MEDICAL RESEARCH COUNCIL
MRC CFS/ME RESEARCH ADVISORY GROUP
CFS/ME RESEARCH STRATEGY
DRAFT DOCUMENT FOR PUBLIC CONSULTATION
17 December 2002
Table of Contents
SUMMARY 3
INTRODUCTION 5
BACKGROUND 6
Method of Working 7
Terminology 7
TAKING FORWARD RESEARCH INTO CFS/ME 8
Research and Refinement of Case Definition 11
Developing the Epidemiological Framework 12
Descriptive Epidemiology
Aetiology
Outcome Studies
Developing Hypotheses about Pathophysiology 14
Infections
Neurology
Muscle Fatigue and Weakness
Immunology
Neuroendocrinology
Central Nervous System Function
Cognitive Performance
Psychological factors
INTERVENTIONS 22
Clinical trials of interventions for CFS/ME
Musculoskeletally-Based Interventions
Psychologically-Based Interventions
Other Interventions
HEALTH SERVICES RESEARCH 27
Health Care Needs Assessment
Descriptive Health Services Research
Health Technology Assessment
Service Delivery and Organisation
RESEARCH CAPACITY AND THE INTERFACE WITH SERVICES 29
Strengthening Research Capacity
Nurturing the Research – Service Interface
THE VALUE OF LAY PARTICIPATION 29
Research agenda
Within specific research studies
CONCLUSIONS AND RECOMMENDATIONS 33
SPECIFIC REFERENCES and OTHER SOURCES OF INFORMATION 33
Annex 1 Membership of MRC CFS/ME Research Advisory Group 35
Annex 2 PHRU Report on Consultation Exercise 37
1. SUMMARY
2. This research strategy for CFS/ME has been developed by a Medical
Research Council CFS/ME Research Advisory Group. The Research
Advisory Group was convened in response to the request of the Department
of Health in England for the MRC to develop a broad strategy for advancing
biomedical and health services research on CFS/ME, following the publication
of the Report of the CMO’s Independent Working Group in January 2002.
3. The MRC CFS/ME Research Advisory Group fully endorses the conclusions
of the Report of the CMO’s Independent Working Group, namely that
CFS/ME is a real, serious and debilitating condition, and that research into all
aspects of CFS/ME is needed.
4. The MRC CFS/ME Research Advisory Group has used the term “CFS/ME”.
The Research Advisory Group acknowledges that the descriptive term
“CFS/ME” does not refer to a specific diagnosis. In the same manner, the
singular term “condition” is used, but this does not indicate that the MRC
CFS/ME Research Advisory Group holds any particular position on whether
CFS/ME is one condition with heterogeneity of cause, pathogenesis and
severity, or is a number of similar conditions with different individual
characteristics.
5. The MRC CFS/ME Research Advisory Group met formally (insert number)
times between September 2002 and (insert date), and held numerous other
discussions. A consultation exercise was undertaken over July and August
2002 using a set of structured questions, which was independently analysed.
The lay members of the MRC CFS/ME Research Advisory Group met with
ME charities, and CFS/ ME patients and their carers, to better understand
their perspectives. Further details on the process to be drafted in due course.
6. The MRC CFS/ME Research Advisory Group has not provided a detailed
plan for the science, nor set out an agenda of the many research projects that
might merit support. A strategy is proposed which reflects the current state of
knowledge in CFS/ME, and which aims to provide a rational framework for
advancing the understanding of the illness and to reduce suffering.
7. In considering ways to advance research on CFS/ME, the Group has focused
on a number of strategic themes: case definition, an epidemiological
framework, pathophysiology, interventions, health service research, research
capacity and the value of lay participation.
8. The MRC CFS/ME Research Advisory Group recommends that research
studies should aim to be as inclusive as possible in terms of the recruitment
of participants, and due consideration should be given to sample size to allow
for possible subgroup effects. There should be clearly stated inclusion and
exclusion criteria, with detailed justification if certain types of patients are not
included.
9. The MRC CFS/ME Research Advisory Group considers there should be an
agreed standardised case definition and a classification of severity and any
other relevant characteristics that define subgroups. Improved definition of the
phenotypes of potential subgroups that may come under the CFS/ME
spectrum, and overlaps with other conditions, will underpin research on
causes, mechanisms, and management. A definition of a clinically important
improvement in disease status, with a classification of the degree of
improvement, is essential for natural history and intervention studies.
