By Erica Verrillo
On December 9 and 10, 2014, the Pathways to Prevention (P2P) workshop was held on the NIH campus in Bethesda, Maryland. The workshop was sponsored by the Office of Research on Women’s Health (ORWH), which is the division of the NIH responsible for ME/CFS. The purpose of the workshop was to identify gaps in ME/CFS research, and to address key questions about incidence, prevalence, diagnosis and subtyping. (See Dr. Green’s presentation below.)
The P2P Workshop has sustained criticism from ME/CFS experts and advocates because P2P panel members are not experts in the illness, nor do they necessarily need to have a medical background. Advocates and experts have pointed out that not having expertise in an illness as complex as ME/CFS is a detriment, especially if the NIH bases future research funding on the recommendations of the panel.
The morning sessions on December 9 consisted of an overview of the workshop, the patient perspective (Robert Miller), case definition (Dr. Leonard Jason and Dr. Lea Steele), social determinants of health (Abigail Brown), and epidemiology (Dr. Luis Nacul). Each presentation lasts 20 minutes. At the end of the morning session there was a question and answer period in which P2P panel members and the audience could address questions to the speakers.
The draft report of the meeting is available HERE. Members of the public can make comments, which will then be incorporated into the report, until January 16, 2015.
You can read the program book HERE.
You can read the meeting agenda HERE.
You can watch the December 9 presentations HERE.
You can read information about panel members HERE.
You can submit comments HERE. (Deadline is January 16, 2015.)
NIH Pathways to Prevention: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Day 1)
Air date: Tuesday, December 09, 2014, 8:30:00 AM
Time displayed is Eastern Time, Washington DC Local
Runtime: 06:38:17 VIDEO
James M. Anderson, M.D., Ph. D. – Opening Remarks
(7 minutes) (begins at 0:05)
Director, Division of Program Coordination, Planning, and Strategic Initiatives, NIH
Dr. Anderson opened by describing the purpose of the P2P, which is to identify gaps and priorities in the research and take steps towards “focusing on the research that will result in improved treatments for patients and ultimately a cure.” Dr. Anderson stressed that to take these steps, biomedical research is required, and that NIH is the nation’s premier source of funding, which is awarded through competitive grants. Dr. Anderson stated several times that scientific rigor is a priority in selecting grants, which are expected to meet the highest scientific standards. Dr. Anderson pointed out that because ME/CFS occurs with other comorbid conditions, such as IBS, FM, chronic headaches, and TMJ disorder, there may be a common underlying cause, and that understanding comorbid conditions may shed some light on the cause of ME/CFS and help define targets for specific therapy. Dr. Anderson closed with the statement that “ultimately it is the voices of the patients that will help advance research on ME/CFS.”
Dr. Anderson then thanked the panel members, saying “This will be a productive event.”
David M. Murray, Ph. D. – Charge to the Panel
(7 minutes) (begins at 8:11)
Director, Office of Disease Prevention. Division of Program Coordination, Planning, and Strategic Initiatives, NIH
Dr. Murray explained that the mission of the Office of Disease Prevention (ODP) is to improve public health by “increasing the scope, quality, dissemination, and impact of prevention research funded by the NIH.” One of the ODP’s priorities is to identify gaps in areas of research that could benefit from additional investment. Dr. Murray explained that the outcome of the P2P Workshop is a panel report that will identify research gaps based on an “unbiased and evidence-based assessment of this complex issue.” In addition, the report will detail “methodological and scientific weaknesses and suggestions for research needs.” Murray mentioned that “people sometimes complain in advance of these workshops that there is no one who is an expert on the panel. That’s on purpose,” he said. “We don’t want people coming in with preconceived notions … we have an independent and unbiased panel.” Dr. Murray went over the two-year process for holding a P2P workshop, and stressed the importance of having a panel with no relationship to the illness they would be addressing. Dr. Murray closed his presentation with thanks to everyone involved, including the Trans-NIH ME/CFS Research Working Group, which sponsored the P2P Workshop, the speakers, and the panel who would be “getting very little sleep over the next two days.”
