There has been a lot of discussion in the media lately about cytokine storms. This is referring to an inflammatory response to an insult such, as a pathogen or injury, to which the immune system overreacts and runs out of control. It has been well documented that the severity and increased risk of death of COVID-19 is associated with a cytokine storm, where inflammation runs away and therefore the body’s own inflammatory response becomes more dangerous than the infection itself. The main problems are therefore not brought about by the virus itself, but by the extreme immunological response in some people to the ineffective organisms.
It is important to note that if you have a robust immune system you are not at an increased risk of a cytokine storm. A hyper-inflammatory response is more indicated that the immune system may be dysfunctional not that it is over strong.
What are cytokines?
Cytokines are a group of molecules which are a part of the body’s innate immune system. Their function is to induce inflammation within the body in response to an insult. Inflammation is a defence mechanism without which we would be extremely susceptible to infection and would die pretty quickly. Inflammation is categorised by:1
- Rubor- redness
- Tumor- swelling
- Calor- heat
- Dolor – pain
- Functio laesa – loss of function
Appropriate levels inflammation aid healing by preventing use or movement of an affected area, alerting the host via pain, destroying pathogens by increase of temperature and signalling to other parts of the immune system to aid defence against pathogens and repair of tissue. These responses often occur at the expense of local organ function, particularly when tissue oedema causes a rise in extravascular pressures and a reduction in tissue perfusion (reduce passage of fluid into tissues therefore a reduction in oxygen and nutrient availability). Compensatory repair processes are initiated soon after inflammation begins, and in many cases the repair process completely restores tissue and organ function. When severe inflammation or the primary aetiological (causative) agent triggering inflammation damages local tissue structures, healing occurs with fibrosis (thickening and scaring of tissue), which can result in persistent organ dysfunction.1–3
There are many different types of cytokines that are involved in innate immunity, some are anti-inflammatory and some are pro-inflammatory and some are anti-inflammatory, however today we will mostly discuss pro-inflammatory cytokines. These are released, as mentioned in response to an insult to the body, thereby promoting inflammation (which is necessary for subsequent tissue remodelling and repair).
Some major types and actions of cytokines are;1
|Interferons||Regulation of innate immunity, activation of antiviral properties, anti-proliferative effects|
|Interleukins||Growth and differentiation of leukocytes; many are pro-inflammatory|
|Chemokines||Control of chemotaxis, leukocyte recruitment; many are pro-inflammatory|
|Colony-stimulating factors||Stimulation of hematopoietic progenitor cell proliferation and differentiation|
|Tumour necrosis factor||Pro-inflammatory, activates cytotoxic T lymphocytes|
Studies so far have shown that in the early stages of covid-19 infection there is a delayed release of cytokines, keeping the inflammatory response moderate. However, in the later stages with increasing severity the cells secrete low levels of the antiviral factors interferons (IFNs) and high levels of pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, and tumour necrosis factor (TNF)) and chemokines. Afterwards, the rapidly increased cytokines and chemokines attract many inflammatory cells, such as neutrophils and monocytes, resulting in excessive infiltration of the inflammatory cells into lung tissue and thus lung injury. It appears from other studies that dysregulated and/or exaggerated cytokine and chemokine responses by SARS-CoV-infected or MERS-CoV-infected cells could play an important role in pathogenesis of SARS or MERS.1,4,5
Some cytokines play a significant role; of particular interest are:1
IL-1β– a key cytokine driving pro-inflammatory activity in bronchoalveolar fluid of patients with lung injury. Intense inflammation in the lungs also can have systemic effects on other organs, as the combination of severe injury in the lungs and mechanical ventilation has been shown, in in vivo studies, to cause renal dysfunction and evidence of apoptosis in renal tubular epithelial cells. High levels of expression of IL-1β have been detected in patients with COVID-19.
1L-6 – when released, IL-6 begins the “inflammatory cascade”, which is the sequential coordinated activation of your immune response. This is a very complex process, but essentially, it’s similar to an assembly line – each step triggers another step to happen until there’s an end product. Serum levels of IL-6 are positively correlated with the severity of the disease.
TNFα – TNFs are key inflammatory factors that trigger a cytokine storm. They are attractive targets for controlling the cytokine storm. It is perhaps the best known and most intensely studied of the pro-inflammatory cytokines, and it plays a prominent role in the cytokine storm literature. TNF is now considered a central cytokine in acute viral diseases, including those caused by influenza virus, dengue virus, and Ebola virus.
