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New era for ME/CFS research as top cytokine study attracts media headlines

Dr Mady Hornig

Study leader Dr. Mady Hornig in her lab

Simon McGrath describes ME/CFS research presently in the media spotlight

The immune systems of patients who have recently developed ME/CFS look markedly different from those who have been ill for much longer, according to a major new study from Drs. Ian Lipkin and Mady Hornig at Columbia University. This shift in immune profile hadn’t been seen before.

“Perhaps the most significant evidence yet that chronic fatigue syndrome has a biological basis”, said the Wall Street Journal. The immune signature discovered might eventually be the “basis of the first diagnostic test for the illness”, said The New York Times. The prestigious New Yorker magazine mentions the study too.

This feels like a new era of ME/CFS research: big, rigorous studies by top researchers and clinicians, with media interest to match. Many more such studies are in the pipeline, including Dr. Montoya’s related immune profiling work, the large Open Medicine Institute immune gene sequencing project, and the huge CDC multi-clinic studies.

If other researchers can confirm the finding that there is an important difference between short and long duration patients — an important qualification — this work could change how we understand, study and look for treatments in ME/CFS.

Distinct plasma immune signatures in ME/CFS are present early in the course of illness (Hornig and colleagues 2015)

Doing it right

One of the most exciting aspects of this study was simply that it was big: nearly 300 patients and 350 controls. Most ME/CFS studies to date have had just a few dozen patients.

And it was designed meticulously. Patients were carefully diagnosed (mainly using Canadian Consensus criteria) by the clinics of leading U.S. ME/CFS physician-researchers including Drs. Montoya, Klimas, Bateman, Peterson and Komaroff. The study matched healthy controls and patients by age and sex, as both affect the immune system.

“The study is an important step forward in trying to track the biological basis of ME/CFS.”

Professor Jonathan Edwards

And they went further in trying to minimise anything else that might skew immune profiles. The immune system has daily cycles and is sensitive to stress, so all blood samples were drawn within two hours of midday and after a common mild stressor (the necessary patient paperwork!).

Controls were also matched by season of the year, as infections (even ones we aren’t aware of but our immune system are busy fighting) are more common in winter, as well as also by region, as infections vary by location.

Not so much difference between all patients and controls

The researchers, led by Dr. Hornig, analysed cytokines — small messenger molecules that play a central role in regulating the immune system. Because cytokines are a window to the immune system, ME/CFS researchers have focused on them before, and numerous smaller studies did find unusual cytokine levels in patients.

But cytokines come in many different flavours that perform distinct roles in the immune system, and there was little consistency among these previous studies about which types of cytokines had unusual levels. Generally, cytokines linked with inflammation were higher in patients, but some studies found no differences at all.

The current researchers shared the view that cytokines were critical immune markers and believed that variation in diagnostic criteria and laboratory methods may have contributed to the variation. So they looked at more different kinds of cytokines than most previous studies had — 51 — and they hoped a large rigorous study would give a clear picture.

It didn’t — at least not at first. Several inflammatory cytokines were a little lower in patients than controls, contradicting both previous studies and intuition. But overall, there didn’t seem to be a huge amount going on, which surprised the researchers.

Changes in cytokine levels mirror each other in short and long duratiion patientss. Modified from study Table S6 (click image)

Changes in cytokine levels mirror each other in short- and long-duration patients. Modified with permission from study Table S6 (click image to access original)

However, when they looked at the raw data more closely, Hornig and her colleagues could see that something was up.

Most research cohorts are made up of patients who have been ill for a long time, but Hornig’s group had carefully included newly-ill patients as well: 52 who had been ill for under three years (an average of 20 months) alongside 246 patients who had been ill for longer (an average of 13 years).

When they split the patients into those two groups, the data suddenly formed a striking pattern: cytokine levels were mostly up in the short duration patients and down in the long duration.

The graphic on the left makes this clear.

Red bars indicate lower cytokine levels than controls while green bars indicate higher. White bars indicate there was no significant differences between the two groups.

Because the cytokine levels mirror each other (e.g., up in short and down in long duration) they tend to cancel each other out in the combined group, which explains why there was not much to see when researchers compared all patients with controls.

More than half of the 51 cytokines studied were significantly different between the short and long duration patients.

A few of these differences may be false positives, but their high number makes for a compelling pattern. Also, for 11 of the cytokines, the statistics showed that there was a 1 in 100,000 chance of a false positive or less (i.e., the p value was .00001 or less, when the accepted standard for significance is .05 or less).

“It appears that ME/CFS patients are flush with cytokines until around the three-year mark, at which point the immune system shows evidence of exhaustion and cytokine levels drop … This shows there are distinct stages to the disease.” — Dr. Mady Hornig

What’s going on?

So do these findings explain ME/CFS? Not yet. At this stage they are more like clues. The average cytokine differences between short- and long-duration patients are modest, and furthermore, the patients whose cytokine levels were more abnormal didn’t necessarily have worse symptoms. Abnormal cytokine levels, then, cannot be the direct, sole cause of symptoms.

Professor Jonathan Edwards explained on Phoenix Rising that immunological diseases such as rheumatoid arthritis set off very complex networks of cytokine signals, but it’s very hard to tell which of these signals actually causes the trouble. In fact, what you can measure may not be the signals that cause the trouble, but chatter about it.

