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The Massachusetts ME/CFS & FM Association, a 501(c)3 founded in 1985, exists to meet the needs of patients with ME (Myalgic Encephalomyelitis), CFS (Chronic Fatigue Syndrome) or FM (Fibromyalgia), their families and loved ones. The Massachusetts ME/CFS & FM Association works to educate health-care providers and the general public regarding these severely-disabling physical illnesses. We also support patients and their families and advocate for more effective treatment and research.

Research articles

IACFS/ME Conference 2014 Summary - Rosamund Vallings

by Rosamund Vallings MB BS
March 20-23rd, 2014

The day before the main scientific conference there was a joint session with those attending the patient conference, followed by professional workshops. There was a brief introduction by Prof Jose Montoya (Stanford, USA) when he emphasized the importance of a multidisciplinary approach to the illness and complimented the Chronic Fatigue Initiative on their collaborative approach. Focus should be on clinical and translational research using strict methodology.

Dr. Lipkin and the search for microbes in CFS/ME

Prof Ian Lipkin (New York, USA) was the special guest speaker and his talk was entitled “Small Game Hunting”. He said they were still able to use the earlier XMRV samples. He explained how one started with a hunt for “possible” microbes and then moved onto the “probable” when one could consider treatment options, followed by the “confirmed” when one looked at drugs and vaccines.

He told us how emerging diseases usually came from animal sources. He explained how micro-array techniques moved onto unbiased sequencing. There are 24 million peptide micro-arrays needed to investigate the vertebrate organism. He discussed as an example Kawasaki Disease, an autoimmune condition in children. Often diseases are due to an immunological response to an environmental trigger.

He then went on to discuss the human microbiome—abnormalities of which can create gastrointestinal symptoms, which in children are sometimes predictors for autism. He is interested in this relation to autism. There maybe reduced enzyme and transporter RNA. The organism suterella is increased in autism and there may be an antibiotic cause, and a lack of the gene affecting gastrointestinal metabolism.

He then talked about his involvement with the Chronic Fatigue Initiative, who are doing multiplex assays. He is working closely with Montoya looking at viruses. HHV-6 has been found in the plasma of 4 out of 6 cases. Looking for HHV-6 in PBMCs, 13% were positive in patients and 11% positive in controls. Annellovirus was found in 75% of the samples—this may not be useful, but negative findings are as important as positive.

Looking immunologically at CFS/ME, IL-17 was elevated in the first 3 years and then decreased. Lower levels were found in the CFS/ME patients’ cerebrospinal fluid. They are doing RNA sequencing looking at biomarkers in 100 cases compared to 100 controls. This equates to 117million reads divided into 3 “libraries”. But there is a need to control for library effects, as the “library” construction reflected the results—i.e., processing may be different.

They are also looking for chemicals produced by bacteria which may have systemic effects. He confirmed that there was zero evidence now for XMRV. Contamination is always a problem and contaminants must be eliminated prior to any analysis.

Eight professional workshops were then held throughout the first day. I attended the immunology workshop outlined below.

How do we recognize autoimmune disease?

The main scientific conference opened with the plenary address by Dr Noel Rose (Johns Hopkins, USA) with his discussion on how we recognize auto-immune disease. The main complaint in all autoimmune diseases is fatigue. Autoimmunity is an immune response to the normal antigens of the host.

Autoimmune disease is disease caused or significantly promoted by autoimmunity—with production of self-reactive T and B-cells. We are in fact developing lymphocytes and are “auto-immune” all the time, but we have mechanisms which recognize and control them. Disease occurs as a result of an uncontrolled response. Having antibodies is normal and not “disease”. A cause of disease by autoimmunity is hard to prove, but may be promoted by existing disease or make it worse.

There is prevalence of 80 diseases affecting every organ system. These diseases are among the 10 leading causes of death in women under 65. These diseases equate to up to 23 million people in the USA. They are diseases which share common features, are expensive and lifelong, and for which there are no cures. They are diseases which are on the rise. Systems affected most commonly include blood, connective tissue, endocrine, neuroloic, gastrointestinal, skin, kidneys and heart.

