COVID-19 is linked to a deadly immune system malfunction

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The name ‘cytokine storm’ is apt: It describes a furious gale-force swarm of molecules unleashed by the body’s immune system that causes extreme inflammation, tissue damage, even death.

Cytokines—from the Greek cyto for cells and kinos for movement—are important in the fight against viral infections.

But they worsen those same infections in the extreme, a phenomenon that is proving lethal for older COVID-19 patients.

“The immune system is a double-edged sword,” says Andrea Cox, a professor of medicine in the Johns Hopkins School of Medicine.

“There’s a critical role for it in an antiviral response. But it also can be pro-inflammatory in a pathological way.

It’s like trying to kill a bug with a hammer. You can put a hole in the wall while you’re trying to smush the bug.”

Cox is among several Hopkins scientists studying cytokine storms and their relationship to COVID-19.

Her lab is analyzing blood and lung tissue samples from infected patients to identify specific cytokines involved. They want to know why they turn dangerous, especially among the elderly.

Other researchers are testing drugs they hope will prevent the onset of cytokine storms, or stop them after they begin.

The goal, ultimately, is to save those at greatest risk from this potentially deadly complication of SARS-CoV-2 infection.

There are several dozen cytokines—protein messengers—that affect the immune system.

In some cases, they activate certain responses, while in others, they slow them down. Sometimes the system goes awry, triggering too many cytokines, too rapidly.

This also occurs in auto-immune diseases, other infections, and as a side effect of certain immunotherapies.

In COVID-19, cytokine storms disproportionately strike the elderly, “for reasons that are not clear,” Cox says.

“Immune system balance is regulated differently at different ages. It’s not that the immune system is weaker or stronger in older versus younger–but different. It’s possible that older people make a more damaging immune response than the young.”

Most commonly, patients seem to be holding their own against the initial SARS-CoV-2 infection before suddenly turning gravely ill. Often, the outcome is grim.

“Cytokines tell other cells to do things that in this case may enhance tissue damage and disease severity,” Cox says.

“With blood vessels, for example, it can cause the vascular system to leak fluids and blood, and make it harder for oxygen to go where it’s supposed to go because there is fluid where oxygen should be, like in the lungs.”

Understanding a cytokine storm’s role in COVID-19 is a multidisciplinary effort at Hopkins, including researchers taking a new look at old drugs.

Scientists are testing Clazakizumab, a medication that prevents organ rejection in kidney transplant recipients. It works by suppressing interleukin-6 (IL-6), an immune system cytokine found elevated in the sickest COVID-19 patients.

“We know this drug very directly affects IL-6 and believe that neutralizing it will help stop cytokine storm, or prevent it from progressing,” the team says.

Researchers from the Kimmel Cancer Center are testing another drug, Prazosin, an alpha blocker used to treat hypertension, enlarged prostate, and post-traumatic stress disorder.

They think it could prevent cytokine storms by blocking a surge of molecules known as catecholamines, substances made in the brain and adrenal glands that—based on an earlier mouse study—typically precedes the onset of a cytokine storm.

The researchers first examined a national database of patients with Acute Respiratory Distress Syndrome, or ARDS, a condition characterized by fluid accumulation in the lungs, not unlike what happens with COVID-19.

They found fewer deaths and less need for ventilators among those who had been taking drugs like Prazosin, leading them to speculate that the drug could similarly benefit patients with COVID-19.

The team recently began a controlled trial to see if Prazosin, given early after infection, can stave off a cytokine storm.

“The problem with these pandemic viruses is that no one in the world has seen anything like them,” Cox says.

“There is no immunity. What’s worse, the rules for who does well and who does badly are different for this virus than for other viruses, and, right now, we don’t understand the rules at all.”

Written by Marlene Cimons.