Annikki
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(Revised) Death from Covid-19 is caused from an overproduction of cytokines in certain patients according to a new research. Cytokines are a problem ME/CFS. It's unclear how our differing cytokine levels could interact with Covid-19. However, the good news is that the cytokine, interleukin-6 (IL-6), which causes death in coronavirus patients, is lowered in ME/CFS patients.
I have included in this post a helpful article about how to reduce your levels of IL-6, written by a knowledgeable IBS patient. Sorry for all the edits, I'm using Linux and I've had a problem with my cursor jumping erratically when I type. Please forgive typos, it is very hard to type on this computer right now.
Information about the "cytokine storm" associated with Covid-19:
Study about Covid-19 and cytokines in The Lancet:
"COVID-19: consider cytokine storm syndromes and immunosuppression"
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext
Study on Covid-19 and cytokines from China:
"Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China"
https://link.springer.com/article/10.1007/s00134-020-05991-x
Article about cytokines and Covid-19 from The Oregonian:
IL-6 is a significant factor in fatal Covid-19 infections:
"Are IL-6 inhibitors one key to COVID-19? EUSA Pharma joins Sanofi, Regeneron in rolling out trials"
https://www.fiercepharma.com/pharma...rma-joins-sanofi-regeneron-rolling-out-trials
On a positive note, there are drugs which control IL-6:
"Anti-IL-6- Wikipedia"
https://en.wikipedia.org/wiki/Anti-IL-6
I was surprised to learn from this article that after aerobic exercise, IL-6 are increased. Speaking about ME, it makes me wonder if increased IL-6 levels after exercise have anything to do with PEM?
Article with important information on how to regulate IL-6 levels:
Cytokines in ME/CFS
I've heard the term "cytokine storm," in discussions about elevated cytokines in ME/CFS.
I think Covid-19 could be a problem if it elevates the same cytokines already elevated in ME. Since it's a different sort of disease/infection, it elevates different cytokines. I haven't directly compared Covid-19 cytokines to ME cytokines, yet. It's hard finding a simple, concise list about ME cytokines. Most studies on ME cytokines which I viewed tested only certain cytokines. I will have to go over about 3 studies and compile a complete list.
One study looked at cytokines which were elevated at night in ME and fibromyalgia. The purpose of the study was to account for sleep problems in each disease. Cytokines can be a complex subject.
On the bright side, many of us are already on drugs which decrease cytokines and reduce inflammation. Some of the medications used to control cytokines in ME and other autoimmune diseases are anti-histamines, immuno-suppressants, and steroids (like Prednisone). Some drugs target only specific cytokines.
I think most of us here are familiar with how cytokines are linked to ME/CFS symptoms. This is a brief refresher about elevated cytokines in ME/CFS for anyone not familiar with this subject:
Cytokines that are elevated/lowered in ME/CFS patients:
How Cytokines Affect ME symptoms:
How does this compare to Covid-19?
This video gives a list of which cytokines are elevated during Covid-19 infection:
"Study Helps Explain ‘Brain Fog’ in Chronic Fatigue Syndrome"
https://www.healthline.com/health-n...rain-fog-in-chronic-fatigue-syndrome-033115#1
"...Many of the cytokines were less common in the CFS group, most notably interleukin 6. In animal research, scientists have shown that the brain needs interleukin 6 in order to form memories. CFS and MS patients did have higher levels of one cytokine — eotaxin — than the healthy volunteers.
I have included in this post a helpful article about how to reduce your levels of IL-6, written by a knowledgeable IBS patient. Sorry for all the edits, I'm using Linux and I've had a problem with my cursor jumping erratically when I type. Please forgive typos, it is very hard to type on this computer right now.
Information about the "cytokine storm" associated with Covid-19:
Source: https://www.cusabio.com/COVID-19-Cytokine-Storm
COVID-19 Cytokine Storm
"On January 25, 2020, Prof Bin Cao's team published a research paper titled "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.". The paper revealed that the immune system of critical patients with COVID-19 (a disease caused by SARS-CoV-2 infection) exists a lethal cytokine storm. So what is the COVID-19 cytokine storm? Why does COVID-19 lead to cytokine storm? And how to treat the cytokine storm caused by COVID-19?
