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| National Institutes of Health              Chronic Fatigue Syndrome              State-of-the-Science Consultation**February 6-7, 2000            Bethesda, Maryland**
IntroductionSummary of Recommendations by the ConsultantsAreas Addressed by the Consultants
- Research Opportunities   Research StrategiesAdministrative Strategies
An 11-member consultation panel, chaired by Dr. Gail Cassell, met             on 6-7 February 2000 to review the state-of-the-science in Chronic             Fatigue Syndrome (CFS) and to suggest to NIH staff and scientists             optimal approaches to CFS research. 
This review is part of an NIH process intended to improve the quality,             direction and extent of CFS research supported by NIH, and is conducted             in a manner consistent with other NIH consultations regarding other             research efforts. Prior to the meeting, the consultants received a             number of published reviews and papers in various areas of CFS research.             They also received a list of currently funded NIH research projects.             As part of the deliberative process, the consultants presented their             thoughts on the state-of-the-science in CFS and on CFS research opportunities             and directions. Additionally, the consultants had a presentation from             a CFS patient, Ms. Kathy Rabin. Comments and questions from members             of the DHHS CFS Coordinating Committee were also sought. A list of             the participants and an agenda             are attached (Appendix A). 
INTRODUCTION
"The chronic fatigue syndrome is a clinically defined condition characterized             by severe disabling fatigue and a combination of symptoms that prominently             features self-reported impairments in concentration and short-term             memory, sleep disturbances, and musculoskeletal pain. Diagnosis of             the chronic fatigue syndrome can be made only after alternative medical             and psychiatric causes of chronic fatiguing illness have been excluded.             No pathognomic signs or diagnostic tests for this condition have been             validated in scientific studies; moreover, no definitive treatments             exist. Recent longitudinal studies suggest that some persons affected             by the chronic fatigue syndrome improve with time but that most remain             functionally impaired for several years."1
In many ways, this statement from the 1994 CFS case definition still             summarizes the conundrum facing the CFS research and patient communities.             CFS-like illnesses have been described in the medical literature for             at least 150 years; thus, this type of illness is not new. It is also             not alone in medicine as a symptom-based illness of unknown etiology.             Fibromyalgia, irritable bowel syndrome, and Gulf War Syndrome (GWS)             are only a few of the illnesses whose etiologies and pathogeneses             have puzzled the medical and scientific communities. A key addition             to the quote from the 1994 CFS definition is that the duration of             symptoms is not limited to 'several years', but for most patients             remains a lifelong issue. 
Since the initial (1988) and revised (1994) case definitions of CFS             were widely adopted in the U.S. and a number of other countries, researchers             have pursued several possible etiologies and markers for CFS. No pathogen             nor consistent primary immunologic abnormality has emerged. A variety             of treatments have been tried, with many studies involving small case             series or anecdotal reports. Cognitive behavioral therapy, cognitive             behavioral stress management, graded exercise, and anti-depressant             medications have benefited some patients, but their overall efficacies             remain to be established. Of the true clinical trials that have been             undertaken, benefits have typically been limited to subsets of patients.
Initial studies of CFS prevalence indicated rates of 7-10 per 100,000.             More recent community-based studies using the 1994 CFS case definition             have suggested rates of 200 or more per 100,000.
Although research progress has been slow, many ideas about etiology             and pathogenesis have been explored. The positive results, as well             as the negative and variable results, can provide ideas for new areas             of research opportunity and new research strategies. The consultants             noted that many of the current strategies for preventing and/or treating             diseases were developed empirically.
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SUMMARY OF RECOMMENDATIONS BY THE CONSULTANTS
After discussion of the current state-of-the-science, the consultants             identified the following broad areas for research opportunities that             would allow the better understanding of the pathogenesis of CFS, with             the long-term goal of developing treatment and prevention strategies.
Definitive trials of antidepressants, other currently-prescribed               medications, interferon, cognitive-behavioral therapy, graded exercise,               etc., to determine the effectiveness of treatments currently being               prescribed as well as to provide insights into pathogenesis.
