Subsets, Subsets, Subsets

Everyone with ME/CFS who’s been around a bit must ask themselves at some point, “Do I have what she or he has?” Some people do great on treatments that others fail on. Some people get really, really sick while others maintain at least a modicum of health. The variety of symptoms, treatment responses, illness progressions, even illness triggers is astonishing. For every person who remembers the exact day their illness came crashing down, there’s another who doesn’t remember the day, week or even month they became ill, because their illness came on gradually.

There’s the relapsing-remitting group which gets better and then worse, the plateaued group in which things remain much the same for decades and the progressive group where the illness gets progressively worse – sometimes to levels rarely seen in any nonlethal disease.

Most researchers concluded decades ago that ME/CFS must be littered with subsets. Just what those subsets are is a critical question, because as Jared Younger notes – a treatment that works for one subset probably won’t work for another.

Some subsets appear to be showing up. Dr. Peterson’s atypical subset typically has an unusual onset, an unusual course, has unusual comorbidities and is sicker than the rest of us. The immune systems of short duration patients (one subset) are on fire while the immune systems of longer duration patients (another subset) have run out of gas.

Jared Younger, in an unusual move, has released some early results from his big daily immune monitoring “good-day, bad-day” study to spread some early news on his findings.

Younger’s “good-day, bad-day” study is an example of what the NIH does best: throw a boatload of money (> $1,000, 000 over three years) at a complex study. Younger’s study allows him to track which immune factors track with a person’s fatigue. A substance that rises and falls depending on how fatigued a person is, very likely has something significant about it.

The scale of testing is extraordinary. The study includes seventy people with ME/CFS, 20 healthy controls and 20 fatigued people with thyroid issues. The study involves twenty-five straight days of blood sampling from all 110 people, and each sample is tested for 51 substances associated with inflammation.  If my math is right, that’s approximately 140,000 tests for inflammatory substances over the life of the study. Each person will also report their fatigue levels daily on a personal handheld computer. All this data will be thrown into a computer to see what patterns emerge.

It’s still early yet – the study is slated to run for several years – but in his YouTube video, Younger reported that some patterns may be starting to emerge.

The Infection Group?

C-reactive protein (CRP) levels are tracking with fatigue in about thirty percent of the ME/CFS participants. This suggests that a significant number of ME/CFS patients may have an underlying infection that’s popping out during their bad days.

 C-reactive protein is an “acute-phase” protein produced by the liver which shows up early in an infection, in cancer or in response to a tissue injury. Once immune cells called macrophages come into contact with dead or dying (infected) cells they release a substance called IL-6 which triggers the production of CRP (and fibrinogen) by the liver. When CRP binds to the surface of those cells, it gets the complement system involved which, in turn, helps more macrophages to find, engulf (phagocytyze) the infected cells and begin clearing them away.

The key to high C-reactive protein levels is plenty of dead or dying cells – something which usually occurs in the context of some infection (bacterial, viral, fungal), inflammatory diseases, malignancy or injured tissues. A very large (n=1125) fibromyalgia study recently found increased CRP levels in FM. It’s not clear how high the CRP levels in the ME/CFS subset was relative to other diseases. but what is clear is that the high CRP levels would probably be swamped by the lower CRP levels in the two other ME/CFS subsets; i.e. CRP would not be elevated in the group as a whole.

Autoimmune diseases like lupus, Scleroderma, polymyositis, and dermatomyositis, on the other hand, generally have little effect on CRP levels.  (In fact, one researcher proposed that CRP protects against autoimmune diseases.) That brings up the next group.

The Autoimmune/Autoinflammatory Group?

A substance called fractalkine – which is elevated in many autoimmune and inflammatory disorders – is tracking with the fatigue levels of another third of ME/CFS patients. Fractalkine, whose release is also triggered by damaged cells, promotes the production of pro-inflammatory cytokines.

CRP, fatigue and chronic fatigue

CRP and Fatigue: Check out how closely CRP levels track with fatigue levels

Fractalkine is released by T-cells and other immune cells, endothelial cells and, most prominently, in the central nervous system.

In contrast to CRP, fractalkine is elevated in autoimmune diseases like rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, and scleroderma, as well as diseases associated with systemic inflammation. In rheumatoid arthritis fractalkine directs immune cells to the joints. Fractalkine is also elevated in systemic inflammatory diseases like atherosclerosis and inflammatory cardiomyopathy.

Because fractalkine appears to be intimately involved in producing pathological pain, one wonders if these are the fatigue and high pain patients. One study has found increased fractalkine levels, not in the blood, but in cerebral spinal fluid in fibromyalgia. The study suggested that damaged neurons were triggering fractalkine release.

Because fractalkine plays a prominent role in producing inflammation, anti-fractalkine agents are being examined. Several existing drugs and supplements (baclofen, Apo-A1, resveratrol, epigallocatechin-3-gallate) may be able to suppress fractalkine production.

The Non-Immune Group?

In the last third of patients, Younger hasn’t yet found a pattern, which suggests that the fatigue symptoms of this group may not be driven by the immune system. This, Younger suggested, could be a metabolic or other group.


Younger’s “Good Day – Bad Day” study is looking for biomarkers in an entirely new way. Very different from the one-time shots at assessing immune problems that we usually see, Younger’s study is tracking immune changes as they occur over time and pulling out the immune factors shown to be most associated with fatigue. Many other symptoms exist in ME/CFS, but as Dr. Lerner used to say, when the fatigue lifts the other symptoms follow.

Thus far the study suggests that the fatigue in ME/CFS may be being produced differently in the three subsets of patients: by an ongoing infection in one, by an autoimmune or autoinflammatory process in another, and by something outside the immune system in the third.

The most intriguing thing about Younger’s study is its intensity. No one has examined the immune basis of fatigue in ME/CFS with Younger’s intensity. It’s no surprise, then, that Younger is getting results (CRP, fractalkine) new to ME/CFS – results that also, interestingly enough, fit with what we already know. Infection and autoimmunity, after all, have long been thought to be present in ME/CFS. Younger’s early results suggests that they are present – but in different sets of patients.

If Younger’s early results prevail and are validated, we should ultimately see radically different treatments for the two different subsets – immune activators and anti-pathogen treatments for one, and immune suppressants for the other. We’ll also see studies focused on each subset and that could make all the difference in research.


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