Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are serious, debilitating conditions that impose a burden of illness on millions of people in the United States and around the world. Somewhere between 836,000 and 2.5 million Americans are estimated to have these disorders (Jason et al., 1999, 2006b). The cause of ME/CFS remains unknown, although in many cases, symptoms may have been triggered by an infection or other prodromal event, such as “immunization, anesthetics, physical trauma, exposure to environmental pollutants, chemicals and heavy metals, and rarely blood transfusions” (Carruthers and van de Sande, 2005, p. 1). Over a period of decades, clinicians and researchers developed separate case definitions and diagnostic criteria for ME and CFS, although the terms denote conditions with similar symptoms. The literature analysis conducted in support of this study took into consideration the variability in the definitions used in the studies reviewed. For the purposes of this report, the umbrella term “ME/CFS” is used to refer to both conditions.
Diagnosing ME/CFS in the clinical setting remains a challenge. Patients often struggle with their illness for years before receiving a diagnosis, and an estimated 84 to 91 percent of patients affected by ME/CFS are not yet diagnosed (Jason et al., 2006b; Solomon and Reeves, 2004). In multiple surveys, 67 to 77 percent of patients have reported that it took longer than 1 year to get a diagnosis, and about 29 percent have reported that it took longer than 5 years (CFIDS Association of America, 2014; ProHealth, 2008). Seeking and receiving a diagnosis can be a frustrating process for several reasons, including skepticism of health care providers about the
serious nature of ME/CFS and the misconception that it is a psychogenic illness or even a figment of the patient’s imagination. Less than one-third of medical schools include ME/CFS-specific information in the curriculum (Peterson et al., 2013), and only 40 percent of medical textbooks include information on the disorder (Jason et al., 2010). ME/CFS often is seen as a diagnosis of exclusion, which also can lead to delays in diagnosis or to misdiagnosis of a psychological problem (Bayliss et al., 2014; Fossey et al., 2004; Jason and Richman, 2008). Once diagnosed, patients frequently complain that their health care providers do not know how to deliver appropriate care for their condition, and often subject them to treatment strategies that exacerbate their symptoms.
ME/CFS can cause significant impairment and disability that have negative economic consequences at both the individual and the societal level. At least one-quarter of ME/CFS patients are house- or bedbound at some point in their lives (Marshall et al., 2011; NIH, 2011; Shepherd and Chaudhuri, 2001). The direct and indirect economic costs of ME/CFS to society have been estimated at $17 to $24 billion annually (Jason et al., 2008), $9.1 billion of which has been attributed to lost household and labor force productivity (Reynolds et al., 2004). High medical costs combined with reduced earning capacity often have devastating effects on patients’ financial status.
Literature on mortality associated with ME/CFS is sparse. One study found that cancer, heart disease, and suicide are the most common causes of death among those diagnosed with ME/CFS, and people with ME/CFS die from these causes at younger ages than others in the general population. However, the authors note that these results cannot be generalized to the overall population of ME/CFS patients because of the methodological limitations of the study (Jason et al., 2006a).
CONTEXT FOR THIS STUDY
This study was sponsored by the Office on Women’s Health within the Department of Health and Human Services (HHS), the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration, the Agency for Healthcare Research and Quality, and the Social Security Administration. The study was commissioned in response to a recommendation from HHS’s Chronic Fatigue Syndrome Advisory Committee (CFSAC), which comprises 11 voting members, including the chair, who provide advice and recommendations to the Secretary of HHS on issues related to ME/CFS. In 2012, the CFSAC recommended that HHS “promptly convene … at least one stakeholders’ (ME/CFS experts, patients, advocates) workshop in consultation with CFSAC members to reach a consensus for a case definition useful for research, diagnosis and treatment of ME/CFS beginning with the 2003
Canadian Consensus Definition for discussion purposes.”1 Given the well-established and well-regarded consensus process used by the Institute of Medicine (IOM), HHS contracted with the IOM in September 2013 to conduct this study.
In the weeks that followed, many advocates were greatly disappointed that HHS did not follow the CFSAC’s specific recommendation. Patients, advocates, researchers, and clinicians expressed strong opposition to the study, arguing that the IOM lacks the expertise to develop clinical case definitions and that the inclusion of non-ME/CFS experts in this process would move the science backward. An open letter was sent to the Secretary of HHS, signed by 38 U.S.-based biomedical researchers and clinicians, declaring that consensus had been reached on the use of the Canadian clinical case definition (often called the Canadian Consensus Criteria [CCC]) for diagnosis of ME/CFS, and requesting that the IOM study be canceled and the funds used to support further ME/CFS research instead (An Open Letter, 2013).
