Circulating cardiomyocyte-derived extracellular vesicles reflect cardiac injury during systemic inflammatory response syndrome in mice.

The release of extracellular vesicles (EVs) is increased under cellular stress and cardiomyocyte damaging conditions. However, whether the cardiomyocyte-derived EVs eventually reach the systemic circulation and whether their number in the bloodstream reflects cardiac injury, remains unknown. Wild type C57B/6 and conditional transgenic mice expressing green fluorescent protein (GFP) by cardiomyocytes were studied in lipopolysaccharide (LPS)-induced systemic inflammatory response syndrome (SIRS). EVs were separated both from platelet-free plasma and from the conditioned medium of isolated cardiomyocytes of the left ventricular wall. Size distribution and concentration of the released particles were determined by Nanoparticle Tracking Analysis. The presence of GFP + cardiomyocyte-derived circulating EVs was monitored by flow cytometry and cardiac function was assessed by echocardiography. In LPS-treated mice, systemic inflammation and the consequent cardiomyopathy were verified by elevated plasma levels of TNFα, GDF-15, and cardiac troponin I, and by a decrease in the ejection fraction. Furthermore, we demonstrated elevated levels of circulating small- and medium-sized EVs in the LPS-injected mice. Importantly, we detected GFP+ cardiomyocyte-derived EVs in the circulation of control mice, and the number of these circulating GFP+ vesicles increased significantly upon intraperitoneal LPS administration (P = 0.029). The cardiomyocyte-derived GFP+ EVs were also positive for intravesicular troponin I (cTnI) and muscle-associated glycogen phosphorylase (PYGM). This is the first direct demonstration that cardiomyocyte-derived EVs are present in the circulation and that the increased number of cardiac-derived EVs in the blood reflects cardiac injury in LPS-induced systemic inflammation (SIRS).

Comparison of First and Second Wave Cohorts of Multisystem Inflammatory Disease Syndrome IN Children.

Comparing first and second wave MIS-C cohorts at our quaternary pediatric institution, second wave were older, presented more frequently with shortness of breath, higher maximum troponin and N-terminal BNP, and more frequently required advanced respiratory and inotropic support. Despite increased severity in the second cohort, both cohorts had similar rates of coronary artery abnormalities, systolic dysfunction, and length of stay.

Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications.

The global propagation of SARS-CoV-2 leads to an unprecedented public health emergency. Despite that the lungs are the primary organ targeted by COVID-19, systemic endothelial inflammation and dysfunction is observed particularly in patients with severe COVID-19, manifested by elevated endothelial injury markers, endotheliitis, and coagulopathy. Here, we review the clinical characteristics of COVID-19 associated endothelial dysfunction; and the likely pathological mechanisms underlying the disease including direct cell entry or indirect immune overreactions after SARS-CoV-2 infection. In addition, we discuss potential biomarkers that might indicate the disease severity, particularly related to the abnormal development of thrombosis that is a fatal vascular complication of severe COVID-19. Furthermore, we summarize clinical trials targeting the direct and indirect pathological pathways after SARS-CoV-2 infection to prevent or inhibit the virus induced endothelial disorders.

Spectrum of SARS-CoV-2-Related Clinical Syndromes in Children: A Year in the Life.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a wide pediatric clinical spectrum. Initial reports suggested that children had milder symptoms compared with adults; then diagnosis of multisystem inflammatory syndrome in children (MIS-C) emerged. We performed a retrospective cohort study of hospitalized patients at a children's hospital over 1 year. Our objectives were to study the demographic and clinical profile of pediatric SARS-CoV-2-associated diagnoses. Based on the clinical syndrome, patients were classified into coronavirus disease 2019 (COVID-19; non-MIS-C) and MIS-C cohorts. Among those who tested positive, 67% were symptomatic. MIS-C was diagnosed in 24 patients. Both diagnoses were more frequent in Caucasians. Both cohorts had different symptom profiles. Inflammatory markers were several-fold higher in MIS-C patients. These patients had critical care needs and longer hospital stays. More COVID-19 patients had respiratory complications, while MIS-C cohort saw cardiovascular involvement. Health care awareness of both syndromes is important for early recognition, diagnosis, and prompt treatment.

Midterm Outcomes and Cardiac Magnetic Resonance Imaging following Multisystem Inflammatory Syndrome in Children.

At midterm follow-up visits performed at a median of 7 months (IQR 6.0-8.4 months), 16 patients with multisystem inflammatory syndrome in children had resolution of left ventricular dysfunction and most had resolution of coronary aneurysms. On cardiovascular magnetic resonance imaging, no patients had late gadolinium enhancement.

