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CBT edit
Previously CBT has been considered as moderately effective for treating chronic fatigue syndrome. however a National Institutes of Health Pathways to Prevention Workshop stated that in respect of improving treatment options for ME/CFS that the modest benefit from cognitive behavioral therapy should be studied as an adjunct to other methods. The Centres for Disease Control advice on the treatment of ME/CFS makes no reference to CBT while the National Institute for Health and Care Excellence  states that cognitive behavioural therapy (CBT) has sometimes been assumed to be a cure for ME/CFS, however, it should only be offered to support people who live with ME/CFS to manage their symptoms, improve their functioning and reduce the distress associated with having a chronic illness."

References in Pathophysiology sub article meeting MEDRS
''Hempel S, Chambers D, Bagnall AM, Forbes C (July 2008). "Risk factors for chronic fatigue syndrome/myalgic encephalomyelitis: a systematic scoping review of multiple predictor studies". Psychol Med 38 (7): 915–26. . .''


 * Reference not listed in IOM Report
 * Reference used in Main article in Section: Risk Factors
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''The pathophysiology of chronic fatigue syndrome is unknown. Several potential causes for the development of chronic fatigue syndrome have been proposed, including neurological factors, psychological or psychosocial factors or influences, infections, immunological factors, endocrinal factors and genetic factors. Other, less-common theories have also been articulated. No clinically meaningful risk factor has been identified.[1]''

A systematic scoping review included one retrospective study which reported that childhood trauma was significantly associated with the development of adult CFS, one prospective study which reported that genetics and self-reported stress sensitivity could contribute to CFS-like illness 25 years later, and one prospective study on fatigued employees which took measurements of current psychological distress and recent "shocking life events" (within last 12 months) at baseline and 12/24 month followup but did not find these to predict CFS-like caseness at 44 month followup.[1] ______________________________________________________

''Goldstein DS, Robertson D, Esler M, Straus SE, Eisenhofer G (2002). "Dysautonomias: clinical disorders of the autonomic nervous system". Annals of Internal Medicine 137 (9): 753–63. . .''


 * Reference not listed in IOM Report
 * Reference used in Main article in Section: Pathophysiology
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''Dysautonomia is the disruption of the function of the autonomic nervous system (ANS) which controls many aspects of homeostasis. In CFS this is mostly orthostatic intolerance - the inability to stand up without feeling dizzy, faint, or nauseated.[10]'' ______________________________________________________

''Margutti P, Delunardo F, Ortona E (2006). "Autoantibodies associated with psychiatric disorders". Curr Neurovasc Res 3 (2): 149–57. . .''


 * Reference not listed in IOM Report
 * Reference not used in Main article: CFS reference is speculative only
 * Sub Article text

''The brain and immune system influence each other, especially in the HPA axis and sympathetic nervous system. Mental stress causes suppression of the immune system by hormones such as cortisol and epinepherine. Release of stress hormones, caused by diseases outside the brain, can result in neurological symptoms due to the influence of stress hormones on neurotransmitters. Neuropsychiatric disorders present in CFS may be related to autoantibodies to neuronal or endothelial (interior surface of blood vessels) targets,[17]''

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''Cho HJ, Hotopf M, Wessely S (2005). "The placebo response in the treatment of chronic fatigue syndrome: A systematic review and meta-analysis". Psychosom Med 67 (2): 301–13. . . Retrieved 2008-12-12. http://journals.lww.com/psychosomaticmedicine/Abstract/2005/03000/The_Placebo_Response_in_the_Treatment_of_Chronic.21.aspx''


 * Reference not listed in IOM Report
 * Reference used in Main article in Section: Management
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Some individuals with CFS firmly reject any psychological involvement and believe strongly that their condition has a physical cause.[22] ______________________________________________________

''Prins JB, van der Meer JW, Bleijenberg G (2006). "Chronic fatigue syndrome". Lancet 367 (9507): 346–55. . . http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)68073-2/fulltext''


 * Reference not listed in IOM Report
 * Reference used in Main article in Section: Management
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Neuroticism and introversion have previously been reported as risk factors for developing CFS.[26]

Some research suggests that CFS may be perpetuated when patients fixate on a physical cause for their symptoms or when exercise is avoided.[26][30

A lack of support, or the reinforcement of illness behavior by social networks, may be associated with delayed recovery for some patients.[26] ______________________________________________________

''van Geelen SM, Sinnema G, Hermans HJ, Kuis W (January 2007). "Personality and chronic fatigue syndrome: Methodological and conceptual issues" (PDF). Clin Psychol Rev 27 (8): 885–903. . .''


 * Reference not listed in IOM Report
 * Reference not used in Main article: Not used main article   - self negating
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''Although personality seems to play a role in CFS, it is difficult to draw general conclusions on the relation between personality and CFS. A systematic review of personality and CFS found an association with neuroticism, but stated that it was often accounted for by co-morbid depression and levels were similar to those in patients with other chronic diseases. It found no firm evidence for introversion.[27]''

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''Natelson BH, Lange G (2002). "A status report on chronic fatigue syndrome". Environ. Health Perspect. 110 Suppl 4 (Suppl 4): 673–7. . . .''