CHARGE TO THE COMMITTEE
To conduct this study, the IOM convened the Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. The HHS sponsors charged the committee with evaluating the current criteria for diagnosis of ME/CFS and recommending clinical diagnostic criteria that would address the needs of health care providers, patients, and their caregivers. Specifically, the committee was asked to
- conduct a study to identify the evidence for various clinical diagnostic criteria for ME/CFS using a process with input from stakeholders, including practicing clinicians and patients;
- develop evidence-based clinical diagnostic criteria for ME/CFS for use by clinicians, using a consensus-building methodology;
- recommend whether new terminology for ME/CFS should be adopted; and
- develop an outreach strategy for disseminating the new criteria nationwide to health professionals.
The committee was also asked to distinguish among disease subgroups, develop a plan for updating the new criteria, and make recommendations for the plan’s implementation. The statement of task requested that the committee’s recommendations consider unique diagnostic issues facing people
1 CFSAC recommendations can be accessed at http://www.hhs.gov/advcomcfs/recommendations/10032012.html (accessed January 13, 2015).
with ME/CFS, related specifically to gender and particular subgroups with substantial disability and extending across the life span. The committee was not asked to investigate the etiology, pathophysiology, pathogenesis, or treatment of ME/CFS. The complete statement of task is provided in Chapter 1.
THE COMMITTEE’S APPROACH
The Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome comprised 15 members with expertise in clinical care for ME/CFS, pediatrics, infectious disease, epidemiology, immunology, rheumatology, behavioral health, pain, sleep, primary care, genetics, exercise physiology, neurology/neuropathology, clinical case definitions, and consensus processes. In addition to their scientific expertise, two committee members are or have been patients, and one is a family member/caregiver of a patient with ME/CFS.
The committee engaged in a number of activities to inform its work:
- The committee heard testimony, primarily from patients and advocates, on two occasions. The agendas for these sessions are provided in Appendix A.
- The committee carefully considered hundreds of public comments submitted through its public portal for this study.2
- The committee heard testimony from selected experts in this field (see Appendix A).
- The committee conducted a comprehensive literature review. The review included a search of eight databases for all articles published since 1950 related to ME, CFS, ME/CFS, and other terms used to describe this disorder (criteria for the literature search are presented in Chapter 1). Additional citations and grey literature (i.e., non-commercially published) were identified by the IOM staff, committee members, and the public and from references in pertinent articles. After a preliminary review of the literature, the committee directed the IOM staff to divide the articles into topics most central to its work: eight symptoms or symptom categories (for children/adolescents and adults) and three additional topics. For some of these topics, the committee reviewed abstracts of all of the relevant literature. For other topics, the committee developed specific questions with inclusion/exclusion criteria, which the IOM staff used to exclude irrelevant abstracts. In all cases, research groups of two
2 Public testimony and other materials submitted to the committee are available by request through the National Academies’ Public Access Records Office.
to five committee members assigned to each topic reviewed the abstracts to determine which articles were pertinent to the committee’s charge. These groups then read the full text of these articles, extracting their findings and using an adapted “GRADE grid” to record judgments as to whether there was sufficient evidence that certain symptoms and abnormalities define either ME/CFS or a particular subtype of the disorder (see Appendix B for the grid template) (Guyatt et al., 2008; Jaeschke et al., 2008).
- The committee received and considered preliminary findings from CDC’s ongoing Multi-Site Clinical Assessment of CFS. The committee was unable, however, to obtain input from NIH’s Evidence-based Methodology Workshop for ME/CFS until after this study was concluded.
- The committee consulted with a health communications specialist and a statistician to obtain additional expertise in addressing the statement of task.
In deliberating on its recommendations, the committee carefully considered the above sources of information. The collated judgments were used to facilitate discussion. Final recommendations regarding diagnostic criteria were made by consensus after deliberation by the committee as a whole.
OVERVIEW OF THE REPORT
Chapters 1 through 3 of this report summarize the history and background of ME/CFS and compare various existing definitions and terminology for the disorder proposed to date. They also address the extensive concerns that have been raised by patients and advocates regarding public perceptions of this disorder, in particular the term “chronic fatigue syndrome.” Chapters 4 and 5 review the scientific evidence to identify which symptoms are necessary to diagnose this disease. Chapter 6 examines this evidence further with a particular focus on pediatrics. Chapter 7 presents the committee’s recommendations, including new diagnostic criteria and a new name for ME/CFS, and operationalizes the new criteria. Finally, Chapter 8 details a dissemination strategy for the committee’s recommendations.
The primary message of this report is that ME/CFS is a serious, chronic, complex, and systemic disease that frequently and dramatically limits the activities of affected patients. In its most severe form, this disease can consume the lives of those whom it afflicts. It is “real.” It is not appropriate to dismiss these patients by saying, “I am chronically fatigued, too.”