10. In the short term, the MRC CFS/ME Research Advisory Group considers that
the research community should be encouraged to develop high quality
research proposals for funding that address key issues for CFS/ME research
that are amenable for study at the present time: case-definition,
understanding symptomology, and new approaches to management.
11. In view of the probable multiplicity of causal factors and the widely disparate
findings so far reported, the MRC CFS/ME Research Advisory Group
considers that studies investigating potential causal pathways and
mechanisms, whilst having merit, would not have the same immediate impact
on increasing understanding of CFS/ME, nor reducing the suffering of
patients.
12. The MRC CFS/ME Research Advisory Group considers it is appropriate to
explore potential interventions for CFS/ME in the absence of knowledge of
causation or pathogenesis. Randomised controlled trials of adequate size,
using standardised case definitions, eligibility criteria, and baseline and
outcome assessments, could be used to evaluate one or more of the
interventions which have been shown in one or more trials to have a benefit.
Standardisation will allow results to be more widely generalised and
compared between studies.
13. Given the present difficulties in identifying priorities for health services
research in CFS/ME, it is not clear whether it is appropriate to make HSR a
priority at this time.
14. It is essential that the researcher–funder-lay partnership is nurtured, to ensure
that the best evidence is easily available to all, and to facilitate the growth of
consumer involvement in the design, conduct and dissemination of research -
as a means to enhancing its quality, relevance, and credibility. The MRC
CFS/ME Research Advisory Group considers that there is a key role for
patient organisations to help attract participants to research, especially the
severely ill, and to help in the dissemination of research results.
15. INTRODUCTION
16. The Medical Research Council (MRC) CFS/ME Research Advisory Group
fully endorses the conclusions of the Report of the Chief Medical Officer’s
(CMO) Independent Working Group (2002) that CFS/ME is a real, serious and
debilitating condition.
17. The MRC CFS/ME Research Advisory Group agrees with the CMO’s
Independent Working Group that research into all aspects of CFS/ME is
needed, and welcomes the opportunity to help advance research into this
illness.
18. In considering ways to advance research on CFS/ME, the Group has focused
on a number of strategic themes, which are reflected in the headings used in
the remainder of this document. They correspond with the topics outlined in
the research recommendations of the report of the CMO’s Independent
Working Group.
! Research and refinement of case definition
! Development of an epidemiological framework
! Developing and testing hypotheses about pathophysiology
! Design and evaluation of interventions
! Health service research
! Research capacity and the interface with services
! The value of lay participation
19. The MRC CFS/ME Research Advisory Group has not presumed to provide a
detailed plan for the science, nor set out a prescriptive portfolio of the many
research projects that might merit support. A strategy is proposed which
reflects the current state of knowledge in CFS/ME, and which aims to provide
a rational framework for advancing the understanding of the illness and its
management.
20. The Group considers that this strategy should be available to all interested
parties, to help take forward research in CFS/ME.
21. BACKGROUND
22. In 1998, the Chief Medical Officer (CMO) in England requested that an
Independent Working Group be set up, whose terms of reference were:
! “to review management and practice in the field of CFS/ME with the
aim of providing best practice guidance for professionals, patients, and
carers to improve the quality of care and treatment for people with
CFS/ME, in particular to:
! develop good clinical practice guidance on the healthcare
management of CFS/ME for NHS professionals, using best available
evidence;
! make recommendations for further research into the care and
treatment of people with CFS/ME;
! identify areas which might require further work and make
recommendations to CMO."
23. The Report of the CMO’s Independent Working Group on CFS/ME was
published in January 2002, recommending research on all aspects of CFS /
ME. The Department of Health asked the MRC to develop a broad strategy
for advancing biomedical and health services research on CFS/ME.
24. The MRC agreed to convene a CFS/ME Research Advisory Group
(membership at Annex1), made up of individuals who were not active in the
CFS/ME field, but had the relevant scientific expertise, to discuss the CMO’s
Independent Working Group report and make research recommendations to
the MRC of possible ways forward.
25. The Terms of Reference for the MRC CFS/ME Research Advisory Group
were:
! To consider the Report of the CMO’s Independent Working Group on
CFS/ME, including its recommendations for research,
! To consider other recent reviews of current knowledge and understanding
of CFS/ME,
! To take account of patient and lay perspectives,
! To recommend to MRC a research strategy to advance understanding of
the aetiology, epidemiology and biology of CFS/ME and,
! In the light of current knowledge suggest what areas of further research
are needed with regard to possible prevention, management (including
diagnosis) and treatment.
