The 12th International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFS/ME) Conference was held in Fort Lauderdale, USA from 27–30 October 2016. The conference had a theme of ‘Emerging science and clinical care’. Here is part 2 of Dr Rosamund Valling’s summary of the discussion. Read part 1 here
Session 6: Symptom provocation studies 1
J.Mark Van Ness and his team (Stockton CA, USA) showed how cardiopulmonary exercise testing demonstrates post-exertional chronotropic incompetence. This is the inability of the heart to increase its rate commensurate with increased functional demands. He concluded that those with ME/CFS appear to display post-exertional reductions in the peak heart-rate response to exercise. This could contribute to exercise intolerance and observed reductions in oxygen consumption during PEM. The combination of elevation in resting heart rate and reduction in peak exercise heart rate may contribute to the impaired quality of life. For the test, they used the fittest of the patients, so admit the results may not be entirely accurate.
Lily Chu (California, USA) explained how the symptoms of PEM are sometimes delayed and often prolonged. Of 150 subjects studied, 129 (89%) experienced PEM with both physical/cognitive exertion and emotional distress. Fatigue was the most commonly exacerbated symptom, but subjects also experienced many of the characteristic symptoms of ME/CFS. Eleven per cent reported a post-trigger delay of at least 24 hours, and 23% endured PEM for three or more days. It is important that, in the future, researchers need to enquire about the wide range of symptoms experienced associated with PEM, and capture the various time courses of PEM.
Sarah Knight (Melbourne, Australia) had looked at cognitive function in adolescents with ME/CFS. She found that adolescents with ME/CFS are slower to process information, and have less capacity to sustain attention before and following cognitive exertion. Clinicians and schools need to be aware of these difficulties. Schools need to support these young people appropriately in the school environment.
Session 7: Public health
Leonard Jason (Chicago, USA), in estimating the rates of paediatric ME/CFS in a community-based sample, said that children were under-diagnosed or misdiagnosed. Deciding which case definition to use to estimate prevalence data is imperative. Exclusion of other illnesses will be more restrictive, while the IOM criteria are more general and encompassing, clinically.
Peter Rowe (Baltimore, USA) discussed a two-year follow-up on impaired range of motion (ROM) in adolescent ME/CFS. He found that those with impaired ROM noticed significant improvement in ROM scores over two years in association with multi-modal therapy. This was also associated with some functional outcomes. The independent contributions of specific forms of physical therapy versus general increases in activity to improvement in ROM scores warrant further study.
Susan Levine (New York, USA) presented work on allergic disorder phenotypes and patterns of medical co-morbidity and clinical dysfunction. Their object was to determine whether certain allergic disorders are more common in ME/CFS. They found that a history of sinusitis and hives is predictive of an ME/CFS diagnosis, and appears to define a novel phenotypic subset, with distinct patterns of co-morbidity and exaggerated pain symptoms. Further studies will look at whether there is a Th2 shift and secretion of mast cells, which may alter pain pathways. Mast cell-associated disorders may include: migraine, CRPS, FM, etc. Those with ME/CFS coupled with sinusitis/hives may be a distinct subgroup, with unique patterns of co-morbidity. This could help predict possible therapeutic responses.
Gordon Broderick (Alberta, Canada) explored the role of sex hormones in driving symptom severity. Women are more often affected with this illness, often with disruption in menstrual cycles and immune function. Results of their study indicate that, particularly, the effects of testosterone and oestradiol on fatigue severity in ME/CFS vary according to progesterone levels when controlling the menstrual cycle and menopause.
- Sagherian (Baltimore, USA) reported on fatigue in nurses and absence from the workplace. This is particularly relevant in shift workers. Insomnia (27.5%) and sleep apnoea (17.5%) were found to be associated with fatigue, and were often associated with ongoing chronic fatigue, leading to work absence. Nursing management needs to monitor for fatigue, including screening of nurses for sleep apnoea.
Raymond Perrin (Manchester, UK) discussed the accuracy of a physical screening tool for ME/CFS, using his osteopathic background. Five specific physical signs were used. The most accurate signs used to achieve an ME/CFS diagnosis were thoracic spine dysfunction, coeliac plexus tenderness and chest tenderness. These signs can be an effective aid to diagnosis.
Katherine Rowe (Melbourne, Australia) discussed the demographics of young people diagnosed with ME/CFS in Victoria, Australia. The male to female ratio was 1:3, and mean age of onset was 14.6 years. The rural/urban mix was proportionate to the population, but the ethnic mix was not representative of the population of the state or of the hospital clientele. Eighty per cent had an Anglo-Celtic background (approximately 25% of the population), predominantly of Scottish/Irish descent. Another 11% had a northern European background. No Middle-Eastern or African patients were seen. Three out of five of Asian descent had a Caucasian parent.
