THE COVID19 CYTOKINE STORM.

What you need to Know:

The most damaging and threatening effects of the COVID19 virus is the cytokine storm. A cytokine storm results from an out of control immune system response. A cytokine storm can be the result of both infectious and non-infectious causes. Targeting the COVID19 cytokine storm should be the target in those individuals with associated pneumonia. The cytokine storm is an immune system link between COVID19 pneumonia and cancer to be exploited for treatment.

The COVID19 virus is almost certainly headed for Time magazine’s word of the year. That or social distancing. Whether the direct COVID19 virus or an associated effect, it is clear the topic of the year or the words/phrase of the year will involve something to do with the current viral Pandemic. No continent, no country, no state, no family, and no individual is left untouched or ignorant on the topic.  All the updates, the press releases, the experts…is simply exhausting.

In these frequent publications, press conferences, and expert opinions, the phrase “cytokine storm” has frequently been mentioned. The phrase cytokine storm was first used and described in 1993 in the description of the out of control inflammatory effects found in the Graft-versus-Host disease. Since that time, it has been described to occur as a result of infectious (viral, bacterial, fungal, parasitical…) and non-infectious (medications, autoimmune disease, pancreatitis, cancer…) sources. The worst manifestation of a cytokine storm is found in sepsis and septic shock.

What is the relevance of cytokine storm to COVID19?

In the current COVID19 quarantine world that we now exist in, the only thing that might help ease the fear in this current environment is a self-imposed quarantine from the news. Expert after expert is paraded across the TV screen. Who knew there were so many experts on a virus and pandemics. This parade of experts creates a different storm—a storm of experts. As a result of this expert storm, confusion has reigned. If everybody is an expert, then nobody is an expert.  This has done nothing but helped to spread fear. But some silver linings has come from all of this craziness. The phrase “cytokine storm[1] is one of these positives.

The cytokine storm is front and center in the COVID19 viral effects. This cytokine storm is a direct connection between the virus, the lung damage that results, the Acute Respiratory Distress (ARDS) and the primary cause of mortality in individuals afflicted with the COVID19 induced pneumonia. It is important to clarify that this cytokine storm only applies to pneumonia associated with the COVID19 virus and does not apply to those asymptomatic or those with milder symptoms. This is also why the immunocompromised are so vulnerable. Their immune system begins the viral assault at a level of dysfunction.

In part 1 part of this series, I will discuss the following points on a cytokine storm:

  • What is a cytokine storm?
  • What are the different causes of the cytokine storm?

What is a cytokine storm?

According to the National Cancer Institute, cytokine storm is “A severe immune reaction in which the body releases too many cytokines into the blood too quickly.” A better working definition is a triggered immune system response that has gone wrong that promotes overwhelming inflammation and creates cataclysmic, collateral damage to affect different organs in the body. In the case of COVID19–the lungs.

Over the short life-span of this topic, many different titles have come to identify the same process. These different names include:

  • Cytokine storm
  • Cytokine burst
  • Inflammatory burst
  • Inflammatory storm
  • Immune storm
  • Cytokine releasing syndrome (CRS)
  • Hypercytokinesis

Many different names for the same underlying process. Names, titles, and categorization are one of the things that conventional medicine does very well. But, does name-calling, titles, and groupings every help provide a solution? Or worse, does it help one critically think? Ah, but that is a topic for another post.

Why is the cytokine Storm important?

The most often used term is cytokine storm. I believe cytokine storm is the most consistent description of the underlying process and should be the term applied to this inflammatory process. It is a massive surge of inflammatory signaling—a storm of inflammatory cytokines.

