Fruitful and encouraging – that how we’d sum up the second CFS/ME Research Collaborative (CMRC) conference held in Newcastle from 13–14 October. The CMRC – the first of its kind in the world – was launched in 2013 at a event that included the Duke of Kent and our Patron the Countess of Mar (read the report) . Its aim is to promote the highest quality of basic and applied evidenced-based and peer reviewed research into ME/CFS by bringing together national agencies, ME/CFS charities, and working researchers from across the UK who wish to work towards that common goal.
In 2015, many of the main presentations were livestreamed, so people with ME and their families could watch the proceedings from home. As well as a series of keynote addresses (summarised below), there were presentations from MRC-funded research project leaders, followed by questions. Conference numbers were impressive, with over 75 professional delegates registered for the research conference, and around 30 Associate Member delegates (mainly patients and families) registered for the workshop, which included many of the researchers, on the first day.
Prof Stephen Holgate, Chair of the CMRC, opened by welcoming delegates. He was particularly enthused by the reports published in the US by the Institute of Medicine and the National Institutes of Health in 2015 which made recommendations about the way forward for ME/CFS. These have been summarised in an excellent report by the Advisory Committee which advises the Secretary of Health and Human Services in the USA (read the report). Prof Holgate pointed out that some of the recommendations mirror the concerns and objectives of the CMRC itself. The Institute of Medicine, for example, makes clear that ME/CFS can cause significant functional impairment and disability, and believes that rapid scientific discovery is within reach, even though there has been a long history of minimal funding for scientific research. As it said, “Innovative biomedical research is urgently needed to identify risk and therapeutic targets, and for translation efforts.“ Given this, Prof Holgate proposes to institute a “Grand Challenge” to clinicians and researchers to agree a case definition; to deliver a pan-UK approach to sub-phenotype ME/CFS using modern statistical approaches applied to clinical, physiological and routine pathological data; to collect biological samples suitable for ‘omics analyses’; and to use pathway analyses to identify causal mechanisms of disease. His welcome can be heard at this link.
In the keynote lecture, Prof José Montoya of Stanford University gave an overview of ‘Stanford ME/CFS: Collaboration, Innovation & Discovery’. He began his talk by asking for a minute’s silence in memory of Prof Martin Lerner, formerly Chief of the Division of Infectious Diseases at Wayne State University, who had been invalided by ME/CFS between 1988 and 1996, and who subsequently became a pioneer in the recognition and investigation of the illness.
Prof Montoya stated his “wish and dream that medical and research societies in the USA apologise to ME/CFS patients” for their attitudes in the past. He too described the 2015 Institute of Medicine report as a step forward, particularly in its recognition that ME/CFS is a physical illness. Interestingly, he gives cautious support to the Institute of Medicine’s proposed new clinical definition – Systemic Exertion Intolerance Disease (SEID) – which includes post-exertional symptoms and orthostatic problems. He thinks it may be a simple yet just-as-specific way for clinicians to make a diagnosis, and he cited recent work at Stanford showing a ‘good concordance’ between the SEID, Fukuda 1994 and Canadian 2003 definitions.
He outlined the background to his involvement in ME/CFS – and Stanford University’s interest in researching it, given the scale of the problem and the role of infections as precipitating factors. The large program of work now being undertaken at Stanford was pump-primed by an anonymous donation of $5 million, and today it has grown to include a range of collaborative studies involving randomised clinical trials, longitudinal and case-control studies, and smaller hypothesis generating investigations (see the list of studies at Stanford ME/CFS Initiative). The belief at Stanford is that a subset of cases of ME/CFS cases may be related to infection – symptoms may be triggered by the persistent activity of a bacteria or virus, or by the body’s own immune response to it. Prof Montoya is particularly open to collaborative ventures with other scientists, and has a special interest in the role of antiviral therapies (particularly valgancyclovir) for ME/CFS, feeling that they can help some patients if given for a lengthy period of time (see background). The evidence over last 33 years, he explained, is that ME/CFS is often triggered by infection leading to a neuro-inflammatory process. Fortunately, there is now “a precious opportunity to crack the most exciting scientific mystery” – we need to dream together and use all expertise to “turn a big corner and realise our dream”. His lecture can be heard at this link (begins 16 mins in).
