Research

Chronic fatigue syndrome (CFS) was first defined in 1988 by the U.S. Centers for Disease Control and Prevention (CDC)¹ as an illness of at least six months duration which begins suddenly with flu-like symptoms, causes a minimum of 50% reduction in activity, and cannot be explained by alternate medical or psychiatric diagnoses.

Since that time, researchers have tried to solve the mysteries surrounding CFS such as its causes and prevalence. Despite years of study, there is still no laboratory marker or universal treatment for CFS, but progress is being made.

Association-Sponsored Research

The first program funded by the Association was its research grant program. Since 1987 the Association has provided nearly $5 million in direct support of CFS research studies, has hosted scientific symposia and has cosponsored meetings to identify promising areas of investigation. The CFIDS Association of America regularly issues funding announcements as part of its research grants program. Its most recent Request for Applications was issued on March 3, 2008. For more information about the Association’s research program, please visit http://www.cfids.org/profresources/association-grants.asp. For a synopsis of recent research news, please visit http://www.cfids.org/sparkcfs/research-news.asp.

Diagnosis
In 1994, the CDC revised its CFS case definition.² The primary goal of this document was to provide standardized symptom criteria for researchers. The case definition, although designed for research purposes, also serves as a guideline for clinical practitioners.

Because no simple laboratory test can identify CFS, the primary care provider (physician, physician assistant or nurse practitioner) must exclude other possible causes of the symptoms before diagnosing a patient with CFS.

To meet the definition for CFS, a person must have clinically evaluated, unexplained persistent or relapsing chronic fatigue that is of new or definite onset (i.e., not lifelong), is not the result of ongoing exertion, is not substantially alleviated by rest and results in substantial reduction in previous levels of occupational, educational, social or personal activities. In addition, the person must have at least four of the following symptoms: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multi-joint pain without swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and post-exertional malaise lasting more than 24 hours.

In 2003, the CDC further revised the case definition to clarify ambiguities in the 1994 case definition. The intention of this work was to provide recommendations for use of the 1994 definition, standardization of classification instruments and to address study design issues that would improve the precision of the case recognition³.

Epidemiology
CFS affects more than one million Americans. In technical terms, every 100,000 Americans, 422 have CFS. Only 16% who meet the strict definition have been diagnosed.⁴ CFS is most common in women (522 cases per 100,000) and minorities, especially Latinos (726 cases per 100,000). CFS is not limited to any specific race, age or socioeconomic group.

The economic impact of CFS is significant, estimated to be $9.1 billion in lost productivity annually in the U.S. This amount does not include medical costs or disability payments. This cost estimate is comparable to such losses seen in digestive, immune and nervous system diseases⁵.

"Recovery" rates for CFS are unclear. According to one of the few published studies, the probability of significant improvement was about 30% during the first five years of illness and 48% during the first 10 years. However, even "recovered" patients stated that they still had some CFS symptoms, and one-third had relapsed six months later⁶.

A CDC study in 2003 reported⁷ that the clinical course for CFS is characterized by an intermittent pattern of relapse and remission. Fifty-seven percent of study participants reported a partial or total remission. It was also found that more severe fatigue and a greater number of total symptoms decreased the likelihood of illness remission.

Fifty-seven percent of study participants reported a partial or total remission; in addition, more severe fatigue and a greater number of total symptoms decreased the likelihood of illness remission . The study also noted that shorter illness duration was a predictor of sustained remission. This fact highlights the importance of early detection and treatment for people with CFS.

People with CFS (PWCs) who have been ill for many years have special needs; please see our resources for long-term PWCs.

Viral Triggers
Because most cases of CFS begin with a flu- or mono-like illness, many viruses, bacteria and toxins have been studied as possible causes of CFS. Nearly all the most notable being the Epstein-Barr virus have been excluded because of their relative commonness in the general population and the inability to link any pathogen to all cases CFS.

Even so, there is still much debate in scientific circles over whether either of these pathogenic agents will emerge as the only cause of CFS. Current thinking indicates that there may be multiple triggers of CFS in genetically, environmentally or otherwise susceptible individuals.

Several studies have looked at common agents that may trigger CFS. A September 2006 study⁴⁰ found that CFS followed 12%of cases acutely infected with Epstein-Barr virus (EBV), Ross River virus and coxiella burnetti. The severity of symptoms at the onset of the acute illness was found to be the greatest predictor for who remained ill at the 6 month point.

Immune Dysregulation
Immune system abnormalities have been found in CFS patients, although none has emerged as a diagnostic marker. The most common are diminished natural killer cell function⁸, generalized immune system upregulation⁹, immunological differences in cytokine patterns¹⁰ and dysfunction in the 2-5A synthetase RNase L antiviral pathway¹¹.

RNase L fights infection by degrading the RNA of viruses. Temple University researchers have found that CFS patients have a novel low molecular weight (37kDa) form of this enzyme and low levels of normal RNase L (80kDa). Studies are underway to determine if the unique RNase L is present in other diseases and whether it might serve as a marker for CFS^12,13.

