Background: The incidence of acute complications and mortality associated with COVID-19 remains poorly characterized. The aims of this systematic review and meta-analysis were to summarize the evidence on clinically relevant outcomes in hospitalized patients with COVID-19. Methods: MEDLINE, EMBASE, PubMed, and medRxiv were searched up to April 20, 2020, for studies including hospitalized symptomatic adult patients with laboratory-confirmed COVID-19. The primary outcomes were all-cause mortality and acute respiratory distress syndrome (ARDS). The secondary outcomes included acute cardiac or kidney injury, shock, coagulopathy, and venous thromboembolism. The main analysis was based on data from peer-reviewed studies. Summary estimates and the corresponding 95% prediction intervals (PIs) were obtained through meta-analyses. Results: A total of 44 peer-reviewed studies with 14,866 COVID-19 patients were included. In general, risk of bias was high. All-cause mortality was 10% overall (95% PI, 2 to 39%; 1687/14203 patients; 43 studies), 34% in patients admitted to intensive care units (95% PI, 8 to 76%; 659/2368 patients; 10 studies), 83% in patients requiring invasive ventilation (95% PI, 1 to 100%; 180/220 patients; 6 studies), and 75% in patients who developed ARDS (95% PI, 35 to 94%; 339/455 patients; 11 studies). On average, ARDS occurred in 14% of patients (95% PI, 2 to 59%; 999/6322 patients; 23 studies), acute cardiac injury in 15% (95% PI, 5 to 38%; 452/2389 patients; 10 studies), venous thromboembolism in 15% (95% PI, 0 to 100%; patients; 3 studies), acute kidney injury in 6% (95% PI, 1 to 41%; 318/4682 patients; 15 studies), coagulopathy in 6% (95% PI, 1 to 39%; 223/3370 patients; 9 studies), and shock in 3% (95% PI, 0 to 61%; 203/4309 patients; 13 studies). Conclusions: Mortality was very high in critically ill patients based on very low-quality evidence due to striking heterogeneity and risk of bias. The incidence of clinically relevant outcomes was substantial, although reported by only one third of the studies suggesting considerable underreporting. Trial registration: PROSPERO registration ID for this study is CRD42020177243 (https://www.crd.york.ac.uk/prospero/ display_record.php?RecordID=177243).

Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3dependent ubiquitination of ASC.

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Background: Activation of the NLRP3 inflammasome is a primary driver of sterile inflammation in response to myocardial ischemia reperfusion. Pharmacologic inhibitors of the NLRP3 inflammasome are being developed. We proposed that OLT1177 (dapansutrile), a novel NLRP3 inflammasome inhibitor, could preserve myocardial function after ischemia reperfusion injury in the mouse. Methods: We used an experimental murine model of myocardial ischemia reperfusion injury through transient ligation of the left coronary artery and measured the effects of OLT1177 (6, 60, or 600 mg/kg intraperitoneal dose) on infarct size at pathology and on systolic cardiac function at echocardiography. To simulate a clinical scenario, we investigated the time window of therapeutic intervention with OLT1177 (60 mg/kg) administered 60, 120, or 180 minutes after reperfusion. Results: OLT1177 was rapidly detectable in the plasma following intraperitoneal injection and had no effect on cardiac function in healthy mice. OLT1177 treatment at reperfusion showed significant dose-dependent reduction in infarct size (−36%, −67%, and −62% for 6, 60, and 600 mg/kg, respectively; P < 0.001 for linear trend, P = 0.010 vs. vehicle for 6 mg/kg, and P < 0.001 vs. vehicle for 60 and 600 mg/kg) and preserved cardiac systolic function measured as left ventricular fractional shortening at 24 hours and 7 days after injury (P = 0.015 for 6 mg/kg and P < 0.01 for 60 and 600 mg/kg). OLT1177 reduced infarct size also when given after 60 minutes of reperfusion (−71%, P < 0.001 vs. vehicle). Conclusion: OLT1177 (dapansutrile) limits infarct size and prevents left ventricular systolic dysfunction when given within 60 minutes following ischemia reperfusion injury in the mouse.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a dysregulated hyperinflammatory response. Areas covered: Authors review evidence on IL-6 and IL-6 blockade in coronavirus disease 2019 (COVID-19) and discuss the pathophysiological and prognostic roles of this cytokine and the clinical impact of pharmacological blockade of IL-6 . The material includes original articles and reviews published from March 2020 to March 2021 and searched on PubMed, medRxiv, and bioRxiv. Expert opinion: IL-6 is one of the most prominent pro-inflammatory cytokines. Increased levels are recorded in COVID-19 patients, especially those with severe-to-critical disease. Evidence is accumulating on the relevance of IL-6 as a prognostic marker in COVID-19. Since IL-6 is a druggable target for several inflammatory diseases, pharmacological blockers of the IL-6 signaling pathway were repurposed to blunt the abnormal SARS-CoV-2-induced cytokine release. Data are limited to few randomized controlled trials that reported encouraging, though not conclusive, results, indicating the usefulness of IL-6 blockade early in the course of the disease in patients with hyperinflammation and no or limited organ damage. Further research is warranted to explore the role of IL-6 in different COVID-19 phenotypes and identify subgroups of patients who may mostly benefit from IL-6 pathway inhibition.

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Acute myocardial infarction (AMI) leads to myocardial cell death and ensuing sterile inflammatory response, which represents an attempt to clear cellular debris and promote cardiac repair. However, an overwhelming, unopposed or unresolved inflammatory response following AMI leads to further injury, worse remodeling and heart failure (HF). Additional therapies are therefore warranted to blunt the inflammatory response associated with ischemia and reperfusion and prevent long-term adverse events. Low-density lipoprotein receptor-related protein 1 (LRP1) is a ubiquitous endocytic cell surface receptor with the ability to recognize a wide range of structurally and functionally diverse ligands. LRP1 transduces multiple intracellular signal pathways regulating the inflammatory reaction, tissue remodeling and cell survival after organ injury. In preclinical studies, activation of LRP1-mediated signaling in the heart with non-selective and selective LRP1 agonists is linked with a powerful cardioprotective effect, reducing infarct size and cardiac dysfunction after AMI. The data from early phase clinical studies with plasma-derived α1-antitrypsin (AAT), an endogenous LRP1 agonist, and SP16 peptide, a synthetic LRP1 agonist, support the translational value of LRP1 as a novel therapeutic target in AMI. In this review, we will summarize the cellular and molecular bases of LRP1 functions in modulating the inflammatory reaction and the reparative process after injury in various peripheral tissues, and discuss recent evidences implicating LRP1 in myocardial inflammation and infarct healing.