• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To become a member, simply click the Register button at the top right.

Lipkin finds biomarkers not bugs

View the Post on the Blog

The CDC PCOCA telephone broadcast on 10 September 2013, featured a lengthy presentation from Dr Ian Lipkin who revealed some stunning initial results from the study that is primarily hunting for pathogens in ME/CFS. Simon McGrath and Russell Fleming (Firestormm) review this exciting and possibly game-changing news...


Dr Ian Lipkin
Lead Researcher
Chronic Fatigue Initiative (CFI)
Pathogen Discovery and Pathogenesis Study

Read the full Lipkin Transcript: Here.

Dr Ian Lipkin has been a human whirlwind in ME/CFS research since he became involved a few years back, and he's just surprised us all by announcing the first results from the world's largest ever biomedical ME/CFS study in a public broadcast!

He started off by lowering expectations: their results thus far do not implicate a single infectious agent and they have not discovered the cause of CFS. But he then wowed the hundreds listening to the conference call by revealing they had found strong evidence for immune overstimulation, both in blood plasma and in cerebro spinal fluid; and that they were now hard at work trying to identify what could be causing these abnormalities.

The big pathogen hunt draws a blank thus far

This study is looking exhaustively for any pathogen: viral, bacterial, fungal or parasitic, to see if a chronic infection could explain ME/CFS. Many of the results are in, but so far there is no clear sign of viruses at least. It is every bit a collaborative effort, with patients provided by long-established physicians including Dr Dan Peterson and Professor Jose Montoya.

The Key Players

Lipkin began by thanking the clinicians who had provided the all-important samples. Effectively it was a roll call of America's top ME/CFS physicians:

Professors Jose Montoya, Anthony Komaroff and Nancy Klimas; and Drs Dan Peterson, Lucinda Bateman, Sue Levine and Donna Felsenstein.

The study itself was run by Dr Mady Hornig (CFI Principal Investigator) at the Centre for Infection and Immunity at Mailman School of Public Health; where Lipkin is also based.

He went on to acknowledged the very necessary support of the Chronic Fatigue Initiative, the Evans Foundation and an anonymous donor supporting Montoya's work.​

First the researchers looked at blood plasma for 285 CFS patients and 201 controls from Jose Montoya at Stanford (these are serious numbers). They searched for genetic evidence of infection using a panel that was able to detect 20 specific bacteria, viruses or parasites; including Epstein-Barr virus, Human Herpes Virus 6, enteroviruses, Influenza A and Borrelia bacteria.

Next they used high throughput sequencing, a method that was pioneered by Lipkin and colleagues that was used to discover over 500 viruses – so they felt fairly confident that if a virus was present, then they would have found it.

But they effectively drew a blank using both methods - only 1.4% of CFS patients were found to have HHV6 infection, but so did 1% of controls.

Other findings...

Lipkin said they also found Anelloviruses in 75% of those studied in plasma samples, but it was not specific for Chronic Fatigue Syndrome (we don't currently have separate figures for patients and controls). Anellovirus is believed to cause widespread chronic infection in the human population, but has not yet been associated to any specific disease. "I really don’t know at this point what this finding means" said Lipkin.

They also found retroviruses in 85% of the sample pools. However, Lipkin expressed caution:

"It is very difficult at this point to know whether or not this is clinically significant. And given the previous experience with retroviruses in Chronic Fatigue, I am going to be very clear in telling you – although I am reporting this at present – in Professor Montoya’s samples neither he nor we have concluded that there is a relationship to disease ...if I were to place bets and speculate, I would say that this is not going to pan out."

Window on the brain: Cerebrospinal fluid samples

Both Lipkin and Hornig were clearly excited to have had access to the 60 cerebrospinal fluid samples from Peterson, and kindly donated by his ME/CFS patients. Cerebrospinal fluid bathes our brain and spinal cord so it gives access to what goes on in the brain, a prime site of interest to researchers, but hard to access; so these spinal tap samples are precious.

However, using the same molecular techniques to track down pathogens as they had applied to Jose Montoya's samples, Lipkin's team again drew a blank.

