This is a journal article we’ve been needing. That long COVID is a real and serious problem has been established. Media articles frequently note the similarity between chronic fatigue syndrome (ME/CFS) and long COVID. Plus, Avindra Nath and the Long COVID Alliance have been beating the drum about ME/CFS and long COVID. It’s hard to tell, though, if the broad research community has gotten the message.
ME/CFS experts assert ME/CFS research has much to offer long COVID researchers.
It’s important for us that it does. We are going to learn a ton about long COVID, and as long COVID turns into its version of ME/CFS, we’re going to learn a lot about “long-COVID ME/CFS”. That’s great, but it’s not necessarily the same as learning about ME/CFS.
The first long-COVID grant opportunities mostly fund large studies that are tracking and studying long-COVID patients in ways we could hardly have conceived, and will surely provide impressive insights into “long-COVID ME/CFS”. Later studies will provide even more. Take clinical trials. We’ve been unable to get the NIH to support any clinical trials in ME/CFS, but the NIH has already committed itself to clinical trials – probably very large clinical trials – in long COVID.
We vitally need, though, studies that include the other long haulers – the 1-2 million people in the U.S. who’ve had ME/CFS for years. The only mention of ME/CFS I could find in the NIH long-COVID grant descriptions showed up in the 14-page (!) list of FAQs accompanying the grant descriptions. It asked, “Would formation of a ME/CFS sub-cohort be acceptable to enable deep phenotype comparisons?” i.e. is it possible to use this grant money to compare people with ME/CFS to the long haulers?
I think the answer was yes. The authors anticipated that the ‘investigator consortium” (whatever that is) would develop protocols and sub-studies that compared ME/CFS patients (not necessarily of long-hauler origin) to the long haulers.
“We anticipate that applicants will propose to address specific hypotheses in the overall group and subgroups of PASC participants and the investigator consortium will develop an overall protocol and sub-studies to address these questions.”
That was good to hear. But then a grant opportunity that funded studies to assess the risk of developing further diseases somehow failed to mention the one disease that’s been most associated with long COVID – chronic fatigue syndrome. (It did include dysautonomia, neurocognitive impairment, and exercise intolerance.)
That raised a few alarm bells. The brand spanking new RECOVER (Researching COVID to Enhance Recovery) website from the NIH that showed up yesterday, though, silenced them for now. (RECOVER is the new name given to the NIH initiative to study long COVID). ME/CFS, in one form or another, was mentioned twice on the small one-page website.
One of the four FAQs on the page asked if the long-COVID research will help the millions of Americans with post-viral illnesses as well. RECOVER stated: “It may also help improve our understanding of other post-viral syndromes, such as chronic fatigue syndrome, and autoimmune diseases—conditions in which the body’s immune system attacks healthy cells.” RECOVER also reported that the long-COVID studies will include participants from “established NIH-supported studies of other diseases and conditions“.
That was good, but now comes the task of acquainting the research community with the many intriguing insights ME/CFS researchers have uncovered. As Emily Taylor of the Solve ME/CFS Initiative said in the Community Advocacy talk yesterday (paraphrasing), “We don’t want long-COVID researchers to reinvent the wheel – we want them to use what we’ve learned to sprint forward.”
The Paper
The “Insights from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Help Unravel the Pathogenesis of Post-Acute COVID-19 Syndrome” paper will help them do that. This is the first journal article, I’m aware of, that explicitly spells out the potentially important role ME/CFS research could play in informing the understanding of long COVID. It will also surely be an opener for many. Long-time ME/CFS advocate and researcher Anthony Komaroff and the “virus hunter” himself, Ian Lipkin, penned the paper.
The article begins with a bang by reminding researchers that long COVID is simply the latest and greatest in a long line of post-infectious illnesses. Noting that the infections were ‘well-documented’, the authors listed 16 pathogenic events (Epstein-Barr virus, human cytomegalovirus, human herpesviruses 6A and 6B, SARS-COV-1, Ebola virus, West Nile virus, dengue virus, Ross River virus, Borrelia burgdorferi, enteroviruses, human parvovirus B19, Mycoplasma pneumoniae, Giardia lamblia, Coxiella, and Candida sp.) which have been shown to cause post-infectious illnesses.