Endothelial injury in COVID-19 and septic patients.

Systemic inflammatory response, as observed in sepsis and severe COVID-19, may lead to endothelial damage. Therefore, we aim to compare the extent of endothelial injury and its relationship to inflammation in both diseases. We included patients diagnosed with sepsis (SEPSIS group, n = 21), mild COVID-19 (MILD group, n = 31), and severe COVID-19 (SEVERE group, n = 24). Clinical and routine laboratory data were obtained, circulating cytokines (INF-γ, TNF-α, and IL-10) and endothelial injury markers (E-Selectin, Tissue Factor (TF) and von Willebrand factor (vWF)) were measured. Compared to the SEPSIS group, patients with severe COVID-19 present similar clinical and laboratory data, except for lower circulating IL-10 and E-Selectin levels. Compared to the MILD group, patients in the SEVERE group showed higher levels of TNF-α, IL-10, and TF. There was no clear relationship between cytokines and endothelial injury markers among the three studied groups; however, in SEVERE COVID-19 patients, there is a positive relationship between INF-γ with TF and a negative relationship between IL-10 and vWF. In conclusion, COVID-19 and septic patients have a similar pattern of cytokines and endothelial dysfunction markers. These findings highlight the importance of endothelium dysfunction in COVID-19 and suggest that endothelium should be better evaluated as a therapeutic target for the disease.

Characterization and Outcomes of Hospitalized Children With Coronavirus Disease 2019: A Report From a Multicenter, Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) Registry.

OBJECTIVES: Multicenter data on the characteristics and outcomes of children hospitalized with coronavirus disease 2019 are limited. Our objective was to describe the characteristics, ICU admissions, and outcomes among children hospitalized with coronavirus disease 2019 using Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 registry. DESIGN: Retrospective study. SETTING: Society of Critical Care Medicine Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) registry. PATIENTS: Children (< 18 yr) hospitalized with coronavirus disease 2019 at participating hospitals from February 2020 to January 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was ICU admission. Secondary outcomes included hospital and ICU duration of stay and ICU, hospital, and 28-day mortality. A total of 874 children with coronavirus disease 2019 were reported to Viral Infection and Respiratory Illness Universal Study registry from 51 participating centers, majority in the United States. Median age was 8 years (interquartile range, 1.25-14 yr) with a male:female ratio of 1:2. A majority were non-Hispanic (492/874; 62.9%). Median body mass index (n = 817) was 19.4 kg/m2 (16-25.8 kg/m2), with 110 (13.4%) overweight and 300 (36.6%) obese. A majority (67%) presented with fever, and 43.2% had comorbidities. A total of 238 of 838 (28.2%) met the Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children, and 404 of 874 (46.2%) were admitted to the ICU. In multivariate logistic regression, age, fever, multisystem inflammatory syndrome in children, and pre-existing seizure disorder were independently associated with a greater odds of ICU admission. Hospital mortality was 16 of 874 (1.8%). Median (interquartile range) duration of ICU (n = 379) and hospital (n = 857) stay were 3.9 days (2-7.7 d) and 4 days (1.9-7.5 d), respectively. For patients with 28-day data, survival was 679 of 787, 86.3% with 13.4% lost to follow-up, and 0.3% deceased. CONCLUSIONS: In this observational, multicenter registry of children with coronavirus disease 2019, ICU admission was common. Older age, fever, multisystem inflammatory syndrome in children, and seizure disorder were independently associated with ICU admission, and mortality was lower among children than mortality reported in adults.

Sulforaphane-Dependent Up-Regulation of NRF2 Activity Alleviates Both Systemic Inflammatory Response and Lung Injury After Hemorrhagic Shock/Resuscitation in Mice.