Another keynote lecture was by Prof Jo Nijs who leads a unique program of research into ME/CFS in Brussels, and his focus was the problems experienced by ME/CFS patients after exercise and the role of the autonomic nervous system. He emphasised that ME/CFS is characterised by a dramatic increase in pain and other symptoms after exercise, a phenomenon not seen to the same extent in other illnesses. The main determinants of post-exertional symptoms can involve the immune or autonomic nervous systems and central sensitisation, and he discussed each of these in turn. Exercise has large immune effects in healthy people, but there is evidence that in ME/CFS it can increase complement activation, oxidative stress, or gene expression (read a review).
In the past, Prof Nijs has implicated brain-derived neurotrophic factor (BDNF), also produced by immune cells, in the development of ME/CFS, and this protein may also increase the excitability of the nervous system. Looking at the autonomic nervous system, he suggested that while Prof Julia Newton’s work had shown sympathetic impairment in ME/CFS, the role of the parasympathetic system may also be important. The vagus nerve, for example, contains 70% of the parasympathetic branch of the autonomic nervous system, but it also informs the brain about inflammation, and could be involved in dysfunctional responses to exercise, including in the recovery phases which may lack appropriate parasympathetic activity in ME/CFS, increasing pain. Prof Nijs also discussed the possibility that ME/CFS patients might have a dysfunction of endogenous analgesia (the body’s own way of reducing pain), something not seen in patients with other chronic illnesses such as rheumatoid arthritis. This aspect is, of course, allied to the problem of central sensitisation (an abnormal increase in the firing of nerve cells lying deep within the central nervous system) observed in ME/CFS and fibromyalgia patients. Prof Nijs’ full presentation can be viewed at this link (begins 3.40 min in).
Dr Øystein Fluge, University of Bergen, also gave a keynote lecture which reviewed his studies using rituximab in ME/CFS patients. He sketched out the scientific background to the rituximab programme, which started when researchers at Haukeland University Hospital noticed that one patient with ME/CFS experienced “unexpected and marked recovery of CFS symptoms lasting for five months during and after cytotoxic chemotherapy for Hodgkin’s disease”. The researchers conducted a pilot case series in 2009, and thereafter a phase II study of 30 ME/CFS patients. As the results were promising, further studies were planned and these are ongoing (read more background). They include a randomized, double-blind, placebo-controlled phase III study of 152 patients from five centres in Norway (four in university hospitals), who are being followed up for 24 months. The authors are also conducting a series of smaller studies, including one on patients with severe or very severe ME/CFS, using the same rituximab treatment protocol. The others are on endothelial functioning, similar to studies in Dundee showing that endothelial dysfunction can be present in ME/CFS; on exercise involving cardiopulmonary exercise testing; and on gastrointestinal function. Prof Fluge is clear, however, that he does not encourage the use of rituximab for ME/CFS outside of approved clinical trials, so we await the results of the phase III trial with great interest. Prof Fluge’s talk was not recorded.
Prof Jim Horne is a sleep neuroscientist at Loughborough University, and he gave a keynote lecture on sleep and its importance in human health. His main interests are the effects of sleep loss on body and brain, especially the prefrontal cortex; the influence that ageing has on sleep; and the different types of ‘sleepiness’ that can occur. As sleep disturbances are common in ME/CFS (see review), and are one of the key symptom complaints, he gave an overview of the range of sleep problems that can happen, particularly sleep apnoea and restless legs syndrome. Prof Horne stressed that very short (but not longer) daytime naps can be helpful, and that melatonin may be useful in some cases. Unfortunately, there seems to be no consensus as yet on the science behind sleep derangement in ME/CFS, but problems with initiation of sleep (i.e. with dropping off) and reduced slow-wave stage (non-rapid eye movement) sleep have been reported. Prof Horne’s talk was not recorded, but he has produced an informative review, Sleep – a thumbnail overview.