Plus, they added a new and, it turns out, a quite timely trigger, that’s been brought to the fore by a member of the ME/CFS community, no less – being in an intensive care unit (ICU). In a series of blogs on Health Rising, and then in a series of journal articles with Lars Larson and Jonas Bergquist, Dominic Stanculescu identified, for the first time, the possible links between post-ICU syndrome and ME/CFS.
Causes
Next, Komaroff and Lipkin identified insights from ME/CFS that might help explain long COVID.
The Gut – The gut is an intriguing place to look given its role in regulating the immune system (and its possible connection to very severe ME/CFS). Besides growing evidence of dysregulated gut flora, studies suggest that increased gut wall permeability may allow gut bacteria to enter the circulation.
The Immune System – various immune system problems have surfaced (NK and T-cell functioning; increased pro-inflammatory cytokines), problems with T-cell regulation, increased autoantibody levels), with the authors focusing on the appearance of immune exhaustion over time.
Metabolomics – no field is more intriguing in ME/CFS than metabolism. The authors identified three main findings:
- reduced energy (ATP) production from fatty acids, glucose, amino acids and oxygen with reduced levels of amino acids.
- a general hypometabolic state characterized by depressed levels of most metabolites as occurs in hibernating animals.
- redox imbalance – increased levels of free radicals/reduced levels of antioxidants.
Neurological – noting that while depression is present in ME/CFS, it occurs as a result of the disease – and is not a risk factor for it. The authors noted the many neurological findings including: cognitive issues, pain hypersensitivity, functional deficits demonstrated by fMRIs, widespread neuroinflammation, impaired HPA axis functioning, dysregulated autonomic nervous system (ANS) functioning, elevated levels of autoantibodies attacking the ANS, reduced anaerobic threshold, increased lactic acid and other problems found in two-day exercise studies, and the need to recruit more brain regions during cognitive tasks.
A Long-COVID Connection?
We’re just beginning to learn about long COVID, but some possible connections have shown up. Besides the wide overlap in symptoms, the mixed results from attempts to find evidence of the virus in the central nervous system suggest that it’s the “host response to the virus and microvascular damage” occurring from that – rather than the direct effects of the virus – that is probably causing symptoms. Indeed, they believe the virus probably does much of its damage via its effects on the vascular system (blood vessels). The widespread “microinfarcts” found in COVID-19 could be contributing to the cognitive problems found.
These findings alone present plenty of potential overlap with ME/CFS and fibromyalgia, with several studies suggesting the microcirculation, in particular, has been disturbed. Wirth and Scheibenbogen have proposed that vascular problems are key to ME/CFS.
It’s intriguing that those “microinfarcts” found in long COVID seem close to one of the first neurological findings in ME/CFS – the widespread white matter hyperintensities found in ME/CFS patients’ brains over 30 years ago.
The Core Problem in ME/CFS
Two ME/CFS experts propose that problems with energy production and neuroinflammation play a central role in both ME/CFS and long COVID.
What links all these problems together? Bob Naviaux surely smiled when he saw the “Distinguished Simcox-Clifford-Higby Professor of Medicine at Harvard Medical School” (Anthony Komaroff) and the internationally recognized virologist (Ian Lipkin) – point a finger straight at his cell danger response and hibernation hypothesis.
That will surely open some eyes. One wonders how many long COVID researchers entertained the idea that a hypometabolic response and “hibernation” might help explain long COVID? Probably not many.
The authors proposed that the “unchecked persistence of a response” to a stressor had triggered a cell danger response at the cellular level, and an “integrated stress response” at the organism level. That ongoing response left ME/CFS patients in a hibernation-like state where “essential energy-consuming processes” were “throttled down” – leaving only small amounts of energy left to be used for the basics of maintaining life.
They speculated that neurons in the hypothalamus had induced the “torpor” found in ME/CFS and long COVID. The hypothalamus links the nervous system to the endocrine system, and regulates both the HPA axis and the autonomic nervous system. With its link to the limbic system, it could contribute to a wide array of symptoms including fatigue, metabolic issues, autonomic nervous system problems, cognitive and sleep issues, hypersensitivities, etc.
They are not alone in their focus on the lower parts of the brain. In 2014, following her stint on the Institute of Medicine panel for ME/CFS, Lucinda Bateman proposed that a “limbic encephalitis” or inflammation in the lower brain (hypothalamus, thalamus, and pituitary) was likely triggering many of the symptoms of ME/CFS.
