Environmental and other risk factors affecting Chronic fatigue, fibromyalgia or myalgic encephalomyelitis

Chronic fatigue associations and societies worldwide ME/CFS Worldwide Patient Alliance

Ongoing clinical trails, worldwide, can be interrogated at ClinicalTrials.Gov a service of the US National Institutes of Health

Pubmed CoQ // /Omega-3

Proteins of the XMRV retrovirus implicated in chronic fatigue syndrome and prostate cancer are homologous to human proteins relevant to both diseases.Nature precedings

Genes ACE ADRB2 AGER APOE BDNF COMT CRHR1 DISC1 DRD3 GRIK2 . HLA-DRB1 HLA-DQA1 HTR2A IFNG IL4 IL17 IL17F HDAC7A. HOXA1 . HTR2A KIR3DL1 KIR3DS1 KIRREL MAOA MAOB NPAS2 .NR3C1 NUP98 .OPRM1 POMC PRUNE . SERPINA6 SLC6A4 TH TNF TNK2 . TNFRSF1B . TPH2 WASF3

GWAS from Genome.gov [AFAP1 ARHGAP20 C10ORF59 CFLP1 CLYBL DGKH (BG220650.1 blasted) DTX4 FBXO42 FLJ41278 FRA10AC1 GRIK2 GRIN2B HS6ST3 KCNJ6 KLHL32 KRTHA3A LILRB4 LOC100131813 LOC100507140 LOC642587 MAGI3 MSH3 MTAP NLRP11 NLRP13 NPAS2 OTOG PIP5K1B PPFIBP1 RASGRF2 SCN8A SIX6 SLC5A12 TCERG1 TECTB Smith et al, 2011 ]

Infectious agents

• Originally known as post-viral fatigue syndrome
• which can be observed several years after an attack of polio (post-poliomyelitis syndrome) Bridgens et al, 2010
• The XMRV virus has been implicated in chronic fatigue and prostate cancer Lombardi et al, 2009
• The murine leukemia virus has been detected in the blood of chronic fatigue patients Lo et al, 2010 Hanson et al, 2011
• The Epstein Barr and enterovirus have been implicated in CF Zhang et al, 2010
• Fatigue can be a consequence of Hepatitis C infection Jacobson et al, 2010
• and of Hepatitis A Lee et al ,2008
• or Hepatitis B infection Wilkins et al, 2010
• and can be triggered by H1N1 influenza (swine flu) Vallings , 2010
• and associated with herpes virus HHV-6 Ongradi et al, 2010
• and with Nipah virus infection Ng et al, 2004
• Chikungunya virus infection is associate with chronic fatigue and musculoskeletal pain Chopra et al, 2011
• GB virus C (hepatitis G) was identified in a small number of cases in a twin study Sullivan et al, 2011
• Childhood gastrointestinal symptoms and parental reports of many colds have been associated with the subsequent development of chronic fatigue Clark et al, 2011
• High levels of Parvovirus B19 in the intesinal mucosa have been recorded in chronic fatigue Fremont et al, 2009
• Many different viral or bacterial infections including the Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis) can contribute to chronic fatigue Hickie et al, 2006.
• Increased infection with Candida albicans has been observed Evengard et al, 2007
• Infection with the toxigenic fungus, Stachybotrys chartarum from water-damaged buildings can cause fatigue Johanning et al, 1996
• as can chronic aspergillosis Sugino et al, 2008
• Infectious mononucleosis in adolescents can cause chronic fatigue Katz et al, 2009
• Q fever, caused by Coxiella burnetii can be associated with chronic fatigue Limonard et al, 2010
• Ciguatera poisoning , from contaminated fish, can lead to chronic fatigue Ting and Brown, 2001
• Chronic fatigue can be associated with Lyme neuroborreliosis Djucic et al, 2010
• Chronic fatigue has been associated with Giardia lamblia, a common cause of gastroenteritis Wensaas et al, 2011
• Fatigue can be associated with Tropheryma whipplei bacteremia (Whipples disease) Fennolar et al, 2010
• Seropositive status for Borrelia burgdorferi and Epstein-Barr virus was identified in 66% of chronic fatigue cases in this study in paediatric patients Petrov et al, 2011.
• Helicobacter pylori seropositivity has been associated with fibromyalgia Akkaya et al, 2011
• Sick building syndrome, possibly related to mould and mycotoxins can be related to chronic fatigue Schoemaker and House 2005
• Macrophagic myofasciitis (caused by vaccinations containing aluminium) has been associated with chronic fatigue Israeli et al, 2010
• Parental physical abuse , childhood gastrointestinal symptoms and parental reports of many colds have been associted with chronic fatigue Clark et al, 2011

