Scientific Abstracts Relating to COVID-19 Induced
Cytokine Release Syndrome
(also known as “cytokine storm”)

The advent of electronic communication/ publication has resulted in a rapid release of studies and hypothesis covering many aspects of COVID-19 disease.

The link below titled “What is Cytokine Storm” provides a good lay overview of how pro-inflammatory cytokines contribute to significant tissue damage in COVID-19 patients.

We then list scientific abstracts that discuss potential ways of reducing the cytokine storm.

The challenge as of this writing is when to aggressively turn down hyper-inflammation and /hyper-immune responses that may be needed to kill the SARS/Cov-2 virus.

If effective anti-viral drugs become widely available, hospital/ ICU physicians may be in better position to implement cytokine suppressing drugs earlier in the COVID-19 disease process.

Sulforaphane Inhibits Lipopolysaccharide-Induced Inflammation, Cytotoxicity, Oxidative Stress, and miR-155 Expression and Switches to Mox Phenotype through Activating Extracellular Signal-Regulated Kinase 1/2–Nuclear Factor Erythroid 2-Related Factor 2/Antioxidant Response Element Pathway in Murine Microglial Cells

Front. Immunol., 23 January 2018 | https://doi.org/10.3389/fimmu.2018.00036

Sulforaphane (SFN) is a natural product with cytoprotective, anti-inflammatory, and antioxidant effects. In this study, we evaluated the mechanisms of its effects on lipopolysaccharide (LPS)-induced cell death, inflammation, oxidative stress, and polarization in murine microglia. We found that SFN protects N9 microglial cells upon LPS-induced cell death and suppresses LPS-induced levels of secreted pro-inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6. SFN is also a potent inducer of redox sensitive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), which is responsible for the transcription of antioxidant, cytoprotective, and anti-inflammatory genes. SFN induced translocation of Nrf2 to the nucleus via extracellular signal-regulated kinase 1/2 (ERK1/2) pathway activation. siRNA-mediated knockdown study showed that the effects of SFN on LPS-induced reactive oxygen species, reactive nitrogen species, and pro-inflammatory cytokine production and cell death are partly Nrf2 dependent. Mox phenotype is a novel microglial phenotype that has roles in oxidative stress responses. Our results suggested that SFN induced the Mox phenotype in murine microglia through Nrf2 pathway. SFN also alleviated LPS-induced expression of inflammatory microRNA, miR-155. Finally, SFN inhibits microglia-mediated neurotoxicity as demonstrated by conditioned medium and co-culture experiments. In conclusion, SFN exerts protective effects on microglia and modulates the microglial activation state.

Naproxen Exhibits Broad Anti-influenza Virus Activity in Mice by Impeding Viral Nucleoprotein Nuclear Export

Cell Reports Volume 27, Issue 6, 7 May 2019, Pages 1875-1885.e5

https://doi.org/10.1016/j.celrep.2019.04.053

https://www.sciencedirect.com/science/article/pii/S2211124719305261

Naproxen is a non-steroidal anti-inflammatory drug that has previously been shown to exert antiviral activity against influenza A virus by inhibiting nucleoprotein (NP) binding to RNA. Here, we show that naproxen is a potential broad, multi-mechanistic anti-influenza virus therapeutic, as it inhibits influenza B virus replication both in vivo and in vitro. The anti-influenza B virus activity of naproxen is more efficient than that of the commonly used neuraminidase inhibitor oseltamivir in mice. Furthermore, the NP of influenza B virus (BNP) has a higher binding affinity to naproxen than influenza A virus NP (ANP). Specifically, naproxen targets the NP at residues F209 (BNP) and Y148 (ANP). This interaction antagonizes the nuclear export of NP normally mediated by the host export protein CRM1. This study reveals a crucial mechanism of broad-spectrum anti-influenza virus activity of naproxen, suggesting that the existing drug naproxen may be used as an anti-influenza drug.

Broad-spectrum antiviral activity of naproxen: from Influenza A to SARS-CoV-2 Coronavirus

BioRXiv preprint doi: https://doi.org/10.1101/2020.04.30.069922

https://www.biorxiv.org/content/10.1101/2020.04.30.069922v1

There is an urgent need for specific antiviral drugs directed against SARS-CoV-2 both to prevent the most severe forms of COVID-19 and to reduce viral excretion and subsequent virus dissemination; in the present pandemic context, drug repurposing is a priority. Targeting the nucleoprotein N of the SARS-CoV-2 coronavirus in order to inhibit its association with viral RNA could be a strategy to impeding viral replication and possibly other essential functions associated with viral N. The antiviral properties of naproxen, belonging to the NSAID family, previously demonstrated against Influenza A virus, were evaluated against SARS-CoV-2. Naproxen binding to the nucleoprotein of SARS-CoV2 was shown by molecular modeling. In VeroE6 cells and reconstituted human primary respiratory epithelium models of SARS-CoV-2 infection, naproxen inhibited viral replication and protected the bronchial epithelia against SARS-CoV-2 induced-damage. The benefit of naproxen addition to the standard of care is tested in an on-going clinical study.

Inhibition of Bruton tyrosine kinase in patients with severe COVID-19

American Association for the Advancement of Science first published 05 Jun 2020, Science Immunology 05 Jun 2020: Vol. 5, Issue 48, eabd0110 DOI: 10.1126/sciimmunol.abd0110 https://immunology.sciencemag.org/content/5/48/eabd0110

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation – C-reactive protein and IL-6 – normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.

