ABSTRACT
The etiopathogenesis of severe COVID-19 remains unknown. Indeed given major confounding factors (age and co-morbidities), true drivers of this condition have remained elusive. Here, we employ an unprecedented multi-omics analysis, combined with artificial intelligence, in a young patient cohort where major co-morbidities have been excluded at the onset. Here, we established a three-tier cohort of individuals younger than 50 years without major comorbidities. These included 47 "critical" (in the ICU under mechanical ventilation) and 25 "non-critical" (in a noncritical care ward) COVID-19 patients as well as 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cells proteomics, cytokine profiling and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing and structural causal modeling led to key findings. Critical patients were characterized by exacerbated inflammation, perturbed lymphoid/myeloid compartments, coagulation and viral cell biology. Within a unique gene signature that differentiated critical from noncritical patients, several driver genes promoted severe COVID-19 among which the upregulated metalloprotease ADAM9 was key. This gene signature was replicated in an independent cohort of 81 critical and 73 recovered COVID-19 patients, as were ADAM9 transcripts, soluble form and proteolytic activity. Ex vivo ADAM9 inhibition affected SARS-CoV-2 uptake and replication in human lung epithelial cells. In conclusion, within a young, otherwise healthy, COVID-19 cohort, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients. The key driver, ADAM9, interfered with SARS-CoV-2 biology. A repositioning strategy for anti-ADAM9 therapeutic is feasible. One sentence summaryEtiopathogenesis of severe COVID19 in a young patient population devoid of comorbidities.
Subject(s)
COVID-19 , Inflammation , Blood Coagulation Disorders, InheritedABSTRACT
Background: During COVID-19 pandemic, visitations have been prohibited in most French ICUs. We aimed to assess psychological effects, for reference persons (RPs), of experiencing remote-only communication with both caregivers and the patient during COVID-19 pandemic.Methods: All RPs of patients referred to ICU for COVID-19 were included. HADS, IES-R, and satisfaction were evaluated at admission, discharge/death and 3 months. At 3 months, an interview with a psychologist provided a qualitative description of RPs’ psychological distress.Results: Eighty-eight RPs were interviewed at patient admission and discharge, and 33 accepted the 3rd month-interview. Prevalence of anxiety and depression symptoms was 65% and 32% respectively at patient admission and 27% and 24% at discharge/death, with a significant decrease between ICU admission and discharge/death (23 [16;31] versus 16 [9;21] points, p<0.01). At 3 months, lower HADS decrease was associated with patient death/continued hospitalization, and/or sleeping disorders in RPs (p<0.01). Despite visit prohibition, 99% RPs felt the patient was safe (9 [7;10]/10 points, Likert-type scale). They also felt confident with caregivers, therapeutic decisions (10 [9;10]/10 points) and satisfied with the manner/frequency information was provided (10 [9;10]/10 points). All RPs stressed the specific-type of “responsibility” associated with being an RP in a remote-only context. The 3 salient themes turned out to be dichotomous variables: positive (9 RPs, 27%) vs. negative (24 RPs, 73%) subjective experience; wide (11 RPs, 33%) vs. narrow (22 RPs, 67%) information diffusion strategies: only a third chose to transmit the information to many relatives. Only 10 RPs (30%) related the situation to a prior traumatic experience.Conclusion: In a distressing situation, remote-only communication allowed RPs to remain involved in decision processes and maintain contact with patient and caregivers.Trial registration: NCT04385121. Registered 12 May 2020. https://clinicaltrials.gov/