Program Updates: 2001

CFS Program Objectives

Chronic fatigue syndrome (CFS) is a complex, debilitating disorder characterized by at least 6 months of severe persistent or relapsing fatigue and a group of characteristic but nonspecific symptoms. Despite more than a decade of extensive research, the cause of CFS remains unknown and no diagnostic tests exist. Effective prevention and control thus remain elusive. In its role as the nation's lead public health agency, the Centers for Disease Control and Prevention (CDC) carries out a multifaceted, integrated program to study CFS in the United States. The program's objectives are to:

1. Estimate the magnitude of the problem.
2. Determine if CFS represents a single illness or a final common response to a variety of insults.
3. Define diagnostic and physiologic markers for CFS.
4. Provide appropriate technical information on CFS to various audiences.

CDC will ultimately use information from the first 4 objectives to develop control and prevention measures.

CFS Program Strategy

The program's research objectives are achieved through an integrated, population-based strategy that includes the following components:

• surveillance of large defined populations
• clinical studies of persons with CFS and other fatiguing illnesses
• molecular epidemiology and bioinformatics
• discovery of novel pathogens associated with CFS
• education activities

Integration is achieved by using similar data collection instruments in all program components, developing clinical studies to pursue new hypotheses from population-based studies, and conducting appropriate laboratory studies (gene expression, neuroendocrine, immune function, and pathogen discovery) on specimens from each component of the program.

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Surveillance Program

Objectives of the surveillance program are to:

• Estimate the magnitude of CFS as a health problem in the United States.
• Describe the clinical course of CFS.
• Revise the case definition.
• Collect biologic specimens to identify markers of disease activity.
• Identify subjects for enrollment in clinical studies.

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Wichita Surveillance

CDC has conducted surveillance for CFS and other fatiguing illnesses in Wichita from 1998 to 2001.

Prevalence and incidence of CFS

The CFS weighted point prevalence at baseline was 235 per 100,000 (95% confidence interval 142 to 327). CFS prevalence was elevated among women, 373 per 100,000 (95% confidence interval 210 to 536), and highest among nonwhite women, 495 per 100,000 (95% confidence interval 0 to 1,310). CFS was extremely rare in adolescents 12-17 years of age. None of the fatigued adolescents brought to clinic over the 4-year period was diagnosed with CFS. Four new adult CFS patients were identified (all were white; 3 women and 1 man). Calculation of weighted incidence rates is in process. However, new cases are extremely rare.

Clinical course of CFS

At baseline, approximately 3,500 fatigued and 3,500 non-fatigued adults 18-69 years of age were interviewed. After the baseline survey, approximately 1,100 fatigued and 3,000 non-fatigued subjects were followed annually for 3 years. In all, 97 CFS cases were identified and considerable fluctuation in illness state was observed 1 year after identification in the study. Only 26% of the CFS cases remained in a CFS state, 60% had transitioned into a non-fatigued or insufficient symptoms/fatigue severity state, and the others had medical or psychiatric exclusions. Among fatigued subjects who reported episodes of reduced fatigue during the follow-up year, 35% reported using alternative treatments such as herbal remedies, acupuncture, and homeopathy. We defined full CFS remission as a case in which a patient transitioned to a non-fatigued state, had fewer than 4 CFS symptoms, and was fully active at work and at their personal, social, or educational activities. We estimated that 9% of the CFS patients had full remission 12 months after being identified in the study and 4% after 24 months.

Besides clinical information, the program collected serial blood specimens over a 3-year period; these specimens will be used for molecular epidemiology studies (discussed below) and the test results will be correlated with epidemiologic and clinical findings. These specimens will also be assayed for novel pathogens as necessary. CDC will not continue surveillance of the entire Wichita population cohort beyond 3 years. However, clinical studies of subjects with CFS, other fatiguing illnesses, and non-fatigued controls will continue through FY 2002 and are described below.