• The elimination of monosodium glutamate and other excitotoxins from the diets of subsets of patients with fibromyalgia .has been reported to be beneficial Smith et al, 2001
• Low levels of magnesium are associated with fatigue Barbagallo et al, 2009
• Pesticides and disease database
• Mercury toxicity has been linked to fatigue Wojkik et al, 2006
• Aluminium based vaccines have been associated with Macrophagic myofasciitis (Symptoms include myalgias, arthralgias, marked asthenia, muscle weakness, chronic fatigue, and fever Israeli et al, 2011
• A previously overactive lifestyle has been linked to chronic fatigue Van Houdenhove et al, 2001
• Chronic pain has been associated with smoking in women Mitchell et al, 2011
• Excessive energy in childhood and being overweight as an adult have been linked to fatigue Harvey et al, 2009
• Low ferritin levels (iron deficiency) and low levels of vitamin D in chronic fatigue patients Antiel et al, 2011
• Chronic fatigue has been linked to obesity , low alcohol intake, less healthy food, a less active lifestyle and the use of analgesics, and is more common in women van't Leven et al, 2010

Hormonal effects

• Higher blood levels of alpha-MSH have been recorded in chronic fatigue Shishioh-Ikejima et al, 2010
• Decreased plasma antidiuretic hormone and increased serum osmolality and plasma renin activity have been recorded. Serum concentration of aldosterone, cortisol, NT-proBNP and sex hormones were not significantly different in the two groups Wyler et al, 2010.

Association with other diseases/conditions

• Chronic Fatigue is associated with Gulf War syndrome Coughlin et al, 2011 itself tentatively associated with excessive vaccination
• Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is characterized by myalgia, myositis, muscle weakness, arthralgia, arthritis, chronic fatigue, sleep disturbances, cognitive impairment and memory loss, and occasionally a demyelinating autoimmune disease caused by systemic exposure after vaccines and adjuvants Barros and Carvalho, 2011.
• Chronic fatigue has been associated with irritable bowel syndrome Wojczynski et al, 2007
• Postural Tachycardia Syndrome (standing up increases heart rate) is commonly associated with chronic fatigue Ocon et al, 2011
• Interstitial cystitis / painful bladder syndrome has been associated with chronic fatigue Nickel et al, 2010
• Fatigue is associated with Primary biliary cirrhosis, a chronic, autoimmune, cholestatic liver disease Abbass et al, 2010
• Fatigue is associated with interstitial pneumonia which was treated with megadose vitamin C with dehydroepiandrosterone/cortisol supplementation Kodama and Kodama 2005.
• Chronic fatigue has been associated with low blood pressure, more extensible skin and stiffer arteries Van de Putte et al, 2005
• Chronic fatigue has been associated with the metabolic syndrome Maloney et al, 2010
• Chronic fatigue associated with Systemic lupus erythematosus Urbanska-Krawiec and Hrycek, 2011
• Chronic fatigue has been observed as a consequence of breast cancer treatment Reinertsen et al, 2011
• Fibromyalgia has been associated with ankylosing spondylitis Almodovar et al, 2010
• Fatigue precedes the onset of multiple sclerosis by several years Medscape (requires registration)
• Major depression has been associated with chronic fatigue in women Ciccone and Natelson, 2003
• Interferon-alpha treatment of viral infections has been associated with chronic fatigue and depression Felger et al, 2011
• ß-thalassemia has been associated with fibromyalgia Altinoz et al, 2011
• Chronic fatigue has been associated with Ehlers-Danlos syndrome a group of inherited disorders caused by problems with collagen synthesis Castori et al, 2011
• Chronic fatigue can be a consequence of traumatic brain injury Reeves and Panguluri, 2011
• Chronic fatigue has been associated with prior premorbid psychopathology Goodwin et al, 2011
• The prevalence of chronic fatigue is higher in women Evangard et al, 2005
• Women with chronic fatigue reported higher levels of pelvic pain unrelated to menstruation, endometriosis and periods of amenorrhea The number of pregnancies and gynecological surgeries was also higher Boneva et al, 2010
• Smoking , allergies, and a history of extreme morning sickness may be related to the development of fibromyalgia in women Choi et al, 2010.
• Obesity and low levels of exercise have been associated with fibromyalgia in women Mork et al, 2010
• Older age, retirees, housewife status , existing long-term health problems, higher Hospital Anxiety and Depression Scale scores, poor quotient of living , and low self-perceived health associated with increased risk of chronic fatigue: Regular exercise was associated with decreased risk of chronic fatigue Wong and Fielding 2010
• Parental physical abuse has been associated with chronic fatigue Clark et al, 2011