What is COVID-19 Cytokine Storm?
"Before introducing COVID-19 cytokine storm, we must get the knowledge of cytokine storm. As describled in the article entilted "What You Have to Know about Cytokine Storm and Virus Infection", cytokine storm is the phenomenon that a variety of cytokines in the body fluids are rapidly and massively produced after the body is infected with microorganisms. This is actually a large number of viral infections triggering the "suicide attack" of the human immune system.
COVID-19 cytokine storm acturally refers to the cytokine storm caused by COVID-19. Some reports have revealed the direct cause of death from acute COVID-19 is that the novel coronavirus destroy the human immune mechanism and trigger excessive immunity causing cytokine storm. Moreover, cytokine storm damages lungs and multiple organs of the human body (heart, kidney, liver, etc.) , and eventually leading to multiple organ functions exhaustion.
Why Does COVID-19 Lead to Cytokine Storm?
"The cause of COVID-19 is SARS-CoV-2 (formerly known as 2019-nCoV), one of coronavirus. The SARS-CoV-2 infected humans for the first time, and the human immune system didn't recognize the virus. Studies have shown that the SARS-CoV-2 enters cells through angiotensin-converting enzyme 2 (ACE2). For this reason, lung tissue has become the main invasion target of the SARS-CoV-2 with high expression of ACE2. After the virus entered the lung, the immune system sent a large number of immune cells to the lung tissue to kill the virus. This formed pneumonia, and the patient showed fever, cough, and difficulty breathing.
However, these immune cells cannot locate the virus accurately because they are not recognize it. They only attack indiscriminately and recruit more immune cells to kill the virus. Once a cytokine storm is formed, the immune system may not be able to kill the virus, but it will certainly kill a large number of normal cells in the lung, which will seriously damage the function of the lung. Patients will have respiratory failure until they die of hypoxia.
What are The Cytokines of Cytokine Storm Caused by COVID-19?
"According to the publication of Prof Bin Cao's team, they found that severe patients have significantly higher levels of plasma pro-inflammatory factors (IL2, IL7, IL-10, GSCF, IP-10, MCP-1, MIP1A, TNF-α) than mild patients with COVID-19, and these inflammatory indicators indicate a cytokine storm in severe patients.
Acturally, since the outbreak of the SARS epidemic, the "cytokine storm" has aroused great attention. Furthermore, the alignment between SARS-CoV-2 and 2002 SARS CoV has about 70% sequence similarity and 40% sequence similarity with MERS CoV. And all of them are belong to coronavirus. Although the study of SARS-CoV-2 is not very large, we can refer to the study of 2002 SARS CoV and MERS CoV. Accumulating studies indicated that the cytokine storm caused by SARS is mainly related to IL-1β, IL-6, IL12A, IFN-γ, IP10 and MCP1, and the cytokine storm caused by MERS is mainly related to IFNγ, TNFα, IL15 and IL17A.
For the cytokine storm detction, mainly depends on the detection of elevated inflammatory factors in the blood. And different viruses do not trigger cytokine storms through exactly the same mechanism, so they will cause different cytokine changes.
Study about Covid-19 and cytokines in The Lancet:
"COVID-19: consider cytokine storm syndromes and immunosuppression"
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext
Study on Covid-19 and cytokines from China:
"Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China"
https://link.springer.com/article/10.1007/s00134-020-05991-x
Article about cytokines and Covid-19 from The Oregonian:
"The coronavirus turns deadly when it leads to ‘cytokine storm’; identifying this immune response is key to patient’s survival: report"
https://www.oregonlive.com/coronavi...ponse-is-key-to-patients-survival-report.html
Covid-19, the disease caused by the novel coronavirus that has swept across the globe, is not like a bad case of the flu. For one thing, a new study indicates that Covid-19 triggers in some people something called a cytokine storm, where one’s own immune system goes berserk. This “virus-activated” immune response can be deadly, causing severe respiratory distress and the subsequent shutdown of multiple organs.
Indeed, how one’s immune system reacts appears to be central to Covid-19′s severity. “The virus matters, but the host response matters at least as much, and probably more,” University of Iowa virologist Stanley Perlman told The Scientist magazine last month.
