Text Note MRC CFS/ME Research Workshop
MRC CFS/ME Research Workshop
19th and 20th November 2009
Heythrop Park Hotel, Oxfordshire
1. Day 1 - Welcome & introduction
1.1 Professor Holgate welcomed the participants to the workshop and introduced the format for the two days.
1.2 An overview was provided of the MRC CFS/ME Expert Group and its Terms of Reference. The aims of the workshop were then detailed as follows:
Identifying the underlying causes
o Clinical phenotypes
o Novel technologies and methodologies to help identify sub-phenotypes
o Molecular and cellular mechanisms of pathogenesis
Consensus of priority areas.
Encouraging new researchers into the field.
Areas proposed for consideration during the workshop included:
o capitalising on current issues and UK scientific strengths including national resources e.g. patient cohorts
o new technologies and technological platforms
o partnership models
o other issues
1.3 Professor Holgate referred to the recent interest in the publication of research linking the retrovirus XMRV to CFS/ME, before going on to summarise the key challenges in the field:
A large clinical need without sufficient underpinning research.
Low research capacity; need to encourage a multi-disciplinary approach.
Grant applications that did not meet current competitive standards for funding.
Absence of a clear pathogenetic mechanism(s) meant it was difficult to develop therapies targeted towards specific biological pathways. As a result current therapies tended to be directed towards symptom support rather than prevention or modifying/halting progress of the condition.
The need to consider both physiological and psychological mechanisms in developing therapeutic approaches.
The difficulties inherent in defining phenotype and sub-phenotypes for a complex condition without good knowledge on underlying mechanisms.
Knowing how best to incorporate new science and technological platforms.
1.4 Professor Holgate advocated a more collaborative approach to move the field forward.
A recent example of where such an approach had proved successful in increasing research capacity and impact was in respiratory research.
(Full slide sets for each presentation are available at Annex 1)
2.1 Dr Esther Crawley provided an overview on the epidemiology of CFS/ME and the current research on phenotyping. The role of the British Association of CFS/ME (BACME) and the current specialist services available for patients were explained. The key points raised were as follows:
Definitions of CFS/ME were important when investigating prevalence of the disease.
In adults there were at least 3-6 different phenotypes identified to date and there were currently 3 paediatric phenotypes, suggesting the possibility of a stratified or targeted approach to treatment.
CFS/ME was considered to be a heritable condition, and several latent factors and risk factors had been identified. Further gene/environment interaction studies were needed to understand the mechanisms at play in disease progression.
BACME in 2009 the 13 clinical service centres funded by Department of Health in 2004 were merged with the CFS/ME network. It was estimated that there would be 7,000-8,000 new patients/year assessed by the clinical teams.
There were currently 30 teams contributing to the CFS/ME National Outcomes Database. Assessment data for more than 3,500 patients (adults and children) since summer 2009 had been collated. It was anticipated that this number would increase to 5,000 patients per year.
2.2 Professor Julia Newton presented an overview of the current research into the role of autonomic dysfunction in CFS/ME and briefly explained the research from her laboratory. She discussed the possible upstream and downstream mechanisms of autonomic dysfunction, such as those relating to control of blood pressure and heart rate, as well as treatment options. The key points raised were as follows:
With regard to autonomic dysfunction in CFS/ME, there were currently problems regarding diagnosis of both CFS/ME itself as well as with the diagnosis of autonomic dysfunction. Further issues remained concerning the reproducibility, insensitivity of detection equipment and data interpretation.
New assessment tools with increased sensitivity were progressively being made available.
Studies have shown that 50% of CFS/ME patients have neural-mediated hypotension.
There were overlaps between hypotension in CFS/ME and other diseases e.g. cirrhosis and rheumatoid arthritis.
A new treatment for patients with hypotension involving repeated daily tilt training was described. 2.3 Professor Jim Horne gave an overview of research into sleep disorders and the role of sleep dysfunction in CFS/ME. The key points raised were as follows:
Some sleep disorders (eg apnoea/hypopnoea, restless leg syndrome, nocturnal myoclonus) can be manifested as CFS/ME, and it was important to screen for these.
CFS/ME can produce sleep problems that can rebound back onto CFS/ME. For example, a disruption of the body clock (circadian rhythm), leading to sleeping excessively at the wrong time of day, to cause post-sleep inertia (rather like jet-lag) with symptoms similar to/further aggravating CFS/ME.
Stabilisation of the circadian rhythm can be helped by: 1) remaining under daylight/ fairly bright indoor light throughout daytime hours, and 2) using melatonin about 2h before bed-time (and avoiding bright light at night).
Nevertheless, some patients with fairly normal circadian rhythms do take too many naps in the day, thus reducing sleep need at night and causing disrupted, unrefreshing night-time sleep. 2.4 Professor Maria Fitzgerald provided a comprehensive overview of the complex mechanisms and processes involved in pain. The role of pain in CFS/ME was also discussed. She highlighted the importance of pinpointing when pain became chronic. The key points raised were as follows:
The purpose of pain was primarily defensive and a warning mechanism. However this mechanism could become maladaptive.
Pain processing occurred at multiple sites. Furthermore, pain mechanisms were complex, combining sensory, motor, autonomic and affective components which could also lead to altered brain function resulting in, for example, anxiety and insomnia. These changes were dependent on individual differences, age, gender and culture.
It was unclear whether pain in CFS/ME comprised either of peripheral components, altered central nervous system (CNS) processing and altered endogenous factors or a combination of these. In other conditions such as fibromyalgia, both altered CNS processing and altered endogenous factors were a feature of pain. There was also evidence of altered cortical pain processing in the brain.
Potential causes of pain in CFS/ME may include an increased limbic system involvement, decreased endogenous descending control, enhanced temporal summation, nociceptor sensitisation, genetic determinants and early life experience.
Improved animal models of pain in CFS/ME were needed as a basis for research into underlying mechanisms, as were improved ways of defining and quantifying fatigue.
2.5 Professor Gijs Bleijenberg presented an overview of current research in clinical psychology in CFS/ME and outlined possible future directions in this area. The key points raised were as follows:
The aetiology of CFS/ME could be divided into multi-factorial predisposing, precipitating and maintaining factors.
Predisposing factors included neuroendocrine dysfunction; gender; psychiatric illness; high physical activity in adulthood; low physical activity in childhood.
Precipitating factors included infectious triggers; fatigue; pain; physical inactivity.
Less was known about perpetuating factors and the key question was how and when did certain factors become perpetuating.
Current treatments were aimed at symptom management and included cognitive behavioural therapy and graded exercise therapy.
Neurobiological changes were reported in CFS/ME e.g. changes in patterns of cerebral activity and decreased grey matter volume. However, it was not yet known whether these changes were as a result of the condition or whether they were central to the disease process.
Possible future directions for research: o Large population based studies to increase insight in the development of CFS/ME.
o Smaller cohort studies of groups at high risk for developing CFS/ME with an emphasis on the development of the maintaining factors.
o Research and mediation analyses of treatment studies; experimental studies to discover mechanisms.
o Studies investigating neurobiological or physiological markers of CFS/ME in relation to treatment effect.
o Early detection of CFS/ME by physicians and promoting healthcare seeking by patients.
2.6 Professor Phil Cowen provided a summary of imaging techniques and studies in CFS/ME and other disorders. The key points raised were as follows:
Technologies such as PET/SPECT, ligand PET, MRI, MR Spectroscopy and fMRI could be useful tools in helping to understand CFS/ME pathophysiology.
In some respects, imaging studies of CFS/ME patients have shown similar findings to those using subjects with depression. For example:
o Structural morphometry studies have shown reduced grey matter volume.
o Decreased binding of brain 5-HT1A receptors using PET. o Increased neural activation during tasks of working memory. Specifically in CFS/ME patients proton MRS detected an increase in ventricular lactate, which had been postulated as a potential biomarker for CFS/ME, perhaps representing evidence of mitochondrial dysfunction.
Currently there was an overall lack of understanding of neural correlates of central fatigue in relation to functional brain imaging.
The current evidence base in the field was unreliable due to the small patient numbers involved and the lack of consistency in experimental design. Increased sample sizes were needed coupled to more robust methodological approaches.
2.7 Professor Chris Ponting discussed new technologies in relation to genetic studies and their potential for use in CFS/ME research. The key points raised were as follows:
Susceptibility: were viral or other environmental triggers impacting on a vulnerable host? Further study of gene/environmental interactions was needed.
For successful genome wide association studies (GWAS) large sample numbers from well phenotyped patients were needed.
It was possible to identify gene variants for low-moderate effects, which may be an issue for CFS/ME. For example a GWAS on height found that 40 genes account for only 5% of heritability.
It was important to discover biological pathways implicated by genetic studies, as opposed to single abnormalities as these might prove to be more informative.
Most complex disease associations appear in non-coding regions of the human genome whose mechanisms mostly remain enigmatic.
There were currently limitations in analysis, storage and interpretation of the large data sets that will be generated in genomics and genetics in the next 5 years.
