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New Horizons 2008: International Conference on ME/CFS Biomedical Research

• Morning session
• Afternoon session

Afternoon session

The afternoon session began with an overview of the Whittemore Peterson Institute for NeuroImmune Disease, University of Nevada, by Dr Dan Peterson one of the co-founders, who also discussed some of the work currently underway or planned. The aim of the Institute is to be a comprehensive medical research facility devoted to patients with neuro-immune diseases such as ME/CFS, atypical multiple sclerosis, fibromyalgia, and other similarly presenting illnesses which account for billions in lost wages and increased healthcare costs yet receive relatively little attention or funding at the National Institutes of Health or the CDC. At present, the institute is under construction within the Center for Molecular Medicine on the campus of the University of Nevada, Reno, School of Medicine, and is scheduled to open formally in late summer 2010. This $70 million project brings basic researchers, clinical doctors and patients together to facilitate the exchange of new ideas and better communication.

Since its inception, the Institute has focused on research into the pathogenesis and aetiology of a subset of ME/CFS patients manifesting primarily neurological symptoms and concomitant laboratory abnormalities of the innate immune system. Additionally, translational studies have been instituted with respect to techniques to determine functionality and to explore promising therapeutic agents. In addition, as ME/CFS is a significant contributor to the financial burden, as well as functional disability, of the society at large, new approaches with respect to patient management are being encouraged and a structure to implement these patient-centred cost-effective approaches are being designed and implemented.

Dr Peterson (pictured) explained that disability carriers, as well as pharmaceutical companies, are seeking objective endpoints to determine the extent of disability and measure improvement in patients undergoing therapeutic strategies. Exercise tolerance testing with expired gas exchange has been widely published as a technique that is useful diagnostically, as well as for establishing therapeutic endpoints. A recent study done in collaboration with the University of the Pacific documented significant changes in a unique fashion in a sequential exercise tolerance test performed over a two-day interval. Additional studies to reproduce this finding and determine utility in therapeutic trials are currently being planned.

A subset of patients severely affected with ME/CFS with evidence of viral reactivation has been documented to demonstrate a gamma T-cell clonal rearrangement. Studies are currently underway to determine the monoclonality and antigen specificity of this unusual T-cell rearrangement, as well as intensive studies into the possible role of viruses in development of neoplastic disorders in a subset of chronically affected ME/CFS patients. Again, perturbations of the RNase L/2-5A synthetase antiviral pathway have been widely reported in a subset of patients, and RNase L studies are currently underway to further characterise this previously described abnormality and its significance to symptom development in people with ME/CFS.

Collaborative studies are ongoing, utilising a standardised viral array with the goal of identifying potentially treatable subsets of patients with a common virally induced aetiology that may be amenable to specific antiviral therapy. Cytokines have widely been implicated as mediators of symptomatology, both in the CNS and peripherally in patients suffering from ME/CFS. Dr Peterson explained that large-scale studies will be carried out to explore the presence of a variety of cytokines and functionality in patients and a large number of controls to further characterise potential patterns that may be useful diagnostically and potentially therapeutically. Recently, the specialised field of informatics has been utilised to analyse and manage complex inter-relationships involving multiple variables longitudinally; a model for applying informatics to mine data and reset the paradigm for ME/CFS has been proposed.

Dr Faisel Khan (The Institute of Cardiovascular Research, University of Dundee) described how his keynote lecture represented the work of a very active group which has uncovered a range of findings on ME/CFS patients in scientific papers from 2003 to 2007. These include increased oxidative stress, abnormally sensitive acetylcholine metabolism, and increased neutrophil apoptosis — specifically a larger proportion of dying (apoptotic) cells than in healthy subjects — consistent with an activated inflammatory process which is possibly the consequence of a past or present infection.

Dr Khan described his specific work on vascular function, and began by explaining the accumulating evidence that many patients have associated cardiovascular symptoms such as autonomic dysfunction, and attenuated heart rate and blood pressure regulation with increased vasomotor tone and loss of beat-to-beat heart rate control; such symptoms can contribute to destabilisation of blood pressure and orthostatic intolerance and, in the more severe CFS cases, a reduced cardiac output. Endothelial function is an important regulator of vascular function and is a well established marker of future cardiovascular events.