For some people whose immune systems are compromised by age or for often-subtle genetic or environmental reasons, the normal immune response doesn’t retreat when it should. It goes into overdrive, leading to “a flood of immune cells into the lung.” This has a rapid cascading effect in the body.
Key to the patient’s survival is their doctors quickly recognizing this is happening. Dr. Randy Q. Cron and Dr. W. Winn Chatham, in a report for Vox, wrote that --
- All Covid-19 patients sick enough for hospitalization should be given a cheap, quick, and readily available serum ferritin blood test. Indeed, elevated serum ferritin values have recently been reported in Chinese hospitalized patients with Covid-19. This is a good first screening tool for the possibility of a cytokine storm syndrome in sick patients with high fevers.
The question then remains how best to treat a cytokine storm syndrome once it is identified. The treating physician is often placed between a rock and a hard place. Corticosteroids can be powerfully broad immunosuppressive agents, and they are inexpensive and readily available throughout the world. However, it can be frightening for a physician to treat a severely ill, infected individual with such powerful and wide-ranging immune suppression.
Cron and Chatham pointed out that there are other, more targeted drugs available as well, though trials will be needed to figure out which ones work best for Covid-19.
In China, coronavirus patients exhibiting signs of cytokine-storm syndrome reportedly are being treated with the anti-inflammation drug Actemra (tocilizumab). Actemra is used in the U.S. for rheumatoid arthritis.
-- Douglas Perry
IL-6 is a significant factor in fatal Covid-19 infections:
"Are IL-6 inhibitors one key to COVID-19? EUSA Pharma joins Sanofi, Regeneron in rolling out trials"
https://www.fiercepharma.com/pharma...rma-joins-sanofi-regeneron-rolling-out-trials
On a positive note, there are drugs which control IL-6:
"Anti-IL-6- Wikipedia"
https://en.wikipedia.org/wiki/Anti-IL-6
I was surprised to learn from this article that after aerobic exercise, IL-6 are increased. Speaking about ME, it makes me wonder if increased IL-6 levels after exercise have anything to do with PEM?
Article with important information on how to regulate IL-6 levels:
"Inhibiting Interleukin-6 (IL-6): The Key To Health"
https://selfhack.com/blog/interleukin-6/
What is Interleukin-6?
Interleukin-6 (IL-6) is a cytokine with well-defined pro- and anti-inflammatory properties [1]. It regulates the immune system and plays a role in cognitive function.
IL-6 is elevated when you are sick and after exercise, especially aerobic exercise [2].
If exercise increases inflammatory markers, then why is exercise healthy? Well, when you exercise, your muscles release IL-6, which is anti-inflammatory. However, when your immune cells (macrophages) release it, it’s pro-inflammatory [2]. The harmful effect has to do, in part, with it being released with other immune cells that synergize in a negative way.
IL-6 also suppresses Th1 cells, while it induces Th2 cells [3], so it’s worse for Th2 dominant folks. It also increases B cells, which is what produces antibodies and contributes to allergies and autoimmunity [4].
People who aren’t predisposed to autoimmune issues can also have elevated IL-6. It’s the cytokine that is involved in the diseases of modern civilization. The most common cause is probably obesity.
There are two ways that IL-6 can activate cells. One way is anti-inflammatory and helps in tissue regeneration. Another is pro-inflammatory and causes all kinds of problems. See below for a more detailed explanation.
The most common reasons for elevated IL-6 are obesity [5], chronic stress [6], too little sleep [7], eating too much – specifically, eating too much sugar or refined foods [8], smoking [9], excess alcohol, [10] and exercising too much [11] (more than 2 hours of intense exercise a day is probably not a good idea for most).
The Bad
IL-6 levels are increased in nearly all disease states [1].
It decreases Treg cells, which in turn blocks our ability to create tolerance for proteins we ingest – causing allergies [12]. It also increases the production of neutrophils, which is inflammatory [2].
Interleukin-6 is a decent predictor of cognitive decline in late midlife. A 10-year decline in reasoning was greater among people with high IL-6 than those with low IL-6. In addition, people with high IL-6 had 1.81 times greater odds of a decline in a test that measures normal cognitive function [13].
