Evidence Report/Technology Assessment

Number 66

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
2101 East Jefferson Street
Rockville, MD 20852

www.ahrq.gov

Contract No. 290-97-0016

Prepared by:
MetaWorks Inc. Evidence-based Practice Center, Medford, MA
Susan D. Ross, MD, FRCPC
Program Director
Cindy Levine, MD
Principal Investigator

Nelson Ganz, MD
Diana Frame, MEM
Rhonda Estok, RN, BSN
Linda Stone, RN, MS, CPNP
Veronica Ludensky, BA
Investigators

AHRQ Publication No. 03-E007

December 2002

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakers--patients and clinicians, health system leaders, and policymakers--make more informed decisions and improve the quality of health care services.

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.

Levine C, Ganz N, Estok R, et al. Systematic Review of the Current Literature Related to Disability and Chronic Fatigue Syndrome. Evidence Report/Technology Assessment No. 66 (Prepared by MetaWorks Inc. Evidence-based Practice Center under Contract No 290-97-0016). AHRQ Publication No. 03-E007. Rockville, MD: Agency for Healthcare Research and Quality. December 2002.

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.

The authors are grateful to the following individuals for their diverse contributions throughout the course of this project: Catherine Cella, Janet Connelly, Kyle Fahrbach, Kimberly James, Michael Rozinsky, members of the Technical Expert Panel, peer reviewers, representatives from the Social Security Administration, and representatives from the Agency for Healthcare Research and Quality.

The objective of this evidence report was to perform a systematic review of the published literature to provide the Social Security Administration (SSA) with the best available evidence and most current medical knowledge regarding disability in persons with Chronic Fatigue Syndrome (CFS).

English language and adult population published literature from 1988 to November 2001 was searched using MEDLINE, Current Contents, Cochrane Library, and PsychINFO databases and supplemented by a manual review of bibliographies of all accepted papers.

Interventional or observational studies of at least two adult patients reporting CFS according to either the CDC 1988, CDC 1994, Oxford 1991, or Australia 1990 criteria were accepted. Studies were required to report disability (evidence of a medically determinable physical or mental impairment) and data regarding employment or work.

Data on patients, interventions, and outcomes were extracted from accepted studies. Studies were scored for quality and level of evidence. Data were summarized for study, patient, and treatment level characteristics as well as outcomes of interest. A panel of diverse technical experts and peer reviewers provided review and commentary on the draft report.

Of 3,840 citations identified, 53 studies describing 4,558 patients with CFS met all eligibility criteria. Twenty-two of these studies described comparator groups of healthy controls totaling 775 patients. The majority of CFS patients represented in the 37 studies reporting employment status were unemployed. The evidence suggests that some individuals with CFS have cognitive or affective impairments on neuropsychological tests, but results are not consistent. Depression of greater severity is associated with unemployment, but no other impairment appeared to be consistently associated with disability or work outcomes. No specific interventions have been proven to be effective in restoring the ability to work. No specific patient characteristics have been identified as best predictors of positive employment outcomes in CFS patients. The patient's level of functioning at the time of diagnosis should be compared to functioning prior to the onset of illness especially as it relates to work, school, social and home activities.

The major limitations of this review are related to the weaknesses inherent in the current medical and scientific published literature regarding CFS. Study designs were not sufficiently homogeneous to allow quantitative synthesis of individual study results, and external validity was low. While some studies reported test and scale results, this was highly variable with relatively sparse and inconsistent reporting of both baseline and outcome data. No studies specifically measured the impact of baseline impairment data or treatment interventions on work function or employment outcomes.

While relationships between various impairment measures and work/disability status might be explored in some cases, the best available evidence from the literature did not allow for determination of causality. The limitations inherent in the current literature review are noted and the research community is urged to conduct methodologically rigorous, longitudinal, interventional studies to determine what baseline characteristics are associated with inability to work, and what interventions are effective in restoring the ability to work in the CFS population.

This purpose of this project, nominated by the Social Security Administration (SSA), and contracted through the Agency for Healthcare Research and Quality (AHRQ) was to develop an evidence base that would provide SSA with the most current medical and scientific knowledge for evaluating disability as defined by the SSA in persons with Chronic Fatigue Syndrome (CFS). This review will also serve to highlight gaps in the current literature and areas ripe for future research.

This database of best available evidence was established through a systematic review of the CFS literature pertinent to diagnosis, measurement, and treatment of disability resulting from any medically determinable physical or mental impairment.

Several key questions guided this review. Questions were originally posed by SSA and refined in collaboration with expert panel members and representatives from SSA and AHRQ to focus on the issues of disability and impairment in CFS. The revised key questions are as follows:

A multidisciplinary panel of professionals with a broad range of clinical expertise in CFS was assembled early on to provide guidance and direction regarding:

Members of the panel served throughout the course of the project as the Technical Expert Panel (TEP), responding to questions during the review and commenting on the draft evidence report. The systematic review followed a prospective protocol that was developed a priori and shared with the nominating partner (SSA), the TEP, and the Task Order Officer at AHRQ. The protocol outlined the literature search methods, study eligibility criteria, data elements for extraction, and methodological strategies to minimize bias and maximize precision during the process of data collection, extraction, and synthesis.