Diagnosis requires that the patient have the following three symptoms:
- A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest,
- Post-exertional malaise,* and
- Unrefreshing sleep*
At least one of the two following manifestations is also required:
- Cognitive impairment* or
- Orthostatic intolerance
* Frequency and severity of symptoms should be assessed. The diagnosis of ME/CFS should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.
Based on a comprehensive review of the evidence and input from the patient, advocacy, and research communities, the committee decided that new diagnostic criteria (see Box S-1), which are more focused on the central symptoms of ME/CFS than many other definitions, are warranted for this disorder. These more focused diagnostic criteria will make it easier for clinicians to recognize and accurately diagnose these patients in a timelier manner. These new criteria led the committee to create the diagnostic algorithm shown in Figure S-1.
The committee weighed several factors in reaching consensus on these diagnostic criteria: (1) the frequency and severity with which these symptoms were experienced by patients, (2) the strength of the scientific literature, and (3) the availability of objective measures supporting the association of particular symptoms with the diagnosis. Patient reports and symptom surveys as well as scientific evidence consistently showed that impaired function, post-exertional malaise (an exacerbation of some or all of an individual’s ME/CFS symptoms after physical or cognitive exertion, or orthostatic stress that leads to a reduction in functional ability), and unrefreshing sleep are characteristic symptoms almost universally present
in ME/CFS; thus, the committee considered them to be core symptoms. The committee also found that cognitive impairment and orthostatic intolerance are frequently present in ME/CFS patients and have distinctive findings in these individuals that, particularly when viewed together with the core symptoms, distinguish ME/CFS from other fatiguing disorders. It is essential that clinicians assess the severity and duration of symptoms over an extended period of time because moderate or greater frequency and severity of symptoms are required to distinguish ME/CFS from other illnesses. Regarding the duration of the illness, the proposed criteria require 6 months to make a diagnosis in light of evidence that many other causes of similar fatigue do not last beyond 6 months (Jason et al., 2014; Nisenbaum et al., 1998).
The central point the committee wishes to emphasize is that ME/CFS is a diagnosis to be made. One of the committee’s most important conclusions is that a thorough history, physical examination, and targeted work-up are necessary and often sufficient for diagnosis. The new criteria will allow a large percentage of undiagnosed patients to receive an accurate diagnosis and appropriate care. Patients who have not yet been symptomatic for 6 months should be followed over time to see whether they meet the criteria for ME/CFS at a later time. The committee emphasizes that although some patients previously diagnosed with ME/CFS may not meet the proposed criteria, clinicians should address their symptoms and concerns.
Recommendation 1: Physicians should diagnose myalgic encephalomyelitis/chronic fatigue syndrome if diagnostic criteria are met following an appropriate history, physical examination, and medical work-up. A new code should be assigned to this disorder in the International Classification of Diseases, Tenth Revision (ICD-10), that is not linked to “chronic fatigue” or “neurasthenia.”
To assist clinicians in making a diagnosis of ME/CFS, the committee developed a table that includes terms commonly used by patients to describe their symptoms; potential questions clinicians can use to elicit the presence of symptoms as well as their frequency and severity; in-office tests and observations that support the diagnosis; and more complex tests that may be helpful in cases of diagnostic uncertainty or long-term management (see Tables 7-1 and 7-2 in Chapter 7).
Recommendation 2: The Department of Health and Human Services should develop a toolkit appropriate for screening and diagnosing patients with myalgic encephalomyelitis/chronic fatigue syndrome in a wide array of clinical settings that commonly encounter these patients, including primary care practices, emergency departments, mental/behavioral health clinics, physical/occupational therapy units,
and medical subspecialty services (e.g., rheumatology, infectious diseases, neurology).
CDC’s CFS Toolkit (CDC, 2014) and the International Association for CFS/ME’s Primer for Clinical Practitioners (IACFS/ME, 2014) may be potential places to start, but both need updating in a number of areas in light of the findings presented in this report. The development of clinical questionnaire or history tools that are valid across populations of patients and readily usable in the clinical environment should be an urgent priority. The DePaul Symptom Questionnaire, which has been used extensively in research (DePaul Research Team, 2010), as well as CDC’s Symptom Inventory (Wagner et al., 2008), may provide a solid basis from which to begin developing questionnaires and interview guides that can be validated for clinical use.
It has become increasingly clear that many patients with ME/CFS have other disorders as well, some of which—including fibromyalgia, irritable bowel syndrome, metabolic syndrome, sleep disorders, and depression—may have symptoms that overlap with those of ME/CFS (Buchwald and Garrity, 1994; Johnson et al., 1996; Maloney et al., 2010). Some of these other disorders may develop in response to the burdens of this disorder. The committee decided against developing a comprehensive list of potential comorbid conditions, but it does point to conditions identified by the ME-International Consensus Criteria (Carruthers et al., 2011) and the CCC (Carruthers et al., 2003). The committee recognizes that diagnosis and treatment of comorbid conditions is necessary when caring for patients.