ABSTRACT: Hemorrhagic shock/resuscitation (HS/R) is closely associated with overwhelming oxidative stress and systemic inflammation. As an effective activator of the nuclear factor-erythroid factor 2 related factor 2 (Nrf2) pathway, sulforaphane (SFN) exerts antioxidant and anti-inflammatory effects. We explored SFN's effects on alveolar macrophages (AMs), systemic inflammation, and pulmonary damage in an isolated murine HS/R model. Male C57/BL6 wild type and transgenic antioxidant response element (ARE)-luciferase (luc) mice (both n = 6 per group) were exposed to either pressure-controlled HS/R (mean arterial pressure 35-45 mm Hg for 90 min) or sham procedure (surgery without HS/R) or were sacrificed without intervention (control group). Fluid resuscitation was performed via the reinfusion of withdrawn blood and 0.9% saline. Sulforaphane or 0.9% saline (vehicle) was administrated intraperitoneally. Mice were sacrificed 6, 24, or 72 h after resuscitation. Bioluminescence imaging of ARE-luc mice was conducted to measure pulmonary Nrf2 activity. Plasma was collected to determine systemic cytokine levels. Alveolar macrophages were isolated before measuring cytokines in the supernatant and performing immunofluorescence staining, as well as Western blot for intracellular Nrf2. Histological damage was assessed via the acute lung injury score and wet/dry ratio.Hemorrhagic shock/resuscitation was associated with pulmonary Nrf2 activation. Sulforaphane enhanced pulmonary Nrf2 activity and the Nrf2 activation of AM, while it decreased lung damage. Sulforaphane exerted down-regulatory effects on AM-generated and systemic pro-inflammatory mediators, while it did not have such effects on IL-10.In conclusion, SFN beneficially enhances pulmonary Nrf2 activity and promotes Nrf2 accumulation in AMs' nuclei. This may exert not only local protective effects but also systemic effects via the down-regulation of pro-inflammatory cytokines. The administration of Nrf2 activator post-HS/R may represent an innovative treatment strategy.

Coronary Artery Changes in Patients with Multisystem Inflammatory Syndrome in Children: Los Angeles Experience.

We compared cardiac findings in patients with multisystem inflammatory syndrome in children and Kawasaki disease in the first 6 months of the 2020 coronavirus disease pandemic to patients with Kawasaki disease during 2016-2019. We saw a high rate of coronary aneurysms in 2020, with a similar rate of coronary involvement but greater volume and incidence of cardiac dysfunction compared with previous years.

Plasmin drives burn-induced systemic inflammatory response syndrome.

Severe injuries, such as burns, provoke a systemic inflammatory response syndrome (SIRS) that imposes pathology on all organs. Simultaneously, severe injury also elicits activation of the fibrinolytic protease plasmin. While the principal adverse outcome of plasmin activation in severe injury is compromised hemostasis, plasmin also possesses proinflammatory properties. We hypothesized that, following a severe injury, early activation of plasmin drives SIRS. Plasmin activation was measured and related to injury severity, SIRS, coagulopathy, and outcomes prospectively in burn patients who are not at risk of hemorrhage. Patients exhibited early, significant activation of plasmin that correlated with burn severity, cytokines, coagulopathy, and death. Burn with a concomitant, remote muscle injury was employed in mice to determine the role of plasmin in the cytokine storm and inflammatory cascades in injured tissue distant from the burn injury. Genetic and pharmacologic inhibition of plasmin reduced the burn-induced cytokine storm and inflammatory signaling in injured tissue. These findings demonstrate (a) that severe injury-induced plasmin activation is a key pathologic component of the SIRS-driven cytokine storm and SIRS-activated inflammatory cascades in tissues distant from the inciting injury and (b) that targeted inhibition of plasmin activation may be effective for limiting both hemorrhage and tissue-damaging inflammation following injury.

Multisystem Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Role of Oxidative Stress.

With the appearance of the SARS-CoV-2 virus in December 2019, all countries in the world have implemented different strategies to prevent its spread and to intensively search for effective treatments. Initially, severe cases of the disease were considered in adult patients; however, cases of older school-age children and adolescents who presented fever, hypotension, severe abdominal pain and cardiac dysfunction, positive for SARS-CoV-2 infection, have been reported, with increased pro-inflammatory cytokines and tissue damage, condition denominated multisystemic inflammatory syndrome (MIS-C); The emerging data from patients with MIS-C have suggested unique characteristics in the immunological response and also clinical similarities with other inflammatory syndromes, which can support as a reference in the search for molecular mechanisms involved in MIS-C. We here in propose that oxidative stress (OE) may play a very important role in the pathophysiology of MIS-C, such as occurs in Kawasaki disease (KD), severe COVID-19 in adults and other processes with characteristics of vascular damage similar to MIS- C, for which we review the available information that can be correlated with possible redox mechanisms.

Cardiogenic shock complicating multisystem inflammatory syndrome following COVID-19 infection: a case report.