Carmen R. Green, M.D. – Workshop Overview and Panel Activities
(9 minutes) (begins at 15:17)
Associate Vice President and Associate Dean for Health Equity and Inclusion; Professor of Health Management and Policy, Anesthesiology, and Obstetrics and Gynecology, Office for Health Equity and Inclusion, University of Michigan Health System
Dr. Green began by thanking Paris Watson for shepherding everyone through the process, and described ME/CFS as a multi-faceted disorder characterized by “fatigue that can last many days, a lifetime, making daily activities impossible for over a million adults.” Like the previous two speakers, she stressed the fact that there is no single test to confirm ME/CFS, or approved treatment, and funding is lacking. Dr. Green then presented the questions the panel would address:
- What is the incidence and prevalence of ME/CFS, and whom does it affect?
- Given the unique challenges to ME/CFS, how can we foster innovative research to enhance the development of treatment for people living with the disease?
- What does research on ME/CFS tell us about the presentation and diagnosis of ME/CFS in the clinical setting?
- What tools, measures, and approaches help define individuals with ME/CFS?
- How are tools and measures used to distinguish subsets of patients with ME/CFS?
Dr. Green stated that on Thursday, December 18, 2014 the report would be posted on the website, and would be open for comments for 30 days. In March the report will be finalized. Dr. Green stressed that the panel is not an advisory board to the NIH. Dr. Green then asked the panelists to introduce themselves. (You can read their bios HERE.)
Susan E. Maier, Ph. D. – Overview of Topic
(15 minutes) (begins at 25:07)
Deputy Director, Office of Research on Women’s Health, NIH
Dr. Maier introduced ME/CFS as a “complex chronic condition, no known cause and no cure.” Research, she said, is both necessary and urgent because “this is an unmet public health need.” “Why is it necessary?” she asked. “People are sick, okay?” Like other presenters Dr. Maier reiterated that there many problems facing the ME/CFS patient population:
- There is no validated diagnostic test so physicians have to rule out other illnesses to achieve a diagnosis.
- There are few specialists to access to health care is limited.
- The current treatment paradigm is to treat symptoms, not treat the core pathology of ME/CFS because we don’t know what that is.
In spite of these obstacles, Dr. Maier stressed that biomedical research could be useful, and gave a few examples of how research can be used for diagnosis and treatment.
- Abnormalities in brain function can be easily observed in MRIs.
- Fatigue can be measured by using daily tracking measures of pro-inflammatory cytokines.
- Energy metabolism is also affected in ME/CFS, so fatigue in ME/CFS may be due to a defect in cellular energy produced by mitochondria. Enhancing mitochondrial function may be useful for improving energy in ME/CFS individuals.
We need to move the science into the clinic, Maier said, and then transfer clinical observations back to the bench. The question is, how do we know who has the illness? Findings are inconsistent because there is a lack of consistency in case definition. Comprehensive understanding is lacking, and results are not broadly reflective of all subjects in the group. Dr. Maier pointed out that Ampligen trials were successful, but not all patients responded to the drug. [Editor’s comment: a 100% response rate is not found in any drug.] Studying both sexes in a clinical design is important.
Dr. Maier recommended that researchers seek out funding in alternative fields – for example, research in chronic pain conditions. Dr. Maier exhorted researchers to seek NIH funding. “How many people play the lottery?” she asked. “If you don’t buy a ticket you can’t win.” [Editor’s comment: Dr. Nancy Klimas has remarked that although she has submitted numerous grant proposals to NIH, they have not been approved.] Dr. Maier encouraged collaboration. “We need to nail down the cause of ME/CFS. We need to understand the pathology, identify therapies, and get the treatments to market.” She closed with the statement that NIH is committed to funding scientifically rigorous research into ME/CFS, “which is a complex medical condition.”
Robert Miller – Patient Perspective
(20 minutes) (begins at 41:25)
Patient and Advocate
Robert Miller began by stating that in some ways his 25-year experience with ME/CFS mirrored that of most patients – being dismissed, ridiculed and outcast, especially by doctors who do not believe ME/CFS patients are truly sick. But he went on to call himself one of the “lucky ones,” because in 1997 he was treated by Dr. Daniel Peterson, who used more sophisticated tests to diagnose the illness than most doctors use today. According to Miller, Dr. Peterson, who has treated over 9,000 patients, also has the highest treatment success rate, because he identifies patient subgroups and treats them accordingly. Miller emphasized that there is much to learn from Dr. Peterson’s and a few other expert clinicians’ experience.
Miller issued a challenge to the P2P panel. “You on this committee have a powerful responsibility,” he said. “You hold patients’ lives in your hands. You can change the prevailing attitude of medical research that ME/CFS is not a serious or productive research field. You must change that. You can do it by identifying a strong and serious direction for future research that builds on immunological abnormalities and more clinical trials. That is the charge our patient community gives to you.” Miller pointed out that for 30 years casting a wide net of “unwellness” to define CFS and negligent levels of research funding have prevented medicine from solving CFS.
Miller went on to explain why people with ME/CFS are truly afraid that a panel of scientists who have no understanding or experience in the complexities of ME/CFS could possibly do more harm to “our underfunded and neglected research field.” He warned that if the panel recommends continuing the ineffective research focus on cognitive behavioral therapy (CBT), graded exercise and psychological traits, they will repeat a 30-year history of ineffective research that harms the patient. Miller pointed out that the AHRQ literature review missed the most promising new research on ME/CFS. It purposely excluded biomarker research, for example, which is the most important area of investigation needed for diagnosis. He explained that while the AHRQ review is correct in stating that the bulk of ME/CFS research is mediocre, it is because NIH only funds $6 million per year of research for an illness that costs an estimated loss of $20 billion annually. Miller pointed out that “scientists won’t work in this illness if NIH doesn’t support it.”
Scientific research directions to prioritize:
- Removing antidepressants from the recommended first line of treatments for ME/CFS. “If you give antidepressants to patients with no abnormal brain chemistry, it’s dangerous and even deadly,” Miller said.
- NIH needs to devote resources at a substantial level, comparable to the severity of the illness.
- The government must fund clinical trials because the private sector and FDA has failed patients with ME/CFS.
- Follow recommendations made by CFSAC to focus research on biomarkers, immunity, clinical trials, etiology, and establish centers of excellence.
Leonard A. Jason, Ph. D. – Case Definition
(22 minutes) (begins at 1:01:17)
Professor of Psychology, Director Center for Community Research, DePaul University
Dr. Jason began his presentation by explaining the importance of having a good case definition. He explained that ambiguities in case definitions can result in difficulty replicating research findings, estimating prevalence, identifying biomarkers, and determining which treatments help patients.
The problem faced by ME/CFS researchers, and clinicians is that over 20 ME/CFS case definitions have been developed, but these have only rarely been guided by the scientific method. The challenge to researchers is to identify which case definition to use so that the core symptoms are identified. This means that decisions need to made in order to establish whether a core symptom is severe enough to meet the definition, and standardized procedures need to be in place for assessing symptoms.
Fatigue is particularly problematic as a defining symptom because it is widely experienced. Short-term fatigue is experienced by 15-25% of the general population. However only 4% of the population experiences fatigue for six months or longer. Half of those can be explained by clear-cut illnesses (e.g. cancer). The key question is to identify how many of the remaining 2% have CFS or ME.
Dr. Jason then went on to review case definitions: The first case definition (Holmes, 1988) was so broad that it inadvertently selected a large number of patients with psychiatric conditions (i.e. depression). The second case definition developed in the US (Fukuda) was intended to rectify this problem, but several cardinal symptoms of CFS were not required, such as post-exertional malaise (PEM), neuro-cognitive problems, and unrefreshing sleep. The drawback of the Fukuda definition is that by using polythetic criteria (criteria in which not all symptoms are required for a diagnosis), patients with the illness may be excluded, while patients without the illness may be included. For example, in the Wichita study (CDC, 2003), 78.5% of the participants had PEM, and 76.9% had cognitive problems (thinking, concentrating, and remembering). When patients were followed up three years later, 70% of them no longer had CFS. This figure is substantially higher than the 5% complete recovery rate reported by specialized care clinics. “Why were recovery rates so high?” asked Dr. Jason. He suggested that it is possible that the broad Fukuda definition identified patients who were less disabled and more likely to recover. [Editor’s comment: All of the patients in the Wichita study were working full time.]
