Many coronavirus patients seem to get better at first, then rapidly decline and are overtaken by an overwhelming immune response that causes the body to turn on itself.

This “cytokine storm” was once an arcane phenomenon familiar mainly to rheumatologists who study when and how the immune system’s safeguards fail.

But it has become increasingly clear in the past few months that, at least in a subset of people who have the virus, calming the storm is the key to survival.

At least a dozen candidate drugs to treat the coronavirus rely on this premise. A few devices that purify the blood, as dialysis machines do, are also being tested. One promising drug made by Roche is in several clinical trials, including a late-stage trial in combination with the antiviral drug remdesivir. And a recent paper in the journal Science Immunology described preliminary data on a drug that stems the flood of cytokines at its source, and seems to lead to rapid recovery.

When immune cells first encounter a pathogen, they release molecules called cytokines to recruit even more cells to the fight. Once the danger recedes, the immune system usually turns itself off. But occasionally “it doesn’t shut up,” said Dr. Jose Scher, a rheumatologist at New York University Langone Health. “The immune system goes on and on and on and on.”

This unrelenting response can exhaust the immune system; shut down lungs, kidneys and liver; and prove fatal. It can do so even in young people and children who have no underlying conditions. In a milder form, this same mechanism is at play in autoimmune diseases like lupus and rheumatoid arthritis. Most of the drugs that doctors have tried for the coronavirus, including steroids and hydroxychloroquine, are treatments for those diseases, disrupting their supplies.

“Our medicines have been co-opted from us,” said Dr. Scher, adding that they are often being deployed with little insight into their proper use or pitfalls.

Early in the pandemic, doctors in China and Italy recognized the telltale signs of a body in cytokine shock — fever, a racing heart and plummeting blood pressure — and treated patients with the drug tocilizumab. That drug is marketed by Roche as Actemra, which blocks a cytokine called interleukin-6.

Anecdotal evidence and preliminary trials soon confirmed their hunch. Since then, several studies have shown that high levels of IL-6 portend respiratory failure and death, and that Actemra lowers these risks.

Other drugs that quell IL-6 activity have shown promising results, as has Kineret, a drug that quiets a different cytokine called IL-1.

A more efficient solution than blocking any single cytokine would be to break the cycle of inflammation at its origin, experts said. For example, blood pressure drugs that mute the chemical signals that precede cytokines have shown some benefit in mouse studies and are being tested in people.

In the paper published in Science Immunology, scientists identified that the cancer drug Calquence, made by AstraZeneca and also called acalabrutinib, can cut off the cytokine supply at its source.

Treating patients with drugs like tocilizumab is “like cutting the branches off a tree,” said Dr. Louis Staudt, a scientist at the National Cancer Institute who was one of the lead investigators of the study. “Acalabrutinib is going for the trunk of the tree.”

The study was small and did not have a control group, but the results were promising: After about two weeks of treatment, eight of 11 people who had needed supplemental oxygen and two of eight people who were on ventilators could breathe on their own and went home. Another two on ventilators were able to come off the machines, and two others died.

The two patients who died had been sick for a long period, the researchers said, but overall the drug appears to be safe. The patients who did respond also showed a rapid decrease in levels of IL-6, as well as another measure of inflammation.

The team identified macrophages — scavenger cells that chew up bacteria and viruses — as the key source of the cytokine surge in Covid-19, the disease caused by the coronavirus.

“These patients get in trouble because their house is on fire in their lungs,” Dr. Staudt said. “This drug can put out this inflammatory fire by disabling macrophages.”

The involvement of macrophages might also explain why some people suddenly deteriorate weeks into infection. Large number of the cells would become involved only after the virus had substantially damaged the lungs. “There’s a time delay there,” he said.

People who have diabetes, obesity and hypertension have a higher baseline of inflammation, so it’s also possible, he said, that this may explain why they are particularly vulnerable to becoming seriously ill. AstraZeneca plans to test Calquence in larger trials.

The insights gained from studying Covid-19, especially because of the large numbers of people affected, might allow researchers to understand inflammatory syndromes that have long remained mysterious, Dr. Staudt said.

The pandemic has also popularized an approach that is commonplace for treating some diseases, but has not been proved in clinical trials to work for coronavirus patients.