At the Invest in ME conference in May, Hornig said they had tentative findings that there might just be a novel pathogen or pathogen candidate in these samples - but it was too early to say for sure. In reply to a question yesterday, Lipkin said there is no more to report:

"we do not yet have a novel pathogen nor do we have a pathogen candidate in which I would have any confidence. So at this point we have no plans to publish anything."
Nonetheless, he also said they hadn't finished all the DNA sequencing work on these samples, so this is not yet a dead end.

Immune stimulation and biomarkers

Up to this point we'd heard a lot of very impressive negative findings, based on large, well-defined samples of patients and controls, and using powerful research techniques. But what we most wanted to hear about was positive leads - and Ian Lipkin duly obliged:

blood1.jpg

Plasma is the clear fluid left when blood is separated

They took plasma from the CFI cohort of 200 very well-defined ME/CFS cases and 200 controls collected by clinicians (See 'Key Players' above). Then they searched for cytokines and chemokines, which are regulators and controllers of the immune system.

The big finding was a decrease in levels of Interleukin's IL-17, IL-2, IL-8 and in TNF-alpha - all of which have a role in pro-inflammatory responses. Lipkin believes these significant differences are worth follow-up in larger cohorts to better understand what they mean.

Professor Jonathan Edwards (who is an adviser to the planned UK Rituximab trial) commented on this forum yesterday, that it was a surprise to see TNF-alpha levels decrease, and suggested it could mean that 'inflammation' is too crude a concept for the process.

Lipkin and colleagues also found upregulation in Leptin, a hormone that plays a key role in regulating energy uptake and use, and Serpin, a protein family with multiple roles. More obscure cytokines, and and their cousins chemokines, were also affected but Lipkin didn't give any further detail.

Two new patient types revealed

Ian Lipkin said they found something very surprising in their data: there appear to be substantial differences in profiles between those people who have had the disease for 3 years or less and those who have had the disease for more than 3 years. And that this is important because, "it could have implications for therapy as well as for diagnosis".

In the ‘early group’, who have been ill for less than 3 years, there seem to be a number of markers suggestive of some sort of allergy aspect. For example there are often increased numbers of eosinophils in blood, with more differences in cytokines. But while this is tentative, he was more confident in the finding the IL-17 was elevated in these 'early' patients, compared with reduced levels in patients ill for over three years.

Lipkin said that he thought this 3-year division could be very important and that it hadn't been something they were looking for; but would be looked at in any future work they did.

Cerebrospinal fluid: different differences

Lipkin's team also found differences in cerebrospinal fluid biomarkers between patients and controls. I'm not sure from what he said if there were significant differences between the 'early' group and patients who had been ill for more than three years. However, they did find that patients had elevated levels of the TH-2 type cytokines IL-10 and IL-13 and elevated levels of four TH-1 cytokine: IL-1 beta, TNF-alpha, IL-5, and IL-17. Lipkin said this is compatible with a profile of some particular types of response that may provide insights into immunological dysregulation in Chronic Fatigue Syndrome.

So, overall they found clear differences between patients and controls in both plasma and spinal fluid. Many immune differences have been detected before, but findings are not very consistent and none had used such a large and robustly-defined patient cohort (meeting Fukuda and Canadian criteria), or with such carefully matched controls.

HEALTH WARNING

Dr Ian Lipkin again was very clear that he did NOT recommend anyone act on these provisional findings: he doesn't want anyone to get a spinal tap, or measure the cytokine levels and hope to modulate them with drugs based on this research: it's too early for that.​

The lost years...
Back in 1999 Ian Lipkin published his first paper on CFS, which ruled out a connection between the illness and Borna Disease Virus (one of the many viruses he's discovered). But crucially they found evidence of polyclonal B-cell reactivity. He commented that back then:

"there was a very strong sentiment in some portions of the scientific and clinical communities – not always and not everywhere – but in some portions of the community, that this was a psychological illness. What I said was that based on our findings we had very strong evidence that people with Chronic Fatigue Syndrome were truly ill with a physical illness and they deserved a "Deep Dive" to find out why they were ill."
He noted that was a long time ago and dryly added "I am pleased to see that people are now paying much more attention to this disorder and what we can do about it".
What next?