2.8 Professor Anthony Pinching gave an overview of the possible role of immunity and infection triggers in CFS/ME. The key points raised were as follows:
Whilst chronic infection has been investigated for many years as a possible pathogenetic mechanism, the balance of evidence now tends to favour persistent immune activation or dysregulation, triggered by infection or other events that have similar impact.
Patient histories indicate the common triggering role of a wide range of infections, and also provide clues to altered immune function in association with ongoing disease.
Altered immune factors, e.g. decreased natural killer cell function, Th1-Th2 cell imbalance, elevation of both pro and anti-inflammatory cytokines have been associated in CFS/ME, and may be further elevated two days after exercise or activity.
The relationships between predisposing and perpetuating factors in these changes have yet to be established, but prior genetic and environmental factors are both likely to influence immune responses to infections.
The recent XMRV retrovirus study had produced interesting results. However the involvement of XMRV remained unproven and the study would need to be replicated using fresh biological samples, different methodologies, other cohorts and disease controls. It would be premature to use tests for this agent in diagnosis, or to initiate treatment studies, until such replication had been achieved.
2.9 Professor Paul Moss discussed the possible role of virology in CFS/ME and presented a review of the current research in this area. The key points raised were as follows:
Many studies have shown that infection is a strong candidate for triggering CFS/ME.
Chronic infection was often linked to mood changes. CFS/ME had been associated with multiple viruses e.g. herpes viruses (CMV, EBV, HHV-6, HHV-7) as well as parvoviruses, enteroviruses and retroviruses such as XMRV.
An imbalance between memory and nave circulating and lymph node T cells has been shown in some studies.
Small studies had been undertaken to investigate possible novel therapeutic interventions using antiviral approaches, e.g. acyclovir, monoclonal antibodies.
A model was proposed by which a chronic response to infection might lead to fatigue and lack of exercise which could potentially escalate to a self-reinforcing cycle.
2.9 During the open session, the recent findings implicating a role for the XMRV retrovirus in CFS/ME were discussed. Attendees agreed that it would be important that the XMRV findings were replicated before treatment options could be considered, as well as extending the study to other CFS/ME patient groups in other countries. A consensus should be reached regarding the methodologies to be utilised between different research laboratories while research should be undertaken in well characterised cohorts. Studies in patients that have been recently diagnosed with CFS/ME should also be considered in order to minimise the number of patients with co-morbidities which could produce confounding results.
2.10 During the group discussion Sir Peter Spencer and Dr Charles Shepherd outlined a feasibility study for setting up CFS/ME post mortem and in vivo tissue banks which was being funded jointly by Action for ME and the ME Association. Sir Peter emphasised that the charities in this area were very small compared to other disease-related charities and therefore obtaining funding for large studies was challenging.
2.11 Attendees highlighted that there were potentially many opportunities that could open up research into CFS/ME. For example, little was known about fatigue mechanisms and investigating fatigue in healthy individuals could provide useful clues in understanding the aetiology of CFS/ME.
Since anxiety and depression comprised a large part of the symptoms of CFS/ME alongside other symptoms such as pain, the interaction between biological and psychological mechanisms should be explored, particularly as there was scope to investigate anxiety from the perspective of autonomic nervous dysfunction. Another cross-cutting area that could prove fruitful to explore was that of mitochondrial function and energy metabolism.
2.12 In summing up the days discussions, Professor Holgate noted the many potential interesting avenues for research. Going forward, the right infrastructure needed to be in place, aided by the adoption of a collaborative approach.
3. Day 2 - Working group discussions
3.1 Participants were divided into three mixed groups for discussions at the beginning of the second day, before reporting back in a plenary session. Each group was asked to identify the research priorities and raise any other issues that they felt had not been addressed thus far during the workshop, as well as the following areas:
o group 1 - current UK strengths and resources
o group 2 - partnership models
o group 3 - new technologies and technological platforms
3.2 The reports from each group highlighted the following points:
Group 1 Research priorities and UK strengths
Existing research cohorts of CFS/ME patients there were several well characterised cohorts already established including trial cohorts such as PACE.
Birth cohorts (e.g. 1958 and ALSPAC cohorts which had genetic information) for hypothesis generation. Whilst these were less well characterised it would still be possible to generate results in research studies. CFS/ME National Outcomes Database.
Strong research teams particularly in epidemiology, imaging, gene sequencing, health psychology and non-pharmacological intervention. This was further enhanced by a general willingness to work in multi-disciplinary teams.
