Cracking the code of chronic fatigue syndrome–it’s driven by inflammation
Press release from Stanford University School of Medicine, July 31, 2017:
Researchers at the Stanford University School of Medicine have linked chronic fatigue syndrome to variations in 17 immune-system signaling proteins, or cytokines, whose concentrations in the blood correlate with the disease’s severity.
The findings provide evidence that inflammation is a powerful driver of this mysterious condition, whose underpinnings have eluded researchers for 35 years.
The findings, described in a study published online July 31 in the Proceedings of the National Academy of Sciences, could lead to further understanding of this condition and be used to improve the diagnosis and treatment of the disorder, which has been notably difficult.
More than 1 million people in the United States suffer from chronic fatigue syndrome, also known as myalgic encephomyelitis and designated by the acronym ME/CFS. It is a disease with no known cure or even reliably effective treatments. Three of every four ME/CFS patients are women, for reasons that are not understood. It characteristically arises in two major waves: among adolescents between the ages of 15 and 20, and in adults between 30 and 35. The condition typically persists for decades.
“Chronic fatigue syndrome can turn a life of productive activity into one of dependency and desolation,” said Jose Montoya, MD, professor of infectious diseases, who is the study’s lead author. Some spontaneous recoveries occur during the first year, he said, but rarely after the condition has persisted more than five years.
The study’s senior author is Mark Davis, PhD, professor of immunology and microbiology and director of Stanford’s Institute for Immunity, Transplantation and Infection.
‘Solid basis for a diagnostic blood test’
“There’s been a great deal of controversy and confusion surrounding ME/CFS — even whether it is an actual disease,” said Davis. “Our findings show clearly that it’s an inflammatory disease and provide a solid basis for a diagnostic blood test.”
any, but not all, ME/CFS patients experience flulike symptoms common in inflammation-driven diseases, Montoya said. But because its symptoms are so diffuse —sometimes manifesting as heart problems, sometimes as mental impairment nicknamed “brain fog,” other times as indigestion, diarrhea, constipation, muscle pain, tender lymph nodes and so forth — it often goes undiagnosed, even among patients who’ve visited a half-dozen or more different specialists in an effort to determine what’s wrong with them.
“I have seen the horrors of this disease, multiplied by hundreds of patients,” he said. “It’s been observed and talked about for 35 years now, sometimes with the onus of being described as a psychological condition. But chronic fatigue syndrome is by no means a figment of the imagination. This is real.”
Antivirals, anti-inflammatories and immune-modulating drugs have led to symptomatic improvement in some cases, Montoya said. But no single pathogenic agent that can be fingered as the ultimate ME/CFS trigger has yet been isolated, while previous efforts to identify immunological abnormalities behind the disease have met with conflicting and confusing results.
Still, the sporadic effectiveness of antiviral and anti-inflammatory drugs has spurred Montoya to undertake a systematic study to see if the inflammation that’s been a will-o’-the-wisp in those previous searches could be definitively pinned down.
To attack this problem, he called on Davis, who helped create the Human Immune Monitoring Center. Since its inception a decade ago, the center has served as an engine for large-scale, data-intensive immunological analysis of human blood and tissue samples. Directed by study co-author Holden Maecker, PhD, a professor of microbiology and immunology, the center is equipped to rapidly assess gene variations and activity levels, frequencies of numerous immune cell types, blood concentrations of scores of immune proteins, activation states of intercellular signaling models, and more on a massive scale.
This approach is akin to being able to look for and find larger patterns — analogous to whole words or sentences — in order to locate a desired paragraph in a lengthy manuscript, rather than just try to locate it by counting the number of times in which the letter A appears in every paragraph.
The scientists analyzed blood samples from 192 of Montoya’s patients, as well as from 392 healthy control subjects. The average age of patients and controls was about 50. Patients’ average duration of symptoms was somewhat more than 10 years.
Importantly, the study design took into account patients’ disease severity and duration. The scientists found that some cytokine levels were lower in patients with mild forms of ME/CFS than in the control subjects, but elevated in ME/CFS patients with relatively severe manifestations. Averaging the results for patients versus controls with respect to these measures would have obscured this phenomenon, which Montoya said he thinks may reflect different genetic predispositions, among patients, to progress to mild versus severe disease.