“What this study is saying is that if you listen at the door of the immune system you can definitely hear some plotting of crime inside, but you don’t know which of the people speaking is going to go out and commit it”, he said.

 

Trouble elsewhere?

Hornig agrees that the cytokine pattern may be a sign of a problem in another part of the immune system, perhaps as a consequence of problems with particular immune cells. Each immune cell secretes many cytokines, so a problem with one type of immune cell is likely to affect the levels of many cytokines.

Intriguingly, one clue points at B cells, the very immune cell targeted by the drug rituximab (which has shown promise in treating CFS in early trials). Short-duration patients have less of a cytokine called CD40L that is critical to the development of properly functioning B cells.

In addition, CD40L levels in short-duration patients break free from the levels of other cytokines, varying up or down out of step with the rest. In healthy controls and long-duration patients, on the other hand, they correlate closely.

Another possibility is that what matters most of all are the levels of cytokines in the brain, and that the abnormal cytokine levels seen in the blood in this study are an echo of a bigger problem there. Because patients can have such striking cognitive problems, the brain has long been a suspect in ME/CFS. Hornig and colleagues have a new paper on cytokines in cerebrospinal fluid (which bathes the brain) coming out soon.

Viral hit and run?

One of the most eye-catching findings of the study was that the level of the inflammatory cytokine interferon gamma was crucial in distinguishing short-duration from long-duration patients. Short-duration patients consistently had higher interferon gamma levels than long-duration patients (albeit not much higher).

The strength of this association can be quantified through a number called an “odds ratio,” which in this case was a staggering 100 — normally anything over 3 is considered pretty exciting.

The increased cytokine levels could be the results of a 'hit and run' virus

The increased cytokine levels could be the results of a ‘hit-and-run’ virus

The authors say the increase in  interferon gamma is consistent with a viral trigger (or disrupted immune regulatory networks), and of course many patients report a viral-like illness triggering their illness. However, to date, searches in blood from the same patients have yet to find signs of an infection.

Hornig believes a hit-and-run scenario is possible, where a virus infects someone and is defeated, but for some reason the immune system remains ‘stuck in a high gear’. It’s possible that around the three-year mark, the immune system becomes exhausted, leading to the lowered cytokine levels in long-ill patients.

The finding here of elevated cytokines in short-duration patients differs from the famous Dubbo post-infectious studies, which found that cytokine levels were normal in ME/CFS after the initial acute illness, a disparity that’s currently hard to explain.

But other studies have found a link between cytokines and ongoing fatigue — for example, researchers found elevated levels of interferon gamma in those left with fatigue after West Nile virus infection.

What next?

These fascinating findings suggest a whole range of possible research avenues. The first thing needed is confirmation, as Hornig herself has stressed. One way to check them is to see if the cytokine levels for individual patients are changing over time the way this study suggests, and Columbia already has such a study in progress looking at some of these patients one year on.

But the best way to really understand what’s happening with cytokines in this illness is to get in there at the beginning and see what happens in the immune system as the illness first kicks off and then progresses. Hornig is exploring ways to make such a study happen.

A biomarker – and a unique opportunity for treatment?

“This is an exciting step forward in a historically challenging field.”

Professor Julia Newton

A biomarker has long been a ‘Holy Grail’ of ME/CFS research. Is the cytokine signature found in this study for early patients finally ‘it’, a test that will say “yes, you have ME/CFS”? And can it help researchers be sure they are studying people with the same illness?

Not yet. First, the findings need confirmation in other studies. In addition, the pattern of cytokine changes needs to be compared with those from other fatiguing illnesses, like multiple sclerosis or even unknown causes of fatigue.

Doctors can usually tell ME/CFS patients from the healthy. It’s separating these patients from those with other illnesses that’s so important. Hornig is eager to do the biomarker research that would take the study from the lab to the clinic. All they need is the funding.

The findings also raise the possibility that targeting the early immune dysregulation can prevent the illness settling into a long-term pattern. The first and crucial step is to identify what’s driving the cytokine abnormalities. Then, Hornig points out, therapies might be able to target those abnormalities in short-duration patients to stop the illness before it develops into its long-duration form.

A few years of ME/CFS are bad enough, but for many of us that would have been a dream outcome. And if these results are right, then it’s likely that newly ill patients will need different treatments from long-ill patients.

Clearly there is a long way to go before patients can expect a diagnostic test or, better still, effective treatment. But this new study, and others under way, gives me hope that we have entered a new era of bigger and better research that is finally capable of cracking ME/CFS.

You can donate to Dr. Hornig’s and Dr. Lipkin’s work on ME/CFS at The Center for Infection and Immunity, Columbia University, here

Simon McGrath tweets on ME/CFS research:

Thanks to Dr. Mady Hornig for talking to me and for supplying the photo; to Anne Griffith for ‘hit-and-run’ graphic created from Open Clip art images; to Sasha and oceiv (oceiv on UK media) for their summaries of media coverage.

Sign the petition to get ME/CFS a research budget of $250 million a year!
There's a US petition and a global solidarity petition here with a long-term target of 50,000 signatures. Time we were on an equal per-patient funding basis with similar diseases!

