Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Genetic mechanisms of critical illness in COVID-19.

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

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Levels of Malondialdehyde-Deoxyguanosine in the gastric mucosa: Relationship with lipid peroxidation, ascorbic acid, and Helicobacter pylori

Helicobacter pylori infection is associated with elevated gastric mucosal concentrations of the lipid peroxidation product malondialdehyde and reduced gastric juice vitamin C concentrations. Malondialdehyde can react with DNA bases to form the mutagenic adduct malondialdehyde-deoxyguanosine (M1-dG). We aimed to determine gastric mucosal levels of M1-dG in relation to H. pylori infection and malondialdehyde and vitamin C concentrations. Patients (n = 124) attending for endoscopy were studied. Levels of antral mucosal M1-dG were determined using a sensitive immunoslot-blot technique; antral mucosal malondialdehyde was determined by thiobarbituric acid extraction, and gastric juice and antral mucosal ascorbic acid and total vitamin C were determined by high-performance liquid chromatography. Sixty-four H. pylori-positive patients received eradication therapy, and endoscopy was repeated at 6 and 12 months. Levels of M1-dG did not differ between subjects with H. pylori gastritis (n = 85) and those with normal mucosa without H. pylori infection (n = 39; 56.6 versus 60.1 adducts/108 bases) and were unaffected by age or smoking habits. Malondialdehyde levels were higher (123.7 versus 82.5 pmol/g; P < 0.001), gastric juice ascorbic acid was lower (5.7 versus 15.0 µmol/ml; P < 0.001), and antral mucosal ascorbic acid was unchanged (48.0 versus 42.7 µmol/g) in H. pylori gastritis compared with normal mucosa. Multiple regression analysis revealed that M1-dG increased significantly with increasing levels of malondialdehyde, antral ascorbic acid, and total antral vitamin C. M1-dG levels were unchanged 6 months (63.3 versus 87.0 adducts/108 bases; P = 0.24; n = 38) and 12 months (66.7 versus 77.5 adducts/108 bases; P = 0.8; n = 13) after successful eradication of H. pylori. M1-dG thus is detectable in gastric mucosa, but is not affected directly by H. pylori

Aryl propanolamines: comparison of activity at human β(3) receptors, rat β(3) receptors and rat atrial receptors mediating tachycardia

1. The in vitro activity of four aryl propanolamines was compared to two prototypic β(3) receptor agonists, CGP 12177 and CL316243 at the human β(3) receptor, the rat β(3) receptor in the stomach fundus and receptors mediating atrial tachycardia. 2. L-739,574 was the most potent (EC(50)=9 nM) and selective agonist at the human β(3) receptor with high maximal response (74% of the maximal response to isoproterenol). 3. A phenol-biaryl ether analogue possessed modest affinity for the human β(3) receptor (EC(50)=246 nM), but was highly efficacious with a maximal response 82% of the maximal response to isoproterenol. The other derivatives were intermediate in potency with low maximal responses. 4. These agonists at the human β(3) receptor did not activate the rat β(3) receptor in the rat stomach fundus. In fact, the aryl propanolamines (10(−6) M) inhibited CL316243-induced activation of the rat β(3) receptor. Thus, agonist activity at the human β(3) receptor translated into antagonist activity at the rat β(3) receptor. 5. L739,574 and the phenol biaryl ether increased heart rate via β(1) receptors. 6. Although CGP12177 produced atrial tachycardia, neither the indole sulphonamide nor biphenyl biaryl ether did, although both had high affinity for the human β(3) receptor. Thus, the atrial tachycardic receptor was not identical to the human β(3) receptor. 7. These studies (a) characterized four aryl propanolamines with high affinity at the human β(3) receptor, (b) found that they were antagonists at the rat β(3) receptor, an observation with profound implications for in vivo rat data, and (c) established that the rodent atrial non-β(1), β(2) or β(3) tachycardic receptor was also unrelated to the human β(3) receptor