He explained how the group at Dundee had previously studied the vascular response in the forearm skin microcirculation to an endothelium-dependent vasodilator (acetylcholine, ACh) and found that CFS patients exhibited significantly enhanced vascular responses to ACh compared with control subjects. In a further study, they have demonstrated that the ACh sensitivity may be explained by prolonged action of the vascular response to ACh. Enhanced sensitivity to ACh is not normally consistent with elements of endothelial dysfunction and increased cardiovascular risk. ACh sensitivity in CFS patients may be a consequence of a free radical attack on acetylcholinesterase expression on the vascular endothelium giving rise to a reduced expression of the enzyme, resulting in the prolongation of the ACh response.

Dr Khan (pictured with his student Ken Chan and Dr Neil Abbot of ME Research UK) explained that his recent work concerned arterial stiffness, and the fact that the results showed arterial stiffness to be significantly elevated in CFS patients compared with control subjects (click here for a more exhaustive discussion of this work). The degree of “stiffness” was associated with levels of serum C-reactive protein (CRP), pointing to a role of low grade inflammation and oxidative stress. Thus the combination of augmented arterial stiffness and increased inflammation and oxidative stress may result in unfavourable haemodynamics. Increased arterial stiffness and inflammation might be regulated by levels of vitamin D, and the group are currently exploring the possible association between vitamin D and vascular function in these patients. In addition, the group is testing both focal endothelial function in the brachial artery and global endothelial function in smaller pre-resistance arteries, and also coronary flow reserve.

In his keynote lecture, Dr Jonathan Kerr (Department of Cellular and Molecular Medicine, St George’s University of London) described the background to the molecular studies that he has been conducting over the past four years. In previous work, he characterised gene expression in peripheral blood from 25 patients with ME/CFS, and 50 normal blood donors using the Affymetrix U133+2 microarray. Genes showing differential expression were further analysed using quantitative polymerase chain reaction in 55 patients with ME/CFS and 75 normal blood donors. Differential expression was confirmed for 88 genes, 85 of which were upregulated and three downregulated. Highly represented functions were haematological disease and function, immunological disease and function, cancer, cell death, immune response and infection. Clustering of data from patients with ME/CFS revealed seven distinct subtypes with distinct differences in Medical Outcomes Survey Short Form-36 scores, clinical phenotypes and severity.

In the most recent study which he described, the group determined for each CFS subtype the fold difference of each of the 88 CFS-associated genes compared with normal persons. Using a fold-difference cut-off of greater than 1.5, those genes that were differentially expressed in each CFS subtype were determined. As Dr Kerr (pictured right with Dr Enlander) explained, genomic analysis revealed some common (neurological, haematological, cancer) and some distinct (metabolic, endocrine, cardiovascular, immunological, inflammatory) disease associations among the subtypes. Subtypes 1, 2 and 7 were the most severe, and subtype 3 was the mildest. Clinical features of each subtype were as follows: subtype 1 (cognitive, musculoskeletal, sleep, anxiety/depression); subtype 2 (musculoskeletal, pain, anxiety/depression); subtype 3 (mild); subtype 4 (cognitive); subtype 5 (musculoskeletal, gastrointestinal); subtype 6 (postexertional); subtype 7 (pain, infectious, musculoskeletal, sleep, neurological, gastrointestinal, neurocognitive, anxiety/depression).

Dr Kerr explained that it was particularly interesting that there was evidence that the seven genomically derived subtypes were associated with distinct clinical syndromes, and that those which were most severe were also those with anxiety/depression, as would be expected in a disease with a biological basis. It remains to be determined what these subtypes represent, as they appear to be biologically meaningful, and to discover their natural history and possibilities for treatment. The team have already begun a study to develop a test based on human single nucleotide polymorphisms (SNPs) (read more here) which could reliably determine subtype status in individuals.

Prof. Birgitta Evengård (Clinic Infectious Diseases, Umeå University, Sweden) gave the pentultimate lecture of the day on the role of the Swedish twin registry in searching for a biomarker for the illness. She described the ongoing work on characterising the epidemiological patterns and the role of genes and environment in the most severe phenotype of fatigue illnesses, the chronic fatigue syndrome (CFS), in a representative sample of the Swedish population. In the project, collection of epidemiological data, clinical and biological data, psychological and socio-demographic data are included, all evaluated with a gender perspective. The aim is to describe the prevalence of conditions characterised by chronic fatigue and their risk factors in patients and affected twins, the latter compared to their healthy co-twins. The population-based design enables the possibility of evaluating the validity of the CFS definition and, through molecular epidemiology, identify biological determinants of potential value for diagnosis.