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Credit…Dominik Gutzler

For example, the Food and Drug Administration has authorized the use of a cartridge that continually filters excess cytokines from the blood, similar to the way a dialysis machine removes toxins. The purified blood is then pumped back into the body.

The device, called CytoSorb, is about the size of a drinking glass and is filled with coarse polymers, each roughly the size of a grain of salt. Every grain, or bead, has millions of pores and channels that add up to a surface area of roughly seven football fields and filter out molecules roughly the size of cytokines. One cartridge can purify an entire body’s blood volume roughly 70 times in a 24-hour period.

Bigger objects like cells go around the beads and are unaffected, and smaller things like electrolytes go straight through, said Dr. Phillip Chan, the chief executive of CytoSorbents Corporation, which makes the device. CytoSorb may also remove some proteins that the body needs.

But “in a life-threatening illness when you have a cytokine storm,” Dr. Chan said, “it’s more or less a race to remove what will kill you versus the temporary inconvenience of removing things that your body manufactures all the time anyway.”

  • Frequently Asked Questions and Advice

    Updated June 5, 2020

    • Does asymptomatic transmission of Covid-19 happen?

      So far, the evidence seems to show it does. A widely cited paper published in April suggests that people are most infectious about two days before the onset of coronavirus symptoms and estimated that 44 percent of new infections were a result of transmission from people who were not yet showing symptoms. Recently, a top expert at the World Health Organization stated that transmission of the coronavirus by people who did not have symptoms was “very rare,” but she later walked back that statement.

    • How does blood type influence coronavirus?

      A study by European scientists is the first to document a strong statistical link between genetic variations and Covid-19, the illness caused by the coronavirus. Having Type A blood was linked to a 50 percent increase in the likelihood that a patient would need to get oxygen or to go on a ventilator, according to the new study.

    • How many people have lost their jobs due to coronavirus in the U.S.?

      The unemployment rate fell to 13.3 percent in May, the Labor Department said on June 5, an unexpected improvement in the nation’s job market as hiring rebounded faster than economists expected. Economists had forecast the unemployment rate to increase to as much as 20 percent, after it hit 14.7 percent in April, which was the highest since the government began keeping official statistics after World War II. But the unemployment rate dipped instead, with employers adding 2.5 million jobs, after more than 20 million jobs were lost in April.

    • Will protests set off a second viral wave of coronavirus?

      Mass protests against police brutality that have brought thousands of people onto the streets in cities across America are raising the specter of new coronavirus outbreaks, prompting political leaders, physicians and public health experts to warn that the crowds could cause a surge in cases. While many political leaders affirmed the right of protesters to express themselves, they urged the demonstrators to wear face masks and maintain social distancing, both to protect themselves and to prevent further community spread of the virus. Some infectious disease experts were reassured by the fact that the protests were held outdoors, saying the open air settings could mitigate the risk of transmission.

    • How do we start exercising again without hurting ourselves after months of lockdown?

      Exercise researchers and physicians have some blunt advice for those of us aiming to return to regular exercise now: Start slowly and then rev up your workouts, also slowly. American adults tended to be about 12 percent less active after the stay-at-home mandates began in March than they were in January. But there are steps you can take to ease your way back into regular exercise safely. First, “start at no more than 50 percent of the exercise you were doing before Covid,” says Dr. Monica Rho, the chief of musculoskeletal medicine at the Shirley Ryan AbilityLab in Chicago. Thread in some preparatory squats, too, she advises. “When you haven’t been exercising, you lose muscle mass.” Expect some muscle twinges after these preliminary, post-lockdown sessions, especially a day or two later. But sudden or increasing pain during exercise is a clarion call to stop and return home.

    • My state is reopening. Is it safe to go out?

      States are reopening bit by bit. This means that more public spaces are available for use and more and more businesses are being allowed to open again. The federal government is largely leaving the decision up to states, and some state leaders are leaving the decision up to local authorities. Even if you aren’t being told to stay at home, it’s still a good idea to limit trips outside and your interaction with other people.

    • What’s the risk of catching coronavirus from a surface?

      Touching contaminated objects and then infecting ourselves with the germs is not typically how the virus spreads. But it can happen. A number of studies of flu, rhinovirus, coronavirus and other microbes have shown that respiratory illnesses, including the new coronavirus, can spread by touching contaminated surfaces, particularly in places like day care centers, offices and hospitals. But a long chain of events has to happen for the disease to spread that way. The best way to protect yourself from coronavirus — whether it’s surface transmission or close human contact — is still social distancing, washing your hands, not touching your face and wearing masks.