Dr. Jason also pointed out that prevalence rates are also affected by using polythetic criteria. In another use of the Fukuda criteria (Wessely et al. 1996), only 63% of patients experienced PEM, and only 64% had sleep disturbances. Wessely et al. found a prevalence rate of 2.6%, but if psychological disorders had been removed, the prevalence would have been substantially lower, at .5%.
Because of these problems, the CDC tried to operationalize the Fukuda definition by including standardized instruments for symptoms, fatigue, and disability. This definition is known at the Empiric criteria. However, because of the inclusion of emotional problems (role emotional), every clinically depressed patient could be diagnosed with CFS using the Empiric criteria. While the Empiric criteria could correctly diagnose patients with CFS (sensitivity), its ability to correctly identify patients without CFS (specificity) was low. The result is that many people without CFS have been incorrectly diagnosed using the Empiric criteria.
As a case in point, the prevalence of CFS using the Empiric criteria is 2.4%, but, as it turns out, the incidence of major depressive disorder is 2.2%. Thus it is possible the Empiric criteria may include many people with MDD.
Dr. Jason stated that it is possible to distinguish ME/CFS from MDD, but you have to use the right predictors, i.e. PEM, unrefreshing sleep, confusion or disorientation, shortness of breath and severity of self reproach (which is more typical of MDD than ME/CFS).
Because the Fukuda and Empiric criteria capture people who do not have ME/CFS, the Canadian Consensus Criteria (CCC – 2003) was developed to address specificity. It requires PEM, unrefreshing sleep and other cardinal symptoms of the disease. A subsequent set of criteria, the International Consensus Criteria (ICC – 2011) required that symptom severity must result in a 50% reduction in the patient’s pre-morbid activity. The problem with the ICC is that there is no scientific basis for the choice of 3 out of 5 symptoms, and the choice of symptoms is quite similar to the Holmes criteria.
In the patient sample Jason used to demonstrate this point, 95% met the Fukuda criteria, 75% met the CCC, while only 60% met the ICC. The increasing selectivity corresponded to increased physical disability. And in a recent study, Jason et al. found only three core symptoms, post-exertional malaise (PEM), neuro-cognitive problems, and unrefreshing sleep, could be used to correctly identify patients.
In summary, Jason stated that the CFS case definition needs to reduce unreliability in order to select those with the illness, while excluding those without. CFS is a broad category – it is vague and imprecise – while ME can refer to either the CCC or ICC. Consensus for explicit criteria must be reached by researchers, with clear rules for assessing core symptoms so that findings can be replicated and operationalized. To this end there is a need for standardized questionnaires. (The DSQ is one such instrument.) And there is need for an open transparent process.
[Note: The PeDaul Symptom Questionnaire for ME/CFS can be found HERE.]
Session 1: What is the incidence and prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and whom does it affect?
Heidi D. Nelson, M.D., M.P.H. – Overview of Systematic Review Methodology (19 minutes) (begins at 1:24:33)
Medical Director of Cancer Prevention and Screening, Providence Cancer Center; Vice-Chair and Research Professor, Departments of Medical Informatics and Clinical Epidemiology Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University
Dr. Nelson began her presentation by explaining that the evidence review adhered to guidelines developed by the Agency for Healthcare Research & Quality (AHRQ) and the Institute of Medicine (IOM). The AHRQ Evidence-based Practice Centers Program (EPC) involves 11 centers around the US, one of which is the Pacific Northwest Evidence-based Practice Center in Oregon, which is the center Dr. Smith and Dr. Nelson are associated with.
The first step of the systematic review involved the development of key questions. The next defined the scope of the review, which was followed by definition of inclusion criteria. Key questions were then refined by the NIH and the Pacific Northwest Evidence-based Practice Center.
The key questions were:
1. What methods are available to clinicians to diagnose ME/CFS and what conditions are required to be ruled out or excluded before assigning a diagnosis of ME/CFS?
- What is the accuracy and concordance of methods used to diagnose ME/CFS?
- How does the use of these methods vary by patient subgroups?
- What harms may be associated with undergoing or being assigned a diagnosis of ME/CFS?
2. What interventions are available for treating ME/CFS?
- What are the benefits of therapeutic interventions for patients with ME/CFS and how do they vary by patient subgroups?
- What are the harms of therapeutic interventions for patients with ME/CFS and how do they vary by patient subgroups?
- What are the characteristics of responders and non-responders to interventions
Inclusions: Clinical trials of at least 12 weeks, in which the outcome measures were based on symptoms experienced by patients.
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Exclusions: Intermediary results, such as blood tests, and any symptoms common to other illnesses, such as pain (but not fatigue).
The selection of studies received guidance from the Technical Expert Panel, including patients, a literature search, and examination by two reviewers. The randomized controlled trial (RCT) was considered the most reliable. Out of 6,175 abstracts, 71 were included, of which 36 related to diagnosis. There were three quality ratings:
- Good – likely to be valid.
- Fair – Some methodological deficiencies.
- Poor – Significant flaws that may invalidate results.
Applicability to “real world” situations, which Dr. Nelson described as “Main Street, USA” rather than a lab, was a very important consideration for the usefulness of the studies. Grading the strength of the evidence was based on study limitations, consistency of results, how directly the evidence links the intervention and health outcome, precision (same results across studies), and publication bias.
Lea Steele, Ph. D. – Quantifying ME/CFS in the Population: Consideration of Case Definition and Insights From Gulf War Illness and Other Symptom-Defined Conditions
(20 minutes) (begins at 1:43:20)
Director, Veterans Health Research Program Institute of Biomedical Studies, Baylor University
Dr. Steele introduced herself as a researcher for Gulf War Illness, but stated that ME/CFS and GWI share some of the same problems in establishing a case definition. According to Dr. Steele the “elephant in the room” is quantifying patients. Establishing prevalence is contingent on a case definition. The lack of general consensus on a case definition for ME/CFS makes it difficult to establish prevalence rates, neither is there general consensus on what to call it. To add to the complexity, prevalence (how many people have the illness at a specific time) and incidence rates (how many people are contracting the illness yearly) can vary widely, depending on whether they are established using sporadic cases or outbreaks. Dr. Steele pointed out that there have been numerous outbreaks and clusters since the 1950s, and recommended that the panel read those early accounts.
Of the 20 case definitions, 8 have been used to assess the prevalence of ME/CFS, with the broader case definitions finding higher prevalence rates. There is also a broad range of incidence rates. However, most of these studies did not make clear how ME/CFS was established in the patients. Occupational settings, such as GWI and “sick building syndrome” can lead to ME/CFS, as can infectious diseases.
Case definition alone does not account for the broad range of prevalence rates. Although, overall, the Holmes definition and CCC give lowest prevalence rates, while the Reeves (Empiric) definition gives the highest. Sampling also influences prevalence rates. For example, in population-based studies people are asked to take a survey or fill out a questionnaire with no clinical assessment. These studies produce prevalence rates that are much higher. Using the Fukuda definition, there are 600,000 to a million people with ME/CFS in the US.
Steele concluded with a recommendation to rely on expert consensus combined with a comprehensive analytic effort to devise a case definition.
Abigail A. Brown, M.A. – Social Determinants of Health
(21 minutes) (begins at 2:01:53)
Doctoral Candidate, Clinical-Community Psychology, DePaul University
Social determinants of health is a broad area that refers to all the personal, social, economic and environmental factors that can affect health as well as the societal mechanisms that are used to manage health problems. Risk factors can be either prospective (established before patients develop an illness) or regressive (established after people develop an illness). In ME/CFS only 11 studies using an accepted case definition have looked at risk factors, but of these, only two produced the same results (Hempel 2008).
Studies have identified the following risk factors: female, higher childhood socioeconomic level, low education (Brown pointed out that these two factors appear to be in conflict), and ethnic minority. Ultimately, risk factor studies have found that socioeconomic status does not affect prevalence, which indicates that ME/CFS affects a wide group of people. Brown did not spend mush time reviewing the literature on psychosocial risk factors, except to point out that a White et al. study (2001) using an empirical case definition found that pre-morbid psychological conditions did not predict who would develop ME/CFS following mono and/or upper respiratory conditions. However, when using the Oxford or Fukuda case definition, mood disorders as played a role. [Editor’s comment: This would seem to indicate that both the Oxford and Fukuda definitions are capturing patients with depression.] Some of the health risk factors included childhood illnesses, fatigue following a viral illness, and severity of the triggering viral illness (rather than psychological factors).
