Author: Gina Shaw
Some of the most severe cases of COVID-19—and many of those seen in younger patients—appear to be linked to a severe immune system overreaction called “cytokine release syndrome” or “cytokine storm,” and clinicians are scrambling to find treatments that can slow its deadly occurrence.
A massive release of cytokine immune proteins produces dangerously high fevers, extreme fatigue, difficulty breathing and a sharp drop in blood pressure. This uncontrolled reaction can occur in a variety of conditions, including infections and autoimmune disorders. Oncology clinicians at institutions providing chimeric antigen receptor (CAR) T-cell immunotherapy for certain types of cancer are certainly familiar with cytokine storm as a common side effect of treatment.
Whether the cytokine storm found in COVID-19 patients is the same phenomenon as that seen in CAR T-cell therapy—and can be treated the same way—remains to be determined.
“Cytokine storm syndrome is a kind of umbrella term,” said Randy Cron, MD, PhD, a pediatric rheumatologist at the University of Alabama at Birmingham. “Underneath that umbrella are several different conditions, including a genetic/familial form called hemophagocytic lymphohistiocytosis), the macrophage activation syndrome that occurs in patients with conditions like lupus, the cytokine release that can be triggered by CAR T-cell therapy, and of course the virus-triggered cytokine storm. You could put COVID in that last category, but from what we’re learning on the fly, it seems to be somewhat different [from] even your typical viral-induced cytokine storm.”
Look Out for Organ Damage
One distinguishing characteristic of COVID-19-associated cytokine storm is severe damage to the lungs. “Although we do see the acute respiratory distress syndrome in other cytokine storms, this seems to be worse and more focused, maybe because the virus has a predilection for the cells in the bottom of the airway,” Dr. Cron said. “On the other hand, while it definitely makes the liver unhappy, liver reaction is less than we see in other cytokine releases. Serum ferritin is elevated in the thousands [ng/mL] range, which is significantly higher than normal, but not nearly as high as with CAR T-cell therapy, where we might see numbers in the tens or hundreds of thousands.”
Nonetheless, tracking serum ferritin in COVID-19 patients still offers a useful early marker, Dr. Cron said. “We had an adult patient with serum ferritin levels at about 1,200 to 1,500 when he came into the hospital. A couple of days later, when he entered the ICU, it was up to 1,800. It’s definitely something to keep an eye on.”
Kidney damage in COVID-19 patients is another concern. When researchers in Wuhan, China conducted autopsies on people who died of COVID-19, they found that nine of 26 had acute kidney injuries and seven had particles of the coronavirus in their kidneys, the researchers reported in Kidney International
An Extended Trajectory
A COVID-19-triggered cytokine storm follows a more extended trajectory than with CAR T-cell therapy. The latter typically manifests around three to four days after infusion. “With COVID patients, on the other hand, you have the original viral prodrome, with fever, body aches and chills. Then the viral illness seems to wane before—in some patients, a week or more after infection—the storm hits,” said Anthony Proli, PharmD, a clinical pharmacy specialist in bone marrow transplantation at Memorial Sloan Kettering Cancer Center in New York City. “We’ve had several patients who were looking OK to the point that we had thought about possibly discharging them, but decided to hold off. Then the second wave hit with the cytokine release [and the accompanying] oxygen requirements and returning fever.”
The fevers in COVID-19 and CAR T-related cytokine storm “are probably relatively similar, in that the patients will spike for hours without any relief from [acetaminophen] or other medications,” Dr. Proli added.
Tracking via Biomarkers
Memorial Sloan Kettering is tracking a variety of disease biomarkers in its patients, including the cytokine interleukin (IL)-6, ferritin, C-reactive protein and D-dimer levels. “One study of 80 patients in Germany showed that IL-6 levels greater than 80 [pg/mL] were associated with patients requiring increased oxygen support, intubation and development of ARDS [acute respiratory distress syndrome],” Dr. Proli said. “That might be a break point where people will look at treatment with IL-6-directed therapies.” (The German study was not peer-reviewed.)
Other agents being studied include the IL-6 receptor blocker tocilizumab (Actemra, Genentech), which the FDA approved for the treatment of severe cytokine release syndrome in patients receiving CAR T-cell therapy. A case report from China detailed some success in using the drug to slow COVID-19-associated cytokine storm (Blood Adv 2020: 14;4:1307-1310).
Other drugs being investigated in this setting include an IL-1 blocker, anakinra (Kineret, Amgen), approved by the FDA to treat rheumatoid arthritis and an infantile multisystem inflammatory disease, and emapalumab (Gamifant, Novimmune/Sobi), already approved for hemophagocytic lymphohistiocytosis, the genetic predisposition to cytokine storm. “There are other theoretical cytokine-targeting agents you could use, such as ruxolitinib [Jakafi, Incyte/Novartis], which inhibits downstream signaling of IL-6 and other cytokines,” Dr. Cron said.
The FDA has fast-tracked phase 3 clinical trials for all three agents in patients with COVID-19-associated cytokine storm. “There are lots of potential options; we’re desperately hoping one or more of these trials gives us the information we need,” Dr. Cron said. “But it’s very hard to say anything without data, and we don’t yet know which ones will be valuable. If any of them are, or if several are, will we have enough to go around? That’s the next question.”
Steroids a Mixed Bag
Steroids have been used effectively to manage CAR T-cell therapy–associated cytokine storm, especially those with neurologic toxicities, but the evidence for using them in COVID-19 patients is less encouraging.
“Methylprednisolone has been looked at in SARS [severe acute respiratory syndrome] and MERS [Middle East respiratory syndrome], and it did not show a benefit and perhaps even had a detrimental effect in those patients, possibly owing to an observed decreased rate of viral clearance,” Dr. Proli said (Am J Respir Crit Care Med 2018;197:700-701). “Major bodies right now are not recommending empiric steroids unless there’s a clear indication, for example, if a patient has a condition such as asthma that is known to be steroid responsive. Other than that, the conventional wisdom is to avoid steroids in COVID patients.”
Whatever the choice of treatment, time is of the essence. “If it’s a cytokine storm, the sooner you treat, the better,” Dr. Cron said. “If we wait until the patient is intubated and lung tissue has been destroyed, it may be too late. So if you have a hospitalized patient with evidence of cytokine storm—fever, maybe some CNS [central nervous system] findings, and some confirmatory labs like elevated ferritin, increased liver enzymes, and signs of coagulopathy like D-dimers being off and platelets trending down, that’s when you want to start your treatment of choice as opposed to waiting a few days until they are really sick.”