26. The MRC CFS/ME Research Advisory Group agreed not to revisit the areas
considered by the CMO’s Independent Working Group, but to recommend
how research that would improve understanding and treatment of CFS/ME
might be undertaken. It was agreed that it was beyond the remit of the
Research Advisory Group to decide how the recommendations for a research
strategy should be implemented, as this would be the responsibility of funders
and sponsors.
27. Whilst acknowledging the seriousness of the illness, not only to the affected
individual but also to their carers, families and society, the MRC CFS/ME
Research Advisory Group did not consider the issue of service provision as
this area was not within its role.
28. Method of Working – to be finalised
29. The MRC CFS/ME Research Advisory Group met formally (insert number)
times between September 2002 and (insert date), and held numerous other
discussions. A public consultation exercise was undertaken over July and
August 2002 using a set of structured questions. The NHS Public Health
Resource Unit, Oxford (PHRU) undertook an independent qualitative analysis
of the 187 responses received, and prepared a report for consideration by the
Group (Annex 2).
30. The lay members of the MRC CFS/ME Research Advisory Group met with
ME charities, and CFS/ ME patients and their carers, to better understand
their perspectives. Their understanding of the illness was enhanced by
numerous letters from individuals who gave a personal perspective.
31. All members of the Research Advisory Group contributed preliminary drafts in
areas relevant to their expertise, which were brought together into a single
document, which was discussed by the Research Advisory Group at its
second meeting and revised subsequently.
32. A preliminary draft research strategy was made available for external, open
consultation to key stakeholders, national and international researchers, and
also considered by the MRC Research Boards between December 2002 and
February 2003. t
33. – to be completed and finalised in due course
34. Terminology
35. Chronic fatigue syndrome (CFS) and myalgic encephalomyelitis or
encephalopathy (ME) are two terms that have been used most often as the
illness description given to patients with a combination of non-specific
symptoms, but always with unexplained disabling fatigue. The CMO’s
Independent Working Group report discussed at length the issues
surrounding nomenclature, and the MRC CFS/ME Research Advisory Group
did not revisit this topic.
36. In order to develop a research strategy in this area without delay, the MRC
CFS/ME Research Advisory Group agreed with CMO’s Independent Working
Group and used the term “CFS/ME”. The Research Advisory Group
acknowledges that the descriptive term “CFS/ME” does not refer to a specific
diagnosis, and that a number of diagnostic criteria are being used to define
patients. There are separate entries in the World Health Organisation’s
International Classification of Diseases (ICD-10) for “chronic fatigue
syndrome” and “myalgic encephalomyelitis”, but it is not clear whether such a
distinction has empirical validity. In the same manner, this report may use the
singular term “condition”, but this should not indicate that the MRC CFS/ME
Research Advisory Group holds any particular position on whether CFS/ME is
one condition with heterogeneity of cause, pathogenesis and severity, or is a
number of similar conditions with different individual characteristics.
37. To avoid potential confusion, in this report “CFS” will be used when
discussing research findings where the specific diagnostic criteria for chronic
fatigue syndrome were used in those studies, and “CFS/ME” will be used as
the descriptive term for the illness.
38. It is acknowledged that, as our understanding of the area increases, such an
umbrella term as CFS/ME may no longer be appropriate. However, at the
present time it is considered that an inclusive approach is beneficial in the
development of a research strategy.
39. TAKING FORWARD RESEARCH INTO CFS/ME
40. There are a number of challenges to advancing the understanding of
CFS/ME, which arise from the heterogeneous nature of the condition, the
individual symptoms that may be associated with it and their variation in
severity, co-morbidity with other conditions, and the variability of response to
potential interventions.
41. The MRC CFS/ME Research Advisory Group recognises the urgent need for
research into CFS/ME, and that there are certain groups of patients who have
not been adequately included in research. The report of the CMO’s
Independent Working Group highlighted the severely ill, children, ethnic
minorities and the recovered patient. In the consultation exercise undertaken
at the start of the process of developing a research strategy for CFS/ME, the
inclusion of these patient groups was emphasised as being essential. The
MRC CFS/ME Research Advisory Group reaffirms the need for these groups
to be fully involved in the research effort to understand CFS/ME.
