IDEAS AND OPINIONS
Annals of Internal Medicine
Redefining the Chronic Fatigue Syndrome Theodore G. Ganiats, MD
T
he chronic fatigue syndrome, a disease that devastates patients' lives and affects between 836 000 and 2.5 million Americans (1), is often ignored or mismanaged by clinicians. The disease affects both children and adults and both males and females. Affected individuals present with persistent, intense exhaustion that worsens after physical, cognitive, or emotional effort. Even basic household chores can be exhausting, and such tasks as grocery shopping may only be possible on a “good day.” People with the condition may also have trouble with cognition, finding simple questions hard to answer and describing themselves as having “brain fog” and having trouble “finding the right words.” Despite the intense exhaustion, they find sleep unrefreshing. Persons with the disease experience frustrating effects on their daily functioning and desperately want their old lives back. Although these patients have severe disability, many clinicians misdiagnose—and, unfortunately, sometimes dismiss—the condition as a psychological problem. This may be because many clinicians believe there is no objective evidence of pathology. Adding to the confusion, since Holmes and colleagues proposed the name and case definition for “chronic fatigue syndrome” in 1988 (2), several different diagnostic strategies for the disease have been developed (3, 4), and various names, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), have been used. With this background, the U.S. Department of Health and Human Services (HHS), together with the National Institutes of Health, Social Security Administration, U.S. Food and Drug Administration, Centers for Disease Control and Prevention, and Agency for Healthcare Research and Quality, asked the Institute of Medicine (IOM) to convene an expert committee to examine the evidence base for ME/CFS. The committee was charged with developing evidencebased clinical diagnostic criteria for ME/CFS for use by clinicians and recommending whether new terminology for ME/CFS should be adopted. To accomplish this, the 15-member committee, with the help of IOM staff, conducted a comprehensive literature review; heard testimony from patients, clinicians, and researchers; and reviewed almost 1000 public comments. The literature review found sufficient evidence that ME/CFS is a disease with a physiologic basis. It is not, as many clinicians believe, a psychological problem that should not be taken seriously. A primary message of the report (5) is that: ME/CFS is a serious, chronic, complex, multisystem 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.” This message should reassure the millions of people with the condition that their concerns are, indeed, legitimate, while sounding a wake-up call to clinicians and research funders that ME/CFS deserves closer attention. Much has been written about possible causes of ME/CFS, with immune impairment, viral infection, and neuroendocrine pathology often discussed. In fact, there may be several causes that precipitate a “final common pathway” that results in the signs and symptoms of ME/CFS. The committee reviewed the literature to identify clinical and laboratory markers of the disease. It found sufficient evidence to support findings of immune dysfunction in patients with the disease. For example, poor natural killer cell cytotoxicity (in function, not number) correlates with illness severity (6). This might serve as a biomarker for disease severity, but it is not specific for the condition. Similarly, the committee found sufficient evidence that the condition can follow infection with Epstein–Barr virus (7) and possibly other infections. In contrast, the committee found insufficient evidence to conclude that patients with ME/CFS have pathognomonic neuroendocrine abnormalities. To address its major task of developing evidencebased clinical criteria for ME/CFS, the committee turned to the signs and symptoms of the disease. These include chronic, profound fatigue that has a major impact on functioning. Patients describe the fatigue as “exhaustion, weakness, a lack of energy, feeling drained, an inability to stand for even a few minutes, an inability to walk even a few blocks without exhaustion, and an inability to sustain an activity for any significant length of time” or even describe themselves as being “too exhausted to change clothes more than every 7 to 10 days” (8). Other key findings are unrefreshing sleep and postexertional malaise, where exertion from activity (even seemingly mild activity, such as walking or active cognition) can trigger a “collapse” or “relapse” of malaise that lasts days or longer, far in excess of what would normally be expected. There may be a delay between the trigger and the collapse. Physiologic abnormalities after exertion are seen (9), which supports patient reports that forcing a person to “push” themselves can lead to profound exacerbation of symptoms. Many patients also note cognitive impairment (specifically slow information processing) and orthostatic intolerance (a clinical condition where the symptoms worsen when the person assumes or maintains an upright posture and improve when the person reclines) (10).
