April 17, 2020 -- One of the great mysteries of the new coronavirus is why it causes only mild disease in most people, but turns fatal for others. In many cases, it seems the worst damage may be driven by a deranged immune response to the infection, rather than the virus itself.
In many of the sickest patients with COVID-19, their blood is teeming with high levels of immune system proteins called cytokines.
Scientists believe these cytokines are evidence of an immune response called a cytokine storm, where the body starts to attack its own cells and tissues rather than just fighting off the virus.
Cytokine storms are known to happen in autoimmune diseases like juvenile arthritis. They also occur during certain kinds of cancer treatment, and can be triggered by infections, like the flu. One study of patients who died of H1N1 influenza, for example, found that 81% had features of a cytokine storm.
Though the virus that causes COVID-19 has been circulating for only a few months, early research shows that like other infections, it, too, may cause this kind of catastrophic immune problem, and researchers say the size of the storm it triggers is gale-force.
How Cells Die
Dozens of studies have been launched to see whether drugs and devices that sop up cytokines, or prevent their release in the first place, may keep COVID-19 patients from dying.
Mukesh Kumar, PhD, is a virologist and immunologist at Georgia State University in Atlanta. He studies how the body responds to infections. In experiments in his high-security lab, he has been infecting cells and animals with SARS-CoV-2 to learn what happens.
One thing he has observed is that the virus copies itself very quickly once it infects a cell.
“That’s a lot of stress on the cell in a small amount of time,” Kumar says.
The cell begins to send SOS signals.
“When any cell senses that there is something foreign, that there is something bad happening, the immediate response of the cell is to kill itself,” he says, “It’s a protective mechanism so it doesn’t spread to other cells.”
Certain kinds of cytokines trigger cell death. When you have many cells doing this at the same time, a lot of tissue can die. In COVID-19, that tissue is mostly in the lung. As the tissue breaks down, the walls of the lungs’ tiny air sacs become leaky and fill with fluid, causing pneumonia and starving the blood of oxygen.
“Basically, most of your cells will die because of the cytokine storm. It eats away at the lung. They cannot recover,” Kumar says. “It seems to play a role in death in a large number of cases.”
When the lung becomes greatly damaged, respiratory distress syndrome follows. Then other organs start to fail.
Researchers aren’t sure what percentage of severely ill patients will die from a cytokine storm, or even why some people who are infected will go on to have this reaction, while others won’t. COVID-19 patients die from other puzzling problems, too, like heart arrhythmias.
The haywire immune attack does seem to play a role in how severe the disease is. One study of 21 COVID-19 patients admitted to a hospital in China, for example, found that the 11 patients who were classified as severely ill because they needed oxygen were much more likely than those who were deemed to be just moderately ill to have higher levels of cytokines. A separate study of 191 COVID-19 patients from two hospitals in China found that higher levels of the cytokine IL-6 were linked to the risk of death from the disease.
Trying to Prevent the 'Storm"
For some patients, drugs that may blunt the body’s attack on itself could be lifesaving.
Ryan Padgett, MD, an emergency room doctor in Washington state, began having symptoms of COVID-19 in early March. He spent nearly 2 weeks on a ventilator and an ECMO machine, and recovered after receiving IV infusions of the rheumatoid arthritis drug Actemra, which blocks the cytokine IL-6 receptor, one of several that soar in the COVID-19 cytokine storm.
Another doctor, Jeff Brown, MD, in Richmond, VA, also recovered from a serious COVID-19 infection after several doses of Actemra. His story was reported by the Richmond Times-Dispatch.
While stories like these are encouraging, researchers caution the drugs were experimental, and the cases don’t really provide solid scientific information about whether the drugs work the way we think they should, or offer any guidance about when they should be used.
To tease out that information, you need randomized controlled clinical trials, which test a drug against a placebo. Dozens of studies are underway testing Actemra and other drugs to see if they can curb the body’s over-the-top response to the virus. Kumar is planning to test another arthritis drug, called auranofin, for example. He’s seen signs that it can eliminate the virus from infected cells.
These drugs are often expensive. Actemra can cost thousands of dollars per dose, for example. While it’s widely used to help people who have autoimmune diseases, doctors are more cautious about giving it to people with active infections since it tamps down immune functions that may be needed to fight off the virus.
Max Konig, MD, a rheumatologist at Johns Hopkins University, has paused his regular research to study cytokine storms in COVID-19 patients.
He says there’s something unique about the virus that causes COVID-19.
“This virus acts different than other viruses, especially common viruses. Most people who get infected with Epstein-Barr or influenza, they don’t mount this response,” Konig says.
Yet a significant portion of patients who are hospitalized for COVID-19 have higher cytokines.
Rather than blocking cytokines, Konig thinks it may be possible to head off the storm altogether by blocking some of the chemicals that can trigger its release, which are called catecholamines.
“In those situations, we know that before the cytokines become so excessively elevated, there is a surge of catecholamines. If you prevent that surge,” he says, “the immune response just falls flat.”
In theory, this approach might prevent more damage, he says, since the cytokines never get the chance to destroy tissue.
Konig has found some preliminary evidence to support that idea. In a recent study published to medRxiv, Konig and his colleges analyzed the medical records of more than 12,673 people with acute respiratory distress syndrome, or ARDS, the same diagnosis given to many of the severely ill COVID-19 patients. These patients were not infected with the virus that causes COVID-19, however.
He found that patients who were taking medications that block the release of catecholamines -- as some kinds of blood pressure drugs do -- in the year before their diagnosis were about 20% less likely to need to be placed on a ventilator after their diagnosis, compared to others, an effect that was statistically significant.
The study hasn’t been peer-reviewed. It’s part of an effort to get scientific findings out more quickly in the midst of a pandemic. Konig says more research will be needed to find out if this approach will help keep COVID-19 patients out of the hospital, or off ventilators, in the real world.