Photography Courtesy Hugh Rosen and Michael Oldstone, Scripps Research Institute
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Immune system cells produced by a cytokine storm appear as green and red dots in a microscopic image of lung tissue infected with influenza.

Photography Courtesy Hugh Rosen and Michael Oldstone, Scripps Research Institute

How quieting 'blood storms' could be key to treating severe COVID-19

In some coronavirus patients, the body turns its attacks on itself. Anti-inflammatory drugs may be able to help stop this friendly fire.

For many patients with severe COVID-19, the greatest threat to survival isn’t the coronavirus itself, but the deadly forces that the human body rouses to fight it.

While essential for defending against pathogens, the immune system can be a blunt and potent weapon that sometimes harms healthy cells. One version of a runaway immune response, called a “blood storm” or cytokine storm, causes excessive inflammation. It’s suspected to play a major role in some of the most critical COVID-19 cases—including those that land patients in the ICU or saddle them with ventilators.

Cytokine storms are “one of the main ways that people with COVID-19 end up passing away,” says Anna Helena Jonsson, a rheumatologist at Brigham and Women’s Hospital in Boston.

Clinicians and researchers are still trying to figure out how common cytokine storms are among those with COVID-19, as well as the factors that trigger them. Because these types of immune overreactions aren’t exclusive to the coronavirus, scientists have already identified several existing anti-inflammatory therapies that could help rein them in. Coupled with other promising drugs that directly target the virus SARS-CoV-2, these treatments could speed recovery times and perhaps even reduce death rates while researchers race to develop a vaccine.

“That’s sort of the key to this puzzle,” says Marion Pepper, an immunologist at the University of Washington.

Too much of a good thing

Like any well-secured system, the body has ways to detect and vanquish invaders that have breached its barriers. Signaling molecules called cytokines are crucial for coordinating this response. Released by cells to rally the body’s defensive forces, they act like microscopic burglar alarms that alert the rest of the immune system to the presence of an interloper.

Under typical circumstances, cytokine signaling mobilizes defensive cells and molecules to an infected region. Several cytokines are responsible for sparking spates of inflammation, the process by which immune forces are marshaled to the site of damage or infection, sometimes leading to swelling, redness, and pain. Once the threat at a site has begun to wane, the cytokine signaling typically shuts off and allows the defensive forces to clear.

In a cytokine storm, however, “the immune system gets out of whack,” says Angela Rasmussen, a virologist at Columbia University. Rather than quieting down, the cytokine alarm continues to sound, enlisting an unnecessary army of fighters that can end up doing more harm than the germ itself. It’s akin to sending an entire battalion of soldiers to subdue a single assassin—a misguided counterattack that can turn the entire body into a war zone.

During these storms, blood vessels can become clogged with hordes of immune cells, causing traffic jams that starve organs of oxygen and nutrients. Toxic immune molecules intended for infected cells can leak out of the blood circulation and devastate healthy tissues. In some patients, these molecular maelstroms can even trigger clotting cascades that gum up the lungs and make it harder to breathe. If the storm can’t be stopped, it catapults patients toward tissue damage, organ failure and, ultimately, death.

When cytokine storms occur, they seem to take hold of the body within several days of the first symptoms appearing, and can progress to gale force at alarming speeds. At least two scenarios could allow this situation to play out. In one, the immune system fails to purge SARS-CoV-2 from the body, prompting a never-ending deluge of cytokines. In the other, the molecules continue to surge throughout the body even after the infection has ebbed.

Quelling the storm

Cytokine storms have been associated with several diseases—not all of them infectious—including Ebola, influenza, malaria, lupus, and certain types of arthritis. They manifest differently in each case, and the particularities of severe cases of COVID-19 haven’t yet been worked out, likely varying from patient to patient. Researchers are also still unsure of the characteristics that put certain people at higher risk of these exaggerated responses, though genetics and age both appear to play contributing roles.

Still, these immunological tempests are familiar enough that doctors have developed tools to treat them—and are now trialing their effectiveness with COVID-19. Much of the attention has focused on a cytokine called interleukin-6 (IL-6), which has been found at high levels in many patients with serious COVID-19; one promising treatment could involve tocilizumab, an arthritis drug that blocks the receptors for IL-6, effectively deafening cells to its alarm.

Based on several early reports, tocilizumab seems promising. A subset of seriously sick patients who received the drug appear to improve in the following days, says Jasmine Marcelin, an infectious disease physician at the University of Nebraska Medical Center. However, most research so far remains “exploratory,” she says, tracking patients who were spontaneously treated outside of a pre-planned experiment.

Without comparing these patients to a control group that did not receive tocilizumab, it’s hard to draw firm conclusions about just how well the drug is working to treat COVID-19. “We don’t know if these people would have gotten better on their own, without medication,” Marcelin says.

Dozens of clinical trials with control groups are now underway worldwide to suss out these answers. Early results from an ongoing trial in France, for example, found that tocilizumab ultimately reduced the rate of death and the need for ventilator support in a group of 64 patients with “moderate to severe” cases of COVID-19, compared to 65 patients who received only standard care.

A delicate balance

Other inflammatory molecules such as interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) can be part of cytokine storms as well, and each represents a potential target for treatment.

Alternatively, clinicians could try treatments that quell inflammation before it starts, says Kate Fitzgerald, an immunologist at the University of Massachusetts Medical School. These options include corticosteroids and another arthritis drug called baricitinib; both medications stop cells from manufacturing many types of cytokines. Yet another treatment that has been trialed for other diseases involves mechanically filtering cytokines out of the blood, accelerating the storm’s resolution.

But experts are understandably wary of using treatments that tamp down the body’s immune defenses when a deadly virus is present.

“The risk of these medications is taking it all the way to the opposite side,” Marcelin says. A drug that hits the immune system too hard, for instance, could render it incapable of battling the coronavirus, or could allow another disease-causing microbe (such as a bacterium or fungus) to join SARS-CoV-2 in the body. These dangerous co-infections have caused several COVID-19-related deaths.

Another major factor to consider is the timing of treatment, Rasmussen says. If a doctor administers a cytokine-blocking drug too early, the virus could take the opportunity “to run wild.” But wait too long, and the treatment may come too late to save the patient.

Studies have hinted at the existence of this crucial window. A drug called Kevzara—which, like tocilizumab, renders cells incapable of hearing IL-6 alarm bells—seems to help patients in “critical” condition who require ventilators or a stay in the intensive care unit. But the treatment has no apparent benefits in less sick individuals whose cases are considered “severe,” the next tier down.

A one-two punch to fight COVID-19

Experts remain hopeful that cytokine-blocking therapies will become a fixture of COVID-19 treatments, though such treatments may be most effective with additional antiviral drugs to target the virus itself.

“We might be chasing our tails if we only focus on the immune response and not the thing that’s causing it,” Marcelin says.

Last week, the National Institute of Allergy and Infectious Diseases released preliminary data indicating that the antiviral drug remdesivir, which impairs SARS-CoV-2’s ability to replicate, appears to modestly hasten recovery from COVID-19. Adding medicine to treat cytokine storms—a combo some ongoing trials are now testing—could improve patients’ outcomes even further.

The strategy isn’t foolproof though, Marcelin says. Different medications can interact with each other, diminishing their effectiveness and, in some cases, leaving the patient worse off than before.

As trials continue alongside the evolving pandemic, “it’s easy to jump to conclusions,” Jonsson says. “But we all need to remember that we have to wait for the evidence. Every week, we’ll be learning more.”