Variables associated with prognosis
Most studies find that severity of symptoms and disability are the best predictors of how long a patient will be ill. Brown’s group found that severity of symptoms, such as unrefreshing sleep, headaches, and cognitive problems, contributed to poor prognosis, but not psychological comorbidity. Early management of symptoms is predictive of improved prognosis over time.
Some of the problems with risk factor studies are a reliance on self-reported diagnosis (i.e. “Do you have ME/CFS?”) rather than a physician’s evaluation. A further complication is that case definitions are inconsistently applied. Prospective methods are not used, so we often end up with a prognosis of a “CFS-like” illness. There is also a psychogenic bias in the literature, as well as a lack of transparency, with researchers not reporting exactly how they analyzed their data. But the real problem is definition. If we can’t agree on what defines ME/CFS, how can we predict who will get it?
At this point in her presentation, Brown took a moment to argue against the psychogenic model, and proposed an empirically-driven and consistently applied case definition, while taking into account subtypes of the illness.
Systems that are in place to manage ME/CFS
Coverage in medical school is insufficient, with only 40% including ME/CFS. In a survey conducted by Brown and Peterson, out of 71 medical schools in the US, only 30% reported that their institutions treated patients with ME/CFS, and only four schools reported that they not only treated patients, but conducted research, as well as including ME/CFS in their curricula. The problem here is that because qualified doctors do not get trained, they can’t treat patients with ME/CFS. They then develop negative attitudes, which are passed on to their trainees in a vicious cycle. As a consequence, doctors question the legitimacy of the illness, with half not familiar with criteria for diagnosis. (28% did not accept ME/CFS as a clinical entity.)
What is needed?
- Informed health care providers (e.g. coverage in medical schools and continuing education)
- More funding for basic research
- Centers of Excellence, and an increased number of affordable specialists.
- A solidified case definition really must be the foundation for understanding risk factors.
Contact information: firstname.lastname@example.org
@DePaul_MECFS (mortality study)
https://redcap.is.depaul.edu/surveys/?s=DHxuYxScEn (mortality study survey)
Luis Nacul, M.D., Ph. D., M.F.P.H. – Epidemiology of ME/CFS: Making Sense of What We Know
(20 minutes) (begins at 2:22:38)
Chief Investigator, CURE-ME, London School of Hygiene & Tropical Medicine
Dr, Nacul began by stating that contrary to popular opinion, ME/CFS is not a disease of developed nations, but is a worldwide problem, affecting all age groups. (Although it peaks in the late teens and 30s, which Dr. Nacul suggested may have something to do with hormones.)
What is ME/CFS?
There is very little agreement on what constitutes ME/CFS. The Fukuda criteria, for example, is non-specific. It is a negative criteria (i.e. not relieved by rest, not explained by other conditions, not due to exertion, or co-morbidity, etc.) In addition, not all criteria need to be met. This results in a possible 163 combinations of symptoms that may define a person with ME/CFS. There would be an advantage in having more restrictive criteria. For example, if PEM were added as a requirement the the Fukuda definition, the number of symptom combinations would drop to 35.
If there are patients who do not have the condition being studied, due to a case definition that is not specific, they may “contaminate” the pool, yielding results that are spurious.
How a diagnosis evolves
Parkinson’s is a good example of how a diagnosis evolves over time. For over 100 years Parkinson’s had no treatment, but once a marker was found, treatment was rapidly developed (2 years). The same was true of diabetes. Once insulin was discovered, a treatment was developed within one year.
What should be happening with ME/CFS is to evolve from ill-defined syndromes to stratified, more specific, syndromes, after which we should invest heavily in finding a marker – whether it is diagnostic, or pathophysiological.
Dr. Nacul proposed the following research priorities:
- Discovery of biomarkers followed by
- Treatment studies
- Specific case definitions must be adopted in order to identify biomarkers.
Dr. Nacul recommended using a combination of criteria, for example the Fukuda with CCC, in order to identify phenotypes for both research and clinical trials. This would also open the door to testing a wide range of individuals, identifying subgroups, and devising effective treatments for different subgroups.
