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The cytokines stimulated by Covid-19 infection are the main cause of death in patients and cytokines in ME/CFS


Senior Member
(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.

"Study Helps Explain ‘Brain Fog’ in Chronic Fatigue Syndrome"
"...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"


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"

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"

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"

On a positive note, there are drugs which control IL-6:
"Anti-IL-6- Wikipedia"

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"
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

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].


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:

  • 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].
Top Ways to Inhibit IL-6
Factors That Increase Interleukin-6 Levels
  • 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].
  • 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].
  • 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].
Interleukin-6 Inhibitors
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 shouldnt 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].


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"
"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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Senior Member
Very interesting findings, (a Cytokine (storm) syndrome is also a (very dangerous) MCAS symptome)
The thing I was all the time curious that I never had increased IL6 nor TNF-a (also not after doing exercises), instead off it I had high TGF-ß, IFN-y, IL4, IL8. (some off these Cytokine make somewhat similar trouble like IL6 and shift the immune system to TH2 mode, so btw. my postviral CFS improved from MCAS therapy)

Since there are some studies around confirming high Cytokine in ME/CFS, I guess that there is at last a (postviral) CFS subgroup where the disease is triggered or spur on by whatever so kind off mastcell activation (from chronic virus load or however so)


Senior Member
Very interesting findings, (a Cytokine (storm) syndrome is also a (very dangerous) MCAS symptome)
The thing I was all the time curious that I never had increased IL6 nor TNF-a (also not after doing exercises), instead off it I had high TGF-ß, IFN-y, IL4, IL8. (some off these Cytokine make somewhat similar trouble like IL6 and shift the immune system to TH2 mode, so btw. my postviral CFS improved from MCAS therapy)

Since there are some studies around confirming high Cytokine in ME/CFS, I guess that there is at last a (postviral) CFS subgroup where the disease is triggered or spur on by whatever so kind off mastcell activation (from chronic virus load or however so)

Our cytokines are out of whack. I wish I could provide a clearer picture of exactly how.
I've had trouble compiling a clear list of differing cytokine levels in ME, because some studies have differing results. I wasn't surprised to find a study that tries to resolve and negotiate conflicts in results of ME cytokine studies:

This explained why I was struggling to provide a clear list for this article. I couldn't read that study without feeling like there are differing levels of dedication to solving ME among researchers. I still see studies which treat ME like it is influenced psychological factors, though that study may be performing biological tests at the same time.

I think with ME and other autoimmune diseases, we are still crawling out of the morass of ignorance and bias which has plagued research into these conditions for years. This can make answers slow in coming. Bias in research is a bane to research.

I'm certain that ME patients have some cytokines which are abnormally high and some which are abnormally low. Cytokine levels can differ in various ME patients and subsets of ME patients. Also our levels of cytokines vary at different times of the day. When patients get tested for these studies will also lead to confusing results.

Cytokines play a huge role in a plethora of autoimmune diseases. Dampening down cytokine levels has led to symptom reduction in a host of autoimmune diseases. Cytokine targeted therapies in autoimmune disease are very helpful. It's symptom control, but it typically works.

Calming down cytokines also heals medical conditions outside the realm of autoimmunity.
Video eliminating cytokines in the critically ill:

The next video explains cytokine storms. The graphics in the video help make this complex subject understandable.

I'm sorry if the most anyone gets out this article is to watch their IL-6 levels if they get Covid-19. I wish I had better data on how coronavirus could act in the body of an ME patient. I guess we need more research so let's keep the pressure on to get the research. In the meantime, you know your own body and it's limitations. Try to work within these limits. At least most of us have been already social distancing.


Senior Member
There where also studies about Cytokine and PEM:

The main problem is like you said that there is no clear list and line,
it remained also in the PEM study somewhat unclear if these or that high Cytokine were at last CFS or FMS related (or perhaps just stress-related). So another problem exspecially with (abnormal increased) IL6 is that this Cytokine has also been linked in some studies to stress-related (psychiatric) disorders and some other diseases as well.
This makes it somewhat difficult (if not nearly impossible) to forcast if abnormal levels off a single Cytokine is at last a sign for this or that diseases.
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Senior Member
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.

