FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation

SARS-CoV-2 can cause acute respiratory distress and death in some patients1. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood2. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD), leading to inflammatory death (pyroptosis) and release of potent inflammatory mediators3. Here we show that about 6% of blood monocytes in COVID-19 patients are infected with SARS-CoV-2. Monocyte infection depends on uptake of antibody-opsonized virus by Fcγ receptors. Vaccine recipient plasma does not promote antibody-dependent monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in infected monocyte culture supernatants. Instead, infected cells undergo inflammatory cell death (pyroptosis) mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from COVID-19 lung autopsies have activated inflammasomes. These findings taken together suggest that antibody-mediated SARS-CoV-2 uptake by monocytes/macrophages triggers inflammatory cell death that aborts production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90. INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19. FUNDING: US National Institutes of Health and Operation Warp Speed

BAF complex maintains glioma stem cells in pediatric H3K27M glioma

Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell–like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas. Significance: Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1–BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma

Sepsis

Sepsis accounts for approximately one in three hospital deaths, and is associated with very high health care costs due to prolonged lengths of stay in the intensive care unit and hospital. Sepsis is essentially an immunologic response to infection that is propagated systemically, leading to diffuse cellular and microcirculatory dysfunction, vasodilation, vital organ hypoperfusion, and eventual failure. This review covers the pathophysiology, stabilization/assessment, diagnosis, treatment, and disposition and outcomes of sepsis. Figures show the inflammatory and thrombotic response to infection, the action of nitric oxide on vascular smooth muscle cells, accelerated glycolysis and increased lactate production as a result of the catecholamine surge seen in septic shock, sepsis mortality associated with number of organ failures identified in the emergency department (ED), and protocolized therapy for septic shock. Tables list definitions of sepsis syndromes; frequently cited scoring systems for mortality prediction in emergency department patients with sepsis; Sequential Organ Failure Assessment (SOFA) score; current recommendations regarding treatment bundles at 3 and 6 hours of resuscitation; antibiotic recommendations based on suspected source; and vasopressors used in septic shock with recommended dosing, mechanism of action, and indications. This review contains 5 figures, 7 tables, and 57 references. Keywords: Sepsis; Surviving Sepsis Campaign guidelines, definitions, SEP-1 sepsis quality measure, time-to-antibiotics, volume resuscitation, lactated ringers  </jats:p

Sepsis

Sepsis accounts for approximately one in three hospital deaths, and is associated with very high health care costs due to prolonged lengths of stay in the intensive care unit and hospital. Sepsis is essentially an immunologic response to infection that is propagated systemically, leading to diffuse cellular and microcirculatory dysfunction, vasodilation, vital organ hypoperfusion, and eventual failure. This review covers the pathophysiology, stabilization/assessment, diagnosis, treatment, and disposition and outcomes of sepsis. Figures show the inflammatory and thrombotic response to infection, the action of nitric oxide on vascular smooth muscle cells, accelerated glycolysis and increased lactate production as a result of the catecholamine surge seen in septic shock, sepsis mortality associated with number of organ failures identified in the emergency department (ED), and protocolized therapy for septic shock. Tables list definitions of sepsis syndromes; frequently cited scoring systems for mortality prediction in emergency department patients with sepsis; Sequential Organ Failure Assessment (SOFA) score; current recommendations regarding treatment bundles at 3 and 6 hours of resuscitation; antibiotic recommendations based on suspected source; and vasopressors used in septic shock with recommended dosing, mechanism of action, and indications. This review contains 5 figures, 7 tables, and 57 references. Keywords: Sepsis; Surviving Sepsis Campaign guidelines, definitions, SEP-1 sepsis quality measure, time-to-antibiotics, volume resuscitation, lactated ringers </jats:p

Sepsis

Sepsis accounts for approximately one in three hospital deaths, and is associated with very high health care costs due to prolonged lengths of stay in the intensive care unit and hospital. Sepsis is essentially an immunologic response to infection that is propagated systemically, leading to diffuse cellular and microcirculatory dysfunction, vasodilation, vital organ hypoperfusion, and eventual failure. This review covers the pathophysiology, stabilization/assessment, diagnosis, treatment, and disposition and outcomes of sepsis. Figures show the inflammatory and thrombotic response to infection, the action of nitric oxide on vascular smooth muscle cells, accelerated glycolysis and increased lactate production as a result of the catecholamine surge seen in septic shock, sepsis mortality associated with number of organ failures identified in the emergency department (ED), and protocolized therapy for septic shock. Tables list definitions of sepsis syndromes; frequently cited scoring systems for mortality prediction in emergency department patients with sepsis; Sequential Organ Failure Assessment (SOFA) score; current recommendations regarding treatment bundles at 3 and 6 hours of resuscitation; antibiotic recommendations based on suspected source; and vasopressors used in septic shock with recommended dosing, mechanism of action, and indications. This review contains 5 figures, 7 tables, and 57 references. Keywords: Sepsis; Surviving Sepsis Campaign guidelines, definitions, SEP-1 sepsis quality measure, time-to-antibiotics, volume resuscitation, lactated ringers </jats:p

Sepsis

Sepsis accounts for approximately one in three hospital deaths, and is associated with very high health care costs due to prolonged lengths of stay in the intensive care unit and hospital. Sepsis is essentially an immunologic response to infection that is propagated systemically, leading to diffuse cellular and microcirculatory dysfunction, vasodilation, vital organ hypoperfusion, and eventual failure. This review covers the pathophysiology, stabilization/assessment, diagnosis, treatment, and disposition and outcomes of sepsis. Figures show the inflammatory and thrombotic response to infection, the action of nitric oxide on vascular smooth muscle cells, accelerated glycolysis and increased lactate production as a result of the catecholamine surge seen in septic shock, sepsis mortality associated with number of organ failures identified in the emergency department (ED), and protocolized therapy for septic shock. Tables list definitions of sepsis syndromes; frequently cited scoring systems for mortality prediction in emergency department patients with sepsis; Sequential Organ Failure Assessment (SOFA) score; current recommendations regarding treatment bundles at 3 and 6 hours of resuscitation; antibiotic recommendations based on suspected source; and vasopressors used in septic shock with recommended dosing, mechanism of action, and indications. This review contains 5 figures, 7 tables, and 57 references. Keywords: Sepsis; Surviving Sepsis Campaign guidelines, definitions, SEP-1 sepsis quality measure, time-to-antibiotics, volume resuscitation, lactated ringers </jats:p