Thanks to Simon and MEAction for allowing Health Rising to post Simon’s exposition of the truly remarkable chronic fatigue syndrome (ME/CFS) study about to take place at the NIH. This blog first appeared on MEAction. Most images and captions were added by me – Cort)
Blink and you’d missed it. In just six minutes and six slides, Dr Avindra Nath unveiled one of the most in-depth, comprehensive and innovative ME/CFS studies ever proposed: it’s the first fruit of Director Dr Francis Collins’s ‘new start’ for ME/CFS at the US National Institutes of Health (NIH). There wasn’t a lot of detail, but even from the preliminary information that’s available it’s clear that we’re looking at a very impressive project.
Since it was first announced, concerns about the study—including the selection criteria, the choice of control groups and the views of some of the researchers on the team—have dominated discussion in the ME/CFS community. During questions after his presentation, Nath said he was keen to have input from patients, citing his admiration for the role the patients’ group ACT UP played in research during the early AIDS epidemic. Carol Head, CEO of the Solve ME/CFS Initiative, has had encouraging discussions with Dr Vicky Whittemore of the NIH about patients’ concerns. She’ll discuss further with the NIH on March 8th, and I hope the NIH will engage with those criticisms then.
But looking closely at what we know so far about what the NIH is planning, it’s clear that it’s applying some extraordinary science to the problem of ME/CFS, science that could make a huge difference—despite the potential pitfalls.
The NIH is devoting some of the remarkable firepower available at its Intramural Center to probe deeply into the disease. When the study is done, researchers will probably know more about the 40 patients included than any other individuals in the history of ME/CFS, with the possible exception of the severely ill patients being studied by the End ME/CFS Project.
The NIH will train some of its clinical research center’s firepower on ME/CFS
Dr Nath, who is Chief of the Section of Infections of the Nervous System at the NIH’s National Institute of Neurological Diseases and Stroke, will lead the study: and he believes the immune system is where the action is.
He commented that many studies find interesting — but mostly inconsistent — immune abnormalities in patients, and that ME/CFS often begins with an infection. He said the promising results from pilot treatment studies with rituximab (which targets antibody-producing B cells) also pointed to a key role in the immune system, at least for some patients.
“Our hypothesis is that post-infectious ME/CFS is triggered by a viral illness that results in immune-mediated brain dysfunction”. Dr. Nath
The NIH is taking a very thorough approach to investigating immune (and other) problems. Although it’s relatively small, with 40 patients and 60 controls, the study is extraordinarily comprehensive, with two more studies due to build on its results, culminating, it’s planned, in trials of immunomodulatory agents.
Study Highlights
- The study will take an astonishingly in-depth look at the immune system, both via the blood and spinal fluid. On the basis of the initial findings, the NIH will decide where to target even more sophisticated tests.
- The researchers will use a wide range of measures: thinking tests, metabolic tests that even measure how much energy patients burn as they sleep, autonomic function tests, and self-reported fatigue alongside activity measurement.
- Best of all, the study will look at how most of these measures are changed by exercise, focusing on the core feature of ME/CFS.
- And they will use two types of technology to probe what happens in the brain when patients are hit by exercise.
- The most ambitious part of the study will use cutting-edge technology to try to reproduce in the laboratory the clinical or biological abnormalities seen in patients. It could dramatically speed up understanding of the illness and the development of treatments.
The hope is that this intensive approach will crack open the illness so researchers can see more clearly what’s inside – providing clues that could help reveal the mechanism of the illness, and lead to treatments.
Details of the Study
Please note that most of this article is based on Dr Nath’s brief talk and slides at the CDC Grand Rounds in February 2016, and because details were quite sparse I’ve included a little information from the prematurely published (and then withdrawn) study protocol. I haven’t had the chance to fact-check my report with the NIH and so any errors are mine.
Patients and Controls
Will the pieces in the ME/CFS puzzle finally start to fit together?
