Article - Cytokine Inflammation and Management of CFS/ME/FM


Senior Member
IMHO, this is one of the most important articles on CFS todate ... Although, I'd certainly put diet first before all the other treatments. tc ... X

Cytokine Inflammation and Management in Fibromyalgia and Chronic Fatigue Syndrome

by John W. Addington
July 24, 2002

Inflammation in an otherwise healthy person is a natural response to injury or infection and is part of the normal healing process. Chronic inflammation, on the other hand, can reflect an improperly functioning immune system.

Many researchers feel that chronic inflammation along with an altered immune system may either be the cause or contribute to fibromyalgia (FM) and chronic fatigue syndrome (CFS) symptoms. Fortunately, some treatment options are emerging to manage such inflammation and thus limit the discomfort and pain brought on by these ailments.

Cytokine Inflammation

Chemical messengers called cytokines form an integral part element of the immune system. As messengers, cytokines tell other immune cells to activate, grow or even die. Dr. Lionel Ivashkiv, a rheumatologist, explains that “cytokines regulate the immune system responses and can drive the inflammatory process.” In this and other ways, cytokines aid white blood cells in fighting infection.

Not all cytokine involvement is positive, however. It is thought that highly elevated cytokine levels found in the brains of Alzheimer's patients contribute to their symptoms.

Abnormal cytokine activity in rheumatoid arthritis leads to damaged joints. Cytokine disturbances have been implicated, but not always well understood, in other autoimmune disorders as well.

According to Dr. Ivashkiv, there are hundreds of cytokines and their network of activity is very complicated. He states, "It has become clear that the cytokine networks can be perturbed at different levels and have very significant and strong effects on the overall autoimmune process."

Elevated Cytokines in FM and CFS

Besides inflammation, excess cytokines can bring on flu-like symptoms including fever, achiness, and fatigue. In studies, doctors found that fibromyalgia symptoms temporarily resulted when particular cytokines were administered to persons who did not normally have the syndrome.

Additionally, some cytokines are known to increase substance P, which transmits pain messages. Thus, it is no wonder that researchers wanted to know whether cytokine levels were elevated in persons with fibromyalgia.

While the latest research published found some fibromyalgia patients had excessive cytokines, the results are considered preliminary only because of the small number of patients studied. Dr. Daniel Wallace headed up an investigation in Los Angeles discovering that patients sick for over two years were more likely to have high cytokines levels.

Although the researchers found altered cytokine production in early-stage fibromyalgia, the cytokines were seen to increase with the duration of the sickness. The authors of this work, published in the July 2001 issue of the journal Rheumatology, conclude that their results underscore "the argument for earlier, aggressive intervention to prevent a chronic pattern from developing."

It has not yet been determined, however, whether elevated cytokines are the direct cause of fibromyalgia or merely secondary to another factor.

Factors that could contribute to cytokines increase and be a more direct cause of the ailment are other immune problems, abnormal hormone activity, or sleep disturbances. For example, elevated cytokines levels can be induced through sleep deprivation, so perhaps disordered sleep could be the real root of fibromyalgia.

Immune dysfunction as a contributing cause to the related condition of CFS has also been researched. Dr. Nancy Klimas is an immunologist in Miami who has spent considerable time studying CFS. She explains, "with regard to the immune system, we have a system that is hyperactive but not working properly."

As part of this hyperactive state, Dr. Klimas has seen unusually high amounts of cytokines in CFS patients, and she feels that this in turn may cause the hormonal imbalances of such persons.

Other researchers feel the same about this possible cause of CFS, despite the mixed result seen in studies performed. Dr. Stephen Straus writes, "An immune disturbance of some type, though, is in line with one favored theory that many of the symptoms of chronic fatigue syndrome derive from excessive cytokine release."

Management of Cytokine Inflammation

--Drug Therapy

While cytokine related drug therapies are starting to have some benefit for conditions like rheumatoid arthritis, that is not the case yet for FM and CFS. Dr. Roberto Patarca has extensively studied the topic and he says medications are not available "mainly because nobody knows which cytokine system in particular to target and because of the [complexity] of the cytokine network components."