IL-6 may cause feelings of “hopelessness“. This state strongly correlated with IL-6 levels [14] and we know this cytokine can cause brain changes that lead to a worsened mood. IL-6 is also correlated with violent suicide, impulsivity, and monotony avoidance [15].
IL-6 causes elevated blood sugar levels, which we know is problematic for general health [16].
IL-6 levels are higher in people with IBS [17, 18].
Studies have found that IL-6 aggravates the effects of stress hormones (CRH) on our gut mucosa, which causes IBS [19]. It also causes IBS by activating gut neurons [20], which alters peristalsis. IL-6 can cause leaky gut [21].
IL-6 may lessen fatigue by stimulating the HPA axis and suppressing TNF-alpha (thereby increasing orexin). Specifically, it stimulates the release of the corticotrophin-releasing hormone (CRH) by the hypothalamus (reversed by a COX inhibitor) [22].
It increases nitric oxide [4], which can be good or bad, depending on the situation.
At higher levels, IL-6 increased the release of vasopressin and oxytocin [22], which acts to decrease urination, among other effects.
IL-6 suppresses or ‘hypermethylates‘ gene expression in the brain, which leads to a variety of problems [2].
For example, it decreases BDNF, a brain growth factor, which is how it contributes to depression [2].
People with major depressive disorder have elevated IL-6 (TNF-alpha) [23] and it likely contributes to a worse mood overall.
It can also lead to lower testosterone levels [24].
While IL-6 decreases testosterone in normal cells, it increases production in prostate cancer cells, which is required for this cancer to grow [25]. So it’s a double whammy – it decreases testosterone in normal cells and increases it in cancer cells. Damn you, IL-6!
IL-6 also decreases performance by decreasing the conversion of T4 to T3 (thyroid hormones), resulting in lower levels of T3. This occurs as a result of IL-6 causing oxidative stress and lowering glutathione levels [26, 27].
IL-6 contributes to schizophrenia by inhibiting (or hypermethylation) a gene (GAD67) that is important for GABA to work properly [2].
HDAC inhibitors are beneficial for cognitive disorders because they increase gene expression for growth factors like BDNF. IL-6 does the opposite by increasing HDAC [28]. Resistant starch is a powerful way to inhibit HDAC and therefore increase BDNF.
IL-6 is the most potent inducer of CRP, an inflammatory marker, but as I will explain below, you can have normal CRP levels and abnormal IL-6 levels.
It can create and worsen food sensitivities and autoimmune issues by increasing IgG and IgM antibodies [29]. Testosterone decreases these antibodies, but IL-6 is capable of increasing them even with high levels of testosterone [29]. (Estrogen increases these antibodies) [30].
IL-6 can also cause skin problems. When your natural skin fungus gets out of control the body attacks it with cytokines that include IL-6 (also IL-1b, TNF, IL-8), which recruits other aspects of the immune system [31]. IL-6 is elevated in people with tinea versicolor, a skin fungus [32]. IL-6 also increases Th22 cells, which disrupts skin microbial balance [33].
IL-6 (or IL-21 according to some) can increase Th17 cells, which are pro-inflammatory. To do this, you also need elevated TGF-β [34].
IL-6 can keep you from getting into ketosis [35].
The Good
I would say IL-6 is mostly bad if elevated, but brief spikes can be beneficial, just like brief bouts of intense exercise.
TNF and IL-1b increase IL-6 [36], but IL-6, in turn, suppresses both of these cytokines, which are more harmful than IL-6 itself. In this way, it’s an anti-inflammatory [37, 38].
IL-6 increases liver regeneration [39] and helps form emotional memories while sleeping [2].
IL-6 Makes Us Thinner
It also inhibits TNF, breaks down fat cells and decreases insulin resistance [40].
Science has discovered that exercise can help you lose weight more than by just burning calories; exercise changes your hypothalamus [41].
IL-6 is part of this mechanism by which exercise can help us lose weight [41].
IL-6 decreases insulin and leptin resistance in the hypothalamus, the gland that controls appetite (requires IL-10 to inhibit Nf-kB) [42].