Evidence for autoimmune disease includes:

  • Direct transmission—e.g., via serum or maternal/foetal (lupus).
  • Indirect transmission when the antigen is defined and introduced to replicate the disease using animal models.
  • Circumstantial—no evidence of causation, but much evidence of disease—e.g., auto-antibodies, clustering, sex bias (75% female), HLA association, response to immunosuppression.

Some diseases look autoimmune but there is no evidence of self-reactive T-cells. They are more likely “auto-inflammatory” (caused by an innate immune response).

Factors leading to autoimmune disease

A combination of genetic predisposition, environmental factors and endocrine effect lead to autoimmune disease.

Genetic predisposition includes:

  • Evidence from family history. There may be evidence of multiple autoimmune diseases in a family. There is 30% identical twin concordance.
  • Major histocompatibility complex
  • Immunoregulatory genes. There are gene changes due to insertion of methyl groups etc. leading to changes in CD4, T-cell and B-cell changes.

Environmental factors include:

  • Viruses (e.g., EBV and MS), bacteria (e.g., B haem strep and rheumatic fever)
  • Food (e.g., iodine and its effect on the thyroid)
  • Pollutants (e.g., mercury)

Other effects include:

  • Hormones
  • Stress
  • Drugs

Pregnancy has a profound effect on autoimmune disease—some types become better, some worse.

We should use autoantibody presence in the blood with caution. This is NOT proof of autoimmune disease. Autoimmune diseases develop very slowly and a patient may have multiple antibodies over time.

The main conference papers were then presented, and the first session covered the latest research in immunology.


Allergy-related immune signatures and duration of CFS/ME

Susan Levine (Columbia, USA) discussed allergy-related immune signatures and the duration of illness in CFS/ME. She discussed the importance of allergy mediators and links between IL-4 and IL-13 (both produced by TH-2 cells), and IL-17 produced by TH-17 cells, IL-10 produced by CD4 TH-2 cells and eoxtaxin produced in asthmatics.

For her study, she divided patients into groups with recent and longer lasting illness (less than or greater than 3 years). Unique immune signatures were found in short duration patients. Higher levels of cytokines associated with the allergic response were found in short duration patients compared to the longer duration patients. A TH-2 shift was supported. She stressed the need for future studies to include measures of histamine levels, total and specific IgE, prostaglandin E2, tryptophan and serotonin.

Plasma cytokines and exercise in CFS/ME

Ludovic Giloteaux (New York, USA) reported on his study of plasma cytokines in patients before and after a cardiopulmonary exercise test. Tests were done 24 hours apart. Baseline VO2-max was compared with healthy controls. There was a significant difference. The difference was also more significant after the 2nd test. Cytokines were measured at baseline and after exercise. There were no significant differences in cytokines between CFS/ME and healthy controls, but the chemokine IP-10 decreased significantly after exercise in the CFS/ME group. Results implied an abnormal immune response with immune suppression.

NK-cell degranulated related to release of lytic proteins?

Tellah Huth (Gold Coast, Australia) presented on Natural Killer (NK) cell degranulation and lytic proteins in CFS/ME. She looked at 2 natural killer cells: CD-56 and CD-16, both involved in cytotoxic lysis. She explained how granzymes and perforin are involved in the secretory pathway to the target cell. In CFS/ME there is significant reduction in Granzyme B, which when elevated inhibits the pathogenic activation signals. When down, there is delayed target cell apoptosis. Her results showed decrease in Granzyme B is CFS/ME patients. This may contribute to reduced NK-cell activity seen in CFS/ME. Further studies are needed to determine if there is a link between dysfunctional NK cell degranulation and release of lytic proteins.

Shorter telomere lenght in CFS/ME

Mangalathu Rajeevan (Atlanta, USA) then discussed a genome-wide analysis of differential methylation associated with CFS/ME. His results concluded that this differentiation was identified in CFS/ME, but only TERT was correlated with a corresponding change in gene expression. There was decreased methylation in CFS/ME, and increased expression of TERT, with shorter telomere length. Telomeres (the ends of chromosomes) are shorter in CFS/ME than in controls. Short telomeres are a marker for aging.