42. CFS/ME patients may vary in the intensity and nature of their symptoms, both
between patients and over time for individuals, and it will be important to
ensure that adequate consideration is given to how these potential
confounding factors are addressed. An important question is the extent to
which CFS/ME overlaps with other disorders.
43. In addition to these symptomatic issues, CFS/ME affects the whole age
range, which brings additional complexities to undertaking research. The
understanding of the aetiology and outcome for children with CFS/ME is, at
present, an area that is under-researched. It is likely that interventions
developed for an adult may need significant modification before they could be
evaluated in children. There are particular ethical dimensions to children
participating in research which must be considered in great depth by
researchers, and the rights of the child must remain paramount. Whilst
acknowledging the importance of research with children, the MRC CFS/ME
Research Advisory Group endorses the principle that for ethical reasons
research involving children should only be undertaken when it is not
appropriate to undertake such studies in adults.
44. The report of the CMO’s Independent Working Group highlighted the
importance of understanding the particular problems experienced by the most
severely ill patients. This patient group was also identified by many
respondents of the MRC consultation exercise as being a priority area for
research. There are many potentially informative comparisons to be made
between severely affected patients, who tend to have a poor prognosis, and
those individuals who recover, to a greater or lesser extent, both in terms of
understanding aetiology and of the reported differential outcomes to a number
of potential management or treatment strategies. Such comparisons may help
to identify subgroups, either in terms of aetiological mechanisms or predictors
of response to interventions. The pathways to chronicity and severity are not
at present understood, and this is a key area for research. There should be a
concerted effort to engage severely affected patients in research. At present
there is a danger that these individuals, who sometimes experience difficulties
in accessing care, might not be included in studies either based in, or
recruited from, that care setting.
45. The MRC CFS/ME Research Advisory Group recommends that research
studies should aim to be as inclusive as possible in terms of the recruitment of
participants, and due consideration should be given to sample size to allow
for possible subgroup effects. There should be clearly stated inclusion and
exclusion criteria, with detailed justification if certain types of patient are not
included.
46. The range and severity of symptoms for people with CFS/ME mean that
researchers must bear such variability in mind when designing studies. It is
important that the possibility of selection bias is considered at the earliest
stages of any study, as symptomatic patients referred to speciality clinics may
not reflect accurately the majority of patients in the general medical setting.
47. An integrated approach to determining causal pathways is needed. It could
combine structural, functional, behavioural and possibly genetic approaches.
As is the case for many chronic diseases, there is limited utility in considering
particular symptoms in isolation. It is likely that a more holistic approach may
be more fruitful in understanding CFS/ME, and potential therapeutic
interventions. There is undoubted benefit to employing a multidisciplinary
approach to research on CFS/ME, where experience and expertise from
appropriate disciplines can be brought together.
48. The current understanding of CFS/ME would imply that there are a number of
potential triggering factors for the illness. The report of the CMO’s
Independent Working Group cited infections, immunisations, life events,
physical injuries and environmental toxins as potential triggers, although the
strength of evidence is extremely variable, as discussed by the recent report
of a Working Group convened under the auspices of the Royal Australasian
College of Physicians (2002). Predisposing factors included gender, familial,
personality, other disorders and previous mood disorder. Given that the
causes of CFS/ME are probably diverse and multi-factorial, identification of
specific causal pathways may be of limited value in understanding and
treating the illness. It is entirely possible that an original precipitating factor
may no longer be detectable in a person with CFS/ME, or was present at a
subclinical level, and thus reported abnormalities may not reflect a true causal
association.
49. Many reported findings in the area of pathophysiology are not published in the
peer-reviewed literature, or are not well described. Such preliminary findings
need to be confirmed by independent replication in other centres. Currently,
the low volume of research and the lack of methodological rigour and
independent replication mean that many of these claims find little support
from the wider scientific community, but may have strong currency among
some patients and practitioners.
50. Findings need be subjected to rigorous and objective scientific analysis and
published in high quality, peer reviewed journals, not least so that the
methods can be replicated and the findings and hypotheses tested
independently by other approaches. Where independent replication and
different approaches fail to demonstrate a significant association, the case for
further work is likely to be weak. Well substantiated, refined hypotheses can
then be tested through a variety of other designs.
51. The MRC CFS/ME Research Advisory Group is aware of the difficulty in
publishing negative results, especially in peer-reviewed journals. The Group
considered it important, especially in an area as complex as CFS/ME, that the
results of such research should be disseminated to avoid unnecessary
repetition of studies and the inefficient use of resources. There may be a need
for funders and sponsors of research to investigate additional alternative
mechanisms of dissemination, preferably involving an independent peerreview
mechanism to provide scientific credibility to the results. The MRC has a
reputation for rigorous peer-review, and may need to take the lead in such an
endeavour, in partnership with other funders and sponsors if necessary.
52. The MRC CFS/ME Research Advisory Group has been mindful throughout
the development of the research strategy for CFS/ME of the importance of
following existing guidance and approval systems in research. The MRC,
amongst others, has published a number of relevant guidance documents, to
which researchers should refer (e.g. MRC Ethics Series Human Tissue and
Biological Samples for Use in Research, Good Clinical Practice in Clinical
Trials). It is the responsibility of all researchers to ensure that any research
they wish to undertake has obtained the relevant ethical approvals.
53. The MRC CFS/ME Research Advisory Group acknowledges the importance
of understanding the international research effort for CFS/ME, in order to
optimise the likely success of any research strategy. There are substantial
programmes of research currently underway in other countries, such as the
United States of America, Australia, and a number of European countries.
The Research Advisory Group was grateful for the information provided by
the US Center for Disease Control about its current research programmes. It
will be important that researchers and funders take an international
perspective when considering the funding of specific research proposals.
54. Research and Refinement of Case Definition
55. Improved definition of the phenotypes of potential subgroups that may come
under the CFS/ME spectrum, and overlaps with other conditions, will underpin
research on causes and mechanisms. Accuracy and consistency of case
definition and diagnosis is a crucial issue both for services and for research.
Improvements will help researchers compare different studies with each other
and across time. Further research is needed to develop and evaluate the
tools for case definition. The lack of validated biological markers for CFS/ME
has further hampered diagnosis.
56. Case definition is fundamental for the assessment, frequency, causes,
outcomes and management of any disease or illness. The development and
validation of instruments for use in research and in services is currently a key
area for research. Consistency between studies and over time can
significantly affect the interpretation of research findings.
57. There is clearly an overlap between the need for case definitions that have
utility in the clinical and service context with those specifically designed for
research. For this reason a continuing cross-reference between research
targeting fundamental questions and that aimed at developing and evaluating
tools for services is essential.
58. There is some international consensus on the broad criteria used to identify
people with CFS, as demonstrated by the current consensus-based
definitions from the US Centers for Disease Control (CDC), currently known
as the Fukuda criteria (Fukuda et al. 1994). However, questions remain
about the interpretation of conditions that fall within these broad criteria. Some
consider that this inclusive approach compromises research on specific
groups of individuals whose symptoms are considered to be predominantly
neurological, as indicated in the Consultation exercise.
59. The MRC CFS/ME Research Advisory Group is aware of the ongoing
effort of the CDC, through an International CFS Study Group, to refine the
current research case definition of CFS. There have been three meetings
of international experts from a wide range of disciplines and perspectives,
coordinated by the CDC, in an effort to identify ambiguities in the current
CFS case definition and to recommend improvements. We understand that
this International CFS Study Group is currently preparing a report for peer-
reviewed publication in an academic journal, and we would anticipate that
this consensus-derived research case definition will help in the development
of well-designed studies. Any new or revised case definition must be subjected
to rigorous and objective scientific analysis and testing to demonstrate its
usefulness.
60. The MRC CFS/ME Research Advisory Group has noted that there is support
among some sections of the community for the use of the description of M.E.
from Ramsay (Ramsay, 1998) to identify and study a discrete population of
patients. Whilst acknowledging the potential importance of the identification
of subgroups, the Group does not consider that the current descriptive nature
of these criteria has sufficient methodological rigour to be used in an
epidemiologically robust manner for research. The MRC CFS/ME Research
Advisory Group believes that researchers who wish to pursue this approach
will need to operationalise the Ramsay criteria and then demonstrate their
validity through peer-reviewed publication.
61. The MRC CFS/ME Research Advisory Group considers that case definition is
a key area for research, but believes that it is possible that some studies can
be undertaken without delay in reaching consensus. The use of broad, but
clearly and explicitly defined, inclusion and exclusion criteria should allow
subsequent re-appraisal of experimental results in the light of developments
in case definition. It would not be possible to identify potential subgroups
unless inclusion criteria are broad enough to encompass the necessary
heterogeneity.
