A Matter of Caution: Coagulation Parameters in COVID-19 Do Not Differ from Patients with Ruled-Out SARS-CoV-2 Infection in the Emergency Department.

COVID-19 (coronavirus disease 2019) patients often show excessive activation of coagulation, associated with increased risk of thrombosis. However, the diagnostic value of coagulation at initial clinical evaluation is not clear. We present an in-depth analysis of coagulation in patients presenting to the emergency department (ED) with suspected COVID-19. N = 58 patients with clinically suspected COVID-19 in the ED were enrolled. N = 17 subsequently tested positive using SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) polymerase chain reaction (PCR) swabs, while in n = 41 COVID-19 was ruled-out. We analyzed both standard and extended coagulation parameters, including thromboplastin time (INR), activated partial thromboplastin time (aPTT), antithrombin, plasminogen, plasminogen activator inhibitor-1 (PAI-1), D-dimers, and fibrinogen at admission, as well as α2-antiplasmin, activated protein C -resistance, factor V, lupus anticoagulant, protein C, protein S, and von Willebrand diagnostics. These data, as well as mortality and further laboratory parameters, were compared across groups based on COVID-19 diagnosis and severity of disease. In patients with COVID-19, we detected frequent clotting abnormalities, including D-dimers. The comparison cohort in the ED, however, showed similarly altered coagulation. Furthermore, parameters previously shown to distinguish between severe and moderate COVID-19 courses, such as platelets, plasminogen, fibrinogen, aPTT, INR, and antithrombin, as well as multiple nonroutine coagulation analytes showed no significant differences between patients with and without COVID-19 when presenting to the ED. At admission to the ED the prevalence of coagulopathy in patients with COVID-19 is high, yet comparable to the non-COVID-19 cohort presenting with respiratory symptoms. Nevertheless, coagulopathy might worsen during disease progression with the need of subsequent risk stratification.

At the Crossroads: COVID-19 and Immune-Checkpoint Blockade for Cancer.

The immunomodulatory effects of immune-checkpoint blockade (ICB) therapy for cancer may act at the crossroads between the need to increase antiviral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to decrease the inflammatory responses in severe cases of coronavirus disease 2019 (COVID-19). There is evidence from preclinical models that blocking programmed death receptor 1 (PD1) protects against RNA virus infections, which suggests that patients with cancer receiving ICB may have lower rates of viral infection. However, given the heterogeneity of patient characteristics, this would be difficult to demonstrate using population-based registries or in clinical trials. Most studies of the impact of ICB therapy on the course of COVID-19 have centered on studying its potential detrimental impact on the course of the COVID-19 infection, in particular on the development of the most severe inflammatory complications. This is a logical concern as it is becoming clear that complications of COVID-19 such as severe respiratory distress syndrome are related to interferon signaling, which is the pathway that leads to expression of the PD1 ligand PD-L1. Therefore, PD1/PD-L1 ICB could potentially increase inflammatory processes, worsening the disease course for patients. However, review of the current evidence does not support the notion that ICB therapy worsens complications from COVID-19, and we conclude that it supports the continued use of ICB therapy during the COVID-19 pandemic provided that we now collect data on the effects of such therapy on COVID-19 vaccination.

Myocarditis and inflammatory cardiomyopathy: current evidence and future directions.

Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.

Association between Cardiovascular Burden and Requirement of Intensive Care among Patients with Mild COVID-19.

BACKGROUND: Information regarding the impact of cardiovascular (CV) conditions on disease progression among patients with mild coronavirus disease 2019 (COVID-19) is limited. METHODS: This study evaluated the association of underlying CV conditions with disease progression in patients with mild COVID-19. The primary outcome was the need to be transferred to the designated hospital for intensive care due to COVID-19 disease progression. The patients were divided into with and without CV conditions as well as stable and intensive care groups. RESULTS: Of the 332 patients with mild COVID-19, the median age was 51 years (IQR, 40-59 years), and 200 (61.2%) were female. Of the 48 (14.5%) patients with CV conditions, 23 (47.9%) progressed to severe disease status and required intensive care. Compared with patients without CV conditions, patients with CV conditions were older and more likely to have fatigue, chest tightness, and myalgia. The rate of requiring intensive care was significantly higher among patients with CV conditions than in patients without CV conditions (47.92% vs. 12.4%; P < 0.001). In subgroup analysis, the rate of requiring intensive care was also higher among patients with either hypertension or coronary heart disease (CHD) than in patients without hypertension or CHD. The multivariable regression model showed that CV condition served as an independent risk factor for intensive care (odds ratio (OR), 2.652 (95% CI, 1.019-6.899)) after adjustment for various cofounders. CONCLUSIONS: Patients with mild COVID-19 complicating CV conditions are susceptible to develop severe disease status and requirement for intensive care.

Is diabetes mellitus a risk factor for COronaVIrus Disease 19 (COVID-19)?