Cytokine studies in ME/CFS are notoriously inconsistent, showing contradictory results. This study for example shows that IL-6 is high in ME/CFS.

I believe the only consistent finding is that TGF-beta is elevated in ME/CFS.


Senior Member
I believe the only consistent finding is that TGF-beta is elevated in ME/CFS.
Yes, as far as I rememeber Dr. Montoya also mentioned it and that high TGF-ß +ME/CFS is associated with a high risc for Hodkins cancer. Btw. TGF+ß is also used (depending on the lab) as mastcell mediator released Cytokine for diagnosing MCAS (together with Histamine, Tryptase, Leukotriene and so on).
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Senior Member
Yes, as far as I rememeber Dr. Montoya also mentioned it and that high TGF-ß +ME/CFS is associated with a high risc for Hodkins cancer. Btw. TGF+ß is also used (depending on the lab) as mastcell mediator released Cytokine for diagnosing MCAS (together with Histamine, Tryptase, Leukotriene and so on).
TGF-alpha is associated with IL-6. Do you know if TGF-alpha is abnormal in CFS/ME?


Senior Member
I dont know if there were any studies around CFS + TGF-alpha. The Dr. tested a bunch off Cytokines in my case, but they didnt test TGF-alpha - so I guess it isnt that important part in CFS.


nucleus caudatus et al
Ik waak up
Here already a review on IL-6, though not already peer reviewed.

Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis
Eric Anthony Coomes, View ORCID ProfileHourmazd Haghbayan
doi: https://doi.org/10.1101/2020.03.30.20048058
Purpose: Coronaviruses may activate dysregulated host immune responses. As exploratory studies have suggested that interleukin-6 (IL-6) levels are elevated in cases of complicated COVID-19 and that the anti-IL-6 biologic tocilizumab may be beneficial, we undertook a systematic review and meta-analysis to assess the evidence in this field.

Methods: We systematically searched MEDLINE and EMBASE for studies investigating the immunological response in COVID-19 or its treatment with tocilizumab; additional grey literature searches were undertaken. Meta-analysis was undertaken using random effects models.

Results: Eight published studies, three pre-prints, and five registered trials were eligible. Meta-analysis of mean IL-6 concentrations demonstrated 2.9-fold higher levels in patients with complicated COVID-19 compared with patients with non-complicated disease (six studies; n=1302; 95%CI, 1.17-7.19; I2=100%). A single non-randomized, single-arm study assessed tocilizumab in patients with severe COVID-19, demonstrating decreased oxygen requirements, resolution of radiographic abnormalities, and clinical improvement. No adverse events or deaths were observed.

Conclusions: In patients with COVID-19, IL-6 levels are significantly elevated and associated with adverse clinical outcomes. While inhibition of IL-6 with tocilizumab appears to be efficacious and safe in preliminary investigation, the results of several ongoing clinical trials should be awaited to better define the role of tocilizumab in COVID-19 prior to routine clinical application.
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nucleus caudatus et al
Ik waak up
It had been proposed that covid-19 deaths correlate with NO2 pollution (this may indeed appear to be the case, see post after next post).
In this case, mechanism of action should be a bit different than it seemed at first sight:

The Dose–Response Association between Nitrogen Dioxide Exposure and Serum Interleukin-6 Concentrations
Jennifer L. Perret et al 2017
Systemic inflammation is an integral part of chronic obstructive pulmonary disease (COPD), and air pollution is associated with cardiorespiratory mortality, yet the interrelationships are not fully defined. We examined associations between nitrogen dioxide (NO2) exposure (as a marker of traffic-related air pollution) and pro-inflammatory cytokines, and investigated effect modification and mediation by post-bronchodilator airflow obstruction (post-BD-AO) and cardiovascular risk. Data from middle-aged participants in the Tasmanian Longitudinal Health Study (TAHS, n = 1389) were analyzed by multivariable logistic regression, using serum interleukin (IL)-6, IL-8 and tumor necrosis factor-α (TNF-α) as the outcome. Mean annual NO2 exposure was estimated at residential addresses using a validated satellite-based land-use regression model. Post-BD-AO was defined by post-BD forced expiratory ratio (FEV1/FVC) < lower limit of normal, and cardiovascular risk by a history of either cerebrovascular or ischaemic heart disease. We found a positive association with increasing serum IL-6 concentration (geometric mean 1.20 (95% CI: 1.1 to 1.3, p = 0.001) per quartile increase in NO2). This was predominantly a direct relationship, with little evidence for either effect modification or mediation via post-BD-AO, or for the small subgroup who reported cardiovascular events. However, there was some evidence consistent with serum IL-6 being on the causal pathway between NO2 and cardiovascular risk. These findings raise the possibility that the interplay between air pollution and systemic inflammation may differ between post-BD airflow obstruction and cardiovascular diseases.
In a cross-sectional analysis of middle-aged adults, we have described an incremental pattern of pollution-related responses for serum IL-6 with regard to NO2 exposure, which was not observed for other pro-inflammatory cytokines, namely, IL-8 and TNF-α. Although case numbers were limited, we have shown that this NO2-IL-6 relationship was neither modified nor mediated by the presence of post-BD-AO. In contrast to this lack of influence from post-BD-AO, serum IL-6 was found to act on cardiovascular risk, which is consistent with IL-6 being on the causal pathway between NO2 and cardiovascular disease. While it is important to examine the cardiorespiratory effects of pollutant co-exposures including PM2.5, overall, these findings reinforce public health recommendations to reduce exposure to outdoor air pollutants. This includes the avoidance of combustion-derived pollution from gasoline and diesel, industry and sources of biomass burning, which is relevant even in low-pollution settings.

Effects of NO 2 Exposure on Daily Mortality in São Paulo, Brazil
Amine Farias Costa et al 2017
Background: Recent reports have suggested that air pollution mixtures represented by nitrogen dioxide (NO2) may have effects on human health, which are independent from those of particulate matter mass. We evaluate the association between NO2 and daily mortality among elderly using one- and multipollutant models.

Methods: This study was a daily time series of non-accidental and cause-specific mortality among the elderly living in São Paulo, Brazil, between 2000 and 2011. Effects of NO2, particulate matter smaller than 10µm (PM10), carbon monoxide (CO) and ozone (O3) were estimated in Poisson generalized additive models. The single lag effect at lags 0 and 1 days and the cumulative effect from 0 to lag 10 days were evaluated in one-, two-, three- and four-pollutant models. The cumulative risk index (CRI) recently proposed to analyze associations with health of multiple correlated pollutants was additionally estimated for each multipollutant model.

Results: An association between NO2, PM10, CO and O3 exposures and non-accidental and cause-specific deaths was found in one-pollutant models. NO2 effects remained significant in multipollutant models for non-accidental and circulatory deaths. The estimated CRIs suggested that circulatory deaths were mainly associated with NO2, and respiratory deaths mainly with CO and O3, regardless the lag. For non-accidental deaths, multipollutant models were associated with the highest CRI, with the main pollutants depending on the chosen lag.