The NIH will recruit 40 ME/CFS patients, who will be thoroughly assessed and diagnosed according to the Canadian Consensus Criteria (generally thought to be the most rigorous case definition for diagnosis), as well as meeting the 1994 Fukuda/CDC criteria. Patients must also have a documented infectious onset at the start of their illness, such as glandular fever — because this study is pursuing the hypothesis that an initial infectious illness triggers long-term problems in the brain.
By focusing only on those with an infectious onset the NIH believe they will get a cleaner, more consistent group, making it easier to detect real, relevant differences among the inevitable random variation between patients. Patients also need to have been ill for between six months and five years and to have post-exertional malaise — the cardinal symptom of ME/CFS.
Those with a confirmed diagnosis then come back for a week as in-patients for an incredibly detailed evaluation.
Along with 20 healthy controls will be 20 post-Lyme disease patients who no longer have fatigue and 20 patients with functional movement disorder. These are patients with movement problems that are considered to be psychologically caused—one of the concerns that the ME/CFS community has about the study.
That’s a total of 100 people, making this a relatively small study and increasing the chance of false positives. However, the next phase of the study will be a validation of findings from this initial phase, which increases the likelihood of robust findings emerging.
Four Aims
Nath outlined four goals of the study.
1. Detailed Assessment of Patients (Phenotyping)
Phenotyping aims to describe patients in as much detail as possible. Beyond the assessments needed for diagnosis itself, researchers will check patients for neurological problems (including a brain scan) and will test basic autonomic body functions such as sweating and breathing, blood pressure, heart rate and tolerance of being upright. Experts in infectious diseases will assess patients. And researchers will also test memory and thinking performance, and monitor fatigue and activity levels — and test exercise capacity. Not a bad start.
2. Understanding the Biology Behind Patients’ Problems with Exercise
Researchers will home in on the central feature of this illness — how exertion wreaks havoc — by looking under the hood both before and, critically, after exercise.
They will focus on the brain using functional MRI scans, which show which brain circuits are in action (the provisional protocol said patients would be doing thinking and exercise tasks during these brain scans). This should help reveal what’s happening in the brain when patients are exhausted.
For the first time in ME/CFS, researchers will also be using a remarkable technique called transcranial magnetic stimulation to probe brain function. It uses magnets placed around the head to generate tiny electrical pulses in specific places in the brain, and researchers can check if the body responds to, say, activation of the brain’s movement centre, in the way it should. The technique has been used to diagnose conditions such as multiple sclerosis and Alzheimer’s disease.
Not only will the researchers measure patients’ energy use during exercise, they will also measure how much energy patients use as they sleep and rest before and after exercise, using a sealed metabolic chamber. This is another first in ME/CFS research.
The thinking and memory tests, and body function (autonomic) tests done before exercise will be repeated after to see what changes.
An possible downside of using exercise testing – which could prove so valuable – is that it might only attract patients who don’t have a strong reaction to exercise, which might bias results. Though the fact patients are in hospital for a week eases the strain, and patients might be willing to suffer a lot from exercise if the believe the study is important.
3. Identifying Immune System and Microbiome Abnormalities
This is where the researchers will zoom in on cellular and molecular problems.
The study will take an in-depth look at herpes viruses
The NIH will cover the basics by measuring cytokines, which essentially show the immune system talking to itself and to the rest of the body, and by identifying the number and type of different immune cells (such as antibody-producing B cells and natural killer cells).
These have been studied quite a bit in ME/CFS, as in last year’s finding from Columbia University that cytokine levels are elevated in patients who’d been ill for under three years, compared with those who’d been ill for longer. But the NIH will be going beyond previous work by doing this for spinal fluid as well as blood in the same patients. This will give an indication of what’s happening in the brain, and in addition, they’ll look for autoantibodies that could attack the brain.
The researchers will also look for any viruses that might be present, with a particularly in-depth approach for Herpes viruses.
But there’s a lot more.
Researchers will be sequencing T-cell receptors, which are a part of the immune system and are similar to antibodies in that they show which targets the immune system has already learned to identify as a threat. Each person has at least 100,000 of these receptors, and this will be one of the first ME/CFS studies to look at them. This may provide clues as to what might be driving problems in the immune system.