Tocilizumab Might Attenuate the “Cytokine Storm” in COVID-19 Patients

Proceedings of the National Academy of Sciences first published April 29, 2020 https://doi.org/10.1073/pnas.2005615117

New England Journal of Medicine Group review by Anthony L. Komaroff, MD

Review

Oxygen saturation levels stabilized in 21 patients who received this drug in an uncontrolled trial.

Excessive immune response to infection with the SARS-CoV-2 virus has been incriminated in the respiratory distress and multiorgan failure that is seen in some patients — the so-called “cytokine storm.” Previous studies of the cytokine storm associated with other coronavirus and influenza virus infections, and with CAR (chimeric antigen receptor)-T cell therapy, have shown high levels of interleukin (IL)-6 and other cytokines.

Chinese investigators conducted a retrospective, uncontrolled study of 21 patients (average age, 57) with severe COVID-19 symptoms (as defined by prespecified criteria) who received treatment with the IL-6 blocker tocilizumab (Actemra; approved in the U.S. to treat rheumatoid arthritis and juvenile idiopathic arthritis). All patients required supplemental oxygen (2 were on ventilators), had worsening ground-glass opacities on chest computed tomography, and showed deterioration of other clinical and laboratory measures. Within 24 hours of starting tocilizumab therapy, fevers and elevated C-reactive protein levels resolved, and levels of IL-6 and other proinflammatory cytokines declined. Use of supplemental oxygen dropped in 15 patients, oxygen saturation levels stabilized or improved in all patients, the 2 ventilated patients were weaned, and all patients subsequently were discharged alive.

Cytokine release syndrome in severe COVID-19

Science 01 May 2020: Vol. 368, Issue 6490, pp. 473-474 https://doi.org/10.1002/art.41285

Abstract

In December 2019, a new strain of coronavirus, severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), was recognized to have emerged in Wuhan, China. Along with SARS-CoV and Middle East respiratory syndrome–coronavirus (MERS-CoV), SARS-CoV-2 is the third coronavirus to cause severe respiratory illness in humans, called coronavirus disease 2019 (COVID-19). This was recognized as a pandemic by the World Health Organization (WHO) in March 2020 and has had considerable global economic and health impacts. Although the situation is rapidly evolving, severe disease manifested by fever and pneumonia, leading to acute respiratory distress syndrome (ARDS), has been described in up to 20% of COVID-19 cases. This is reminiscent of cytokine release syndrome (CRS)–induced ARDS and secondary hemophagocytic lymphohistiocytosis (sHLH) observed in patients with SARS-CoV and MERS-CoV as well as in leukemia patients receiving engineered T cell therapy. Given this experience, urgently needed therapeutics based on suppressing CRS, such as tocilizumab, have entered clinical trials to treat COVID-19.

Cytokine Storm in COVID-19 and Treatment

Arthritis Rheumatol. 2020 Apr 15. https://doi:10.1002/art.41285. Online ahead of print.

Abstract

Cytokine storm is an excessive immune response to external stimuli. The pathogenesis of the cytokine storm is complex. The disease progresses rapidly, and the mortality is high. Certain evidence shows that, during the coronavirus disease 2019 (COVID-19) epidemic, the severe deterioration of some patients has been closely related to the cytokine storm in their bodies. This article reviews the occurrence mechanism and treatment strategies of the COVID-19 virus-induced inflammatory storm in attempt to provide valuable medication guidance for clinical treatment.

On the Alert for Cytokine Storm: Immunopathology in COVID-19 Treatment

First published:15 April 2020 https://doi.org/10.1002/art.41285

Abstract

Coronavirus disease 2019 (COVID-19) is sweeping across the globe. Most patients have mild to moderate symptoms, but a subgroup will become severely ill. Sepsis, respiratory failure, and acute respiratory distress syndrome (ARDS) are common complications of the disease.(1) Factors associated with ICU admission and death include older age, comorbid conditions, elevated body mass index, lymphopenia, and elevated transaminases, LDH, D-dimer, ferritin, and soluble IL-2 receptor (sIL-2R).(1-4).

The Pathogenesis and Treatment of the `Cytokine Storm' in COVID-19

April 10, 2020 https://www.ncbi.nlm.nih.gov/pubmed/32283152

Abstract

COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression

Published: March 16, 2020 Lancet. https://doi.org/10.1016/S0140-6736(20)30628-0

Abstract

As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%,1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality.

COVID-19: A New Virus, but a Familiar Receptor and Cytokine Release Syndrome

April 19, 2020 https://www.ncbi.nlm.nih.gov/pubmed/32325025

Abstract

Zhou et al. (Nature) and Hoffmann et al. (Cell) identify ACE2 as a SARS-CoV-2 receptor, and the latter show its entry mechanism depends on cellular serine protease TMPRSS2. These results may explain proinflammatory cytokine release via the associated angiotestin II pathway and a possible therapeutic target via the IL-6-STAT3 axis.

The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China

Clinical Immunology

May 2020, 108393 Volume 214,

The pandemic outbreak of coronavirus disease 2019 (COVID-19) is rapidly spreading all over the world. Reports from China showed that about 20% of patients developed severe disease, resulting in a fatality of 4%. In the past two months, we clinical immunologists participated in multi-rounds of MDT (multidiscipline team) discussion on the anti-inflammation management of critical COVID-19 patients, with our colleagues dispatched from Chinese leading PUMC Hospital to Wuhan to admit and treat the most severe patients. Here, from the perspective of clinical immunologists, we will discuss the clinical and immunological characteristics of severe patients, and summarize the current evidence and share our experience in anti-inflammation treatment, including glucocorticoids, IL-6 antagonist, JAK inhibitors and choloroquine/hydrocholoroquine, of patients with severe COVID-19 that may have an impaired immune system.