When comparing patients versus control subjects, the researchers found that only two of the 51 cytokines they measured were different. Tumor growth factor beta was higher and resistin was lower in ME/CFS patients. However, the investigators found that the concentrations of 17 of the cytokines tracked disease severity. Thirteen of those 17 cytokines are pro-inflammatory.
TGF-beta is often thought of as an anti-inflammatory rather than a pro-inflammatory cytokine. But it’s known to take on a pro-inflammatory character in some cases, including certain cancers. ME/CFS patients have a higher than normal incidence of lymphoma, and Montoya speculated that TGF-beta’s elevation in ME/CFS patients could turn out to be a link.
One of the cytokines whose levels corresponded to disease severity, leptin, is secreted by fat tissue. Best known as a satiety reporter that tells the brain when somebody’s stomach is full, leptin is also an active pro-inflammatory substance. Generally, leptin is more abundant in women’s blood than in men’s, which could throw light on why more women than men have ME/CFS.
More generally speaking, the study’s results hold implications for the design of future studies of disease, including clinical trials testing immunomodulatory drugs’ potential as ME/CFS therapies.
“For decades, the ‘case vs. healthy controls’ study design has served well to advance our understanding of many diseases,” Montoya said. “However, it’s possible that for certain pathologies in humans, analysis by disease severity or duration would be likely to provide further insights.”
- July 31, 2017 at 4:40 pm
It’s great to see Dr Montoya is still working on this. I’m still not convinced that CFS is distinct from neuroinflammatory conditions like MS or chronic Lyme. My doctor actually used some of these very cytokines to diagnose my Lyme (and yes they are sky high, particularly c4a). My worry is that some new cytokine test will convince everyone that “CFS” is some distinct illness without a pathogenic etiology and we’ll waste decades looking in the wrong direction as I fear we have with Alzheimer’s.
- August 1, 2017 at 4:35 am
I agree. We know Lyme is caused by a bacteria along with other co-infections. I would guess chronic fatigue syndrome, MS, and Alzheimer’s all have some kind of infection behind them. Probably multiple infections as their causes, including Lyme in some cases. This study is a start in the right direction. Maybe test them for a wide variety of infections and see if any common ones come up.
- August 1, 2017 at 6:57 am
I agree Jonathan. I think CFS/fibromyalgia are useless terms. Have they tested people with these diagnoses for tick diseases, mold toxicity/CIRS?
- July 31, 2017 at 5:02 pm
Nutrition — is anyone researching what one is ingesting to reduce/eradicate inflammation. My son recovered from late stage Lyme Disease with a protocol that was heavy into organic fruits, vegetables, Vegan, no dairy, no gluten (big inflammatory), lots of water w/ organic lemon, Apple Cider Vinegar (with the mother) 1 tsp in filtered water 3X per day, Buehner’s protocol of herbal supplements; 9 drops of Burbur in filtered water for herxing, daily soaks in bath w/ 1 cup Epsom Salts, daily exercise walking is good,,,good luck everyone; it is a long, but worthwhile road.
- August 1, 2017 at 11:28 am
There is one important factor that may be overlooked and contributing to the chronic nature of Lyme and chronic inflammation: structural aspects of the central nervous / musculoskeletal system which contribute to poor CSF/blood flow. Scoliosis is a risk factor, as it can cause torque to the sacrum and upper neck, and I suspect change the tension and permability of the blood brain barrier. I led a fibro/chronic fatigue support group 13 years and scoliosis kept coming up. The fact that scoliosis is very common in fibro patients is published in The Fibromyalgia Syndrome: A Clinical Case Definition for Practitioners, edited by I. Jon Russell, MD, PhD. Also, women more commonly have scoliosis. Most cases are idiopathic – still unknown why this develops.