62. Developing the Epidemiological Framework
63. Epidemiology has a central role in addressing questions about prevalence,
incidence and their relation to time, place and person within populations. It is
key in formal testing of causal hypotheses, specifically in working out the
contributions of environment and genetic influences. Such a framework is
also necessary for research on case definition, co-morbidity, natural history
and outcome.
64. Population-based studies that identify affected individuals using active
ascertainment and agreed diagnostic criteria have several advantages,
including the provision of adequate numbers of affected individuals, identified
using a common methodology, to test important hypotheses about causes
and to provide unbiased estimates of outcome. The fact that CFS/ME affects
the whole age-range, including children, means that such population-based
studies will need to have considered the adequacy of case ascertainment
across the whole age spectrum.
65. Considerable advances are being made internationally towards identifying
candidate genes for a wide variety of disorders. New, large epidemiological
studies that include genetic data could allow such advances in CFS/ME to be
taken forward fairly rapidly, in the context of a general population sample, to
address questions about genes and environment. While there is excitement
about these advances, examples from other areas of biomedicine make it
clear that to identify genetic susceptibility loci and determine how they interact
is a complex task requiring a substantial, multidisciplinary research effort. As
with all other genetic studies, precise case definition and phenotypic
categorisation of each case is vital, and it may be premature at this stage to
undertake large scale genetic studies of CFS/ME until there are clearly
agreed and validated diagnostic tools.
66. Large epidemiological studies can contribute well-characterised cohorts for
prospective investigation of longer term outcomes. Such a cohort, of affected
people ascertained over a relatively short period of time, is likely to be
qualitatively different from health service registers developed for needs
assessment and health service planning. However, some overlap may exist
where researchers work particularly closely with health services.
67. There is a lack of basic epidemiological evidence to help develop effective
prevention strategies and management options for CFS/ME. This may stem
from difficulties about definition and diagnosis of CFS/ME, as well as from the
historical failure to recognise CFS/ME as an illness. Once these constraints
are removed a programme of epidemiological research will become an
important priority. Three types of study are needed: descriptive epidemiology,
studies of aetiology, and epidemiological studies of characteristics associated
with outcome.
68. Descriptive Epidemiology
69. Basic descriptive epidemiology of population patterns is required to describe
both the incidence and prevalence of CFS/ME, and its duration, nature, and
severity, in terms of patient characteristics. Studies should pay particular
attention to the duration and nature of the symptoms experienced, especially
in terms of whether CFS/ME is a single syndrome or whether there are
several distinct sub-groups; the severity of symptoms, especially in terms of
the extent and types of disability (physical and cognitive) and pain
experienced and the age, sex and ethnicity of patients.
70. The UK is uniquely placed to undertake studies of prevalence and incidence
through primary care. Primary care research networks, such as the MRC
General Practice Framework, could provide a study population. If studies
were undertaken in practices which are linked into computerised practice
management systems, incidence could be studied as well as prevalence.
Fundamental to such a study would be an agreed research case definition.
71. A linked natural history study might be undertaken based on primary care and
using those practices in computer-based networks, relying largely on routine
health records. A standardised follow-up of cases identified either from
prevalence or incidence studies would be a much larger undertaking but not
impossible within primary care networks. An important caveat to be borne in
mind is the quality and reliability of computerised health records.
72. Aetiology
73. Aetiological studies could be used to identify characteristics of people, their
physical, work, and social environments, and health histories associated with
the development of CFS/ME by duration, nature and severity of CFS/ME.
These studies would need to follow on from basic research into possible
mechanisms of the development of chronic fatigue so that hypotheses about
aetiological factors can be clearly formulated (e.g. to environmental factors),
and will need to pay particular attention to physical and psychological
challenges. Such studies could be conducted as prospective cohort studies
comparing populations exposed and unexposed to putative aetiological
agents. However, it is possible that incidence would be too low to make such
studies feasible and it may be necessary to consider case-control studies that
retrospectively examine exposure.
74. It would be particularly helpful if such studies were designed so that they
could answer important outstanding issues around whether neurological and
psychological symptoms found in CFS/ME patients are causally related, are
consequences of the illness, or a combination of the two.
75. Outcome Studies
76. The current evidence indicates that CFS/ME patients exhibit wide variation in
the time to recovery, with some seriously affected patients never fully
recovering. There is, however, little evidence about which patients recover, or
what factors pre-dispose to recovery. Once outcomes have been clearly
defined, longitudinal studies of cohorts of CFS/ME patients are needed to try
to identify these factors. Very few studies have looked at patterns of
recovery, which the MRC CFS/ME Research Advisory Group considers to be
a potentially fruitful area of research.
