http://www.mrc.ac.uk/index/public-interest/public-topical_issues/public-cfs_me/public-cfs_draft_research_strategy.htm 

 

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