Preventing a “cytokine storm” alleviates the severe symptoms of COVID-19

In some COVID-19 patients, the body’s immune response may be as disruptive as the disease-causing virus. The persistent high fever, severe dyspnea, and lung injury seen in some critically ill patients are all signs of an overdriven immune system.

Now a new clinical trial will test treatments that target this overactivity Immune reactionSays Howard Hughes, MD, Bert Vogelstein. He and his team at Johns Hopkins University School of Medicine are currently seeking individuals to participate in the study, including patients aged 45 to 85 at Johns Hopkins Hospital who have COVID-19 but are not on a ventilator or ICU. I will.

Their treatment, a common type of prescription drug called an alpha blocker, can break the cycle of hyperinflammation before it increases. According to a mouse study and recent analysis of medical billing data,

“The approach we advocate is to treat people at high risk at an early stage of an infection before they have severe symptoms, even if they are known to be infected,” Vogelstein said. I will. If the results of the trial suggest that the drug is safe and effective against COVID-19, it may help many people recover safely at home and reduce the strain on hospital resources. He says.

Runaway reaction

The hyperactive immune response is not unique to COVID-19. With autoimmune disease Cancer patient Similar symptoms can occur with immunotherapy. These reactions are called macrophage activation syndrome, Cytokine release syndrome— Or simply “Cytokine storm. “

When macrophages (and other types of immune cells) detect viral particles, they release various proteins called cytokines that send warning messages. These cytokines recruit other immune cells into the field. The inflammatory response, to a moderate extent, helps the body fight the virus. However, macrophages also release other signaling molecules called catecholamines, which further amplify this response, causing the release of more cytokines. The result is a steep feedback loop. For example, a snowball grows larger as you go down a snowman hill.

“Once this process begins, it doesn’t seem to be able to switch it off properly,” says Maximinian Konig, a rheumatologist at Hopkins who helps coordinate the case.

Before the COVID-19 hit, Vogelstein’s team was looking for ways to mitigate the hyperinflammatory immune response in cancer patients already treated with immunotherapy. The researchers were interested in a drug called alpha blocker that is widely prescribed for prostate conditions and hypertension. It also interferes with cell signaling that causes the cytokine storm. Theoretically, alpha blockers may stop the cytokine storm before it begins.

Administering alpha-blockers to mice with bacterial infections reduced cytokine storms and reduced mortality, Vogelstein’s team said Journal Nature In 2018.. And the researchers found that the treatment did not harm other aspects of the immune response.

Go away from the storm

The idea of ​​testing alpha blockers in humans has become urgent as the COVID-19 pandemic has expanded in the United States over the past few months and severely ill patients have shown symptoms of a cytokine storm. Recently discussed In Journal of Clinical Investigation..

To obtain approval for the Alpha Blocker clinical trial, Vogelstein’s team first examined medical billing data. They combed records of people hospitalized for pneumonia and acute respiratory distress and analyzed whether patients’ outcomes were better when they were taking alpha-blockers in an unrelated state. The team’s tentative conclusion: Taking alpha-blockers reduced the risk of death from respiratory distress.

That alone isn’t enough evidence to prescribe an entirely new disease drug like COVID-19, says Susan Asay, an economist at Stanford University who worked with Vogelstein’s team on claim analysis. However, it helps strengthen the team’s clinical trial case.

In this trial, COVID-19 patients will gradually increase their alpha blocker called prazosin, which is marketed under the brand name Minipress, over 6 days. Chekin Bettegowda, a neurosurgeon at Hopkins, trial.. The team then assesses whether those receiving this treatment have lower rates of ICU hospitalization or ventilator use than those receiving standard care. They follow each patient for 60 days, but preliminary data for the first patient may be available within a few weeks to months, Bettegowda says.

If the results of the study indicate the safety and efficacy of alpha blockers, the team hopes to conduct a second trial in patients who have been diagnosed with COVID-19 but have not been hospitalized yet. I’m out. We also encourage colleagues in other hospitals to participate in clinical trials to gather patient data more quickly.

Vogelstein believes that the treatment, if successful, would be a secondary prevention, rather than stopping the infection from the beginning, but relieving it before it becomes severe. “In the end, hopefully a vaccine will be produced, which will be the essence of prevention,” he says. “But secondary prevention makes a lot of sense until a vaccine is available.”