CFI Spinal Fluid study from Lipkin and Hornig is out.

[leokitten]

In the first few months of the illness my ESR went up to 7 or so and then after 6 months or so went and stayed down at 0 or 1. hs-CRP in the beginning and now were always low at 0.1 - 0.35. Don't think CRP would ever tell us anything.

 

[heapsreal]

The problem with the pathogen theory is that there is no single pathogen that is associated with ME or CFS. It is too much of a stretch to believe that all these widely varying pathogens will have no major symptoms, except those of ME.

Maybe these varying pathogens cause problems in ME as they generally have low nk function and recent research in australia showing low cd8 t cell function. Quite easy to understand how these different infections could be an issue.

Not to unlike HIV when their cd4 cells drop, patients then can become infected by varying infections and reaction of different pathogens. In HIV they know the exact cause, in ME we dont know the exact cause yet.

 

[heapsreal]

As far as I know no plausible model has been proposed for this hypothesis, other than autoimmunity. I find the chronic infectious model so much more convincing, especially considering the work of Chia, Kerr, Montoya, Lerner, and others.

I have wondered about the magical 3 year mark which is mentioned in recent research is when ME splits in two.

One group may go down the autoimmune line, with the immune system cranking up, increased cytokines and inflammation,this could also be the hit and run group.

The other group end up being in the immune exhaustion group with the low nk function, low cd t cell function, low immunoglobulins, decreased neutrophil bursts, RNaseL pathway dysregulation. This group seem to be the one showing active infections for the different herpes viruses and common bacterial infections found in ME. Also remember gut infections such as entroviruses as well as lactic acid producing bacteria in intestinal dysbiosis.

I dont think there will be one treatment to treat all this, plus we havent even mentioned orthostatic dysfunction that can be the most disabling.

 

[leokitten]

The problem with the pathogen theory is that there is no single pathogen that is associated with ME or CFS. It is too much of a stretch to believe that all these widely varying pathogens will have no major symptoms, except those of ME.

I've always thought the pathogen theory is too simplistic and narrow to possibly be true, that really that the reactivation of ubiquitous mostly intracellular pathogens is just a secondary sign of underlying immune dysfunction associated with the disease or an initial somewhat subtle shift in immune function due to genetic or environmental factors causes infections to become active and then these infections over time tax the immune system and push it into further disarray until there is a tipping point when it all goes to pot and you get ME/CFS.

So it's this complex interplay between the immune system and pathogens, not really any pathogens being the root cause. I think the only way the pathogen theory would ever come to be true is if they do discover some new virus or organism we've all been infected with but that likelihood is low.

 

[Jonathan Edwards]

The problem with the pathogen theory is that there is no single pathogen that is associated with ME or CFS. It is too much of a stretch to believe that all these widely varying pathogens will have no major symptoms, except those of ME.

I think that is a very succinct way of delineating the problem. Infections have signatures, even low grade chronic ones.

 

[aimossy]

@Jonathan Edwards I wonder what you think this paper tells us. I wonder if it at least speaks to things not functioning normally. But there seems to be some difficulty around samples being old or even the control group being problematic. I will be honest I am finding this paper frustrating for solid meaning. Is there anything really good/ useful about it. I hope no one jumps on me for my lack of understanding.

 

[aimossy]

I should add that I am not meaning to be disrespectful in any way about the researchers or the paper. We want everything investigated and they find what they find I am just struggling to understand what this paper is saying because I am not a scientist but dearly do want to understand what this paper means.

 

[duncan]

Not all infections, even low grade chronic ones, have recognized persistent signatures, that are uniform across a given patient/pathogen population.

Many have signatures, yes, but depending on what pathogen is being scrutinized, those signatures can be inconsistent and unreliable and lacking in predictability. I suspect it depends both on the pathogen and the level of sophistication of the metrics being employed, as well as the accrued knowledge at researchers' disposal.

 

[Jonathan Edwards]

@Jonathan Edwards I wonder what you think this paper tells us. I wonder if it at least speaks to things not functioning normally. But there seems to be some difficulty around samples being old or even the control group being problematic. I will be honest I am finding this paper frustrating for solid meaning. Is there anything really good/ useful about it. I hope no one jumps on me for my lack of understanding.

I also find it difficult to draw any conclusion from. The blood study seemed to give us more of a foothold.

 

[aimossy]

Thanks @Jonathan Edwards at least I am not being dim with this then.

 

[Jonathan Edwards]

Thanks @Jonathan Edwards at least I am not being dim with this then.

@aimossy Either that, or we er ....

