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An overview of current biomedical research being carried out for Myalgic Encephalomyelitis. There are other sites where other research may be covered in more detail -  see our web links page.

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Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study

Øystein Fluge, Ove Bruland, Kristin Risa, Anette Storstein, Einar K. Kristoffersen, Dipak Sapkota Halvor Næss, Olav Dahl, Harald Nyland, Olav Mella

ABSTRACT

Background

Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.

Methods and Findings

In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m2 or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients.

The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8–44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6–10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.

Conclusion

The delayed responses starting from 2–7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS.

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Carcinoid tumour associated with enterovirus infection

EV Med Research, Lomita, California, USA.

ABSTRACT

Enteroviruses commonly infect the gastrointestinal tract, and replication of enteroviruses has been well documented in the Peyer patches of the small bowel.

Chronic enterovirus infection has been found in the stomach and terminal ileum of patients with myalgic encephalomyelitis/chronic fatigue syndrome. The authors report the unexpected finding of enterovirus VP1 protein, by immunoperoxidase staining, in carcinoid tumours found in one patient with myalgic encephalomyelitis/chronic fatigue syndrome and another patient with chronic lower quadrant abdominal pain, and suggest a possible association between enteroviruses and tumorigenesis. PMID: 21278394

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Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence

J Chia, A Chia, M Voeller, T Lee, R Chang

ABSTRACT

Aims: Enteroviruses are well-known causes of acute respiratory and/or gastrointestinal infections and nonspecific flu-like illness. Although enterovirus protein, RNA and non-cytopathic viruses have been demonstrated in the stomach biopsies of patients with myalgia encephalomyelitis/chronic fatigue syndrome (ME/CFS), causality for chronic diseases is difficult to establish without having well-documented cases of acute enterovirus infections. The aim of this study was to link acute enteroviral infection to viral persistence in patients with ME/CFS.

Method: Patients admitted to the hospital with acute febrile illnesses were screened for enteroviral infections. Acutely infected patients were followed longitudinally, and those who developed symptoms of ME/CFS underwent oesophagogastroduodenoscopy and biopsies of the antrum to document viral persistence by immunoperoxidase staining for viral protein and viral RNA assay.

Results: Three representative patients with different manifestations of acute enterovirus infections progressed to have chronic symptoms of ME/CFS. Persistent viral infection was demonstrated in the antrum years later.

Conclusion: After acute infections, enteroviruses can persist in patients resulting in manifestation of ME/CFS. Chronic enterovirus infection in an immunocompetent host may be an example of a stalemate between attenuated, intracellular viruses and an ineffective immune response.

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Intestinal intussusception in adults due to acute enterovirus infection

We report 3 adult cases of intestinal intussusception associated with enteroviruses occurring in the same geographic areas within a three-week period. Virologic studies include viral RNA detection in stool samples and staining for enterovirus protein by immunoperoxidase technique of the resected intestines. A new mechanism for intussusception associated with enterovirus is proposed. Tap water was implicated in the outbreak. Better monitoring of drinking water may prevent other cases of non-polio enterovirus infections.

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What are Enteroviruses - click here

CDC - Enteroviruses and Drinking Water - click here

 

 

 

Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome

Researchers at the Whittemore-Peterson Institute (WPI), the Cleveland Clinic and the National Cancer Institute report that 67% of 101 chronic fatigue syndrome (CFS) patients tested positive for infection with xenobiotic murine retrovirus (XMRV), a gammaretrovirus associated with a subset of prostate cancer. Only 3.7% of 218 healthy subjects tested were positive for the virus.

Abstract:
Chronic fatigue syndrome (CFS) is a debilitating disease of unknown etiology that is estimated to affect 17 million people worldwide. Studying peripheral blood mononuclear cells (PBMCs) from CFS patients, we identified DNA from a human gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV), in 68 of 101 patients (67%) compared to 8 of 218 (3.7%) healthy controls. Cell culture experiments revealed that patient-derived XMRV is infectious and that both cellassociated and cell-free transmission of the virus are possible. Secondary viral infections were established in uninfected primary lymphocytes and indicator cell lines following exposure to activated PBMCs, B cells, T cells, or plasma derived from CFS patients. These findings raise
the possibility that XMRV may be a contributing factor in the pathogenesis of CFS.

The WPI at the Invest in ME International ME/CFS Conferences -

 

 

Orthostatic symptoms predict functional capacity in chronic fatigue syndrome: implications for management

Objectives: To establish the relationship between the functional impairment experienced by Chronic fatigue syndrome (CFS) patients and the symptoms frequently experienced by those with CFS; specifically cognitive impairment, fatigue and orthostatic symptoms.

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See 2008 Conference Presentation Review

 

 

Increased D-Lactic Acid Intestinal Bacteria in Patients with Chronic Fatigue Syndrome

Patients with chronic fatigue syndrome (CFS) are affected by symptoms of cognitive dysfunction and neurological impairment, the cause of which has yet to be elucidated. However, these symptoms are strikingly similar to those of patients presented with D-lactic acidosis. A significant increase of Gram positive facultative anaerobic faecal microorganisms in 108 CFS patients as compared to 177 control subjects (p<0.01) is presented in this report. The viable count of D-lactic acid producing Enterococcus and Streptococcus spp. in the faecal samples from the CFS group (3.5×107 cfu/L and 9.8×107 cfu/L respectively) were significantly higher than those for the control group (5.0×106 cfu/L and 8.9×104 cfu/L respectively). Analysis of exometabolic profiles of Enterococcus faecalis and Streptococcus sanguinis, representatives of Enterococcus and Streptococcus spp. respectively, by NMR and HPLC showed that these organisms produced significantly more lactic acid (p<0.01) from 13C-labeled glucose, than the Gram negative Escherichia coli. Further, both E. faecalis and S. sanguinis secrete more D-lactic acid than E. coli. This study suggests a probable link between intestinal colonization of Gram positive facultative anaerobic D-lactic acid bacteria and symptom expressions in a subgroup of patients with CFS. Given the fact that this might explain not only neurocognitive dysfunction in CFS patients but also mitochondrial dysfunction, these findings may have important clinical implications.

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Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients.

Abstract: Chronic fatigue syndrome (CFS) is characterized by immune dysfunctions including chronic immune activation, inflammation, and alteration of cytokine profiles. T helper 17 (Th17) cells belong to a recently identified subset of T helper cells, with crucial regulatory function in inflammatory and autoimmune processes. Th17 cells are implicated in allergic inflammation, intestinal diseases, central nervous system inflammation, disorders that may all contribute to the pathophysiology of CFS. IL-17F is one of the pro-inflammatory cytokines secreted by Th17 cells. We investigated the association between CFS and the frequency of rs763780, a C/T genetic polymorphism leading to His161Arg substitution in the IL-17F protein. The His161Arg variant (C allele) antagonizes the pro-inflammatory effects of the wild-type IL-17F. A significantly lower frequency of the C allele was observed in the CFS population, suggesting that the His161Arg variant may confer protection against the disease. These results suggest a role of Th17 cells in the pathogenesis of CFS.

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Dr. Jonathan Kerr's work

Microbial infections in eight genomic subtypes of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME)

Lihan Zhang1, John Goudh1, David Christmas2, Derek Mattey3, Selwyn Richards4, Janice Main5, Derek Enlander6, David Honeybourne7, Jon Ayres8, David J Nutt2, Jonathan Kerr1,*

1 St George's University of London, United Kingdom;
2 University of Bristol, United Kingdom;
3 Staffordshire Rheumatology Centre, United Kingdom;
4 Poole Hospital NHS Trust, United Kingdom;
5 Imperial College London, United Kingdom;
6 New York ME / CFS Service, United Kingdom;
7 Birmingham Heartlands Hospital, United Kingdom;
8 University of Birmingham, United Kingdom

Correspondence to: Jonathan R Kerr, Dept of Cellular & Molecular Medicine, St George's University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom; jkerr@sgul.ac.uk

Accepted November 3, 2009

Abstract

We have previously reported genomic subtypes of CFS/ME based on expression of 88 human genes. In this study we attempted to reproduce these findings, determine specificity of this signature to CFS/ME, and test for associations between CFS/ME subtype and infection.