Broader clinical, epidemiological, and behavioral comparisons               of CFS and similar symptom-based and psychiatric syndromes.
Prospective studies of natural history and of incident disease.
Major epidemiological investigations of incidence in various heterogeneous               populations.
Studies of individual dimensions of CFS.
Development of methodological approaches for measurements of disease               severity, quality of life, and outcomes.
Better studies of sleep abnormalities.
Larger controlled studies of the HPA axis.
Meaningful studies of brain imaging.
Studies of exercise to identify physiological correlates of symptoms               and performance.
Gene expression studies using microarrays.
Search for microbial agents using differential display technologies.
Use of animal models to explore CFS pathology including the role               of neurotropic viruses and of stress pathways.
Blinded studies of the 2'5'-oligoA pathway.
Health services research.
Enhancement of research infrastructure

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AREAS ADDRESSED BY THE CONSULTANTS
A central question that confounds CFS research and treatment is whether             CFS is a single entity with a single cause, a single entity of multiple             or complex causality, or an endpoint that can follow from a variety             of physical or mental stresses (e.g., viral infections, emotional             stress). 
RESEARCH OPPORTUNITIES
**Epidemiology**
Population-based studies allow one to characterize a disease or syndrome             in terms of its frequency, natural history, and spectrum of signs             and symptoms. However, large studies are limited by logistical issues,             cost, and accuracy of information obtained. Molecular epidemiological             components can provide additional information. Thus far, gene expression             assessments have not been done in an epidemiological study of CFS.             (The Centers for Disease Control and Prevention (CDC) are currently             undertaking a gene expression assessment in specimens from an Atlanta             CFS Case Control study.)
*Major epidemiological investigations of incidence in various             heterogeneous populations*. These types of studies would identify             populations at risk for CFS. Such large-scale studies could be made             more cost effective if they included a broad group of overlapping             syndromes, such as fibromyalgia, in which fatigue and other CFS symptoms             are a predominant feature. Although difficult to do, studies of predisposing             factors would be important to include. The issue of chronic life stresses             also needs to be explored as a risk factor. Cells and serum derived             from such large-scale studies could be studied by a multidisciplinary             range of scientists.
*Prospective studies of natural history*. Information about             persons who fully recover, partially recover, or whose conditions             worsen is needed to better understand CFS and to develop treatment             and prevention strategies. 
*Broader clinical, epidemiological, and behavioral comparisons             of CFS and similar syndromes*. Cross-comparisons of syndromes             with symptoms overlapping those of CFS could provide insights into             these illnesses individually and as a group. 
Fatigue and its role in co-morbid conditions is also important. For             example, persons with cancer and fatigue do worse than those without             fatigue.
**Pathogenesis**
*Search for microbial agents using differential display technologies*.             Although the evidence to date for a microbial cause of CFS is not             strong, and the epidemiology is inconsistent with an infectious cause,             newer differential display assays may allow the search for rarer microbes.             Such studies would need incident case patients and thus interlink             with the recommendation for investigations of CFS incidence. While             the 6-month illness period of the case definition appears to be a             time period that does clearly distinguish CFS from other types of             fatigue, it means that an organism that triggers disease and then             disappears will probably not be detected. Organisms whose persistence             or expression perpetuates illness should remain, and presumably their             nucleic acids could be detected. It is also noted that while it seems             unlikely that infectious agents cause CFS, they may well be among             a variety of stressors that precipitate it.
*Gene expression studies using microarrays*. Immune function             abnormalities are an area where studies of the nature and degree of             changes have yielded highly variable results. Microarray technology             would allow studies of an entire regulatory network of cytokines,             neurotransmitters, etc. Previous studies have of necessity been limited             to the study of a few molecules at a time.
Biomarker and diagnostic studies are often considered "shotgun" approaches             or "fishing expeditions". However, they are worthwhile if they can             be done rapidly on appropriately controlled samples and using a small             number of specimens. Nervous system markers may be important in this             respect. Biological plausibility is an important consideration for             selecting markers for these types of studies, as broad assays of multiple             markers are bound to turn up significant associations by chance alone.             This has already been problematic with immunologic studies of CFS.
