The immune system response triggered by Covid-19, causing an overproduction of cytokines, has been big news during the pandemic.
While Covid-19 deaths are usually caused by acute respiratory distress syndrome (ARDS), especially in older adults and those with co-morbidities, some younger Covid-19 patients have suffered severe symptoms because of an overreaction by their immune systems, rather than the virus itself.
Now, a new clinical trial will test a treatment that targets this immune response, according to a press release from the Howard Hughes Medical Institute.
The mechanism behind the cytokine storm
According to leading immunologists in Japan, a molecular mechanism could lead to possible ways to treat this overreaction by the immune system. The research was published in the journal Immunity.
The immune system response to the coronavirus may lead to ARDS, causing patients to struggle for oxygen in their inflamed, fluid-filled lungs.
"To rescue the patients from this condition, it is vital to understand how SARS-CoV-2 triggers the cytokine storm that leads to ARDS," stated Masaaki Murakami, the head of the immunology laboratory at Hokkaido University's Institute for Genetic Medicine.
His study suggested that the novel coronavirus enters human cells by attaching to the ACE2 surface receptor. Then, a human enzyme called TMPRSS2 is utilised.
"Drugs that block the ACE2 receptor or that inhibit the enzyme could help treat the initial stages of the disease," says Murakami. "However, ARDS with cytokine storm starts to appear in the later phase of infection even when the numbers of the virus decrease. So, there must be another pathway that causes the cytokine storm,” Murakami explained in a news statement.
Closer to a treatment?
The treatment that will be tested in a clinical trial by the Howard Hughes Medical Institute involves a common type of alpha-blocker. Through mouse studies, the team determined that this drug might break the hyperinflammation before it causes the severe symptoms seen in Covid-19 patients.
"The approach we're advocating involves treating people who are at high risk early in the course of the disease, when you know they're infected but before they have severe symptoms. If the trial's results suggest the drug is safe and effective against Covid-19, it could potentially help many people recover safely at home and lessen the strain on hospital resources,” stated Howard Hughes Medical Investigator Bert Vogelstein.
Together with his team at the John Hopkins University School of Medicine, Vogelstein is currently recruiting patients aged 45 to 85 at the John Hopkins Hospital to participate in the trial. The prerequisites are that they have to be hospitalised, but not ventilated or in ICU.
How will an alpha blocker stop the cytokine storm?
A hyperactive immune system isn’t a new response solely seen in Covid-19. Usually, this type of response is seen in people already suffering from autoimmune diseases or cancer.
What happens during a cytokine storm is that cells called macrophages, which are either found in the tissues or in the blood as white blood cells, are activated to detect and fight the pathogen. As soon as this happens, cytokines are released to help the body fight off the intruder.
Unfortunately, the macrophages don’t only release cytokines, but also molecules called catecholamines, which trigger the immune system to release even more cytokines.
According to the news release, Vogelstein’s team was already investigating how this reaction in cancer patients could be halted with immunotherapy.
They then looked at alpha-blockers which are usually prescribed for prostate conditions and high blood pressure. This medication is meant to help curb the cells that trigger cytokine storms.
The initial research in mice was published in the journal Nature in 2018.
How likely is this method to be successful?
While alpha-blockers were already approved for human use, Vogelstein’s team needed to look at medical claims data to see how patients with pneumonia and ARDS responded to alpha-blockers for unrelated conditions.
The conclusion was that the use of alpha-blockers were correlated to lower death risk, but this simply wasn’t enough evidence for a new condition such as Covid-19.
Now, the patients on trial will take increasing doses of an alpha-blocker over six days. The team will then evaluate whether those patients had lower risk of ICU admission and being placed on ventilators.
A second trial will be needed to establish whether this approach is safe and effective. According to Vogelstein, this method may be great for helping to mitigate symptoms before they become severe and deadly.
"Eventually, hopefully, a vaccine will be produced, and that will be the essence of prevention," he stated. "But until vaccines are available, secondary prevention makes a lot of sense."
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