Dr. Klimas spoke on the IOM report on ME/CFS at the recent federal advisory panel for chronic fatigue syndrome (CFSAC) meeting. She explained how the report was done and addressed some rather hot controversies that have sprung up since its publication. This was the first time an IOM report panel has publicly done so.
She said the IOM panel for chronic fatigue syndrome was a bit different. IOM panels are typically weighted towards experts in literature review and processing information. This panel (surely in response to concerns from the ME/CFS community) probably had more content experts (Chu, Bateman, Lerner, Klimas, Rowe, Natelson, Lerner, Keller, Davis) and fewer “process experts” than usual. She was surprised to find that some of the “process” experts had family members with the illness.
The panel members included Margarita Alegria, Lucinda Bateman, Lily Chu, Charles Cleeland, Ronald Davis, Betty Diamond, M.D. Theodore Ganiats, Betsy Keller, Nancy Klimas, A. Martin Lerner, Cynthia Mulrow, Benjamin Natelson, Peter Rowe, Michael Shelanski. The report was also reviewed by a long list of ME/CFS experts.
Dr. Klimas said the report was an enormous amount of work. In between four long meetings the panel members assessed thousands of articles. The public workshops also greatly influenced the panel’s report, with the committee being greatly touched by the patient stories.
The press, of course, was very favorable (and continues to be favorable. Two more articles in the last week focused on the IOM report.) The JAMA article was downloaded 43,000 times by non-subscribers. Six months later the IOM report for ME/CFS is still one of the top ten downloads on the IOM website – something the Institute of Medicine was very pleased to see. (Since the ME/CFS report was released in February the IOM has produced over 60 reports on issues ranging from cancer to obesity to emerging viral diseases.) That high interest could be good news for the next report Dr. Klimas believes should be produced – on therapeutics.
All that attention suggests, of course, that for all the inattention given to ME/CFS by the NIH and CDC, the medical community is actually quite interested in this disease.
The Almost Biomarker
The panel agreed that reduced NK dysfunction (reduced cytotoxicity) discriminates ME/CFS from healthy controls, but NK cell dysfunction did not make the diagnostic criteria. The reason for this was that outside of specialized labs – which most doctors don’t have access to – the quality of NK cell cytotoxicity tests is poor. (This is because most labs take 48 hours to process the test but the test is only good for 8 hours.)
Dr. Klimas noted that the CDC is doing work on NK cell testing now. She hoped that a widely available, high quality NK cell test will be on the market by the time the diagnostic criteria are revised. (A biomarker indicating that part of the immune system is whacked in ME/CFS, would, of course, be a very big deal in helping to change the conversation around this disease.)
Dr Klimas noted the IOM panel was prevented from delivering more positive findings because of a lack of follow up for many research studies.
Dr. Klimas said that the primary factor driving the committee’s report was the 85% of chronic fatigue syndrome patients who have not been diagnosed. Getting that number up played a role in every decision the panel made. Doctors who know little or nothing about the disease were the focus of the criteria.
Their primary goals were
- to have doctors understand that ME/CFS is a serious disease they should be on the lookout for
- to have doctors be able to easily recognize and diagnose it
- to have doctors treat the symptoms present in it and
- to avoid misdiagnoses and harmful therapies.
To that end the IOM panel produced a simple diagnostic algorithm doctors could easily memorize. Even though Dr. Klimas helped to develop the ICC and CCC definitions she said she still needed a cheat sheet to remember them and the Fukuda definition.)
The panel strove to incorporate symptoms that were common and which discriminated ME/CFS from other illnesses. They agreed that post exertional relapse is the key discriminatory symptom in ME/CFS. It’s rarely, if ever, found with the severity that occurs in ME/CFS.
The cognitive impairment and dysautonomia (orthostatic intolerance) symptoms help differentiate the illness from other illnesses, plus unrefreshing sleep is very common. (Questions have been raised regarding orthostatic intolerance because it’s not as common as the other symptoms. It appears to have been included because it’s a standout symptom that alerts doctors to the possibility that ME/CFS is present.)
Symptoms such as pain, infectious triggers, gut and urinary problems, sore throat, painful lymph nodes, sensitivity to stimuli that are important were not discriminating enough, not common enough or there wasn’t enough data on them to include them in the definition.