Ninety per cent reported a defined onset following infection (commonly EBV), and gradual onset was more commonly associated with OI and hyperextensible joints. There was occasional association with endocrine disorders, overtraining in athletes or after neurological insult. Depression and anxiety were reported at only marginally higher rate than in the adolescent population.
Session 8: Research on autonomic functioning and co-morbidities
Madison Keefe (Washington DC, USA) — Her study was to determine if those with ME/CFS developed postural tachycardia after exercise, and to look at the contributions of heart-rate variability, sympathetic and parasympathetic dysfunction. Two groups were studied: START (Stress Test Activated Reversible Tachycardia) and STOPP (Stress Test Originated Phantom Perception). There was a significant increase in ΔLFa (sympathetic modulation) after exercise in the START group, suggesting the postural tachycardia was due to sympathetic activity. The postural tachycardia was dependant on exercise, which differentiates this finding from OI identified by tilt-table testing. This may relate to brain stem atrophy as reported in the START groups, and may relate to autonomic dysfunction.
James Baraniuk (Washington DC,USA) — Dolorimetry is used for pain measurement. The objective of the study was to determine the distribution of pressure-induced tenderness using dolorimetry for 18 tender points in ME/CFS, FM, GWI and SC women, and to see if this could discriminate between the groups. GWI was distinct from ME/CFS and the other groups both by their history, symptoms and systemic hyperalgesia.
Kunihisa Miwa (Miwa Naika, Japan) focused on truncal ataxia in ME/CFS. He found that those with ME/CFS and a positive Romberg test had not only OI, but also experienced sitting intolerance. Truncal ataxia or disequilibrium appears to play an important role in the genesis of postural intolerance and is a useful sign of advanced disease.
Session 9: Advances in brain research and neurological studies
Benjamin Natelson (New York, USA) reviewed the assessment of neurobiological dysfunction in ME/CFS. There were no differences in neurobiological abnormalities between ME/CFS patients, with or without psychiatric diagnosis. However, significant differences in the number of abnormal spinal fluids, ventricular lactate, cortical glutathione and cerebral blood flow between ME/CFS and control groups were found. Future research may show these to be potential biomarkers in ME/CFS.
James Baraniuk (Washington DC,USA) found disruptional connectivity in GWI and concluded that the simple 0-back test (see a letter, push a button) was sufficient to identify significant differences in brain function between controls and GWI phenotypes. These patterns offer models for potential pathological differences that may discriminate between ME/CFS phenotypes.
Dane Cook (Madison WI, USA) had looked at functional neural consequences of PEM in ME/CFS. Acute exercise was shown to exacerbate symptoms, impaired cognitive performance, and affected brain function. This illustrates the potential detrimental effects of PEM for ME/CFS patients.
Session 10: Symptom provocation studies 2
Betsy Keller (New York, USA) chaired this session and summarised the important studies described at this conference so far, leading to the current state of our knowledge. These included the work of:
- Olav Mella and Øystein Fluge — immunology and treatment
- David Patrick — metagenomics
- Ludivic Giloteaux — microbiome
- Peter Rowe — dysautonomia
- Susan Levine — allergy profile.
Katarina Lien (Oslo, Norway) found that blood lactate increases more rapidly after a previous exercise challenge in those with ME/CFS. She found they had a higher level of lactate at baseline and work rate compared to healthy controls. The first exercise test seems to induce an earlier lactate accumulation in patients when retested the next day. The ME/CFS patients had a decreased physical capacity compared to healthy controls, but the change in peak VO2 after repeated CPET did not discriminate between patients and controls. The lactate increase also occurs in excessive overtraining in athletes, as they begin to produce more lactate. This finding overlaps with ME/CFS.
Betsy Keller (New York, USA) had looked at subsets of ME/CFS patients’ responses to a two-day CPET. She looked for a change of more than 7% in VO2 peak on day two and at a decrease in VO2@VAT of more than 13%. Disruption of autonomic and ventilatory responses as indicators of inappropriate recovery (PEM) should be considered. In addition, she incidentally reported that of a pair of twins, the microbiome of the affected twin showed less variety of bacteria.
Peter Rowe (Baltimore MD, USA) discussed how their studies have shown that longitudinal neural and soft tissue strain can provoke symptom intensity in ME/CFS, particularly in the limbs and spine, for up to 24 hours. This helps to understand why exercise and other activities of daily living might be capable of provoking symptoms.