The immune system communication dysfunction found in a cytokine storm involves both cytokines and chemokines. Think of cytokines as the communication signals of the immune system. Think of them as a language for communication. Just as communication can be positive and negative, cytokines can produce both a pro-inflammatory signal and an anti-inflammatory signal. Cytokines are meant to be more a local communication and not that of systemic communication. In many ways, cytokines are very similar to hormones in their signaling, but more on a local, what is called the paracrine, effect. Some of the pro-inflammatory cytokines [2] [3] [4] [5] implicated in a cytokine storm include:

  • increased TNF-alpha
  • increased IL-1alpha
  • increased IL-1beta
  • increased IL-6
  • increased IL-8
  • increased IFN-alpha
  • Increased IFN-beta
  • Increased IFN-gamma

Chemokines are also involved in a cytokine storm. Chemokines are a type of cytokine signals mobilization and activation of the different parts of the immune system. Chemokines are like the traffic cop directing traffic at an intersection. Some of the pro-inflammatory chemokines [6] [7] [8] implicated in a cytokine storm include:

  • increased CXCL8
  • increased CCL2
  • increased CCL11
  • increased MCP1

In essence, with the increase in the pro-inflammatory signaling of cytokines and chemokines, the immune system is yelling at the top of its voice without any counter signals to quiet down. If anybody has a house full of kids as I do, the chaos of that experience is understandable. However, the immune system does have the capacity to turn down this excessive, pro-inflammatory signaling with the likes of the suppressing cytokines IL-10, TGF-beta, Th2, and what are called T regulator cells. In a cytokine storm, these signals prove too little and too late to contain the massive immune dysfunction to provide any benefit against the storm.

Take a look at the current COVID19 pneumonia cytokine storm. The cells that line the respiratory (lung) system become infected with the virus. This viral infection leads to a localized cytokine and chemokine reaction. As a result, the immune system is called to battle. The immune cells that have been called to battle become infected. Significant destruction of the front-line immune cells results in increased inflammatory response. This inflammatory process cycles on its self. Mass destruction ensues with localized, collateral damage occurring to the lung and surrounding tissue. The localized inflammatory reaction then spills into the systemic circulation to spread the immune system mayhem throughout the entire body.  Essentially, the cytokine storm timeline includes:

  • Local inflammation
  • Overwhelming oxidative stress
  • Acute Lung Injury
  • Systemic inflammation (cytokine storm)
  • Acute Respiratory Distress Syndrome (ARDS)
  • Multi-Organ Failure
  • Death

The immune system is a wonderful thing—that is when it does its job correctly. When left unchecked or dysfunctional, the immune system can become a source of great damage to the body i.e. autoimmune disease. Sepsis and septic shock [9] are two of the most extreme forms of a cytokine storm. Cytokine storm occurs early in sepsis as suppression of the immune system dominates late in sepsis. Of course, with these extreme forms of cytokine storm, the mortality rate often exceeds > 20% [10]. A cytokine storm implies that the immune system can cause great damage to the body, including death, when communication runs amuck.

What are the possible causes of a cytokine storm?

There are both infectious and non-infectious causes of a cytokine storm. The infectious causes are the more common and include:

  • Viral infections
  • Bacterial infections
  • Fungal infections
  • Parasitic infections

Many different viral infections have been shown to cause the potential for a cytokine storm. From the common influenza virus to some of the more historically well-known influenza virusEs [11] including the 1918 H1N1 Spanish flu, the 1957 H2N2 Asian Flu, the 1968 H3N2 Hong Kong flu, the 2009 H1N1 pandemic also known as the swine flu, many different avian influenza viruses, of course, the coronavirus and its many recent types (SARS-CoV and MERS-CoV) to include the current COVID19, the well known and feared E. bola virus [12], dengue, and associated dengue hemorrhagic fever, to even the more common virus types of EBV [13] and CMV [14], all have all been shown to precipitate the potential for a cytokine storm.

Even bacteria get in on the cytokine storm act. Group A streptococcus [15] has been shown to precipitate a cytokine storm response. The gram-negative bacterium Francisella tularensis [16] has been shown to trigger a cytokine storm. Even the endotoxin, Lipopolysaccharide (LPS), produced by bacteria in the gut like E. Coli [17] and the parasite Leishmania [18] can precipitate a cytokine storm response. As listed above, even fungi and their associated mycotoxins [19] can get in on the act.

