Medical staff treat a patient who wears a ventilator with helmet in Houston, United States.
When two brothers fell seriously ill with COVID-19 around the same time in March, their doctors were baffled. Both were young – 29 and 31 – and in good health. Yet within days they couldn’t breathe on their own and tragically one of them died.
Two weeks later, when a second pair of Covid-stricken brothers, both in their 20s, also appeared in the Netherlands, geneticists were called in to investigate. What they found was a path leading from severe cases, genetic variation and gender differences to loss of immune function that could ultimately lead to a new approach to treat thousands of coronavirus patients. .
The common thread of the research is the absence of a substance called interferon which helps orchestrate the body’s defense against viral pathogens and can be infused to treat conditions such as infectious hepatitis. Now, more and more evidence suggests that some Covid-19 patients are getting very sick due to an impaired response to interferon. Historic studies published Thursday in the journal Science showed that an interferon insufficiency could be hiding at a dangerous turning point in SARS-CoV-2 infections.
“Looks like this virus has a big thing,” said Shane Crotty, a professor at the Center for Infectious Disease and Vaccine Research at the La Jolla Institute of Immunology in California. “This great trick is to avoid the initial innate immune response for a significant period of time and, in particular, to avoid an early response to type 1 interferon.”
The work highlights the potential of interferon-based therapies to expand a slowly accumulating range of Covid-19 treatments. These include remdesivir and convalescent plasma from Gilead Sciences Inc., a component of the blood of recovered patients that may contain beneficial immune factors.
These treatments offer limited benefits and are typically used in very ill hospital patients. The possibility that interferon might help some people is appealing because it appears to be more effective in the early stages of infection, when life-threatening respiratory failure could still be avoided. Dozens of studies on interferon treatment are currently recruiting Covid-19 patients.
“We believe that timing can be essential because it is only in the very early phase that one can really fight viral particles and defend against infection,” said Alexander Hoischen, head of the genomic technologies group. and immunogenomics at the Radboud University Medical Center in Nijmegen analyzed the DNA of the two groups of brothers.
A health worker uses a nasal swab to test for Covid-19 in Florida.
Being male, elderly, and having underlying medical conditions can all increase the risk for life-threatening Covid-19 patients. But even within these groups, the severity of the disease varies widely. Scientists hypothesized that other factors influence susceptibility, including pre-existing levels of inflammation and immunity, the amount of virus that triggers infection, and the genetic makeup of patients.
The role of interferon represents a new link in the complex interaction of Covid-19 with the human immune system. Many patients suffer from their worst complications from an overreaction sometimes called a cytokine storm and may benefit from dexamethasone, an inexpensive generic that calms these storms.
“This is a very interesting disease because too little immunity is not good,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said on September 10 in an online briefing for staff at Massachusetts General Hospital. “Too much immunity is really, really bad.”
Some people are known to have trouble fighting off infections because they make antibodies that turn off their own interferon. On Thursday, a global consortium of researchers said such immune reactions to the protein could explain potentially fatal Covid-19 pneumonia in at least 2.6% of women and 12.5% of men.
Interferon-blocking antibodies appeared in 101 of 987 patients with severe disease, but none of 663 people with asymptomatic or mild cases, according to the Science study. Patients over 65 were also more likely than younger ones to have the autoimmune abnormality, which was “clinically silent until patients became infected with SARS-CoV-2,” said the group of more than 100 scientists.
“These results provide a first explanation for the excess of men among patients with potentially fatal Covid-19 and the increased risk with age”, the researchers led by Jean-Laurent Casanova, director of the laboratory of Rockefeller University of St. Giles’ human genetics of infectious disease in New York said. “They also provide a way to identify those at risk of developing potentially fatal Covid-19.”
Genetic analysis of Covid-19 patients published in the same journal revealed two dozen genetic mutations that remained “silent” until the patients were infected with SARS-CoV-2. The researchers – many of whom were also involved in the antibody study – sequenced the genomes of 659 patients with life-threatening illnesses; 3.5% carried genetic variations that inhibit interferon production.
These genetic defects were similar to those that Hoischen and his colleagues at a dozen Dutch centers described in the Journal of the American Medical Association two months ago. Both groups of brothers had inherited a genetic mutation that altered the response to interferon, preventing their immune systems from fighting the coronavirus until it had replicated for days.
Among the Dutch, the effects were cruel. The first, a young father from a town in the south of the Netherlands, suffered from shortness of breath, cough and fever at home for eight days before being admitted to intensive care. He was to spend 33 days in hospital, 10 of which were on a ventilator.
Her 29-year-old brother succumbed to Covid-19 in an intensive care unit in Rotterdam, after being treated for shock and a fever that climbed to 44 degrees Celsius (111 degrees Fahrenheit). When Radboud’s doctors learned of his younger brother’s case, along with a second pair – 21 and 23-year-old brothers also with respiratory failure – they looked for a genetic cause.
They found a mutation that was carried on the X chromosome. Defects on this chromosome are more likely to affect men, who only have one copy, while women have two.
Male mutations are rare – occurring in 1 in 10,000 people – and an unlikely explanation for the vast majority of severe cases of Covid-19. But Science studies indicate that various forms of interferon dysfunction can cause up to one in eight critical patients, and that screening and targeted treatment could prevent serious illness and death.
“If we can get them into our university medical center early enough,” Hoischen said, “our clinicians may be able to treat them with interferons.”
Other ways to overcome autoimmunity, such as removing antibodies to interferon from the blood, called plasmapheresis, may also help patients.
“Rare diseases and the more common forms of the same disease can converge, and we can learn from each other,” Hoischen said. “It is hope.”