*Meaningful studies of brain imaging*. If brain imaging studies             are to be pursued, they must be hypothesis-based. Patients need to             be carefully selected and patient factors such as medication use must             be carefully considered and controlled for. In general, medication             usage should be avoided, as it will confound the results. As an example,             comparisons could be made between persons with CFS who do and do not             have depression. Comparisons with healthy volunteers are not worthwhile.             It was noted that studies with CFS-affected and unaffected twins did             not identify any distinctions between the twin with CFS and the one             without CFS. Approaches used in studying mood disorders may be helpful             as models for CFS imaging studies. Ligands are available to study             particular brain functions.
*Studies of sleep abnormalities*. Previous studies in this             area have not been well controlled, and confounding factors such as             medication use may not have been considered. The consultants noted             that there is reciprocity of daily function and sleep. Thus, how one             functions during the day affects how one sleeps, and how ones sleeps             affects how one functions during the day. Function during sleep may             hold clues in terms of CNS dysfunction. The issue of excess arousal             during sleep may provide clues as to who may develop full-blown CFS.             Additionally, the autonomic nervous system can be studied and probed             for evidence of enhanced daytime or nighttime arousal, by such measures             as hormone profiles over a 24-hour period. Anecdotally, there appear             to be CFS patients whose circadian rhythms are disrupted and who appear             to be helped when the rhythm is normalized.
*Larger controlled studies of the HPA axis*. Many CFS symptoms             could be explained by changes in HPA axis function or regulation.             The HPA axis has been well-studied in mood disorders and so there             is a body of experience and published literature to draw on. Further             studies of the system can lead to testing of hypotheses about CFS             pathogenesis. 
A number of approaches can be used to probe the stress axis mechanisms             at all levels using hormone manipulation challenges, through waking             and sleep, and with environmental manipulations, e.g., constant routine             (to determine circadian and homeodynamic components). The role of             hypocortisol as a vulnerability factor for disorders can be investigated,             as can the effects of HPA activation patterns (e.g., hypocortisol)             on neurobiology and behavior.
*Studies of exercise to identify physiological correlates of symptoms             and performance*. Thus far, the only physiological differences             detected in CFS patients are subtle. Advantage may be taken of the             "CFS crisis" to try to study physiological factors. This is based             on the hypotheses that whatever is abnormal in CFS would be more abnormal             in a crisis situation, and that whatever precipitated CFS initially             may initiate a crisis. While the ethical issues related to formal             studies inducing CFS crisis are acknowledged, the etiology of the             CFS crisis remains an important and understudied part of CFS.
Additional studies, such as those of Peter White and his colleagues2,             which use graded exercise for the management of CFS, may provide additional             insights on CFS patient management.
*Studies of individual dimensions of CFS*. A dimensional approach             would consider symptoms, disability, beliefs, physiological abnormalities,             mood disturbance, etc., as dimensions of illness. The research would             then focus on the subgroups defined by this approach. These types             of studies might, for example, explore fatigue versus effort.
*Use of animal models to explore disease pathology including the             role of neurotropic viruses and stress pathways*. There are infectious             agents that can result in neurological damage which is not seen for             many years, and for which little or no residue of the agent may be             detectable. In exploring the potential role of neurotropic viruses             in disease precipitation, one needs to consider the natural history             of the virus, e.g., the cell tropism or brain regions targeted, and             then whether CFS symptomatology is concordant with these tropisms.           
There are several animal models of chronic stress that could be used             to characterize the stress activation pattern, link it to symptoms/illness,             and to determine the contributing factors to this pattern.
**Treatment**
*Development of methodological approaches for measurements of             disease severity, quality of life, and outcomes*. These methods             are needed for better design and assessment of patient studies, whether             epidemiological, pathological or treatment. 