Q: Dr. Rasmussen, P2P panelist: I have heard that viral infections are associated with the diagnosis of ME/CFS. Have any studies looked specifically at herpes viral infections or any viral infections as disease markers that could potentially be used for diagnosis?
A: Dr. Jason: There certainly are a number of studies that have looked at that particular possibility. I might suggest Ron Glaser, who is one of the preeminent authorities in the world. Glaser has been doing research on this for a number of years. There are also studies of early proteins that are more marked in individuals with ME/CFS than controls. Dr. Lerner has authored some of those papers with Ron Glaser. (See press release HERE.) The best studies in that area might be prospective. What you really want to do is get a large group of people, and follow them over time. If they do get an infection like mono, gather data on them prior to the infection, find out what happens to them during the infection, and follow them over time. A college age population is perfect for that. Currently, in Chicago, we have a study going on that is following 6,000 students. Hopefully, in a couple of years we will have a better association between viral titers and the illness.
A: Dr. Lea Steele: It used to be called Chronic Epstein-Barr in the 1980s, so there are many studies that looked at EBV antigens. Later HHV6 became a prominent player in the research. One of the take-home messages is that you have to look longitudinally. If you do a cross-section, you don’t see the same things that you do if you look at patients over time. As the symptoms wax and wane, so do the viral titers. More recently there have been treatment studies looking at treatment of herpesviruses that have shown an improvement in patients after herpesvirus treatment.
A: Dr. Nacul: One of the attractions of herpesvirus is their ability to become latent. This could help explain fluctuations in symptoms.
Q: Dr. Green, moderator: How confident are you that we are treating one disease?
A: Dr. Lea Steele: I think that there could be different triggers and etiologic pathways that come together in the cascade of events. For example, you could have an infection, then your body responds in a certain way, and there is a cascade of immunological and neurological events. Or you could have a different inciting factor that also brings you to the same cascade of events through a different pathway. I don’t think we are looking at one etiology but we could be looking at a common pathophysiology.
A: Dr. Jason: To expand on that, certainly environmental toxins could be implicated with some individuals, particularly mold. I think it is very important to differentiate what kicked off the illness, what predispositions might have occurred in genetic factors, and what is maintaining the illness now.
Q: Dr. Jon Kaiser, patient (2:48:42): Isn’t it possible that the different diagnostic criteria for ME/CFS are identifying patients with different severity levels across the same disease spectrum? For instance, while all CFS patients are required to have debilitating fatigue for six months or greater not due to any other medical cause, the presence of severe sleep disturbance or PEM might be more prevalent in patients with a more severe manifestation of the same disease process. Finally, CFS/ME might be more properly considered as a disease continuum, with CFS representing a more mild or moderate stage of the disease, and ME representing a more progressed, disabling stage of the condition. The treatment implications of not excluding patients with an early or mild form of the disease are profound, especially given the data that intervening early in the disease process has more positive outcomes.
A: Dr. Jason: I would agree that severity is a critical issue as well as symptoms such as PEM, and memory and cognitive problems. There is a group called the 25% Group, which refers to the patients who are home bound or bedbound. We often don’t bring severely ill patients into our studies because it’s hard to get to them. There is an incredibly important push right now to include the most severely affected, because if all our research is focusing on those who are healthier, that is those who can come to clinics and research settings, then we are missing a large group of individuals. In Chicago we’ve been able to include patients who are home bound. What is fascinating is that when we looked at our data set, that group was 25%. It is critically important for us to focus research on that high-risk group because they might be very different from the groups we have been studying all these years.
Q: Suzanne Vernon, Scientific Director, Solve ME/CFS Initiative (2:52:09): I’d like to make a point of clarification on one of the studies that Abigail cited, and that was the post-infection fatigue study from Australia. That study included three different types of pathogens, so it wasn’t limited to viruses. It included an RNA virus, a DNA virus and a rickettsial agent. The finding was that the post-infectious response was highly stereotyped, and was associated with the severity of the acute infection rather than the agent itself.
Q: Mary Ann Fletcher, researcher, NOVA (2:52:57): This question is for Dr. Nelson. How much did this review cost, and who paid the bill? Also, there seems to be a failure on the part of the committee to realize that exercise and psychosocial behavioral interventions are not nearly as expensive as trials of drugs. It should also be realized that NIH has never funded a clinical trial of a drug for ME/CFS.