The researchers will also be looking at all the proteins in blood and spinal fluid: Dr Nath said they can detect at least 1,500 different proteins — proteins that will give clues about how cells are functioning, which types of cell are most active and how they are interacting with one another.
On top of that, the team will spy on what cells are doing using metabolomics. As cells do their work, they leave fingerprints behind in the form of specific chemicals, and these can provide a snapshot of how the cell is functioning at that moment. If unusual patterns are found in these chemical fingerprints, that could provide a clue about what’s making patients sick.
This in-depth approach to the immune system might sound familiar — Professor Ron Davis is using similar approaches to the immune system, including sequencing T cell receptors, as part of the Open Medicine Foundation’s Severely Ill study (as well as probing the immune system in other sophisticated ways that don’t feature in the NIH study).
Extraordinarily, Nath said the detailed immune profiling is just an initial screen to spot where the real problems are likely to be, so that the researchers can home in on them with the most appropriate tests. He said that this two-step approach was needed “because there are innumerable amounts of very time-consuming, tedious assays for each cell type that you could potentially do, or interactions between cell types”.
Researchers will take a systems biology approach to understand the working of the immune system
Note that point about interactions between different cell types. Nath said he’d consulted with NIH systems-biology and immune-cell expert Dr Ronald Germain, who specialises not just in how each type of immune cell works (or goes wrong) but also in how they interact.
Perhaps the problem in ME/CFS will be in how different immune cell types interact rather than in a single cell type. And the phenomenally complex immune system is all about how the many different immune cells come together to produce a co-ordinated response.
And if all that isn’t enough, the study will look at both the gut and oral microbiomes, both before and after exercise.
4. Reproducing ME/CFS in living systems in the laboratory
Up to this point, the NIH plan is largely to pursue existing research angles, often pushing them further and bringing together many, many approaches in a single intensive study. But they are also cutting loose and trying to recreate the illness in the laboratory, using tissue from patients.
Growing ME/CFS Neurones in the Lab
A challenge in studying a disease like ME/CFS that affects the brain is that you can’t snip neurones out of the brains of living patients to find out what’s wrong with them (at least not without doing grievous harm!). The NIH is planning to use some amazing new technology to get around this problem: they’ll take blood stem-cells from patients and use adult stem-cell technology to turn those cells into neurones — neurones that are still essentially patients’ cells.
From patient blood stem cells to neurones. Image from Dr Nath’s recent presentation.
Researchers will check the functioning of these neurones, including their mitochondria and the neurones’ ability to generate and respond to electrical signals. Next, researchers will see if spinal fluid or blood plasma will trigger functional problems in these neurones: maybe it’s something in these fluids that’s causing the problem in ME/CFS.
Creating ‘Humanised Mice’ Using Patient Cells
NIH researchers will create ‘humanised mice’ that essentially have immune systems seeded by patients’ cells. They will then test if spinal fluid or antibodies from patients will lead to fatigue or other ME/CFS-like symptoms in the mice.
Dr Nath pointed out that if these experimental systems are able to reproduce the clinical or biological abnormalities seen in these patients, it would be a huge step towards understanding the biology of the disease. And it could help develop new treatments faster.
A Promising Start From the NIH
In a remarkably short period of time the NIH have planned a small but incredibly comprehensive study. It not only zeroes in on the key problem of the effect of exertion, but also looks deeply at both the immune system and the brain — two areas that many researchers believe play a major role in the illness. And the NIH will try to develop disease models in the lab that could revolutionize how researchers study ME/CFS.
Before this suite of studies is done we could have a breakthrough in ME/CFS
Nath explained that this study is just the first phase. Phase Two will follow patients longer-term and aims to validate the findings of Phase One, particularly for biomarkers. Nath said that If they manage to identify causes of the illness or symptoms, Phase Three will be an initial treatment study of immunomodulatory drugs.
