Genetic mechanisms of critical illness in COVID-19

Nature, Journal Year: 2020, Volume and Issue: 591(7848), P. 92 - 98

Published: Dec. 11, 2020

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with may identify mechanistic targets for therapeutic development3. Here we report results of GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study 2,244 critically ill patients COVID-19 from 208 UK intensive care units. We have identified replicated following new significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 OAS3); 19p13.2 (rs74956615, 2.3 near tyrosine kinase 2 (TYK2); 19p13.3 (rs2109069, 3.98 10-12) within dipeptidyl peptidase 9 (DPP9); 21q22.1 (rs2236757, 4.99 interferon receptor IFNAR2. potential repurposing licensed medications: using Mendelian randomization, found evidence low expression IFNAR2, or high TYK2, are life-threatening disease; transcriptome-wide tissue revealed monocyte-macrophage chemotactic CCR2 severe COVID-19. Our robust signals relating to key host defence mechanisms mediators inflammatory organ damage Both be amenable targeted treatment existing drugs. However, large-scale randomized clinical trials will essential before any change practice.

Language: Английский

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The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity

The Lancet Respiratory Medicine, Journal Year: 2021, Volume and Issue: 9(6), P. 622 - 642

Published: May 7, 2021

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into epidemiology of COVID-19, important questions remain about clinical complexities and underlying mechanisms disease phenotypes. Severe most commonly involves respiratory manifestations, although other systems are also affected, acute is often followed by protracted complications. Such complex manifestations suggest dysregulates host response, triggering wide-ranging immuno-inflammatory, thrombotic, parenchymal derangements. We review intricacies pathophysiology, its various phenotypes, anti-SARS-CoV-2 response at humoral cellular levels. Some similarities exist between failure origins, but evidence for many distinctive mechanistic features indicates constitutes a new entity, emerging data suggesting involvement an endotheliopathy-centred pathophysiology. Further research, combining basic studies, needed advance understanding pathophysiological characterise immuno-inflammatory derangements across range phenotypes enable optimum care patients COVID-19.

Language: Английский

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Therapeutic strategies for COVID-19: progress and lessons learned

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 449 - 475

Published: April 19, 2023

Language: Английский

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Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(40), P. 25018 - 25025

Published: Sept. 17, 2020

Significance The new SARS-CoV-2 pandemic leads to COVID-19 with respiratory failure, substantial morbidity, and significant mortality. Overactivation of the innate immune response is postulated trigger this detrimental process. complement system a key player in immunity. Despite few reports local activation, there lack evidence that degree systemic activation occurs early patients, whether associated failure. This study shows number products are systemically, consistently, long-lastingly increased from admission during hospital stay. Notably, terminal sC5b-9 complex was Thus, inhibition an attractive therapeutic approach for treatment COVD-19.

Language: Английский

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Inflammasome activation at the crux of severe COVID-19

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 21(11), P. 694 - 703

Published: Aug. 9, 2021

Language: Английский

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Ventilator-associated pneumonia in critically ill patients with COVID-19

Critical Care, Journal Year: 2021, Volume and Issue: 25(1)

Published: Jan. 11, 2021

Pandemic COVID-19 caused by the coronavirus SARS-CoV-2 has a high incidence of patients with severe acute respiratory syndrome (SARS). Many these require admission to an intensive care unit (ICU) for invasive ventilation and are at significant risk developing secondary, ventilator-associated pneumonia (VAP).

Language: Английский

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Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium

Nature Reviews Cardiology, Journal Year: 2022, Volume and Issue: 19(7), P. 475 - 495

Published: Jan. 13, 2022

Language: Английский

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Neutrophils in COVID-19

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: March 25, 2021

Strong evidence has been accumulated since the beginning of COVID-19 pandemic that neutrophils play an important role in pathophysiology, particularly those with severe disease courses. While originally considered to be a rather homogeneous cell type, recent attention uncovered their fascinating transcriptional and functional diversity as well developmental trajectories. These new findings are better understand many facets neutrophil involvement not only but also other acute or chronic inflammatory diseases, both communicable non-communicable. Here, we highlight observed immune deviation summarize several promising therapeutic attempts precisely target reactivity patients COVID-19.

Language: Английский

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Microthrombi as a Major Cause of Cardiac Injury in COVID-19

Circulation, Journal Year: 2021, Volume and Issue: 143(10), P. 1031 - 1042

Published: Jan. 22, 2021

Background: Cardiac injury is common in patients who are hospitalized with coronavirus disease 2019 (COVID-19) and portends poorer prognosis. However, the mechanism type of myocardial damage associated severe acute respiratory syndrome 2 (SARS-CoV-2) remain uncertain. Methods: We conducted a systematic pathological analysis 40 hearts from dying COVID-19 Bergamo, Italy, to determine mechanisms cardiac injury. divided according presence or absence myocyte necrosis then determined underlying Results: Of examined, 14 (35%) had evidence necrosis, predominantly left ventricle. Compared subjects without tended be female, have chronic kidney disease, shorter symptom onset admission. The incidence coronary artery (ie, >75% cross-sectional narrowing) was not significantly different between those necrosis. Three (21.4%) showed infarction, defined as ≥1 cm area whereas 11 (78.6%) focal (>20 necrotic myocytes an ≥0.05 mm but <1 ) thrombi were present cases (14.2%) having epicardial thrombi, 9 (64.3%) microthrombi capillaries, arterioles, small muscular arteries. compared COVID-19–positive autopsy intramyocardial thromboemboli well aspirated obtained during primary percutaneous intervention uninfected COVID-19–infected presenting ST-segment–elevation infarction. Microthrombi greater fibrin terminal complement C5b-9 immunostaining COVID-19–negative thrombi. There no significant differences constituents –negative Conclusions: most cause microthrombi. composition retrieved Tailored antithrombotic strategies may useful counteract effects infection.

Language: Английский

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Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy

Clinical Immunology, Journal Year: 2020, Volume and Issue: 220, P. 108598 - 108598

Published: Sept. 19, 2020

Language: Английский

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