IL-6 also increases spontaneous energy expenditure. Mice lacking IL-6 became obese [41].
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IL-6 Can Fight Infections
IL-6 plays a protective role in many bacterial, viral, and fungal infections.
It has a protective role in the flu, H pylori, and EMCV [43]. Mice deficient in IL-6 are significantly more susceptible to some fungal infections like candida [44].
In mice, IL-6 helps prevent common herpes infection (HSV-1), but it doesn’t prevent its reactivation [45].
Diseases Associated With Interleukin-6
IL-6 is responsible for causing many autoimmune diseases [46]. There are many theories about how this occurs, but the point is that it’s causal and not just correlated. One way IL-6 does this is by decreasing the cells that regulate the immune system from attacking itself (Treg cells) [2].
If you decrease IL-6, you will decrease the progression of many inflammatory conditions.
This is a partial list:
Top Ways to Inhibit IL-6
- Heart disease [47]
- Cancer (Myeloma [28], Prostate [28], Breast [48], etc…)
- Diabetes [28]
- Pain [49]
- Rheumatoid arthritis – strongest evidence [50], Fibromyalgia [51], Multiple Sclerosis [52], Behcet’s [53], SLE [54], System Sclerosis [46].
- Asthma. IL-6 promotes Th2 activation and allergic responses and inhibits the activity of regulatory T cells (Tregs), which helps get rid of substances you’re allergic to.
- IBS [18], IBD, Crohn’s [46]
- Major depression [55], Bipolar [55], Schizophrenia [55], Alzheimer’s [28], Intellectual disability [56]
- Osteoporosis (postmenopausal) [57]. IL-6 promotes osteoclasts, which degrade bones [2].
- PCOS [58]
- Others: Diabetic neuropathy [59], Chemotherapy-induced neuropathy [60], Tinea versicolor, a skin fungus [32], Carpal Tunnel Syndrome [61], Polymyalgia Rheumatica [62].
Factors That Increase Interleukin-6 Levels
- Spices: Bay leaves [63], Black pepper [63], Nutmeg [63], Oregano [63], Sage [63]
- Resistant starch [64]
- Zinc [65]
- Magnesium [66]
- Probiotics: B. infantis [67], S. boulardii [68], L. casei [69], L. Salivarius [70]
- Trehalose [71, 72]
- Jasmine Tea/EGCG[73]
- Vitamin D3 [74]
- PQQ [75]
- Andrographis/Andrographolide [76] – Out of 20 plants tested, Andrographis inhibited IL-6 the most and was more potent than dexamethasone. (IC50= .74mcg/ml)
- Black Cumin Seed Oil/Thymoquinone [77]
- Curcumin [78, 79]
- Licorice [80]
- Fish oil/DHA [81]
- Fisetin [82]
- Cinnamon [63] /Sodium Benzoate
- Molecular hydrogen machine [83]
- Aspirin [84]
- Boswellia [85]
- Lithium[86]
- Hydroxytyrosol [87]
- Apigenin [63]
- Luteolin [88]
- Quercetin [63]
- Resveratrol (500 mg, with 5 g leucine) [79, 89]
- Red Yeast Rice/Lovastatin [90]
Diet
Lifestyle
- High blood sugar levels – High blood sugar levels activate immune cells like monocytes and increase inflammation [91].
- PHA (lectin) [92], ConA (lectin) [92]
- High glycemic index foods [8]
- High-fat diet [93]
- Coffee [94] – People who drank more than a cup had 50% greater IL-6 (association). Seems to be confirmed in a randomized control trial in people with diabetes, which showed a similar 60% increase [95].
- Acrylamide [96] – found in starchy foods such as potato chips (potato crisps), French fries, and bread that had been heated higher than 120°C (248°F) (production of acrylamide in the heating process was shown to be temperature-dependent). It was not found in food that had been boiled. Acrylamide is also found in black olives, prunes, dried pears, coffee, cocoa powder, and chocolate, formed during cacao bean roasting [97].
Hormones
- Chronic insomnia [98] – Elevates IL-6 in the day time.