 * Reference not listed in IOM Report
 * Reference used in Main article in Section: Pathophysiology
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In response to a version of the cognitive behavioural model described in the book "Chronic Fatigue and Its Syndromes", the authors of a status report on CFS state, "Although this model may explain continued illness in some CFS patients, it certainly does not pertain to all CFS patients and is thus not too satisfactory."[29]       -

However, although symptoms of CFS can occur after severe infection, strong data do not yet exist to support an infectious process in disease maintenance.[29 but they may not represent the entire picture[99] and some CFS experts doubt they are responsible.[29] ______________________________________________________

''Deary V, Chalder T, Sharpe M (October 2007). "The cognitive behavioural model of medically unexplained symptoms: a theoretical and empirical review". Clin Psychol Rev 27 (7): 781–97. . .''

Sub Article text
 * Reference not listed in IOM Report
 * Reference not used in Main article: Not used main article - not pathology, speculative and argumentative with stronger sources.

Some research suggests that CFS may be perpetuated when patients fixate on a physical cause for their symptoms or when exercise is avoided.[26][30] ______________________________________________________

''Whitehead WE, Palsson O, Jones KR (2002). "Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications?". Gastroenterology 122 (4): 1140–56. . .''

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 * Reference not listed in IOM Report
 * Reference not used in Main article: - not pathology, speculative and argumentative with stronger sources

The presence of multiple comorbid disorders could be a marker for psychological influences on etiology.[33] ______________________________________________________

''Klimas NG, Koneru AO (December 2007). "Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions". Curr Rheumatol Rep 9 (6): 482–7. . .''

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or a factor in reactivation.[64]

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''Appel S, Chapman J, Shoenfeld Y (2007). "Infection and vaccination in chronic fatigue syndrome: myth or reality?". Autoimmunity 40 (1): 48–53. . .''

Reference not listed in IOM Report


 * Reference used in Main article in Section: Pathophysiology
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Immunological factors including a chronic activation or suppression of the immune system may contribute to symptoms of CFS,[98

High levels of Th2-type cytokines and the cells that make them are also found in CFS.

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''Cho HJ, Skowera A, Cleare A, Wessely S (2006). "Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology". Current Opinion in Psychiatry 19 (1): 67–73. . .''


 * Reference not listed in IOM Report
 * Reference used in Main article in Section: Pathophysiology
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Immunological factors including a chronic activation or suppression of the immune system may contribute to symptoms of CFS,[98] but they may not represent the entire picture[99]

A 2006 update in the journal Current Opinion in Psychiatry stated, "Recent advances in understanding the pathophysiology of chronic fatigue syndrome continue to demonstrate the involvement of the central nervous system. Hyperserotonergic state and hypoactivity of the hypothalamic-pituitary-adrenal axis (HPA axis) constitute other findings, but the question of whether these alterations are a cause or consequence of chronic fatigue syndrome still remains unanswered."[99] ______________________________________________________

Lorusso L, Mikhaylova SV, Capelli E, Ferrari D, Ngonga GK, Ricevuti G (February 2009). "Immunological aspects of chronic fatigue syndrome". Autoimmun Rev 8 (4): 287–91. ..


 * Reference not listed in IOM Report
 * Reference used in Main article in Section: Pathophysiology
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A ''2009 review into the immunological aspects of CFS reported that patients do seem to have a specific immune dysfunction profile involving an enhanced baseline activation of lymphoid subsets but a suppression of certain immune responses, particularly Th1-driven ones such as the anti-viral and anti-tumour responses. Reported findings from various studies include an alteration in cytokine profile (high level of pro-inflammatory cytokines and dysregulation of anti-inflammatory cytokines), decreased function of natural killer (NK) cells, the presence of autoantibodies, reduced responses of T cells and abnormal activation of T lymphocyte subsets. The authors note that the immune alteration pattern of CFS "has a striking resemblance to the one caused by developmental immune toxicology", perhaps due to a combination of factors such as xenobiotics, infections and stress.[100]'' ______________________________________________________

''Nijs J, Nees A, Paul L, De Kooning M, Ickmans K, Meeus M, Van Oosterwijck J (2014). "Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review" (PDF). Exerc Immunol Rev 20: 94–116. . Retrieved 2015-06-19.''


 * Reference is listed in IOM Report
 * Reference used in Main article in Section: Pathophysiology
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''A systematic literature review published in 2014 concluded persons diagnosed with the illness have an abnormal immune response to exercise. Specifically, complement products are increased, larger oxidative stress is generated along with reduced anti-oxidant immune response, and larger interleukin-10 and toll-like receptor 4 gene expression are seen verses healthy controls. Many of these immune responses correlate with the symptom of post-exertional malaise.[101]'' ______________________________________________________

''Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG (2001). "Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors". Appl Neuropsychol 8 (1): 51–64. . .''