The report also offered a list of signs and questions doctors can ask to get clearer on the symptoms present in ME/CFS. For instance, with regard to post-exertional malaise, it suggests doctors be on the lookout for patient that talk of “crashing or relapsing”. They recommended doctors ask questions such as:
- What happens to you as you engage in normal physical or mental exertion? Or after?
- How much activity does it take you to feel ill?
- What symptoms develop from standing or exertion?
- How long does it take to recover from physical or mental effort?
- If you go beyond your limits, what are the later consequences?
- What types of activities do you avoid because of what will happen if you do them?
The report also states that the immune dysfunction found is severe enough that doctors should be concerned about viruses reactivating. With regards to the HPA axis the adrenals are OK but there is evidence of HPA dysfunction and serotonergic signaling problems.
The report concluded EBV can clearly trigger ME/CFS but there’s insufficient evidence to conclude that all ME/CFS is caused by it or that it is sustained by an ongoing EBV infection. (Dr. Lerner surely fought hard for a more definitive statement :)) With regard to bacterial or other infections they concluded they may be present and may reflect an immune dysfunction. More research is needed in all these areas.
Then Dr. Klimas cleared up an important misconception about the report and she addressed some of Lenny Jason’s concerns. First some background (from me – not Dr. Klimas)
Lenny Jason’s critiques have undoubtedly lead many in the ME/’CFS community to take a jaundiced view of the report. A recent Facebook comment saying something to the effect that “if only the IOM panel had had Lenny Jason they wouldn’t have made so many mistakes” probably summed up the view of many.
Jason has pointed out in a string of papers and blogs, major mistakes he believes the panel made. In a recent blog titled the “Battle for Justice” he, if anything, sharpened his criticism of the report. He portrayed the report as such a set-back that he wondered if there was “any way to salvage the damage inflicted on the larger patient community by well-intentioned scientists from the IOM?”
That this panel – packed with the experience and brain-power it had – would have made so many major mistakes has always been bewildering to me.
Dr. Klimas’ testimony was the first time an IOM panel member has chosen to respond to Jason’s critiques.
Clinical Definition – Not Research Definition
Dr. Klimas reiterated (perhaps for the fifth time in her presentation) that the IOM definition was a clinical definition – not a research definition. (To my regret I had missed this distinction entirely.)
It’s an important one. Clinical definitions are by their nature inclusive; they’re drawn up so that no one with a disease is missed. Research definitions, on the other hand, are exclusive – they’re drawn up to ensure that only people with a more or less pure form of a disease are included in research studies. By their nature they exclude a substantial number of people who have the disease but who also have confounding factors.
All of the complaints regarding the new definition – that it’s too broad, that it brings in too many people, that it doesn’t have exclusionary factors, that some people with depression fit it – are based on the idea that it’s a research definition.
It’s not…. The IOM report clearly states the panel was tasked with developing an
“evidence-based clinical diagnostic criteria for ME/CFS for use by clinicians” and that
“These more focused diagnostic criteria will make it easier for clinicians to recognize and accurately diagnose these patients in a timelier manner.” Plus
“the committee hopes that the diagnostic criteria set forth in this report …will promote the prompt diagnosis of patients with this complex, multisystem, and often devastating disorder; enhance public understanding; and provide a firm foundation for future improvements in diagnosis and treatment.”
Research is never mentioned. That distinction removes several issues (prevalence, exclusionary factors) that have been dogging this report.
Jason’s analyses indicated the definition would increase prevalence rates significantly – so much so that he recently compared it to the CDC’s infamous Empirical Definition.
“Our published work now suggests that these new criteria would almost triple the prior CFS prevalence rate….This inadvertent action accomplished much of what Bill Reeves and the CDC had attempted to do a decade ago when they proposed an ill-fated expansion of the case definition.”
These are strong, provocative words. Associating the IOM diagnostic criteria with Dr. Reeves and his hated “Empirical Definition” is sure to assign it to the second circle of hell for many people with ME/CFS. Jason also indicated that the IOM criteria identifies a group comparable in size, produced by the much maligned Fukuda criteria.