Chronic pelvic pain and enterovirus infection of ovarian tubes

This session started with a presentation by John Chia (Lomita, USA). His study was looking to see if chronic pelvic pain in ME/CFS patients was associated with chronic enterovirus infection of the ovarian tubes. Chronic pelvic pain has to have been present for at least 6 months and not necessarily associated with menstruation before a diagnosis is made. Enterovirus VP-1 (enteroviral protein) was found in the tubes of most patients with ME/CFS, but not in controls. Furthermore, injection of the lysate into SCID mice caused infection. Enterovirus was also detected in the vaginal secretions of 2 women. It should be noted that as the egg travels down the tube, there is a possibility of vertical transmission.

Human parvo-virus B-19

Human parvo-virus B-19 was discussed by Santa Rasa (Riga, Latvia) in relation to typical symptoms and markers in ME/CFS. Patients who have suffered infection with this virus can end up with the characteristic symptoms for a diagnosis of ME/CFS. A large study of 190 patients compared to controls was reviewed, and B-19 genomic sequence was detected more frequently (41/190) in the patients’ DNA isolated from plasma (a marker for active infection) than from whole blood (15/190) (a marker for latent infection), and this was more frequent than in controls. Most symptoms were slightly less frequent in the patients in the latent phase of their illness, apart from muscle and joint pain, which was worse in the latent group. Activation and reactivation of this virus may be a risk factor for ME/CFS. It should be noted, too, that there was increased incidence of infertility.

Chronic enterovirus infection of the stomach tissues

John Chia (Lomita, USA) then spoke again about the pathogenesis of chronic enterovirus infection in ME/CFS looking at stomach tissues. Patients with enterovirus in the gastro-intestinal tract usually have functional dyspepsia, and irritable bowel symptoms in the lower G.I. tract. 82% and 63% of the stomach biopsies stained positive for VP-1 and dsRNA respectively (significantly higher than controls). 24 mice were injected with the VP-1+,RNA+ stomach biopsies , and 66% of their spleen biopsies tested positive for VP-1. Other organs were also involved. Only one control specimen tested positive.Enteroviral dsRNA was frequently demonstrated in the stomach biopsies, and as it may play a central role in pathogenesis, it should be targeted for anti-viral therapy. (It was noted that there are over 150 enteroviruses and the Chia lab can only test for 11.)

Treatment studies

Orthostatic intolerance and midodrine

Treatment of Orthostatic Intolerance (O.I) using midodrine was addressed by Nicole Baldwin (Salt Lake City, USA). She described O.I. as treatable with midodrine and there are 2 FDA trials happening. Hours of vertical activity (HVA) was used as a measure to assess effectiveness. A pilot study of 23 patients was undertaken, but 12 never started the medication, 5 did not continue (lack of compliance) and 6 ended up taking it at the full therapeutic dose (10mg 3-4 hourly during hours of being upright). Those taking the full dose showed a small but meaningfully useful increase in HVA. Those who continued the medication tended to be those who were worse at baseline. There were improved symptom scores particularly for headaches. Lack of compliance was due to side effects and rebound effects. The drug has a short half life, so frequent dosing is needed. The benefits were small but significant and outweighed the side effects.

Effect of Baduanjin qigong exercises on fatigue

A presentation then followed by Tian-fang Wang (Beijing, China)—the first time we had had attendees from mainland China. She talked about the intervention effect of Baduanjin on the fatigue state in fatigue-predominant sub-health. Baduanjin is a set of qigong exercises. She showed a video to begin with to demonstrate the technique. The exercises were very gentle and simple, and were undertaken for 2 periods of 15 minutes each day. 129 subjects were assessed (62 in the treatment group and 52 controls). Symptom scores declined significantly in the treated group.

Isometric yoga

Takakazu Oka (Kyushu, Japan) then discussed the use of isometric yoga in CFS/ME. The technique consists of 6 slow and simple poses with associated breathing exercises. It is done in a sitting position (mainly because space is very limited in the hospital.) The study had to be designed to avoid post-exertional malaise, bearing in mind also that these patients are deconditioned. The technique also needed to be “mentally” simple. The exercises lasted 20 minutes, and the study was done over 8 weeks. Of the 24 patients studied (in 2 groups—one using yoga and one with conventional pharmacotherapy), one yoga patient complained of dizziness. No one’s fatigue was exacerbated by the yoga. All said their bodies became lighter and warmer and severity of pain decreased. DHEA-S increased and prolactin levels decreased significantly in the yoga group.