This article was published online first at www.annals.org on 10 February 2015. © 2015 American College of Physicians 653
Downloaded From: http://annals.org/ by a Penn State University Hershey User on 05/28/2015
IDEAS AND OPINIONS Table. Diagnostic Criteria Diagnosis requires that the patient have each of the following 3 symptoms: A substantial reduction or impairment in the ability to engage in preillness 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 Postexertional malaise* Unrefreshing sleep* At least 1 of the following 2 manifestations is also required: Cognitive impairment* Orthostatic intolerance
* Frequency and severity of symptoms should be assessed. The diagnosis should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.
Redefining the Chronic Fatigue Syndrome
temic exertion intolerance disease will be better served. From the Miller School of Medicine, University of Miami, Miami, Florida. Disclosures: Disclosures can be viewed at www.acponline
.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15 -0357. Requests for Single Reprints: Theodore G. Ganiats, MD, Pro-
fessor, Department of Family Medicine and Community Health, Miller School of Medicine, University of Miami, 1801 NW 9th Avenue, #470, Miami, FL 33136. Author contributions are available at www.annals.org. Ann Intern Med. 2015;162:653-654. doi:10.7326/M15-0357
Good diagnostic criteria can facilitate timely and accurate diagnosis. The proposed criteria from the IOM committee are outlined in the Table. These new criteria highlight the critical importance of postexertional malaise, which is so characteristic that the committee believes that the concept of exertion intolerance should be part of a new name. Hence, the committee proposes that patients who meet these criteria be given the diagnosis of systemic exertion intolerance disease. It is important to emphasize that the precipitating exertion can be physical, cognitive, or emotional. Despite the evidence supporting a new name and new diagnostic criteria, more work is needed on the diagnosis and management of this devastating condition that affects so many. Is systemic exertion intolerance disease one disease or a common final pathway for several disease processes? What are the causes? Are there potentially preventive strategies? What are optimal treatments? How can we develop new treatments? How can we best support affected patients and their families? What are the most promising areas for future research? The IOM committee proposes a new name and new diagnostic criteria, but a new name by itself will not improve the lives of people with systemic exertion intolerance disease. Improved knowledge and acceptance among clinicians, in addition to an enhanced research agenda, will go far to bridge the gap between current practice and helping persons with this condition. The HHS has received the report; the committee now hopes that its advice, including a recommendation for a new, unique International Classification of Diseases code, will be accepted by the HHS, clinicians, and patients and their families so that those with sys-
References 1. Jason LA, Torres-Harding SR, Njok MC. The face of CFS in the U.S. CFIDS Chronicle; 2006. 2. Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988;108:387-9. [PMID: 2829679] doi:10.7326 /0003-4819-108-3-387 3. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953-9. [PMID: 7978722] doi: 10.7326/0003-4819-121-12-199412150-00009 4. Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. J Chronic Fatigue Syndr. 2003;11:7-115. 5. Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Washington, DC: National Academies Pr; 2015. 6. Fletcher MA, Zeng XR, Maher K, Levis S, Hurwitz B, Antoni M, et al. Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26. PLoS One. 2010;5: e10817. [PMID: 20520837] doi:10.1371/journal.pone.0010817 7. Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. IgM serum antibodies to Epstein–Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome. In Vivo. 2004;18:101-6. [PMID: 15113035] 8. U.S. Food and Drug Administration. The voice of the patient: chronic fatigue syndrome and myalgic encephalomyelitis. Silver Spring, MD: U.S. Food and Drug Administration; 2013. 9. Keller BA, Pryor JL, Giloteaux L. Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO2peak indicates functional impairment. J Transl Med. 2014;12:104. [PMID: 24755065] doi:10.1186/1479-5876-12-104 10. Gerrity TR, Bates J, Bell DS, Chrousos G, Furst G, Hedrick T, et al. Chronic fatigue syndrome: what role does the autonomic nervous system play in the pathophysiology of this complex illness? Neuroimmunomodulation. 2002;10:134-41. [PMID: 12481153]
654 Annals of Internal Medicine • Vol. 162 No. 9 • 5 May 2015
Downloaded From: http://annals.org/ by a Penn State University Hershey User on 05/28/2015
www.annals.org
Annals of Internal Medicine Author Contributions: Conception and design: T.G. Ganiats.