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National Survey for CFS

It is extremely important to determine if the Wichita prevalence estimates can be generalized to the United States and to explore the occurrence of CFS in racial/ethnic minorities and adolescents in more detail. To do this, CDC will conduct a National Survey for CFS to estimate sex, age, race/ethnic, socioeconomic-specific prevalence ratios of CFS and other fatiguing illnesses. Specific aims are to:

• Determine if findings from the Wichita study can be generalized to the US population.
• Describe the occurrence and clinical features of CFS in racial/ethnic minorities and adolescents.
• Estimate the geographic occurrence of CFS, so as to detect any regional differences.
• Determine if the occurrence of CFS exhibits metropolitan, urban, or rural differences.
• Collect information to estimate the economic burden of CFS.
• Collect information that can be used to derive an empiric case definition.
• Identify populations at unusual risk for CFS in which to conduct case-control studies.
• Derive information for use in designing a national or regional CFS registry.

A pilot national survey to test questionnaires and methods, verify response rates, field-test physical examination protocols, and address issues of response bias began in August 2001, and the National Survey for CFS will begin in March 2002.

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CFS Case Definition Activities

For years, CDC has had a lead role in developing case definitions for CFS. CDC was responsible for the first such definition in 1988, and an international group convened by CDC published the current international CFS Research Case Definition in 1994. It is now clear that the 1994 case definition is inadequate and CDC has taken the lead internationally to derive an empiric case definition. In May 2000, CDC sponsored a workshop to discuss possible revisions to the 1994 case definition. CDC invited an international nidus of investigators actively involved in case definition issues who could collaborate to resolve issues. This meeting was followed by a CDC-sponsored satellite session during the January 2001 American Association for CFS Annual Meeting. The objectives of the satellite session were to discuss outcomes of the May 2000 meeting and outline future plans. In May 2001, CDC sponsored a second workshop, which was attended by participants from the 2000 workshop and additional subject-area experts. The workshop was designed to follow up on 3 areas identified previously:

1. Use of the case definition to identify ambiguities in the 1994 case definition that must be resolved (e.g., symptoms and exclusionary conditions).
2. Standardization of classification instruments to identify how investigators currently measure variables in the case definition, and which standard instruments should be used in research to revise the case definition.
3. Study design and sample collection in defined populations to identify target populations and study designs that will generate data for use in revising the case definition.

The group agreed to prepare a review article critiquing the 1994 CFS Research Case Definition and to submit the paper for publication before the end of 2001. CDC also began plans to form an international collaborative group to test standard instruments and collect data to develop an empiric case definition by 2003.

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Clinical Studies Program

Clinical Assessment of CFS and Other Fatiguing Illnesses in Wichita

CFS has no confirmatory physical signs or laboratory abnormalities, and its etiology and pathophysiology are unknown. The current research case definition of CFS was derived from clinical consensus. Therefore, research is needed to obtain data required for developing an empirically derived case definition and to discover the underlying etiology or etiologies of CFS. CDC has initiated a clinical study to further characterize the pathophysiology of CFS, evaluate the current CFS research case definition, and derive an empiric case definition of CFS. The study is being developed collaboratively with the Department of Psychiatry and Division of Endocrinology at Emory University, and the University of Toronto Sleep Center. The study will enroll subjects previously classified in the Wichita surveillance study as:

• Meeting the CFS research case definition.
• Meeting the CFS research case definition but accompanied by a major depressive disorder with melancholic features (CFS+MDD/M).
• Chronically fatigued but not meeting the CFS research case definition because of insufficient number of symptoms or fatigue severity (ISF).
• ISF accompanied by MDD/M.
• Non-fatigued controls matched to CFS subjects on age, race/ethnicity, sex, and body mass index.

