Cytokine storms play a limited role in moderate-to-severe COVID-19

Rather than life-threatening hyperinflammation, most adults with moderate-to-severe COVID-19 have a suppressed viral immune response when compared to adults with another viral respiratory infection, influenza. St. Jude Children's Research Hospital and Washington University School of Medicine in St. Louis led research that suggests most COVID-19 patients are not candidates for treatment with steroids such as dexamethasone. The research appears in Science Advances.

Fewer than 5% of the COVID-19 patients in this study, including some of the sickest individuals, had the life-threatening, hyperinflammatory immune response known as cytokine storm syndrome. Cytokines are small proteins secreted by blood cells that help coordinate the immune response and trigger inflammation. Cytokine storms develop when excess or abnormally regulated cytokine production leads to hyperinflammation and tissue damage. While dexamethasone and other steroids are prescribed to treat cytokine storms, the drugs can backfire in patients whose immune response is already suppressed.

Cytokine storms have been proposed as the cause of respiratory failure in COVID-19 patients.

"We did identify a subset of COVID-19 patients with the broadly upregulated array of cytokines, which is a hallmark of cytokine storm," said co-corresponding author Paul Thomas, Ph.D., of the St. Jude Department of Immunology. "But, overall, the average person with COVID-19--even patients with moderate-to-severe disease--had less inflammation than the average person with flu.

"The findings suggest that treatment suppressing inflammation might only be effective in that minority of patients with the hyperinflammatory profile," Thomas said. He, Ali Ellebedy, Ph.D., and Philip Mudd, M.D., Ph.D., of Washington University School of Medicine, are corresponding authors of the study.

What's needed, researchers said, is a fast, reliable and inexpensive test to measure cytokines and identify patients who are most likely to benefit from immunosuppressive treatment.

"Current clinical studies do not adequately target these therapies to the patients who many benefit the most," said Mudd, a scientist and emergency medicine physician who treats patients with COVID-19 at Barnes-Jewish Hospital in St. Louis. "Directing immunosuppressive therapies to the small subset of COVID-19 patients who have an overactive immune response is the only way to know if these approaches are ultimately helpful."

Immune responses: COVID-19 vs flu

What's also needed is a better understanding of the immune response to COVID-19, including the cause of respiratory failure that has been reported in as many as 8% of patients.

Researchers sought to do that in this report, which stems from one of the largest and most comprehensive comparisons yet of the human immune response to flu and SARS-CoV-2, the virus that causes COVID-19. Unlike COVID-19, the immune response to flu has been studied for decades and is better understood.

The research included 168 adults with COVID-19, 26 adults with flu and 16 healthy volunteers. More than 90% of the COVID-19 patients were hospitalized, about half in the intensive care unit. Twenty-three percent of those hospitalized died. More than half of flu patients were hospitalized, 35% in the ICU, and 8% of those hospitalized died.

To understand the immune response, researchers measured a variety of immune cells and factors, including 35 different cytokines. Seven COVID-19 patients, or 4%, met the study definition of cytokine storm, meaning that about half or more of the 35 cytokines were significantly elevated compared to patient averages. Statistically, the elevation was defined as at least two standard deviations above the mean.

Patients with cytokine storm syndrome had individual cytokine levels as much as 10- to 100-times higher than the average. But when researchers included age and other factors, COVID-19 patients had lower overall cytokine levels than flu patients.

If not cytokine storm, what?

"The lack of hyperinflammation in most COVID-19 patients does not mean they had less disease," said co-first author Jeremy Chase Crawford, Ph.D., of St. Jude Immunology. "We are saying that in most cases the disease was not caused by broad hyperinflammation from cytokine storm, which has important implications for developing generalizable COVID-19 therapeutics."

The analysis revealed that the antiviral immune response was profoundly suppressed in COVID-19 patients compared to flu patients. Along with measuring cytokines, researchers analyzed cytokine transcription in individual blood cells in patients with flu, COVID-19 and healthy volunteers. COVID-19 was associated with significantly reduced production of and response to Type I and Type II interferons, cytokines that play a central role in the antiviral immune response.

Researchers also found evidence that SARS-CoV-2 alters pathways controlling the immune response to promote steroid production by patients. "Our results suggest that most COVID-19 patients are perhaps already producing high levels of glucocorticoids prior to treatment, possibly leading to the blunted immunity we see in most of them," Thomas said. "These patients may need therapy to turn up their immune response to knock the virus down."

Philip A Mudd, Jeremy Chase Crawford, Jackson S Turner, Aisha Souquette, Daniel Reynolds, Diane Bender, James P Bosanquet, Nitin J Anand, David A Striker, R Scott Martin, Adrianus CM Boon, Stacey L House, Kenneth E Remy, Richard S Hotchkiss, Rachel M Presti, Jane A O'Halloran, William G Powderly, Paul G Thomas, Ali H Ellebedy.
Distinct inflammatory profiles distinguish COVID-19 from influenza with limited contributions from cytokine storm.
Science Advances, 2020. doi: 10.1126/sciadv.abe3024

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