 

[leokitten]

Whenever I hear someone with ME/CFS say they tested negative for Lyme, I want so much to ask WHICH tests? I want to say, do you know you're only being tested for a single strain - B31 - and in the United States, a single species? Which is extraordinarily presumptuous of me. Fortunately, I usually manage to bite my tongue (obvious I failed this time - my apologies). But the point is, there is a shitload of people who have been told they tested negative for Lyme - and they have Lyme. I am one example. Then again, I also have ME/CFS.

May I ask how do you know definitively that you have Lyme when all your labs have turned up negative? Did you have the bullseye bite/rash? Is it based only on clinical symptoms?

If it's based only on clinical symptoms without a bite or labs then you know it's impossible to say for sure that you have Lyme because there are no distinct clinical symptoms that differentiate it from ME/CFS.

In the past I did think like you, did a lot of research and saw that you have to rule Lyme and other vector-borne pathogens as a possible cause to the ME/CFS.

I've spent $1000s of dollars with IGeneX and other specialty labs doing all kinds of tests for borrelia and all the related co-infections babesia, bartonella, ehrlichia, etc, etc. Like @Eeyore they always come up negative!

At the request of the expert LLMD I was seeing even after all the negative results because like you said the diagnostics could miss something and based on clinical symptoms we decided to try empirical therapy with the best known combinations of antibiotics and antiparasitics and supplements, the latest and most aggressive therapies because my body could take it, did that for a year and guess what? The treatment did nothing to make my clinical symptoms go away. You would not believe all the different combos of drugs I did, strong drugs at high dosages for so long, they would've definitely obliterated any Lyme, babesia, bartonella or other related organism.

I just don't think for most of us this disease is caused by Lyme or any other related pathogens.

 

[halcyon]

@Jonathan Edwards I wonder what you think this paper tells us. I wonder if it at least speaks to things not functioning normally. But there seems to be some difficulty around samples being old or even the control group being problematic. I will be honest I am finding this paper frustrating for solid meaning. Is there anything really good/ useful about it. I hope no one jumps on me for my lack of understanding.

These were my main takeaways from the paper:

Others have reported cytokine abnormalities in CSF from subjects with ME/CFS;21 however, this study is the first to employ comprehensive cytokine panels, include both normal control and MS comparator subjects and apply logistic regression and network analysis models. Our results indicate a markedly disturbed immune signature in the CSF of ME/CFS subjects that is consistent with immune activation in the CNS. Persistent secretion of cytokines by activated microglia, brain immune cells of macrophage monocyte lineage, may contribute to this pattern. IL1ra, an endogenous downregulator of IL1 and its inflammatory cascades, has been used to address pathological fatigue in conditions other than ME/CFS, such as histiocytosis.41 Our finding that IL1ra has a negative influence on CSF1, CSF2 and IL17F in ME/CFS, without effects on IL1α or IL1β, suggests a disturbance in IL1 signaling pathways. The role of IL1ra in inhibition of allergic responses42,43 is consistent with reports of an increased prevalence of allergic disorders in some studies of ME/CFS.44,45 IL1ra mediated downregulation of responses to allergic stimuli is associated with lower levels of CSF2 (GMCSF), a key regulator of granulocyte and macrophage maturational pathways.46 The inverse relationship we found between IL1ra and CSF2 in the CSF of cases using a network analysis approach suggests that neuroimmune responses may be shifted toward allergic or Th2 (autoimmune) patterns in the CNS of individuals with ME/CFS. One prior study of CSF cytokines in ME/CFS also found decreased levels of CSF2 (GMCSF),21 a molecule that shifts macrophages toward an M1-like, or inflammatory, phenotype.47 The presence of an allergic-type diathesis in the CNS of individuals with ME/CFS is further supported by the finding of increased CSF levels of CCL11 (eotaxin, a chemokine involved in the selective recruitment of eosinophils, an allergy-associated white blood cell subset48) in ME/CFS subjects relative to ND control subjects. CSF, as a reflection of the microenvironment of the CNS, may provide unique clues to the pathogenesis of ME/CFS. Although increased CSF CCL11 and CXCL10 levels in ME/CFS subjects, along with dysregulation of IL1 signaling, suggest the possibility of an allergic process in central compartments,49,50 such patterns may also be seen in a wide range of CNS infections.51–54 Additional studies focused on delineating the relationships of clinical phenotypes of ME/CFS to immune profiles in both the CSF and the peripheral blood are of paramount importance to investigating potential causes and biomarkers for disease

 

[duncan]

leokitten, most of my labs have come back positive - not just once but consistently over many years, even after IDSA recommended therapy. But yes, I've had the bull's eye rash, and more than once. And yes, I have clinical signs as well.

You may be right. ME/CFS for most may not be associated with Lyme. It may not be associated with Lyme, period.

What I am saying, in part, is we really cannot know that based on Bb diagnostics. That having a negative Lyme test doesn't mean you don't have Lyme. So, someone saying they have ME/CFS and they KNOW it cannot be Lyme because their Lyme tests came back negative...well, it may or may not be true. The negative predictive value of a serologic test for Bb may be close to nil.

If you accept that premise, and you know that late stage Lyme frequently can look almost identical to ME/CFS, then it leaves open the possibility that at the very least there is some overlap.

Being on the receiving end of a questionable clinician is nothing new for any of us. I have communicated with IDSA and ILADS and ME/CFS experts - and I have had my share of charlatans and saints among them all.

I have embraced all kinds of treatments, too. And like you, I remain sick.

But when I know I am being lied to or misled, or a disease and the people it infects is being misrepresented, then that makes me question things all the more.

 

[leokitten]

Again, I would point to the work of Chia, Kerr, Montoya, Lerner, and many others. There are a number of well known triggering pathogens for ME, and these same pathogens have been found persistently in ME patients. Further, treating these infections has shown improvement in symptoms, which gives us a clue that the persistent infections are maintaining the disease.

I would love to believe the chronic infection theory the be true, but none of the experts above have proven causation only association, and there are so many open questions in their research, in particular even with their carefully selected subsets the treatment doesn't work for so many.

I agree that some of the symptoms of CFS are caused by these infectious reactivations and the disease is likely made worse by allowing them to proliferate, but by treating and squashing them the disease does not go away, so they aren't the complete answer as to what is maintaining this disease.

 

[leokitten]

leokitten, most of my labs have come back positive - not just once but consistently over many years, even after IDSA recommended therapy. But yes, I've had the bull's eye rash, and more than once. And yes, I have clinical signs as well.

Very sorry @duncan I must have misread your post thought you said all your tests came back negative.

 

[halcyon]

The problem with the pathogen theory is that there is no single pathogen that is associated with ME or CFS. It is too much of a stretch to believe that all these widely varying pathogens will have no major symptoms, except those of ME.

Why does it have to be just one single pathogen responsible? I agree it would be lovely if this disease matched Koch's postulates, but we've discovered that they were a bit simplistic. Nature is not such a simple place.

I don't see why it's a stretch. The thing we keep finding in common is immune activation. The symptoms we all have in common are symptoms of immune activation. This means that potentially anything that can cause a persistent immune activation could be a suspect.

 

[halcyon]

I would love to believe the chronic infection theory the be true, but none of the experts above have proven causation only association, and there are so many open questions in their research, in particular even with their carefully selected subsets the treatment doesn't work for so many.

I agree that some of the symptoms of CFS are caused by these infectious reactivations and the disease is likely made worse by allowing them to proliferate, but by treating and squashing them the disease does not go away, so they aren't the complete answer as to what is maintaining this disease.

That's because there aren't any drugs available that can completely eradicate the pathogens in question. You can knock down viral load, and symptoms improve, but once treatment is stopped the viral load increases and symptoms return.

 

[Jonathan Edwards]

Why does it have to be just one single pathogen responsible? I agree it would be lovely if this disease matched Koch's postulates, but we've discovered that they were a bit simplistic. Nature is not such a simple place.

I don't see why it's a stretch. The thing we keep finding in common is immune activation. The symptoms we all have in common are symptoms of immune activation. This means that potentially anything that can cause a persistent immune activation could be a suspect.

Except that Dr Hornig found the opposite after 3 years in the blood study, and the symptoms continue. I think maybe the key conclusion from that study is that relating symptoms to 'immune activation' does not work. Something more complicated is going on. And to be honest the CSF findings do not look obviously like 'immune activation' to me. A lot of cytokines are lower than the controls. I do not see any support for a continuing infection hypothesis in these studies.

 

[leokitten]

PCR is not always the best way to show active infection. Many pathogens during active infection do not shed/circulate DNA in plasma or whole blood. For example, unlike HSV-1/2 which do constantly shed DNA, the other herpesviruses rarely do and PCR testing is not very sensitive. Also these viruses have multiple levels of activity, infection is not binary active or dormant.

Positive IgM antibodies are indicative of active primary infection but after primary infection will never likely be positive again.

Significant increase in positive IgG between two time points is indicative of active infection as well.

For EBV there is a particular early antigen (EA) IgG antibody that can be tested and if this is positive this is indicative of active infection.