‘Can we do any better?’: Biomarkers, more data needed to reduce cytokine storm mortality
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A more nuanced understanding of COVID-19-related cytokine storm syndrome may hold the key to minimizing fatalities, noted a presenter at the Basic and Clinical Immunology for the Busy Clinician symposium.
“This started from an early, data-deprived hypothesis that cytokine storm has a mechanistic basis of critical COVID-19 pathogenesis,” Puja Mehta, MD, a clinical research fellow in respiratory medicine at University College London, told attendees. “Given the success of immunomodulation, it is now widely accepted that a subgroup of patients with severe COVID-19 have a dysregulated hyperinflammatory immune response.”
While it has been determined that cytokine storms reported in other settings — including hemophagocytic lymphohistiocytosis (HLH) or individuals who have undergone chimeric antigen receptor T-cell transplantation — is largely driven by high concentrations of interleukin-6, the nature of cytokine storm in COVID-19 is slightly different, according to Mehta.
“It is abundantly clear that the mean serum IL-6 concentrations in severe COVID patients are elevated but low compared to other populations,” she said, noting that this has made it difficult to develop clear treatment paradigms.
Another challenge pertains to what Mehta called the “biphasic” nature of COVID-19. She described the initial viremic phase, followed by the “exuberant immune response” around day 10, bringing about the cytokine elevation. It is for this reason that she suggested a “Goldilocks” immune response is critical to surviving the virus. If the response is too weak, then the virus can proliferate and cause damage; too strong, and the cytokine storm can set in.
Despite the conundrum posed by these patients, clinicians have improved in managing severe COVID-19 and the heightened inflammatory response, according to Mehta. “Dexamethasone plus IL-6 receptor agonists or JAK inhibitors have become standard of care for severe COVID,” she said. “But in the absence of a head-to-head, it is difficult to determine the positioning of IL-6 [receptor agonism] vs. JAK inhibitors and the combination with antivirals.”
In addition, drug classes like those targeting IL-1 and granulocyte-macrophage colony-stimulating factor (GMCSF) have shown promise but require further investigation.
“We currently have therapies that reduce mortality but can we do any better?” Mehta said. She noted, as has often been heard in the rheumatology space, that better studies with better patient selection are necessary, as are predictive biomarkers.
“Biomarker discovery needs to move from prognostic to predictive to optimize therapy,” she said. “Also, the impact of host factors, vaccines and variants on therapeutic responses are currently unclear.”
In closing, Mehta described hyperinflammation in COVID-19 as a “new and distinct entity” for which several criteria have been proposed. “But we need multivariate models and immune profiling,” she said. “We need to apply all the criteria to a large data set to see if we can predict treatment responses.”
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Mehta P. In-patient use of immunomodulatory therapies in COVID-19: anti-cytokine antibodies, targeted synthetic DMARDs and novel therapies. Presented at Basic and Clinical Immunology for the Busy Clinician; Feb. 26, 2022. (virtual meeting).
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