In 2018, Angus Mackay, another ME/CFS patient and researcher proposed that inflammation was causing the paraventricular nucleus (PVN) of the hypothalamus to set off an integrated stress response in ME/CFS.
Komaroff and Lipkin proposed that the “fatigue nucleus” in the hypothalamus was probably triggered by inflammation in the brain.
Neuroinflammation
But where the heck is the neuroinflammation coming from? Komaroff and Lipkin suggested it was caused either directly caused by infection or injury, or indirectly by inflammation in the body, or by autoantibodies (like those found by Scheibenbogen). (Direct infection seems unlikely but could be happening.)
It should be noted that in an ME Research UK-funded study, Jarred Younger is determining whether immune cells from the body are making their way into the brain.
Key Components
Unfortunately, the paper – a preprint – seems to be missing a section called “Outstanding Questions”, but the authors end by highlighting what they believe the key components of ME/CFS are – chronic inflammation, redox (oxidative stress) imbalance, defective energy metabolism – and show several different ways these factors could combine to cause the symptoms in ME/CFS.
They also assert that “the underlying biology” of long COVID “is similar to that of other post-infectious fatigue syndromes in the past, to post-critical illness syndrome, and to that of ME/CFS, and “involves the central and autonomic nervous system, and a persistent, dysregulated immune and metabolic response to any of multiple infectious agents”.
I imagine that the immune system would be at the top of most long-COVID researchers’ lists of usual suspects. Not so much the metabolic response, hibernation and the autonomic nervous system. Let’s hope this paper gets widely read, and that metabolism and neuroinflammation are front and central in long-COVID research.
The long Covid/ME research connection. Curiously I’m not finding any detail on the current House Bill, 2754 – not even the bill text on the congressional website.
Hi Douglas, ME/CFS is not specifically named in most parts of the bill. Instead, the authors used the term “post-viral illnesses” or “post-infectious” illnesses. (Post-infectious is clearly better as post-viral leaves out things like chronic Lyme disease.) For instance, the bill instructs the NIH to use patient registries to assess the effectiveness of treatments ” in long COVID “and related post-viral illnesses overlapping with PASC.
The NIH will also assess treatment “disparities and inequities (of long COVID) and related post viral illnesses overlapping with PASC
The AHRQ will assess how effective the health care system is at responding to and treating long COVID and “post-infectious diseases”
The CDC will disseminate information on long COVID, ME/CFS, etc .
https://solvecfs.org/wp-content/uploads/2021/05/covid-19_long_haulers_act_117th.pdf
I’d suggest neither post-viral nor post-infectious is accurate for the general case. According to this MEpedia article ME/CFS can result from other types of events, both physical and psychological, that are stressful to the body:
https://me-pedia.org/wiki/Postviral_fatigue_syndrome
Ron Davis makes the same point in this talk:
https://www.youtube.com/watch?v=63ERNV1Bjoo
(5:45) “There’s a lot of other things that can cause this disease – any stressor …many types of infections … Ross River virus … Giardia … any other types of stressors like an auto accident, surgery, child birth, anything that is a major body stressor can cause this disease so everybody as far as we can tell is vulnerable to this and there’s nothing you can do to really protect yourself.”
This suggests to me the ultimate cause is something other than viral/bacterial action.
Robert Olney – I’m with you on that. Ray Perrin (UK) has long proposed that viral ME-onsets are really secondary to a specific type of underlying physiological dysfunctioning, the signs of which are always identifiably pre-dating.
He believes the common issue is sympathetic nervous system breakdown, and reports finding that *all ME sufferers he’s seen over the past 32 years have the same recurring types of structural issues which create a susceptibility to SNS strain from a combination of mechanical disorder and stressors of multiple kinds – the former causing overstimulation of the SNS, and the latter adding to the strain, leading to it’s functional breakdown.
Dr Perrin contends that this results in disordered lymphatic circulation (which the SNS can no longer control normally) – this further leading to toxins backing up into the central nervous system instead of being processed by the body as should be.
In this eventuality, all types of toxins, (including viral), and all forms of stress – whether physiological and/or psychological – will cause big problems (prolonged psychological stress apparently also being significantly neuro-toxic).