Another research finding is the discovery of autoantibodies to lamin B-1, a component of the cellular structure, which has led to increased speculation that CFS may be an autoimmune disease¹⁴. In 2004, a new theory was postulated that hypothesized that neuropeptide dysfunction may be a potential cause of loss of immunological tolerance, which could lead to CFS¹⁵.

Orthostatic Intolerance
In 1995, Johns Hopkins researchers reported that up to 95% of CFS patients have neurally mediated hypotension, a condition in which blood pressure falls when it should rise¹⁶. This has become a dynamic area of CFS research and scientists are actively debating the nature of this and other forms of orthostatic intolerance¹⁷. Studies in recent years have focused on three possible keys to understanding orthostatic intolerance in CFS: low blood volume, abnormal sympathetic tone and neurological dysfunction^18,19,20.

Brain Abnormalities
Abnormalities on brain scans have been reported by several research groups^21,22,23. Bright signals in the white matter of the brain have been found on MRI scans in about half of CFS patients in research studies. Abnormalities on SPECT scans are more striking and appear to correlate with clinical status. CFS patients show SPECT brain perfusion deficiencies most commonly in the lateral frontal and temporal cortexes and basal ganglia.

A few small studies have also used magnetic resonance imaging (MRI) to detect irregularities in people with CFS^24,25,26. An article in the summer 2006 issue of the CFIDS Chronicle summarizes two studies that showed reductions in gray matter in the brains of CFS patients.

Neuropsychological testing has been helpful in quantifying the disabling cognitive problems patients report. Research has shown that the memory and concentration deficits are independent of any depression experienced by CFS patients^27,28.

Endocrine Dysfunction
Disruption in the hypothalamic-pituitary-adrenal axis, as part of the neuroendocrine system, has been implicated as a possible cause of CFS²⁹.

Historically this research area shows that scientists at the National Institutes of Health (NIH) attempted to treat low levels of circulating cortisol, which has been found in CFS patients³⁰ with hydrocortisone. While two-thirds of treated patients saw symptomatic improvement over the course of the study, the researchers concluded that hydrocortisone was not an advisable treatment for CFS because of the high risk of adrenal suppression while on this therapy³¹. Others feel that its benefits outweigh risks, provided there is close medical supervision of therapeutic responses.

Scientists in the U.K. have found that CFS patients' with low cortisol have abnormally small adrenal glands³². In CFS patients the adrenal glands were half the size of normal, while in a comparison group with depression they were enlarged up to 70%.

Biopsychosocial
Most recently, much attention is being paid to the biopsychological and social aspects of CFS - how the mind and body interact to trigger and/or perpetuate symptoms and who may be at risk for getting CFS. Significant research has been done in the field of cognitive behavioral therapy, a form of psychotherapy that assists people with coping behaviors. It has been shown to be beneficial for some people³³, helping them better manage the emotional trauma brought on by living with a chronic illness, but it has not improved the fatigue factor.

Other Areas of Interest
Another new area of study involves CFS and energy management. Scientists have looked at defective energy metabolism at the cellular level³⁴, defective motor neural signals³⁵, microcirculation changes³⁶, as well as the possibility of cardiopulmonary problems³⁷.

Exercise challenge has also been postulated as a diagnostic test for CFS, by looking at immune changes that occur under physiological exertion³⁸. In addition, exercise testing may help to subclassify people with CFS to better identify research participants³⁹ that have similar symptom patterns, illness onset, etc. Using exercise and activity limitations to better determine levels of disability are also being investigated.

Future Explorations
Scientists are focusing on the next steps in CFS research. Researchers are exploring ways to understand the cause and progression of CFS, identify diagnostic markers and discover new, effective treatments. Research has established the existence of CFS. We must look to future research to teach us how to detect, diagnose and manage the disease until we find a cure.

For an overview of recent CFS research, search of PubMed Chronic Fatigue Syndrome (CFS) Literature at http://orwh.od.nih.gov/cfs/cfsLitReviews.html.

Related Information

• Case Definition
• Long-term patient resources
• Orthostatic Intolerance
• Viruses

References

¹ Holmes GP, et al. Chronic fatigue syndrome: A working case definition. Ann Int Med 1988;108:387-89.

² Fukuda K, et al. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann Int Med 1994;121:953-59.

³ Reeves WC, et al. International Chronic Fatigue Syndrome Study Group. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res 2003 Dec 31;3(1):25. Review.

⁴ Jason L, et al. A community-based study of chronic fatigue syndrome. Arch Int Med 1999;159:2129-37.

⁵ Reynolds KJ, et al. The economic impact of chronic fatigue syndrome. Cost Eff Resour Alloc 2004 Jun 21;2(1):4.

⁶ Reyes M, et al. Chronic fatigue syndrome progression and self-defined recovery: evidence from the CDC surveillance system. JCFS 1999;5(1):17-27.

⁷ Nisenbaum R, et al. A population-based study of the clinical course of chronic fatigue syndrome. Health Qual Life Outcomes 2003 Oct 3;1(1):49.

