In the first clinical trial of its kind in the United States, physicians at the University of Alabama at Birmingham are testing a treatment to halt the potentially fatal immune over-reaction known as cytokine storm syndrome in patients with COVID-19.
Before the current coronavirus crisis, two UAB clinician-scientists were already in the middle of a clinical trial of the drug anakinra (rhIL–1Ra), designed for rheumatoid arthritis, as a treatment for cytokine storm syndrome in patients with herpes virus family infections, Still’s disease and other conditions.
Reports from China and elsewhere indicate that patients critically ill from COVID-19 often have elevated levels of the immune-signaling molecules (cytokines) interleukin 6 (IL-6) and interleukin–1 beta (IL-1b), said Winn Chatham, M.D., professor in the Division of Immunology and Rheumatology at the UAB School of Medicine and principal investigator of the new study.
Blocking interleukin-1 beta
There are FDA-approved drugs to reduce both IL-6 and IL-1-beta levels in the context of autoimmune diseases. Early reports have shown that anti-IL-6 treatment has generated favorable outcomes, but these have lacked control patients for comparison, Chatham noted. One concern with blocking IL-6 is its important role in the adaptive immune response that allows the body to successfully remove the novel coronavirus that causes COVID-19. IL-1-beta, on the other hand, appears to play a limited role in adaptive immunity. Drugs to block IL-1-beta include anakinra, a quick-acting recombinant human IL-1 receptor agonist.
| “We’re really trying to confirm that we can identify cytokine storm syndrome very early in COVID-19 patients with routine labs and intervene.” |
Trials at UAB and elsewhere have found anakinra to be “remarkably safe” and effective at treating cytokine storms in a number of diseases and conditions, said Randy Cron, M.D., Ph.D., professor of pediatrics and medicine at UAB, and a co-investigator on the new study. These include herpes virus family infections, sepsis syndromes, ehrlichiosis, adult Still disease (and its pediatric form, systemic juvenile ideopathic arthritis) and systemic lupus.
Cytokine storm syndrome occurs when the body’s protective immune reaction spins out of control. “Cytokines are inflammatory immunologic proteins that are there to fight off infections and ward off cancers,” said Cron, author of Cytokine Storm Syndrome, the first medical textbook on the syndrome, published in 2019. “But when they’re out of control they can make you very ill.”
Serum ferritin in cytokine storm syndrome
“We’re really trying to confirm that we can identify cytokine storm syndrome very early in COVID-19 patients with routine labs and intervene,” Chatham said. “This protocol is targeted to early intervention.” When a patient with confirmed or suspected COVID-19 and respiratory compromise is admitted to UAB Hospital, physicians will keep a close eye on several early markers of cytokine storm syndrome, including serum ferritin, d-dimer and C-reactive protein. Patients who meet the diagnostic criteria (elevated serum ferritin, above 700 ng/ml, and either elevated d-dimer, LDH, leucopenia/lymphopenia or thrombocytopenia) and enroll in the study will have additional studies obtained — including a comprehensive metabolic panel, erythrocyte sedimentation rate, fibrinogen, haptoglobin, triglycerides and natural killer-cell function.
What makes serum ferritin a good warning sign for cytokine storm syndrome? “When you get prolific interleukin–1 production, that drives liver cells, as well as monocytes and macrophages wherever they are in the body to upregulate ferritin,” Chatham said.
This UAB research could provide answers to a pressing question: How common is cytokine storm syndrome in patients with COVID-19? “Certain older people who have senescent immune responses may simply get overwhelmed by the virus — but certainly in younger patients, this could be a major cause of death,” Chatham said. Severe pneumonia and ARDS — acute respiratory distress syndrome — are often cited as the main driving factors in seriously ill patients with COVID-19. “The cytokine storm could be why they are getting severe pneumonia,” Chatham said. “This is a disease that primarily targets the lung, so that’s going to be the first organ affected. From what we’ve seen in some of the few reported biopsies and autopsies, the histology is what you would see with viral pneumonia or cytokine storm syndrome. You see lots of monocytes, macrophages and lymphocytes, which is what you would expect to see in patients who have ARDS with cytokine storm.”
The new study is one of 14 UAB research grants — selected from more than 50 applications — to share $650,000 in funding from School of Medicine philanthropic gifts and the UAB Hugh Kaul Precision Medicine Institute.
“We will see how anakinra performs in a small trial,” Chatham said. “If it works really well, the 20 patients in this study may be sufficiently powered to meet the primary endpoint, but this is intended to be more of a pilot study.”
Genetic cause of disparity in COVID-19 deaths?
A second goal of Chatham and Cron’s study is to obtain genetic samples that will be sequenced to determine if patients who experience cytokine storm syndrome harbor mutations associated with enhanced IL-1-beta responses or perforin pathway mutations. This genetic evaluation eventually could be used to identify patients at high risk for cytokine storm syndrome.
Unfortunately, the distribution of some of these mutations in the population is unequal, Chatham noted. And that could explain part of the reason why African Americans have been disproportionately affected by COVID-19. Genetic polymorphisms associated with enhanced IL-1 production are present in about 40% of African Americans but only 6% of Caucasians,” Chatham said. “That’s one of the interesting aspects of what we want to look for.”
Previous research has pointed to mutations in the perforin pathway — the series of proteins that work together to deliver perforin — as a driver behind cytokine storm syndrome. The immune system’s cytotoxic T-cells and natural killer cells use perforin to punch holes in the walls of infected, cancerous or otherwise undesirable cells. Mutations in the genes responsible for “any one of the 10-plus proteins that get perforin to do what it does” are linked to a higher risk of cytokine storm syndrome, Cron said.
Some 10% to 15% of the population may carry these mutations, according to Cron’s calculations. Adults with these mutations usually have one mutated copy and one normal copy. “Generally, that’s enough to produce all the killing you need,” Cron said. “But if you get the wrong organism or the wrong inflammatory state it may push you over the edge.”
Plans to study steroids as well
Chatham and Cron also are submitting a proposal to the Biomedical Advanced Research and Development Authority, known as BARDA, which is an office of the U.S. Department of Health and Human Services, for a multi-center trial of early steroid intervention in patients with COVID-19. The idea is to “get them on treatment quickly” before they develop severe cytokine storm syndrome, Chatham said.
Patient data from the earlier SARS and MERS epidemics “suggested that severely ill patients did not fare as well with steroids, but there is some very compelling survival data that one of our collaborators at Temple University has accumulated that suggests this needs to be looked at with a more controlled approach in patients with earlier, less severe lung disease,” Chatham said. “There are certainly some reasons to think this might be effective.”
If this approach proves a success, “that might have a greater impact worldwide” because, while biologic drugs such as anakinra are expensive and only available in limited quantities worldwide, “nearly every hospital” has steroids, Chatham said. “It might turn out that 40–60 milligrams of prednisone will turn out to make a big difference. We thought the study needed to be done and thus far no one else is doing a controlled trial.”
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