Assessments include the following:

• clinical evaluation of medical and psychiatric status
• sleep characteristics
• cognitive functioning
• measures of stress and coping mechanisms
• laboratory testing for neuroendocrine status, autonomic nervous system function, and cytokine profiles

Finally, peripheral blood gene expression patterns and polymorphisms in genes involved in neurotransmission and immune regulation will be measured. Findings from this study will suggest future studies needed to identify the underlying pathophysiology of CFS and will provide essential information for efforts to develop an empirically based CFS case definition. A study protocol has been written and is pending submission to the CDC Institutional Review Board. The study proposal has been submitted to the subcontractor and a business contract is currently being negotiated. A potential clinical site in Wichita where the study may be conducted has been identified. Given the substantial progress in the study development in the past months, we plan to begin data collection in Wichita as of January 2002.

Use of Model Systems to Study CFS

Studies of the pathophysiology of CFS are complicated by patient heterogeneity with respect to chronicity and co-morbid illnesses. A model system in which symptom-free subjects develop CFS-like illness following exposure to a known stimulus obviates these problems and permits controlled studies of the pathophysiology of fatigue and associated symptoms.

Modeling studies: alpha interferon-induced fatigue

Patients with chronic hepatitis C or malignant melanoma who have been treated with interferon-alpha (INF-a) frequently develop symptoms of CFS. Thus, a CDC/Emory University Collaborative Group has undertaken a series of studies using INF-a-associated fatigue to model CFS. The cornerstone of these studies is a project under way in the Emory University Clinical Research Center that measures immune and neuroendocrine parameters, sleep, metabolism, mood changes, and mRNA expression patterns in INF-a recipients who develop a CFS-like illness compared with those who do not. To date, 8 patients have been enrolled (target enrollment: 50 subjects). Findings from this study will be integrated with results of a similar analysis of these functions in CFS patients (see Wichita clinical studies discussed below). Other studies by this collaborative group include an integration of comprehensive fatigue measures in ongoing assessments of patients receiving IFN-a for malignant melanoma and hepatitis C. Early findings from these studies indicate that the development of fatigue is distinct from the development of mood disorders (depression) both in terms of symptom evolution and treatment responsiveness (fatigue appears early during interferon administration and does not respond to antidepressant treatment, whereas depressive symptoms develop later and are antidepressant responsive). These results are consistent with findings in subjects with post-infectious fatigue and are under review for publication.

Modeling studies: exercise- and allergy-induced fatigue

The objective of CDC's component of this collaborative project with the National Jewish Medical Center in Denver is to identify differences in gene expression following allergen and exercise challenge of CFS patients and controls. Observed differences should provide insight into the pathogenesis of CFS. The study enrolled CFS patients between 18 and 45 years of age and sex matched controls. Subjects were evaluated at baseline and then those (cases and controls) with allergies received three challenges: nasal allergens, exercise, and histamine. Subjects without allergies received the last two challenges. Allergies are quite common in CFS patients, and the allergen challenge is included to test for unusual responses in CFS patients compared with controls. Exercise challenge is included because exertion frequently produces an increase in CFS symptoms. Differences in response between cases and controls could identify abnormal gene regulation in CFS. Histamine challenge is a control for the allergic response, because it will produce local symptoms of itchy-runny nose and sneezing but will not produce systemic immunologic activation (e.g., cytokine production).

Modeling studies: post-infection fatigue

Fatigue, cognitive disability, sleep disturbances, and myoarthralgia (i.e., the symptoms of CFS) are common during the acute phase of many infectious diseases and appear to correlate with the normal immune response. A sizeable proportion of patients with post-infection fatigue will continue to have such symptoms for >6 months following resolution of the acute infectious illness. In August 2001, CDC funded a cooperative agreement (awarded competitively) to the University of New South Wales, Australia, to conduct a cohort study of post-infectious fatigue after acute disease caused by Q-fever (a rickettsia), Ross River virus (an RNA virus), and Epstein Barr virus (a DNA virus). Incident cases occurring in the Macquarie Health Service district will be followed prospectively for 3 years. A pilot study has shown that approximately 30% of patients develop persistent fatigue through 3 months, which is accompanied by symptoms of CFS. Approximately 10% of patients continue with CFS beyond 6 months. The overall objective is to define the disease processes leading to the development of post-infectious fatigue. Specific aims are to test the hypotheses that:

1. Chronic cytokine release in response to persistent microbial antigens mediates the symptoms of post-infective fatigue and CFS.
2. Post-infective fatigue and subsequent CFS is initiated by abnormal persistence of the causative microorganism.
3. Psychological factors perpetuate physical symptoms after infection.
4. Genetic factors predispose to post-infective fatigue and CFS.