{ 36 comments… add one }

  • wastwater March 5, 2015, 8:31 pm

    What happened to Oslers Web,skyhigh levels of interleukin 2.Does il-2 have another name.

  • alex3619 March 5, 2015, 10:44 pm

    On the hit and run idea, I asked the question some years ago now – what happens when an infection enters a critical organ? Like the brain? Is it possible the immune system is more primed to trigger dramatically when critical organs appear to be infected? Could this lead to ME?

  • Forbin March 5, 2015, 11:33 pm

    Not that I know much about this, but I wonder…

    Could an unusually strong immune reaction to a hit-and-run virus alter the balance of organisms in the microbiome, somewhat as an antibiotic can alter the balance? Might then the altered microbiome look like a chronic infection to the immune system?

  • Kati March 6, 2015, 1:10 am

    Keep an eye for a response to an Op-ed in the NYT by IACFSME soon

  • Jon_Tradicionali March 6, 2015, 1:12 am
    Forbin

    Not that I know much about this, but I wonder…

    Could an unusually strong immune reaction to a hit-and-run virus alter the balance of organisms in the microbiome, somewhat as an antibiotic can alter the balance? Might then the altered microbiome look like a chronic infection to the immune system?

    You may be right, you may not be.

    The possibilities are endless you see.

    That's why Lipkin has approached this with the "it could be anything" attitude and testing cytokines, bacteria, viruses, metabolites in the blood, spinal fluid, intestine, pharynx. Etc.

  • Sasha March 6, 2015, 2:29 am

    Excellent article, @Simon, very clear – even I understood it (which is saying something)!

  • Simon March 6, 2015, 3:27 am
    Forbin

    Not that I know much about this, but I wonder…

    Could an unusually strong immune reaction to a hit-and-run virus alter the balance of organisms in the microbiome, somewhat as an antibiotic can alter the balance? Might then the altered microbiome look like a chronic infection to the immune system?

    Mady Hornig and Ian Lipkin are actively looking to see if changes in the microbiome are what's driving the changes they see in the immune system – that was one of the driving ideas behind the crowdfund project
    http://www.microbediscovery.org

  • oceiv March 6, 2015, 4:14 am

    This article really helped me to understand this study in a complex and in-depth way. Great science to English translations are always appreciated. The thorough explanations of the study, the contextual information of where the field is and of what the future holds because of this study's findings are particularly interesting to see laid-out in one place.

    Table 6 provides both an overall visual snapshot of the illness and a detailed richness. It's interesting to note that leptin wasn't singled out in this study, but did correlate with symptom severity in the much smaller Jared Younger study (if I'm reading Table 6 correctly – all the scientific terms in the table are new to me). I wonder what the in-progress Columbia study will show about how cytokine levels for individual patients are changing over time. I also hope that we see replication studies soon for both this Hornig/Lipkin study and the Jared Younger leptin study. As the saying goes "reading is fundamental." In the ME/CFS world, our new saying could be "funding is fundamental."

    I loved this metaphor from Professor Jonathan Edwards (@Jonathan Edwards). It humorously explains and sums up this study well:

    “What this study is saying is that if you listen at the door of the immune system you can definitely hear some plotting of crime inside, but you don’t know which of the people speaking is going to go out and commit it”,

  • Forbin March 6, 2015, 6:04 am
    Sasha

    Excellent article, @Simon, very clear – even I understood it (which is saying something)!

    Yes, thank you for the excellent article, Simon!

    In reading the Lipkin/Hornig paper, I don't recall if they mentioned the length of the shortest duration since onset for the samples taken from patients who had had the disease <3 years. I'm just wondering if the cytokine profiles might show yet more differences the closer you get to onset, or if they just get stuck in the "on" position following some infection, as has been mentioned. One problem with looking for that kind of thing is, obviously, that you can't technically get a diagnosis prior to onset+6 months. I had blood drawn within 3 days after onset, but, of course, only routine tests were run on it. That was a long time ago, but, even today, no one is going to preserve your blood sample if they think you just have a prolonged case of the flu.

  • Simon March 6, 2015, 6:21 am
    oceiv

    This article really helped me to understand this study in a a complex and in-depth way. Great science to English translations are always appreciated. The thorough explanations of the study, the contextual information of where the field is and of what the future holds because of this study's findings are particularly interesting to see laid-out in one place.

    You certainly know how to make a blogger happy – thank you.

    oceiv

    able 6 provides both an overall visual snapshot of the illness and a detailed richness. It's interesting to note that leptin wasn't singled out in this study, but did correlate with symptom severity in the much smaller Jared Younger study (if I'm reading Table 6 correctly – all the scientific terms in the table are new to me). I wonder what the in-progress Columbia study will show about how cytokine levels for individual patients are changing over time. I also hope that we see replication studies soon for both this Hornig/Lipkin study and the Jared Younger leptin study.

    The paper also highlights this about Leptin

    Among short-duration subjects, the levels of the adipose-related cytokine leptin were only correlated with IL-12p40, CSF2 (GM-CSF), and serpin E1 [plasminogen activator inhibitor-1 (PAI1)], whereas leptin was tightly related to most of the other 51 cytokines in both the long-duration ME/CFS and the control groups. Leptin also had an inverse relationship to PDGFBB among controls.

    So Leptin seems oddly out of whack in short duration patients, suggesting it is still a cytokine to investigate.