BACKGROUND: With the high prevalence of COVID-19 infections worldwide, the multisystem inflammatory syndrome in adults (MIS-A) is becoming an increasingly recognized entity. This syndrome presents in patients several weeks after infection with COVID-19 and is associated with thrombosis, elevated inflammatory markers, hemodynamic compromise and cardiac dysfunction. Treatment is often with steroids and intravenous immunoglobulin (IVIg). The pathologic basis of myocardial injury in MIS-A, however, is not well characterized. In our case report, we obtained endomyocardial biopsy that revealed a pattern of myocardial injury similar to that found in COVID-19 cardiac specimens. CASE PRESENTATION: A 26-year-old male presented with fevers, chills, headache, nausea, vomiting, and diarrhea 5 weeks after his COVID-19 infection. His SARS-CoV-2 PCR was negative and IgG was positive, consistent with prior infection. He was found to be in cardiogenic shock with biventricular failure, requiring inotropes and diuretics. Given concern for acute fulminant myocarditis, an endomyocardial biopsy (EMB) was performed, showing an inflammatory infiltrate consisting predominantly of interstitial macrophages with scant T lymphocytes. The histologic pattern was similar to that of cardiac specimens from COVID-19 patients, helping rule out myocarditis as the prevailing diagnosis. His case was complicated by persistent hypoxemia, and a computed tomography scan revealed pulmonary emboli. He received IVIg, steroids, and anticoagulation with rapid recovery of biventricular function. CONCLUSIONS: MIS-A should be considered as the diagnosis in patients presenting several weeks after COVID-19 infection with severe inflammation and multi-organ involvement. In our case, EMB facilitated identification of MIS-A and guided therapy. The patient's biventricular function recovered with IVIg and steroids.

The Cross-Talk between Thrombosis and Inflammatory Storm in Acute and Long-COVID-19: Therapeutic Targets and Clinical Cases.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) commonly complicates with coagulopathy. A syndrome called Long-COVID-19 is emerging recently in COVID-19 survivors, characterized, in addition to the persistence of symptoms typical of the acute phase, by alterations in inflammatory and coagulation parameters due to endothelial damage. The related disseminated intravascular coagulation (DIC) can be associated with high death rates in COVID-19 patients. It is possible to find a prothrombotic state also in Long-COVID-19. Early administration of anticoagulants in COVID-19 was suggested in order to improve patient outcomes, although exact criteria for their application were not well-established. Low-molecular-weight heparin (LMWH) was commonly adopted for counteracting DIC and venous thromboembolism (VTE), due to its pharmacodynamics and anti-inflammatory properties. However, the efficacy of anticoagulant therapy for COVID-19-associated DIC is still a matter of debate. Thrombin and Factor Xa (FXa) are well-known components of the coagulation cascade. The FXa is known to strongly promote inflammation as the consequence of increased cytokine expression. Endothelial cells and mononuclear leucocytes release cytokines, growth factors, and adhesion molecules due to thrombin activation. On the other hand, cytokines can activate coagulation. The cross-talk between coagulation and inflammation is mediated via protease-activated receptors (PARs). These receptors might become potential targets to be considered for counteracting the clinical expressions of COVID-19. SARS-CoV-2 is effectively able to activate local and circulating coagulation factors, thus inducing the generation of disseminated coagula. LMWH may be considered as the new frontier in the treatment of COVID-19 and Long-COVID-19. Indeed, direct oral anticoagulants (DOACs) may be an alternative option for both early and later treatment of COVID-19 patients due to their ability to inhibit PARs. The aim of this report was to evaluate the role of anticoagulants-and DOACs in particular in COVID-19 and Long-COVID-19 patients. We report the case of a COVID-19 patient who, after administration of enoxaparin developed DIC secondary to virosis and positivity for platelet factor 4 (PF4) and a case of Long-COVID with high residual cardiovascular risk and persistence of blood chemistry of inflammation and procoagulative state.

The clinical course and short-term health outcomes of multisystem inflammatory syndrome in children in the single pediatric rheumatology center.