    • What are the symptoms of coronavirus?

      Common symptoms include fever, a dry cough, fatigue and difficulty breathing or shortness of breath. Some of these symptoms overlap with those of the flu, making detection difficult, but runny noses and stuffy sinuses are less common. The C.D.C. has also added chills, muscle pain, sore throat, headache and a new loss of the sense of taste or smell as symptoms to look out for. Most people fall ill five to seven days after exposure, but symptoms may appear in as few as two days or as many as 14 days.

    • How can I protect myself while flying?

      If air travel is unavoidable, there are some steps you can take to protect yourself. Most important: Wash your hands often, and stop touching your face. If possible, choose a window seat. A study from Emory University found that during flu season, the safest place to sit on a plane is by a window, as people sitting in window seats had less contact with potentially sick people. Disinfect hard surfaces. When you get to your seat and your hands are clean, use disinfecting wipes to clean the hard surfaces at your seat like the head and arm rest, the seatbelt buckle, the remote, screen, seat back pocket and the tray table. If the seat is hard and nonporous or leather or pleather, you can wipe that down, too. (Using wipes on upholstered seats could lead to a wet seat and spreading of germs rather than killing them.)

    • Should I wear a mask?

      The C.D.C. has recommended that all Americans wear cloth masks if they go out in public. This is a shift in federal guidance reflecting new concerns that the coronavirus is being spread by infected people who have no symptoms. Until now, the C.D.C., like the W.H.O., has advised that ordinary people don’t need to wear masks unless they are sick and coughing. Part of the reason was to preserve medical-grade masks for health care workers who desperately need them at a time when they are in continuously short supply. Masks don’t replace hand washing and social distancing.

    • What should I do if I feel sick?

      If you’ve been exposed to the coronavirus or think you have, and have a fever or symptoms like a cough or difficulty breathing, call a doctor. They should give you advice on whether you should be tested, how to get tested, and how to seek medical treatment without potentially infecting or exposing others.


In Europe, where CytoSorb has been commercially available since 2013, it has been used more liberally. But in the United States, the device had been allowed only for patients who had exhausted all other options. Even now, during the pandemic, its use is authorized only in coronavirus patients who are critically ill, with imminent or confirmed respiratory failure.

Dr. Stephan Ziegeler, who leads a specialized pulmonary intensive care unit at a hospital in Ibbenbüren, Germany, has so far treated eight people with CytoSorb. (Since 2018, he has received speaking fees from CytoSorb’s manufacturer, totaling 5,000 euros, or about $5,600.) Of these people, three have been discharged, three are being weaned off ventilation and two have died.

Patients with bacterial sepsis typically need a maximum of three cartridges — one per day at $1,200 — but coronavirus patients have such astronomical levels of cytokines, Dr. Ziegeler said, that some have needed dozens of cycles, with two fresh cartridges per day.

“It seems that Covid-19 has a prolonged cytokine storm — a prolonged, really effective inflammatory state compared to other sepsis states,” he said.

Some patients who are severely ill have only moderately high levels of cytokines, however, and Dr. Ziegeler said it was not yet clear whether they would benefit.

He recalled the case of one 45-year-old physician who had been hooked up for three weeks to an extracorporeal membrane oxygenation machine, or ECMO, which removes blood from the body, infuses it with oxygen and then returns it to the body. Coronavirus patients who get to that point tend to stay sick for a long time, Dr. Ziegeler said, and since they are already having their blood pumped out to be oxygenated, adding on the CytoSorb filter does not add risk.

So, even though this patient did not have levels that were “sky-high,” doctors treated him with 14 rounds of cytokine adsorption. The man responded well, Dr. Ziegler said, and was discharged soon after.

CytoSorb is not the only mechanical approach being used; the F.D.A. has also authorized the use of another device, called Oxiris, for coronavirus patients. And there are plans to try CytoSorb in combination with tocilizumab.

All of these approaches are worth pursuing, Dr. Scher said, but they all must be tested in rigorous clinical trials with the right control groups: “That will be the only way to learn for sure.”