    And yes, great line from @Jonathan Edwards.

    oceiv

    I loved this metaphor from Professor Jonathan Edwards. It humorously explains and sums up this study well:

    Forbin

    Yes, thank you for the excellent article, Simon!

    In reading the Lipkin/Hornig paper, I don't recall if they mentioned the length of the shortest duration since onset for the samples taken from patients who had had the disease <3 years. I'm just wondering if the cytokine profiles might show yet more differences the closer you get to onset, or if they just get stuck in the "on" position following some infection, as has been mentioned.

    You're welcome!

    When I spoke to Mady Hornig she said that it seemd fairly stable up to three years, but they weren't sure how fast it dropped afterwards as they didn't have too many patients in the 3-8 year bracket. Their ongoing longitudinal study (tracking cytokine levels in the same patient one year on – or and and two years on for a few) should help throw light on this. I they plan more analysis and research on this, still early days.

  • peggy-sue March 6, 2015, 6:32 am

    This study also highlights a major failing in just about all psychology research.
    Complete failure to take into account all confounding variables. :bang-head:

    Thank goodness these researchers had the basic common scientific sense to "eyeball the data" – the phrase used in labs to describe the very first thing you do with it.:):thumbsup::)

    Thanks for this, Simon. A beautiful, clear explanation. :thumbsup:

  • duncan March 6, 2015, 6:46 am

    Simon, this is a nice piece of writing.

    Why the emphasis on fatigue? What do you mean by "fatiguing illnesses"? Don't most diseases cause varying degrees of fatigue? Are there any febrile infections, for instance, that don't generate fatigue as a by-product?

  • alex3619 March 6, 2015, 8:56 am
    Forbin

    One problem with looking for that kind of thing is, obviously, that you can't technically get a diagnosis prior to onset+6 months.

    That is why you need large prospective cohort studies. Recruit a whole lot of people, do baseline tests. Some get sick. Follows those more closely, do all the tests. Some of those get ME or SEID or whatever. You now have a timeline of tests up until they got ME, and can continue into the future.

  • free at last March 6, 2015, 9:21 am

    The hit and run idea, is a good one, But certain things for me seem to stick out like a sore thumb.
    Not so much hit and run. More like Hit run, and come back again.

    1 I had numerous Viral Flu like attacks that occurred over this three to five year period. At first, classic flu symptoms, With measurable very high fevers. And respiratory chest symptoms. Cold shivering. Burning hot. Classic Flu. Often at first, with long with gaps in time, between the attacks. EG twelve weeks, very early on.

    2 No one in my family seemed to catch these Flu type illnesses. Not once ?

    3 The illness, at first, was being controlled to some extent by the immune system.
    I have the distinct impression. The immune system was putting the virus to bed, so to speak. But not ridding it. As it reactivated numerous times. Which eventually led to ME/CFS.

    4 A virus that becomes part of the persons DNA like a retro virus, or chicken pox, type virus. or other ? One that can not be rid from the body, But can re activate itself after a period of time. seems apparent to me.

    5 The longer this went on for, the more the symptoms altered. Meaning the long gaps that had initially happened.
    Became shorter and shorter. But almost as a consequence, the symptoms started to change in parallel with this change.

    They became less sever, the temperatures stopped. It seemed to become a balancing act between the immune system coping with such a virus, The symptoms becoming less sever, But also more constant in time. Now with no long gaps. Gaps now measured in days. Not weeks. With many of the Flu symptoms that started the ball rolling. But now to a less sever extent.

    6 Over many years, this working out of the immune system, how to keep such a virus in check, continued. As the years rolled by. So the attacks strength and time duration weakened, and shortened more and more. The more the years passed. It has now been twenty years for me, and I am not as ill as I was. Infact much less so. I consider myself partly recovered.

    I can only speculate for me, what all this means. But for me, this was NOT just a simple hit and run Scenario.

    But more numerous HIT AND HIDES and combacks.

    likely reactivation of the same virus, clearly the body was NOT able to rid itself of. But had to learn to co exist with, and learn to fight the best way it could. over the rest of my life.

    Yes it become Chronic, But not just fatigue. More like chronic virally ill.

    What viruses behave like this. What could it be ? why hasn't it been discovered ?

    Either I did not have ME. Or clearly there is indeed subsets. As not everyone has the same historical picture as mine ?
    Not sure what to make of all this. And please forgive my simplistic, story, and explanations.
    But I do know I was more ill the first five years. which seemed to suggest cytokines would have been more super elevated early on than later on.
    Hope this means something to those that understand these things more than I do. I apologize if it does not.
    Lets hope this research is really the first key to unlock the door.
    Thank you to all those involved in this study. Its heartening to see such brilliant minds trying to crack a very confusing, misleading, and often contradictory nut.
    Thank you Doctors Lipkin and Hornig
    Thank you Simon for your hard work.

  • msf March 6, 2015, 10:02 am

    A very good summation of the paper, but I think the viral hit-and-run theory was a bit too prominent. I haven't heard Dr. Hornig's comments on this, but just going by the paper it would seem that this is not the only thing the results might suggest. I assume the reference to viruses is because the same pattern of cytokines appears in HCV and HIV infection (as stated in the paper), but these are chronic infections, not hit-and-runs. So a chronic infection seems equally (if not more) likely, based on the paper's findings.

