Might 22, 2020 — For some COVID-19 sufferers, the physique’s immune response could also be as damaging because the virus that causes the illness. The persistent excessive fevers, extreme respiratory misery, and lung harm seen in some critically ailing sufferers are all indicators of an immune system in overdrive.
Now, a brand new scientific trial will check a therapy that targets this overactive immune response, says Howard Hughes Medical Investigator Bert Vogelstein. He and his group on the Johns Hopkins College Faculty of Drugs are at the moment recruiting people for the trial, which incorporates sufferers ages 45 to 85 on the Johns Hopkins Hospital who’ve COVID-19 however who aren’t on a ventilator or within the ICU.
Their therapy, a typical kind of prescription drug referred to as an alpha blocker, may break a cycle of hyperinflammation earlier than it ramps up, their findings from mouse research and a latest evaluation of medical claims information counsel.
“The strategy we’re advocating entails treating people who find themselves at excessive threat early in the middle of the illness, when you understand they’re contaminated however earlier than they’ve extreme signs,” says Vogelstein. If the trial’s outcomes counsel the drug is protected and efficient towards COVID-19, it may probably assist many individuals recuperate safely at residence and reduce the pressure on hospital assets, he says.
A hyperactive immune response is not distinctive to COVID-19. Folks with autoimmune ailments and most cancers sufferers receiving immunotherapy can expertise related signs. These responses are known as macrophage activation syndrome, cytokine launch syndrome — or just “cytokine storms.”
When macrophages (and another sorts of immune cells) detect virus particles, they ship out alert messages by releasing numerous proteins often known as cytokines. These cytokines recruit different immune cells to the scene – an inflammatory response that, carefully, helps the physique combat off a virus. However macrophages may also launch different signaling molecules, referred to as catecholamines, that amplify this response additional, triggering the discharge of extra cytokines. The result’s a runaway suggestions loop, like a snowball getting greater because it barrels down a hill.
“It appears that evidently as soon as this course of begins, there’s this incapacity to correctly swap it off,” says Maximilian Konig, a rheumatologist at Hopkins who helps to coordinate the trial.
Earlier than COVID-19 hit, Vogelstein’s group was already exploring methods to ease the hyperinflammatory immune response in most cancers sufferers handled with immunotherapy. The researchers have been excited by medication referred to as alpha blockers, that are broadly prescribed for prostate situations and hypertension — and likewise intervene with the cell signaling that triggers cytokine storms. In concept, alpha blockers may cease a cytokine storm earlier than it begins.
Giving mice with bacterial infections an alpha blocker lessened cytokine storms and decreased deaths, Vogelstein’s group reported within the journal Nature in 2018. And, the researchers discovered, the therapy did not appear to hurt different facets of the immune response.
Staving off the storm
Because the COVID-19 pandemic escalated in the US over the previous few months and severely ailing sufferers introduced with cytokine storm signs, the thought of testing alpha blockers in people has develop into extra pressing, Vogelstein’s group lately argued within the Journal of Medical Investigation.
To acquire approval for an alpha blocker scientific trial, Vogelstein’s group first surveyed medical claims information. They combed by means of data from individuals hospitalized for pneumonia and acute respiratory misery and analyzed whether or not sufferers’ outcomes have been higher if that they had been taking alpha blockers for unrelated situations. The group’s tentative conclusion: taking alpha blocker medication correlated to a decrease threat of dying from respiratory misery.
By itself, that is not robust sufficient proof to prescribe the drug for a completely new illness like COVID-19, says Susan Athey, an economist at Stanford College who collaborated with Vogelstein’s group on the claims evaluation. However it helps bolster the case for the group’s scientific trial.
Within the trial, COVID-19 sufferers will take step by step rising doses of an alpha blocker referred to as prazosin, bought below the model title Minipress, over six days, says Chetan Bettegowda, a neurosurgeon at Hopkins who helps to design and run the trials. Then, the group will consider whether or not individuals who acquired this therapy had a decrease ICU admission price or ventilator use than sufferers who acquired the usual therapy. They’re going to observe every affected person for 60 days, however preliminary information from the primary sufferers might be out there inside weeks to months, Bettegowda says.
If the trial’s outcomes counsel alpha blockers are protected and efficient, the group hopes to run a second trial with sufferers who’ve been identified with COVID-19 however are usually not but hospitalized. They’re additionally encouraging colleagues at different hospitals to affix their scientific trial efforts, to assemble affected person information extra rapidly.
This therapy, if it really works, could be a secondary type of prevention, Vogelstein says, mitigating signs earlier than they develop into extreme, reasonably than stopping an infection within the first place. “Finally, hopefully, a vaccine can be produced, and that would be the essence of prevention,” he says. “However till vaccines can be found, secondary prevention makes quite a lot of sense.”