Rogue immune system reactions hint at an early treatment for COVID-19

In severe cases of COVID-19, a person’s immune system throws everything it has at the coronavirus, but some of the weapons it lobs end up hurting the patient instead of fighting the virus.  

Now researchers have new clues for getting the immune system back on target, before the disease becomes severe. One of the most comprehensive looks to date at the immune system of COVID-19 patients pinpoints where things go awry. The findings suggest that bolstering the body’s first line of defense against the virus using drugs known as interferons may help prevent severe illness.

In a study of 113 patients admitted to Yale New Haven Hospital from March 18 to May 27, researchers monitored immune system chemicals and cells in two groups: severely ill COVID-19 patients who needed intensive care and moderately ill patients who were hospitalized but didn’t end up in the ICU. For comparison, the team also looked at healthy health-care workers.

This study characterized the nuances of the immune response and “characterizes the inflammation at its nittiest, grittiest level,” says Michal Tal, an immunologist at Stanford University who was not involved in the study.

Moderately ill patients had an initial spurt of immune chemicals that fight viruses and fungi, then those levels gradually went back to normal, Akiko Iwasaki, an immunologist at Yale University, and colleagues found.But in the severely ill patients, levels of those chemicals remained high, the researchers report July 27 in Nature. In addition, allergy-producing antibodies and immune chemicals and cells usually dedicated to expelling parasitic worms got enlisted against the virus. As in other studies, the severely ill patients also had low levels of T cells, immune cells involved in recognizing and killing viruses.

That catalog of all the different ways the immune system misfires is striking, Tal says. “The immune system is just throwing the whole kitchen sink at this [virus],” she says. That desperation may end up hurting patients with tissue-damaging inflammation.

One of those weapons is interferon alpha, normally one of the body’s first defenses against viruses. Those chemicals are usually produced in the first couple of days of an infection, then wane as other parts of the immune system take over the fight. But in people with severe disease, levels of interferon either don’t dip as they should, or become part of the kitchen sink of immune chemicals that can end up being harmful, the researchers discovered.

If a patient comes into the hospital after 10 days of being sick, Iwasaki says, “and their blood levels of interferon alpha are sky high, that’s probably an indication that that person needs more attention and [will] potentially need mechanical ventilators.” People in the study with high levels of interferon alpha had a 4.5 times greater risk of being admitted to the ICU or dying than people with normal levels. 

Interferon alpha itself may not be making the illness worse, says Eleanor Fish, an immunologist at the University of Toronto. Instead, it may be an issue of timing. In severely ill COVID-19 patients, elevated levels of interferon may be a consequence of extreme inflammation, rather than the cause, she says. These interferons come “too little, too late, but whether it’s exacerbating disease needs to be teased out,” she says. “What we know is that absence of interferon early on in disease is not a good thing.”

Normally, interferons are produced when cells’ virus alarms are tripped. Interferons flood into the infected area, signal uninfected cells to raise their defenses, and help kill infected cells. “It both removes the viral factory and prevents new infections,” Iwasaki says. With most viruses, “if you generate a robust interferon response within a few minutes of exposure to the virus, you’re likely going to be fine.”

But, says Iwasaki, “in the case of COVID, this well-orchestrated line of events isn’t happening.” The virus shuts down the interferon response early on. That allows the virus to invade the lungs and do damage without setting off early intruder alarms. Other immune chemicals, called cytokines and chemokines, flood the damaged area attempting to expel invaders and heal the tissue, but can set off a “cytokine storm” that further batters tissues. The high levels of interferon alpha seen in severely ill patients may be produced by cells that don’t normally make those chemicals in a last-ditch effort to combat the virus, Iwasaki says.

“The earlier you can control the virus, the less damage you’re going to get,” Iwasaki says. And one promising way of potentially controlling the virus early is by giving people interferons.

Fish and others have already compiled data suggesting that two forms of the drug, interferon alpha and interferon beta, may help fight the coronavirus. In a small study of 77 people with COVID-19, Fish and colleagues found that interferon alpha helped clear viral infections almost seven days sooner on average than people given arbidol hydrochloride, a drug thought to block viral entry to cells.

What’s more, ramping up interferon didn’t lead to an overzealous immune response, as feared. In fact, people taking interferon had lower levels of an inflammatory protein called IL-6 in their blood than those taking the other drug, the researchers reported May 15 in Frontiers in Immunology. Another study of interferon beta, given in combination with anti-HIV drugs, suggested that interferon speeds recovery from COVID-19 (SN: 5/8/20). And the U.K.-based drug company Synairgen reported July 20 in a news release that inhaled interferon beta reduced the risk of developing severe disease among patients enrolled in a small trial compared with those taking a placebo.

More trials of interferon alpha, beta and of interferon lambda are in the works. The U.S. National Institute of Allergy and Infectious Diseases announced August 5 that it has begun a clinical trial of about 1,000 hospitalized people with COVID-19 that will test interferon beta 1a in combination with the antiviral drug remdesivir (SN: 7/13/20). But Iwasaki’s study hints that it may be too late to give interferons once a person is already sick enough to be hospitalized.

Giving interferons as soon as possible after detecting a coronavirus infection may prevent severe illness and speed recovery, Fish and other scientists say. Interferons might also be given as a preventative for people at high risk of contracting coronavirus. Some trials of the early use of interferons are also under way or in the planning stage.