*Definitive trials of antidepressants and other currently-prescribed             medications, interferon, cognitive behavioral therapy, graded exercise,             etc., to determine the effectiveness of treatments currently being             prescribed as well as to provide insights into pathogenesis*.             For many patients, treatment is currently empirically guided and based             on individual beliefs. It is important to undertake well-designed             trials in order to demonstrate efficacy; there is merit in such studies             even if the trials are negative, as such results would encourage patients             to avoid taking ineffective and at times costly medications. Trials             need a multidisciplinary approach and need input from neurobiology             and the mental health disciplines.
As for any chronic illness, multicomponent rehabilitation strategies             are useful for CFS. Strategies need to be demonstrated to work, need             to be refined, and made acceptable and deliverable. Rehabilitation             may also need to be specific for individual patients and targeted             to their particular symptoms. Strategies can target problems such             as fatigue, depression, pain, and/or abnormalities such as cortisol             levels. Strategies need to consider the heterogeneity of patients             and the multiple perpetuating factors including illness validation,             beliefs, behavior, and the role of interpersonal and iatrogenic factors.
Other important insights that can develop from these trials include:             characterizing individuals who respond to particular types of treatment;             understanding the placebo effect and characterizing those individuals             who are responsive to placebo; limited hypothesis testing; and the             development of new hypotheses.
*Blinded studies of the 2'5'-oligoA pathway*. This remains             an area of controversy and inconclusive studies. The availability             of newer forms of Interferon-( may provide an opportunity to explore             this area.
**Infrastructure Enhancement**
*Health services research*. The process of seeking health             care for a symptom-based disease may in and of itself contribute to             morbidity. Understanding this process and developing strategies to             identify problems at the community and primary care level may provide             for better patient outcomes and more effective delivery of complex             services to those in need of them. There is a need to identify currently             available useful therapies and develop innovative approaches to bring             these treatments to people, even if these treatments are not cures.           
The CFS case definition requires six months of illnesses; many cases             are not seen until long after, often years after, the onset. The value             of early management is not known, nor is it known whether treatment             before six months is of value. 
*Enhancement of the research infrastructure*. There is a need             to increase the critical mass of CFS investigators and especially             to involve investigators from different disciplines. Among the barriers             to CFS research are money, acrimony (from patient support groups toward             individual investigators), as well as methodological barriers (need             for pre-morbid samples, need for subgroup studies, case definition             issues). 
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Research Strategies
Future research strategies could employ two divergent tactics, broadening             and/or narrowing of populations and clinical factors to be studied,             depending on the goal of the research. Both of these approaches may             provide new insights into CFS. Such strategies include the broadening             of studies to include other conditions with overlapping symptomatology             and unexplained etiology such as fibromyalgia and irritable bowel             syndrome. The narrowing approach would involve studying particular             dimensions of illness, such as fatigue, in more detail, for example             by comparing fatigue versus effort, and by studying that dimension             over a spectrum of illnesses, including those of known etiology in             addition to CFS.
**Patient Populations:** A number of approaches and             issues related to patient populations were raised.
It is important to distinguish between the research case definition             that is intended to help design research studies and the identification             of individual patients at the community and clinical level. The case             definition was developed by physicians who see patients and by the             characteristics of those patients who are seen by physicians. They             are therefore likely to be highly selected and unrepresentative of             the true spectrum of illness.
Empirical case definitions using information from people in population             surveys may be derived from factor analysis, e.g., data from persons             studied in population surveys. Factor analysis may be a useful exploratory             tool for further refining the case definition. However, lacking any             biological marker, there is no assurance that any complex of symptoms             corresponds to a biological state.
Countries such as the United Kingdom having socialized medicine may             provide a good milieu for cohort studies. National birth cohort studies             as well as DOD-GWS studies may allow for the study of a whole population.             The DOD studies of GWS may also allow for the identification of persons             at high risk. It was noted that long-term follow up of persons with             GWS reveal that some go on to meet diagnostic criteria for CFS. It             is a cardinal premise of epidemiology that case-control studies should             enroll incident cases. With CFS this is difficult to do, as many patients             have already had the disease for quite a while and are from tertiary             medical care. In any event, the case definition requires at least             six months of fatigue.
In persons with chronic unwellness, there seem to be two categories             of predominant symptom patterns that can be broadly classified as             cognitive and inflammatory (although there is no definitive evidence             of inflammation).
