In a new study, researchers found that one of the immune system’s oldest branches, called complement, may be influencing the severity of COVID-19 disease.
Among other findings linking complement to COVID, the researchers found that people with age-related macular degeneration—a disorder caused by overactive complement—are at greater risk of developing severe complications and dying from COVID.
The connection with complement suggests that existing drugs that inhibit the complement system could help treat patients with severe disease.
The researchers also found evidence that clotting activity is linked to COVID severity and that mutations in certain complement and coagulation genes are associated with hospitalization of COVID patients.
Together these results provide important insights into the pathophysiology of COVID-19 and paint a picture for the role of complement and coagulation pathways in determining clinical outcomes of patients infected with SARS-CoV-2
The research was conducted by a team at Columbia University Irving Medical Center.
The idea to test the role of coagulation and complement in COVID began with a sweeping survey of viral mimicry across all viruses on earth—over 7,000 in all.
Viruses have proteins that can mimic certain host proteins to trick the host’s cells into aiding the virus with completing its life cycle.
Coronaviruses, the survey found, are masters of mimicry, particularly with proteins involved in coagulation and proteins that make up a complement, one of the oldest branches of the human immune system.
Complement proteins work a bit like antibodies and help eliminate pathogens by sticking to viruses and bacteria and marking them for destruction.
Complement can also increase coagulation and inflammation in the body. Unchecked, these systems can also be quite detrimental.
In the study, the team says that the new coronavirus—by mimicking complement or coagulation proteins—might drive both systems into a hyperactive state.
If complement and coagulation influence the severity of COVID, people with pre-existing hyperactive complement or coagulation disorders should be more susceptible to the virus.
That led the team to look at COVID patients with macular degeneration, an eye disease caused by overactive complement, as well as common coagulation disorders like thrombosis and hemorrhage.
Among 11,000 COVID patients who came to Columbia University Irving Medical Center with suspected COVID-19, the researchers found that over 25% of those with age-related macular degeneration died, compared to the average mortality rate of 8.5%, and roughly 20% required intubation.
The greater mortality and intubation rates could not be explained by differences in the age or sex of the patients.
They found complement is also more active in obesity and diabetes. This may help explain, at least in part, why people with those conditions also have a greater mortality risk from COVID.
People with a history of coagulation disorders also were at increased risk of dying from COVID infection.
The researchers then examined how gene activity differed in people infected with the coronavirus.
That analysis revealed a signature in COVID-infected patients indicating that the virus engages and induces robust activation of the body’s complement and coagulation systems.
More evidence linking severe COVID with coagulation and complement comes from a genetic analysis of thousands of COVID patients from the U.K. Biobank, which contains medical records and genetic data on half a million people.
The authors found that variants of several genes that influence complement or coagulation activity are associated with more severe COVID symptoms that required hospitalization.
The team says physicians treating COVID patients have noticed coagulation issues since the beginning of the pandemic, and several clinical trials are underway to determine the best way to use existing anti-coagulation treatments.
Complement inhibitors are currently used in relatively rare diseases, but at least one clinical trial is testing the idea with COVID patients.
One author of the study is Sagi Shapira, Ph.D., MPH.
The study is published in Nature Medicine.
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