My guess is that this first phase will cost at least a million dollars (a hundred people will be in-patients for a week of extensive testing) and maybe a great deal more.
An enormous amount of thought and imagination has gone into designing this intensive study, and it seems to me that Dr Nath is taking this disease extremely seriously. The study plan isn’t perfect, but it isn’t final yet, either. And it could prove to be the beginning of a new era for ME/CFS at the NIH — one that finally delivers for patients.
FURTHER LINKS
Video footage of Dr. Nath’s talk at CDC Grand Rounds begins at 42:35 here, and a transcript of his presentation, along with his slides is here.
Breaking News
I’d asked Dr Vicky Whittemore is she had any corrections to the content and got this reply:
The only correction I have at this time is that it has been decided that they will not include individuals with functional movement disorders in this study
Amazingly comprehensive study. Hope it helps you ME folks, seems like it would be reasonable to do for FM folks also. Expensive but we all cost the system a lot of money every year.
I wonder if ME and FM would be better served if packaged conceptually together a bit like Crohn’s and ulcerative colitis as IBD.
Absolutely Steve. I think the study is the culmination of a lot of advocacy work over the years – which just has not happened with FM for some reason. I think FM advocates should push hard for IOM and P2P reports. Those were key to the progress we’ve made.
I would be shocked, though, if the results from this study didn’t provide new avenues for FM research.
Unfortunately most FM research at the NIH is behavioral. We’ve got to change that emphasis – there is so much FM could do to inform chronic pain research.
I would love to be part of this study. I know I can’t but just saying:….I have been plagued with this pain since my first memories a young 3 or 4yrs old. The fatigue started around 94 as an off and on thing, I never thought much of it since it came and went. But I got really sick in 97,had mono again, then Epstein Bar. The fatigue part set in for the long run. I might also mention I have had shingles off and on since 1970.
Thanks for all you guys do.
I think the study could benefit all of us but one part of the study that might particularly impact longer duration patients is the detailed herpesvirus study Simon reported they are going to be doing. I don’t know how they are doing – and it will be important to find out – but that small part of the study could be very important. The herpesviruses were the hole in the Lipkin/Hornig study – there was quite a bit of disagreement about how they were assessed in that study.
Is the herpes virus study the one being conducted by Dr. Pridgeon? Any updates on that?
Hello Cort,
I know that this is not brand new anymore, but as someone with CFS, it is really exciting to me. The part that excited me most was where it said the study is planned to culminate with trials of immunomodulatory agents. Does that mean that we could see trials of Rituximab and other drugs like it for CFS happen in America? If so, when might that start occurring?
For sure….If they find problems that look like a fit for those or other drugs – absolutely. In fact, outside this study there has been talk of the NIH being interesting in Rituximab and Ampligen….Trials would be a bit off but it sounds like they are possible.
Wow! That is really exciting, and I can’t help but feel like I am going to have some really good treatment options a decade or so from now! Thanks for taking the time to respond, and for everything else you do for the CFS community.
Jared Younger said in his Q & A session last week ( https://youtu.be/HfFleMxOBBA ) that his working hypothesis is that FM and CFS are the same thing.
Thanks for the article, Simon.
Jarred Younger did not say that ME/CFS and FM are the same thing, according to his hypothesis. Similar only, is my recollection. His view is that each may be marked by neuro inflammation as a result of immune system changes after an infection. This doesn’t mean that the kind of neuroinflammation or type of immune system changes are identical–it is a generalization. He also does not assume that the same medications will work in both though he is starting to test to find out if LDN helps in ME/CFS as it does with those he tested with FM.
hi merry, nope FM & M.E. are NOT the same as having a friend with fm and shes able to DO things, cook, clean, babysits, shops, drives, take care of her dog, BUT with M.E. NOT able to do any of these. simple MOVEMENT is M.E. enemy. totally different illnesses. I don’t know WHY they still say their the same when so DIFFERENT?