One interesting connection with the COVID19 virus is malaria. Malaria is caused by the parasite Plasmodium. Malaria has also been shown to precipitate a cytokine storm [20]. Currently, a world-wide debate exists around the evidence and the use of the anti-malarial drugs, chloroquine, and hydroxychloroquine, for the treatment of  COVID19 pneumonia. It is the cytokine storm that connects the two different infection types. Isn’t it interesting that a cytokine storm, whether from a parasite or a virus, can be treated by the same drugs? The point is not that the effects of the drugs are primarily both anti-parasitic and anti-viral. It is the cytokine storm that connects the drugs benefit with malaria and COVID19 pneumonia. I propose that it is the anti-cytokine storm effects of the drugs chloroquine and hydroxychloroquine that is the most beneficial effect. Another example to prove the cytokine storm connection is the anti-malarial drug artesunate. Artesunate is derived from wormwood. This natural, anti-malarial therapy also co-functions as a very effective alternative cancer therapy [21] [22] [23] [24]. Artesunate has been shown to have a wide variety of anti-cancer effects, including immune system modulation—cytokine storm [25] [26]. Just a tease for part 2 and part 3 of this post series.

In addition to infectious causes, there also are non-infectious causes of a cytokine storm. These include:

  • Graft-versus-host disease
  • Medications
  • Pancreatitis
  • Cancer
  • Chemotherapy
  • Tumor Lysis Syndrome

 

In part 2 and part 3 of this series on cytokine storm, I will discuss:

  • What, if any, relevance does the cytokine storm have in cancer?
  • What are effective ways to counter a cytokine storm?

Nathan Goodyear, MD, MD(H), ABAARM, FMNM

___________________________________________

 

[1] Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012;76(1):16–32. doi:10.1128/MMBR.05015-11

[2] Teijaro, J.R. Cytokine storms in infectious diseases. Semin Immunopathol 39, 501–503 (2017). https://doi.org/10.1007/s00281-017-0640-2

[3] Srikiatkhachorn A, Mathew A, Rothman AL (2017) Immune-mediated cytokine storm and its role in severe dengue. Semin Immunopathol. doi:10.1007/s00281-017-0625-1

[4] La Gruta NL, Kedzierska K, Stambas J, Doherty PC. A question of self-preservation: immunopathology in influenza virus infection. Immunol Cell Biol. 2007;85:85–92. doi: 10.1038/sj.icb.7100026.

[5] Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007;45(2):27–37. doi:10.1097/AIA.0b013e318034194e

[6] Shinya K, Gao Y, Cilloniz C, Suzuki Y, Fujie M, Deng G. Integrated clinical, pathologic, virologic, and transcriptomic analysis of H5N1 influenza virus-induced viral pneumonia in the rhesus macaque. J Virol. 2012;86:6055–6066. doi: 10.1128/JVI.00365-12.

[7] de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. 2006;12:1203–1207. doi: 10.1038/nm1477

[8] D’Elia RV, Harrison K, Oyston PC, Lukaszewski RA, Clark GC. Targeting the “cytokine storm” for therapeutic benefit. Clin Vaccine Immunol. 2013;20(3):319–327. doi:10.1128/CVI.00636-12

[9] Chousterman BG, Swirski FK, Weber GF. Cytokine Storm and Sepsis Disease Pathogenesis. Semin Immunopathol. 2017 Jul;39(5):517-528. doi: 10.1007/s00281-017-0639-8.

[10] Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC, Reinhart K, International Forum of Acute Care T (2016) Assessment of global incidence and mortality of hospital-treated sepsis Current estimates and limitations. Am J Respir Crit Care Med 193(3):259–272. doi:10.1164/rccm.201504-0781OC

[11] Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol. 2016;13(1):3–10. doi:10.1038/cmi.2015.74

[12] Younan P, Iampietro M, Nishida A, et al. Ebola Virus Binding to Tim-1 on T Lymphocytes Induces a Cytokine Storm. mBio. 2017;8(5):e00845-17. Published 2017 Sep 26. doi:10.1128/mBio.00845-17

[13] Imashuku S. 2002. Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Crit. Rev. Oncol. Hematol. 44:259–272.

