COVID-19 cytokine storm correlations with HLH and MAS offer treatment road map

Successful treatments for cytokine storms triggered by hemophagocytic lymphohistiocytosis (HLH), and macrophage activation syndrome (MAS) offer a road map for the most serious COVID-19 patients, according to Kenneth N. Schikler, M.D., a pediatric rheumatologist with Norton Children’s Rheumatology, affiliated with the UofL School of Medicine.

The overwhelming host response with the most serious COVID-19 cases correlates well with features seen in these cytokine storm syndromes.

“We really should be thinking about treating this just as we would MAS or HLH,” Dr. Schikler said in the online “Pediatric Grand Rounds: COVID-19 the Virus and the Host Response” continuing medical education activity. “There are probably things we can and should be doing from an immunologic standpoint to minimize the severity of COVID-19 infection.”

A recent abstract in The Lancet recommends patients with severe sickness from COVID-19 be screened for cytokine storm. There are a number of biomarkers for cytokine storm. These include C-reactive protein, cytopenias, D-dimers, fibrinogen, transaminase, lactate dehydrogenase (LDH) and ferritins. Procalcitonin can be used to monitor progress of the disease.

“Once we get into that cytokine storm system where macrophages are activated, we have targets that we can use to then regulate this process from really proliferating,” Dr. Schikler said.

Glucocorticoids are readily at hand and are effective at reducing inflammation and suppressing the immune system. Even though the Centers for Disease Control and Prevention (CDC) recommends against glucocorticoids for COVID-19, according to Dr. Schikler, the influenza studies the CDC used to reach that conclusion didn’t control for degree of disease.

“We know with cytokine storm from MAS and secondary HLH from other conditions, glucocorticoids are very effective,” he said.

Anakinra (Kineret), an interleuken-1 (IL-1) receptor antagonist biologic, is very helpful in MAS and HLH and does not have concerning side effects, according to Dr. Schikler. Canakinumab (Ilaris) also blocks IL-1.

IL-1 is one of 11 cytokines with a central role in the immune response. IL-1 beta recruits neutrophils to heart and lung tissue by increasing adhesion molecules on both endothelial cells and neutrophil surfaces, both of which cause local inflammation. IL-1 also provokes an increase in the cytokine TGF beta in the lung, which can lead to fibrosis. Blocking IL-1 beta also downregulates production of IL-6.

One study found anakinra improved survival over baseline for secondary HLH. Another looked at the benefit of using anakinra in eight children admitted to an intensive care unit with secondary HLH.

“In the study, we see in all these patients good proximity between starting anakinra and getting out of the ICU,” Dr. Schikler said. “There are clear-cut benefits to giving anakinra to these patients who are sick with COVID-19 infection.”

IL-6 blockage using the monoclonal antibodies tocilizumab (Actemra) and sarilumab (Kevzara) is helpful with the cytokine release syndrome seen with CAR-T immunotherapy, though tocilizumab shouldn’t be used if platelet counts are low or transaminases or liver dysfunction is high, according to Dr. Schikler.

Emapalumab (Gamifant), approved by the Food and Drug Administration for HLH, is a monoclonal agent that binds and neutralizes interferon gamma and also could be used to lessen the host response in COVID-19, as could intravenous immunoglobulin (IVIG), Dr. Schikler said.

JAK inhibitors baricitinib (Olumiant), tofacitinib (Xeljanz) and upadacitinib (Rinvoq) also have a place in treating the cytokine storm associated with COVID-19 but should not be first-line drugs because their use can result in cytopenia of both white cells and platelets and increase susceptibility to infection, according to Dr. Schikler.

COVID-19 Pediatric Update CME

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