- Sleep deprivation [7]
- Excessive exercise/Marathons [11]
- Obesity [5]
- Circadian Rhythm disruption [99]
- Smoking [9]
- Excess alcohol [10]
- Chronic stress [6]
- Viruses, like Herpes Virus (HHV8), can produce a protein similar to IL-6 that is even more inflammatory [50].
- Infections (some). For example, people with lingering symptoms from Lyme have elevated IL-6 [100].
Nutrition
- Leptin [101]
- Thyroid hormones/T3 [102, 103]
- Melatonin [104]
- Angiotensin II [105]
Supplements/Drugs
- Vitamin D deficiency [106]
- Zinc deficiency [65]
- Magnesium deficiency [66]
- Calcium deficiency [106]
- Vitamin C deficiency [107]
- Choline Deficiency [108] – People who consumed more than 310 mg per day had a 26% lower concentrations of IL-6 than those who consumed less.
Interleukin-6 Inhibitors
- Aloe [109] – (in cancer cells)
- 5-HTP (at lower and higher concentrations) [110]
- Reishi [111]
- Grapeseed extract [112] – in astrocytes, which is neuroprotective.
- Astragalus [113]
- Cat’s Claw [109]
- Rooibos [114]
- Grape powder [115] (LPS)
- Creatine at very high dosages (116)
- Phosphatidyl Choline – in response to infection [117]
- Antidepressants: Imipramine and venlafaxine (at the higher concentration) [110]. A combination of 5-HTP and fluoxetine (antidepressants) (both at the lower concentration) [110].
Lifestyle/Diet
Nutrients
- Positive emotions were associated with lower IL-6 (especially awe, wonder, and amazement) [118].
- Calorie Restriction [119]
- Wim Hof Breathing/Meditation [120]
- Napping after sleep loss [121]
- Vegetables/Phytosterols [122]
- LLLT [123, 124, 125]
- Legumes [126]
- Nuts [127]
- Oat polyphenols [128]
- Mediterranean diet [129]
- Olive oil [130]
- Ancient wheat [131]
- Fish oil [132]
- Phytic acid [133]
- Blueberry [134]
- Music [135]
- Honey [136]
- Elemental diet in Crohn’s disease [137]
- Broccoli sprouts/Sulforaphane [138]
- Soy [139]
- Oats [140]
- Cashew [96]
- Spirulina [141]
- Stevia [142, 143]
- Garlic [144] (raw is better)
- Red raspberries [145]
- Jasmine Tea [146]
Hormones
- Vitamin B-12 [92]
- Fish oil [147, 148]
- Magnesium [149]
- Chromium [150]
- Arginine [151]
- Histidine [152]
- Vitamin E [153] – rats fed oxidized oils.
Supplements
Mechanisms
- Bile [157]
- Glycine [158]
- Inositol [159]
- Bromelain [160]
- Ginkgo [161]
- Sialic Acid [162, 163]
- Berberine[164]
- Elm bark [165]
- Apple polyphenols [166]
- Chinese Skullcap [167]
- Carnosine [168]
- LDN [169]
- Grape Seed Extract [170]
- Betulin/Chaga [171]
- Cocaine [172]
- Honokiol [173]
- Artemisinin [174]
- Baicalin [175]
- RLA (Lipoic Acid) [176]
- Lactoferrin [177]
- Mastic gum [178]
- Ashwagandha
- Alfalfa – potent [179]
- Caffeic acid (Chlorogenic acid has caffeic acid) [180]
- Ellagic acid [180]
- Fucoidan [181]
- Astaxanthin [182]
- Astragalus [183]
- Danshen [184]
- Dandelion [185]
- Genistein [186]
- Hesperidin [187]
- Tart Cherry [188]
- Vitamin E/Tocotrienols [189]
- Antler velvet [190]
- Quercetin [82]
- Rutin [82]
- Myricetin [82]
- Echinacea [191]
- Rosmarinic acid [192]
- Red clover [193]
- Bitter melon [194]
- Magnolol [195]
- Glutamine [196]
- Allegra/Fexofenadine [197]
- Metformin [198]
- MSM
- Chrysin [199]
- Electroacupuncture [200], Structured water [201], Mizolastine (antihistamine) [197], Oxymatrine [202], Methotrexate (drug) [203], Sumac [204], Perilla [205], Tibetan medicated-bath [206].
