespread infrastructures for detailed prognostic and diagnostics study of severe acute respiratory syndrome (SARS CoV-2). This review discussed nearly all the globally developed diagnostic methodologies reported for SARS CoV-2 detection. We have highlighted in detail the approaches for evaluating COVID-19 biomarkers along with the most employed nucleic acid- and protein-based detection methodologies and the causes of their severe downfall and rejection. As the variable variants of SARS CoV-2 came into the picture, we captured the breadth of newly integrated digital sensing prototypes comprised of plasmonic and field-effect transistor-based sensors along with commercially available food and drug administration (FDA) approved detection kits. However, more efforts are required to exploit the available resources to manufacture cheap and robust diagnostic methodologies. Likewise, the visualization and characterization tools along with the current challenges associated with waste-water surveillance, food security, contact tracing, and their role during this intense period of the pandemic have also been discussed. We expect that the integrated data will be supportive and aid in the evaluation of sensing technologies not only in current but also future pandemics.
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After analyzing the immune characteristics of patients with severe coronavirus disease 2019 (COVID-19), we have identified that pathogenic T cells and inflammatory monocytes with large amount of interleukin 6 secreting may incite the inflammatory storm, which may potentially be curbed through monoclonal antibody that targets the IL-6 pathways. Here, we aimed to assess the efficacy of tocilizumab in severe patients with COVID-19 and seek a therapeutic strategy. The patients diagnosed as severe or critical COVID-19 in The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Fuyang Second People’s Hospital were given tocilizumab in addition to routine therapy between 5 and 14 February 2020. The changes of clinical manifestations, computerized tomography (CT) scan image, and laboratory examinations were retrospectively analyzed. Fever returned to normal on the first day, and other symptoms improved remarkably within a few days. Within 5 d after tocilizumab, 15 of the 20 patients (75.0%) had lowered their oxygen intake, and 1 patient needed no oxygen therapy. CT scans manifested that the lung lesion opacity absorbed in 19 patients (90.5%). The percentage of lymphocytes in peripheral blood, which decreased in 85.0% of patients (17/20) before treatment (mean, 15.52 ± 8.89%), returned to normal in 52.6% of patients (10/19) on the fifth day after treatment. Abnormally elevated C-reactive protein decreased significantly in 84.2% of patients (16/19). No obvious adverse reactions were observed. All patients have been discharged on average 15.1 d after giving tocilizumab. Preliminary data show that tocilizumab, which improved the clinical outcome immediately in severe and critical COVID-19 patients, is an effective treatment to reduce mortality.
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We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells’ potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org. An analysis of single-cell transcriptomics datasets from different tissues shows that ACE2 and TMPRSS2 are co-expressed in respiratory, corneal and intestinal epithelial cell populations, and that respiratory expression of ACE2 is associated with genes involved in innate immunity.
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Introduction There is an urgent need to identify patients at high risk during the ongoing coronavirus disease (COVID-19) pandemic. Whether a history of stroke is associated with increased severity of disease or mortality is unknown. Method We pooled studies from published literature to assess the association of a history of stroke with outcomes in patients with COVID-19. Results A pooled analysis of 4 studies showed a ∼2.5-fold increase in odds of severe COVID-19. While a trend was observed, there was no statistically significant association of stroke with mortality in patients with COVID-19 infection. Discussion Our findings are limited by a small number of studies and sample size. Conclusion There is a ∼2.5-fold increase in odds of severe COVID-19 illness with a history of cerebrovascular disease.
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Rationale: Use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. Objective: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in COVID-19 patients with hypertension. Methods and Results: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [IQR 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [IQR 57-69]; 53.5% men), who were admitted to nine hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. Unadjusted mortality rate was lower in the ACEI/ARB group versus the non-ACEI/ARB group (3.7% vs. 9.8%; P = 0.01). In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted HR, 0.42; 95% CI, 0.19-0.92; P =0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted HR, 0.37; 95% CI, 0.15-0.89; P = 0.03). Further subgroup propensity score-matched analysis indicated that, compared to use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted HR, 0.30; 95%CI, 0.12-0.70; P = 0.01) in COVID-19 patients with hypertension. Conclusions: Among hospitalized COVID-19 patients with hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB non-users. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.
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Coronavirus disease 2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, due to excessive inflammation, platelet activation, endothelial dysfunction, and stasis. In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy. Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease. Herein, we review the current understanding of the pathogenesis, epidemiology, management and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, and of those with preexisting thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.
