Rigors and night sweats, link inflammatory cytokines to pain sensitivity in PWME

[boolybooly]

I am inspired to start a thread on rigors and night sweats after a dreadful night, looking around for information about what causes these symptoms, which are sometimes part of my experience of ME and night sweats certainly are commonly reported by other PWME.

The discoveries summarised by google AI indicate the following.

what causes rigors?

Rigors are caused by the body's response to chemicals called pyrogens, which are released during infection or inflammation. These pyrogens act on the hypothalamus, the body's thermostat, causing it to raise the temperature set point, triggering shivering to generate heat. The body also constricts blood vessels to minimize heat loss, leading to cold extremities and pallor.

what endogenous pyrogens cause rigors?

Endogenous pyrogens... like interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon-α (IFN-α), act on the brain's thermoregulatory center (hypothalamus) to alter the body's temperature set point, leading to the feeling of coldness and shivering.

are IL-1 TNF or interferon raised in ME CFS?

Yes, elevated levels of IL-1 and TNF-α, and some forms of interferon (IFN), are often observed in people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). These are inflammatory cytokines, meaning they play a role in the body's inflammatory response.

etc following the rabbit hole leads to... possible links to fibromyalgia, endometriosis and tentatively I wonder if this might be part of the explanation for why ME/CFS causes harms to women more than men.

how do pyrogens cause fever?

... endogenous pyrogens, such as cytokines (e.g., IL-1, IL-6, TNF) ... travel to the hypothalamus, a part of the brain that regulates body temperature, where they ... trigger the production of prostaglandin E2 (PGE2) by cyclooxygenase-2 (COX-2).

PGE2 acts on neurons in the hypothalamus, causing the thermoregulatory set-point to rise. This means the body "thinks" it's cold and needs to generate more heat... The body responds by increasing heat production (through shivering, for example) and reducing heat loss (through vasoconstriction)... The combination of increased heat production and reduced heat loss leads to a rise in body temperature, resulting in fever.

is PGE2 raised in ME/CFS patients?

Yes, research suggests that PGE2 (prostaglandin E2) levels are elevated in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) patients. This elevation is linked to pain, inflammation, and other symptoms associated with the condition.

PGE2 is a bioactive lipid mediator that can affect pain perception, inflammation, and immune regulation...

PGE2 is a key player in pain sensitivity, and its elevated levels in ME/CFS are thought to contribute to hyperalgesia (increased sensitivity to pain) and chronic pain.

PGE2 is a pro-inflammatory mediator, and its increased levels in ME/CFS are linked to the chronic inflammation often seen in the condition.

Research suggests PGE2 may also be involved in other ME/CFS symptoms, such as fatigue, sleep disturbances, and the flu-like symptoms some patients experience.

Some research proposes PGE2 production in endometriosis may contribute to the development of ME/CFS, particularly in women.

In essence, while not a direct cause of ME/CFS, elevated PGE2 levels are a significant factor in the pathophysiology of the disease, contributing to pain, inflammation, and other debilitating symptoms.

At a personal level I thought this was interesting how inflammatory cytokines known to be raised in many PWME can cause hypothalamic responses like this because it validates my experience of last evening, feeling like I was in the middle of the arctic for hours with uncontrollable rigors causing muscle spasms and shivering at the slightest whiff of cool air, this often due to my own sweat, in a centrally heated bedroom measured at 37.5°C, followed by night sweats which dropped my body weight by at least two pounds as I tried to sleep and avoid further rigors.

OK, I get its all part of the ME thing and fluctuates with the immune activity cycle I experience, just thought I would start a thread so people can discuss this inflammatory symptom and the science behind it in relation to ME ... and to protest because its horrible!

 

[Jonathan Edwards]

At a personal level I thought this was interesting how inflammatory cytokines known to be raised in many PWME

Except that cytokines are not raised in ME/CFS on any well-documented basis as far as I am aware.
I would not use AI for this sort of enquiry. You are likely to pick up on all sorts of Chinese whispers in the literature.

 

[boolybooly]

Except that cytokines are not raised in ME/CFS on any well-documented basis as far as I am aware.
I would not use AI for this sort of enquiry. You are likely to pick up on all sorts of Chinese whispers in the literature.

I understand AI is not very reliable and agree one should be very circumspect of its output but honestly I do not have the stamina of focus to do anything else, not without making myself iller which I am not going to do.

I accept there are conflicting results between individual papers which are hard for us to make sense of. Its pretty frustrating but if one waits for them all to agree it will be a long wait, possibly an eternity. The most likely explanation for variance imho is different cohorts have different collections of subtypes due to insufficiently perspicacious criteria. Some variation might be due to local epidemiology and or timings of sampling relative to phases in an unrecognised cyclical process, certainly in my case, or disease progression over time.

