A longitudinal study will be conducted of clinical presentation, immune phenotype, gene expression and virus infection among ME/CFS patients and MS and population controls frequency-matched by geographical area of residence, age-group (within 5 years), and sex. Clinical samples will be collected for studies of NK cell function virology (herpesvirus infection), and gene expression and for banking as a resource for future ME/CFS research. Hypothesis: ME/CFS is associated with immune dysfunction, which results from - or predisposes to - herpesvirus infections. Immune dysfunction will present as alterations in NK cell function that may lead to, or result from, alterations in cytokine production and altere expression of diverse immune-associated genes. Finally, we predict that the ME/CFS immune phenotype may fluctuate over time and in association with clinical presentation and that the majority of patients clinically characterized as having ME/CFS will show a biosignature distinct from that of controls, and that further alterations will be seen during episodes of clinical exacerbation. Activities and objectives: i) Collect clinical and other data and venous blood samples at baseline and 6 months or at another time during the 6-month follow-up period when there is a perceived """"""""significant"""""""" deterioration in symptoms;ii) Analyze blood samples for NK cell phenotype and function;iii) Screen samples for evidence of herpesvirus infection and viral load, focusing on Epstein Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus-6 (HHV-6);iv) Describe clinical phenotype and fluctuations over time;v) Correlate the presence of symptoms and severity with markers of virus activity and immune function;vi) Investigate gene expression profiles associated with ME/CFS and how they vary in relation to changes in disease severity, virus activity, NK cell function, and other markers of immune function;and vii) Securely store blood samples from patients and controls, anonymously linked to clinical and other data, as an open resource for researchers to conduct ethically-approved studies of ME/CFS. Recruitment: 150 ME/CFS cases (50 severe, 100 non-severe), 75 MS controls, and 75 healthy controls will be recruited. For immunology and virology, 100 cases, 50 MS controls, and 50 healthy controls will be sampled at 2 time points. For gene expression, we will analyze 50 ME/CFS cases, 25 MS and 25 healthy controls, each at recruitment and one follow-up. Cases will be selected from UK ME/CFS Disease Register and NHS ME/CFS specialty and primary care services in London and Norfolk, Suffolk, and Great Yarmouth and Waveney, UK;MS controls via the NHS;and healthy controls will be identified by ME/CFS patients (excluding blood relatives) or GPs. Outcomes: Identification of putative biomarkers for diagnosis, severity, and prognosis of ME/CFS, which can be evaluated in larger (ideally prospective) future studies. In the long term, identification of robust biomarkers will allow clinicians to correlate ME/CFS phenotype (including clinical presentation, genetic, immune, and viral markers) with disease severity and prognosis and may reveal new options for interventions research.

Public Health Relevance

This is, to our knowledge, the first longitudinal study of ME/CFS to incorporate both mild and severe cases, age, sex, and residence-matched Multiple Sclerosis (MS) and healthy controls, and to incorporate virological, immunological and gene expression data into the same study. There is a clear need for research in these areas, and the inclusion of severe cases using home visits will allow for research on a subset of patients often neglected in ME/CFS studies. Because approximately 1-4 million Americans have ME/CFS, this study has the potential to impact the lives of a large patient population in the US as well as advance the state of the field in the US, UK, and globally through the potential identification of evidence related to disease etiology and pathophysiology as well as disease subtypes and biomarkers, revealing potential routes for treatment.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CFS-M (80))
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Beisel, Christopher E
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London School/Hygiene & Tropical Medicine
United Kingdom
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Nacul, Luis; Lacerda, Eliana M; Kingdon, Caroline C et al. (2017) How have selection bias and disease misclassification undermined the validity of myalgic encephalomyelitis/chronic fatigue syndrome studies? J Health Psychol :1359105317695803
Nacul, Luis; Kingdon, Caroline C; Bowman, Erinna W et al. (2017) Differing case definitions point to the need for an accurate diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome. Fatigue 5:1-4
Lacerda, Eliana M; Bowman, Erinna W; Cliff, Jacqueline M et al. (2017) The UK ME/CFS Biobank for biomedical research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Multiple Sclerosis. Open J Bioresour 4: