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

Correction to: Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study

Correction to: Intensive Care Med (2016) 42:1865\u20131876 DOI 10.1007/s00134-016-4571-

Resolved versus confirmed ARDS after 24 h: insights from the LUNG SAFE study

Purpose: To evaluate patients with resolved versus confirmed ARDS, identify subgroups with substantial mortality risk, and to determine the utility of day 2 ARDS reclassification. Methods: Our primary objective, in this secondary LUNG SAFE analysis, was to compare outcome in patients with resolved versus confirmed ARDS after 24\ua0h. Secondary objectives included identifying factors associated with ARDS persistence and mortality, and the utility of day 2 ARDS reclassification. Results: Of 2377 patients fulfilling the ARDS definition on the first day of ARDS (day 1) and receiving invasive mechanical ventilation, 503 (24%) no longer fulfilled the ARDS definition the next day, 52% of whom initially had moderate or severe ARDS. Higher tidal volume on day 1 of ARDS was associated with confirmed ARDS [OR 1.07 (CI 1.01\u20131.13), P = 0.035]. Hospital mortality was 38% overall, ranging from 31% in resolved ARDS to 41% in confirmed ARDS, and 57% in confirmed severe ARDS at day 2. In both\ua0resolved and confirmed\ua0ARDS, age, non-respiratory SOFA score, lower PEEP and P/F ratio, higher peak pressure and respiratory rate were each\ua0associated with mortality. In confirmed ARDS, pH and the presence of immunosuppression or neoplasm were also associated\ua0with mortality. The increase in area under the receiver operating curve for ARDS reclassification on day 2 was marginal. Conclusions: ARDS, whether resolved or confirmed at day 2, has a high mortality rate. ARDS reclassification at day 2 has limited predictive value for mortality. The substantial mortality risk in severe confirmed ARDS suggests that complex interventions might best be tested in this population. Trial Registration: ClinicalTrials.gov NCT02010073. \ua9 2018, Springer-Verlag GmbH Germany, part of Springer Nature and ESICM

Death in hospital following ICU discharge : insights from the LUNG SAFE study

Altres ajuts: Italian Ministry of University and Research (MIUR)-Department of Excellence project PREMIA (PREcision MedIcine Approach: bringing biomarker research to clinic); Science Foundation Ireland Future Research Leaders Award; European Society of Intensive Care Medicine (ESICM), Brussels; St Michael's Hospital, Toronto; University of Milan-Bicocca, Monza, Italy.Background: To determine the frequency of, and factors associated with, death in hospital following ICU discharge to the ward. Methods: The Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE study was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted across 459 ICUs from 50 countries globally. This study aimed to understand the frequency and factors associated with death in hospital in patients who survived their ICU stay. We examined outcomes in the subpopulation discharged with no limitations of life sustaining treatments ('treatment limitations'), and the subpopulations with treatment limitations. Results: 2186 (94%) patients with no treatment limitations discharged from ICU survived, while 142 (6%) died in hospital. 118 (61%) of patients with treatment limitations survived while 77 (39%) patients died in hospital. Patients without treatment limitations that died in hospital after ICU discharge were older, more likely to have COPD, immunocompromise or chronic renal failure, less likely to have trauma as a risk factor for ARDS. Patients that died post ICU discharge were less likely to receive neuromuscular blockade, or to receive any adjunctive measure, and had a higher pre- ICU discharge non-pulmonary SOFA score. A similar pattern was seen in patients with treatment limitations that died in hospital following ICU discharge. Conclusions: A significant proportion of patients die in hospital following discharge from ICU, with higher mortality in patients with limitations of life-sustaining treatments in place. Non-survivors had higher systemic illness severity scores at ICU discharge than survivors. Trial Registration: ClinicalTrials.gov NCT02010073