The popular media began using the term. “cytokine storm”, first employed in connection with skin graft reactions, in the wake of avian H5N1 influenza virus infection (aka “bird flu”) in 2005. An uncontrolled and generalized hyperinflammatory response, this “storm” has also been observed in sepsis, trauma, and hemorrhagic stroke. Public radio has broadcasted reports of its afflicting younger COVID-19 patients, although the medical literature emphasizes its association with immune senescence.

Cytokines are an important part of the immune system. Specifically, they are a broad category of relatively small proteins (< 40 kDa) which are produced and released with the aim of self-signaling. They are polypeptides secreted by leukocytes and other cells that act principally on hematopoietic cells, the effects of which include modulation of immune and inflammatory responses. Synchronizers of immune system responses, their concentrations vary during the course of a disease. Cytokines can have either pro or anti-inflammatory effects, depending on the context. They are classified according to their cell of origin or their mechanism of action. Some, such as epidermal growth a tor, tumor necrosis factor alpha, and interleukin 1-6, can cross the blood-brain barrier; others, such as transforming growth factor alpha & beta-1, accumulate in the vicinity of the barrier and are degraded in the blood circulation.

As noted, the cytokine storm is a hyperinflammatory reaction which cannot turn itself off, thus wreaking damage throughout the body. A subgroup of patients with severe COVID-19 can experience this syndrome, which is characterized by a “fulminant” and fatal hypercytokinemia associated with multi-organ failure. The idea of this hyperinflammation emerged from the observation that COVID-19 patients requiring ICU admissions displayed higher concentrations of CXCL10, CCL2, and TNF-alpha as compared to those in which the infection was less severe and did not require an ICU admission. Moreover, in patients with SARS-Cov-2 infection as opposed to SARS-Cov infection, there is also an increased secretion of Th2-immune-oriented cytokines such as IL-4 and IL-10, whose main effect is to suppress inflammation. The cytokine storm and the subsequent ARDS result from the effects of a combination of many immune-active molecules. Interferons,interleukin, chemokines, colony-stmulating factors, and TNF-alpha represent the main components in the development of the phenomenon. (Colony-stimulating factors are proteins associated with inflammatory conditions and are components of an amplification cascade which increases cytokine production by macrophages at sites of inflammation.)

Developed by Hoffman-LaRoche, tocilizumab is an immunosuppressant drug proposed as a therapeutic agent against the cytokine storm. This is a “humanized” anti-IL-6 receptor immunoglobulin G1 monoclonal antibody used for the treatment of rheumatoid arthritis and other chronic inflammatory diseases. (Humanized antibodies are those from non-human species the protein sequences whereof have been modified to increase their similarity to antibody variants produced naturally in humans. The International Non-proprietary Names of humanized antibodies end in -zumab.)

In a University of Michigan study, critically ill Covid-19 patients who received a single dose of IV tocilizumab were 45% less likely to die overall, and more likely to be out of the hospital or off a ventilator one month after treatment, compared to who didn’t receive the drug. The lower risk of death in these patients happened despite the fact that they also had twice the risk of developing an additional infection on top of the novel coronavirus.

~ Rylan Dray, Ph.D. – November 2020