Maureen Hanson (Ithaca NY, USA) showed that by mass spectrometry, hundreds of metabolites can be identified in the circulation; 361 metabolites were reviewed. Plasma metabolites differed between patients and controls at baseline, and before and after exercise by a pair of identical twins discordant for ME/CFS. Twenty-nine metabolites were lower in the ME/CFS patients, and four were higher — this is described as a hypometabolic state. Amino acids, fat metabolism and energy and sugar metabolism are all affected. It is probable that a diagnostic test can be developed using blood metabolites, but these results need to be replicated in a larger cohort at baseline.
Session 11: Genetics research
Benjamin Eike (Davie FL, USA) had looked at 203 Single Nucleotide Polymorphisms (SNPs) in ME/CFS. Review of the genetic data resulted in three SNP variants of interest. These three SNPs reside within the NDUFS7 gene, which codes for a subunit of NADH dehydrogenase. NADH dehydrogenase is an important complex within the mitochondrial electron transport chain, and takes part in the production of ATP in aerobic respiration. These SNPs did not meet the criteria for a genome-wide association study, but future studies should be performed to determine their significance.
Mary Jeffrey (Miami FL, USA) reported on using gene expression modules to identify gender-specific treatments in ME/CFS. The focus was on finding expression patterns related to the immune and inflammatory processes. There was evidence of immune dysregulation. Identification of these gene modules and relevant pathways associated with immune and inflammatory biology can lead to the development of immune-modulating based treatment strategies. Immuno-suppressants and hormone-based therapies were identified as potential candidates for treatment.
Wilfred de Vega (Toronto, Canada) — Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. The objective for this study was to examine the DNA methylome in immune cells in ME/CFS to determine its association with the cellular response to glucocorticoids, and its interaction with symptoms. Results indicate that the epigenetic modifications are a feature of ME/CFS, and there is a potential role for epigenetic modifications in disease manifestation and glucocorticoid hypersensitivity in some patients. The differentially methylated loci could direct work towards biomarkers to improve diagnosis and clinical subtyping.
Paula Waziry (Ft Lauderdale FL, USA) discussed miRNA analysis, in-situ hybridization and STAT1 localization upon stress trigger. The STAT1 pathway is the first line of defence against viral infections. Preliminary studies showed that ME/CFS patients might express higher levels of EBV proteins, and are therefore more prone to viral reactivation from latency. Abnormal nuclear morphology of ME/CFS resembles aging disease. Cells tend to be wrinkled and puckered and show large nucleoli. Further studies should lead to key strategies for therapy.
Jose Montoya (Stanford CA, USA) reported on a very large gene expression study on ME/CFS patients, which provides support for an inflammatory or immune-mediated basis for this disease. By understanding the biologic basis of this disease better, development of future diagnostics and therapy will likely be possible.
Medical education proposals for ME/CFS
Susan Levine (Ithaca NY, USA) chaired this discussion session, where each of the three participants presented an overview of what was happening in their areas.
Mady Hornig (Columbia University , USA) discussed their fellowship training programme in medical schools. They are developing a training programme to create awareness, fill gaps in understanding and pathogenesis. It is hoped to develop a new cohort of clinicians and scientists who will be knowledgeable about the range of clinical and laboratory findings found in complex immune-mediated disorders such as ME/CFS. What happens at first is often an introduction to research experience, focused on clinical study design, epidemiology and key strategies for biomarker identification. This covers many disciplines, as well as training in medical ethics.
Anthony Komaroff (Boston, USA) then discussed potential post-graduate programme development. He emphasised that a researcher needs clinical experience. ME/CFS is not taught in their medical schools, so additional training is needed. There are two types of research: laboratory (test tube) and clinical (people). Attention to analysing data must then be included. The curriculum should include the following: clinical epidemiology, biostatistics, analysing outcomes, defining quality of care, health service research and conduct of clinical trials.
Dan Peterson (Nevada, USA). In his area, there are no programs that are accredited for fellowships in ME/CFS. The Simmaron Institute has an established two-year clinical program with multi-site collaboration. He presented a flow chart showing the building of a three-year fellowship opportunity. He described a number of obstacles in building the program, including recruiting and funding.
There were 80 posters displayed demonstrating the enormous amount of research and work now going into solving the many riddles of this complex illness. This certainly shows much hope on the horizon for the many with the illness and for those involved in the clinical aspects.
Summary of conference
Anthony Komaroff (Boston, USA) gave his usual brilliant overview of the conference with reference to many of the papers and posters presented.
He began by stating that the IOM reports this as a biologically based illness. There have been announcements of expanded research activities by the NIH and educational efforts by the CDC.
Evidence from this meeting covered PEM, immunological findings, microbiome studies, brain research, epigenetics, energy metabolism, diagnostic testing, treatments and the formation of multi-site consortia.