We determined expression levels of 88 human genes in blood of 61 new patients with idiopathic CFS/ME (according to Fukuda criteria), 6 patients with Q-fever associated CFS/ME form the Birmingham Q-fever outbreak (according to Fukuda criteria), 14 patients with endogenous depression (according to DSM-IV criteria) and 18 normal blood donors. In patients with CFS/ME differential expression was confirmed for all 88 genes. Q-CFS/ME patients had similar patterns of gene expression to idiopathic CFS/ME. Gene expression in endogenous depression patients was similar to that in the normal controls, except for upregulation of five genes (APP, CREBBP, GNAS, PDCD2, PDCD6).

Clustering of combined gene data in CFS/ME patients for this and our previous study (n=117 CFS/ME patients) revealed genomic subtypes with distinct differences in SF-36 scores, clinical phenotypes, severity and geographical distribution. Antibody testing for Epstein-Barr virus (EBV), enterovirus, Coxiella burnetii and parvovirus B19 revealed subtype-specific relationships for EBV and enterovirus, the two most common infectious triggers of CFS/ME.

http://jcp.bmj.com/content/early/2009/11/26/jcp.2009.072561.abstract

Antibody to parvovirus B19 nonstructural protein is associated with chronic arthralgia in patients with Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME)

Jonathan R. Kerr1,7, John Gough1, Selwyn C. M. Richards2, Janice Main3, Derek Enlander4, Michelle McCreary5, Anthony L. Komaroff5 and John K. Chia6

1 St George's University of London;
2 Poole Hospital NHS Trust;
3 Imperial College London;
4 New York ME/CFS Service;
5 Brigham & Women's Hospital, Harvard Medical School;
6 ID Med, Torrance, CA

Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) is a neuro-immune disease of uncertain pathogenesis.
Human parvovirus B19 infection has been shown to occur just prior to development of the onset of CFS/ME in several cases, although B19 seroprevalence studies do not shown any significant differences between CFS/ME and controls.

In this study, we analysed parvovirus B19 markers in CFS/ME patients (n=200), diagnosed according to Fukuda CDC criteria, and normal blood donors (n=200). Serum from each subject was tested for anti-B19 VP2 IgM and IgG (by Biotrin ELISA), anti-B19 NS1 IgM and IgG (by immunoflourescence), and B19 DNA by real-time PCR. CFS/ME patients and normal blood donors had a similar B19 seroprevalence (75% versus 78%, respectively).

Eighty-three CFS patients (41.5%) as compared with fourteen (7%) of normal blood donors tested positive for anti-B19 NS1 IgG ({chi}2= 64.8; P<0.0001; Odds ratio = 9.42, CI 5.11 – 17.38). Of these 83 patients, 61 complained of chronic joint pain, while 22 did not.

Parvovirus B19 DNA was detected in serum of 11 CFS patients and none of the controls by Taqman real-time PCR ({chi}2 = 9.35, P<0.002. Positivity for anti-B19 NS1 IgG was associated with higher expression levels of the human CFS-associated genes NHLH1 and GABPA.

As NS1 antibodies are thought to indicate chronic or severe courses of B19 infection, these findings suggest that although the seroprevalence of B19 in CFS patients is similar to controls, the immune control of the virus may not be efficient.

Full text - http://vir.sgmjournals.org/cgi/content/abstract/vir.0.017590-0v1

Dr Jonathan Kerr of Imperial College London, supported by the CFSRF, published a paper containing early results in the Journal of Clinical Pathology (J Clin Path 2005; 8:860-863, pdf format) in August 2005.

Fifteen genes were discovered to be up to 4 times as active in ME sufferers compared with a control group. Dr. Kerr is continuing his studies using a larger group of patients.

 


Last Updated: 10/11/2011