Measurements will include immune, hormonal, and gene expression profiles of the population-based cohort of patients with RNA virus, DNA virus, and rickettsial infections, beginning at the documented time of acute infection.

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Molecular Epidemiology and Bioinformatics Program

Molecular Epidemiology

The molecular epidemiology component of the CFS program was established 4 years ago. The current major laboratory effort focuses on analysis of gene expression in peripheral white blood cells to profile systemic patterns in CFS patients and controls, and to identify molecular markers that distinguish CFS patients. This approach uses two complementary gene expression-monitoring technologies (high-density filter arrays and glass microarrays and differential display polymerase chain reactions [DD-PCR]). Results should direct attention to pathways detected as abnormal and may also identify different pathologic entities within the syndrome. Preliminary studies of gene expression in cases and controls from a study in Atlanta demonstrated that gene expression profiling was feasible on peripheral blood and yielded intriguing results indicating that case gene expression was distinct from control gene expression. The Molecular Epidemiology Program has incorporated gene expression using microarrays and DD-PCR into most of the CFS program studies in which it is possible to collect a peripheral blood sample.

Genetic expression testing, or gene profiling, examines the activity or transcription of genes by quantitatively measuring messenger RNA in cells. Gene expression is altered by many factors, including cell differentiation, metabolic states, and disease status. New techniques allow quantitative analysis of RNA transcripts from thousands of genes at the same time and reveal the pattern of genes that are active at the time of sampling; gene expression patterns characterize disease states. By comparing the gene expression pattern between samples, characteristic differences can be identified. These differences, known as differential gene expression, can point to markers for diagnosis or to metabolic pathways that are altered.

Bioinformatics

CDC requires additional bioinformatics support to analyze gene expression data and integrate these data with epidemiologic information. To hasten this process, CDC began a collaboration with the National Cancer Institute's Center for Information Technology (CIT) Microarray Database, maintained at the Computational Biology and Engineering Laboratory (CBEL), National Institutes of Health (NIH) in Bethesda, MD. This collaboration is supported technically through a contract with Systems Research and Applications Corporation (SRA). SRA will do the following work:

• Provide programming support to give CDC researchers the ability to use the CBEL database to upload microarray data from high-density nylon filter arrays and glass microarrays.
• Modify the CBEL analysis tools to analyze the data and access genetic databases.
• Integrate epidemiologic data with the micro array data.
• Provide training and user support for CDC researchers.

SRA has considerable experience supporting research linking genetic expression to human disease. In particular, the systems they are providing are "user friendly" and tailored to specific questions while maintaining an overall comprehensive link to the universe of gene expression studies conducted by NIH.

Pathogen Discovery Program

CDC has developed an extramural program to search for novel or poorly characterized infectious agents in CFS patients. The search for such agents is done both at the nucleic acid level (RNA and DNA) using state of the art molecular methods, and at the antibody/antigen level using epitope discovery degenerate primer polymerase chain reaction. We currently support 4 collaborative efforts that have both extramural and intramural components.

Bacteria and mycoplasma 16S rRNA detection and characterization in plasma DNA samples from CFS cases and controls

DNA coding for small subunit ribosomal RNA (16S) molecules are highly conserved in bacteria/rickettsia and can be detected using broad-range PCR primers. PCR products are subsequently sequenced for specific identification. A mycoplasma specific PCR will also be used to determine the presence of mycoplasma DNA sequences Funds have been awarded to the Marshfield Medical Research Foundation in Wisconsin to conduct such analyses on plasma DNA samples from the first time point of collection in the longitudinal Wichita study. By September 20, 2001, Marshfield will provide VEHB results of 16S rDNA PCR tests and sequence analysis of amplified products and mycoplasma specific PCR on samples from the longitudinal Wichita study.

