Influence of genetic and immunologic factors identified in 15% of severe COVID-19 patients

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Influence of genetic and immunologic factors identified in 15% of severe COVID-19 patients

  • An international study involving the participation of CHN and Navarrabiomed has shown that these patients present abnormalities that affect the interferon pathway, a crucial system for defending against the virus.

The international collaborative study COVID Human Genetic Effort (COVIDHGE), in which the Hospital Complex of Navarre (CHN) and the Navarrabiomed Clinical Trials Platform took part, has shown that genetic and immunologic factors that affect the severity of the disease are found in approximately 15% of severe cases of COVID-19. These cases are directly linked to the malfunctioning of the protein type I interferon pathway.

Interferon is a protein produced by the immune system. Its function is to signal other immune cells about the presence of viruses. Abnormality in this molecule is due to genetic or immunologic factors that prevent the body’s cells from defending themselves against the coronavirus, which may leave the patient in a severe clinical condition.
Thanks to this global collaborative effort, which includes CHN patients, it has been possible to use genome analysis to identify innate errors in type I interferon-mediated immunity in the genome of 23 out of 659 patients with severe pneumonia caused by COVID-19 who presented no prior severe disease (3.5%), compared to a control group of 534 individuals with asymptomatic or benign infection. In these 23 patients, researchers found 6 genetic defects known to be associated with risk of severe viral infection, although none of these people had been ill until the arrival of SARS-CoV-2. Four genetic defects were also found that were unknown to date and that are behind the severe symptoms suffered by these people when exposed to the new coronavirus.

Moreover, the consortium found that 101 of 987 patients aged between 25 and 87 years with a severe form of COVID-19 (10.2%) presented antibodies to their own interferon from the onset of the infection or even before, compared to just 4 out of 1227 people in the general population (0.33%) and none of the 63 patients studied with mild COVID-19. In vitro studies have shown that these antibodies neutralize the blocking action of type I interferon against SARS-CoV-2.

We know that there is considerable variability among infected individuals, ranging from asymptomatic infection to fatal pneumonia due to COVID-19. It is known that men tend to be at a greater risk of severe complications than women and that the probability of severe illness increases notably in the elderly and in patients with pre-existing conditions, such as high blood pressure, cardiovascular and respiratory diseases, diabetes and obesity. In this collaborative study, the COVIDHGE consortium has found that the presence of these anti-interferon antibodies is much more common in men than in women with a severe form of COVID-19 (12.5% vs. 2.6%), and that the probability increases with age. This helps researchers understand part of this variability between individuals with severe SARS-CoV-2 infection.

Genomic Medicine Applied to COVID-19

The results recently published in two articles in the journal Science partially solve the mystery of why some young, healthy people suffer severe COVID-19 by linking incidence to genetic and immunologic factors. These factors can result in admission to the ICU and even death. In fact, in the group of patients with anti-interferon antibodies, mortality was 36.6% (37 out of 101 patients).

The research involved the participation of Dr. Sergio Aguilera, a pediatrician and neuropediatrician at the CHN Pediatrics Department, who is the coordinator of this study at CHN and Navarrabiomed in collaboration with Dr. Aurora Pujol, a geneticist with IDIBELL (Barcelona) who networks with COVIDHGE. The Rockefeller University in New York and Necker Hospital in Paris led this consortium, which includes more than 50 genome-sequencing centers, research groups, and hundreds of hospitals around the world.

The work provides evidence of the susceptibility of some people to suffering a severe SARS-CoV-2 infection, even though previously healthy and without having suffered any other previous relevant infections. “These findings will make it possible to more accurately select candidates for the different clinical trials in progress to assess the utility of treatment with interferon or blockers of these antibodies, aimed at counteracting the consequences of these genetic and immunologic factors involved in some severe forms of COVID-19”, said Dr. Aguilera.

More than 250 patients were recruited from several hospitals in Spain, including the following: CHN in Navarre, Hospital Infanta Leonor and Clínica Universidad de Navarra in Madrid, Hospital Universitario de Burgos in Burgos, and Hospital del Mar and Hospital Universitario de Bellvitge in Barcelona. The National Center for Genome Analysis took part in sequencing the patients’ genomes.