  • msf March 6, 2015, 10:18 am

    I forgot it referred to West Nile Virus too, but when I googled it I found this: http://jid.oxfordjournals.org/content/201/1/2.full

    So it seems that this might not be a hit-and-run either.

  • Simon March 6, 2015, 10:49 am
    msf

    A very good summation of the paper, but I think the viral hit-and-run theory was a bit too prominent. I haven't heard Dr. Hornig's comments on this, but just going by the paper it would seem that this is not the only thing the results might suggest.

    I suspect the graphic (can't control the size it appears in the forum version) may have given too much prominence to this :). I've also edited the blog to say IFN-g levels as consistent with a viral trigger trigger 'or disrupted immune regulatory networks', as per paper. You'll have seen the suggestion about CD40L too, a cytokine critical in B cell development, and the possibility that cytokine levels in the brain are driving this:

    Simon

    Intriguingly, one clue points at B cells, the very immune cell targeted by the drug rituximab (which has shown promise in treating CFS in early trials). Short-duration patients have less of a cytokine called CD40L that is critical to the development of properly functioning B cells.

    In addition, CD40L levels in short-duration patients break free from the levels of other cytokines, varying up or down out of step with the rest. In healthy controls and long-duration patients, on the other hand, they correlate closely.

    Another possibility is that what matters most of all are the levels of cytokines in the brain, and that the abnormal cytokine levels seen in the blood in this study are an echo of a bigger problem there. Because patients can have such striking cognitive problems, the brain has long been a suspect in ME/CFS. Hornig and colleagues have a new paper on cytokines in cerebrospinal fluid (which bathes the brain) coming out soon.

    msf

    I assume the reference to viruses is because the same pattern of cytokines appears in HCV and HIV infection (as stated in the paper), but these are chronic infections, not hit-and-runs. So a chronic infection seems equally (if not more) likely, based on the paper's findings.

    IFN-g is a general antiviral cytokine, not specific to HCV or HIV. Certainly a chronic infection remains a possibility, but to date the pathogen hunt using blood samples from the same cohort hasn't found any sign of chronic infections. Dr Ian Lipkin reported somewhere last year that intial testing on WBCs for HCV drew a blank.

    edit: interesting re persistent WNV in kidney tissue.

  • msf March 6, 2015, 11:02 am

    Yeah, I probably wouldn't have said anything without the graphic…I don't know enough about cytokines to be sure on this, but I think IFN-g is also raised in bacterial infection, at least I saw one paper where it was raised in acute Lyme. I asked on another thread, and no one knew, but you seem very informed, so I will ask you: do you know when the pathogen paper is coming out? I would like to know exactly which pathogens they tested for, and whether some of these were bacteria.

  • msf March 6, 2015, 11:06 am

    Oh, and when I said the same pattern of cytokines I was remembering it slightly wrongly, the 3-year separation was used because this they had observed a similar divide in HCV, HIV and West Nile Virus.

  • Forbin March 6, 2015, 2:05 pm

    Just curious if anyone knows if the immune system could produce the kind of effect found in the paper if a toxin were involved instead of a pathogen. I don't know if it could do this, but if the immune system regarded a toxin as a pathogen it wouldn't be able to "kill it," so might it then stay in the "on" position in a futile effort to rid the body of it? Or is this just a looney idea?

  • Simon March 6, 2015, 2:29 pm
    msf

    Yeah, I probably wouldn't have said anything without the graphic…I don't know enough about cytokines to be sure on this, but I think IFN-g is also raised in bacterial infection, at least I saw one paper where it was raised in acute Lyme. I asked on another thread, and no one knew, but you seem very informed, so I will ask you: do you know when the pathogen paper is coming out? I would like to know exactly which pathogens they tested for, and whether some of these were bacteria.

    Yes, graphic issue (made it smaller above)
    To my knowledge IFN-g is primarily anti-viral though I saw some papers found it promoted killing intracellular bacteria too. Sorry, no news re that pathogen results, which is odd as the first ones were reported in Sep 2013.

  • Simon March 6, 2015, 2:44 pm

    Dr Mady Hornig has been answering questions on Reddit (people vote on questions in advance, she answers the most p popular ones). Here are her answers relating to this study:

    Q from potscfs >

    1) Do you think me/cfs is inflammatory, and if so does it cause damage? I have been ill two decades and am uncomfortable that there is no long term research on prognosis.

    2) Is is blood work the best way to measure cytokines? For example, if there were present in nerve tissue would they spill into blood? All of the cytokines studies on cfs seem so inconsistent and I wonder why?

    Like everyone else says, THANK YOU. I've heard researchers getting ostracized among their peers for choosing to study the "lazy/crazy" disease, I hope this hasn't happened to you.

    • Prof_Mady_HornigProfessor|Columbia University|Mailman School of Public Health[S] 22 points an hour ago

      The inflammation of ME/CFS appears to give way, over time (in our analysis, >3 years), to what appears to be a pattern not dissimilar to premature aging of the immune system (“immune exhaustion” or “immunosenescence”). Typically, high levels of inflammation are associated with high rates of cardiovascular disease, through a process whereby inflammatory cytokines drive atherosclerosis and potentially myocardial infarctions (heart attacks). This does not seem to be the case in ME/CFS over time, at least not in the majority of patients. Thus, we believe that there is a much different process that is affecting the function of the immune system – and we’re working actively to understand that process. Why the immune system is so dysregulated must be understood.