Anomalies like these raise questions which deserve to be answered. I am Pollyanna optimistic the AI reflects the text of current literature based on statistical calculations regarding words used in relevant papers, offering a kind of instant review more worthwhile than Cochrane currently at any rate and worth discussing at least at the level of hypothesis formation to challenge or debunk or take forwards. The search output does offer elaborations and links to sources which is why I provided links to the searches I used, to show the chain of reasoning and sources.

I think its a discussion worth having, certainly after last night.

 

[Jonathan Edwards]

I accept there are conflicting results between individual papers which are hard for us to make sense of.

I don't think that is the situation, though. More or less all the studies are negative for almost everything and importantly, negative for any sign of the sort of pyrogen stimulus that produces rigors. If cytokines like IL-1, TNF or IL-6 were doing anything much the CRP would rise and the ESR would rise and they don't. And that is not so surprising because there isn't any inflammation anywhere to drive these. Authors of studies like to highlight some small changes here or there to have something to say but the big message is nothing to find.

Yes, cytokines are what produce fever, and cytokines may well be involved in ME/CFS but at present nothing is known about it except that it isn't accounted for by findings in blood.

 

[boolybooly]

I appreciate we should not get hyped about interim research findings, I am not, just so ticked off with rigors I decided it was time to take a look at it, but the premise nothing is happening doesn't ring true for me from my own experience and is hard to square with AI deciding there is a finding here.

There is not much consistency, but ME is not a consistent condition. It is marked by fluctuation for many people and for myself a distinct cycle, currently about one to two weeks long. Phases in the cycle can last 12 to 72 hours. The rigors lasted about 3pm to 9am, 18 hours.

What I have read of Dr Michael VanElzakker suggests a credible neuro-immune model for CNS inflammation in the brain stem in ME/CFS involving glial cells and mirror responses across the BBB (blood brain barrier) which would explain a lot of neurological symptoms, as well as blood flow rate data from other investigations, bearing in mind this is still not the half of ME symptoms. The point is biological systems rarely stand still, they are always moving dynamically.

How many cytokine investigations have even daily resolution for repeated sampling over time? If they sampled at midday they could miss an 18 hour long event of raised cytokines. Many investigators just dont think like that, yet. High resolution sampling is expensive.

If I look at the sources Google AI used on the specific question "are IL-1 TNF or interferon raised in ME CFS", besides the answer being yes, sources as follows agree repeat testing over time and cohort selection are helpful...

"The clinical value of cytokines in chronic fatigue syndrome" Yang et al https://pubmed.ncbi.nlm.nih.gov/31253154/

comprehensive consideration of the changes in individual circulating and CNS cytokines may be a better approach for understanding the pathophysiology of CFS

The references in this review refer to a paper by Michael Maes, Frank Twisk and Cort Johnson who wisely distinguished CFS cohorts based on PEM response.

"Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data." https://pubmed.ncbi.nlm.nih.gov/22521895/
And they found...

Patients with ME had significantly higher scores on concentration difficulties and a subjective experience of infection, and higher levels of IL-1, TNFα, and neopterin than patients with CFS.

... which exemplifies what can happen if investigators tackle cohort selection and demonstrates why studies using standard criteria lose statistical coherence.

Another paper referenced... Moneghetti KJ et al. 2018.
"Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome"
https://pubmed.ncbi.nlm.nih.gov/29426834/
... used an 18 hour post exercise testing interval and found...

...cytokine profiles 18 hours post exercise offered the most reliable discrimination between ME/CFS and controls (κ = 0.62(0.34,0.84)). The most discriminatory cytokines post exercise were CD40L, platelet activator inhibitor, interleukin 1-β, interferon-α and CXCL1. In conclusion, cytokine profiling following exercise may help differentiate patients with ME/CFS from sedentary controls.

I think the message is just because some people did not find stuff does not mean stuff is not there to be found, because other people are finding stuff.

lunch, hope that makes sense

P.S. Also worth mentioning re ESR (erythrocyte sedimentation rate), low ESR aka sticky blood is considered by many to be commonly associated with ME.

 

[boolybooly]

Nancy Klimas has spent many years looking at cytokines in relation to ME/CFS. One of her papers seems relevant so I thought I would add it to the thread.

"Poor sleep quality is associated with greater circulating pro-inflammatory cytokines and severity and frequency of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) symptoms in women" 2017 Klimas et al.

https://www.jni-journal.com/action/showFullTextImages?pii=S0165-5728%2816%2930449-0

Poor sleep quality predicted pro-inflammatory cytokines IL-1β, IL-6, and TNF-α.

These three cytokines are considered to be pyrogens if I am not mistaken, which could be consistent with widely reported night sweats for people with ME/CFS.