But research on this topic continues. And, a number of cytokine altering medications are currently being developed. So, it may be that in the not too distant future, medications to regulate cytokine difficulties for FM and CFS may exist.


Drs. Charles Lapp and Paul Cheney both recommend hydrotherapy as a means of reducing cytokine levels. They recommend 15-30 minutes of being vertically immersed (standing) in water that is around 85 degrees [Fahrenheit], 2-3 times a week.

Dr. Lapp explains, "when the temperature of the water is 85-95 degrees, it is cooler than your body temperature, so you are cooling down the core. When you cool down the core, it cuts down on the cytokines as well, and those cause the flu-like symptoms."

The rationale behind this therapy is that the increased pressure at your feet, which decreases upward, causes a squeezing action in your lymph system. This forces lymph fluids to enter your blood stream and signals your body that enough cytokines are already circulating in your blood stream. This, in turn, results in downregulation of your immune system.

Regarding this process, the book, Chronic Fatigue Syndrome: A Treatment Guide, relates, "In patients experiencing the effects of excess cytokine production, downregulation of immune system chemicals can provide tremendous relief."


The Life Extension magazine notes that the DHA fish oil is the best documented supplement to suppress certain inflammatory cytokines. Actually, supplements containing any essential fatty acids are very important.

These would include evening primrose oil, borage oil, flax seed oil, and Omega 3 and 6 [essential fatty acids]. Other anti-inflammatory supplements include Vitamins B, C, E, and K, and DHEA. Herbs that act as natural inflammation fighters are nettle leaf, boswellia, cat's claw and tumeric.

Dr. Zoltan Rona recommends bovine colostrum as a "powerful immune system modulator—stimulating a sluggish immune system or dampening an overactive immune response."

He also encourages the use of digestive enzymes whether pancreatic or plant derived, particularly bromelain, because of how well these supplements counter inflammation.

To stabilize an overactive immune system, Dr. Paul Cheney advocates the use of undenatured whey protein (as in Pro Health's ImmunPlex). Whey protein is useful because of its ability to replenish proper glutathione levels that are low in some with CFS.

Dr. Cheney believes that deficient glutathione coupled with excessive cytokines is what promotes activation of harmful microbes like EBV [Epstein-Barr Virus], HHV-6 [Human Herpes Virus-6] as well as chlamydia pneumonia, candida and other mycoplasmas.

In a small study on CFS patients, Cheney found whey protein to be very effective in wiping out these harmful microorganisms. Thus, by raising glutathione levels, undenatured whey protein apparently counteracts some of the damaging effects of excessive cytokines.


Diet can play a significant roll in managing cytokine related symptoms. This is true both in what foods are best to consume and those that should be avoided.

As to which foods to avoid, many researchers are finding that patients with FM and CFS may have food sensitivities that can aggravate their symptoms. Food sensitivities, also called food intolerance, are not the same as food allergies but can nonetheless contribute to illness.

Research published recently in the Lancet medical journal involved a small group of patients with CFS in Norway, who for over four years had benefited from substantial improvement by dietary exclusion of wheat and milk.

After reintroducing these foods into their diets, doctors found a "striking rise" in the patients' cytokine levels along with an increase in abdominal discomfort and joint and muscular pain. These doctors state that "the pronounced increase in release of [particular cytokines], suggests that food intolerance is accompanied by a general immune activation…possibly related to the more general symptoms in these patients."

The foods most likely to be the culprits when it comes to intolerance are wheat, yeast, milk, sugar, peanuts, corn, eggs, citrus, alcohol, caffeine and soy.

Various tests can detect food sensitivities but the elimination and challenge method is one of the best means to determine this kind of problem. This involves completely avoiding the suspect food (including traces of it in other foods) for 7-10 days, and then noting if symptoms reoccur when the food is reintroduced into the diet.