Sounds like your friend doesn’t have very severe fm
I agree they aren’t the same but fm can be as disabling as me/cfs
I concur with Dee. I have a close relative with FM who for years boasted about all the things she managed to do despite her illness …comparing herself to me. She even gave an FM autobiography book to my parents boasting the same thing. My parents then gave it to me in an attempt to encourage me to do more. The effects were damaging in so many ways. The saddest thing is my parents died forgetting the old Nicola and being disappointed with the Nicola affected by ME/CFS. Sorry to have made this personal but it is.
Nicola, it affects everyone differently. I know some patients who have a mild, generalized malaise and others who are nearly incapacitated (I’m somewhere in the middle). The person who gave your parents that autobiography sounds like a narcissistic jerk who was fortunate to have milder symptoms. Don’t dwell on this, and certainly do not discuss your ME/CFS with her ever again…we have enough negativity without people like her adding guilt or shame into the mix. I’d like to say I hope hers progresses so she can feel how bad it can be, but I wouldn’t wish it on anyone. Hang in there, progress is being made.
Sorry to hear that Nicola. I think your parents desperately wanted you to be like your relative. Unfortunately that was not to be.
I wonder why they say that too Dee !!!! I actually hope it is true because all of this amazing research in to ME/CFS could be then used to help those with FM – imagine that !!! It’s hard to know isn’t it ? For 25 years I was a pretty high functioning FM’er. Sometime in the past five years things took a turn and one-by-one I had to let go of almost everything. My life is now very limited. I sometimes wonder if the speculation that FM is not progressive has been given too much weight. I have never seen a longitudinal study and the limited research that has been done seems to indicate that FM does not get better over time, but probably worse. I have a sister with MS and for the first twenty years, she was completely able bodied. Now – she has extreme pain, sleeplessness, severe fatigue, and many other symptoms, that she never had until now. MS is a disease that manifests itself differently in each patient, changing dramatically over time. Are we willing to leave the door open that FM may also follow this path ? I have to say, after living with FM for 25 years, I was pretty sure I knew myself, but have been proven so wrong. Not disagreeing with you, just wondering out loud 🙂 And Nicola, you are so right how damaging that type of comparison can be. I do it to myself every day when I try to be the “old me” and realize I just can’t. I am so sorry you had to endure that, and your post has reminded me that I was probably like that when I was more able-bodied. Thank you for the lesson in humility.
I have a friend with FM who is the same way. She says she has fatigue, but she walks for miles as a hobby a few times a week, does another exercise class, takes care of grandchildren frequently and is very involved in other social activities. Her main symptom is pain.
Thanks for the great write up, fascinating study, very hopeful indeed!
Did they give any idea of time frames?
If Gregory likes it it must be special 🙂 My understanding was that it will start up in the next month or two. We should know more soon.
Thanks, Gregory! As Cort says, hopefully we will know more soon
The study is expected to start this summer and it will take about a year – 1 ME/CFS patient a week.
This does indeed sound very intensive. Positive direction. For me, I have been so hopeful before– only to be dashed on the rocks. But, this may prove to be the opening. I believe that since there are so many variables in this disease it only makes sense it is immune regulated. And CFS and FM definitely overlap. It has been a damn long road for many of us. I hope they will question Dr. Cheney, Petterson, Lapp, etc……As I lay in my bed I will hope, hope and hope. It really should be like THE MANHATTEN PROJECT. Put them all in a room and don’t come out till you have the answer. Love and admiration to you, Cort. I depend on your vigilant reporting. Hipjaven@gmail.com
Thanks Javen! I like the Manhattan project analogy. We have the beginnings of one in this study and the Ron Davis Severely Ill study. Ron said there is actually not a lot of overlap between the two study, which demonstrates how vast biology has become and how much opportunity there is to find something. Davis thinks researchers are digging too deeply not to find answers….(!)
The main thing is that this study gets significant results and starts to build a beachhead for us at the NIH that we can widen and widen.
I would note as well that this kind of exploratory study is very unusual for the NIH. They greatly prefer hypothesis driven research; the fact that they’re willing to devote so many resources to this study is quite gratifying in that light.
I also wish to express my inexpressible gratitude to Cort for all his time and effort in reporting on all ME/CFS news! Without you Cort, I think it’s safe to say that the U.S. ME/CFS community would be literally lost in the maze of all the published & non-published studies, not be able to educate our treating doctors (when/if they listen), not know how to advocate for ourselves with our personal doctors, not know that with each study there is hope & progress etc….You cannot put a price on hope and you, Cort, provide hope. YOU are a God-send. Thank you! Thank you!! Thank you!!!
+1
+100
Thanks – this stuff provides me hope as well :)and thanks to Simon for writing such an excellent piece. I was going to do one – but after I saw Simon’s piece I realized (somewhat to my dismay (lol)) there was no need..
It certainly sounds impressive. If they can reproduce cfs in a lab environment, that will almost certainly lead to a solution. (Anybody who have debugged knows the reproduction of the problem is the first step toward the solution)
Not sure what will turn up in the metabolic and immune study though. Colombia study already showed that cytokine levels are not explained by the symptom severity. If cfs is mainly caused by hypersensitivity (to exertion/metabolite/inflammation), the brain study could be the most promising place.
An alternative to looking under the hood is a black box approach. If we can precisely profile the response to exercises, that could lead to a clue as to what’s going on under the hood. Right now, all we know is that activities above certain threshold triggers post-exertional sickness and peformance is drastically reduced.
Superb write-up by Simon.
He posted on the #ME Action version that Vicky Whittemore has said that the NIH has agreed to ditch the functional movement disorder control group – which is very welcome news indeed.
I understand the upset that has caused but I actually think it would have shown that ME/CFS is a very different disorder from functional movement disorders and that would have helped. It is nice to see the NIH understand where patients are coming from though and be flexible.
Yes, good to have flexibility. I agree it’s likely the study would have found differences with mecfs and FMD – but the problem is the study is small and with only 20 controls it’s likely any differences would not be statistically significant. I hope they will use those places to beef up other groups.
I’m so excited, while not perfect this study sounds like an excellent beginning. I look forward to hearing more about the follow up studies planned.
As a clinical psychologist I believe FMD is a garbage diagnosis for more “medically unexplained symptoms.” So I am glad it’s gone. Any kind of Lyme control group is problematic given the many controversies about that disease. Better to have a healthy control group and one consisting of a well defined disease such as MS.
Ironically, the best proof of NIH intentions would be if this study produces no meaningful results. Then we would see if NIH dropped ME like a hot potato or pursued its study with even more commitment.
I do hope it produces meaningful results but I worry that once again research into ME will hinge on one small government study.
Michaei Allen, PhD
That would be quite a test of their commitment – I hope we don’t have to subject them to that test :)…
I agree that this is very, very important study, however, more is coming from the NIH. At some point in the not too distant future they’re going to announce several other efforts to increase funding and understanding.
Still, these researchers are primed to follow up on what they find; that’s a huge opportunity we will hopefully be able to take advantage of…Crossing my fingers.
I agree FMD seems more like another disease that has been thrown into the psychogenic basket because they can’t explain what causes it. I also really don’t get why diseases that are exacerbated by stress are thought to be more psychological. What if your stress response systems aka the autonomic nervous and HPA axes are broken? What if they go bananas every time you’re exposed to a mild stress? That seems pretty biological to me.
Thank you for sharing this encouraging news and for all you do to keep us informed. Sharing with my husband and sons asap!
It gives me a real touch of hope to know that a study is underway focussing on the reality of life with ME – it may not be perfect but who knows where it may lead?
Pinkies crossed for a good outcome for us all – SOON would be good! x
I’m interested in the study, and wonder if I must come to it or it will come to me? I cannot find a location listed anywhere for what city and state the study is to be performed. Please help enlighten me about the details if a person seriously wishes to be made part of this study?
Thanks so much,
Gina
I think you have to be a patient of one of the ME/CFS experts engaged in the multi-site study.
I am confused by the word “underway”. Is this study happening now and accepting participants?
It’ll start this summer.
Thanks Cort.