For ME sufferers in which such a toxic cycle has become entrenched (often with accompanying multi-system breakdown and various resulting comorbidities), treatments aimed at ‘untripping’ cell danger responses may not be sufficient (and possibly not always helpful/even problematic?) without addressing these upstream issues.
I wish more research could be put into investigating this ‘neuro-lymphatic’ model of ME.
Great points. For sure all sorts of things can trigger ME/CFS/FM. Toxins for sure, childhood stressors can set people up for immune disorders, and there’s a sizeable portion of people who don’t have an identifiable trigger. Whitney Dafoe had problems with exertion five years before he really started getting ill. While his next triggers were clear (stomach bugs) it seemed as if he was set up somehow to inadequately respond to them by something unidentifiable that happened earlier.
I bet the old guys in congress and our health organizations would be a bit more interested in funding MECFS research if it were *somehow* connected to reduced functionality & vitality involved with advanced old age. They’d likely be *quite* interested if it turned out that normal, evolutionarily preserved immune functioning happens in all of us all the time, that it will slow us down & give us those “off” days when we don’t do so well, and that we naturally accumulate small triggers of it over the course of our lives, until we reach a “old” state that we don’t feel well enough to do much and behave remarkably shutdown like someone who’s had the flu for a week. If we actually worked out how all this functions, we *might not have to* lose so much function and feel that poorly during those years. Maybe knowing that would make them feel invested in that fundamental sort of research that could easily pay off for much of humanity, not just those bozos saying they’re tired all the time.
Nice insight. It reminds me of Ron Davis saying that he believes that ME/CFS is affecting core processes – the understanding of which – will benefit many other diseases. Think if there really is a “fatigue nucleus” in the brain that we can figure out how to manipulate? M.S. researchers have proposed that. We did a blog on that.
https://www.healthrising.org/blog/2020/10/15/fatigue-nucleus-multiple-sclerosis-fibromyalgia-chronic-fatigue-syndrome/
What a difference that would make. (the military would sure be interested in that. I’m not interested in fatigue-free soldiers but think about the funds they could bring to bear.)
I don’t think they get that yet.
Excellent article, Cort, on the most important need the ME/CFS community has—to get into the research projects, both as a completely relevant patient comparison, and as advisors. We have a fund of information and experience to shorten the journey of this upcoming research.
I would be totally surprised if long COVID researchers know much about the possibility of hypometabolism or Naviaux’s cell danger response or the idea that the body might be in a hibernation-like state.
It could take them quite a while to get to that.
I don’t get Why they don’t start with looking at The CNS-autoantibodies (adrenergic & muscarine) Scheibenbogen & orders found.
They cld explain a whole lot of symptoms in people who had neurotropic virusses (HHV6, CMV, sars, sars-cov2, …)
Then look at brain inflammation in the proper way (PET-MRS needed to do that).
Immune system? Mixed results.
Bc ME makes a th1/th2 shift after years.
From lymphopenia going to leukocytosis w/ high Bcells etc.
Metabolic issues? Consequence imo.
The ‘key’ is in the brain.
Now we have people who just had a neurotropic virus attack … so please go & look at their brains first! Thoroughly. Like younger & others did.
And see if it links to the auto antibodies of Scheibenbogen.
They did mention the autoantibodies. The results of those studies are generally positive but have been a bit mixed. The autoantibodies only appear to apply to a subset of patients – a significant subset for sure – but can’t account for everyone. They’re certainly one intriguing option that could explain a lot.
A German team did look into these antibodies:
https://www.sciencedirect.com/science/article/pii/S2589909021000204
They found adrenergic and muscarinergic AABs in up to 90 %. Yet they assume that certain ischemic or inflammatory co-factors may be needed for these AABs to exert pathological effects. And this fits well with the ME/CFS record: beta-2-aabs are found in a subset of patients only, sometimes they correlate with disease severety, sometimes they don´t – so presumably this is not a primary process but just reflects a revved up adrenergic system.
Interesting. I didn’t know about the potential ischemic or inflammatory co-factor idea. I wonder how many things that potentially applies to.
Just another thought in response to your comment, Eliza.
If they consider neuroinflammation, the one marker that needs to be looked at would be glial fibrillary acidic protein (GFAP). (GFAP reflects astrocyte activation)
I am at a loss why this has not been done in ME/CFS.
