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The immune system overactivation known as a “cytokine storm” does not play a major role in more severe COVID-19 outcomes, according to unexpected findings in new research. The findings stand in direct contrast to many previous reports.
“We were indeed surprised by the results of our study,” senior study author Peter Pickkers, MD, PhD, told Medscape Medical News.
In a unique approach, Pickkers and colleagues compared cytokine levels in critically ill people with COVID-19 to those in patients with bacterial sepsis, trauma, and after cardiac arrest.
“For the first time, we measured the cytokines in different diseases using the same methods. Our results convincingly show that the circulating cytokine concentrations are not higher, but lower, compared to other diseases,” said Pickkers, who is affiliated with the Department of Intensive Care Medicine at Radboud University Medical Center in Nijmegen, the Netherlands.
The team’s research was published online on September 3 in a letter in JAMA.
Cytokines Lower Than Expected
Normally, cytokines trigger inflammation and promote healing after trauma, infection, or other conditions.
Although a cytokine storm remains ill defined, the authors note, many researchers have implicated a hyperinflammatory response involving these small proteins in the pathophysiology of COVID-19.
The question remains, however, whether all cytokine storms strike people with different conditions the same way.
Pickkers, lead author Matthijs Kox, PhD, and colleagues studied 46 people with COVID-19 and acute respiratory distress syndrome (ARDS) who were admitted to the ICU at Radboud University Medical Center. All participants underwent mechanical ventilation and were treated between March 11 and April 27, 2020.
The investigators measured plasma levels of cytokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-8 (IL-8). They compared results in this group to those in 51 patients who experienced septic shock and ARDS, 15 patients with septic shock without ARDS, 30 people with out-of-hospital cardiac arrest, and 62 people who experienced multiple traumas. They used historical data for the non-COVID-19 cohorts.
Compared to patients with septic shock and ARDS, the COVID-19 cohort had lower levels of TNF, IL-6, and IL-8. The differences were statistically significant for TNF (P < .01), as well as for IL-6 and IL-8 concentrations (for both, P < .001).
In addition, the COVID-19 group had significantly lower IL-6 and IL-8 concentrations compared with the patients who had septic shock without ARDS.
The researchers likewise found lower concentrations of IL-8 in patients with COVID-19 compared to the out-of-hospital cardiac arrest patients. IL-8 levels did not differ between the COVID-19 and trauma groups.
Furthermore, the researchers found no differences in IL-6 concentrations between patients with COVID-19 and those who experienced out-of-hospital cardiac arrest or trauma.
However, levels of TNF in people with COVID-19 were higher than in trauma patients.
The small sample sizes and single-center study design are limitations.
“The findings of this preliminary analysis suggest COVID-19 may not be characterized by cytokine storm,” the researchers note. However, they add, “Whether anticytokine therapies will benefit patients with COVID-19 remains to be determined.”
Going forward, Pickkers and colleagues are investigating the effectiveness of different treatments to lower cytokine levels. They are treating people with COVID-19, for example, with the IL-1 cytokine inhibitor anakinra and steroids.
They also plan to assess the long-term effects of COVID-19 on the immune system. “Following an infection, it is known that the immune system may be suppressed for a longer period of time, and we are determining to what extent this is also present in COVID-19 patients,” Pickkers said.
Enough to Cause a Storm?
The study “is quite interesting, and data in this paper are consistent with our data,” Tadamitsu Kishimoto, MD, PhD, of the Department of Immune Regulation at the Immunology Frontier Research Center at Osaka University, Osaka, Japan, told Medscape Medical News when asked to comment.
His study, published online August 21 in PNAS, also revealed lower serum IL-6 levels among people with COVID-19 compared to patients with bacterial ARDS or sepsis.
Kishimoto drew a distinction, however: COVID-19 patients can develop severe respiratory failure, suggesting a distinct immune reaction compared to patients with bacterial sepsis. SARS-CoV-2 directly infects and activates endothelial cells rather than macrophages, as occurs in sepsis.
For this reason, Kishimoto said, “SARS-CoV-2 infection causes critical illness and severe dysfunction in respiratory organs and induces a cytokine storm,” even in the setting of lower but still elevated serum IL-6 levels.
Pickkers and Kishimoto report no relevant financial relationships.
JAMA. Published online September 3, 2020. Abstract
Damian McNamara is a Medscape Medical News journalist based in Miami. He covers a wide range of medical specialties, translating research and breaking medical news into easy-to-understand, engaging stories for busy medical professionals. He reports news from major medical conference in the US and abroad. He can be reached on Twitter: @MedReporter.