[14] Barry SM, Johnson MA, Janossy G. 2000. Cytopathology or immunopathology? The puzzle of cytomegalovirus pneumonitis revisited. Bone Marrow Transplant. 26:591–597.

[15] Emgård J, Bergsten H, McCormick JK, et al. MAIT Cells Are Major Contributors to the Cytokine Response in Group A Streptococcal Toxic Shock Syndrome. Proc Natl Acad Sci U S A. 2019;116(51):25923–25931. doi:10.1073/pnas.1910883116

[16] Muniz MGR, Palfreeman M, Setzu N, Sanchez MA, Portillo PS, Garza KM, Gosselink KL, Spencer CT. Obesity Exacerbates the Cytokine Storm Elicited by Francisella tularensis Infection of Females and Is Associated with Increased Mortality. BioMed Research International. Jun 2018; doi.org/10.1155/2018/3412732

[17] Keshari RS, Silasi-Mansat R, Popescu NI, Langer M, Chaaban H, Lupu C, Coggeshall MK, DeMarco S, Lupu F. Complement C5 Inhibition Blocks the Cytokine Storm and Consumptive Coagulopathy By Decreasing Lipopolysaccharide (LPS) Release in E. coli Sepsis. Blood 2015; 126 (23): 765. doi: https://doi.org/10.1182/blood.V126.23.765.765

[18] Santos-Oliveira JR, Regis EG, Leal CR, Cunha RV, Bozza PT, Da-Cruz AM. Evidence that lipopolisaccharide may contribute to the cytokine storm and cellular activation in patients with visceral leishmaniasis. PLoS Negl Trop Dis. 2011;5(7):e1198. doi:10.1371/journal.pntd.0001198

[19] Wu W, He K, Zhou HR, et al. Effects of oral exposure to naturally-occurring and synthetic deoxynivalenol congeners on proinflammatory cytokine and chemokine mRNA expression in the mouse. Toxicol Appl Pharmacol. 2014;278(2):107–115. doi:10.1016/j.taap.2014.04.016

[20] Clark IA, Budd AC, Alleva L, Cowden WB. Understanding the role of inflammatory cytokines in malaria and related diseases. Travel Medicine and Infectious Disease. Mar 2008;6(1-2):67-81.

[21] Bhaw-Luximon A, Dhanjay J. Artemisinin and its derivatives in cancer therapy: status of progress, mechanism of action, and future perspectives. Cancer Chemother Pharmacol. Feb 2017. DOI 10.1007/s00280-017-3251-7

[22] Eling N, Reuter L, Hazin J, Hamacher-Brady A, Brady NR. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience. 2015;2(5):517–532. Published 2015 May 2. doi:10.18632/oncoscience.160

[23] Sagar SM, Yance D, Wong RK. Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-Part 1. Curr Oncol. 2006;13(1):14–26.

[24] Zhang Y, Xu G, Zhang S, Wang D, Saravana Prabha P, Zuo Z. Antitumor Research on Artemisinin and Its Bioactive Derivatives. Nat Prod Bioprospect. 2018;8(4):303–319. doi:10.1007/s13659-018-0162-1

[25] Shang S, Wu J, Li X, Liu X, Li P, Zheng C, Wang Y, Liu S ,Zheng J, Zhou H. Artesunate interacts with Vitamin D receptor to reverse mouse model of sepsis-induced immunosuppression via enhancing autophagy. bioRxiv. Feb 2020. 966143; doi: https://doi.org/10.1101/2020.02.26.966143.

[26] Kuang M, Qin R, Cen Y, Sheng S. Artesunate Attenuates Pro-Inflammatory Cytokine Release from Macrophages by Inhibiting TLR4-Mediated Autophagic Activation via the TRAF6-Beclin1-PI3KC3 Pathway. Cellular Physiology and Biochemistry. May 2018 47(2):475-488.

Would you like to speak with a caring member of our team to answer your specific questions? Call (480) 834-5414