"I still believe the primary cause is likely to be an infectious agent."
Having found clear signs of cytokine abnormalities, Lipkin wants to find out what is causing these changes; he currently thinks that an ongoing stimulus is causing immune system activation which might be resulting in the symptoms we associate with the disease. And interestingly, he still believes that infection lies at the root of it all - despite not yet finding any infections.

The team - working closely with the clinicians he's already mentioned - plan even more extensive work on a cohort of 200 CFI patients and controls. They will further test for viruses and crucially they will also look for bacteria and fungi by sequencing ribosomal RNA (which should detect unknown bacteria and fungi, as well as known ones).

Previous infection detection

The group has looked for current pathogens in the blood and spinal fluid samples they have - and has so far drawn a blank, though there is more work underway. However, what if the trigger for ME/CFS is an earlier infection that has since been cleared: the 'hit and run' scenario Hornig has described? Lipkin says they are looking for "shadows" of previous infections by searching for antibodies against specific infections, rather than the infections themselves (the body will continue to produce low levels of specific antibodies years after an infection has been cleared (the basis of much immunity)).

They will use a technique called LIPS to look for antibodies against particular known infection. In addition, as in their viral sequencing work, they will use an 'unbiased' system (using peptide arrays) that should detect all potential viruses - or rather antibodies against them. They don't currently have an 'unbiased' system that works on bacteria or fungi.

Fecal future?

What excites Ian Lipkin most is the gut microbiome, the community of micro-organisms that live in our gut - which might seem odd given his focus so far on pathogens and the immune system. However, it turns out that the microbiome can have a profound influence on the immune system and may be important in many diseases. Hornig and Lipkin have already developed techniques to study the microbiome, and have shown it could be a factor in autism and even in the severity of colon cancer.

It turns out the best way to find out what lives in the microbiome is to measure what comes out of the gut: fecal matter, or 'poop' to you and me. Their ME/CFS microbiome project has started, but Lipkin felt there wasn't enough material in the first attempt at gathering samples, so things have been delayed as they switch to a new technique (the 'special' collection cups).

The Big Ask: "we can't do this without you"

Microbiome research is very expensive (analysis, not sample collection), and they currently only have the funds to do 10% of what's needed. In fact, throughout the call, Lipkin was stressing the need for more funds, because good research costs and ME/CFS is woefully underfunded: there just isn't enough money to do the work needed. The current science budget cuts (Sequestration) in the US makes the climate even harder.

"It is probably inappropriate for me to be passing the hat, but that’s precisely what I am doing."

He urged patients to contact their representatives in Congress, demanding more funding for ME/CFS research - pointing out that in the early days of HIV, there was little funding until patients demanded it. He also said that if patients were able to afford it, they should invest in research themselves.

Conclusion

ME/CFS research is coming of age. Ian Lipkin has reported these early - and soon-to-be published results - from a huge study, using 285 of Jose Montoya's patients, the 200 patients from the Chronic Fatigue Initiative, plus the 60 'gold-dust' spinal fluid samples from Dan Peterson's patients. Using state-of-the-art techniques, they have largely ruled out a role for a specific pathogen - though that work is incomplete. And they have strong evidence of ongoing immune stimulation in ME/CFS patients, with abnormalities found in both the blood and spinal fluid. The next stage involves deeper searching for bacteria and fungi, looking for 'shadows' of previous infections and investigating the gut microbiome. These are exciting times!

Thanks to the CDC for organizing the presentation and to Firestormm for providing a transcript of this talk, and above all to Dr Ian Lipkin for taking time out to talk to patients.

If you would like to donate to Ian Lipkin's research, click here. In the comments box, put "for M.E/C.F.S Study" to make sure it goes to the right place.


Simon McGrath tweets on ME/CFS research:



Phoenix Rising is a registered 501 c.(3) non profit. We support ME/CFS and NEID patients through rigorous reporting, reliable information, effective advocacy and the provision of online services which empower patients and help them to cope with their isolation.

There are many ways you can help Phoenix Rising to continue its work. If you feel able to offer your time and talent, we could really use some more authors, proof-readers, fundraisers, technicians etc. and we'd love to expand our Board of Directors. So, if you think you can help then please contact Mark through the Forum.