To establish a large cohort with broad case definition identified early in primary care before CFS/ME became established e.g. first presentation following viral illness with fatigue and interference with normal activities. This could be followed up with more intensive phenotyping and obtaining biological samples (including samples for sequencing, metabonomics etc) to identify variables/predictors associated with developing confirmed CFS/ME.
In addition to identifying priority groups for intervention studies this would also allow the exploration of the implications of different definitions/cut off points in defining established CFS/ME.
To identify possible early win interventions for phase 2 and early phase 3 clinical trials - e.g. targeted use of cytokines; melatonin for those with sleep problems.
To undertake genome-wide association studies (GWAS) to identify the genetic components of CFS/ME and possible new targets for intervention. This would be dependent on the availability of well characterised cohorts. To develop more comprehensive outcome measures.
To encourage work across the different existing cohorts (including trial cohorts), e.g. for assessing predictive markers of disease and confirming hypotheses generated in other data sets.
3.3 Group 2 Research priorities and partnership models
A co-ordinated, structured, strategic and collaborative research approach would be needed in moving the field forward.
Exploring the use of other fatigue-related diseases (such as multiple sclerosis and cancer-related fatigue) as control models for CFS/ME, and utilising existing expertise from these areas in the CFS/ME field.
Establishing a multi-disciplinary group involving not only scientists (e.g. immunologists, fatigue experts, neuroscientists, psychologists and psychiatrists, neurologists and geneticists) but also the clinical networks and health professionals.
Pharmaceutical industry involvement would be beneficial, perhaps at a later stage. Research priorities Databases of patients with CFS/ME characterised according to agreed criteria. Phenotype identification could only progress if linked to good infrastructure with all groups using the same criteria. This could provide benefit not only in replication of studies but also of increasing n numbers. It was also essential to collect biological samples from early-stage disease which would have no or minimal confounding factors which occurred with long-term disease. Good clinical diagnosis and standardised measurements and assessments were essential to enable comparisons across data sets. Therefore a collaborative approach with researchers working closely with clinicians and other health professionals would be important.
Patient reported outcomes and quality of life measures.
The establishment of tissue banks with samples from well characterised patients and controls.
Improved definition of fatigue and improved understanding of fatigue mechanisms.
Virology and infection triggers there was potential for virology to be studied in CFS/ME as part of the complex disease pathogenesis. In addition to continued research in this area it would be important for the XMRV study to be replicated before pursuing this avenue of investigation through to clinical trials.
3.4 Group 3 Research priorities and new technologies and technological platforms.
New technologies/technological platforms
Imaging technologies such as fMRI, EEG and MRS and pathological studies using tissue could be utilised for neuroanatomical studies and neurophysiological studies of fatigue.
Better animal models were needed both of the whole disease and aspects of the disease physiology.
Genetic studies (GWAS) needed to be nationally and internationally standardised using well phenotyped samples.
Improved data collection tools were needed. Research priorities
Identification of phenotype and phenotypic subgroups. This would require access by researchers to raw data (not prior filtered) for replication studies and different measurable entities for different studies. It would also be important to extend the minimum clinical data currently collected.
Psycho-physical studies it was important to continue to undertake small and focussed pathophysiological studies investigating perception, behavioural and physiological response in patients.
Establishment of longitudinal population-based studies including natural history cohorts which were well focussed and avoided selection bias. Data generated by these studies could be underpinned by co-ordinated tissue collections and repositories.
Studies on neuro-immunological interactions.
3.5 During the plenary discussion the following points were highlighted:
It was agreed to be important not to stigmatise the condition, both in terms of treating and caring for those with CFS/ME, and for attracting researchers to the field. CFS/ME was a complex disease that comprised the interaction of different biological, physical and psychological mechanisms. The interactions between these different mechanistic pathways were important and further mechanistic studies needed to be undertaken. Pathways may differ between individual patients and therefore the characterisation of phenotype(s) was paramount. Phenotype characterisation would facilitate the identification of biomarkers. However, given the complexity of the disease and the many current unknowns, this objective was likely to be achieved
only in the longer term. The objective for the shorter term should be to increase the current knowledge base of the pathogenesis.
Clarification of the definition of CFS/ME was important. Without this it would be difficult to encourage new researchers from other fields to undertake research in this area.
Successful collaborative approaches required each stakeholder to take ownership of a particular area.
3.6 Professor Holgate briefly summarised the workshop outcomes which would be discussed by the CFS/ME Expert Group during the spring of 2010. The Group would prioritise the opportunities that were tractable for both the short and longer term and feed back the outcome to the community.
Professor Holgate thanked all the participants for their valuable contributions and closed the meeting.
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