Interleukin 6 on SelfDecode
What Are Healthy Interleukin-6 Blood Levels?
In healthy subjects, IL-6 blood levels are barely detectable and range between 2 – 6 pg/ml. Another study mentions that healthy people have a median level of 0.5 pg/ml [208]. Depressed people had IL-6 levels about 1.78 pg/ml greater than healthy people [209].
In people with Rheumatoid Arthritis, levels can increase up to a thousand-fold (not common). In sepsis, which is extremely dangerous, it can increase up to a million-fold [50]. (Sepsis is a potentially fatal whole-body inflammation caused by severe infection).
Chronically elevated levels will cause harm in the long run. One study checked for diseases of aging and IL-6 levels. After adjustment for potential confounders, they found that having a high interleukin-6 level (greater than 2.0 pg/ml) twice over a 5-year period nearly halved the odds of “successful aging” at the 10-year follow-up and increased the risk of future heart disease and overall death [210]. (They only checked IL-6 levels twice).
Note that all of the people in the study were free of cancer and heart disease, so these weren’t what you’d call really sick people. They defined successful aging as “being free of major chronic disease and with optimal physical, mental, and cognitive functioning” [210]. I couldn’t define it better myself.
In people who exercised for 3 – 3.5 hours (marathon exercise), IL-6 increased from 1.5 pg/ml to 94.4 pg/ml immediately post-exercise and to 22.1 pg/ml 2 hours post-exercise (half-life of 1 – 2 hours) [211]. This means blood levels should be completely normal the next day – even after running a marathon.
In a group of people with cirrhosis, everyone with a proven bacterial infection had IL-6 levels above 200 pg/ml. On the other hand, 74% of the people with high IL-6 levels had these bacterial infections [212]. These people had cirrhosis, so it would make sense that many would have high inflammation without bacterial infections. The takeaway is if you have high IL-6 levels without a chronic inflammatory condition, I would suspect some kind of infection.
In another study, patients hospitalized for moderate bacterial and viral infectious diseases were checked for their cytokines. IL-6 was associated with a bacterial rather than a viral infection [213]. This is useful information when trying to figure out if someone’s problems are more likely viral or bacterial. In the study, people who took antibiotics had their IL-6 normalize after only 3 days (from 39 to 2) [213, 214]. The average IL-6 level for people with bacterial infections was 237 pg/ml. It was undetectable for viral infections [215].
I had a client check her IL-6 levels and her result was 528 pg/ml. This client had high IL-6 at 528 pg/ml and her hs-CRP was 0.4, which is very low. Therefore, IL-6 is the main driver CRP, but CRP is not a reliable indicator, as you’ll read below.
It should be noted that these numbers do not take into account the local IL-6 levels at the site of inflammation, which is largely unknown since they are mostly not experimentally accessible [50].
This can be the case where inflammation is more localized, so it won’t be picked up by these tests. Therefore, not having elevated inflammatory cytokines isn’t definitive, but if you do have elevated cytokines, it’s certainly telling.
CRP Isn’t Such A Reliable Factor
The most common way of checking inflammation – high-sensitivity C-reactive protein (hs-CRP) is not very relevant.
CRP is produced by the liver AND fat cells [216], so it makes sense that it’s more elevated in overweight people [217].
CRP is mainly increased by IL-6 [218], but also IL-1b and TNF.
IL-6 will be elevated moderately if you are overweight since IL-6 is also secreted by fat cells.
CRP will only show a spike, however, if you run marathons (maybe), have an acute infection, or incur a serious injury. These are situations where IL-6 spikes.
However, in most people with chronic inflammation who are thin, CRP will likely come back normal.
My CRP levels were low even when I was experiencing chronic, low-grade inflammation, and I didn’t experience fever.
To illustrate my point, many studies show IL-6 is elevated with IBS [17, 18]. However, when a study checked for hs-CRP and IBS, the differences were significant but very small.