The published literature was searched from January 1, 1988 to November 15, 2001, using Medline, Current Contents, Cochrane Library, and PsychINFO databases. In addition, the bibliographies of all accepted studies and review articles from the past two years were searched for potentially relevant citations. The retrieval cut-off date was March 15, 2002.

English language published literature from 1988 to 2001 was sought, utilizing the following search strategy:

fatigue syndrome, chronic [MeSH] or chronic fatigue[syndrome].Limits: English language, human subjects.

All citations and abstracts were printed and screened at MetaWorks. Full papers were obtained for all abstracts that mentioned CFS and disability. The electronic searches noted above were supplemented by a manual search of the reference lists of all accepted studies and relevant review articles. To be included in the review, studies were required to report CFS as diagnosed according to one of the four accepted CFS definitions, evidence of a medically determinable physical or mental impairment, and data regarding employment or work in at least two adult patients.

Data from each accepted study was extracted by one investigator and reviewed by a second. Key data elements sought for extraction from each study included study, patient, and intervention characteristics, as well as outcomes of interest. All eligible papers were evaluated and scored for both internal and external validity, with possible scores ranging from 2 to 8.

No quantitative analyses were performed beyond descriptive statistics to summarize findings. Eleven peer reviewers, drawn from clinicians with expertise in CFS and professional organizations, along with eight TEP members reviewed and provided comments on the draft evidence report. Feedback was incorporated into the final report as appropriate.

Of all 3,840 citations identified, 53 studies met all eligibility criteria. The majority of studies were conducted in the United States or Western Europe. There were 17 interventional and 36 observational studies, covering 4,558 primarily female adult patients with CFS. Twenty-two of these studies described comparator groups of healthy controls totaling 775 patients.

No quantitative syntheses were possible because of insufficient and/or inconsistent reporting or results. The evidence supports the following conclusions:

• Some individuals with CFS have discrete cognitive or affective impairments on neuropsychological tests, but these results are not consistent, nor can any causality associated with decreased rates of employment be inferred due to the cross-sectional design of most of the studies.
• Depression of greater severity is associated with unemployment, but no other impairment appeared to be consistently associated with disability or work outcomes.
• No specific interventions have proven to be effective in restoring the ability to work, and interventional trials describing both baseline and outcome data were sparse. The most commonly reported interventions included drug therapy and cognitive behavioral therapy; the latter lending a possible association between improvement in the ability to work and an increase in the number of patients employed.
• No specific patient characteristics have been defined that serve as best predictors of positive employment outcomes in CFS patients.
• It is important to compare the patient's level of functioning at the time of diagnosis to his/her level of functioning prior to the onset of illness especially as it relates to work, school, social and home activities.
• The major limitations of this review are related to the weaknesses inherent in the current medical and scientific published literature related to CFS. Study designs were not sufficiently homogeneous to allow quantitative synthesis of individual study results, and external validity was low. While some studies reported test and scale results, this was highly variable with relatively sparse and inconsistent reporting of both baseline and outcome data. Longitudinal studies which would allow for assessment of effect of baseline characteristics on long term work outcomes were extremely rare.

It is clear from this review of the literature addressing work status in patients with CFS that more studies are needed to enable researchers to better assess and evaluate disability in this population. Following are priorities for future research:

• Longitudinal, interventional studies are mandatory in order to determine what baseline characteristics are associated with inability to work and which interventions are effective in restoring the ability to work.
• Authors should report more detailed information about impairment and work status at baseline and after intervention, preferably stratified by patient characteristics.
• Future studies of employment status should clarify if employment means full or part time, prior work or new work, and also provide information on duration of return to work.
• Further research is needed to determine the impact cognitive behavior therapy (CBT), graded exercise, and other interventions on the issue of disability.
• The literature would be enhanced if standardized measurements of impairment were developed, defined, and used to evaluate the impact of all interventions, and if some assessment was made regarding the impact of impairment on employability in this specific patient population.
• Further research is needed to determine validity and reliability of self-reported instruments in assessment of impairment and disability in CFS patients who are often formerly high functioning individuals, unlike chronic mentally ill patients or low functioning patients with physical impairments. Validity and reliability of these instruments should be determined in patients with concurrent or prior neuropsychological diagnoses, given the high lifetime incidence of same, and particularly in patients who may have different motivations for determining disability. Instruments should also be validated in compensation settings.
• Further research is needed to determine whether and which validated neuropsychological non-self-reported assessment tools yield sufficient evidence to evaluate functionality as it relates to ability to work.
• Further research in needed to determine whether there are characteristics of care providers or prior work experiences that relate to ongoing CFS disability.