A: Dr. Nelson: I’m not sure what the exact price tag is. Evidence reviews are a fairly modest, efficient form of research and I’m sure we could find that out for you. The funding was provided through the federal offices, I’m not sure how that flowed between NIH and AHRQ, so I’ll have to defer to the programs officers of those two programs as to how that actually worked.
Q: Matina Nicholson, patient (2:54:58): I would like to clarify what disease we are studying, are we studying ME or CFS? Because in 2010 the CDC said CFS is not ME. Now they are educating doctors, and the doctors are confused. CFS has a lot of stigma, and chronic fatigue is just one symptom. I don’t care what the name is, but it seems as if they are merging two diseases together.
A: Dr. Steele: I agree. It’s a problem.
Q: Denise Lopez-Majano, parent of patients (2:56:20): My younger son got sick at the age of 12. My older son got sick at the age of 14. (At this point, she presents to the panel an informally gathered list of 140 people who got sick under the age of 18.) People get sick very young. I do not see them addressed in the evidence review, or in the agenda. In excluding pediatric cases from the evidence review, most of the work on orthostatic intolerance was also excluded. OI is a very severe problem for a number of patients. How is that going to be addressed? It’s like giving the panel an incomplete puzzle.
A: Dr. Jason: There’s a lot of reasons for an adult focus for this panel. But I must say that by understanding what’s going on in youth, we gain an incredible vantage point that we don’t get with adults. Let me tell you why. With adults you often get people who have been sick for a long time. You also get people who have tried many different types of treatments. With youth you have a chance to study the illness better, because it’s the initial manifestation of the illness. I would argue that in terms of our priorities, we should be focusing on youth to really understand this illness. Another point is that people generally say that onset is in the 30s and 40s, but there is another peak, and that is in youth. This is an underinvestigated area. In reference to the other question, I think that the term CFS has done considerable harm to many patients. We ought to understand, not just illnesses, but how people perceive illnesses. Clearly, there is research out there now that names do make a difference. There are many examples of how a name can change people’s attributions of what an illness is (such as MS, and AIDS).
Q: Rene Taylor, researcher (2:59:57): I will be presenting on adolescents tomorrow.
A: Robert Miller: On Denise’s comment, there has to be more emphasis on the pediatric side of this.
Q: Mary Dimmock, parent of patient (3:01:24): The real elephant in the room is what disease we are talking about. Patients and experts have both endorsed the CCC because it requires PEM. This morning we heard from Dr. Nacul that there can be 163 combinations of Fukuda. We heard from Dr. Jason that as few as 25% of patients in Fukuda studies have PEM. Because of definitional issues and confusion around the name, I think it is critically important that you ask the question differently. Do Oxford and Fukuda CFS represent the same disease as ME ICC and Canadian Consensus Criteria? Until you really come to grips with that question, you can’t really come to grips with the problem. So I would ask, do the definitions of CFS and ME encompass the same group of patients?
A: Dr. Nacul: The syndrome is the same. The disease may be different. Sometimes the same disease can have a huge spectrum. In lupus, for example, there are complications, there are severe cases, who will need one type of treatment, but in others there will be mild cases. We have one syndrome, but we have different subgroups. What is important is that we stratify all the people with the same syndrome.
Q: Dianne Lewis, patient (3:04:33): I’ve heard that there are 2-4 more females than males with this disease. I would like to know if the females were moved through the system faster. Are the men just not showing up with the symptoms, or are we only targeting women with this disease so we can stigmatize them further?
A: Dr. Steele: It appears to be a real biological fact that women have a much higher rate of chronic fatigue syndrome than men. This illness affects people of all socioeconomic statuses. We see there is a slightly higher rate among people of lower socioeconomic status and racial minorities. Lower income does not mean higher risk, however. They can actually have a lower income because they are ill. [Editor’s comment: Socioeconomic status refers to an individual’s or group’s position within society. It depends on a combination of variables, including occupation, education, income, wealth, and place of residence. Reduced income does not necessarily affect socioeconomic status if all the other variables remain constant.]
[End of morning session]