The more specific requirements of the ICC however, may select patients that are less clinically diverse. This could improve detection of immunological findings in CFS/ME. Study authors.
How much of a difference the International Consensus Criteria (or any definition) makes is a major question in chronic fatigue syndrome. Proponents of using a more restrictive definition such as the CCC/ICC believe that winnowing out a homogeneous group in research studies could be the key to figuring out ME/CFS. Once ‘non-ME/CFS patients are eliminated, core factor will pop out and be quickly replicated. It’s an enticing vision.
Determining how much of a net to cast in the new research definition will not be easy.
Others worry that a more narrowly focused group might miss some legitimate ME/CFS patients. The ‘wider net’ approach, may have been embodied in the ’empirical definition’, which grabbed a large set of ‘CFS’ patients, from which subsets could conceivably have been winnowed.
This strategy would have the benefit of applying to a larger population (up to 4 million in the US), and might work well if the funds and will had been available. Without that commitment that strategy runs the risk of producing almost meaningless results.
The NCNED’s latest study comparing the immune functioning of ME/CFS patients meeting the International Consensus Criteria vs. those meeting the Fukuda/1994 CDC definition gives us a start on determining the pros and cons of a more narrow vs. a broader approach to ME/CFS research.
Fukuda/1994 CDC Definition
The fact that few research papers in the last twenty years used something other than the 1994 Fukuda definition to define their participants means that virtually all the findings in ME/CFS from the natural killer cell dysfunctions to low blood volume to exercise intolerance, etc., have all been found using the Fukuda definition.
By putting all researchers on the same playing field, the Fukuda definition has played an important place in the history of ME/CFS research, but its vagueness and its inability to highlight what many believe to be the key symptom in ME/CFS means it almost certainly allows several questionable subsets into research studies.
The Study
Sixty-three participants including 41 people with ME/CFS and 22 controls answered questionnaires and gave blood samples. The blood samples were assessed for immune functioning.
All patients had been previously diagnosed with chronic fatigue syndrome at the National Centre for Neuroimmunology and Emerging Diseases, a top a ME/CFS research lab (and soon to be clinic) led by Dr. Marshall-Gradisnik in Australia.
Results
The breakdown was fascinating. Seventeen people met the Fukuda criteria but not the ICC, and 18 people met both the ICC and the Fukuda criteria. Five people — over 10 percent — of the ME/CFS patients met neither criteria.
This was one small study, but it did suggest that a large percentage of people that doctors identify with ‘chronic fatigue syndrome’ may not meet the ICC, and another substantial subset may not meet either criteria. It does not bode well for a more restrictive approach to ME/CFS.
Natural Killer Cells
It was no surprise to see reduced NK cell functioning show up in both the ICC and Fukuda groups. This reduced natural killer cell functioning is believed to inhibit the ME/CFS patient’s ability to clear new infections and/or stop recurring infections.
(Interestingly, reduced NK cell function was not associated with alterations in the cytotoxic factors – granzymes and perforin – that NK cells use to kill cells, as has been seen in the past. The authors suggested, however, that this might have been due to the small sample size.)
Immune Suppression Enhanced in the ICC Group
Both groups demonstrated immune suppression, but the immune suppression was significantly increased in the ICC patients.
The increased prevalence of two inhibitory or suppressive immune factors in the ICC group suggested a) they were a distinct group, (b) the promise of more abnormalities showing up when a more restrictive definition was uses was fulfilled and c) that their immune system was having more trouble than the Fukuda’s groups in becoming properly activated.
Treg or T regulatory cells or ‘suppressor’ T-cells are rather new to the scene in ME/CFS, but this is the third study showing significant increases in these cells. That suggests they may play an important role in chronic fatigue syndrome. High levels of Treg cells could be suppressing natural killer cell functioning in ME/CFS.
Both groups exhibited reduced immune activity, but more immune suppression was found in the ICC group
KIR Receptors – High levels of ‘KIR’ receptors on the NK cells of the ICC group (but not the CDC group) could further suppress NK cell function.
The presence of two ‘profoundly’ inhibiting factors suggested the ICC groups immune systems were getting particularly hammered.
(Increased levels of an ‘activating’ NK cell receptor were also found. The authors felt this resulted from an attempt to balance the ‘overwhelming’ inhibitory signals from the two inhibitory receptors.)
(Receptors on the surface of a cell greatly influence what the cell does. NK cells that are dotted with inhibitory receptors, for instance, can be easily turned off. Conversely, NK cells with few inhibitory receptors will be difficult to turn off.)