      We have work coming out soon that focuses on spinal fluid cytokines. Stay tuned.

    Reddit poster maybesomeday2

    Does your research extend to studying the cytokine levels of patients who have had this disease longer than three years? What are you finding?

    Has your research or your personal medical training led you to conclude that there may be a tipping point in this disease where the patient's likelihood of recovery greatly diminishes?

    • Prof_Mady_HornigProfessor|Columbia University|Mailman School of Public Health

      Our study found that cytokines differed for ME/CFS of short duration (</= 3 years) compared with ME/CFS of long duration (>3 years), as well as from healthy controls. This study, though large by ME/CFS research standards, was cross-sectional. Currently, we are generating data from a longitudinal study of ME/CFS, looking at how cytokines change over the course of a year or more, in relationship to changes in the clinical picture. We believe that these new data will give us a better glimpse of the mechanisms involved in these cytokine changes over the ME/CFS disease trajectory.

    Reddit poster Nihy

    Nihy
    Rituximab is being studied as treatment for chronic fatigue syndrome. What is your opinion on this? Does your research support the idea that B cells are defective in chronic fatigue syndrome?

    Prof_Mady_HornigProfessor|Columbia University|Mailman School of Public Health

    The results of the rituximab studies have been intriguing. I consider them to be highly worthy of intensive follow up. Rituximab, a monoclonal antibody, depletes B cells through its binding to the CD20 receptor. We found evidence in our plasma cytokines study that cytokines produced by different types of B cells are altered differentially in the early vs late phases of ME/CFS. We envision that an even wider range of monoclonal antibodies, such as those directed against the inflammatory cytokine, IL-17A, may also potentially be of benefit for individuals with high plasma levels of that cytokine (largely short duration ME/CFS subjects).

    A study that would be particularly welcome, would be one that looked at the capacity of immune biomarkers to predict who might benefit from rituximab therapy. As with all such monoclonal antibody therapies, extreme caution is required to ensure safety of this type of treatment. Hopefully, the ongoing studies will also shed light on that issue. Who is the right candidate for such therapies? What are the risks?

    One final Q&A that people might find interesting

    Here's an interesting bit of info about that from the speech "Words Matter" by Jørgen Jelstad, a Norwegian journalist who has written a lot about ME/CFS:

    "In one of the books I read during my journalistic research, I found the story of Dr. Elizabeth Forsythe. Bare with me for quickly reading the passage about her in this book

    [cue typical horror story]

    I think I know what you’re thinking. Typical story, isn’t it? You’ve all heard it in your clinics, or from your patients at the hospital. Typical ME/CFS. A bit vague symptoms, a lot of doctors involved, no diagnosis, sent to a psychiatrist.

    And you’re absolutely right. Except that Dr. Forsythe didn’t have ME/CFS. She told her story in the Guardian in 1979 – and she had Multiple Sclerosis. And reading the history of MS, you will be stunned by the similarities.

    Prof_Mady_HornigProfessor|Columbia University|Mailman School of Public Health

    I think that diseases that defy medical explanation will always be the ones at greatest risk of being maligned in this manner. Research that defines reliable biomarkers and that demonstrates treatment responses in blinded clinical trials, using hypothesis-driven interventions, can go a long way to overturning these entrenched assumptions. Of course, the best defense is to uncover the biological causes of ME/CFS. We are hopeful that an adequate funding stream for ME/CFS research will allow us to accelerate the process of finding the causes and discovering appropriate interventions for this disease.

  • Mij March 7, 2015, 9:23 am
    Forbin

    Just curious if anyone knows if the immune system could produce the kind of effect found in the paper if a toxin were involved instead of a pathogen. I don't know if it could do this, but if the immune system regarded a toxin as a pathogen it wouldn't be able to "kill it," so might it then stay in the "on" position in a futile effort to rid the body of it? Or is this just a looney idea?

    Dr. Bryon Hyde also discusses this:
    http://www.nightingale.ca/documents/Nightingale_ME_Definition_en.pdf

    Non-Infectious M.E. Type Disease:
    I have not discussed noninfectious M.E.-type disease. Similar M.E. phenomena can occur due to diffuse CNS injuries from toxic chemical in jury. I have seen this in police officers who have fallen into toxic chemical ponds in pursuit of those suspected of criminal activity. I have seen it in farmers repeatedly exposed to pesticides and herbicides, in hospital and industrial workers and in military personnel in contact with toxic chemicals, specifically toxic gases.
    I will discuss these at a later date as Secondary M.E. They do have one thing in common, and that is they also have a diffuse CNS injury as noted on brain SPECT scans. The diagnosis is made by history, as the actual cases are very difficult to diagnose due to the inability to assess brain levels of toxins in a live patient.
    Often these Secondary M.E. diseases are more severe than the infectious M.E. cases.