They found anti-GFAP to be a consistent marker in GWI – and if there is anti-GFAP there ought to be GFAP… (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563126/)
Also, in studies of neuroinflammatory disorders abnormalities in the tryptophan-kyurenine-metabolisms (remember the metabolic trap hypothesis of Ron Davis?) correlate with GFAP (https://www.nature.com/articles/s41380-019-0401-9)
This marker is being used even in clinical neurology now to monitor neuroinflammation in MS, so again, it is really beyond my humble mind why this has not been looked at in ME/CFS (I have suggested this to a ME/CFS research group here in Germany but they didn´t get it because here the focus is not on neuroinflammation… )
Just a thought, maybe some ME/CFS researchers are reading this 😉
I hope they are. The traditional measures of assessing neuroinflammation have their issues.
I wonder if you’ve seen this on kyurenine in ME/CFS and FM, Herbert, and have any thoughts on it?
https://pubmed.ncbi.nlm.nih.gov/34090138/
@Cort
the first link in Herbert cited:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563126/
makes this remarkable statement: (in section 4. Discussion)
“GWI cases had higher levels of all autoantibodies except for GFAP when compared with ME/CFS controls. The increased GFAP levels in ME/CFS suggest a potential marker and pathobiology for that disorder. ”
I had thought Bateman was heavily involved in Gulf War illness research.
Is this an avenue–GFAP levels– that Bateman is exploring re ME/CFS??
Since Bateman would seem to most have her finger on the pulse of the two similar diseases, would not this remarkable finding be highlighted by Bateman for further study??? Have i missed that Bateman is already working on this remarkable GFAP finding??
Cort, I have looked through this, I think these findings come with quite a few assumptions and subgroup analyses, and I would not put too much weight into the findings (which the authors don´t do either if you read the dicussion…). In general, the activation of the tryptophan/kynurenine system in IDO competent cells both reduces inflammation and promotes immune tolerance by inducing the proliferation of regulatory T-cells: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087860/
So the assumption is that a dysregulated tryptophan/kynurenine system may indicate an activated innate immune system. The fact that the tryptophan/kynurenine system is deranged in major depression and schizophrenia points to a role in CNS inflammation, which may be supported by the fact that those “IDO competent cells” eluded to above are mostly microglia and astrocytes 😉
The tryptophan/kynurenine system also seems to be off in ME/CFS as evidenced by the finding of strongly elevated neopterin levels ME/CFS patients (https://pubmed.ncbi.nlm.nih.gov/22832503/) (neopterine seems to correlate with the kynurenine metabolism). So basically in a neuroimmune disorder like ME/CFS, findings of an abnormal tryptophan/kynurenine system may not be unexpected. Best
Herbert
@sunie and @cort
Referring to GFAP as a marker for neuroinflammation.
@ sunie you noted that the authors of the paper https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563126/ suggested GFAP as a marker for neuroinflammation in ME/CFS
Whle they writ “GFAP” they mean “anti-GFAP” because this is the only protein they measured (see methods and results). I had communicated with the authors a few months ago and suggested to expand their analyses to GFAP (i.e. the antigen) – they replied this was possibly difficult b/o a short half-life… Yet, this may not really be a problem – GFAP is a stable marker that is even used by clinical neurologists for patient care (also has been studied in acute Covid where it is increased in those patients with neurological involvement, go figure…).
I must say we are now seeing gene expression studies that may cost a million bucks and we have not even looked at GFAP in ME/CFS. I just don´t get it.
@cort
@sunie
Just an addition to my previous rant on the GFAP question so that you may understand my frustration. Imagine we´d have a marker for neuroinflammation (as they do and use in Multiple Sclerosis research). Simple protein, can be analyzed after a regular blood draw.
Now imagine what this could mean for research. What if GFAP levels correlate with disease severity/symptoms? What if they show up in a certain subset of patients only? What if GFAP levels increase after exercise? We may then have evidence that PEM may be related to astrocyte activation, i.e. neuroinflammation. We´d then have a pathomechanism to go for instead of poking around in the dark with all sorts of hypotheses about which obscure biochemical pathway in which corner of the cell may be going left or right.
@Herbert,
your insights and comments greatly appreciated,
sunie
Fascinating paper, thanks for the great write up Cort. The results from a Genova ION test I just had done line up exactly with the 4 causes listed.
Nice!