The authors suggested, but could not prove, that the ICC group carried genes that promoted a tendency towards NK inhibition.
Hitting Home – Physical Functioning Affected
One of the vital questions regarding the abnormalities in ME/CFS is how much they matter. Ironically, THE immune finding in ME/CFS, poor NK cell functioning, didn’t pan out in this regard. While low NK cell functioning was associated with poorer health in the healthy controls, it didn’t appear, at least in this small study, to be correlated with poorer health in the ME/CFS groups.
(On an anecdotal note I know of a few people who’s natural killer cell functioning has returned to normal with no significant change in their health. One person related telling his doctor that he was doing horribly only to have him/her respond ” But your natural killer cells are doing so much better!”).
Decreased CD39+ and altered KIR receptors were, however, ‘strongly’ associated with poorer health in the ICC (but not the Fukuda delineated patients). This suggested that immune suppression was having an impact in the ICC delineated patients.
Touchy Situation Ahead
The increased amount of immune suppression in the ICC group suggested that the ICC criteria did select a more immune-challenged set of patients and that group should be set apart for separate study.
The immune findings in the Fukuda group (low NK cell functioning/increased Tregs) were nothing to sneeze at, however. Plus, the high percentage (almost 50%) of patients meeting the Fukuda criteria, but not the ICC criteria indicated that group cannot be ignored. The ten percent of people with ME/CFS that met neither criteria suggested an important subset of people who are sick, but don’t meet either criteria, may be present.
The fact that all the study participants were identified by ME/CFS researchers/doctors working at an ME/CFS lab suggested they were indeed ME/CFS patients.
These researchers proposed that both groups should be included in studies. Since all the people that met the ICC also met the Fukuda/1994 CDC criteria, starting off with the Fukuda criteria and then examining the ICC criteria patients could achieve this.
Conclusion
“These findings are highly suggestive of a need to incorporate both the 1994 CDC and the ICC in future clinical research” Study authors
With a new research definition coming up on the docket, it was good a see a study examining a prominent candidate — the International Consensus Criteria.
With this study suggesting both definitions have merit, determining how wide or narrow of a net to cast in the research definition will not be easy.
The IOM contract for a clinical definition was really just a prelude to the big problem looming ahead, which is creating an appropriate research definition. Since the research definition defines what types of patients participate in a study, its use can fundamentally alter how a disorder is viewed or researched.
The suppressive nature of the immune dysfunctions found in the ICC group suggested, to my mind, that they might be ‘Fukuda plus’ patients dogged by increased levels of immune suppression.
This study gave no clear answers. It suggested that patients that meet the Fukuda criteria but not the ICC criteria are an important subset of ME/CFS, but it also suggested that segregating patients meeting the ICC criteria could help uncover more immune abnormalities.
It’s my belief that until someone understands the underlying mechanism of “fatigue”, be it in polio, cancer, multiple sclerosis, or ME- you can study and quantify all the NK cells, cytokines and other markers til the cows come home but this disease will go on. After that we need to find the cause, mechanism that brings on the fatigue, etc.,.
All this is just more distraction stringing out the 35+ year mystery/misery of our plight.
Greg
Getting right to the core there, Greg..
We need more research on ’cause’.
I think you’re going to like an upcoming blog…Some progress is being made in that area.
Looking forward to reading that upcoming blot, Cort. Doesn’t it usually work that when a cause is found, then a treatment is not that far down the road? Or am I being mislead?
Sorry, typo. Meant “blog” not blot.
Not sure why this doesn’t come up more often but there seems to be a major and perhaps very unjustified assumption that there is only one disease amongst this mess. The problem that keeps coming up is a fear that somebody is going to be left behind every time a reasonable abnormality surfaces. At this point, the odds are not likely that there is a smoking gun that is going to provide answers to all 1-4MM people in the US that potentially has “CFS”.
Is it really that difficult to focus at least some research on known abnormalities like NKC function/other immune dysfunction, various reactivated viruses, objective brain abnormalities, etc. Who – aside from the CDC – thinks that SF-36 questionnaires, fatigue complaints, random subjective symptoms are a better way to go?
I’d also point out that the ICC doesn’t require “fatigue” as a marker for diagnosis. So now we have people that might not have a “fatiguing” illness mixed in as well – I consider myself in that category.