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 * Reference not listed in IOM Report
 * Reference not used in Main article: - '''covered by more recent resources via IOM refs
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''High levels of Th2-type cytokines and the cells that make them are also found in CFS. [104 Therapeutic alterations of cytokine expression patterns are being investigated.[104]'' In contrast, immunodeficiency disorders characterized by abnormal T-cell subset ratios, levels of immunoglobulins, and hypoallergic responses on the French Multitest have been reported in CFS.[104]

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''Papadopoulos, Andrew S.; Cleare, Anthony J. (27 September 2011). "Hypothalamic–pituitary–adrenal axis dysfunction in chronic fatigue syndrome". Nature Reviews Endocrinology 8 (1): 22–32. . .''


 * Reference not listed in IOM Report
 * Reference used in Main article in Section: Pathophysiology
 * Sub Article text

''The hypothalamic-pituitary-adrenal axis (HPA axis) controls levels of hormones such as cortisol and is activated in a circadian rhythm and modulated by factors such as stress, digestion or illness. It is important in regulating energy metabolism, the immune system, stress responses and inflammation in the body''.

''A substantial body of evidence points to the following findings in CFS patients: mild hypocortisolism, an attenuated diurnal variation in cortisol, enhanced cortisol negative feedback, and a blunted HPA axis responsiveness. Women are more likely to exhibit hypocortisolism than men, as well as those who are depressed, inactive or not taking medication. The findings are similar to those seen in atypical depression. Glucocorticoid and mineralocorticoid receptor hypersensitivity appears to be the most probable explanation for the enhanced HPA axis negative feedback. Patients who undergo treatment such as CBT show reversal of the HPA axis changes. Steroid replacement therapy is not recommended due to lack of evidence and possible adverse effects.[108]'' ______________________________________________________

''Cleare AJ (April 2003). "The neuroendocrinology of chronic fatigue syndrome.". Endocr Rev 24 (2): 236–52. .''

It has been debated whether these disturbances would play a primary role in the pathogenesis of CFS, but prospective evidence suggests that the HPA axis is not an important factor during the early stages of CFS, although it has been hypothesized that it might play a role in exacerbating or perpetuating symptoms later on in the course of the illness .[109][110][111]
 * Reference not listed in IOM Report
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''Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ (2007). "Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome." (PDF). Neuropsychobiology 55 (2): 112–20. . .''


 * Reference not listed in IOM Report – although 2014 article by these authors is.
 * Reference used in Main article in Section: Pathophysiology
 * Sub Article text

It has been debated whether these disturbances would play a primary role in the pathogenesis of CFS, but prospective evidence suggests that the HPA axis is not an important factor during the early stages of CFS, although it has been hypothesized that it might play a role in exacerbating or perpetuating symptoms later on in the course of the illness .[109][110][111] ______________________________________________________

''Cleare AJ (March 2004). "The HPA axis and the genesis of chronic fatigue syndrome.". Trends Endocrinol Metab 15 (2): 55–9. . .''


 * Reference not listed in IOM Report
 * Reference not used in Main article: - superceded by more recent resources via IOM refs
 * Sub Article text

It has been debated whether these disturbances would play a primary role in the pathogenesis of CFS, but prospective evidence suggests that the HPA axis is not an important factor during the early stages of CFS, although it has been hypothesized that it might play a role in exacerbating or perpetuating symptoms later on in the course of the illness .[109][110][111] ______________________________________________________

''Tak LM, Cleare AJ, Ormel J, Manoharan A, Kok IC, Wessely S, Rosmalen JG (May 2011). "Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders.". Biol Psychol 87 (2): 183–94. . .''


 * Reference not listed in IOM Report
 * Reference used in Main article in Section: Pathophysiology
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A 2011 meta-analysis reported a small but statistically significant hypocortisolism in CFS.[112] ______________________________________________________

Molecular Epidemiology Program". National Center for Infectious Diseases. 2005-07-25.
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 * Reference not used in Main article: dead resource
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CFS-related abnormalities in gene expression have been studied.[42]

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''Wyller VB (2007). "The chronic fatigue syndrome--an update". Acta Neurol. Scand., Suppl. 187: 7–14. . .''

Reference not listed in IOM Report

Reference not used in Main article: speculative and unsupported


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''*A 2007 review stated that certain genetic polymorphisms might be regarded as predisposing factors.[126''

Nosological Developments
The medical classification (nosology) of CFS is subject to ongoing research which is variously focussed upon epidemiology, upon clinical description and upon the establishment of biomarkers.

Epidemiology
Recent work o the epidemiology of CFS is limited to a single study on prevalence in a developing society.

Clinical Descriptions
In addition to the operative descriptions employed by national health organisations such as the CDC and NICE, research has produced other clinical descriptions which as yet have not met with general medical consensus:

Biomarkers
Successful identification of biomarkers would impact upon future directions in both the epidemiology and in the clinical description of CFS. There is no current general medical consensus on CFS biomarkers however the following have been proposed: