Among the many outstanding questions about COVID-19 is how the same virus, SARS-CoV-2, can kill some patients and leave others unaware they were ever exposed. Clinical evidence combined with hints from laboratory research indicate that for at least some patients with severe cases, the primary danger comes from a runaway immune response that irreparably injures tissue, researchers say. Understanding the mechanisms behind that response could be key to finding a treatment for those patients.

It appears that after infection, the virus replicates itself inside a patient, leading to a disease phase where the immune system mounts an inflammatory response against the invader, says Charles Dela Cruz, a pulmonologist at Yale School of Medicine who is researching COVID-19. Then, in those patients who progress to severe disease, “potentially this inflammatory response is too much and hyper-inflames, causing a lot of side effects in terms of tissue damage and organ failure and things like that,” he says. 

That picture is backed up by early clinical reports that find elevated levels of biomarkers associated with inflammation, such as C-reactive protein. Some studies suggest certain patients with severe disease experience what’s known as cytokine release syndrome, or a cytokine storm, meaning their immune cells ramp up the production of inflammation-driving cytokines to dangerously high levels. 

In a preprint posted in February, for example, researchers in Guangzhou, China, reported that eight of 11 COVID-19 patients with severe acute respiratory distress syndrome had hallmarks of cytokine release syndrome, including fever, an increase in the numbers of CD4/CD8 T cells, and elevated levels of the cytokine IL-6. Similarly, a study of 150 COVID-19 patients in Wuhan found that those who died had significantly higher IL-6 levels than did those who were later released from the hospital. The authors suggest “cytokine storm syndrome” as a possible cause of death from the disease.

“Cytokine storm syndrome is this kind of an umbrella term for a variety of [physiological phenomena] named by different types of physicians for different types of diseases,” explains Randy Cron, a rheumatologist at the University of Alabama at Birmingham whose research focuses on the phenomenon. For example, cytokine storms are known as macrophage activation syndrome when they occur as a result of inflammatory diseases, and cytokine release syndrome when they stem from CAR T cell therapy for leukemia. 

In general, the onslaught of cytokines causes blood vessels to leak, allowing immune cells to get into organs, potentially driving organ failure. Cytokine storms can also cause blood clotting. In influenza infections, cytokine storms are also tied to abberrant glucose metabolism, researchers reported recently based on experiments in mice. 

Cron suspects that the answer to why some patients with COVID-19 develop cytokine storms while others don’t may be partly genetic. His own past research has identified genes that cause familial hemophagocytic lymphohistiocytosis, a rare autoimmune disease involving cytokine storms, when a person inherits two mutated copies. In analyses of patients’ genes and work with cultured cells, he says, his group has found indications that just one mutated copy could cause macrophage activation syndrome if cells are exposed to a trigger such as an infection. He doesn’t know of any current effort to look for such mutations in COVID-19 patients, but expects they will happen eventually. Some studies looking broadly for genetic variants associated with COVID-19 severity are already underway. 

In the meantime, doctors and researchers are scrambling to find therapies to stop the cytokine onslaught. One possibility is tocilizumab, an antibody that binds to receptors for IL-6, inhibiting that cytokine’s action. A recent case report from France found that two doses of the drug were associated with a marked improvement in symptoms of one COVID-19 patient, and trials of tocilizumab for the disease are happening now in multiple countries. 

Another possibility is anakinra, a drug for rheumatoid arthritis and a condition known as neonatal-onset multisystem inflammatory disease that blocks receptors for the cytokine IL-1. Along with other drugs, anakinra is now being trialed as a COVID-19 treatment in separate studies in Greece, Belgium, and Italy. Baricitinib, a drug for rheumatoid arthritis that blocks enzymes that lead to cytokine release, is another drug for which multiple trials are planned.

Dousing the flames of fiery cell death

As clinicians try existing cytokine-blocking drugs against COVID-19, other researchers are looking for potential targets that would head off cytokine storms before they begin, says Dela Cruz. One candidate is a process known as pyroptosis (Greek for “fiery falling”), a form of cell death that often occurs as a result of infection and spurs cytokine production. 

Akiko Iwasaki, an immunologist at Yale who sometimes collaborates with Dela Cruz, says the heightened levels of lactate dehydrogenase (LDH) some studies have reported in the blood of COVID-19 patients points toward pyroptosis as core to the disease. LDH is an enzyme common in the body that converts lactate to pyruvate and is released from cells during pyroptosis, or from tissue damage in general. In addition, she says, pyroptosis would explain elevated levels of two cytokines, IL-1β and IL-6, that have been associated with severe cases. “I’m just thinking this kind of smoldering, fiery death that’s happening inside the person is initiating the downstream cascade...that leads to [a] cytokine storm,” she says.

Unlike apoptosis, in which cells typically die quietly without inciting an immune response, pyroptosis is distinguished by the activation of protein complexes known as inflammasomes by pathogens, says Kate Fitzgerald, an immunologist at the University of Massachusetts Medical Center who studies inflammasomes. That activation sets off a chain of events that includes processing of IL-1 and other cytokines for release from the cell, and the formation of pores in the cell membrane that let out “danger signals” such as the cytokines and LDH. Eventually, the cell ruptures and dies. “It’s thought that this pyroptotic cell death is particularly important for exposing intracellular niches of bacteria,” she says, allowing those bacteria to be destroyed. 

Based on the clinical evidence she’s seen, Fitzgerald says she thinks it may well be the case that pyroptosis gone awry could help explain severe COVID-19 cases, but it’s not yet proven. LDH, she notes, seems to be a nonspecific marker of tissue damage, so may not by itself point to pyroptosis. But inflammasome activation has been found during infections from other RNA viruses, such as influenza, and overall, “I think there’s a really good rationale to think that these pathways could be dysregulated in this disease,” she says.

Another piece of evidence that may point to pyroptosis in severe cases of COVID-19 comes from previous work on SARS-CoV-2’s close relative SARS-CoV, the coronavirus that caused the 2003 SARS outbreak. Two years ago, John Kehrl’s group at the National Institute of Allergy and Infectious Diseases reported that a genetic region called open reading frame 3a is critical for SARS-CoV’s ability to kill mice, and that the protein it codes for triggers the assembly of a type of inflammasome known as NLRP3, indicating that the protein may induce pyroptosis. 

Working in shifts, one person to a room, his team is now working to understand SARS-CoV-2’s arsenal, including whether the protein from its open reading frame 3a acts in the same way as SARS-CoV’s does. “We would be surprised if it’s not doing many of the same things [in SARS-CoV-2] that that open reading frame did in the SARS virus,” he says. “But we obviously want to test that.”

There is an existing drug, disulfiram, that’s thought to inhibit the pore formation that occurs during pyroptosis. Although its approved use is to curb alcohol abuse, it’s also shown up in screens for drugs that could inhibit a key SARS-CoV-2 protein, and it’s been proposed for use in COVID-19 clinical trials. In addition, Fitzgerald notes, several companies have been developing inhibitors of the inflammasome NLRP3 with the goal of halting aberrant pyroptosis in other conditions, and she expects such drugs will be tried for COVID-19. “When you have too much production of inflammatory mediators, that leads to tissue damage, damage to the lung in particular,” she says. “And maybe if you can reverse that with patients who were really in these more severe stages of disease, you could improve their outcomes.”