Recent research has found that high serum IL-6, IL-8, and TNF-α levels at the time of hospitalisation were strong and independent predictors of survival of patients admitted with covid-19.5
It has long been understood that cytokines play an important role in immunopathology during viral infection. A rapid and well-coordinated innate immune response is the first line of defence against viral infection. However, dysregulated and excessive immune responses may cause immune damage to the human body. Although as mentioned inflammation is an essential process a cytokine storm can occur which is a hyper-activation of inflammation and leads to inflammation running away with itself, tipping the balance and leading to an inflammatory cascade that becomes out of control.
Inflammasomes are multimeric protein complexes that assemble in the cytosol after sensing pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMP), these will be release during an infection for example. In general, inflammasomes serve as a scaffold to recruit the inactive zymogen pro-caspase-1 to activate it. Active caspase-1 is an enzyme that cleaves precursor cytokines pro-IL-1β and pro-IL-18 generating biologically active cytokines IL-1β and IL-18, these are both involved in triggering an inflammatory cascade.
The NLRP3 inflammasome initiates an inflammatory form of cell death as well as triggering the release of pro-inflammatory cytokines IL-1β and IL-18. SARS-CoV2 has been shown to activate the NLRP3 inflammasome, which is strongly involved in hyper activation of the innate immune response. The body requires an appropriate inflammatory response to react to initial infection and signal to other parts of the immune system to begin the fight against the infection. Therefore, promoting an appropriate inflammatory response is essential. However, in the case of SARS-CoV2 (the vector responsible for Covid-19) NLRP3 activation may be responsible for, or is certainly associated with, excess inflammation associated with the cytokine storm.
Acute lung injury and acute respiratory distress syndrome3,9–11
We know that most patients who are affected severely by Covid-19 go into acute respiratory distress syndrome (ARDS), which contributes to mortality. The cytokine storm is a major driver of acute lung injury which can develop into ARDS in more severely affected patients.
Infection with SARS-CoV viruses have been shown to induce acute lung injury (ALI), they are demonstrated to infect type II pneumocytes in the alveolar walls. ALI is a common consequence of a cytokine storm in the lung alveolar environment as well as in systemic circulation. In humans, ALI is characterized by an acute mononuclear/neutrophilic inflammatory response followed by a chronic fibroproliferative phase marked by progressive collagen deposition in the lung, this fibrosis causes a reduction in lung function which can persist. Pathogen-induced lung injury can progress into ALI or its more severe form, acute respiratory distress syndrome (ARDS).
Nutritional interventions to modulate inflammation
As mentioned, the body requires an appropriate inflammatory response to react to initial infection and signals to other parts of the immune system to begin the fight against the infection. Promoting an appropriate inflammatory response is, therefore, essential. However clinical and in vivo studies have shown that excessive inflammatory responses are more relevant to death than the virus titre (the concentration of the initial infection).5
Many people already have heightened inflammation as it is a driver of many chronic conditions (CVD, autoimmune disorders, dementia, diabetes type 2 etc) – this may account for the increased risk of a severe infection due to comorbidities. Many suggested interventions are to normalise the inflammatory response to help support resilience and help to normalise activation of cytokine release and of the NLRP3 inflammasome.12
Interventions for modulating Inflammation:
Omega-3 fatty acids
The omeg3 fatty acid EPA is a precursor to 3 series prostaglandins which have membrane stabilising and anti-inflammatory properties, thereby help to regulate inflammation. They are also likely deficient in a typically Western diet. Omega-3 has been shown to reduce inflammatory cytokines and there have been some trials using omega-3 in response to ARDS. Increasing the ratio of omega-3 to omega-6 can help move away from a hyper-inflammatory response to infection. The omega-3 fatty acids, EPA and DHA present at the site of inflammation are enzymatically converted to specialized pro-resolving mediators known as resolvins, protectins, and maresins. These molecules work together to orchestrate the resolution of inflammation and to aid healing, including in the respiratory tract. Notably, nutritional deficiencies in these essential fatty acids can result in delayed or suboptimal resolution of inflammation. This could be crucial in the context of severe COVID-19 which presents as uncontrolled inflammation.13,14
- Quercetin has been shown to have antiviral effects against both RNA (e.g., influenza and coronavirus) and DNA viruses (e.g., herpesvirus). Quercetin has a pleiotropic role as an antioxidant and anti-inflammatory, modulating signalling pathways that are associated with post-transcriptional modulators affecting post-viral healing.11,35,36 It has been shown to favourably modulate viral-induced pathological cellular processes – Modulation of NLRP3 inflammasome activation15
- Curcumin has been shown to modulate the NLRP3 inflammasome and a preprint suggests that curcumin can target the COVID-19 main protease to reduce viral replication. It has also been shown to inhibit Cox-2 enzymes which produce inflammatory prostaglandins.15,16
Dietary factors to modulate inflammation13,17
- Reducing foods high in omega 6 – e.g. farmed meats, dairy products and vegetable oils (such as sunflower and corn oils). These are high in the omega 6 fat Arachidonic acid or Linoleic Acid (precursor to arachidonic acid). Arachidonic acid can be converted to the pro-inflammatory prostaglandin PGE
- Increasing sources of omega 3 from e.g. oily fish and flax, chia seeds and/or a supplement containing EPA. EPA is found in oily fish or can be supplemented; alpha linolenic acid is found in flax and chia seeds and dark leafy green vegetables and can be converted to EPA by the body. EPA is converted into anti-inflammatory prostaglandins.