Analysis and interpretation of the data: T.G. Ganiats. Drafting of the article: T.G. Ganiats. Critical revision of the article for important intellectual content: T.G. Ganiats. Final approval of the article: T.G. Ganiats. Administrative, technical, or logistic support: T.G. Ganiats.
www.annals.org
Downloaded From: http://annals.org/ by a Penn State University Hershey User on 05/28/2015
Annals of Internal Medicine • Vol. 162 No. 9 • 5 May 2015
Annals of Internal Medicine
Redefining the Chronic Fatigue Syndrome Theodore G. Ganiats, MD
T
he chronic fatigue syndrome, a disease that devastates patients' lives and affects between 836 000 and 2.5 million Americans (1), is often ignored or mismanaged by clinicians. The disease affects both children and adults and both males and females. Affected individuals present with persistent, intense exhaustion that worsens after physical, cognitive, or emotional effort. Even basic household chores can be exhausting, and such tasks as grocery shopping may only be possible on a “good day.” People with the condition may also have trouble with cognition, finding simple questions hard to answer and describing themselves as having “brain fog” and having trouble “finding the right words.” Despite the intense exhaustion, they find sleep unrefreshing. Persons with the disease experience frustrating effects on their daily functioning and desperately want their old lives back. Although these patients have severe disability, many clinicians misdiagnose—and, unfortunately, sometimes dismiss—the condition as a psychological problem. This may be because many clinicians believe there is no objective evidence of pathology. Adding to the confusion, since Holmes and colleagues proposed the name and case definition for “chronic fatigue syndrome” in 1988 (2), several different diagnostic strategies for the disease have been developed (3, 4), and various names, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), have been used. With this background, the U.S. Department of Health and Human Services (HHS), together with the National Institutes of Health, Social Security Administration, U.S. Food and Drug Administration, Centers for Disease Control and Prevention, and Agency for Healthcare Research and Quality, asked the Institute of Medicine (IOM) to convene an expert committee to examine the evidence base for ME/CFS. The committee was charged with developing evidencebased clinical diagnostic criteria for ME/CFS for use by clinicians and recommending whether new terminology for ME/CFS should be adopted. To accomplish this, the 15-member committee, with the help of IOM staff, conducted a comprehensive literature review; heard testimony from patients, clinicians, and researchers; and reviewed almost 1000 public comments. The literature review found sufficient evidence that ME/CFS is a disease with a physiologic basis. It is not, as many clinicians believe, a psychological problem that should not be taken seriously. A primary message of the report (5) is that: ME/CFS is a serious, chronic, complex, multisystem 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.” This message should reassure the millions of people with the condition that their concerns are, indeed, legitimate, while sounding a wake-up call to clinicians and research funders that ME/CFS deserves closer attention. Much has been written about possible causes of ME/CFS, with immune impairment, viral infection, and neuroendocrine pathology often discussed. In fact, there may be several causes that precipitate a “final common pathway” that results in the signs and symptoms of ME/CFS. The committee reviewed the literature to identify clinical and laboratory markers of the disease. It found sufficient evidence to support findings of immune dysfunction in patients with the disease. For example, poor natural killer cell cytotoxicity (in function, not number) correlates with illness severity (6). This might serve as a biomarker for disease severity, but it is not specific for the condition. Similarly, the committee found sufficient evidence that the condition can follow infection with Epstein–Barr virus (7) and possibly other infections. In contrast, the committee found insufficient evidence to conclude that patients with ME/CFS have pathognomonic neuroendocrine abnormalities. To address its major task of developing evidencebased clinical criteria for ME/CFS, the committee turned to the signs and symptoms of the disease. These include chronic, profound fatigue that has a major impact on functioning. Patients describe the fatigue as “exhaustion, weakness, a lack of energy, feeling drained, an inability to stand for even a few minutes, an inability to walk even a few blocks without exhaustion, and an inability to sustain an activity for any significant length of time” or even describe themselves as being “too exhausted to change clothes more than every 7 to 10 days” (8). Other key findings are unrefreshing sleep and postexertional malaise, where exertion from activity (even seemingly mild activity, such as walking or active cognition) can trigger a “collapse” or “relapse” of malaise that lasts days or longer, far in excess of what would normally be expected. There may be a delay between the trigger and the collapse. Physiologic abnormalities after exertion are seen (9), which supports patient reports that forcing a person to “push” themselves can lead to profound exacerbation of symptoms. Many patients also note cognitive impairment (specifically slow information processing) and orthostatic intolerance (a clinical condition where the symptoms worsen when the person assumes or maintains an upright posture and improve when the person reclines) (10).