Epitope discovery using phage display random peptide libraries

An antibody response is generally elicited in response to infection. If the infecting agent is not known, specific peptide antigens can be discovered by using a novel approach known as epitope discovery. The epitopes are "discovered" by mining enormous random peptide libraries displayed on the surface of filamentous phage carriers. Funds have been awarded to the University of Missouri to screen sera from CFS patients and controls, using these libraries. This approach will identify antibody profiles that will hopefully distinguish CFS cases from controls. The peptides identified by the antibodies will be sequenced and may identify pathogen-related sequences.

Characterization of a previously uncharacterized retrovirus

Retroviruses represent an important group of infectious agents that have been suggested as having an association with CFS. Recently, Dr. Sidney Grossberg has isolated an apparently novel retrovirus called JHK virus, from a human B-lymphoblastoid cell line established from the peripheral mononuclear cells of a CFS patient. Immunoelectron microscopy demonstrated that a subset of CFS patient sera will bind to the JHK virus particle. It is important to determine if a true association exists with all or a subset of CFS cases. To do this will require development of JHK-specific reagents and appropriate assay systems. Funds have been awarded to the Medical College of Milwaukee - Wisconsin to purify the JHK retrovirus for cloning and sequence analysis. Goals are to characterize the virus and its relatedness to other human and animal retroviruses and to develop reagents that can be used in further seroepidemiologic studies.

Characterization of autoantibodies in CFS

Various infectious agents have been incriminated in the pathogenesis of autoimmune disease. Beta-hemolytic streptococcus has been implicated in rheumatic fever, Epstein-Barr virus in rheumatoid arthritis, Coxsackie virus B4 in diabetes, human herpesvirus type 6 and measles virus in multiple sclerosis, and cytomegalovirus, Chlamydia pneumoniae, and many other infectious agents in coronary artery disease. Because CFS has many characteristics of an autoimmune disease, we were interested in profiling the autoantibody profiles in CFS cases and controls. Funds have been awarded to the Scripps Institute to determine the presence or absence of fifteen common and recently described autoantibodies, some which may be produced in response to infection. Findings from this preliminary study will guide further studies.

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Education Program

Health Communication

Educational activities comprise the fifth component of CDC's CFS program. The program's educational activities involve providing CDC technical liaison, publishing research data in mainstream peer-reviewed medical journals, helping to organize and support scientific/medical conferences and workshops on CFS, preparing and distributing printed materials for patients and health care professionals, and maintaining telephone information lines and the CDC CFS world wide web home page. CDC's major emphasis is to legitimize the illness to health care professionals, state and local public health officials, health maintenance organizations, and insurance professionals. Education of patients and the public, although important, is a lower priority. An outside peer review committee strongly endorsed this focus and recommended it be continued.

CFS Health Professional Education Project

CDC is cosponsoring a cooperative effort between CDC, the Health Resources and Services Administration, the Illinois Area Health Education Centers (AHEC) Program, and the CFIDS Association of America titled, Chronic Fatigue Syndrome: A Diagnostic and Management Challenge. The project's objective is to increase health professionals' awareness and understanding of CFS. A group of CFS experts (including representatives from CDC) developed educational materials designed to improve the ability of primary care professionals to detect, diagnose, and manage CFS. Three Train-the-Trainer sessions have been held this year and included 52 trainers. Sessions involved peer-to-peer continuing education programs conducted by a core group of trained professionals working in various academic and community education settings. Session participants have agreed to teach at least 40 other primary care professionals about CFS before the end of the year. A number of such training sessions are already scheduled. Other components of the project are:

• Develop a web site that includes a study module.
• Produce educational videos.
• Evaluate the effectiveness of these methods to improve health professional knowledge about CFS.

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