Prof Liz Perkins holds the William Rathbone VI Chair of Community Nursing at Liverpool University, and her keynote lecture was called ‘In search of a diagnosis – what the literature tells us about the patient experience’. She made particular reference to the Action for ME survey which found that it can take up to 2 years for patients to receive a diagnosis, during which a “diagnostic limbo-land” ensues. Prof Perkins explained that a diagnosis is a necessity in modern developed societies, but that the inability to identify the causes of illness presents particular problems. There is a vast literature on ‘medically unexplained symptoms’, but most of it is concerned with the healthcare provider experience; very little information exists on how patients defined their own experience of illness – the patient perspective is largely missing. Referring to Lisa Whitehead’s work on the illness trajectory in ME patients (read more), Prof Perkins reviewed the hopes of recovery in the early stages of illness, the experiences with GPs, the quest for treatments, and the individual’s development of strategies for coping with illness, including rest, pacing, pain medication and coping techniques. Prof Perkins presentation can be viewed at this link (begins 2.07 min in).
The final keynote presentation was on ‘big data’ – genomics, epigenetics and metabolomics – from Prof George Davey Smith (University of Bristol), an epidemiologist with a major interest in genetic epidemiology and its application in the identification of disease-causing biomarkers (see a profile). He pointed out that the literature on ME/CFS is replete with smaller studies with low sample sizes; while these may be useful for hypothesis generation, they can lead to erroneous conclusions. For this reason, the application of ‘big data’ to the field could be very useful, and various approaches using ‘omic platforms’ are available (including epigenomics, transcriptomics, proteomics, microbiomics, and metabonomics) and these need to be applied in ME/CFS, as Prof Hogate highlighted in his plans for a ‘Grand Challence”. Prof Davey Smith’s talk was not recorded.
There was an impressive number of posters this year. A call for abstracts had been launched with a closing date of 31 July 2015, and there were 33 successful submissions which were displayed in the poster room beside the main hall. Some described in more detail work already given in the shorter presentations, while others brought scientific work to a wider audience. For example, the poster from the UK ME/CFS biobank described progress to date: to July 2015, it had recruited 390 participants (245 ME/CFS cases, 101 healthy controls, and 44 patients with MS), 22,500 aliquot samples are stored, and the resource aims to open samples to research groups on a cost-recovery basis very soon. Other intriguing posters outlined early work on liver volume and its correlates (Newcastle University); muscle and mitochondrial function (University of Liverpool); cognitive behavioural therapy specifically for insomnia and sleep disturbances (Newcastle University); social care and the problems ME/CFS patients have accessing it (Action for ME); rituximab as a treatment in primary biliary cirrhosis (Newcastle University); immune responses in ME/CFS (University of Northumbria); orthostatic abnormalities in a large Dutch ME/CFS cohort (Radboud University Nijmegen); salivary cortisol levels in ME/CFS and hepatitis C patients (King’s College London); functional MRI studies in working memory tasks (University of Bristol); and multilevel analyses of the prevalence of ME/CFS in the population of Poland (Nicolaus Copernicus University, Bydgoszcz).
Prof Julia Newton discussed the studies that have been undertaken at Newcastle into cardiac anomalies in ME/CFS, with funding from ME Research UK (read more). She then outlined her new cardiac MRI studies, designed to confirm previous results using expanded sample sizes, in which there are preliminary indications of significantly reduced end-systolic and end-diastolic volumes, as well as a decrease in plasma volume. At present, the group is undertaking MIBG imaging of the heart, and this may determine whether abnormalities in cardiac sympathetic innervation underlie the autonomic system dysfunction seen in some people. Afterwards, she took questions on the value of saline infusions to increase blood volume in ME/CFS (see more), and on the potential value of supplying erythropoietin to people with ME/CFS. Prof Newton’s presentation can be heard at this link (43.40 min in).
The University of Bristol’s Dr Whitney General outlined the history of brain grey matter investigations in ME/CFS (see review), and described the voxel-based morphometric experiments she and her colleagues have planned to explore changes in grey matter volume in various brain regions and relate these to fatigue and cognitive performance. On a similar theme, Newcastle University’s Dr Andreas Finkelmeyer discussed the history of ‘brain white matter hyperintensities’ in the context of ME/CFS (read more), and described his recent study using FLAIR imaging which found that these are not commonly found in ME/CFS patients but were more related to ageing and, possibly, cognitive decline.