I think the Komaroff/Lipkin paper is very well balanced and informative. The only issue I have with it is that it does put a fair amount of weight onto the “metabolic” derangements seen in ME/CFS. Yet, as of now, there is not a single piece of evidence that there are any SPECIFIC metabolic changes in ME/CFS. Yes, of course the metabolism in ME/CFS patients is out of whack, but this is no surprise in a disease marked by profound misery perfusion – how should there be anything alse but metabolic tohuwabohu? I found it a little weak to explain the unconsistent metabolic findings in ME/CFS (which they do refer to) with the effects of the blood draws… Why not just say: there is metabolic mess-up but there is metabolic mess-up in all sorts of diseases marked by poor perfusion.
So much for the critique – but they made it up by putting neuroinflammation more or less central. Cudos!
I remember a saying if you shine only one part of your shoes – shine the back of them so that you look good walking out – because that’s how people with remember you.
I’m glad they ended well. 🙂
I think the neuroinflammation idea is quite hopeful given how it’s also being found in highly funded neurological diseases which have money to burn figuring how to reduce it.
(IF double, it didn’t seem to be posted first time)
Thanks for mentioning GFAP. I never heared about it.
It further alligns with ideas Issie and I hold for some time now.
The metabolic trap, If I remember right, says that a lot of tryptophan is converted away from forming kyurene and related products including end product NAD+ and this situation being triggered and getting stuck / trapped. NAD+ is important in energy production. Divertion away from this pathway and much more into the seratonin pathway hence offers a plausible explanation as what goes wrong in ME and offers the hope for this stuck state to be corrected and us to get healthy again.
BUT there is an important but. Several products in this kyurenic part of the pathway are highly toxic and or pro-inflammatory. When looking at the picture on the top right of Wikipedia(Kynurenine_pathway), one sees that the last product before NAD is formed in the chain is quinolinic acid. Wikipedia(Quinolinic_acid) says
“Quinolinic acid is a downstream product of the kynurenine pathway, which metabolizes the amino acid tryptophan. It acts as an NMDA receptor agonist.[2]
Quinolinic acid has a potent neurotoxic effect. Studies have demonstrated that quinolinic acid may be involved in many psychiatric disorders, neurodegenerative processes in the brain, as well as other disorders. Within the brain, quinolinic acid is only produced by activated microglia and macrophages.”
So, it is part of a very potent and toxic (neuro-)inflammatory effect and is, whithin the brain, only produced by activated microglia and macrophages.
If we already would have overactivated (and nasty) immune response in the brain (activated microglia and macrophages), and increased concentrations of quinolinic acid and neuro-inflammation seem to go hand in hand, trying to get this “stuck pathway” *diverting* tryptophan as much as possible away from producing quinolinic acid and “force” it to use that pathway (that produces that very toxic intermediate quinolinic acid) with drugs might be a rather tricky thing to do. I do not volunteer.
So, searching for “glial fibrillary acidic protein quinolinic acid” gives a slew of papers saying that both go often hand in hand in the inflammed regions of the brain.
Some papers tell the gist in their title:
“Induction of Neuroinflammatory Response and Histopathological Alterations Caused by Quinolinic Acid Administration in the Striatum of Glutaryl-CoA Dehydrogenase Deficient Mice”
=> injecting this intermediate of the kyurenic pathway into the brain directly creates neuro-inflammation.
The paper goes on saying:
“A role for quinolinic acid (QA), a key metabolite of the kynurenine pathway, which is activated during inflammatory processes… …Therefore, we investigated whether an acute intrastriatal administration of quinolinic acid (QA) could induce histopathological alterations in the striatum of 30-day-old wild-type (WT) and GCDH knockout (Gcdh-/-) mice. Striatum morphology was evaluated by hematoxylin and eosin, T lymphocyte presence (CD3), and glial activation (GFAP and S100β) by immunohistochemistry and 3-nitrotyrosine (YNO2) by immunofluorescence. QA provoked extensive vacuolation, edema, and especially lymphocyte infiltration in the striatum of Gcdh-/-. QA also enhanced CD3 staining and the number of YNO2 positive cells in Gcdh-/- mice, relatively to WT, indicating T lymphocyte infiltration and nitrosative stress, respectively. QA-treated WT mice also showed an increase of GFAP and S100β staining, which is indicative of reactive astrogliosis, whereas the levels of these astrocytic proteins were not changed in Gcdh-/- QA-injected mice. ”
=> Diverting tryptophan away from the kyurenic path and into the seratonin path seems to have potent anti-inflammatory action. This action seems to be even more potent anti-inflammatory in the brain. It not only reduces amounts of very neurotoxic quinolinic acid in the brain, but also produces more seratonin that has know (fairly strong) anti-oxidant properties, just as several of its metabolites.