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The new type of pneumonia caused by the SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) has been declared as a global public health concern by WHO. As of April 3, 2020, more than 1,000,000 human infections have been diagnosed around the world, which exhibited apparent person-to-person transmission characteristics of this virus. The capacity of vertical transmission in SARS-CoV-2 remains controversial recently. Angiotensin-converting enzyme 2 (ACE2) is now confirmed as the receptor of SARS-CoV-2 and plays essential roles in human infection and transmission. In present study, we collected the online available single-cell RNA sequencing (scRNA-seq) data to evaluate the cell specific expression of ACE2 in maternal-fetal interface as well as in multiple fetal organs. Our results revealed that ACE2 was highly expressed in maternal-fetal interface cells including stromal cells and perivascular cells of decidua, and cytotrophoblast and syncytiotrophoblast in placenta. Meanwhile, ACE2 was also expressed in specific cell types of human fetal heart, liver and lung, but not in kidney. And in a study containing series fetal and post-natal mouse lung, we observed ACE2 was dynamically changed over the time, and ACE2 was extremely high in neonatal mice at post-natal day 1~3. In summary, this study revealed that the SARS-CoV-2 receptor was widely spread in specific cell types of maternal-fetal interface and fetal organs. And thus, both the vertical transmission and the placenta dysfunction/abortion caused by SARS-CoV-2 need to be further carefully investigated in clinical practice.
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Link: https://www.thrombosisresearch.com/article/S0049-3848(20)30119-5/fulltext *Objective To raise awareness for possible benefits of examining known COVID-19 patients presenting sudden clinical worsening with CT pulmonary angiography instead of standard non-contrast chest CT. Highlights • Patients having COVID-19 pneumonia are at risk of coagulopathy and pulmonary embolism • In the absence of contraindications, all patients admitted for COVID-19 should receive prophylactic low molecular weight heparin to prevent thromboembolism • Physicians should be alert to potential pulmonary embolism events in patients with elevated D-dimer levels on admission or sudden clinical deterioration • Selected patients may benefit from CT pulmonary angiography to confirm acute pulmonary embolism and initiate appropriate therapy
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Stopping COVID-19 is a priority worldwide. Understanding which cell types are targeted by SARS-CoV-2 virus, whether interspecies differences exist, and how variations in cell state influence viral entry is fundamental for accelerating therapeutic and preventative approaches. In this endeavor, we profiled the transcriptome of nine tissues from a Macaca fascicularis monkey at single-cell resolution. The distribution of SARS-CoV-2 facilitators, ACE2 and TMRPSS2, in different cell subtypes showed substantial heterogeneity across lung, kidney, and liver. Through co-expression analysis, we identified immunomodulatory proteins such as IDO2 and ANPEP as potential SARS-CoV-2 targets responsible for immune cell exhaustion. Furthermore, single-cell chromatin accessibility analysis of the kidney unveiled a plausible link between IL6-mediated innate immune responses aiming to protect tissue and enhanced ACE2 expression that could promote viral entry. Our work constitutes a unique resource for understanding the physiology and pathophysiology of two phylogenetically close species, which might guide in the development of therapeutic approaches in humans. Bullet points We generated a single-cell transcriptome atlas of 9 monkey tissues to study COVID-19. ACE2 ⁺ TMPRSS2 ⁺ epithelial cells of lung, kidney and liver are targets for SARS-CoV-2. ACE2 correlation analysis shows IDO2 and ANPEP as potential therapeutic opportunities. We unveil a link between IL6, STAT transcription factors and boosted SARS-CoV-2 entry.
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The COVID-19 Pandemic has significantly impacted the US healthcare system. To preserve resources, including personal protective equipment (PPE) and hospital beds to care for COVID-19 patients, the Centers for Disease Control and Prevention (CDC) recommended deferral of elective cardiac procedures (1), including coronary angiography and percutaneous coronary intervention for stable coronary artery disease. Timely reperfusion by means of primary percutaneous coronary intervention (PPCI) is the standard of care for STEMI patients (2). The Society for Cardiac Angiography and Interventions (SCAI) and American College of Cardiology (ACC) continue to recommend PPCI as the standard treatment of STEMI patients during the current pandemic (3). However, anecdotal reports suggest a decline in PPCI volumes in the US and around the world (4). To determine if a decrease in PPCI is occurring in the US in the COVID-19 era, we analyzed and quantified STEMI activations for 9 high-volume ( over 100 PPCI per year) cardiac catheterization laboratories in the US from January 1, 2019 to March 31, 2020.
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Background There is concern about the potential of an increased risk related to medications that act on the renin–angiotensin–aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2). Methods We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive. Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class. A difference of at least 10 percentage points was prespecified as a substantial difference. Results Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness. There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive. Conclusions We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.