And don't forget: you can always support our efforts at no cost to yourself as you shop online! To find out more, visit Phoenix Rising’s Donate page by clicking the button below.


View the Post on the Blog
 
Last edited by a moderator:
It does seem like some pathogens favour tissue but many, including Borrelia, are often enough found in the blood. If any had been missed in the patient exclusion phase then with as many subjects as this (260?) and with the best techniques available being used, you'd have thought if present then at least some cases would have been picked up, but instead we have zero. Borrelia as a cause therefore looks pretty unlikely now, though some other bacteria being responsible is yet to be ruled out as i understand it. It'll be interesting to see if they find anything, or not.


As far as i'm aware Borrelia is an exclusionary criteria from ME anyway although I guess that depends upon which diagnostic criteria the physician is using. This extensive search is certainly worthwhile but I think it's unwise to pin hopes on this given the history pathogens have had in terms of ME research. From a personal standpoint I doubt any infectious agent lies at the heart - perhaps they simply serve to exacerbate the problem in those who have them.

I agree that even if these pathogens are hiding away in tissues there should be some evidence of the active infection. As far as i'm concerned if the pathogen is inert in these tissues there should be no symptoms so I feel that line of thought should be throw out instantly.
 
The microbiome and poo

This is a gentle introduction to the microbiome and also to Jeroen Raes who quite coincidentally I was informed of by Linda Vasteenwinckel when discussing the article on Lipkin above.

Linda produces ME/CFS Evolving Science on Facebook - always my first port of call for new publications - and said of Dr Raes:

"His lab are at the forefront in gut microbiome research nowadays and are now working on Het Vlaams Darmfloraproject, the most ambitious large-scale gut microbiome project in the world.

Their first focus is on obesity, diabetes and IBD, but many ME/CFS patients have sent in samples too, and we're trying to convince them to take a closer look at those in a later stage.

But it would be fantastic to see Lipkin/Hornig's group collaborate closely with Raes' group."
I'd certainly not encountered him before and need to do some reading I think.

Thanks to Antares in NYC for posting the programme on a separate thread.​
I believe DOB is still featured on BBC2 each week - though I may be wrong as I don't have a television.​
:cool:
 
The microbiome and poo

This is a gentle introduction to the microbiome and also to Jeroen Raes who quite coincidentally I was informed of by Linda Vasteenwinckel when discussing the article on Lipkin above.

Linda produces ME/CFS Evolving Science on Facebook - always my first port of call for new publications - and said of Dr Raes:


I'd certainly not encountered him before and need to do some reading I think.

Thanks to Antares in NYC for posting the programme on a separate thread.

I believe DOB is still featured on BBC2 each week - though I may be wrong as I don't have a television.

:cool:


Interesting video - yet again the vagus nerve comes up. Seems to be linked to everything.
 
I still cant get past many of us not having chronic viral infections when most of us have low nk function, who's job it is to kill viruses. if its herpes virus or some other virus, if they cant find them then they probably havent looked in the right places or dont have the right tests.

I think they will find viruses in tissue, but those require different testing.

On the other hand, if our B cell immunity is nuts, and our T cells cranked up, and our RNase L modified and amplified, we might indeed have something like normal virus immunity. The problem is that under these conditions if we get a virus then our immune systems are getting a boot and will go into overdrive. Also I think it more likely we will get more viral infections. Its about frequency, not acute viral severity. It would be about immune severity i.e. how hard the symptoms are going to hit us, and how long it will take to recover. This point of view can be summed up in the phrase "its the immune system, not a virus".
 
I think they will find viruses in tissue, but those require different testing.