The registry assesses twins aged 42 to 65 years old (n=31,406) for chronic fatigue from a telephone-based interview with the aim of identifying candidate twin pairs for further clinical, psychometric and biological sampling. To date, the team have collected and thoroughly reviewed all available medical records (n=2,489) for 1,779 individual twins with the strongest complaints of fatigue. Also, a web-based questionnaire for the age-group 18 to 42 years identified possibly discordant monozygotic twin pairs. In all, 33 pairs of monozygotic twin pairs discordant for CFS have been identified, and most have undergone medical examination, blood chemistry (sedimentation rate, white blood cell count, liver and renal function, thyroid hormones), serum proteomics, and screening of cerebrospinal fluid for molecular virus. In addition, mRNA-expression is under analysis as is the testing for virus and the cytokine array. To date, two known viruses have been detected in the cerebrospinal fluid through the molecular virus screening.

The preliminary results indicate little difference between affected and unaffected twins as regards age, education or occupation. Sleep difficulties, cognitive impairment, myalgia and joint pain seem to be the most common symptoms. Interestingly, oestrogen may be important, as expression of one of the oestrogen receptors was reduced in patients. In addition, an HPA axis disturbance has been observed.

In the final presentation of the day, Dr Stephen Graves (Director, Australian Rickettsial Reference Laboratory, New South Wales, Australia) shared with the audience his wide experience of “Q Fever” (Coxiella burnetii), “Flinders Island Spotted Fever” (Rickettsia honei strain marmionii) and their possible relationship to CFSCFS. He explained that a period of fatigue after an infectious disease is a well-recognised phenomenon, which when it lasts for months and is referred to as “post-infectious chronic fatigue”. The Q-fever research group hypothesise that many cases of CFS are really “post-infectious chronic fatigue” and that a proportion of these cases are sequelae arising from Q Fever (infection with Coxiella burnetii) or Flinders Island Spotted Fever (infection with Rickettsia honei, strain marmionii). These two bacteria have an obligate, intracellular life style (as do viruses), passing between eukaryotic cells of vertebrates (bush mammals, reptiles, humans) and invertebrates (ticks). Post-typhus chronic fatigue Flinders Island Spotted Fever was first reported in Australia in 1940 but recent data (2008) shows the persistence of rickettsiae in peripheral blood mononuclear cells of affected patients.

Post-Q Fever chronic fatigue was first reported in Australia in 1996 and has now been confirmed by others. Antigen from C. burnetii persists in the patient’s bone marrow and peripheral blood mononuclear cells. The persistence of the microbial antigens in the patient appears to cause a dysregulation of the cytokine cascade leading to ongoing fatigue in a genetically predisposed subpopulation. If the group’s hypothesis is correct, public health measures to reduce rickettsial infections (e.g., by enhanced Q Fever immunisation) may have a positive impact on the incidence of CFS.

In a poster presentation accompanying the talk, Dr Graves with the Adelaide Q fever Research Group and collaborators explored further the issue of post-infection fatigue states of varying duration, which are familiar after viral, bacterial and protozoal infections. Of interest was a subgroup observed after infection with a range of obligate or facultative intra-cellular, or cell-dependent bacteria — especially the macrophage pathogens. During the period 1993 to the present, studies of Q fever yielded the following conclusions: that post-Q fever Fatigue Syndrome follows about 10 to 20% of clinically overt cases of acute primary Q fever and matches the standard CFS definitions; that patients with post-Q fever Fatigue Syndrome exhibit significant variant patterns of cytokine responses (IL-6, IFN gamma and IL-2) compared with various controls, when their peripheral blood mononuclear cells are stimulated with Q fever and control antigens in short term cell culture; that immunogenetic studies have shown significant frequency differences (i.e., gene polymorphisms), between post-Q fever Fatigue Syndrome on the one hand, and on the other hand, Q fever endocarditis, asymptomatic Q fever convalescents and unexposed population control panels. Overall, precipitating factors appear to be overt not subclinical infection (perhaps reflecting heavy seeding with coxiella components).

Our thanks go to Regina Clos for some of the photos of the day, and the complete selection of her photos, including of the beautiful town of Cambridge, can be found at her website CFS-aktuell. But our most grateful thanks go to the 130 delegates who came a long way to attend, and who — judging by the overwhelmingly positive feedback forms — found the experience educational and most importantly great fun!

You can order your copy of the 4-DVD set of the presentations by contacting our headquarters; the special “Energising ME Research” price is £5 (P&P included within the UK) for the set, and please make cheques out to “ME Research UK”. We can also take credit/dedit card orders over the phone.

• Morning session
• Afternoon session

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