Home-based self-management for severe ME/CFS

Fred Friedberg (New York, USA) spoke of the results of a randomized trial looking at home-based self-management for severe CFS/ME. The 137 patients studied were mostly disabled and unemployed. They were assigned to 3 categories: 1. Wait list, 2. Home self-management using web diaries and activity monitors and 3. Home self management using paper diaries and step counters. Fatigue, functioning and depression improved in both of the 2 self management strategies, compared to wait-list controls, and were not significantly different from each other. There is therefore a role for home self management activities in generating improved outcomes.

Chronic Fatigue Initiative

Over lunch on that day, we had a group presentation from the Chronic Fatigue Initiative (CFI). This was introduced by Scott Carlsson. Several sites are involved and with a strong group of research scientists and clinicians. Nancy Klimas talked about the already 200 strong patient database with 200 controls for obtaining biosamples. A detailed assessment is done and there will be a biorepository for blood, urine, tears, saliva and rectal swabs. Very sick debilitated patients are included. Already it is evident that acute onset patients have a higher level of inflammatory symptoms. Females are more severely ill than males.

Gail Ironson talked about subgrouping with 4000 variables giving 18 factors associated with the main sets of symptoms. Symptom sets include: fatigue, neuroinflammation, gastrointestinal, FM, POTS, hyperlipidaemia, hypertensive, fever, NMH, increased weight. Other factors include: age/total cholesterol ratio, stress, unsteadiness/dizziness, past infection, asthma, abnormal potassium, no evidence of recent infection, hypothyroidism.

Dana March discussed clinical epidemiological aspects and the aims of the study. There are 4 main sites. They need 1000 completed surveys. They will look at changes over time. 60% patients are of sudden onset. Fibromyalgia is the commonest co-morbid condition. Deaths have been reviewed and so far cancers account for 37.8%, heart disease for 18.9% and suicide for 18.9%. Rate of cancer is higher than norms. Helpful treatments include: self-help 65%, traditional medicine 53% and alternative medicine 17%.

Mady Hornig is involved in pathogen discovery. She is collecting faecal samples to look at the microbiome. Repeat immunological profiling will be used for longitudinal analysis. She will be looking at spinal fluid etc.

Overall future directions of the CFI will include: metabolomics, proteomics, the entire microbiome, sequencing PBMCs and longitudinal analysis of immune signatures.

Tony Komaroff summarized this meeting by saying collection of data is 85% of the “sweat” and analysis about 15%. He reiterated how in such a short period of time, so much has already been achieved.

The afternoon session was interactive with case presentations by Drs C Lapp, L Bateman, R Vallings and D Peterson, chaired by Dr Klimas.

Case definitions

Leonard Jason (Chicago, USA) led this discussion and compared the various case definitons and their evolution over the past 25 years. The main variation in the definitions is the number of symptoms required for making a diagnosis. Case definitions that do not require the cardinal symptoms may not accurately identify the illness. However defintions requiring larger numbers of symptoms may include more psychiatric morbidity. Current consensus based definitions may lack construct validity, resulting in inaccurate diagnosis of CFS/ME.

A study to determine whether immunological, physical and social functioning varies in CFS/ME was presented by Sharni Hardcastle, (Gold Coast, Australia). Findings suggest that the ICC case definition [Canadian] identifies a group within the 1994 Fukuda defined patients with more severe impairment to their physical and social functioning. The ICC may also be more effective at identifying differences in the immune system found in CFS/ME. The presence of immune abnormalities combined with clear clinical measures could potentially serve as an important diagnostic tool in this illness.

Leonard Jason (Chicago, USA) then looked at diagnostic and criterion issues. Studies included looking at the prevalence of chronic fatigue in the general population. In order to progress the search for biologic markers and effective treatments, essential features of the illness might be empirically identified, so that individuals included in samples have the same underlying illness. Advanced statistical techniques, such as data mining are promising methods for identifying these features.