⁸ Patarca-Montero R, et al. Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors. Appl Neuropsychol 2001;8(1):51-64.

⁹ Natelson B, et al. Evidence for the presence of immune dysfunction in chronic fatigue syndrome. Clin Diagn Lab Immunol 2002;9(4):747-52.

¹⁰ Hanson SJ, et al. Detection of immunologically significant factors for chronic fatigue syndrome using neural-network classifiers. Clin Diagn Lab Immunol 2001;8:658-62.

¹¹ Demettre E, et al. Ribonuclease L proteolysis in peripheral blood mononuclear cells of chronic fatigue syndrome patients. J Biol Chem 2002;277(38):35746.

¹² De Meirleir K, et al. A 37 kDa 2-5A binding protein as a potential biochemical marker for chronic fatigue syndrome. Am J Med 2000 Feb;108(2):99-105.

¹³ Suhadolnik RJ, et al. Biochemical evidence for a novel low molecular weight 2-5A-dependent RNase L in chronic fatigue syndrome. J Interferon Cytokine Res 1997 Jul;17(7):377-85.

¹⁴ Mikecz, et al. High frequency of autoantibodies to insoluble cellular antigens in patients with CFS. Arth Rheum 1997;40:295-30.

¹⁵ Staines DR. Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry? Med Hypotheses 2004;62(5):646-52.

¹⁶ Bou-Houlaigah, et al. The relationship between neurally mediated hypotension and the CFS. JAMA 1995;274:961-67.

¹⁷ Gerrity TR, et al. Chronic fatigue syndrome: what role does the autonomic nervous system play in the pathophysiology of this complex illness? Neuroimmunomodulation 2002-2003;10(3):134-41. Review.

¹⁸ Stewart J, et al. Orthostatic intolerance in adolescent CFS. Pediatrics 1999;103:116-21.

¹⁹ Streeten DH and Bell, D. Circulating blood volume in CFS. JCFS 1998;4:3-11.

²⁰ Papanicolaou DA, et al. Neuroendocrine aspects of chronic fatigue syndrome. Neuroimmunmodulation 2004 Feb;11(2):65-74.

²¹ Schwartz RB, et al. Detection of intracranial abnormalities in patients with CFS: comparison of MR imaging and SPECT. Am J Rot 1994;162:935-41.

²² Schwartz RB, et al. SPECT imaging of the brain: comparison of findings in patients with CFS, AIDS dementia complex, and major unipolar depression. Am J Rot 1994;162:943-51.

²³ Lange G, et al. Neuroimaging in CFS. Am J Med 1998;105(3A):50S-53S.

²⁴ Chauduri A, et al. Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome. Neuroreport 2003 Feb 10;14(2):225-8.

²⁵ Chauduri A and Behan PO. In vivo magnetic resonance spectroscopy in chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty Acids 2004 Sep;71(3):181-3.

²⁶ DeLange FP, et al. Neural correlates of the chronic fatigue syndrome - an fMRI study. Brain 2004 Sep 12;127(Pt 9):1948-57.

²⁷ Daly E, et al. Neuropsychological function in patients with chronic fatigue syndrome, multiple sclerosis, and depression. Appl Neuropsychol 2001;8:12-22.

²⁸ Busichio K, et al. Neuropsychological deficits in patients with chronic fatigue syndrome. J Int Neuropsychol Soc 2004 Mar;10(2):278-85.

²⁹Papanicolaou DA, et al. Ibid.

³⁰ Demitrack M, et al. Evidence for impaired activation of the hypothalamic-adrenal-pituitary axis in patients with CFS. J Clin Endocrin Metab 1991;73:1224-34.

³¹ McKenzie R, et al. Low-dose hydrocortisone for treatment of CFS. JAMA 1998;280:1061-66.

³² Scott LV, et al. Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study. Psychoneuroendocrinology 1999;24:759-68.

³³ Deale A, et al. Long-term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. Am J Psychiatry 2001 Dec;158(12):2038-42.

³⁴ McCully KK, et al. Muscle metabolism with blood flow restriction in chronic fatigue syndrome. J Appl Physiol 2004 Mar;96(3):871-8.

³⁵ Siemionow V, et al. Altered central nervous system signal during motor performance in chronic fatigue syndrome. Clin Neurophysiol 2004 Oct;115(10):2372-81.

³⁶ Spence VA, et al. Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty Acids 2004 Apr;70(4):403-7.

³⁷ Peckerman A, et al. Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome. Am J Med Sci 2003 Aug;326(2):55-60.

³⁸ Sorensen B, et al. Complement activation in a model of chronic fatigue syndrome. Allergy Clin Immunol 2003 Aug;112(2):397-403.

³⁹ Vanness JM, et al. Subclassifying chronic fatigue syndrome through exercise testing. Med Sci Sports Exerc 2003 Jun;35(6):908-13.

⁴⁰ Hickie I, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. British Journal of Medicine 2006; 333 (7568):575.