If COVID-19 is a fire, the damaging cycle of inflammation known as a ‘cytokine storm’ is the tsunami that fans the blaze while flattening the rest of the village.
The flood of inflammatory molecules released by an infected person’s immune system to combat COVID-19 can result in a condition called acute respiratory distress syndrome, or ARDS, which causes severe lung damage and prevents oxygen from reaching the rest of the body. Oxygen deprivation can damage vital organs, including the kidneys, brain and circulation and ultimately can lead to shock and death from multi-organ failure.
Clinical trials aimed at disrupting the progression to ARDS in COVID-19 patients are rapidly emerging across the country. These trials are using new drugs or repurposing existing drugs used to treat other conditions, such as the national trial of a rheumatoid arthritis therapy that recently began enrolling patients at CU Anschutz, Denver Health and other sites across the United States.
During recent grand rounds for the Department of Medicine, faculty members from the School of Medicine weighed in on ways to combat the inflammation storm in COVID-19. Grand rounds featured Ivor S. Douglas, MD, professor of Medicine in the Division of Pulmonary Sciences and Critical Care Medicine and division chief at Denver Health Medical Center; Mercedes Rincon, PhD, professor in the Department of Immunology and Microbiology; and Charles Dinarello, MD, distinguished professor of medicine in the Division of Infectious Diseases.
IL-6: harbinger of severe disease?
Rincon identified one key player in the cytokine storm: an inflammatory molecule known as interleukin-6, or IL-6. This cytokine is produced by lung epithelial cells infected with coronavirus. The more cells are infected, the more IL-6 is produced. Several early studies suggest that IL-6 may play a role in severe COVID-19 disease.
“In hospitals, patients with severe COVID-19 have higher levels of IL-6 in their blood compared to patients who don’t have severe disease, and patients who needed ventilators had higher levels of IL-6 than patients who didn’t need ventilators,” Rincon said. She noted that patients with high IL-6 levels were 22 more times more likely to experience respiratory failure. “IL-6 is definitely present in severe disease, but at this point we don’t know if it’s a cause or a consequence.”
The cytokine storm involves many different molecules. So where does IL-6 fit in?
It’s complicated, but Dinarello said that when cells in the lungs become infected with the novel coronavirus and die, they trigger the bone marrow to produce new immune cells. These cells travel to the lungs to respond to the infection but end up triggering a damaging loop where inflammatory molecules like IL-6 amplify the production of more inflammatory molecules.
The amount of IL-6 in someone’s body may factor into how they fare with COVID-19. Rincon said women tend to have lower levels of IL-6 than men; this may contribute to the nearly 2 to 1 rate at which men die of COVID-19 than women. Rincon said the elderly also tend to have higher levels of IL-6.
Early results from studies in China show promise with blocking the IL-6R using a drug approved for treatment of Rheumatoid Arthritis. In one study, patients treated with tocilizumab, a therapy that interferes with IL-6R, showed rapid improvement in fever and less need for extra oxygen. These results have been more recently confirmed in anecdotal cases in other countries including USA.
Despite these promising results, Rincon noted “while exciting, we have to take these early results with caution because these studies were performed with no other treatment regimen or placebo to compare. We need formal trials comparing IL-6R targeting drugs with other drugs or current standard of care.” The good news are that FDA has already approved a Roche’s Phase III clinical trial with tocilizumab for COVID-19. FDA is also evaluating trials with other IL-6R blockers for the treatment of COVID-19.
Genetic clues to predict COVID-19 severity
One key question relative to COVID-19 is the wide range of disease severity. “Two people in a couple get exposed at the same time and one develops much more serious disease. Why?” Rincon asked.
Patient genetics may hold some clues. Several variations have been documented in the genes responsible for making IL-6 and IL-6R proteins in humans. Rincon said about 20% of the population has a gene variant that results in less IL-6 being produced. She suggested that these patients may be at lower risk of developing ARDS in response to COVID-19. This gene variant is fairly rare in African Americans, less than 1% in some studies, which Rincon noted could play a role in the disproportionate deaths due to COVID-19 seen in these patients.
A smaller percentage of the population, only 10-15%, has a gene variant in IL-6R that results in more of the receptor being produced. Rincon said this variant could increase risk of developing severe complications such as ARDS in COVID-19.
Other therapeutic options on the horizon
Dinarello said targeting IL-6 is just one way to target the cytokine storm. If IL-6 is the muscle of the inflammatory response, Dinarello pointed to a protein called NRLP3 as the mastermind. “NRLP3 drives the cytokine storm,” he said. A gout drug called dapansutrile does an effective job of hitting NRLP3. Dinarello said one of the best features of dapansutrile is how it is administered – patients with COVID-19 take a pill by mouth, at home, before they are admitted to the hospital.
“Personally, I believe the best way to prevent ARDS in COVID-19 is to treat patients very early to prevent the cytokine storm from occurring in the first place,” Dinarello said.
Previous treatment paradigm isn’t helpful
ARDS isn’t exclusively a problem produced by COVID-19; it can develop in response to other events like bacterial infections, near-drowning and inhalation of smoke or chemical fumes. As a clinician-scientist, Douglas has previous experience treating patients with ARDS. But he said patients with ARDS caused by COVID-19 usually have clinical features that look different from those seen in ARDS from other causes. ARDS caused by COVID-19 requires different medications, alters biological read-outs, and requires special considerations for patients on ventilators.
Noting that the existing treatment paradigm for ARDS for clinicians has been seriously challenged with COVID-19, Douglas said, “This highlights just how limited our existing treatment approaches are in this disease.”
Guest contributor: Shawna Matthews is a freelancer specializing in science and healthcare.