  • voner March 7, 2015, 9:53 am

    simon,

    thank you for your extremely clear, informative, and well written article. I had read the Hornig paper and I have read numerous blogs about the paper, however I still had numerous areas covered in the paper that I could not understand and had questions about because of my inability to understand some of the complex data analysis they did, etc. Your article answered most of those questions like… study design questions…… did the authors take into account sex differences? Age differences? …..

    your article also sifted through a lot of the side cytokine data and presented it in a format I could easily understand. I can't thank you enough. I suspect your ability to effectively communicate with Dr. Horning also make this article so valuable.

    I guess one inference that could be drawn is that the "chronic fatigue initiative" funders must've decided not to fund the Lipkin/Hornig microbiome study?

    thanks again.

  • Simon March 7, 2015, 10:08 am
    voner

    thank you for your extremely clear, informative, and well written article

    Thanks so much, it doesn't come easily so it's great to hear the blogs do what I'm hoping they do (and I'm much helped by guidance from a very talented writer).

    voner

    I suspect your ability to effectively communicate with Dr. Horning also make this article so valuable.

    As you can imagine, Mady Horning was immensely busy with the launch of the paper but still found time to talk to me at 9am her time last Sunday, about 6 hours after having done an interview with a UK radio station… She's been immensely helpful.

    voner

    I guess one inference that could be drawn is that the "chronic fatigue initiative" funders must've decided not to fund the Lipkin/Hornig microbiome study?

    I think Ian Lipkin has already said publicly that the Hutchins Family Foundation have decided not to put further money into mecfs research (though they've alread put in a lot more than any other private donor). However, they have already funded a smaller and more limited microbiome study with Drs Lipkin & Hornig, which is underway. In a Reddit reply yesterday Mady said they were applying for funding from elsewhere to expand this study.

  • halcyon March 7, 2015, 11:54 am
    free at last

    What viruses behave like this. What could it be ? why hasn't it been discovered ?

    Enteroviruses can do this. They can cause persistent infections lasting years.

  • Dr.Patient March 7, 2015, 1:21 pm

    Great study! We need to show a biological basis for our illness, even if not specific to our illness. It validates it's not all in our heads theory. Most important, however, that these cytokines patterns should definitely be different from the ones in depression, lest they all be attributed to depression.

  • snowathlete March 7, 2015, 1:32 pm

    Thanks @Simon, really good article. As you point out, this was a meticulously designed study. I hope it sets the standard for other good researchers working in the field. Like you, I'm hopeful about this area of research proving fruitful with more study.

  • Navid March 7, 2015, 1:36 pm

    why did the hutchins family decide to no longer finance me/cfs research. i thought they had a family member who was ill with this disease? just curious

    thanks

  • Persimmon March 7, 2015, 7:02 pm

    @Simon
    Thanks for another really helpful blog.

    A few questions:
    (1.) Do we have access to a study design protocol for this study, of the type submitted to clinicaltrials.gov or used in NIH funding applications?
    (ie a detailed description of what they intended to do, that was prepared prior to commencing the study)

    (2.) In the article, they speak of picking a 3-yr cut-off because of the characteristics of the data set and because of findings in studies of certain chronic infectious diseases.

    Do you know when they decided on this particular cut-off? Was it in the initial study design stage; after seeing the characteristics of their cohort; or after they had started analysing their samples?

    Did you learn whether they looked at any other duration cut-offs?

    As the data set was mainly of patients with duration <3yrs or >8yrs, is it fair to say that the same findings might have been obtained had they set their cut-off at 8yrs (or for that matter, at any point bw 3-8yrs)?

    (3.) Their cohort consisted of the combined NIH/XMRV and CFI cohorts. I think the former is restristed to acute-onset virus-like/virus cases; I'm unsure about the latter but suspect it isn't restricted in this way.

    Have you formed a view as to whether this study's findings are more strongly/only supported with respect to acute-onset viral cases?

    (4.) Cheney is well known to have proposed the idea that the disease has distinct stages. For well over a dacade, he's been arguing there are three stages to it.

    Do you know of any previous cross-sectional studies that have attempted to stratify their cohort into disease-progression stages?

  • Simon March 8, 2015, 8:35 am
    Persimmon

    Do we have access to a study design protocol for this study, of the type submitted to clinicaltrials.gov or used in NIH funding applications?

    Nothing posted as far as I know. While pre-study registration is now the norm, or at least expected in clinical trials, the same isn't yet true of other trials though I believe things are moving in this direction.

    Persimmon

    In the article, they speak of picking a 3-yr cut-off because of the characteristics of the data set and because of findings in studies of certain chronic infectious diseases.

    Do you know when they decided on this particular cut-off?

    I know th study was set up so they could study short duration patients as a subgroup; I don't know how the 3 year threshold in particular was set up.

    Persimmon

    As the data set was mainly of patients with duration <3yrs or >8yrs, is it fair to say that the same findings might have been obtained had they set their cut-off at 8yrs (or for that matter, at any point bw 3-8yrs)?

    Because they set out to sample short (but not medium) duration patients they didn't have the data to understand what happens immediately post 3 years, though obviously they would love to know. And the lack of data 3-8 years precludes meaningful analysis of that time

    Persimmon

    Their cohort consisted of the combined NIH/XMRV and CFI cohorts. I think the former is restristed to acute-onset virus-like/virus cases; I'm unsure about the latter but suspect it isn't restricted in this way.

    Have you formed a view as to whether this study's findings are more strongly/only supported with respect to acute-onset viral cases?