On the other hand, if our B cell immunity is nuts, and our T cells cranked up, and our RNase L modified and amplified, we might indeed have something like normal virus immunity. The problem is that under these conditions if we get a virus then our immune systems are getting a boot and will go into overdrive. Also I think it more likely we will get more viral infections. Its about frequency, not acute viral severity. It would be about immune severity i.e. how hard the symptoms are going to hit us, and how long it will take to recover. This point of view can be summed up in the phrase "its the immune system, not a virus".
So this is one of those puzzlers. For some with ME/CFS they have very overt and ongoing signs of illness like swollen lymph nodes, sore throat, headaches etc. My particular thing presented with months of pervasive dizziness as a prelude to a complete collapse with headache and the whole nine yards. But since that three month period I have literally not gotten "sick" while all of my famiy members (kids got to school and wife is a teacher) have brought home all sorts of things. That seems to jive with what some others on this board have also reported. Like the immune system is in overdrive, but while you're not getting "better" you still don't get "sick." Not complaining because if I got flu or a cold on top of this it wouldn't be pretty. But it doesn't make sense to me.
 
"However, they did find that patients had elevated levels of the ⁠TH-2 type⁠ cytokines IL-10 and IL-13 and elevated levels of four TH-1 cytokine: IL-1 beta, TNF-alpha, IL-5, and IL-17."

Haven't elevated cytokines been found in depression and other psychiatric conditions as well as diseases with co-morbid depression, where in the latter, cytokines are thought to play a role in the depression but not the main illness?

Can cytokine profiles serve as reliable biomarkers, and if so, will CFS be distinguishable from psychiatric disorders?
 
The big finding was a decrease in levels of Interleukin’s IL-17, IL-2, IL-8 and in TNF-alpha – all of which have a role in pro-inflammatory responses. Lipkin believes these significant differences are worth follow-up in larger cohorts to better understand what they mean.


Interesting that lowered production of these very cytokines are associated with disease progression and immunological damage in HIV patients – HIV+ long-term nonprogressors retain the ability to make these cytokines, while individuals with progressive disease start producing less of Il-17, TNF-α and IL-2 after a while…


Also interesting to read that this sudden downturn in cytokine levels happened after exactly 3.1 years in this patient
Patient maintained a stable/low viral set point for 3.1 years before control of viral replication was lost … Gradual loss of functionality was observed in these responses, characterized by early loss of IL-2 …



This paper could give us further clues on reduced IL-17 levels in chronic sufferers (also possibly linking to gut barrier breakdown)

Studies in nonhuman primate models of lentiviral infection and in HIV-infected human individuals highlight pathogenic infection to be associated with loss of Th17 cells. IL-17 serves to maintain the integrity of the mucosal barrier. Loss of Th17 cells may permit microbial translocation across the gastrointestinal mucosa and thereby promote immune activation driven by bacterial lipopolyscaacharide, which is associated with disease progression. We demonstrate that …. We demonstrate that …. reduced Treg and IL-17 numbers is a feature of chronic HIV infection
 
I will have to go back and check, but I'm fairly certain the Lyme PCR yield is in the low single digits. In this case, that would mean that if all 200-something people he was studying had proven Lyme disease, only a few would show up as positive using that method. My point is not to argue that Lyme is or isn't the cause here, its to show that for any of the hundreds of pathogens he tested for using the blood and CSF with sequencing, the negative result he got could be enough to rule out their involvement completely, or it could mean nothing – it all depends on the nature of that particular bug.
 
It is somewhat outdated and oversimplified to consider only the Th-1 and Th-2 branches. In fact, the Th-17 branch may be at the root of our difficulties.

From ebioscience:
[my bolding]
Th17 Cells - A New T Cell Lineage

CD4+ T helper cells are critical mediators of the cellular immune response. For many years, due to cytokine expression patterns, it was thought that CD4+ T helper cells existed as a dichotomy of lineages named Th1 and Th2. However, as these subsets were analyzed more closely, it became apparent that the T helper cell population was not limited to these two subsets. Although it has long been appreciated that IL-17 (also known as IL-17A) production by T cells is required for protection against some pathogens, in 2000 it was demonstrated that IL-17A was produced by a unique subset of T helper cells. Subsequently, it was definitively shown that T cells could differentiate into IL-17-producing cells in vitro and in vivo independently of Th1 or Th2 cell development thereby establishing Th17 cells as a unique T helper cell lineage. Functionally, Th17 cells play a role in host defense against extracellular pathogens by mediating the recruitment of neutrophils and macrophages to infected tissues. Moreover, it has become evident that aberrant regulation of Th17 cells may play a significant role in the pathogenesis of multiple inflammatory and autoimmune disorders.
 
