Drivers of severe Covid-19 disease in patients under 50 without comorbidities

Drivers of severe Covid-19 disease in patients under 50 without comorbidities

Last Updated on October 30, 2021 by Joseph Gut – thasso

October 28 , 2021 – One of the most interessant and still unresolved question in connection with Covid-19 disease is the fact that some patients develop a heavy, if not fatal forms of Covid-19 disease after their infection with SARS-CoV-2 while other infected individuals develop mild or no symptoms at all. Some researchers and physicians belief that genetic predisposition and/or genetic susceptibility may play a role in this process.
In fact, in a recently published study in Science Translational Medicine, an international research team led by investigators in France and the US has discovered, by using an multiomic study design, an immune-related gene signature that coincides with severe Covid-19 disease in young and middle-aged patients with no apparent comorbidities. The researchers used a combination of whole-genome sequencing, blood RNA sequencing, mass cytometry and shotgun proteomic analyses on blood plasma and peripheral blood mononuclear cells (PBMC), cytokine profiling, and immunophenotyping on 47 Covid-19 disease patients under the age of 50 who required mechanical ventilation and treatment in the intensive care unit, as well as 25 age-matched Covid-19 disease patients treated in a non-critical setting and 22 healthy uninfected individuals. Within this young, otherwise healthy, cohort of individuals with Covid-19 disease, the researchers identified the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients, strengthening the fact that bevor very few Covid-19 disease severity studies have targeted a young population with no comorbidities to reduce confounding factors that may also drive severity and mortality.
They noted that the Covid-19 disease patients enrolled in the study had been treated in France between March and April of 2020, prior to widespread corticosteroid treatment for SARS-CoV-2 infections.”A comprehensive understanding of the immune responses to SARS-CoV-2 infection is fundamental to develop an explanation as to why some young

patients without comorbidities progress to critical illness whereas others do not, a phenomenon that has been exacerbated with new viral variants in current epidemic waves across the globe.

In particular, knowledge of the molecular drivers of critical Covid-19 disease is needed in order to identify predictive biomarkers and more efficient therapeutic targets that function through drivers of critical Covid-19 disease. By using machine learning, artificial intelligence, and probabilistic programming strategies to analyze the multiomic data generated for the cases and controls, the research team found higher-than-usual levels of inflammation and coagulation factors in the critical Covid-19 disease cohort, as well as altered lymphoid and myeloid cell activation and molecular features related to viral activity. Taken together, the results indicate that critical illness was characterized by a proinflammatory cytokine storm and notable changes in the T-cell, B-cell , dendritic cell, and monocyte cell compartments. These specific changes were independent from the extent of viral infection, as both the global anti-SARS-CoV-2 antibody concentrations and their neutralizing activity were not different in critical versus non-critical patients. When researchers analysed the set of genes that were differentially expressed in samples from the critical Covid-19 disease cases, non-critical cases, and uninfected controls, the researchers found a gene signature associated with severe infection that also coincided with critical cases in a follow-up analysis of 81 more individuals with critical SARS-CoV-2 infections and another 73 individuals who had recovered from Covid-19 disease. Upon these analyses, the team found within the candidate potential driver genes. Of those, the top candidate was ADAM9, a gene encoding a metalloprotease and disintegrin that had elevated expression in the severe cases.

Indeed, the researchers’ subsequent experiments pointed to a role for ADAM9 in SARS-CoV-2 uptake and replication in human lung epithelial cells, and the team found support for the critical COVID-19-related gene signature. These results collectively demonstrate that ADAM9 is an in vivo upregulated driver in critical Covid-19 disease patients. These patients show a higher global proteolytic activity in serum samples and demonstrate that a higher amount of ADAM9 facilitates viral infection and replication in ex vivo cellular models. Still, the predictive performance of ADAM9 as [a] diagnostic marker for disease severity, as well as [a] therapeutic target has to be evaluated in further studies. In any case, these studies on the genetic basis of predisposition to severe Covid-19 disease may allow in case of testing positive for  SARS-CoV-2 infection to inititate personalised treatment regimens according to the risk category individual patients belong to.
See here a sequence on genetic factors affecting severity of Covid-19 disease in individual patients:

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Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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