Vitamins

• 25-OH vitamin D levels are reduced in chronic fatigue Berkovitz et al, 2009
• Coenzyme Q10 levels are reduced in chronic fatigue Maes et al, 2009
• Serum alpha-tocopherol levels (a form of Vitamin E) are low in chronic fatigue and increase during remission Miwa and Fujita, 2010
• Reduced Vitamin B status has been reported in chronic fatigue Heap et al, 1999
• The Myers cocktail (magnesium, calcium, B vitamins, and vitamin C) has been reported to be of benefit Gaby 2002
• Hepar magnesium D10 has been reported to alleviate seasonal fatigue Baars et al, 2008

Antiviral agents

• Valcyclovir has been reported to be of benefit is a subset of patients with Epstein-Barr viral infection Lerner et al, 2007
• Raltegravir is a potent inhibitor of the XMRV virus Singh et al, 2010

Protective Drugs, Diets Vitamins and Vaccines (Clinical Trials)

• Preliminary studies suggest that melatonin may be of benefit Sánchez-Barceló et al, 2010
• Folinic acid has been reported to be of benefit in patients showing signs of Epstein-Barr virus reactivation Lundell et al, 2006
• lixu jieyu has been reported to be effective in a Chinese study Zhang et al, 2009
• Acetyl L-carnitine has been reported to be of benefit in elderly patients Malaguarnera et al, 2008
• High cocoa (dark) chocolate may ameliorate symptoms Sathyapalan et al, 2010
• Low sugar low yeast diets can be effective Hobday et al, 2008
• B lymphocyte depletion with the Anti-CD20 Antibody Rituximab has been reported to be of benefit (see autoimmunity below) Fluge et al, 2011

Biochemical effects

• Low levels of serum acylcarnitine have been reported Kuratsune et al, 1998
• Chronic fatigue is associated with mitochondrial malfunction Myhill et al, 2009.
• Reduced levels of ferritin have been reported in fibromyalgia Ortancil et al, 2010
• Nitric oxide metabolites (nitrates) increase at higher levels than controls after physical exertion in CFS patients Suarez et al, 2010
• Increased lipid peroxidation (free radical damage) positively correlated with triglyceride levels and lower HDL levels has been observed in female patients Brkic et al, 2010
• CFS patients have a lower neutrophil respiratory burst and natural killer cell cytotoxic activity Brenu et al, 2010
• A reduction in natural killer cell associated perforin levels has been noted Maher et al, 2005
• Genes related to immune modulation, oxidative stress and apoptosis are dysregulated in blood monocytes Gow et al, 2009
• Serum Immunoglobulin M levels directed against oleic, palmitic and myristic acid, malondialdehyde , azelaic acid, S-farnesyl-L-cysteine, and the N-oxide derivates, nitro-tyrosine, nitro-phenylalanine, nitro-arginine, nitro-tryptophan, and nitro-cysteinyl were significantly greater in CFS patients than in normal controls Maes et al, 2006
• Decreased serum levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation Maes et al, 2005.
• Reduced mRNA levels of oestrogen receptor beta in blood mononuclear cells Grans et al, 2007
• Elevated plasma concentrations of neuropeptide Y ( NPY ) have been reported Fletcher et al, 2010
• Increased oxidative stress as indexed by plasma peroxides and increased serum oxidised LDL Maes et al, 2011.
• CSF proteomic analysis : alpha-1-Antichymotrypsin alpha-2-Macroglobulin APLP1 Autotaxin , BEHAB CDNP1 Ceruloplasmin Chromogranin B Complement components C3 C4A C4B Gelsolin Haptoglobin IgG Hemopexin Keratin 6C Keratin 14 Keratin 16 Keratin 17 Orosomucoid 1 Orosomucoid 2 Secreted phosphoprotein 1 Baraniuk et al, 2005
• Salivary proteome: calgranulin A, calgranulin C, cyclophilin A, profilin 1, Rho GDP-dissociation inhibitor 2, proteasome subunit-a-type-2 and haptoglobin-related protein precursor: transaldolase and phosphoglycerate mutase I Bazzichi et al, 2009
• Low blood levels of cortisol have been reported, suggesting dysfunction of the hypothalamic-pituitary-adrenal axis Tak et al, 2011
• Upregulation of TGF beta expression in peripheral blood mononuclear cells in chronic fatigue patients Zhang et al, 2011.
  

