Background Little information is available about the geo-economic variations in demographics, management, and outcomes of patients with acute respiratory distress syndrome (ARDS). We aimed to characterise the effect of these geo-economic variations in patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE). Methods LUNG SAFE was done during 4 consecutive weeks in winter, 2014, in a convenience sample of 459 intensivecare units in 50 countries across six continents. Inclusion criteria were admission to a participating intensive-care unit (including transfers) within the enrolment window and receipt of invasive or non-invasive ventilation. One of the trial's secondary aims was to characterise variations in the demographics, management, and outcome of patients with ARDS. We used the 2016 World Bank countries classification to define three major geo-economic groupings, namely European high-income countries (Europe-High), high-income countries in the rest of the world (rWORLD-High), and middle-income countries (Middle). We compared patient outcomes across these three groupings. LUNG SAFE is registered with ClinicalTrials.gov, number NCT02010073. Findings Of the 2813 patients enrolled in LUNG SAFE who fulfilled ARDS criteria on day 1 or 2, 1521 (54%) were recruited from Europe-High, 746 (27%) from rWORLD-High, and 546 (19%) from Middle countries. We noted significant geographical variations in demographics, risk factors for ARDS, and comorbid diseases. The proportion of patients with severe ARDS or with ratios of the partial pressure of arterial oxygen (PaO 2) to the fractional concentration of oxygen in inspired air (F I O 2) less than 150 was significantly lower in rWORLD-High countries than in the two other regions. Use of prone positioning and neuromuscular blockade was significantly more common in Europe-High countries than in the other two regions. Adjusted duration of invasive mechanical ventilation and length of stay in the intensive-care unit were significantly shorter in patients in rWORLD-High countries than in Europe-High or Middle countries. High gross national income per person was associated with increased survival in ARDS; hospital survival was significantly lower in Middle countries than in Europe-High or rWORLD-High countries. Interpretation Important geo-economic differences exist in the severity, clinician recognition, and management of ARDS, and in patients' outcomes. Income per person and outcomes in ARDS are independently associated.

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Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

<u>Background</u> The variability of Covid-19 severity between patients has driven efforts to identify prognosticating laboratory markers that could aid clinical decision making. Procalcitonin (PCT) is classically used as a diagnostic marker in bacterial infections, but its role in predicting Covid-19 disease severity is emerging. We aimed to identify the association between PCT and Covid-19 disease severity in a critical care setting and whether bacterial co-infection is implicated. <u>Methods</u> We retrospectively reviewed Covid-19 patients with PCT levels measured in a critical care setting at our institution between February and September 2020. Laboratory markers including peak PCT values and a range of bacterial culture results were analysed. Outcomes were the requirement and duration of invasive mechanical ventilation as well as inpatient mortality. <u>Results</u> In total, 60 patients were included; 68% required invasive mechanical ventilation and 45% died as inpatient. Univariate analysis identified higher peak PCT levels significantly associated with both the requirement for invasive mechanical ventilation (OR: 3.2, 95% CI 1.3-9.0, p=0.02) and inpatient mortality (OR: 2.6, 95% CI 1.1-6.6, p=0.03). Higher peak PCT levels was an independent predictor of mortality on multivariate analysis (OR 3.7, 95% CI 1.1-12.4, p=0.03). There was a significant positive correlation between increased peak PCT levels and duration on invasive mechanical ventilation. No significant difference was found between peak PCT levels of patients with positive and negative bacterial cultures. <u>Conclusions</u> Elevated PCT levels in Covid-19 patients are associated with respiratory failure requiring prolonged invasive mechanical ventilation and inpatient mortality. This association may be independent of bacterial co-infection.