    You're right about NIH cohort having a viral-like onset and no such restriction for CFI. Most of the short onset cases were from CFI so probably not a particularly 'viral' short cohort. But Mady Hornig said they will be doing more analysis to try to understand the impact of different types of onset esp viral v other.

    Persimmon

    Do you know of any previous cross-sectional studies that have attempted to stratify their cohort into disease-progression stages?

    No.

  • free at last March 8, 2015, 12:52 pm
    halcyon

    Enteroviruses can do this. They can cause persistent infections lasting years.

    Interesting. I have never figured all this out. Though this paper seems to suggest much that seems to fit.
    Even as far back as 1995 Professor Leslie Findley (neurologist) at Harold wood hospital
    muttered Cytokines to he/s colleague, When I described what was happening to me. Clever man.
    Looking forward to seeing the other study when its released.

  • Tally March 8, 2015, 3:12 pm
    oceiv

    This article really helped me to understand this study in a complex and in-depth way. Great science to English translations are always appreciated. The thorough explanations of the study, the contextual information of where the field is and of what the future holds because of this study's findings are particularly interesting to see laid-out in one place.

    Table 6 provides both an overall visual snapshot of the illness and a detailed richness. It's interesting to note that leptin wasn't singled out in this study, but did correlate with symptom severity in the much smaller Jared Younger study (if I'm reading Table 6 correctly – all the scientific terms in the table are new to me). I wonder what the in-progress Columbia study will show about how cytokine levels for individual patients are changing over time. I also hope that we see replication studies soon for both this Hornig/Lipkin study and the Jared Younger leptin study. As the saying goes "reading is fundamental." In the ME/CFS world, our new saying could be "funding is fundamental."

    I loved this metaphor from Professor Jonathan Edwards (@Jonathan Edwards). It humorously explains and sums up this study well:

    “What this study is saying is that if you listen at the door of the immune system you can definitely hear some plotting of crime inside, but you don’t know which of the people speaking is going to go out and commit it”,

    It might be because even in Younger's study Leptin levels were normal, but just seemed to follow the ups and downs of our energy level

  • 5150 March 12, 2015, 10:44 pm
    Jon_Tradicionali
    Forbin

    Not that I know much about this, but I wonder…

    Could an unusually strong immune reaction to a hit-and-run virus alter the balance of organisms in the microbiome, somewhat as an antibiotic can alter the balance? Might then the altered microbiome look like a chronic infection to the immune system?

    You may be right, you may not be.

    The possibilities are endless you see.

    That's why Lipkin has approached this with the "it could be anything" attitude and testing cytokines, bacteria, viruses, metabolites in the blood, spinal fluid, intestine, pharynx. Etc.

    It could be anything: I was in the prime of my life and my health, when struck down by a sudden onset"bad flu about a week-long". I have never recovered or into remission or those good things. Among the group of men I hung out with was someone who had recently returned from living at Lake Tahoe for 6months. He didn't appear to be sick, looked strong in good health. as men will do, we lifted some tankards together and that person was a regular at the house. fairly close quarters. some way, I feel he brought the causal agent for my ME with him. I am hetero… there was no hanky-panky going on with any of us. So i'd say it was the "Close quarters" where pathogens are easily spread that it got me.

    Now you tell me, does that say this particular sub-group is Contagious? It 's the real nasty version. btw, I am not in touch with that group anymore, so seeing "how others are doing" isn't possible. which is a shame; that would be valuable info. If this is a true story, doesn't it conclude that at least "a subset" can be Contagious?

  • Aidan Walsh March 17, 2015, 10:13 am

    'internal ionisation radiation injuries' boken cromosones/translocations…'low level' radiation sickness which explains why no-one has ever been able to identify one single infectious pathogen

    to date including viruses, fungus, bacteria etc 'all' 100% 15 cohorts patients are Positives to radiation isotopes some now are on the Memorial list as a result of the decades of negelct…We have had 3 Mile Island, Chernobyl plus over 2,000+ Nuclear testings not counting now the

    spread of Japan at our doorsteps now…Talk about a massive kill off of people to come this sickness will now only grow a good friend of mine who also works in the Water filtration industry already said this to me 'the entire water table below Philadelphia is contaminated with radiation

    &amp; they do not know what to do about it now except continued chemical treatment processes…If any of you think this in 'not' radiation sickness you seriously need to give your heads a full shake…Think I'm kidding wait until all you kids get sick &amp; they get 'labels' in diagnosis after

    'labels' Blesses you have all been warned I told you so…May be a great idea to look into patterns of Cytokines of Chernobyl victims afterall Russian honest Scientists call CFS Radiation Sickness 'Disease' afterall they already have proof it 'is' radiation sickness the 21st Century cover-up…It's

    'not' HHV6-A or XMRV pure b.s. it's Radiation Sickness 100% even the 'epitope' found at University of Hawaii new that the 'epitope' found was not Ciguatera but something more with

    radiation in the fish…California is now infested with the highest levels of radiation &amp; theincidence of CFS will get much much higher now it will attack thyroids brains etc etc…

  • Misfit Toy March 21, 2015, 4:36 pm
    Sasha

    Excellent article, @Simon, very clear – even I understood it (which is saying something)!

    I love that Sasha! That's how I feel…I got it even with this crazy brain fog!