Originally my multiple neuro/pain/fatigue symptoms began with a forceful chiropractic neck/ pelvis ‘adjustment’ in 1998. Never fully recovered. Just 4 months ago a new naturopath tested for, and found, Lyme. ( Lab Corp/ 5 IgG bands) I had a documented tick bite in Virginia ( live in Calif.) in 2010- with a funny little rash. Yes, I have developed new symptoms since that date.
- August 1, 2017 at 12:54 pm
Interesting, I also have scoliosis. I heard about the Lyme-scoliosis link in a You Tube video, but the guy on the video didn’t know why. (It was a patient made video, not a Lyme doc) Makes sense it could affect blood flow and the blood-brian barrier.
I also had whiplash from a car accident 13 years before I was bit by a deer tick. Sure that didn’t help.
- August 6, 2017 at 10:18 pm
That borrelia live off of collagen may factor in with the neck, etc. problems that we’re having.
- August 8, 2017 at 5:07 am
I had 5 scoliosis surgeries since the age of 14. I was a 38 year old, vivacious mother of 5 kids-and I loved life. Unfortunately at 39 I had to have the most lengthy surgery on my back. When I awoke from recovery-I knew something was different this time. I have had CFS/ME for 18 years now. I have been completely bedridden for the past 7 years. I have never found ONE doctor who would see me after they heard my diagnosis. Now I can’t even travel to visit another clinic. I am having multi organ failure from being bedridden-and not one doc has ever treated me.
- August 1, 2017 at 3:04 pm
I would like to see measurements of environmental toxins and a detailed investigation of the pathobiome (including retroviruses, bacteria, parasites and viruses) for patients vs controls.
- August 1, 2017 at 8:39 pm
Haven’t the LLMD been saying this for years. Give credit where credit is due….to out LLMD!
- August 2, 2017 at 8:34 am
One of the reason’s that a possible root infectious cause of ME/CFS has eluded researchers for years, is that like Lyme disease, the amount of federal dollars allocated to research has been minuscule. For many years federal money for ME/CFS research was less than 5 million dollars per year or only $5 for every American citizen (mostly women), whose life has been derailed by this disease. After promises from Director Francis Collins that the NIH would increase its attention on ME/CFS, funding for 2016 was 7.6 million, a slight increase, with only a fraction looking at two possible infectious causes (Epstein Barr and human herpes viruses) for the illness: http://occupyme.net/2016/11/01/2016-nih-spending-on-mecfs-studies/
- August 4, 2017 at 7:40 am
Hello, I find it hard to believe that all the talk is about understanding the disease…. but there are many people that don’t have the means to fight Lyme or any other co infections . If we are going to beat this crap we need help from the doctors. We don’t have a lot of money…… but we do have a life and can help with a better understanding of Lyme. If you want studies there are many that would help. Peace
- August 5, 2017 at 2:17 pm
I have suffered for 15yrs with tick bourn deserve Dr’s don’t accept it and left me with severe tick bite fever for over 5 months twice I could not get up from pain blood test showed 100% tick bite. I suffer from chronic fatigue and have found stress to be the trigger. The Dr’s keep telling me I have a lot of inflammation and so I take anti inflator is daily for pain. Thank you for this site it’s nice that it is being acknowledged over there.
- August 5, 2017 at 2:17 pm
Ehlers-Danlos syndrome appears to also have some type of connection for some. It is a “rare” connective tissue disorder. Very commonly misdiagnosed……
- August 6, 2017 at 1:39 pm
I’ve been told Ive have tick fever. I’m having pain in my lymphodes and spasms. My Doctor doesn’t know enough. To help me.
- August 6, 2017 at 2:36 pm
Have you looked at NRF2 as a possible path to recovery?
- April 20, 2018 at 11:29 am
“But because its symptoms are so diffuse —sometimes manifesting as heart problems, sometimes as mental impairment nicknamed “brain fog,” other times as indigestion, diarrhea, constipation, muscle pain, tender lymph nodes and so forth — it often goes undiagnosed, even among patients who’ve visited a half-dozen or more different specialists in an effort to determine what’s wrong with them.”
yes, the main culprits are: Borrelia, Bartonella, Babesia, Anaplasma, CMV, EBV.
We invite you to comment on our Facebook page.
Visit LymeDisease.org Facebook Page