People with IBS have an average hs-CRP of 1.17, while healthy controls have a level of 0.72 [219]. The standard value is under 3.0.
No doctor would even blink at the difference between 1.17 and 0.72. They would tell you that you are perfectly healthy.
C-reactive protein correlated only weakly with interleukin-6 levels in people with cirrhosis [212].
Another example is cognitive decline. According to a study, elevated IL-6 but not CRP in midlife predicts cognitive decline [13]. Obviously, these two inflammatory markers aren’t two peas in a pod.
In another example, although CRP levels were significantly lower in SLE than in Rheumatoid Arthritis, the concentrations of circulating TNF-alpha were higher in SLE [54].
I had a client with highly elevated IL-6 but at the same time a very low hs-CRP (0.4).
So we see from the IBS example that hs-CRP can tell us something, but we also see that in conditions with elevated IL-6, CRP can be more or less normal.
This is why we shouldn‘t rely on hs-CRP as an indicator of inflammation and should take other tests.
IL-6: Pro and Anti-Inflammatory Effects
There are two types of IL-6. One is called “Classic signaling” and the other is called “Trans-signaling.”
IL-6 Classic signaling is needed for regenerative and anti-inflammatory roles.
IL-6 Trans-signaling takes place when IL-6 receptors (soluble IL-6 receptors or sIL-6R) in the blood bind with IL-6. This kind of cellular activation by IL-6 is what causes inflammatory problems [50].
In models of inflammation, autoimmune diseases, and inflammation-associated cancer, blockade of IL-6 trans-signaling was sufficient to block the inflammatory progress [50].
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During Coronavirus Pandemic: Stay Away From Anything That Causes Inflammation!
Experts are saying to avoid anything that causes inflammation during this Coronavirus pandemic, but some people have genes that make them more likely to experience inflammation. Check out SelfDecode’s Inflammation DNA Wellness Report for genetic-based diet, lifestyle and supplement tips that can help reduce inflammation levels. The recommendations are personalized based on YOUR DNA.
Cytokines in ME/CFS
I've heard the term "cytokine storm," in discussions about elevated cytokines in ME/CFS.
I think Covid-19 could be a problem if it elevates the same cytokines already elevated in ME. Since it's a different sort of disease/infection, it elevates different cytokines. I haven't directly compared Covid-19 cytokines to ME cytokines, yet. It's hard finding a simple, concise list about ME cytokines. Most studies on ME cytokines which I viewed tested only certain cytokines. I will have to go over about 3 studies and compile a complete list.
One study looked at cytokines which were elevated at night in ME and fibromyalgia. The purpose of the study was to account for sleep problems in each disease. Cytokines can be a complex subject.
On the bright side, many of us are already on drugs which decrease cytokines and reduce inflammation. Some of the medications used to control cytokines in ME and other autoimmune diseases are anti-histamines, immuno-suppressants, and steroids (like Prednisone). Some drugs target only specific cytokines.
I think most of us here are familiar with how cytokines are linked to ME/CFS symptoms. This is a brief refresher about elevated cytokines in ME/CFS for anyone not familiar with this subject:
Cytokines that are elevated/lowered in ME/CFS patients:
"Cytokine signature associated with disease severity in chronic fatigue syndrome patients"
https://www.pnas.org/content/114/34/E7150
"On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration."
How Cytokines Affect ME symptoms:
Dampening inflammation
"Armstrong’s own team have found that the fatigue of CFS may be caused by disrupted metabolism and energy production in the body. “The metabolic changes we found suggest a physiological stressor in the body is affecting the cells,” he says. “The cause of that stress is unknown, but is likely to be immune-based given the mounting evidence in that direction – this new study included.”
A team in Norway has had some early success in treating CFS by targeting the immune system and reducing inflammation. They have been using a drug called rituximab to wipe out the white blood cells that may make inflammatory antibodies.
Montoya says it’s unclear what causes the increase in cytokines they have seen in CFS, but he thinks something is triggering inflammation in the body – possibly an infection like the herpes virus.
Journal reference: PNAS, DOI: 10.1073/pnas.1710519114
How does this compare to Covid-19?
This video gives a list of which cytokines are elevated during Covid-19 infection:
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