The 42-year-old man arrived at a hospital in Paris on March 17 with a fever, cough and the “ground glass opacities” in both lungs that are a trademark of infection with the new coronavirus.
Two days later, his condition suddenly worsened, and his oxygen levels dropped. His body, doctors suspected, was in the grip of a cytokine storm, a dangerous overreaction of the immune system. The phenomenon has become all too common in the coronavirus pandemic, but it is also pointing to potentially helpful drug treatments.
When the body first encounters a virus or a bacterium, the immune system ramps up and begins to fight the invader. The foot soldiers in this fight are molecules called cytokines that set off a cascade of signals to cells to marshal a response. Usually, the stronger this immune response, the stronger the chance of vanquishing the infection, which is partly why children and younger people are less vulnerable overall to the coronavirus. And once the enemy is defeated, the immune system is hard-wired to shut itself off.
“For most people and most infections, that’s what happens,” said Dr. Randy Cron, an expert on cytokine storms at the University of Alabama at Birmingham.
But in some cases — as much as 15% of people battling any serious infection, according to Cron’s team — the immune system keeps raging long after the virus is no longer a threat. It continues to release cytokines that keep the body on an exhausting full alert. In their misguided bid to keep the body safe, these cytokines attack multiple organs, including the lungs and liver, and may eventually lead to death.
In these people, it’s their body’s response, rather than the virus, that ultimately causes harm.
Cytokine storms can overtake people of any age, but some scientists believe that they may explain why healthy young people died during the 1918 pandemic and more recently during the severe acute respiratory syndrome, Middle East respiratory syndrome and H1N1 epidemics. They are also a complication of various autoimmune diseases like lupus and Still’s disease, a form of arthritis. And they may offer clues as to why otherwise healthy young people with coronavirus infections are succumbing to acute respiratory distress syndrome, a common consequence of a cytokine storm.
Reports from China and Italy have described young patients with clinical outcomes that seem consistent with this phenomenon. It’s very likely that some of these patients developed a cytokine storm, Cron said.
In the case of the 42-year-old patient, the suspected cytokine storm led his doctors to eventually try tocilizumab, a drug they have sometimes used to soothe an immune system in distress.
After just two doses of the drug, spaced eight hours apart, the patient’s fever rapidly disappeared, his oxygen levels rose, and a chest scan showed his lungs clearing. The case report, described in an upcoming paper in Annals of Oncology, joins dozens of accounts from Italy and China, all indicating that tocilizumab might be an effective antidote to the coronavirus in some people.
On March 5, China approved the drug to treat serious cases of COVID-19, the disease caused by the coronavirus, and authorized clinical trials. On March 23, the U.S. Food and Drug Administration granted approval to pharmaceutical company Roche to test the drug in hundreds of people with coronavirus infections.
Tocilizumab is approved to quiet the chatter of immune molecules in rheumatoid arthritis and in some types of cancer. It mutes the activity of a specific cytokine called interleukin-6 that is associated with an overexuberant immune response.
“That’s the rationale for using the drug,” said Dr. Laurence Albiges, who cared for the patient at the Gustave Roussy Cancer Center in Paris.
Even as researchers look for treatments, they are trying to learn more about why some people’s immune systems go into this dangerous overdrive. Genetic factors explain the risk, at least in some kinds of cytokine storms.
There are many variations on the phenomenon, and they go by many names: systemic inflammatory response syndrome, cytokine release syndrome, macrophage activation syndrome, hemophagocytic lymphohistiocytosis.
Broadly speaking, they are all marked by an unbridled surge in immune molecules and may all result in the fatal shutdown of multiple organs.
But many doctors are unfamiliar with this niche concept or how to treat it, experts said.
“Everyone’s talking about cytokine storm as if it were a well-recognized phenomenon, but you could have asked medics two weeks ago, and they wouldn’t have heard of it,” said Dr. Jessica Manson, an immunologist at University College London Hospital.
A patient battling a cytokine storm may have an abnormally fast heart rate, fever and a drop in blood pressure. Apart from a surge in interleukin-6, the body may also show high swirling levels of molecules called interleukin-1, interferon-gamma, C-reactive protein and tumor necrosis factor-alpha.
This storm, if it develops, becomes obvious a few days into the infection. But the sooner doctors catch it and treat it, the more likely the patient is to survive. Too late, and the storm may be beyond control or may already have caused too much damage.
There is a relatively simple, rapid and easily available test that can detect whether a patient’s body has been taken over by a cytokine storm. It looks for high levels of a protein called ferritin.
But if the test does suggest a cytokine storm is underway, what then?
The seemingly obvious solution is to quell the storm, Cron said: “If it’s the body’s response to the infection that’s killing you, you need to treat that.”
The reality is trickier, especially given the lack of reliable data for COVID-19. But noting that drugs like tocilizumab are taken regularly by people with arthritis, Cron said the benefit would probably outweigh potential harm if someone is facing death.
“We need evidence-based data, but in a pandemic, where we’re flying by the seat of our pants, we always have to treat the patient in front of us,” he said.
Other drugs might also be useful against cytokine storms. For example, a drug called anakinra mutes interleukin-1, another of the wayward proteins. Clinical trials of anakinra for COVID-19 are also underway. A report published this week suggested that hydroxychloroquine, a much-spotlighted malaria drug that also calms an overactive immune response, might also be effective as a treatment for those who are mildly ill from the coronavirus.
Doctors could also turn to corticosteroids, which broadly turn down the entire immune response. That poses its own danger by exposing the patient to other opportunistic infections, especially in a hospital. “It’s about getting the balance right between suppression of the overexuberant immune response and still allowing the immune response to fight the virus,” Manson said.
A group of experts convened two weeks ago to discuss the best ways to collect more data and treat patients who appear to have cytokine storm. It’s already clear that the complexities of the immune system and the course of the coronavirus means there is no single best treatment.
At the Gustave Roussy Cancer Center, doctors treated another coronavirus patient with tocilizumab. That individual did not show any improvement with the drug.
“The response to the pathogen, the virus, is totally different in different individuals,” said Dr. Fabrice André, an oncologist at the center. “The trials will determine in which patients it works.”