Cytokine Response Syndrome and Use of Immune Stimulant Supplements
By: Julie Ostopchuk
There has been some concern regarding cytokine storm aka Cytokine Release Syndrome in Covid-19 patients that has led to specific concern in consuming elderberry and other immune stimulating supplements. In order to clearly understand this, I’m going to address the known scientific facts from studies in layman’s terms:
What are cytokines?
Cytokines are inflammatory immunologic proteins that are there to fight off infections and ward off cancers. When they are out of control, they make you very sick and may cause Cytokine Release Syndrome (CRS). Data from China has shown that many patients with Covid-19 are reported to have clinical and laboratory features of CRS.
What is the effect of elderberry with regard to cytokine levels?
“Elderberry activates the healthy immune system by increasing inflammatory cytokine production. Sambucol might therefore be beneficial to the immune system activation and in the inflammatory process in healthy individuals or in patients with various diseases. Sambucol could also have an immunoprotective or immunostimulatory effect when administered to cancer or AIDS patients, in conjunction with chemotherapeutic or other treatments.” 
What are the underlying causes of CRS?
“Rheumatic diseases, such as juvenile arthritis and lupus, certain types of blood cancers, like leukemias and lymphomas, can cause cytokine release syndrome”, according to Randy Cron, M.D., Ph.D. “There are a whole slew of infections that can do this, including the herpes virus family (including the bug that causes mono and CMV), Ebola, dengue — there are 80 to 100 bugs that have been associated with it in case reports.” Also reported, although less common, are cases of CRS in patients with rare metabolic disorders and in patients who go on heart-lung bypass machines such as ECMO.
What else can cause CRS?
CRS has arisen with use of some pharmaceuticals indicated for the following:  
- Intended to suppress or activate the immune system
- Prevent rejection of organ transplants
- Treat blood cancers
- Treat multiple sclerosis
- Treat auto-immune disorders, including T-cell therapies
How can an immune response be harmful, and who is most likely to experience this?
When large numbers of white blood cells are activated they release inflammatory cytokines. *Cytokine cells deficient in proteins called perforin release a flurry of cytokines, even though their lack of perforin made them incapable of destroying their target cell. One hypothesis is that these signals could spark the intense inflammatory response seen in CRS syndrome.
Numerous Individuals with Macrophage activation syndrome (MARS), hemophagocytic lymphohistiocytosis (rHLH) and systemic juvenile idiopathic arthritis (SJIA) possess protein-altering mutations. Those mutations cause the lack of perforin in the cytokine cells.
Is there a test for CRS?
A simple test for CRS involves serum ferritin testing. When serum ferritin (blood iron) levels are very high, that is an indicator of CRS.
In conclusion, Individuals listed in the above mentioned conditions should avoid elderberry or any immune stimulant supplement unless under the advice of their medical practitioner. As mortality rates in H1N1 and novel Covid-19 were attributed to CRS, immune stimulants could cause potential problems.
- Barak V1, Halperin T, Kalickman I., Eur Cytokine Netw. 2001 Apr-Jun;12(2):290-6.The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines.
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- Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL (July 2014). “Current concepts in the diagnosis and management of cytokine release syndrome”. Blood. 124 (2): 188–95. doi:10.1182/blood-2014-05-552729. PMC 4093680. PMID 24876563.
- Vidal JM, Kawabata TT, Thorpe R, Silva-Lima B, Cederbrant K, Poole S, Mueller-Berghaus J, Pallardy M, Van der Laan JW (August 2010). “In vitro cytokine release assays for predicting cytokine release syndrome: the current state-of-the-science. Report of a European Medicines Agency Workshop”. Cytokine. 51 (2): 213–5.
- Grant S. Schulert,1 Mingce Zhang,3 Ndate Fall,1 Ammar Husami,2 Diane Kissell,2 Andrew Hanosh,4 Kejian Zhang,2 Kristina Davis,4 Jeffrey M. Jentzen,4 Lena Napolitano,5 Javed Siddiqui,4,7 Lauren B. Smith,4 Paul W. Harms,4,6,7 Alexei A. Grom,1 and Randy Q. Cron3 Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza J Infect Dis. 2016 Apr 1; 213(7): 1180–1188.Published online 2015 Nov 23. doi: 10.1093/infdis/jiv550