In the light of the reports goal of increasing diagnostic rates, Jason’s findings can actually be viewed as an asset, not a failing. Similarly, Jason’s objection that the criteria selects patients with less impairment and fewer symptoms than a more restrictive four symptom criteria fits the IOM panel’s goal of drawing a broad net.
A clinical definition should not only define the more severely impaired. It should capture all permutations of an illness – from severe to mild – so that doctors can make a diagnosis when they see it.
Jason’s taking the report to task for not including exclusionary factors struck a chord with many. He stated that the “the erroneous inclusion of individuals with primary psychiatric conditions…. would have detrimental consequences for the interpretation of epidemiological, etiological, and treatment efficacy findings“.
That made sense if there were findings to be found with this group, but again, there are no findings to be found in this group of patients. The IOM’s diagnostic criteria were developed to help doctors identify and treat ME/CFS patients – not produce research findings about them or to use them in clinical trials.
Another stunning finding from the DePaul group indicated that 47% of people with melancholic depression meet the SEID criteria. Jason argued that the lack of exclusionary factors would hamper clinical trials:
“including individuals in treatment studies who have a primary affective disorder but were misdiagnosed with SEID will lead to difficulties in interpreting treatment effects for individuals with ME.”
Clinicians do need to weed out depressed patients from ME/CFS patients (with or without depression) in their office but that is simply part of the diagnostic protocol they should follow. Jason also argued that the report should have had a recommendation for a mental health evaluation or structured clinical interview. Given the high percentage of people with melancholic depression who meet the criteria that’s seems like a good idea.
Most of the time the misdiagnosis, though, in ME/CFS probably goes the other way; i.e. people with ME/CFS are more likely to be misdiagnosed with depression or misdiagnosed as only having depression than depressed patients are at being misdiagnosed with ME/CFS.
This is only an issue if the IOM definition is used in clinical trials which would be a misuse of the definition.
Dr. Klimas simply stated that the IOM report did not include exclusionary factors because exclusionary factors are not included in clinical definitions.
Lenny Jason – Off the Hook?
Jason has come under some criticism for not serving on the IOM panel or even as one of the expert reviewers. The fact clinical diagnostic criteria, not research criteria were being developed, brings up the question whether Jason was needed as much as was thought. The ME/CFS experts on the panel were mostly physicians – and given that they were tasked with helping other physicians identify ME/CFS – they were clearly the right people to have on the panel.
Lenny Jason On the Hook?
So what about Lenny Jason and his string of highly negative studies and sometimes rather inflammatory blogs? He’s been treating a clinical definition as if it was a research definition and hammering the heck out of it. I asked him about that. He referred to the muddled definition problems that have historically prevailed in ME/CFS; i.e. research definitions treated as clinical definitions.
“Regarding the IOM, as we know, the 1994 (Fukuda) criteria tended to be used both for research and clinical purposes, although that was not the original intention of it. So, when only one criteria is announced, there is always the danger of a similar situation occurring again.
Clearly, what is needed is both a research and clinical criteria, and had both been worked on at the same time, the confusion would be much less. We do need both, and hopefully this will need to occur in the future.
For now, the IOM has one criteria that might very well be, regrettably, used for both purposes and should that occur, the dangers I have alluded to would be evident. I have tried to suggest ways that this can be avoided in my blog.”
Unfortunately, Jason’s papers and blogs don’t make the distinction between the clinical definition the IOM definition is, and its possible misuse as a research definition. They treat the IOM’s clinical definition as if it were a research definition. That has lead to some confusion.
It’s safe to say, though, that Jason’s critiques have so exposed the problems of using the IOM’s diagnostic criteria as research criteria, that it will never be used as such :).
The Research Definition
The outstanding definition issue now is the research definition. Jason stated in an email that a good research definition “is so critical for the field”. A virtual one man band on this subject, he has been ploughing away, publishing study after study on ways to operationalize the symptoms in ME/CFS, and honing the symptom set for a research definition.
He appears to be close to producing a simple research definition that works. More data is needed, though, on how the symptoms in ME/CFS compare to those found in other diseases. Jason’s DePaul group recently released a survey intending to do just that, and Jason said several research papers will be published soon.
Then we can get into the next controversy.