- The ratio of omega 6 to 3 is very important, the majority of people are consuming too high a level of omega 6 to 3 and therefore are often producing excess amounts of pro-inflammatory prostaglandins.
- Using anti-inflammatory foods such as turmeric (curcumin) and ginger.
- Obtaining good levels of vegetables (6-8 portions per day) including dark leafy greens high in anti-inflammatory phytonutrients and antioxidants.
- Vitamin E has been shown to supress inflammatory markers (IL-6, TNFα and NO) and down regulate the transcription factor NF-kB. Sources of Vitamin E are avocados, almonds, green vegetables and olives.
- Optimise gut health (Orally consumed pre- and pro-biotics have been shown to reduce systemic markers of inflammation and oxidative stress)3
Sleep deprivation has been found to significantly increase pro-inflammatory markers and be a major contributor to chronic inflammation. Chronic inflammation is like kryptonite to your immune system. The long-term stimulation overworks your immune system, burning it out and decreasing its ability to effectively protect you.
When it comes to sleep, you want to focus on both quantity and quality. Do your best to get a minimum of six hours of sleep each night – although seven to eight is ideal. To ensure your sleep is high-quality and restful sleep:
- Keeping your room cool and dark
- Shutting off all electronics at least 30 minutes before bedtime
- Using a fan or white noise to block out any outside sounds that might disturb you
Stress is a major player in modern life and can be involved in the progression of chronic diseases. In this incredibly stressful time, it is important to implement stress management techniques to support not only a healthy stress response but also immune system. Large bodies of evidence indicate that stress can activate inflammatory responses locally and systemically. Stress has been directly associated with many chronic inflammatory conditions including atherosclerosis, non-alcoholic fatty liver disease (NAFLD) and depression. On the flip side as well as activating inflammation chronic stress has been associated with the suppression of the immune system. Many studies have shown an association between stress and reduced immune function.
So clearly when supporting immune function, it is important to look at the health of the adrenal (stress) glands. Nutrients that are important for a healthy stress response include1,3:
Vitamins C, B5 and B6 – support normal adrenal function and cortisol production.
Magnesium – an essential cofactor for many enzymes involved in the production of adrenal hormones and therefore depleted in times of stress; it is also a muscle relaxant of both skeletal and smooth muscle.
Phosphatidyl serine – has inhibitory effects on HPA (stress) axis – it has been shown to lower cortisol levels.
Adaptogenic herbs – such as Ashwagandha, Siberian gingseng, Panex gingseng, liquorice and Rhodiola may be used to modulate the stress response.
Lifestyle – many lifestyle factors can help to reduce cortisol levels and calm the mind and body, here are a few examples:20
- Meditation or mindfulness –
- Moderate, enjoyable exercise
Our lifestyles generally set us up for being in a pro-inflammatory state so it is a perfect time to take a step back and re-assess how we can support health an immunity to support an optimal inflammatory response.
- The cytokine storm is an overreaction of the innate immune system and inflammation becomes out of control. This is a major driver of disease severity and death in COVID-19 patients
- Chronic diseases such as diabetes, cardiovascular disease, hypertension and autoimmunity are associated with a heightened levels of inflammation, this may account for the increased risk of a severe infection due to comorbidities
- The inflammasome is a complex of molecules which is designed to activate the enzyme caspase 1 which is turn increases the activation of further cytokines and can therefore contribute to a cytokine storm. In covid-19 patients research has shown that the NLRP£ inflammasome is activated
- Quercetin and curcumin have been shown to inhibit NLRP3 activation.