Conclusions: The results suggest that air pollution mixtures represented by NO2 have an effect on non-accidental and circulatory mortality, which is independent from PM10, CO and O3. The CRI was always larger than the risks associated with single pollutants.
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nucleus caudatus et al
Ik waak up
Interaction of Nitrogen Monoxide With Hemoglobin and the Artefactual Production of S-nitroso-hemoglobin
Herold 2003, a review
Hemoglobin (Hb) is probably the most thoroughly studied protein in the human body. However, it has recently been proposed that in addition to the well known function of dioxygen and carbon dioxide transporter, one of the main roles of hemoglobin is to store and transport nitrogen monoxide. This hypothesis is highly disputed and is in contrast to the proposal that hemoglobin serves as an NO. scavenger in the blood. In this short review, I have presented the current status of research on the much-debated mechanism of the reaction between circulating hemoglobin and NO.. Despite the fact that oxyHb is extremely rapidly oxidized by NO., under basal physiological conditions the biological activity of NO. in the blood vessels is not completely lost. It has been shown that three factors reduce the efficiency of hemoglobin to scavenge NO.: a so-called red blood cell-free zone created close to the vessel wall by intravascular flow, an undisturbed layer around the red blood cells--where the NO. concentration is much smaller than the bulk concentration--and/or the red blood cell membrane. Alternatively, it has been proposed that NO. binds to Cys beta 93 of oxyHb, is liberated after deoxygenation of Hb, and consequently allows for a more effective delivery of O2 to peripheral tissues. However, because of the extremely fast rate of the reaction between NO. and oxyHb, experiments in vitro lead to artefactual production of large amounts of S-nitroso-hemoglobin. These results, together with other data, which challenge most steps of the NO.-transporter hypothesis, are discussed.

Reaction of Hemoglobin With Nitric Oxide and Nitrogen Dioxide in Mice
Oda et al 1980
The reaction of hemoglobin with NO and NO2 was compared in mice exposed to these cases. Nitrosyl hemoglobin (NOHb) and methemoglobin (MetHb) were determined simultaneously by electron spin resonance spectrometry at -140 degrees C. In mice exposed to 40 ppm NO, NOHb became constant (0.7%) in 30 min and declined rapidly with a half-life of several minutes when the mice were removed to room air. An increase of MetHb (5%) was also caused by exposure to NO and the time course was almost the same as that of NOHb. Exposure to 40 ppm NO2 produced only NOHb (0.2%); MetHb did not increase. The time course of NOHb was identical to that observed with NO exposure. Dose-effect relationships were determined with both gases at concentrations ranging from 20 to 80 ppm. A linear relationship could be observed between the concentrations of the gases and NOHb, but NO produced more NOHb than did NO2. There was an exponential increase of MetHb, particularly at high concentrations of NO.


Senior Member
There was some information that anti-histamines could lower cytokines in cytokine storm, any further studies on that?

I would like to hear more about this as well. I know vitamin d can help inhibit cytokine storms. In fact I'm pretty sure lots of COVID victims who passed were D deficient.


Senior Member

Major study finds common steroid reduces deaths among patients with severe Covid-19
By MATTHEW HERPER @matthewherper
JUNE 16, 2020


A cheap, readily available steroid drug reduced deaths by a third in patients hospitalized with Covid-19 in a large study, the first time a therapy has been shown to possibly improve the odds of survival with the condition in the sickest patients.

Full data from the study have not been published or subjected to scientific scrutiny. But outside experts on Tuesday immediately embraced the top-line results. The drug, dexamethasone, is widely available and is used to treat conditions including rheumatoid arthritis, asthma, and some cancers.

CAUTION: Research paper has not been released
So researchers need to look at the data. Trial found it significantly reduced risk of death for patients requiring oxygen or on ventilators by 35%. Effective in cytokine storms & major inflamatory immune response not to be used for mild cases.

The treatment is up to 10 days of dexamethasone and it costs about £5 per patient. So essentially it costs £35 to save a life. This is a drug that is globally available.

Dexamethasone, because it is such a potent anti-inflammatory, might be harmful if given to patients too early or with mild disease. Inflammation is critical for mounting an effective antiviral immune response. Steroids too early in infection could hinder virus clearance.

Many caveats:
It's not great to take corticosteroids long term. It could actually make it worse by suppressing antiviral immunity response decreasing innate T-cell response