Recommendation 3: A multidisciplinary group should reexamine the diagnostic criteria set forth in this report when firm evidence supports modification to improve the identification or care of affected individuals. Such a group should consider, in no more than 5 years, whether modification of the criteria is necessary. Funding for this update effort should be provided by nonconflicted sources, such as the Agency for Healthcare Research and Quality through its Evidence-based Practice Centers process, and foundations.
Although there was sufficient evidence with which to carry out the first steps of its task, the committee was struck by the relative paucity of research on ME/CFS conducted to date. Remarkably little research funding has been made available to study the etiology, pathophysiology, and effective treatment of this disease, especially given the number of people afflicted. Thus, the committee was unable to define subgroups of patients or even to clearly define the natural history of the disease. More research is essential.
Future diagnostic research will be most instructive when protocols include patients identified using the committee’s proposed diagnostic criteria as well as patients with other complex fatiguing disorders. Almost all of the studies conducted to date have compared patients with ME/CFS with healthy controls rather than with patients with these other fatiguing disorders. As a result, there is a paucity of data to guide clinicians in distinguishing among these disorders, a gap that urgently needs to be filled.
Finding the cause of and cure for ME/CFS may require research that enlists large numbers of patients with this disorder from which important subsets can be identified in terms of disease symptomatology, responses to physical and cognitive stressors, brain imaging, the microbiome, virology, immune function, and gene expression. Integrative approaches using systems biology may be useful in unraveling illness triggers. Studies aimed at assessing the natural history of the disease and its temporal characteristics (onset, duration, severity, recovery, and functional deficits) are essential for a better understanding of ME/CFS.
It is encouraging to note that progress already is being made in understanding the etiology, natural history, pathophysiology, and effective treatment of ME/CFS using a variety of physiological and molecular methods. Several large cohort studies are now under way. The committee expects that this research will lead to findings that can be used to further refine the diagnosis of this disorder and the elaboration of clinically pertinent subtypes. As a result, the committee calls for a reevaluation of the evidence in no more than 5 years using the methods recommended in the IOM report Clinical Practice Guidelines We Can Trust (IOM, 2011).
The criteria proposed here will not improve the diagnosis and care of patients unless health care providers use them. The committee developed an outreach strategy for disseminating the clinical diagnostic criteria resulting from this study nationwide to health care professionals so that patients will receive this diagnosis in an accurate and timely manner. The committee believes that focusing dissemination efforts on reaching primary care and other providers who encounter these patients will increase awareness of and familiarity with the new criteria in a way that will be most beneficial to patients with ME/CFS.
Despite misconceptions about ME/CFS and other barriers to its accurate diagnosis among health care professionals, it is important that the dissemination of the new diagnostic criteria proposed in this report build on previous efforts that have helped increase awareness of ME/CFS among health professionals and the public. Key to this effort will be the continued positioning of ME/CFS as a legitimate disease that occurs in both children and adults and should be properly diagnosed and treated. As the dissemination strategy is implemented, it will also be important for HHS to include
an evaluation component to monitor progress. The evaluation should encompass both quantitative and qualitative measures.
The committee devoted significant effort to the question of whether a new name for this disorder is warranted, heeding both the clear call by patients and advocates as well as the sponsors’ request. The committee was swayed by the commonly expressed view of patients that the term “chronic fatigue syndrome” has led to misperceptions on the part of clinicians and the public. The committee deemed the term “myalgic encephalomyelitis,” although commonly endorsed by patients and advocates, to be inappropriate because of the general lack of evidence of brain inflammation in ME/CFS patients, as well as the less prominent role of myalgia in these patients relative to more core symptoms. The committee was convinced of the value of creating a name that conveys the central elements of this disease, a practice for which there is much precedent in medicine for disorders whose etiology or pathophysiology is not yet well understood. After extensive consideration, and being mindful of the concerns expressed by patients and their advocates, the committee recommends that the disorder described in this report be named “systemic exertion intolerance disease” (SEID). “Systemic exertion intolerance” captures the fact that exertion of any sort—physical, cognitive, emotional—can adversely affect these patients in many organ systems and in many aspects of their lives. The committee intends for this name to convey the complexity and severity of this disorder.
Recommendation 4: The committee recommends that this disorder be renamed “systemic exertion intolerance disease” (SEID). SEID should replace myalgic encephalomyelitis/chronic fatigue syndrome for patients who meet the criteria set forth in this report.
In conclusion, the committee hopes that the diagnostic criteria set forth in this report, based on a comprehensive review of the literature, will promote the prompt diagnosis of patients with this complex, multisystem, and often devastating disorder; enhance public understanding; and provide a firm foundation for future improvements in diagnosis and treatment.
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