Dr Caroline Strachan from Leeds described the ME Research UK-funded study into fatigue in chemotherapy cancer patients and people with ME/CFS (read outline). The researchers are in the process of comparing B cell subsets in ME/CFS patients at presentation, breast cancer patients prior to treatment and healthy controls, and Dr Strachan described their early results. As well as comparing B cell phenotypes in the two populations, they are currently assessing the production of B cell cytokines following in-vitro stimulation. Dr Simon Collin (University of Bristol) gave an overview of the Collaborative on Fatigue Following Infection (COFFI) study, which is an international collaboration established to study post-infection fatigue and symptoms though the sharing of samples and data from cohorts around the world (UK, Netherlands, Norway, USA, and Australia). The aim is to understand why acute infections can sometimes trigger long-term debilitating symptoms. By bringing together many datasets, statistical power can be increased to investigate causes and risk factors.
Dr Rebecca Lambson (Newcastle University) presented some descriptive analyses of the MRC-funded work in Newcastle on the causes of fatigue using data from the UK primary Sjogren’s syndrome registry. As most primary Sjogren’s patients report fatigue as one of their most important problematic symptoms, Dr Lambson stressed the need for screening to ascertain all the other possible causes of fatigue in these patients, such hypothyroidism, depression, diabetes or anaemia. Eva Stormorken (University of Oslo), pictured below, described the aftermath of the contamination of public drinking water with the parasite Giardia lamblia in Norway. A small group of people developed post-infectious fatigue syndrome (PIFS), and her study described the course of their illness as determined from in-depth interviews. Her central message was that these patients did not receive proper help when required because of lack of knowledge among health professionals, and that an early diagnosis and interdisciplinary intervention could have been beneficial, avoiding the most severe disability and hastening improvement.
The key event of the first day was the workshop which was open to patients and their families who were Associate Members of the CMRC. The aim of the workshop session is to enhance engagement between researchers and patients, and the format was similar to the highly successful workshop session at the 2014 conference. The workshops fell into 5 groups: patient reported outcome measures, fatigue matters, autonomic nervous system, neuropathology, clinical trials, followed by a panel discussion.
Presentations from groups funded by the MRC
In a new funding announcement from the MRC, Dr Mark Edwards (St Georges London) described his MRC-funded project, which is also supported by the Sussex & Kent ME/CFS Society. It will involve fMRI imaging during a bout of exercise to assess the neural correlates of post-exertional symptom exacerbation to determine whether some symptoms of ME/CFS relate to maladaption of brain responses (see a report). Dr Esther Crawley presented some early results from the Avon Longitudinal Study of Parents and Children (ALSPAC) within which identification is being made of cases of ME/CFS. Dr Wan-Fai Ng (Newcastle University) described his use of primary Sjogren’s syndrome (an autoimmune condition with several clinical features similar to ME/CFS) as a disease model, undertaking a comprehensive analysis of the immune system to identify biological fingerprints and explore whether these biomarkers are present in ME/CFS patients. Prof Julia Newton (Newcastle University) described more of her results from her MRC award on the pathogenesis of ME/CFS, and Dr Alice Russell of King’s College London described work on an immunological model of fatigue, following patients undergoing interferon-alpha treatment for hepatitis C to identify biological measures useful for the prediction of the development of ME/CFS.
ME Research UK was represented by Vice-Chair Sue Waddle and Research & Operations Director Dr Neil Abbot. We were fortunate to meet up again with many old friends and allies, and to have some of the researchers we have funded in attendance, as the photo shows.
Special thanks go to the sponsors of this year’s conference – the MRC, Wellcome Trust and Arthritis Research UK. As the MRC has said of the collaborative, “We have been keen to bring together charities and researchers in this area, which is why we supported the setting up of the CMRC. The MRC hopes that the patients’ session at this conference will be beneficial to those trying to take the field further – both patients and researchers.”