One of the very serious problems – from my perspective anyway – is the difficulty for patients to adequately communicate to the MD their “symptoms”. I’ve seen some very good clinicians and quite frankly I am not confident they “get it” and I don’t think doing a good job of capturing patient symptoms accurately. And quite honestly I don’t trust fellow patients (mostly because I realize I’ve made mistakes of my own in describing things) either.
Do patient cohorts have to be all or nothing, ie could there be multiple cohorts for some studies? Why can’t some/most studies have a group of objectively defined patients? At this point, we know there are potential objective markers/abnormalities. Let’s take advantage of them. The alternative is an epic failure.
I agree Floydguy. I would rather the bulk of money go to defining subsets. If the money and will was available I think the best way to go would be to have a broad research definition and very large studies that looked for the different subsets. Once you definitively found those you would break the disorder up.
The ICC definition is for ME, the Canadian definition is for CFS- two different diseases entirely.
Greg
Getting at the heart of fatigue, no matter the illness it is generated by, is surely fundamental, and there surely are common denominators to all existing types of fatigue.
But the one thing the ICC is on, first of all, is not fatigue per se indeed. The very first “compulsory” criteria is: PENE, post-exertional neuroimmune exhaustion. Or as we call it: “crash”!
This I feel is a slightly different issue: Why does the “energy production system” ALL OF A SUDDEN break down in a given individual, in a most punctual way. Not slowly and gradually over time. All of a sudden. There maybe a ” cause” to this, but it is such a full collapse of the brain and body as a whole that it appears more like a generalized physiological process entire.
NK cells are a great lead, pathogens in the gut as well, but to me THE issue is: The post-exertion collapse. Suppose my NK cells test results are all fine, and so is my
gut “microbiome”, but I still crash right through my anaerobic threshold in two minutes of exertion, and then can’t recover for days, – THAT is the illness I wish to understand. THAT ought to be set apart from all other fatiguing illnesses.
There is saying: ontogenesis recapitulates phylogenesis… Likewise, each single crash in a way recapitulates the illness entire. On a specific day, you all of a sudden came down with chronic fatigue syndrome (the vast majority of us), and each time you crash, it’s like a summary of the whole ordeal you’ve been living for years, decades.
An eminent ME/CFS doctor said that PEM is “an illness within an illness”. Well, who am I but I beg to differ: PEM (or PENE as the ICC more aptly coins it), is the very essence of the illness.
This is what I wish researchers could get at the heart of.
I am so with you on this Christian…Actually the study I want to see is a huge study that has people exercise and then does every measurement possible on them during exercise and then during the critical post-exercise period when it all falls apart.
PEM is the core of the illness for me; everything else is kind of nebulous; there’s pain, there’s fatigue, there’s sensitivities….but throw some exercise is and it all changes dramatically..that is where I think they will discover what happens in ME?CFS and quite frankly, I wish every study included an exercise challenge.
I think this would be fantastic, even if a subset of patients don’t have issues with PEM. If we could prove the “energy production system” is malfunctioning, and begin to understand WHY it does, it seems to me that would lead to great strides in treatments, finding better bio markers, increased interest and funding, etc. and maybe even a name and case definition that actually makes sense.
I also liked what Janelle says below, including that those who don’t fit into these parameters could/should be tested another way.
Christian,
I think you make such a great point. The suddenness of the collapse. If we are talking about defining this illness, the crash does seem to be the defining symptom. And certainly this ‘up one minute down the next’ feature of the illness is greatly responsible for the grievous misunderstanding, as we who suffer it all know. Having been seen, even by our own doctors, standing and walking, we are rarely treated as the mostly bed-confined patients we really are.
I found your statement very clarifying, thanks very much.
Thanks Cort.
Re:
—————————————————-
Others worry that a more narrowly focused group might miss some legitimate ME/CFS patients. The ‘wider net’ approach, embodied in the ‘empirical definition’, proposes grabbing as large a set of severely fatigued patients as possible and then winnowing them down into subsets.
—————————————————-
You raise an interesting issue. However, I don’t recall it was ever explicitly said the empirical definition was chosen to ensure high sensitivity/ensure it grabbed a large group and thus allow subgrouping, even though this can be the effect of having a much broader set of criteria.
Also, one doesn’t even need to have fatigue to satisfy the empirical definition: one could simply score below the median* (i.e. in the bottom 50%) for reduced activity: “We defined severe fatigue as ≥ medians of the MFI general fatigue (≥ 13) or reduced activity (≥ 10) scales.” (see: http://www.biomedcentral.com/1741-7015/3/19 ).
A possibly better example of a broad fatigue criteria is the Oxford CFS criteria (Sharpe et al., 1991)
*I don’t think this was of the general population. I think it was simply for the sample i.e. not criteria that are likely to have high validity.
I don’t think it was ever explicitly said the Empirical definition was designed to create a large group that one could weed out subsets from within; I just don’t see how else it could have worked. We already knew that ME/CFS under Fukuda (@ 1,000,000) people was larded with subsets; how many more would have been present in up to 4 million people? The only possible way to make the Empirical Definition work was to subset it.
I think subsets is an interesting idea, but to do that with a broad inclusion like Empirical, Fukuda, Oxford, or Australian, one would need all the studies to be thousand-patient studies (back of envelope calculation): the incidence of Fukuda is about .74% while those others are closer to about 2.4%.
(Even then, we have some evidence ME patients are sometimes being excluded from many of these inclusions at times due to neurological and immune signs and symptoms being considered a “red flag” for other diseases, as well as, as you mentioned, everyone doesn’t fit a broader criteria simply because it is broader anyway.)
As you said, there is no evidence there is motivation to fund that size of study.
It may be better to work with a narrower set and the evidence we have, focus on diagnosing patients who are misdiagnosed (there is evidence that many patients diagnosed with CFS have other diseases but not also ME), and be sure that whoever is not included also gets studied another way. It would be bad to leave people behind, but that doesn’t justify an unscientific approach of classing too many diverse people together so that diseases cannot be identified in the mix–some other solution needs to be found.
In the end if we study too many patients and never find anything, everyone loses, but if we find a biomarker with a narrower set and it applies to a broader set, everyone wins.
I think that doctors must measure Myoglobine before and after exercise testing. I never read anybody did, can somebody find a study? Cort, maybe you can ask professor klimas etc… to test this marker. When this is to high you can objective measure PEM 100% and prove that exercise is not only bad for ME/CFS patiënts, but also harmful!
Never heard of that being done Gijs. Never heard of myoglobine, actually.
I wonder if this tiny 41 patient study, with its 17 who did not meet the ICC, took into account that the ICC has an “atypical ME” component. Perhaps they would be included under ICC if that were taken into account?
CDC has the following statements in documents they have published on the internet:
– “A number of illnesses have been described that have a similar spectrum of symptoms to
CFS. These include fibromyalgia syndrome, myalgic encephalomyelitis, neurasthenia,
multiple chemical sensitivities, and chronic mononucleosis. Although these illnesses may
present with a primary symptom other than fatigue, chronic fatigue is commonly associated
with all of them.” (CFS Basic Facts 2006), and
– “Various terms are incorrectly used interchangeably with CFS. CFS has an internationally
accepted case definition (/cfs/education/wb1032/chapter2-1.html) that is used in research and clinical settings. The name chronic fatigue and immune dysfunction syndrome (CFIDS) was introduced soon after CFS was defined; there is no case definition for CFIDS, and the name implies an understanding about the pathophysiology of CFS that is not fully supported in the medical literature. The name myalgic encephalomyelitis (ME) was coined in the 1950s to clarify well-documented outbreaks of disease; however, ME is accompanied by neurologic
and muscular signs and has a case definition distinct from that of CFS.” (CME: Diagnosis and Management (WB1032) 2010-2012)
The first statement indicates that CDC think that ME have more specific symptoms than only fatigue, although fatigue is present. In CFS the only mandatory symptom is fatigue. The second statement indicates that CDC think that ME includes neurologic and muscular signs, and that the name CFS should not be used interchangeably with ME.
Both statements indicate that CDC think that the CDC CFS Fukuda 1994 diagnosis should not be set if the patient has ME, although it would have been a great advantage if they had put ME as exclusionary condition in their definition for clarity.
If people would use the CDC view, then no person with an ME diagnosis would simultaneously have a CFS diagnosis, and everybody would be happy. We would have the situation as proposed by the study (2013. Brenu EW, Marshall-Gradisnik SM, et al), and we would have distinct patient populations without overlap, i.e. disjoint sets. Disjoint sets are sets that have no common elements.
Cort, this is a difficult topic for sure. I just wanted to share that as a Canadian, I was first diagnosed with CFS in 1990, later learned about the ME/CFS CCC 2003 and asked if I would be classified under that definition as positive for it. The answer was yes, and then finally I learned more of ME and asked my doc if I also would be diagnosed with ME and yes was the answer under a well-used ME criteria. I have come to realize that although I have a positive diagnosis for all three, that not everyone will. It is dependent on the country we live, the year we are diagnosed, and also the physician or specialty that diagnosed us.
I just know that for me they are all the same thing and I feel the same living with one or all three of them.
In North America, at the time of my diagnosis there was no choice but a CFS diagnosis and I was very lucky to get one so early. Also we have to remember that, as you mentioned, good science and research has come of the CFS although it brings its baggage of a very misleading label. However, ME bring a more concise name and bring a long history and baggage of psychologizing and poor research focus. So until such time that these are blended and dissected, I do not know how we can move forward.
In writing a book about my own 23 year experience, it has been really difficult to even explore this part of it because it is dependent on so many things. So that is my story for today.
Thanks for everything and for the comments from everybody. This is how we learn I guess.
We ignore the complexity at our peril. Looking forward to the book:)
PS sorry for typos. Where is my proofreader when I need one?
Best,
V
I think the easiest way to move forward is for them to start using the ME consensus definationf for research till it is PROVEN and known there are certain abnormalities in ME including of cause the abnormal immune findings. They could then use these abnormalities’/biomarkers which would become well known, then to pull others out of the mixed “CFS” group who before without the biomarkers involved, didnt have obvious ME.
This then would then leave a completely new kind of CFS group and would make it easier to find different abnormalities in this new CFS group.. having the ME group mixed with the CFS group would water down other abnormalities in other subgroups of CFS.
This would be far less expensive to go go about ME/CFS research then having mega large studies in which there is a confused mess of subgroups from the start. A focus on well defined groups is a cheaper way for research to go so is more easily done.
The name of the illness is M.E.- Myalgic Encephalomyelitis, not CFS. CFS is a fabricated name by the CDC, a bogus name.
Fukuda definiton is not a definition and lists the hallmark symtom of the illness at the bottom of their list. Why they are using Fukuda, is beyond me and should be you too. The Fukuda defintion has been a big problem for the last 20 years.
CFS- this word has been a big problem, fatigue is a ridiculous name, it is not fatigue. People get fatigued from a lot of illnesses and can be chroncally fatigued, this illness is not fatigue.
“is an artificial construct created in the US in 1988 for the benefit of various political and financial vested interest groups. It is a mere diagnosis of exclusion (or wastebasket diagnosis) based on the presence of gradual or acute onset fatigue lasting 6 months. If tests show serious abnormalities, a person no longer qualifies for the diagnosis, as ‘CFS’ is ‘medically unexplained.’ A diagnosis of ‘CFS’ does not mean that a person has any distinct disease (including M.E.). The patient population diagnosed with ‘CFS’ is made up of people with a vast array of unrelated illnesses, or with no detectable illness. According to the latest CDC estimates, 2.54% of the population qualify for a ‘CFS’ (mis)diagnosis. Every diagnosis of ‘CFS’ can only ever be a misdiagnosis. ” Dr. Byron Hyde
“Myalgic Encephalomyelitis is a systemic neurological disease initiated by a viral infection. M.E. is characterised by (scientifically measurable) damage to the brain, and particularly to the brain stem which results in dysfunctions and damage to almost all vital bodily systems and a loss of normal internal homeostasis. Substantial evidence indicates that M.E. is caused by an enterovirus. The onset of M.E. is always acute and M.E. can be diagnosed within just a few weeks. M.E. is an easily recognisable distinct organic neurological disease which can be verified by objective testing. If all tests are normal, then a diagnosis of M.E. cannot be correct.
M.E. can occur in both epidemic and sporadic forms and can be extremely disabling, or sometimes fatal. M.E. is a chronic/lifelong disease that has existed for centuries. It shares similarities with MS, Lupus and Polio. There are more than 60 different neurological, cognitive, cardiac, metabolic, immunological, and other M.E. symptoms. Fatigue is not a defining nor even essential symptom of M.E. People with M.E. would give anything to be only severely ‘fatigued’ instead of having M.E. Far fewer than 0.5% of the population has the distinct neurological disease known since 1956 as Myalgic Encephalomyelitis” Dr. Byron Hyde
“There is no such disease/s as ‘CFS’ – the name CFS and the bogus disease category of CFS must be abandoned (along with the use of other vague and misleading umbrella terms such as ‘ME/CFS’ ‘CFS/ME’ ‘CFIDS’ and ‘Myalgic Encephalopathy’ and others), for the benefit of all the patient groups involved.”. Dr. Byron Hyde