=> Our bodies may well *chose* to divert tryptophan away from the kyurenic pathway into the seratonin pathway in order to try and tame neuro inflammation. The likely cost? Strongly reduced NAD production in all of our bodies making aerobic energy production in the mitochondria a lot harder.
Just think of it: thinking too much, long or intense can create a severe tiredness / exhaustion in all of our bodies. Thinking too much, long or intense also is a thing that has high chances to increase brain inflammation on top of its already high value in ME brains. IF the body would respond by turning the pathway producing NAD down (the kyurenic pathway) in order to try and cool this burning brain inflammation, we are set for prolongued reduction in energy production throughout our bodies. The time frame might be part of the PEM period / cycle.
OK, worked now. Was @Herbert but didn’t got posted where I wanted it to.
There was a blog way back in 2015, on this pathway. I posted a lot of links connecting this and questioned if it played into our issues. This may be of interest to others.
https://www.healthrising.org/blog/2015/06/28/neuroinflammation-ii-the-kynurenine-pathway-in-fibromalgia-and-mecfs/
I was reading about long covid a few days ago and interestingly there was a mention of increased allergies.
I developed quite a few food allergies in the first few years of my CFS, they died away after about 10 years, and interestingly the hayfever I have always had (ie. Pre CFS) got much better too. One of the few upsides of my CFS 🙂
It’s very much like in CFS and long covid the immune system is fired up, but then dies down over time.
Has anyone had a similar experience to me with allergies?
Yes Matthias, I became intolerant to most food – various reactions. I can tolerate more food now but have to be very careful. I don’t eat any dairy at all – it affects my brain, mental health, gut and I believe it brings on orthostatic intolerance, so I suddenly feel faint, nauseous and my heart races. I have an issue with fructose too, so I haven’t been eating fruit. High fructose foods like maize are not good for me at all – disrupts my blood/brain sugar levels, I think.
I have a major problem finding food that give me energy, that don’t cause further issues. I’m continually working on this project.
And similar to you my hay fever – actually from hay (like you’d feed to horses) and house dust appears to have gone. However I now have asthma, which I didn’t before.
Thanks! It would be interesting to hear other views too.
Intuitively this supports the idea, which has been demonstrated in studies, that the immune system ramps up earlier in the illness before dying down, and going slightly the other way. So a hyperactive immune system promotes allergy, but many of the allergies disappear as the immune system calms down over time, and goes slightly to the hypoactive side.
In the meantime, the fatigue remains! Which suggests some sort of hit and run damage to the brain, which remains even after the immune system has calmed down. Hence the fatigue remains.
Is anyone doing a study on how many people with long Covid (for longer than 6 months) actually meet the diagnostic criteria for MECFS? They might have some lung and heart issues from Covid, but if it was found that a high percentage of them actually had MECFS, this would strongly encourage researchers to look into MECFS. It could also be a relatively inexpensive and quick study.
Great question. I’m pretty sure that it’s being done in at least two studies – Nancy Klimas and the Open Medicine Foundation study but I imagine it’s being done in other large NIH-funded studies which are tracking long COVID patients over time. I would be shocked if it’s not.
@anon
Ceck this out, a study from Germany on this question
https://www.medrxiv.org/content/10.1101/2021.02.06.21249256v1
How about adverse side effects from Cipro family of antibiotics…
check out ciproispoison.com
I think the logical links between long COVID and ME/CFS are compelling, but suggestions for treatment are looking in the wrong places. Somewhere in my foggy brain I recall that ME/CFS represents an immune attack on the vagus nerve. And one of the best-known postinfectious diseases, Guillain-Barre Syndrome (GBS), represents the sequelae of an immune attack on the peripheral nervous system. No one would argue that GBS is a psychogenic disorder. There are two generalized and fairly successful treatments for GBS – IVIg and plasmapheresis. Have these treatments ever been tested on ME/CFS or on long COVID?