Prime foods that can counter cytokine inflammation are coldwater fish such as salmon, trout, mackerel, sardines, swordfish, shark, cod and halibut. These fish are beneficial because of the omega-3 fatty acids they contain.

It is good to include flax seed, evening primrose oil, and borage oil in one's diet also because of their anti-inflammatory properties. Additionally, fresh pineapple, fresh papaya, spinach, blueberries, strawberries and onions are useful.


Strong preliminary evidence leads many researchers to believe that excess cytokines may be responsible for CFS and FM symptoms. A degree of relief may be possible through present therapies, supplements and diet regimes.

As more research reveals in greater detail the exact nature of immune dysfunction in these ailments, medications will likely be developed to more effectively alleviate cytokine inflammation in CFS and FM.


AFSA, Cytokine Abnormalities Official, AFSA Update, 8(2) (2002)

Balch & Balch, Inflammation in Prescription for Nutritional Healing (2000)

Cheney, Dr. Paul Cheney Discusses Benefits of Undenatured Whey Protein (2000)

Faloon, Chronic Inflammation, Life Extension Magazine (Jan. 2002)

Klimas, Cytokine and Other Immunologic Markers in Chronic Fatigue Syndrome and Their Relation to Neuropsychological Factors, Applied Neuropsychology, 8(1);51 (2001)

Lapp, The Treatment of CFS-Perspective of a Private Specialty Practice in Charlotte, N.C. (2000)

Logan & Wong, Chronic Fatigue Syndrome: Oxidative Stress and Dietary Modifications, Alternative Medicine Review, 6(5):450 (2001)

Mullington, et al., Mediators of Inflammation and Their Interaction with Sleep: Relevance for Chronic Fatigue Syndrome and Related Conditions, Annals of the New York Academy of Sciences, 933:201 (2001)

Patarca, Concise Encyclopedia of Chronic Fatigue Syndrome (2000)

Patarca, Cytokines and Chronic Fatigue Syndrome, Annals of the New York Academy of Sciences, 933:185 (2001), Cytokines in Inflammatory Disease (Interview of Lionel Ivashkiv) (2002)

Straus, Chronic Fatigue Syndrome, in Harrison’s Principles of Internal Medicine. 14th ed. (1998)
Teitelbaum, Food Allergies, in From Fatigued to Fantastic (2001)

Thompson, Chronic Fatigue Syndrome and Food Allergies: How Diet Could Be Effecting Your Symptoms, (2002)

Verrillo & Gellman, Hydrotherapy, in Chronic Fatigue Syndrome: A Treatment Guide (1998)

Wallace, et al., Cytokines Play an Aetiopathogenetic Role in Fibromyalgia: a Hypothesis and Pilot Study, Rheumatology, 40:743 (2001)

West & Maes, Neuroendocrine and Immune Aspects of Fibromyalgia, BioDrugs, 15(8):521 (2001)

Zimmerman, Fight Inflammation, Taste for Life (July 2002)

Zoltan, A Natural Fibromyalgia Treatment Protocol, (2002)

(c) 2002 Pro Health Inc., and


Senior Member
I agree Xchocoholic, I printed it out from in September '09 and gone back to it many times. Thanks for posting. One cautionary note; I've been on high omega 3 oils for 4 months and have started to notice bruising on my legs. After some reading I've discovered this is probably a side effects from the high levels of fish oils. I am continuing to take it but will mention it to Dr Klimas later in the week.


Senior Member
Posting again because I remembered the use of nettle tea, this works very well for inflammation and for sleep, drink a cup at bedtime.
This is my 100th post, has taken 8 months! I think I will go and celebrate, and then head straight for the library stacks.



All shall be well . . .
Santa Rosa, CA
to girlinthesnow



Senior Member
I agree Xchocoholic, I printed it out from in September '09 and gone back to it many times. Thanks for posting. One cautionary note; I've been on high omega 3 oils for 4 months and have started to notice bruising on my legs. After some reading I've discovered this is probably a side effects from the high levels of fish oils. I am continuing to take it but will mention it to Dr Klimas later in the week.

Hi Girlinthesnow,

Good to know this ... I wanted to add that I'd noticed some hypermobility in my joints from taking 4 Metagenics fish oil capsules a day. I don't know why but Carlson's doesn't do this to me ...

I was looking at the list on what tests PWCs should have run and decided to bump this so that we could see what cytokines are, what they do and where they come from. I'm hoping we can find a top down approach for ALL the tests recommended. So far I know how food intolerances cause cytokines but I'm not up on what, if anything, we can use to control cytokines ... And what roll cytokines play in some of those tests recommended.

tc ... x


Senior Member
United States
I was reading a quote by Rich Vank and it seems Cheney (and Rich) aren't really into using the whey anymore
ImmunoPro has quite a history in ME/CFS. It was developed in the 90s by Michael Keenan, a guy who had CFS, and found that raw milk protein helped him ( ). ImmunoPro was the first truly nondenatured whey protein product, meaning that it was the first one that was not made as a byproduct of cheesemaking, so that the milk had not been pasteurized at a temperature high enough to cause the shapes of the proteins to be altered or to fragment them, or acidified with lactic acid to promote curdling, and thus incidentally to cause the cysteine in the whey to be oxidized to cystine. It therefore preserved the lactoferrin and immunoglobulins that are naturally in milk, and it made the nonoxidized cysteine available to the liver cells, where it is usually the rate-limiting amino acid for making glutathione. Elimination of bacteria is performed by ultrafiltration rather than by pasteurization (sort of like Coors beer,which is filtered through a ceramic filter, rather than being heated to kill the bacteria).

Other whey protein products include the isolates (designated by the misnomer "undenatured whey protein"), which are a byproduct of cheesemaking, but have received some additional filtering and processing to remove fragments of damaged proteins), and the cheaper commercial whey that comes straight as a byproduct of cheesemaking and is sold in the big plastic jars. From a nutritional standpoint, whey protein in general has the best proportions of amino acids for human nutrition of all the protein supplements available on the market, including egg, soy and the others.

Dr. Gustavo Bounous, then at McGill University in Montreal, was the person who first showed the value of whey protein as a balanced protein supplement, and he also identified its important role in building glutathione, because of its high cysteine content. The average human diet supplies only about half the cysteine that the body needs. The other half is normally made from methionine via the methylation cycle and the transsulfuration pathway. However, in CFS the methylation cycle is partially blocked, and glutathione becomes depleted.

Before Dr. Bounous did his research, whey protein was considered a waste product from cheesemaking, which uses the curd fraction. When dumping it became an environmental problem, European cheesemakers approached him to find a use for it, which he did. Now the production and sale of whey protein products has become a fairly large industry.

Dr. Bounous and others formed the Immunotec company, which produces a whey protein isolate product called Immunocal. In whey protein isolates, the cysteine is oxidized because of the heating and acidification of the whey as part of the cheesemaking process, but this type of product is superior to the straight commercial wheys, because it is more refined. In some isolates, lactoferrin is added back in. Dr. Bounous discovered the deleterious effect of heating the whey, but he was confused about cysteine, thinking that the heating produced cysteine rather than cystine, which was not correct. I wrote him about this several years ago, but I don't know if he really accepted what I wrote him as fact. He said that they were getting some more equipment and would be able to check this. I never heard any more from him about this. Nevertheless, his work really launched the whole whey protein industry, including all its forms, and also did a great deal for raising the appreciation of the importance of glutathione in the body. Dr. Bounous deserves a lot of credit, in my opinion.

Perhaps the availability of large quantities of processed whey from the cheesemaking industry was a factor in the business decision of Immunotec to produce an isolate, rather than a truly nondenatured whey protein product, starting from raw milk.