The COronaVirus DISease 19 (COVID-19) is a pandemic infectious disease caused by the novel coronavirus Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2). Older age and presence of comorbidities, including diabetes, were shown to be associated with a more severe course and a higher fatality rate. Studies from the most affected countries, including China, United States and Italy, seem to indicate that prevalence of diabetes among patients affected by COVID-19 is not higher than that observed in the general population, thus suggesting that diabetes is not a risk factor for SARS-CoV-2 infection. However, a large body of evidence demonstrate that diabetes is a risk factor for disease progression towards critical illness, development of acute respiratory distress syndrome, need for mechanical ventilation or admission to intensive care unit, and ultimately death. The mechanisms underlying the relationship between COVID-19 and diabetes remain to be elucidated. In particular, it is still unresolved whether is diabetes per se, especially if poorly controlled, or rather the various comorbidities/complications associated with it that predispose patients with COVID-19 to a worse prognosis. In fact, conditions that cluster with diabetes in the context of the metabolic syndrome, such as obesity and hypertension, or complicate chronic hyperglycemia, such as cardiovascular disease and chronic kidney disease, have also been associated with poor prognosis in these individuals and the available studies have not consistently shown that diabetes predict disease severity independently of them.

Monocytopenia, monocyte morphological anomalies and hyperinflammation characterise severe COVID-19 in type 2 diabetes.

Early in the COVID-19 pandemic, type 2 diabetes (T2D) was marked as a risk factor for severe disease and mortality. Inflammation is central to the aetiology of both conditions where variations in immune responses can mitigate or aggravate disease course. Identifying at-risk groups based on immunoinflammatory signatures is valuable in directing personalised care and developing potential targets for precision therapy. This observational study characterised immunophenotypic variation associated with COVID-19 severity in T2D. Broad-spectrum immunophenotyping quantified 15 leucocyte populations in peripheral circulation from a cohort of 45 hospitalised COVID-19 patients with and without T2D. Lymphocytopenia and specific loss of cytotoxic CD8+ lymphocytes were associated with severe COVID-19 and requirement for intensive care in both non-diabetic and T2D patients. A morphological anomaly of increased monocyte size and monocytopenia restricted to classical CD14Hi CD16- monocytes was specifically associated with severe COVID-19 in patients with T2D requiring intensive care. Increased expression of inflammatory markers reminiscent of the type 1 interferon pathway (IL6, IL8, CCL2, INFB1) underlaid the immunophenotype associated with T2D. These immunophenotypic and hyperinflammatory changes may contribute to increased voracity of COVID-19 in T2D. These findings allow precise identification of T2D patients with severe COVID-19 as well as provide evidence that the type 1 interferon pathway may be an actionable therapeutic target for future studies.

[Clinical characteristics and outcome of 64 patients with severe COVID-19].

Objective: To investigate the causes of death in patients with severe COVID-19. Methods: A retrospective analysis was performed on 64 patients with severe COVID-19 admitted to Wuhan Pulmonary Hospital from January 12, 2020 to February 28, 2020. There were 36 males and 28 females, aging from 44 to 85 years[median 68 (62, 72)]. Fifty-two patients (81%) had underlying comorbidities. The patients were divided into the death group (n=40) and the survival group (n=24) according to the treatment outcomes. In the death group, 24 were male, and 16 were female, aging from 49 to 85 years [median 69 (62, 72)], with 31 cases (78%) complicated with underlying diseases. In the survival group, there were 12 males and 12 females, aging from 44 to 82 years[median 66 (61,73)], with 21 cases (88%) with comorbidities. Clinical data of the two groups were collected and compared, including general information, laboratory examinations, imaging features and treatments. For normally distributed data, independent group t test was used; otherwise, Mann Whitney test was used to compare the variables. χ(2) test and Fisher exact test was used when analyzing categorical variables. Results: The median of creatine kinase isozyme (CK-MB) in the death group was 19.0 (17.0,23.0) U/L, which was higher than that in the survival group 16.5 (13.5,19.6) U/L. The median level of cTnI in the death group was 0.03 (0.03, 0.07) µg/L, which was significantly higher than that in the survival group (0.02, 0.03) µg/L, with a statistically significant difference between the two groups (P=0.007). The concentration of myoglobin in the death group was 79.5 (28.7, 189.0) µg/L, which was higher than 33.1 (25.7, 54.5) µg/L in the survival group. The level of D-dimer in the death group was 2.0 (0.6, 5.2) mg/L, which was higher than 0.7 (0.4, 2.0) mg/L in the survival group. The LDH level of the death group was 465.0 (337.5,606.5) U/L, which was higher than that of the survibal group, 341.0 (284.0,430.0) U/L, the difference being statistically significant (P=0.006). The concentration of alanine aminotransferase in the death group was 40.0 (30.0, 48.0) U/L, which was higher than 32.5 (24.0, 40.8) U/L in the survival group, and the difference was statistically significant (P=0.047).Abnormal ECG was found in 16 cases (62%) in the death group, which was significantly higher than that in the survival group (29%), the difference being statistically significant (P=0.024) .The main causes of death were severe pneumonia with acute respiratory distress syndrome (ARDS, n=20), acute heart failure(n=9), atrial fibrillation(n=3) and multiple organ dysfunction syndrome (MODS, n=3). Conclusions: ARDS caused by severe pneumonia and acute heart failure and atrial fibrillation caused by acute viral myocarditis were the main causes of death in severe COVID-19 patients. Early prevention of myocardial injury and treatment of acute viral myocarditis complicated with disease progression may provide insights into treatment and reduction of mortality in patients with severe COVID-19.