A team of researchers at the Osaka University and Osaka Habikino Medical Center in Japan conducted the recent study. They have now published their findings in the journal Proceedings of the National Academy of Sciences.
The global race to develop a vaccine for SARS-CoV-2 continues. In the meantime, researchers are looking for ways to effectively treat COVID-19, testing both existing drugs and new, experimental therapies.
Because scientists do not fully understand the mechanisms behind severe COVID-19, many doctors are treating it by following the sepsis treatment guidelines.
In this recent study, the scientists focused on cytokines. These are a group of small proteins that modulate the immune response to trauma, infection, and conditions such as cancer.
Among other things, cytokines activate inflammation, which is part of the healing process.
Sometimes, the body releases an excess of cytokines. This causes excess inflammation, which can damage tissues. This response is called a cytokine storm.
Cytokine storms, or CRS, occur in a number of conditions, including multiple sclerosis, pancreatitis, and COVID-19.
Without treatment, CRS can cause multiple organ failure and, sometimes, death.
The body releases various cytokines during CRS, including interleukin (IL)-2, IL-6, IL-8, IL-10, interferon-gamma, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-alpha. However, there are no specific immunotherapies for its treatment.
“Despite knowing which cytokines are involved, there is still no specific immunotherapy for CRS, and treatment is limited to supportive care,” says study lead author Sujin Kang.
“To better understand the molecular mechanisms of CRS pathogenesis,” she adds, “we first studied the cytokine profiles of 91 patients diagnosed with CRS associated with bacterial sepsis, acute respiratory distress syndrome, or burns.”
The researchers found that all three groups of people had similar cytokine profiles.
Specifically, the researchers measured high levels of IL-6, IL-8, IL-10, and MCP-1, as well as a protein called plasminogen activator inhibitor-1 (PAI-1). This protein can cause small blood clots in vessels in the lungs and other organs.
Previous studies have shown that increased PAI-1 levels are linked to more severe cases of pneumonia, which is a leading cause of death among people with COVID-19.
“Examination of cytokine profiles in severe COVID-19 patients revealed an increase in IL-6 early in the disease process, causing release of PAI-1 from blood vessels,” says senior study author Tadamitsu Kishimoto, a professor at the Osaka University Immunology Frontier Research Center.
“Interestingly, PAI-1 levels were significantly higher in COVID-19 patients with severe respiratory impediment.”
Higher levels of IL-6 were associated with higher levels of the other cytokines and PAI-1. Therefore, the researchers believe that IL-6 signaling might be an important driver of CRS.
To investigate the role of IL-6 in CRS, the researchers gave the participants injections of a human monoclonal antibody-based drug called tocilizumab (Actemra), which blocks IL-6 signaling. The Food and Drug Administration (FDA) have approved tocilizumab as a treatment for rheumatoid arthritis.
The results showed that when people with severe COVID-19 received tocilizumab, the levels of PAI-1 decreased in the blood. Also, the drug alleviated symptoms and improved critical illness in those with severe COVID-19.
Overall, the researchers conclude that IL-6 signaling blockade with the anti-inflammatory medication tocilizumab may reveal new therapeutic opportunities for the treatment of both CRS and the severe respiratory complications of COVID-19.