Cystine is still usable by the body, but it has to pass through the kidneys to be reduced to cysteine before it is readily usable by the liver. Liver cells do not absorb cystine very well. They absorb N-acetylcysteine (NAC) somewhat more readily, and cysteine the most readily.

Dr. Paul Cheney started recommending whey proteins, including ImmunoPro, in the late 90s, when he found that glutathione was depleted in nearly all his CFS patients. I learned about it from his talks, and later met Michael Keenan at a conference. I have corresponded with Dr. Bounous by email. and have a copy of his book, but have not met him in person.

For about 5 years, I encouraged PWCs to try ImmunoPro, and it did help quite a few, at least temporarily, I think because it raised the glutathione levels somewhat. There were other people who could not tolerate it, and I didn't know why. Some people reported that Immunocal or other whey protein isolates were more helpful to them than ImmunoPro was. I later learned that the DAN! program for autism was not using whey protein because many of the kids are sensitive to casein, and even though casein mostly goes into the curd fraction when the curds and whey are separated, there may still be a small amount of casein in the whey. So perhaps that was one possible problem for some of the people with CFS, also. Freddd, on these forums, also found that whey protein was counterproductive for him and some others, and in his case it may be because when glutathione combines with B12, as it normally does, his cells are not able to utilize the B12, for genetic reasons.

Over time, Dr. Cheney's enthusiasm for using whey protein supplementation cooled, as he also found that it did not produce as much benefit as he had hoped. Because of some lab data that he later received (which I suspect was misinterpreted, a view I have shared with him) he has come to believe that glutathione depletion is not as fundamental an issue in CFS as he originally thought. We continue to interact about this issue.

In late 2004 I learned from the work of S.Jill James et al. in autism that there is a partial block in the methylation cycle in autism, which is upstream of glutathione synthesis in the metabolism, and that if this partial block is lifted, glutathione comes up automatically. I suspected the same might be true in CFS, and it has turned out to be so. So I stopped recommending ImmunoPro to raise glutathione, and switched to methylation treatment. That seems to bring glutathione up on a more permanent basis.

I still think ImmunoPro is a very good supplement, and it has been used by people in my family (who don't have CFS, but benefit from protein and glutathione, as do all of us). So long as a person does not have an unfavorable reaction to it, perhaps for one of the reasons mentioned above, it should be a very good source of amino acids, which are often depleted in PWCs, and it should also help to support glutathione synthesis, in parallel with lifting the partial methylation cycle block.

Best regards,



Senior Member
Thanks lotus. That info could use it's own thread.

I've found getting the toxins out of my diet and environment the best treatment for reducing
cytokines. In fact, I suspect that eliminating a wide variety of toxins, gluten, dairy, soy, chemicals
, etc etc all at one time back
in 2005, helped my body recover as much as it did. And that if I'd only removed one at a time
I wouldn't have seen an improvement.

I've discovered since then that my body over reacts to minute amounts of toxins which
if not removed keeps my body in a state of inflamation. . Tc ... X


Senior Member
United States
I had no idea until a few days ago that taking immune system supplements could have adverse affects until I learned about cytokines. Although some of the immune supplements I was taking were supposed to inhibit cytokines so my symptoms could also have been from my immune system being reactivated and fighting the infections. I guess I'll just have to wait and see. I guess you really have to do a lot of research before taking supplements. I looked up the ingredients of a non denatured whey product and it seems they are supposed to be good for the immune system, but could cause problems for some people. Lactoferrin inhibits cytokines and it also has antibacterial and antimicrobial properties as well as being a prebiotic and binding with iron so pathogenic organisms can't feed off it. Albumin increases cytokines. I'm not sure about immunoglobulins in regards to cytokine activity. I wasn't taking non denatured whey, but of those ingredients I mentioned I was taking immunoglobulins and Lactoferrin separately. I was also taking other immune supplements on top of that. I got really depressed and I couldn't figure out what was going on. I still can't be certain that's what happened, but it seems the most likely. There was another thread where people were having negative symptoms from a non denatured whey product