Creating a Roadmap to Negotiating Cytokine Storm in COVID-19

Cytokine storm syndromes are associated with autoimmune diseases such as systemic juvenile idiopathic arthritis (sJIA), adult onset Still’s disease and systemic lupus erythematosus. Speculation is mounting that they may also play a role in severe cases of COVID-19.

“We don’t know for sure yet if there’s cytokine storm in COVID-19, but it certainly looks that way in some patients,” said Peter A. Nigrovic, MD, director of the Brigham and Women’s Hospital Center for Adults with Pediatric Rheumatic Illness and the principal investigator of a basic science laboratory focused on mechanisms of inflammation. “Based on some of the findings in the blood of the sickest individuals, it may well be that the immune system mediates damage rather than serving to protect the host. We want to be able to recognize those cases where immunosuppression could optimize patient outcomes.”

The challenge, Dr. Nigrovic continued, is knowing when to intervene and what drugs to use. That knowledge will only come over time with the completion of randomized controlled trials. Until then, clinicians will have to act in the absence of solid evidence.

Dr. Nigrovic is senior author of a new paper that aims to help clinicians navigate this period of uncertainty. “On the alert for cytokine storm: Immunopathology in COVID‐19” was first published online in Arthritis & Rheumatology on April 15.

“One goal for this piece was to present the evidence for and against the presence of cytokine storm in COVID-19, he said. “Another was to provide a guide to tests useful to identify cytokine storm and to treatments that might help patients caught in a hyperinflammatory spiral,” potentially including by use of assays for cytokine storm defined in his own laboratory.

Not Ruling out Corticosteroids

Based on data from influenza and previous MERS and SARS infections, the Centers for Disease Control and Prevention and the World Health Organization oppose the current use of corticosteroids in COVID-19. Dr. Nigrovic and his co-authors believe this stance is premature.

“Our take on the literature is that the evidence against corticosteroids is heavily confounded by differences between patients who received and did not receive treatment, and may not translate directly to SARS-CoV-2 infection,” he said. “We don’t really know whether steroids have a role to play in controlling harmful inflammation symptoms in COVID patients. In fact, I think there’s accumulating clinical support for the idea that they may be very important in certain contexts.”

Dr. Nigrovic highlighted recent unpublished experience from colleagues caring for adult COVID patients in Italy and in Philadelphia, as well as from an emerging syndrome of COVID-associated cardiogenic shock in children.

The authors of the cytokine storm paper emphasized the likely importance of early intervention in the disease process, based on experience from hyperinflammation in hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS) and CAR-T cell therapy-associated cytokine release syndrome.

“In COVID-19 patients with evidence for cytokine storm,” they wrote, “treatment with glucocorticoids, [intravenous immunoglobulin], and/or anti-cytokine therapies should be considered with the aim of reverting hyperinflammation” before acute respiratory distress syndrome and other forms of tissue injury ensue.

Dr. Nigrovic expressed uncertainty about tocilizumab and sarilumab, two interleukin-6 (IL-6) inhibitors that are being widely employed in COVID-19. He noted that the evidence for their use in these cases is purely anecdotal at this point.

“The use of these agents represents an extrapolation from CAR-T therapy in cancer, a situation in which levels of IL-6 can be a hundred-fold higher than they are in COVID-19,” he said. “We don’t know if the same mechanisms are at play here. It’s important to be cautious because IL-6 blockade has an impact on infection risk, so COVID patients could potentially develop more secondary infections.”

He added that randomized controlled trials, including one underway at the Brigham, will help define the risks and benefits of IL-6 blockade in COVID-19.

Multidisciplinary Expertise Key to COVID-19 Care

As studies of cytokine inhibitors, glucocorticoids and other drugs continue, Dr. Nigrovic said the best defense against cytokine storm in COVID-19 is a multidisciplinary care team. Cytokine storm presents in a variety of ways. For example, rheumatologists see it as MAS in sJIA, immunodeficiency doctors see it as HLH, and infectious disease and ICU doctors see it during severe sepsis.

“The goal is to bring these people together so that the different perspectives can optimize care of these patients,” he said.

He added that the first author of the cytokine storm paper, Lauren Henderson, MD, MMSc, a pediatric rheumatologist at Boston Children’s Hospital, has exceled in executing and documenting multidisciplinary approaches to cytokine storm. Dr. Henderson, Pui Lee, MD, PhD (also of the Children’s Rheumatology Program), and Brigham rheumatologist A. Helena Jonsson, MD, PhD, have all worked closely with Dr. Nigrovic on the COVID-19 response. Dr. Jonsson has spearheaded a new rheumatology consult service for COVID patients at the Brigham.

“Rheumatologists aren’t typically first-line providers in the ICU,” Dr. Nigrovic concluded. “But we do have the most experience with drugs like corticosteroids, IL-6 blockade and IL-1 blockade, so we can advise our colleagues on these very challenging and sick patients.”