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What Is Cytokine Storm Syndrome? And Why Should You Care?

So, what is a cytokine storm? Something that New England fishermen should be careful to avoid? Most people are unaware that it is something that relates to your cellular biology. During our daily lives, we are secure in the thought that keeping fit, eating a healthy diet, and strengthening our immune system, is something that we should be considering for our long-term health. In particular, the strength of our immune response to disease and trauma is what we are taught we need to increase. In some instances, our immune system can cause us harm, almost like an “exaggerated” reaction to a specific agent or disease. This can take the form of an autoimmune disorder or as hyper inflammation the so-called cytokine storm syndrome!
Cytokine storm by the numbers
So, what are cytokines? Cytokines are a group of proteins and peptides that are secreted by various cells in our immune system (ranging from helper T Cells, B cells, macrophages, fibroblasts and endothelial cells to name a few). They are classified by the cell that they originate from, or by the specific biological mechanism that they regulate or moderate.
Cytokines play an important role in our immune system as signalling molecules, that can regulate our response to disease or mediate normal cell function. This can include but not limited to the production of blood cells, repair and maintenance of tissue etc.
So now we know what cytokines are, what is a cytokine storm? In simple terms, this is the overproduction or uncontrolled production of proinflammatory cytokines as part of any response to disease or traumatic injury.
Associated conditions
Autoimmune Disorders:
The overproduction or inappropriate production of cytokines specifically in the case of Rheumatoid arthritis is associated with cytokines [specifically interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha)] and can cause disease (Ref:1), presenting as illnesses such as rheumatoid arthritis. Rheumatoid arthritis is caused when the immune system targets the synovial lining on a joint and attacks it, this can cause a variety of symptoms, ranging from mild to severe pain, fatigue, reduction in joint mobility and inflammation. In its chronic form, this can also progress to organ involvement.
Other autoimmune diseases that are linked to cytokine production are Lupus and Diabetes.
Viral Respiratory Diseases:
The overproduction of cytokines in respiratory disease ((lung-specific immunopathology) is also associated with cytokine storm syndrome. In particular with Influenza A and H1N1 (Ref:2) and also more recently with COVID-19 (Ref:3) caused by Human SARS-CoV-2 virus. In both diseases. Inflammation caused by a cytokine storm starts in a localised site such as tissue and moves into the circulatory system and becomes distributed, involving organs in the case of viral respiratory diseases the lungs. The progression from local site to systemic often leads to systemic sepsis and in the context of the lungs presents as ALI (Acute Lung Injury) or ARDS (Acute Respiratory Distress Syndrome). Mechanical ventilation as a therapeutic intervention for a patient in an acute care setting is necessary for recovery. There seems to be a huge amount of variation in terms of the resistance and susceptibility of any given patient to ALI and ARDS. Studies are focusing on the genomic mechanisms that may be responsible for this variation (Ref: 4).
Treatments for overproduction of cytokines
Currently, there are several treatments for hyperinflammation associated with viral respiratory diseases, most are protein inhibitors see below (caveat: not an exhaustive list):
  • Mesalamine, Zanamivir – COX inhibitors effective in early-onset for Influenza treatment (Ref:5)
  • PF-04178903 – CCR2 inhibitor (Ref:6) effective in treatment for influenza infections
  • TJM2 – Treatment of Rheumatoid Arthritis (RA) (Ref:7)
Medicinal Cannabis and Hyper Inflammation
Medicinal Cannabis is proven to stimulate the CB1 (central nervous system) and CB2 (immune system) receptors (Ref:8) and can also reduce inflammation by inhibiting or modulating cytokine production, in the case of THC. However, with less application as a therapeutic remedy, CBD also plays a role as an anti-inflammatory treatment.
  • THC therapy for Legionella Pneuomophila infection (Ref:9)
  • THC as a therapy for Multiple Sclerosis (Ref:11)
  • THC as a therapy for RA (Ref:10)
  • MicroPEA is in the clinical trial process at the moment as a therapeutic remedy for cytokine storm in COVID-19 patients (Ref:12)
This is an interesting time for medicinal cannabis as it continues to find multiple therapeutic applications both as a natural medicine or as a synthetic drug. We are also seeing drugs being repositioned in clinical trials for related illness such as RA as a novel treatment for COVID-19 the TJM2 mentioned above as a RA treatment is now in trials as a cytokine storm inhibitor (I-MAB advances repositioned RA drug in early trial to treat COVID-19 cytokine storm). It is only a matter of time before medicinal cannabis trials are also successfully repositioned.
We will be covering the progress of the numerous clinical trials over the coming months and celebrating the success of recognised medicinal cannabis pharmaceutical therapies and drugs.
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1. “Into the Eye of the Cytokine Storm” March 2012 by Jennifer R. Tisoncik, Marcus J. Korth, Cameron P. Simmons,b Jeremy Farrar,b Thomas R. Martin,c and Michael G. Katze https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294426/