Some studies (e.g., neuroimaging studies) may benefit from very homogeneous             and highly screened patient populations. Other studies, such as population-based             incidence studies, may benefit from inclusion of overlapping illnesses             such as fibromyalgia and irritable bowel syndrome.
CFS could be combined with overlapping syndromes and the multidimensional             aspects studied from physiological and psychological perspectives,             e.g., studies of the HPA axis and the role of stress.
Subdivisions of CFS populations could yield important insights. Thus,             comparing persons with rapid onset of CFS to those with insidious             onset may be helpful. Duration of illness may be another important             factor. The patient subgroups selected should be relevant to the hypothesis             to be tested.
Comparison groups for CFS studies should also be carefully selected.             Persons with other illnesses such as rheumatoid arthritis may be more             appropriate than, or used in addition to, healthy persons.
Studies of fatigue, even in groups where there is an underlying cause             such as cancer or hepatitis C, could provide new insights for CFS.
**Mechanistic Issues:** In designing studies of CFS,             a number of mechanistic issues and approaches were discussed.
Fatigue and sleep disorders may be the result of the two predominant             symptom patterns, cognitive and inflammatory. Thus, requiring fatigue             first could be approaching the issue backwards.
Stress reactions and immune regulation are more sensitive in women             than in men. Women's physiology is more cyclical in nature. These             factors need to be taken into account in study design.
The idea of a chronic stress activation pattern may be worthy of             pursuit. There is much evidence for a stress component to CFS. Additionally,             a range of conditions associated with stress or trauma has been related             to hypocortisol. Thus, there is considerable symptom overlap in PTSD,             nurses and "burnout," teachers who report living under chronic stress,             CFS, FMS, and idiopathic chronic pain. 
Predisposing factors, precipitating factors, and perpetuating factors             need to be distinguished and studied. Understanding perpetuating factors             and factors predicting recovery are important issues. Iatrogenic factors,             such as medical treatment, involved in perpetuation or recovery need             also to be considered.
There is a need to accept multifactoriality in the cause of illnesses             such as CFS. Thus, a heart attack is a clinical entity. It may be             an end result of a complex interaction of multiple risk factors such             as smoking, hypertension, obesity and hypercholesterolemia.
When physical measures/illness factors are defined categorically,             rather than dimensionally, an arbitrary categorical line must be drawn             in which, e.g., individual are classified only as healthy vs. ill.             Accepting heterogeneity and a disease continuum rather than imposing             binary divisions may be helpful in studying CFS. 
Studying physical measures/illness factors dimensionally may give             a different perspective from classifying people into distinct syndromes.             Differentiating dimensions such as type and number of symptoms, chronicity,             disability, coping behavior, etc., may provide insights.
A focus on fatigue as a symptom of various illnesses, and on the             mechanisms of fatigue, may provide information on specific illnesses             as well as on general processes.
The physical versus psychiatric split has also been harmful in studying             CFS (and illness in general). Both physical illness and psychiatric             illness are real and based on symptoms. Moreover, scientists understand             that every psychiatric syndrome must have an undying biological basis,             even though none has been identified. Psychiatry is a discipline that             historically deals with symptom-based illnesses such as CFS, which             are experienced physically by patients but for which diagnostic markers             have not been found.
Although making psychiatric diagnoses in CFS is problematic because             of the uncertain etiology of symptoms, some possible bias in symptom             presentation, and the inherent limitations of the categories themselves,             research and clinical experience suggests a higher prevalence in CFS             of depression, generalized anxiety disorder, and panic disorders than             in other ill groups. Data suggest that the majority of CFS patients             may have diagnosable psychiatric illnesses. But it is difficult to             show whether these psychiatric conditions are primary, or secondary             to CFS. Thus, processes related to these disorders and to somatization             disorder should be considered for study-design and hypotheses development,             as opposed to focusing on specific diagnoses (e.g., whether CFS is             or is not a form of depression). 
Beliefs about illness should be explored as an aspect of CFS; psychological             and sociological factors affecting individual patients should be considered.