This article was published online first at www.annals.org on 10 February 2015. © 2015 American College of Physicians 653
Downloaded From: http://annals.org/ by a Penn State University Hershey User on 05/28/2015
IDEAS AND OPINIONS Table. Diagnostic Criteria Diagnosis requires that the patient have each of the following 3 symptoms: A substantial reduction or impairment in the ability to engage in preillness 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 Postexertional malaise* Unrefreshing sleep* At least 1 of the following 2 manifestations is also required: Cognitive impairment* Orthostatic intolerance
* Frequency and severity of symptoms should be assessed. The diagnosis should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.
Redefining the Chronic Fatigue Syndrome
temic exertion intolerance disease will be better served. From the Miller School of Medicine, University of Miami, Miami, Florida. Disclosures: Disclosures can be viewed at www.acponline
.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15 -0357. Requests for Single Reprints: Theodore G. Ganiats, MD, Pro-
fessor, Department of Family Medicine and Community Health, Miller School of Medicine, University of Miami, 1801 NW 9th Avenue, #470, Miami, FL 33136. Author contributions are available at www.annals.org. Ann Intern Med. 2015;162:653-654. doi:10.7326/M15-0357
Good diagnostic criteria can facilitate timely and accurate diagnosis. The proposed criteria from the IOM committee are outlined in the Table. These new criteria highlight the critical importance of postexertional malaise, which is so characteristic that the committee believes that the concept of exertion intolerance should be part of a new name. Hence, the committee proposes that patients who meet these criteria be given the diagnosis of systemic exertion intolerance disease. It is important to emphasize that the precipitating exertion can be physical, cognitive, or emotional. Despite the evidence supporting a new name and new diagnostic criteria, more work is needed on the diagnosis and management of this devastating condition that affects so many. Is systemic exertion intolerance disease one disease or a common final pathway for several disease processes? What are the causes? Are there potentially preventive strategies? What are optimal treatments? How can we develop new treatments? How can we best support affected patients and their families? What are the most promising areas for future research? The IOM committee proposes a new name and new diagnostic criteria, but a new name by itself will not improve the lives of people with systemic exertion intolerance disease. Improved knowledge and acceptance among clinicians, in addition to an enhanced research agenda, will go far to bridge the gap between current practice and helping persons with this condition. The HHS has received the report; the committee now hopes that its advice, including a recommendation for a new, unique International Classification of Diseases code, will be accepted by the HHS, clinicians, and patients and their families so that those with sys-
References 1. Jason LA, Torres-Harding SR, Njok MC. The face of CFS in the U.S. CFIDS Chronicle; 2006. 2. Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988;108:387-9. [PMID: 2829679] doi:10.7326 /0003-4819-108-3-387 3. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953-9. [PMID: 7978722] doi: 10.7326/0003-4819-121-12-199412150-00009 4. Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. J Chronic Fatigue Syndr. 2003;11:7-115. 5. Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Washington, DC: National Academies Pr; 2015. 6. Fletcher MA, Zeng XR, Maher K, Levis S, Hurwitz B, Antoni M, et al. Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26. PLoS One. 2010;5: e10817. [PMID: 20520837] doi:10.1371/journal.pone.0010817 7. Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. IgM serum antibodies to Epstein–Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome. In Vivo. 2004;18:101-6. [PMID: 15113035] 8. U.S. Food and Drug Administration. The voice of the patient: chronic fatigue syndrome and myalgic encephalomyelitis. Silver Spring, MD: U.S. Food and Drug Administration; 2013. 9. Keller BA, Pryor JL, Giloteaux L. Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO2peak indicates functional impairment. J Transl Med. 2014;12:104. [PMID: 24755065] doi:10.1186/1479-5876-12-104 10. Gerrity TR, Bates J, Bell DS, Chrousos G, Furst G, Hedrick T, et al. Chronic fatigue syndrome: what role does the autonomic nervous system play in the pathophysiology of this complex illness? Neuroimmunomodulation. 2002;10:134-41. [PMID: 12481153]
654 Annals of Internal Medicine • Vol. 162 No. 9 • 5 May 2015
Downloaded From: http://annals.org/ by a Penn State University Hershey User on 05/28/2015
www.annals.org
Annals of Internal Medicine Author Contributions: Conception and design: T.G. Ganiats.
Analysis and interpretation of the data: T.G. Ganiats. Drafting of the article: T.G. Ganiats. Critical revision of the article for important intellectual content: T.G. Ganiats. Final approval of the article: T.G. Ganiats. Administrative, technical, or logistic support: T.G. Ganiats.
www.annals.org
Downloaded From: http://annals.org/ by a Penn State University Hershey User on 05/28/2015
Annals of Internal Medicine • Vol. 162 No. 9 • 5 May 2015
