Q&A: Rheumatologist Dr. Randy Cron on COVID-19 and the cytokine storm

In this Q&A, Randy Q. Cron, M.D., Ph.D., a pediatric rheumatologist at the University of Alabama (UAB) at Birmingham, discusses the role of rheumatologists in the diagnosis and treatment of patients with COVID-19, particularly those who are critically ill and experiencing a cytokine storm syndrome.

Dr. Cron and W. Winn Chatham M.D., associate director of clinical immunology and rheumatology at UAB, recently published an article in The Journal of Rheumatology  that addresses the role of rheumatologists during the COVID-19 pandemic highlighting their expertise in managing cytokine storm syndrome.

They write:  “Until results from clinical trials of biologic anti-cytokine agents used to treat COVID-19 CSS are available, physicians will need to rely on a unified approach to treating these desperately ill individuals. As this coronavirus pandemic broadens, rheumatologists are well-positioned to assist in managing cytokine storm syndrome associated with this illness. Rheumatologists have a strong background in understanding the immune system, are familiar with cytokine storm syndrome such as MAS as many of their patients (e.g., adult-onset Still’s disease, systemic juvenile idiopathic arthritis, systemic lupus erythematosus) develop it, and are most practiced with utilizing cytokine targeting therapy (e.g. IL-1 blockade, IL-6 blockade). Rheumatologists can assist and work together with their colleagues in other subspecialties to diagnose and to treat those COVID-19 patients who develop cytokine storm syndrome. This cooperative effort should help reduce mortality during these trying times.”

Q:  Can you provide a brief overview of COVID-19? 

COVID-19 is caused by the novel coronavirus, SARS-CoV-2, which is similar to prior epidemics, SARS and MERS, but unlikely most coronavirus that typically cause a "cold.” We have no immunity for this new virus, which is highly contagious. No one yet knows the true mortality rate, perhaps 1 percent to 2 percent, but it seems likely to be about 10-times more lethal than seasonal influenza, which itself kills 30,000 to 60,0000 Americans annually.

Q:  Who is at greatest risk of COVD-19?

The elderly (older than 60 and increasing with age) and those with chronic medical conditions, such as diabetes, hypertension, heart disease, chronic lung disease and autoimmune conditions.

Q:  What is the rheumatologist’s role in COVID-19? 

The rheumatologist can serve as an expert consultant in helping to identify cytokine storm syndrome among hospitalized COVID-19 patients, as well as provide advice on how to treat cytokine storm syndrome.

Q:  In critically ill COVID-19 patients, is a cytokine storm syndrome common? 

About 80 percent of individuals infected are asymptomatic up to having a bad flu. For the 20 percent requiring hospitalization, perhaps 10 to 15 percent overall may be experiencing a cytokine storm. No one knows for sure at this point.

See "identify cytokine storm syndrome" on next page.

Q:  Why is it necessary to identify cytokine storm syndrome?

While treating the virus is important (unclear if we even have good therapy for the virus as of yet), if cytokine storm syndrome is present, it is equally―if not more important―to treat the host immune response to the virus because that is likely what may ultimately kill the patient.

Q:  What are the signs, symptoms and lab results that may indicate a cytokine storm syndrome? 

Sustained high fever, confusion and other central nervous system findings, coagulopathy, hypotension, ARDS; and elevated serum ferritin, liver function tests (AST, ALT), LDH, D-dimers, C-reactive protein (CRP), pro-inflammatory cytokines (e.g., interleukin-6 or IL-6); and low or falling WBC, lymphocytes, platelets, fibrinogen, ESR.

Q:  Which tests should be carried out on these patients?

Ferritin, CBC, CMP, D-dimers, LDH. 

Q:  What is the importance of a serum ferritin value?

In the setting of cytokine storms, it typically runs very high (10,000 to 100,000 ng/mL, typically <200); for COVID-19, it is elevated but usually in the range of 1,000 to 6,000 ng/mL. It is very sensitive for detecting a cytokine storm syndrome in a febrile hospitalized patient, and becomes more specific for cytokine storm syndrome, the higher the value.

Q:  What treatments are available for patients with COVID-19? 

There are standard of care as for anyone with respiratory distress and/or requiring intensive care support. There is therapy directed against the virus (new or repurposed anti-viral meds, hydroxychloroquine), but it is unclear which if any of these will be of significant benefit.

If the patient develops a cytokine storm syndrome, then there are a variety of therapies of potential value. There are broad spectrum immunosuppressants likely corticosteroids, which are not recommended by the World Health Organization based on prior experience with SARS, MERS, and bad strains of influenza. However, in the right patient population those with features of cytokine storm syndrome, and when given at the right time (e.g., prior to intubation/ICU care), they may have a beneficial role. Drugs like cyclosporine broadly target lymphocytes and are used in other cytokine storm syndrome but may not be appropriate for COVID-19 cytokine storm syndrome (no one knows).

There are also targeted cytokine approaches that specifically lower various pro-inflammatory cytokines, like IL-1 and IL-6.

Q: What treatment approach should be taken for patients with COVID-19 induced CSS?

No one knows at this point, but whatever drug(s) is chosen, if the patient is not enrolled in a clinical trial, the sooner the treatment the more likelihood of a successful outcome.

Q:  What cytokine targeted approaches are being considered?

There are clinical trials targeting IL-1, IL-6, interferon-gamma, and considering GM-CSF.

Q:  Do you have anything else to add? 

Only to reiterate that we must not only treat the virus but also treat the host immune response to the virus if a cytokine storm syndrome is present.

REFERENCE

Randy Q. Cron, W. Winn Chatham. “The Rheumatologist's Role in Covid-19.” The Journal of Rheumatology. March,24 2020. DOI: 10.3899/jrheum.200334