77. Possibilities for research into potential treatments and management strategies
are considered in more detail below.
78. Developing Hypotheses about Pathophysiology
79. A wide range and variety of factors have been suggested to play a role in the
pathophysiology of CFS/ME, but the evidence is generally either weak or
contradictory. Greater methodological rigour and independent replication are
crucial in much of this work.
80. Many of the observations are interesting and in principle worth investigating.
Moreover, potentially modifiable risk factors are possible targets for
interventions. A useful start might be made to test such hypotheses in robust
but relatively simple research designs, so that the less likely ideas can be put
to one side and further effort and investment can focus on the areas that
preliminary evidence identifies as more likely to be productive.
81. In all studies, choices of sampling strategy, case-definition, measures and
controls are crucial and a multidisciplinary collaborative approach is likely to
be beneficial. Some studies will be amenable to case-control or other
epidemiologically- and genetically-sensitive designs, and others to
investigation in experimental models.
82. The MRC CFS/ME Research Advisory Group has not undertaken a detailed
review of the current level of scientific knowledge on the aetiology or
pathogenesis of CFS/ME, as this was not its function. The Group notes that
the recent report of a Working Group convened under the auspices of the
Royal Australasian College of Physicians (2002) has assessed the strength of
evidence for a number of factors in the pathophysiology of CFS, including
infections, immunological factors, central nervous system disturbances and a
number of other factors postulated to be involved. In most cases, the
evidence base was not large, with information coming from only a few studies,
and often conflicting. As a consequence of the lack of consistent evidence,
the MRC CFS/ME Research Advisory Group has considered a number of
broad thematic areas with regard to research on CFS/ME.
83. It should be emphasised that the research areas discussed below are not the
only ones where there is potential for advancing our understanding of the
pathogenesis of CFS/ME, but reflect the areas that currently show the most
promise. As scientific knowledge increases, other avenues of research may
become increasingly attractive.
84. Infections
85. Fatigue, cognitive disability and musculo-skeletal pain are commonly found
during the acute phase of many infectious diseases, and generally disappear
spontaneously with the emergence of a normal immune response. However,
following certain infections, a proportion of patients develop prolonged fatigue.
For example, up to 10% of patients with diagnosed infectious mononucleosis
(infection with the Epstein-Barr virus, EBV) or Q fever (Coxiella burnetti
infection) can develop chronic post-infectious fatigue. However the causes of
these chronic responses to infections in a minority of patients are not known.
86. It is clear that no single infectious cause of CFS/ME has been identified.
Although EBV can lead to CFS/ME, in the great majority of cases no
infectious cause can be found by routine microbiological investigation. There
is reasonably strong evidence that retroviruses and enteroviruses are not
causally related to CFS/ME.
87. Infection with the hepatitis C virus (HCV) may lead to fatigue, and treatment of
HCV-infected patients with interferon-alpha leads to symptoms
indistinguishable from CFS/ME, including fatigue, cognitive dysfunction and
pain. Pathophysiological investigation of well-defined conditions such as this
may represent a reproducible model for CFS/ME.
88. Many studies that report a causal association between an infection and
subsequent CFS/ME have reported the detection of antibodies against the
viral or non-viral agent in patients with CFS/ME, and draw the conclusion that
such raised levels of antibodies reflect chronic active infection. However
healthy individuals may also demonstrate raised antibody levels, many years
after the original infection. The Working Group of the Royal College of
Australasian Physicians noted that raised titres of antibodies against common
viruses are often found, but are not of pathophysiological or diagnostic
significance.
89. Recent advances in virology and bacteriology enable the detection and
quantification of organisms directly through amplification of their genomes, by
the polymerase chain reaction (PCR). PCR technology will provide a more
robust methodology than antibody detection for the association of known
organisms with CFS/ME within cohort studies.
90. The discovery and gene sequencing of new viruses and application of PCR
will allow the investigation of patients with CFS/ME for novel viruses, for
example through the use of degenerative primers or differential display PCR.
91. The application of the novel technologies to bacteriology has allowed the
identification of non-culturable organisms, for example through the 16S rRNA
PCR assay. Assays such as these would allow the exploration of a CFS/ME
patient cohort for novel bacterial infection.
92. Advances in genomics brought about through the human genome programme
will also allow the investigation of DNA from