- Prospective interventions to support a normal inflammatory response may be prudent to helping prevent disease severity
- Inflammation is increased by poor sleep, stress and a pro-inflammatory diet. Therefore, stress management, sleep support and eating a diet high in omega 3, lower in omega 6, high vegetable intake (of different colours, especially dark leafy greens) and which supports digestive health is useful
If you have questions regarding the topics that have been raised, or any other health matters, please do contact me (Helen) by phone or email at any time.
Amanda Williams and the Cytoplan Editorial Team
- 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
- Liu YZ, Wang YX, Jiang CL. Inflammation: The common pathway of stress-related diseases. Front Hum Neurosci. 2017;11. doi:10.3389/fnhum.2017.00316
- Ye Q, Wang B, Mao J. The pathogenesis and treatment of the “Cytokine Storm” in COVID-19. J Infect. 2020;80(6):607-613. doi:10.1016/j.jinf.2020.03.037
- Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-1034. doi:10.1016/S0140-6736(20)30628-0
- Del Valle DM, Kim-Schulze S, Hsin-Hui H, et al. An inflammatory cytokine signature helps predict COVID-19 severity and death. medRxiv Prepr Serv Heal Sci. May 2020:2020.05.28.20115758. doi:10.1101/2020.05.28.20115758
- Guo H, Callaway JB, Ting JPY. Inflammasomes: Mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21(7):677-687. doi:10.1038/nm.3893
- Yang Y, Wang H, Kouadir M, Song H, Shi F. Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis. 2019;10(2):1-11. doi:10.1038/s41419-019-1413-8
- Chen I-Y, Moriyama M, Chang M-F, Ichinohe T. Severe Acute Respiratory Syndrome Coronavirus Viroporin 3a Activates the NLRP3 Inflammasome. Front Microbiol. 2019;10(JAN):50. doi:10.3389/fmicb.2019.00050
- Gralinski LE, Sheahan TP, Morrison TE, et al. Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis. MBio. 2018;9(5). doi:10.1128/mBio.01753-18
- Gralinski LE, Bankhead A, Jeng S, et al. Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. MBio. 2013;4(4). doi:10.1128/mBio.00271-13
- Gralinski LE, Baric RS. Molecular pathology of emerging coronavirus infections. J Pathol. 2015;235(2):185-195. doi:10.1002/path.4454
- Inflammasomes: Mechanism of Action, Role in Disease, and Therapeutics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519035/. Accessed June 8, 2020.
- Bland J et al. Textbook of Functional Medicine.; 2008.
- Brinton EA, Mason RP. Prescription omega-3 fatty acid products containing highly purified eicosapentaenoic acid (EPA). Lipids Health Dis. 2017;16(1):23. doi:10.1186/S12944-017-0415-8
- Zhang L, Liu Y. Potential interventions for novel coronavirus in China: A systematic review. J Med Virol. 2020;92(5):479-490. doi:10.1002/jmv.25707
- Sun Y, Liu W, Zhang H, et al. Curcumin Prevents Osteoarthritis by Inhibiting the Activation of Inflammasome NLRP3. J Interf Cytokine Res. 2017;37(10):449-455. doi:10.1089/jir.2017.0069
- Murray JPM. Textbook of Natural Medicine. 4th Ed.; 2013.
- Cytokine Storm: What Happens When Your Immune System Overreacts? – Jill Carnahan, MD. https://www.jillcarnahan.com/2020/05/09/cytokine-storm-what-happens-when-your-immune-system-overreacts/?utm_source=Flatiron+Functional+Medicine+Newsletter&utm_campaign=65b284a825-EMAIL_CAMPAIGN_2017_10_06_COPY_01&utm_medium=email&utm_term=0_a07715eedd-65b284a825-&mc_cid=65b284a825&mc_eid=%5BUNIQID%5D&utm_source=Flatiron+Functional+Medicine+Newsletter&utm_campaign=a228b6fa24-EMAIL_CAMPAIGN_2017_10_06_COPY_01&utm_medium=email&utm_term=0_a07715eedd-a228b6fa24-137784849&mc_cid=a228b6fa24&mc_eid=ec2817f48f. Accessed June 10, 2020.
- Rosa Neto JC, Lira FS, Venancio DP, et al. Sleep deprivation affects inflammatory marker expression in adipose tissue. Lipids Health Dis. 2010;9(1):125. doi:10.1186/1476-511X-9-125
- Saeed SA, Cunningham K, Bloch RM. Depression and anxiety disorders: Benefits of exercise, yoga, and meditation. Am Fam Physician. 2019;99(10):620-627.