2. Hong Kong Med Journal 2005 Jun;11(3):189-99. “Human Infection by Avian Influenza A H5N1” K Y Yuen 1, S S Y Wong.

3. “The Cytokine Storm in COVID-19: An Overview of the Involvement of the Chemokine/Chemokine-Receptor System” 2020 May 11 Francesca Coperchini 1, Luca Chiovato 2, Laura Croce 2, Flavia Magri 2, Mario Rotondi https://pubmed.ncbi.nlm.nih.gov/32446778/

4. “Genetic Insights Into Sepsis: What Have We Learned and How Will It Help?” M M Wurfel 1 2008;14 https://pubmed.ncbi.nlm.nih.gov/18691101/

5. “Delayed Antiviral Plus Immunomodulator Treatment Still Reduces Mortality in Mice Infected by High Inoculum of Influenza A/H5N1 Virus” 2008 Jun 10, Bo-Jian Zheng 1, Kwok-Wah Chan, Yong-Ping Lin, Guang-Yu Zhao, Chris Chan, Hao-Jie Zhang, Hong-Lin Chen, Samson S Y Wong, Susanna K P Lau, Patrick C Y Woo, Kwok-Hung Chan, Dong-Yan Jin, Kwok-Yung Yuen https://pubmed.ncbi.nlm.nih.gov/18523003/

6. “CCR2-antagonist Prophylaxis Reduces Pulmonary Immune Pathology and Markedly Improves Survival During Influenza Infection” 2011 Jan 1, by Kaifeng Lisa Lin 1, Shari Sweeney, Brian Donghoon Kang, Elizabeth Ramsburg, Michael Dee Gunn https://pubmed.ncbi.nlm.nih.gov/21098218/

7. I-Mab to kick off clinical trials for monoclonal antibody TJM2 in China
15 November 2019 https://www.biospectrumasia.com/news/25/14900/i-mab-to-kick-off-clinical-trials-for-monoclonal- antibody-tjm2-in-china.html

8. The Cannabinoid System and Immune Modulation 2003 Oct, by Thomas W Klein 1, Cathy Newton, Kellie Larsen, Lily Lu, Izabella Perkins, Liang Nong, Herman Friedman https://pubmed.ncbi.nlm.nih.gov/12960289/

9. “Delta 9-tetrahydrocannabinol treatment suppresses immunity and early IFN-gamma, IL-12, and IL-12 receptor beta 2 responses to Legionella pneumophila infection.”
Klein TW, Newton CA, Nakachi N, Friedman H, 2000 Jun 15 https://pubmed.ncbi.nlm.nih.gov/10843702/

10. Suppression of human macrophage interleukin-6 by a nonpsychoactive cannabinoid acid. Parker J, Atez F, Rossetti RG, Skulas A, Patel R, Zurier RB
Rheumatol Int. 2008 May https://www.ncbi.nlm.nih.gov/pubmed/18040689/

11. “Cannabinoids and multiple sclerosis”. Pertwee RG. 2002 Aug; https://www.ncbi.nlm.nih.gov/pubmed/12182963/

12. “FSD Pharma wins FDA nod to design Phase 2a clinical trial of its lead candidate micro-PEA to treat coronavirus patients”
https://www.proactiveinvestors.com/companies/news/921049/fsd-pharma-wins-fda-nod-to-design-phase-2a-clinical-trial- of-its-lead-candidate-micro-pea-to-treat-coronavirus-patients-921049.html