Avoiding The Cytokine Storm

The cytokine storm, a severe, uncontrolled immune reaction characterized by an excessive release of cytokines into the bloodstream in a short period of time. This results in acute, pathological inflammation starting in local sites that spreads throughout the body.
The increased cytokine production during the storm is often due to infection when pathogens and their associated molecules such as endotoxins, DAMPS, and PAMPS are detected by the immune system. Due to the various feedback loops and amplification pathways regulating cytokines, the dysregulated immune response can be difficult to treat once it is established, especially if the infection persists.

The problem

Our understanding of the immune response, conventional therapies, and treatment options remain lacking. The combination of hyper- and hypo-inflammatory phases of the immune response and altered cytokine production of genetically predisposed hyper- and hyporesponders complicates the strategy of immunomodulation therapy. Immunomodulatory drugs can be ineffective or even detrimental to the patient. Some antimicrobials (especially in the case of antivirals) can be similarly ineffective based on the time of administration (Tisoncik, 2012). Despite decades of clinical trials focused on treating inflammation, targeted therapies such as monoclonal antibodies or cytokine capture techniques ultimately fail either to reduce mortality or become an effective treatment for sepsis (Chousterman, 2017). In the case of COVID-19, the use of Tocilizumab, an IL-6 inhibitor, has already been associated with increased secondary infections (Kimmig, 2020).

Early in the COVID-19 pandemic, it was assumed that the cytokine storm was common in severe and critical patients. More recently, this assumption has come under question as the cytokine storm seems rare, even in severe patients. Significantly decreased cytokine levels have been observed in severe COVID-19 patients with ARDS compared to patients with septic shock, both with and without ARDS (Kox, 2020). Also increasing evidence demonstrates that not only does viremia or RNAemia occur during SARs-CoV-2 infection, it also correlates to disease severity.

These findings, and the fact that sepsis originates from an uncontrolled infection, demonstrate that the root of the problem remains the presence of the pathogens, which trigger all the downstream effects. As long as source control is not achieved, the persistent release of pathogenic products, in combination with inflammatory mediators, will disrupt the endothelial function of the blood/tissue barrier. This progresses to a loss of homeostasis and vascular leakage, which further exacerbates the cytokine production, and can lead to sepsis and organ failure. Additionally, coagulopathy associated with severe COVID-19 causes impaired perfusion of organs, resulting in organ damage/failure and death. A recent study indicates excessive Von Willebrand Factor (VWF) multimer release due to endothelial damage as the mechanism underlying this coagulopathy (Doevelaar, 2020).
Controlling the source of the infection as early as possible and preventing the dysregulated immune response from developing (i.e. avoiding the cytokine storm) would be the ideal clinical course. Therefore, a broad-spectrum treatment option to debulk the infectious inoculum is required which can be used regardless of the type of pathogen, strain, or antimicrobial susceptibility.

A Solution

The Seraph® 100 Microbind® Affinity Blood Filter, is the world’s first medical device to obtain the indication to specifically reduce pathogens from the bloodstream in the EU*. The Seraph 100 adsorption beads uses chemically-bonded heparin for its unique binding capacity. The heparin coating on the beads is designed to mimic the behavior of the glycocalyx inside the human body and significantly reduce a wide range of both drug-resistant and drug-susceptible pathogens circulating in the blood.

In addition to the reduction of pathogens, several other positive effects have been observed. Improved hemodynamic stability was observed in all Seraph 100 treatments when combined with hemodialysis therapy (unpublished results). Furthermore, decreased vasopressor requirement has been observed during and following multiple Seraph 100 treatments in both septic and COVID-19 patients (Olson, 2020).
Declines in blood levels of the following parameters have been observed in multiple independent Seraph 100 treatments (Olson, 2020):
· IL-6 · IL-8 · Pro-BNP · CRP · ferritin · D-dimers ·

Additionally, Seraph 100 was found to bind IL-6, VCAM, TNF-α, IFNγ, CXCL1, CCL4, CCL5 from blood in vitro.**
Several of these parameters are associated with inflammation, disease progression, worse clinical outcome, cytokine storm, and mortality (Bustamante, 2020; Soy, 2020). Furthermore, as VWF multimers are heparin -binding, Seraph 100’s unique heparin-functional beads may bind and reduce VWF multimers as well.
The combination of Seraph 100’s positive effects observed in multiple independent treatments: broad-spectrum, significant pathogen binding regardless of antibiotic susceptibility, decreased blood levels of several cytokines, improved oxygen saturation, and decreased vasopressor requirement. All this makes the Seraph 100 an excellent therapy for avoiding the cytokine storm in infectious patients and treating COVID-19.


1. Tisoncik, J. R., Korth, M. J., Simmons, C. P., Farrar, J., Martin, T. R., & Katze, M. G. Into the eye of the cytokine storm. Microbiology and molecular biology reviews : MMBR, 76(1), 16–32. (2012). https://doi.org/10.1128/MMBR.05015-11 

2. Chousterman, BG, Swirski, FK. Weber, GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol 39, 517–528 (2017). https://doi.org/10.1007/s00281-017-0639-8 

3. Kimmig, LM, et al. IL6 inhibition in critically ill COVID-19 patients is associated with increased secondary infections. Front. Med. (2020). https://doi.org/10.3389/fmed.2020.583897 

4. Kox, M. Waalders, NJB. Kooistra, EJ. Gerretsen, J. Pickkers, P. Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions. JAMA. 2020;324(15):1565–1567. doi:10.1001/jama.2020.17052 

5. Doevelaar, AAN. Et al. COVID-19 is associated with relative ADAMTS13 deficiency and VWF multimer formation resembling TTP. MedRxiv 2020.08.23.20177824; doi: hhtps://doi.org/10.1101/2020.08.23.20177824 

6. Olson, SW. et al. Treatment for Severe Coronavirus Disease 2019 With the Seraph-100 Microbind Affinity Blood Filter, Critical Care Explorations: August 2020 – Volume 2 – Issue 8 – p e0180 doi: 10.1097/CCE.0000000000000180 

7. Bustamante Munguira , J. et al. First Report of Use of a New Filter Approved for COIVD-19 Patients in Extracorporeal Circulation. (2020). Online poster. Eastern Cardiothoracic Surgical Society. https://ectss.org/meeting/abstracts/2020/C32.cgi 

8. Soy, M. Keser, G. Atagündüz, P. et al. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol 39, 2085–2094 (2020). https://doi.org/10.1007/s10067-020-05190-5 


** this is yet to be clinically tested in vivo