I'd argue the point that CSF markers serve as proof of an infection, viral or otherwise, of the nervous system. They certainly hint at a form of immune dysregulation within the brain and perhaps entire central nervous system but are not even close to showing an infectious causation, certainly that could be one cause of such a dysregulation but there are numerous others to further explore too.

Also, immune dysregulation can result in multiple infections which, as in HIV infection, cause the vast majority of the negative symptoms. Such infections don't have to be continuous or acute. Recurring or reactivating infections, as well as tissue infections, are not evident 100% if the time in plasma. Finding viral particles in the blood in a population like ours may require taking blood during bad periods or crashes -- just the time when most of us don't go to the doctor.

The lack of evidence of viral DNA in plasma suggests that we don't have an on-going acute infection with a known virus. That is not surprising -- we've been pretty sure of that for a long time. That does not mean that such infections are not reactivating on a regular basis, chronic in tissues not yet studied, or not detectable by current methods.

As the world learned from HIV, viruses to not have to be causative for the illness to be causative for many of the symptoms of the illness. The root cause should be found in most of us, secondary infections can be many and varied.

I think (and it looks like Lipkin thinks so, too) that something is causing immune dysregulation in ME/CFS. That may be an infection that has come and gone, it could be an as yet undetected pathogen, it could be genetic, it could be something else entirely. Lipkin would like to find that something. We would like that, too. :) However, we are also concerned about finding and treating secondary infections. That may not be part of Lipkin's concern at the moment. That doesn't mean investigation of secondary infections should be abandoned.
 
I will have to go back and check, but I'm fairly certain the Lyme PCR yield is in the low single digits. In this case, that would mean that if all 200-something people he was studying had proven Lyme disease, only a few would show up as positive using that method. My point is not to argue that Lyme is or isn't the cause here, its to show that for any of the hundreds of pathogens he tested for using the blood and CSF with sequencing, the negative result he got could be enough to rule out their involvement completely, or it could mean nothing – it all depends on the nature of that particular bug.

I'd be interested to see some data on how accurate the methods being used are and what that might mean in terms of the pathogens being looked for. I know some bacteria for instance are very hard to detect, and it's not uncommon for samples to be left to multiply in various growth mediums before they are of sufficient numbers to be detected by PCR.
 
Here's a story I love to tell but I will keep it brief. What do you do when your beloved college son gets

ME/CFS? Well, that's a problem.

What about if you are one of the richest people in the world and you also are a get it done, hard driving

Harvard business man who is a

doer? Then you do what any loving, dedicated, brilliant billionaire father would do, you fund the ME/CFS

research yourself and you.

bring answers and treatment to your very own son. It's brilliant. Done!

That's what Glenn Hutchins did, the 56 year old mega successful businessman who single handedly out

spent the entire United States government's in funding ME/CFS Research during the last three years. Glenn

has made a habit out of succeeding in life, and his Silver Lake investment firm is one of the most

successful equity firms in the world. Will he do something major for ME/CFS? That's a silly question. Of course he will!

Glenn and his son hit the same road blocks we all do when we were diagnosed with ME/CFS, so Glenn

decided to build a bridge over those blocks by ponying up close to $15 million to buy the services and

interests of the world’s BEST ME/CFS researchers, virologists, and other medical experts that all the money

in the world could buy. One of them was the brilliant and lauded virologists, Dr. Ian Lipkin, who you have

probably seen on the cover or one or another magazines. He is a virus hunter. And he's the best one in the world.

He just completed a monstrous study looking at a very large number of ME/CFS patients to see what if any

pathogens is involved in ME/CFS. He looked for everything. And his findings were surprising. Here is the

complete transcript of a large conference call on Sept. 10. The findings are fascinating and there’s a lot to

about, and I will be writing more about what they probably mean in the weeks and months ahead. There

is that much to write about.

I hope you enjoy this barrier crushing research, with its many ramifications. Isn't it great that we have this

kind of research going on even when we don't know it is? It's happening everywhere, and it's one of the

main reasons why patients will eventually have completely effective treatments and one day even the cure.