Post-exertional malaise (PEM) is triggered physically and cognitively more so than by emotional distress. PEM includes fatigue, cognitive difficulty, sleep disturbances, headache, myalgia and flu-like symptoms. PEM lasts for up to three days in 25% of patients.
Studies of PEM show:
- There are triggers of characteristic gene expression (15 cytokines and growth factors).
- It is produced by exercise, and 24 hours later there is a decline in peak heart rate.
- Leads to tachycardia after exercise (as contrasted to altered tilt table test) — this is due to increased sympathetic activity. This also occurs in GWI.
- Leads to lower oxygen consumption and early conversion to anaerobic metabolism.
- Lactate levels in second test are higher compared to controls, which are lower.
- 15 out of 51 cytokines and growth factors are significantly different.
- Most cytokines were pro-inflammatory, and levels correlated with symptom severity.
- There are errant B-cells, and early rituximab studies show therapeutic benefit.
- There is reduced diversity and increased clonality of B-cells (Japan).
- Microbes in gut synthesise hormones and neurotransmitters (eg norepinephrine, serotonin, dopamine, acetylcholine, GABA).
- There is synthesis of molecules of cytokines and prostaglandins, and elicit production of molecules by the gut immune system.
- Inflammation leads to leaky gut, allowing bacteria and toxins to enter the bloodstream more often in ME/CFS than controls.
- Reduced bacterial diversity, with increased number of caudovirals, bacteriophage viruses. All this leads to low inflammation in the gut.
Brain and nervous system
- Impaired speed in information processing, leading to cognitive deficit.
- Paediatrics: impaired information processing, attention effects worsened by exercise, leading to poor performance.
- Impaired brain blood flow and effects on cortical glutathione. Not affected by a psychiatric diagnosis.
- One-third of patients had a high white-cell count and elevated protein in cerebrospinal fluid.
- Altered heart-rate variability due to low cardiac vagal activity.
- Functional connectivity among different brain regions using: PET, diffusion in MRI in GWI, and EEG in patients at rest (eLORETTA).
- Illness caused not by just mutated genes, but may be caused by non-mutated genes that are not expressed appropriately. Gene expression is controlled by many different epigenetic factors.
- Epigenetic studies being done increasingly.
- Genes are involved in signal transduction (hypomethylated).
- Those involved in immune regulation, hormone regulation and mitochondrial dysfunction give significantly different gene expression.
- In GWI, 19 different groups of genes show significantly altered gene expression. Immuno-suppressant and hormonal therapies might target the dysregulated genes and improve symptoms.
- Thirteen different gene loci involved in glucocorticoid sensitivity that are differently methylated lead to clinical symptoms.
- Expression of two microRNAs in plasma lead to elevated homocysteine in ME/CFS.
- Three SNPs are distinguished and involve a code for a subunit of NADH dehydrogenase, an important energy molecule.
- MicroRNA in spinal fluid predicts orthostatic tachycardia.
- Rituximab studies show a metabolism deficit. Key molecule is pyruvate dehydrogenase (PDH). This deficit may be caused by auto-antibodies. This leads to upregulation of PDH inhibitors in white blood cells (WBCs).
- Peripheral WBCs are less well energised, particularly if exposed to stressors.
- Citric acid metabolism is depleted.
- Glucose is replaced by fatty acids and amino acids. Different metabolomes involve these.
- ME/CFS is a hypometabolomic state.
- Symptoms are worsened with true strain. Physical therapy is likely to help.
- Five specific osteopathic findings on physical examination aid diagnosis.
- There are higher anti-citrillinated protein antibodies.
- Mutations in nucleosome transport genes compared to controls, help with diagnosis.
- A second case was reported of ME/CFS caused by an enterovirus in the brain.
- Dysregulation in the production of hydrogen sulphide could explain symptoms.
- Subjects with sinusitis and hives have more pain and other symptoms.
Possible diagnostic tests
- Four biomarkers — Interleukin 8, SCD14, PGE2, CD3/CD57 count — give 97% correct diagnosis. This needs replication, and comparison with other fatiguing illnesses. A test needs to be inexpensive and easy to perform and needs low false positives.
- Low glutathione in the brain — use of N-acetyl-cysteine can improve glutathione levels.
- Low-dose methylphenindate plus a nutritional regime leads to slight improvement in the severely ill.
- Illness beliefs have not been shown to influence activity levels.
- Multi-modal physical therapy causes symptoms in the young.
- Quantitative modelling can be done on available approved drugs — looking for drugs that might target the glucocorticoid receptor.
Finally, collaboration between many clinics and biobanks is happening with sharing of knowledge and expertise.