Purpose A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed... Show morePurpose A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. Methods This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (.EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. Results 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in.EVLWi between the groups (0.19 ml/kg, 95% CI - 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (- 1.17 ml/kg, 95% CI - 1.87 to - 0.44). Conclusions IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Show less
The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to... Show moreThe genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19(1,2), host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases(3-7). They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease. Show less
Background: Over 2 million people worldwide have been infected with severe acute respiratory distress syndrome-coronavirus-2 (SARS CoV-2). Lung ultrasound has been proposed to diagnose and monitor... Show moreBackground: Over 2 million people worldwide have been infected with severe acute respiratory distress syndrome-coronavirus-2 (SARS CoV-2). Lung ultrasound has been proposed to diagnose and monitor it, despite the fact that little is known about the ultrasound appearance due to the novelty of the illness. The aim of this manuscript is to characterise the lung ultrasonographic appearance of critically ill patients with SARS-CoV-2 pneumonia, with particular emphasis on its relationship with the time course of the illness and clinical parameters.Methods: Adult patients from the intensive care unit of two academic hospitals who tested positive for SARS-CoV-2 were included. Images were analysed using internationally recognised techniques which included assessment of the pleura, number of B-lines, pathology in the PLAPS (posterolateral alveolar and/or pleural syndrome) point, bedside lung ultrasound in emergency profiles, and the lung ultrasound score. The primary outcomes were frequencies, percentages and differences in lung ultrasound findings overall and between short (<= 14 days) and long (>14 days) durations of symptoms and their correlation with clinical parameters.Results: In this pilot observational study, 61 patients were included with 76 examinations available for analysis. 26% of patients had no anterior lung abnormalities, while the most prevalent pathological ultrasound findings were thickening of the pleura (42%), >= 3 B-lines per view (38%) and presence of PLAPS (74%). Patients with "long" duration of symptoms presented more frequently with a thickened and irregular pleura (32 (21%) versus 11 (9%)), C-profile (18 (47%) versus 8 (25%)) and pleural effusion (14 (19%) versus 3 (5%)), compared to patients with short duration of symptoms. Lung ultrasound findings did not correlate with arterial oxygen tension/inspiratory oxygen fraction ratio, fluid balance or dynamic compliance.Conclusion: SARS-CoV-2 results in significant, but not specific, ultrasound changes, with decreased lung sliding, thickening of the pleura and a B-profile being the most commonly observed. With time, a thickened and irregular pleura, C-profile and pleural effusion become more common findings. When screening patients, a comprehensive ultrasound protocol might be necessary. Show less