A quick note, as I would be remiss not to do this. To Glenn Hutchins, on behalf of all Chronic Fatigue

Syndrome and (the more difficult to qualify for) Myalgic Encephalomyelitis patients everywhere, thank you

very, very much.
https://www.facebook.com/photo.php?...a.10150589792146095.443635.57430136094&type=1
 
Also, immune dysregulation can result in multiple infections which, as in HIV infection, cause the vast majority of the negative symptoms. Such infections don't have to be continuous or acute. Recurring or reactivating infections, as well as tissue infections, are not evident 100% if the time in plasma. Finding viral particles in the blood in a population like ours may required taking blood during bad periods or crashes -- just the time when most of us don't go to the doctor.

The lack of evidence of viral DNA in plasma suggests that we don't have an on-going acute infection with a known virus. That is not surprising -- we've been pretty sure of that for a long time. That does not mean that such infections are not reactivating on a regular basis, chronic in tissues not yet studied, or not detectable by current methods.

As the world learned from HIV, viruses to not have to be causative for the illness to be causative for many of the symptoms of the illness. The root cause should be found in most of us, secondary infections can be many and varied.

I think (and it looks like Lipkin thinks so, too) that something is causing immune dysregulation in ME/CFS. That may be an infection that has come and gone, it could be an as yet undetected pathogen, it could be genetic, it could be something else entirely. Lipkin would like to find that something. We would like that, too. :) However, we are also concerned about finding and treating secondary infections. That may not be part of Lipkin's concern at the moment. That doesn't mean investigation of secondary infections should be abandoned.

Whatever that something is that triggers, and perhaps maintains that immune dysfunction, my thinking on secondary infections has changed quite a bit in the last year or so. I think with lots of different viruses having been put forward to have links with ME/CFS over the years, the view that we have a lot of coinfections has become fairly common and I used to think that myself. However, when I thought about this some more, I considered that in a disease like HIV-AIDS where you have immune deficiency and you get these secondary infections, they are quite varied and even a relatively mild pathogen can become lethal. Many of these infections are very easily identifiable - not just through testing - but through symtoms; it is usually clearly apparent that a HIV sufferer has hepatitus, tuberculosis, etc. based on symptoms alone.

Even if we had a less severe immune deficiency than HIV-AIDS, we don't get clear symptoms of secondary infections that allow identification of that secondary infection based on symtoms, as far as I can tell. To me this suggests that we don't have an immune deficiency leading to a variety of seconary infections. Perhaps none at all.

Using the common cold as an example (which it seems many of us - thought not all - don't get), If we had an immune deficiency of some kind then I'd have thought we would be more suseptible to them, not less so. So this suggests to me (and this is just my current thoughts on this and I'm very open to discussion) that as a whole, we have an up-regulated immune system not down-regulated. That isn't to say that we can't have part of our immune system that are deficient, perhaps that is likely given previously reported findings on NK-cells etc. but I think other parts of our immune system are taking up the slack by being on all the time, meaning as a whole our immune system is not deficient. This alone could explain the vast majority of our symptoms I'd have thought.
 
Many of these infections are very easily identifiable - not just through testing - but through symtoms; it is usually clearly apparent that a HIV sufferer has hepatitus, tuberculosis, etc. based on symptoms alone.

Even if we had a less severe immune deficiency than HIV-AIDS, we don't get clear symptoms of secondary infections that allow identification of that secondary infection based on symtoms, as far as I can tell. To me this suggests that we don't have an immune deficiency leading to a variety of seconary infections. Perhaps none at all.

Many of us do have symptoms of herpesvirus infections -- extreme fatigue, sore throat, swollen glands, and elevated antibody titres. The problem is that doctors don't believe that herpesvirus reactivations occur in immunocompetent patients, so they declare that we cannot have those infections. The assumption there is that we are immunocompetent. I actually asked my GP if I had HIV and the symptoms and antibody titres I do, would he believe I had reactivated herpesvirus infections and prescribe antivirals. He said, "Certainly. But you don't have HIV. A healthy person's immune system prevents reactivation of herpesvirus infections, so you can't have reactivations." :rolleyes: That seems to be the ubiquitous thinking in the medical world on herpesvirus reactivations. No one said they teach science or logic in medical school.