OBJECTIVES: Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe condition resulting in excessive response of the immune system after SARS-CoV-2 infection. We report a single-center cohort of children with MIS-C, describing the spectrum of presentation, therapies, clinical course, and short-term outcomes. METHODS: This is a prospective observational study from to a tertiary pediatric rheumatology center including patients (aged 1 month to 21 years) diagnosed with MIS-C between April 2020-April 2021. Demographic, clinical, laboratory results and follow-up data were collected through the electronic patient record system and analyzed. RESULTS: A total of 67 patients with MIS-C were included in the study. Fever was detected in all patients; gastrointestinal system symptoms were found in 67.2% of the patients, rash in 38.8%, conjunctivitis in 31.3%, hypotension in 26.9% myocarditis, and/or pericarditis in 22.4%, respectively. Respiratory symptoms were only in five patients (7.5%). Kawasaki Disease like presentation was found 37.3% of the patients. The mean duration of hospitalization was 11.8 7.07 days. Fifty-seven patients (85%) received intravenous immunoglobulin (IVIG), 45 (67%) received corticosteroids, 17 (25.3%) received anakinra, and one (1.5%) received tocilizumab. Seven of the patients (10.4%) underwent therapeutic plasma exchange (TPE). In 21 (31.3%) patients, a pediatric intensive care unit (PICU) was required in a median of 2 days. The first finding to improve was fever, while the first parameter to decrease was ferritin (median 6.5 days (IQR, 4-11.2 days)). Sixty-five patients were discharged home with a median duration of hospital stay of 10 days (IQR, 7-15 days). CONCLUSION: Patients with MIS-C may have severe cardiac findings and intensive care requirements in admission and hospital follow-up. The vast majority of these findings improve with effective treatment without any sequelae until discharge and in a short time in follow-up. Although the pathogenesis and treatment plan of the disease are partially elucidated, follow-up studies are needed in terms of long-term prognosis and relapse probabilities.

Prognostic implication of systemic inflammatory state on antiplatelet effect in patients after percutaneous coronary intervention for ST-elevation myocardial infarction: A retrospective cohort study.

ABSTRACT: Patients with ST-elevation myocardial infarction (STEMI) show an inflammatory response. The level of systemic inflammation is known to affect platelet aggregation function and antiplatelet therapy, which leads to different clinical prognosis. This study aims to evaluate the prognostic implication of systemic inflammatory state in patients with STEMI undergoing percutaneous coronary intervention.In this study, 203 patients with STEMI who underwent primary percutaneous coronary intervention were included. The patients were divided into 3 groups based on the inflammation levels assessed by tertiles of high-sensitivity C-reactive protein (hs-CRP) level on admission. Platelet aggregation evaluation was performed by residual platelet reactivity, which was assessed by the value of residual ADP-induced light transmittance aggregometry after clopidogrel maintenance dose therapy and in follow-up. Major adverse cardiac events (MACEs) were defined to include all-cause mortality, cardiovascular mortality, reinfarction, target vessel revascularization (TVR), cardiopulmonary resuscitation, advanced heart failure, ventricular fibrillation or ventricular tachycardia, and atrioventricular block.Levels of white blood cell was observed to be significantly higher at high tertile levels. Residual ADP-induced platelet aggregation was significantly higher at high tertile levels after clopidogrel maintenance dose therapy and in follow-up. Multivariate analysis identified that reperfusion time, alanine aminotransferase, platelet count, ADP-induced light transmittance aggregometry in follow-up and hs-CRP was independent predictors of MACEs. Platelet inhibition function of clopidogrel decreases progressively at different inflammation levels. The different levels of hs-CRP were demonstrated to be associated with MACEs at follow-up assessments.The presence of hs-CRP was not only significantly associated with platelet inhibition function, but was also a prognostic marker in STEMI.

Kawasaki Disease and Multisystem Inflammatory Syndrome in Children: An Overview and Comparison.

Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) are inflammatory conditions that present diagnostic and therapeutic challenges to the physician. Although many of their features overlap, they are two distinct conditions. KD is a febrile illness most commonly affecting children younger than five years. It manifests with prolonged fever and at least four of the following features: bilateral bulbar conjunctivitis, mucositis, diffuse maculopapular rash, extremity changes, and cervical lymphadenopathy of 1.5 cm or more in diameter. Patients with MIS-C may have many of the same manifestations but tend to have higher rates of gastrointestinal and neurocognitive symptoms and signs of shock on presentation. Both conditions are associated with cardiac sequelae, including coronary artery aneurysms, although children with MIS-C are at high risk of developing ventricular dysfunction and depressed cardiac output. Lymphocytopenia, thrombocytopenia, elevated troponin, and elevated B-type natriuretic peptide are key laboratory findings of MIS-C that can help distinguish it from KD. The use of intravenous immune globulin is well established in KD and also appears to have a role in the treatment of MIS-C. Aspirin has been used in KD for an anti-inflammatory effect, and low-dose aspirin is recommended for MIS-C to reduce the risk of thrombosis. In addition to supportive care, patients with MIS-C may benefit from immunomodulatory medications, although data on this topic are evolving.