Development and evaluation of pragmatic treatments that can cope             with heterogeneous problems independent of their etiology, such as             cognitive behavioral therapy, may be of value. This type of strategy             has been effective in the management of chronic pain.
Objectively measurable CFS abnormalities identified thus far have             been variable and subtle. Studying the CFS crisis could provide insights             into disease pathogenesis. This would include understanding factors             that produce a crisis, predict the onset of a crisis, and define a             standard crisis response. The concept of overtraining in athletics             may also provide insights. (It was noted that the tilt-table test             or even simulating its effect by having patients stand against a wall             for a long period of time, might be useful to this end. For many patients,             over-exertion will precipitate a crisis.)
Studies of sustainable activity levels in CFS may provide insights             into physiological abnormalities. This is because the primary symptom             of CFS is 'chronic fatigue', which is best characterized as a large             reduction in the level of sustained activity. Changes in levels of             sustained activity might serve as a good measure of CFS severity,             as well as to evaluate the efficacy of interventional studies. 
**Methodological/Study Design Issues:** A number of             issues related to study design were put forward.
Studies should be hypothesis-driven and well-designed. 
Measurement and study design must consider not only the symptoms,             but also illness co-morbidities and appropriate comparison groups.             Diagnostic and dimensional rating instruments are important. 
In addition to the clear definition of patient populations, research             methods and procedures (whether laboratory or survey-based) should             have standard operating procedures and be reproducible. Measurement             instruments should be shared and should include not only the items             investigators wish to measure, but also items that are important to             patients. Scales used in neurological studies may be helpful.
Measurements of treatment outcomes are especially important.
Timing is important when developing study design. Many trophic hormones             peak at night. A number of features of host defense function on a             circadian pattern. 
In terms of specimens to be collected from patients, peripheral blood             appears reasonable since CFS is systemic.
Correlation of degree of disability with changes in physiological             markers should help define markers in which changes, even if subtle,             might have physiological meaning. Subtle changes do not appear likely             to reflect etiology.
Study results should be not only statistically significant, but must             be biologically relevant.
Multidisciplinary approaches and collaborations should be encouraged             and facilitated. The involvement of more neuroscience investigators             and inclusion of psychiatric expertise is particularly important for             studies.
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Administrative Strategies
**Information Issues**
NIH needs to make the patient community and public better aware of             how studies of physiological processes in normal persons (such as             sleep and exercise) as well as other illnesses with overlapping symptomatology             (such as fibromyalgia) provide a knowledge base for understanding             CFS, and how study of CFS within the context of psychiatric disorders             of unknown etiology is of critical importance.
HMO's need education about CFS and how it affects its service population.             (HCFA is trying to develop CFS information for practitioners in order             to get earlier case identification and treatment.)
**Funding/Infrastructure**
Funding mechanisms for CFS should address the need for multidisciplinary/trans-institutional             research and the sharing of materials and reagents. For example, the             CDC will be continuing to collect patient and control specimens during             their epidemiological studies. While CDC does not have an R01 mechanism,             the materials that they have collected could be used by NIH grantees             for CFS studies.
Mechanisms and approaches to address the barriers for CFS research             while maintaining peer review standards need to be developed. Making             scientists aware of the fascinating issues that can be studied in             this patient population may increase the interest of investigators             from other fields and provide prestige and status to CFS research.
Infrastructure issues to support research, such as centers for excellence,             and training of researchers, e.g., via training grants, need to be             developed and/or enhanced.
Funding for systematic reviews of the literature should be considered.             (This is done by organizations such as the AHRQ Evidenced-Based Practice             Centers throughout the U.S.) One topic that might be reviewed is infectious             agents that affect the CNS.
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1Fukuda KF, Straus SE, Hickie I, et           al. The chronic fatigue syndrome: a comprehensive approach to its definition           and study. *Ann Intern Med* 1994;121:325-331.2Fulcher and White. Randomised controlled           trial of graded exercise in patients with chronic fatigue syndrome.           *British Medical Journal* 1997;314:1967-52.

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