I think there is similar thinking in other pathogens as well -- everyone has them, but healthy immune systems keep them in check, so ME/CFS patients can't have them because they aren't immune-impaired. o_O Doctors like Dr Klimas and KDM, who are aware of immune dysfunction in ME/CFS, often prescribe abx and antivirals for secondary infections detected by relatively common methods.

Using the common cold as an example (which it seems many of us - thought not all - don't get), If we had an immune deficiency of some kind then I'd have thought we would be more suseptible to them, not less so. So this suggests to me (and this is just my current thoughts on this and I'm very open to discussion) that as a whole, we have an up-regulated immune system not down-regulated. That isn't to say that we can't have part of our immune system that are deficient, perhaps that is likely given previously reported findings on NK-cells etc. but I think other parts of our immune system are taking up the slack by being on all the time, meaning as a whole our immune system is not deficient. This alone could explain the vast majority of our symptoms I'd have thought.

Not all people with ME/CFS don't get colds. (Daughter and I are both fighting colds now, as a matter of fact) That seems to me to be more of a stage of the illness thing, although I could certainly be wrong. :) In my case, I went through a catching everything phase, an allergic MCS-type phase where I didn't catch common colds, and a more normal but still inclined to catch things phase.

The immune system is far more complicated than up-regulated or down-regulated. It's far from a certainty that if one part fails, another part will compensate, or that if some compensation does occurs, the immune system can maintain that abnormal condition long-term.

I don't know that all of us have the same immune abnormalities. That could explain why we have different secondary infections, and/or different immune reactions. Those different immune abnormalities may be a factor in subsets in the illness.
 
The immune system if far more complicated than up-regulated or down-regulated. It's far from a certainty that if one part fails, another part will compensate, or that if some compensation does occurs, the immune system can maintain that abnormal condition long-term..

I am convinced it will try to compensate but there is no garantee it will succeed. When one thing fails it will try something else and at one point in time it could push the right button.
 
YES! IT COULD BE A COMBINATION OF OUR BAD DNA DETOX GENES AND MOLD( it's a bacteria).
I HOPE ALL CFS PATIENTS TAKE A LOOK AT WHAT FUNCTIONAL ALTERNATIVE DOCTORS THAT SPECIALIZE IN MOLD and the connection IAN LIPKIN HAVE FOUND...

A POSSIBLE BACTERIA OR FUNGI EXPOSURE! LEPTIN HORMONE! IMMUNE INFLAMATION!
Take a look at DR?SHOEMAKER AND SPANOUGLE AND FINDING ON MOLD EXPOSURE! LEPTIN! IMMUNE INFLAMMATION! AND LEAKY GUT. It would make sense mold is an epidemic 25 percent of people have poor detox pathways.

http://www.survivingmold.com/diagnosis/the-biotoxin-pathway
http://sponauglewellness.com/wellness-programs/mold-toxicity/black-mold-used-in-weaponry/



Functional medicine world meets traditional medicine (please work together!)
 
I have always said that since childhood I had an immune system that was over-performing; a very good healer and few colds, flues or viruses. The day I developed severe ME/CFS over twenty-five years ago was when my over-achieving immune system crossed the line and became a full-blown autoimmune disease. The genes for (up-regulated immune function) and many triggers (viruses, bacterias, vaccines, chemicals etc) leave some of us more susceptible to develop ME/CFS.
 
As far as i'm aware Borrelia is an exclusionary criteria from ME anyway although I guess that depends upon which diagnostic criteria the physician is using. This extensive search is certainly worthwhile but I think it's unwise to pin hopes on this given the history pathogens have had in terms of ME research. From a personal standpoint I doubt any infectious agent lies at the heart - perhaps they simply serve to exacerbate the problem in those who have them.

I agree that even if these pathogens are hiding away in tissues there should be some evidence of the active infection. As far as i'm concerned if the pathogen is inert in these tissues there should be no symptoms so I feel that line of thought should be throw out instantly.

He only tested plasma for infection didn't he ?, and CSF ? He didn't test white blood cells. And there is activated immune system, both Th1 and Th2. I wouldn't throw out the infection impact just yet. Others are finding infections - this needs to be explained.