Autoantibodies and immune

• Anti nuclear antibodies Nishikai, 2007
• Cardiolipin autoantibodies Hokama et al, 2009
• Lens epithelium-derived growth factor/transcription co-activator P75 (LEDGF/P75) Kuwabara et al, 2009
• microtubule-associated protein 2 (MAP2) and single stranded DNA Vernon and Reeves, 2005
• Muscarinic cholinergic receptor autoantibodies Tanaka et al, 2003
• Serotonin and phospholipid autoantibodies Klein and Berg, 2002
• An excess of ligand-free killer lectin KIR3DL1 and KIR3DS1 receptors may hamper the clearance of a pathogens via Natural Killer cells Pasi et al, 2011
• Evidence for immune activation including increases in IL-10, IFN-gamma, TNF-alpha, CD4+CD25+ T cells Brenu et al, 2011
• Decreased CD56 natural killer cell activity and increased IL2 receptor levels have been noted Nas et al, 2011
• A gene expression study in plasma identified a signature of 10 cytokines and chemokines which correctly identifies XMRV infected chronic fatigue patients with 93% specificity and 96% sensitivity Lombardi et al, 2011.
• Higher interferon gamma (IFNG), and higher IFNG/interleukin (IL)4 ratio, lower tumor necrosis factor-a and lower IL-10 at baseline were related to fatigue severity Ter Wolbeek et al, 2011
• CFS/ME patients displayed significant increases in IL10, interferon -gamma, TNF-alpha, CD4+CD25+ T cells, and FoxP3 and VPACR2 expression: The cytotoxic activities of natural killer cells were significantly decreased in CFS/ME patients. Additionally granzyme A and granzyme K expression were reduced and expression levels of perforin were significantly increased in CFS/ME Brenu et al, 2011
• Fibromyalgia is relatively common in primary antiphospholipid syndrome Costa et al, 2011
• Depression and fatigue during chronic Interferon alpha treatment were associated with alterations in the expression (OAS2) and transcriptional control (CREB/ATF) of genes linked to behavioral disorders including chronic fatigue syndrome and major depression, supporting an immune contribution to these diseases Felger et al, 2011.

Brain scans and physiology

• White matter volume was observed to decrease with increasing fatigue duration Barnden et al, 2011
• Higher Insular cortex reactivity has been associated with pain processing in fibromyalgia Kim et al, 2011
• Elevated glutamate/creatine levels have been observed in the ventrolateral preforntal cortex Feraco et al, 2011
• Hyperalgesia (increased sensitivity to pain) is seen for a variety of sensory stimuli, including electrical stimulation, mechanical pressure, heat and histamine. Various tissues are affected by generalised hyperalgesia: the skin, muscle tissue and the lungs. Generalised hyperalgesia is increased by sveral stressors like exercise and noxious heat pain. Nijs et al, 2011
• Impaired cardiac function is observed in CFS patients: (reduced cardiac mass and blood pool volumes, low end diastolic volume leading to impairments in stroke volume and cardiac output (the heart pumps less blood) Hollingsworth et al, 2011

The PACE trial involving adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and standardised specialist medical care.

Vaccine Adverse Event Reporting System (VAERS database )