Public health research

Differential diagnosis between CFS/ME and fatiguing illness

Nicolette Carlo-Stella (Pavia, Italy) looked at the differential diagnosis of CFS/ME and fatiguing illnesses from a community-based sample. 89 patients were self referred complaining of post-exertional neuro-immune exhaustion to a specialized CFS/ME clinic. 40% of them were diagnosed as suffering from CFS/ME while 60% were not. The non-CFS/ME patients were suffering from a variety of illnesses: rheumatological 43%, endocrine 4.6%, psychiatric 5.6%, gastrointestinal 4.5%, haematological cancer 2.3% and bladder cancer 1.1%. Caution is therefor warranted before making a final diagnosis of CFS/ME.

Increasing the knowledge of physicians

Increasing medical knowledge about CFS/ME and related diseases was addressed by Tina Tidmore (Alabama, USA). The aim was also to set up a speciality centre. A local politician showed interest as he had a personal interest in Lyme disease. As a result a CME course was set up for medical professionals. The new Primer for clinicians was distributed. Further CME on Fibromyalgia and Tick-borne diseases was planned. Efforts continue to recruit physicians to run a specialized clinic. The long time needed for patient visits can be a barrier, as insurance companies do not re-imburse. First steps in creating a centre are to attract a physician willing to work in this somewhat difficult area.

Family aggregation studies in Spain

Family aggregation studies in CFS/ME were discussed by Jesus Castro-Marrero (Barcelona, Spain). The objective of their study was to know the family history and familial aggregation of Spanish CFS/ME patients. 1140 CFS/ME patients were included in the DNA databank. 36% patients had first degree relatives with CFS/ME and/or related conditions, such as fibromyalgia, immune-mediated diseases or rheumatological conditions.

UK CFS/ME biobank

Eliana Laerdo and Erinna Bowman (London, UK) talked about 2 years’ experience with the UK CFS/ME biobank. This is based at the London School of Hygiene and Tropical Medicine. They first discussed how the lay-scientific partnership had shaped and developed the biobank. A consultation process involved discussion between those with CFS/ME and carers, clinicians, researchers and experts in the field of human tissue banks. Those with CFS/ME were overwhelmingly willing to contribute with blood donations. A robust protocol has been developed. Samples are collected from patients with CFS/ME and controls (without fatigue or with MS). Several diagnostic criteria are being used to provide comparison. Regular follow-ups are planned. Blood samples need to be collected and processed within 6 hours. The biobank infrastructure and procedures were presented. The samples will provide an open resource for research, with the potential to lead to biomarker discovery and work that could translate into treatment. Collaboration with other international biobanks is planned.

Epidemiological study in Canada

Margaret Parlor (Ontario, Canada) presented the results quantifying and interpreting a broad range of health characteristics associated with CFS/ME, FM, and Environmental Sensitivities (ES)/MCS. This was to support health care planning in the area. Results were taken from the 2005 and 2010 Canadian Community Health Study (CCHS). 411,500 Canadians have been diagnosed with CFS/ME, 439,000 with FM and 800,500 with ES/MCS. This equates to a prevalence of 4.9% in 2010, which had increased from 4.2% in 2005. These illnesses were shown to have significant impact on individuals and families with many unmet healthcare needs. The information has been forwarded to health system planners, along with clinical and academic information.

Remissions in CFS/ME 

The group headed by Dana March (New York, USA) determined the natural course of CFS/ME in a multi-site epidemiology study, compared to other studies undertaken. 4 clinical sites were chosen and patients had had to have been in treatment for at least 5 years. The study was conducted by telephone interview by trained interviewers. The survey comprised mainly middle aged educated white women, born in the USA. Approximately 1/3 had experienced at least one remission. Viral type symptoms showed the most improvement over time. Many reported co-morbid conditions such as FM, depression, anxiety and hypothyroidism. Relatively few were engaged in work, school or equivalent activity. There was some variation across sites. The odds for permanent remission seemed low.

Treatments patients find effective

Lucinda Bateman (Salt Lake City, USA) examined the types of treatment which alter the course of CFS/ME in another similar multi-site epidemiology study. The most effective treatments were self-help strategies (65.2%) such as rest, diet and exercise, followed by traditional medicine (53.3%) such as prescription drugs and vitamins. A small percentage reported benefits from alternative/complementary medicine (16.9%) such as herbal remedies, massage, acupuncture. There was variation between sites.

Consequent conditions to CFS/ME and cancer prevalance

The prevalence of CFS/ME and co-morbid and consequent conditions was examined by Salima Darakjy (New York, USA). 84% of the CFS/ME patients reported at least one significant diagnosis after CFS/ME onset. These included FM, depression, anxiety and hypothyroidism. 16.4% reported malignancies, which is 4 times the prevalence in the normal adult US population. Further research is warranted looking at whether some CFS/ME patients are most at risk of cancers particularly in relation to shared pathophysiological mechanisms.

Provocation studies

Aerobic exercise testing

Betsy Keller (New York, USA) talked about the superior ability of a 2-day CPET (cardiopulmonary exercise test) protocol to detect functional impairment in ME/CFS compared to either a single CPET, submaximal exercise test or a VO2 prediction equation. The single CPET failed to identify functional impairment in 20% patients, and diminished functional capacity due to post-exertional malaise (PEM) could not be detected, yet occurred in 55% of subjects. Two serial CPET tests however did identify functional impairment in 98% subjects. Submaximal exercise tests were poor predictors of VO2-max in CFS/ME as was using the predicted VO2 equation. The results demonstrated the superiority of using two serial CPETs to delineate functional impairment in CFS/ME.

J Mark Van Ness (Stockton, USA) showed diminished pulmonary ventilation in CFS/ME patients during graded exercise tests. He postulated that this could be due to deconditioning. A second study showed that post-exertional effects seem to reduce the ventilator response further in CF/MES. These effects may be due to diminished ventilator muscle function during PEM or reduced ventilator neural “drive”.

Mitochondrial dysfunction

David Patrick (Vancouver, Canada) addressed the issue of whether screening for mitochondrial dysfunction and other metabolic disorders was important in CFS/ME. CPET often leads to symptom flare, and so alternative approaches were discussed. Changes in haemoglobin and oxyhaemoglobin in wrist extensors using grip tests were measured. Response to the test was compared between cases and controls by calculating the area under the curve of HHb over time. Submaximal exercise procedure did not distinguish between cases and controls, but HHb levels did vary between the cases and a subset of 19% met criteria that prompted further testing for mitochondrial disease. 3 cases had particularly low levels of HHb and 2 had adverse physical reactions. There was a greater level of self-assessed exertion in the ME/CFS group. Even submaximal testing was intolerable for a subset of ME/CFS patients and we should be mindful of using exercise for testing or treatment.

Oxygen extraction and lactate were found to be low in patients assessed by Ruud Vermeulen (Amsterdam, Holland). This would indicate a metabolic cause for exercise intolerance in the majority of 178 women with CFS/ME studied. The low lactate after exercise in the majority of these patients suggests that physical impairment in this group is caused by downregulation of carbohydrate metabolism.

Advances in paediatric practice

Diagnosis and management of paediatric practice in Australia

Almost a whole morning was devoted to paediatric research. Diagnosis and management of paediatric CFS/ME in Australia was discussed by Sarah Knight (Melbourne, Australia). An online survey was sent to registered paediatricians. She pointed out that there are more challenges in adolescence and most with this illness miss on average a year of school. 39% of the National Network of Paediatricians see patients with CFS/ME. A large number of comorbidities were diagnosed. There was wide variation is diagnostic and management practices, which may reflect a lack of knowledge of diagnostic criteria and a paucity of management guidelines.

Impaired range of motion

Peter Rowe (Baltimore, USA) presented work on the impaired range of motion (ROM) in adolescent CFS/ME. 55 patients and 48 matched “flexible” controls were studied. Impaired ROM was more common in CFS/ME than controls. There was wide overlap with Ehlers Danlos Syndrome (EDS) with a number of postural abnormalities such as slumping. There was abnormal range of movements in the limbs and spine, which were worse for 1-2 days after longitudinal strain therapy in a subset, but there was eventually overall improvement in CFS/ME symptoms after the therapy.

Tracking post-infectious fatigue

Tracking post-infectious fatigue in a clinic using routine lab testing was addressed by Gordon Broderick (Florida, USA). 301 adolescents following diagnosis on infectious mononucleosis were studied and followed over 24 months. Incidence of CFS/ME at 6, 12 and 24 months was 13%, 7% and 4% respectively. Standard lab tests were performed at each point. 13 patients (all female) had a diagnosis of CFS/ME at 24 months. At 6 months, ACTH was lower and glucose was higher in those that were still ill at 24 months. Estradiol was lower and T4 was higher at 12 months. At 24 months neutrophils were above normal and basophils decreased. These results help to support early assessment of those who may go on to develop CFS/ME over time.

Delayed hypersensitivty reactions to foods

A further presentation by Peter Rowe (Baltimore, USA) concerned the prevalence of delayed milk-protein hypersensitivity in young adults with CFS/ME. Children who were “picky” eaters were associated with non-IgE mediated food allergies. Characteristic symptoms were epigastric pain and other gastro-intestinal symptoms. There was no mast cell activiation. There was a higher than expected prevalence in those with CFS/ME. Strict dietary avoidance led to clinical and histological response. The diet needs to be rigid, and supplements with multivitamins and calcium is needed.

Impact of CFS/ME on adolescence

Peter Rowe then looked at the impact of CFS/ME in adolescence. Self-reported quality of life is significantly lower for adolescents and young adults with CFS/ME compared to healthy controls, and lower than scores reported for adolescents with other chronic health conditions, such as cystic fibrosis, epilepsy, diabetes and renal transplants, and comparable to scores for those with fibromyalgia and paraplegic cerebral palsy.

What Australians adolescents find helpful in managing CFS/ME

Katherine Rowe (Melbourne, Australia) had looked at what young people find helpful in managing their chronic illness. She had studied 788 people over 18 years. 1200 questionnaires were returned. An individualized plan of their own allowed them control over their lives again and was very important. Included in this should be a pleasurable out-of-home activity each week. Not being believed was the most difficult thing to handle. “Quacks” saying they could cure the illness was very upsetting and a lot of money was wasted by parents in this way. Loss of social contacts often led to depression, but this is a healthy response. SSRIs were used. Engagement in education was the best predictor of functional outcome.

Her further paper looked at whether functional outcomes were associated with depression at presentation. Average duration of illness prior to first visit was 15 months. 25% were significantly depressed compared to base rate of depression in adolescents of 20%. Not being believed, difficulty remaining engaged with school and severity of symptoms were contributing and perpetuating factors. Functional ratings at follow up were less good than the non-depressed group, but the overall duration of the illness was not significantly different.

Sleep education in Japan

Japanese are one of the most sleep-deprived groups of people, and Seiki Tajima (Hyogo, Japan) talked about sleep education carried out since 2007, to help prevent school non-attendence in junior high school and to help prevent risk of paediatric CFS/ME. Teachers and lifestyle educators were involved. 83% of patients (66) with school non-attendence fitted the criteria for CFS/ME. Incidence of school non-attendence decreased year by year, with all of the group attending regularly by 2012.

Advances in brain research

PET scanning

Neuroscience of fatigue and CFS/ME using PET was presented by Yasuyoshi Watanabe (Osaka, Japan). PET molecular and functional imaging is used to demonstrate brain dysfunction. Results of large studies in Japan showed reduced binding potential of 5HTT in CFS/ME patients, and this correlated with the pain scores. PET scanning could also be used for differential diagnosis. There were correlations between gastrointestinal symptoms and binding potential of 5HTT, and PET studies on neuroinflammation corresponded to activated microglia. fMRIs showed changes or reversible atrophy in the prefrontal cortex and a mirror system of fatigue (MEG). There were also changes in circulation from acute to chronic phases. Watanabe stressed now the need to look more at what is happening in healthy people.

EEG peak alpha frequency

Marcie and Mark Zinn (California, USA) then discussed their work on EEG peak alpha frequency associated with CFS/ME, as disabling fatigue and cognitive impairment are cardinal symptoms. The first presentation was to evaluate the relationship between EEG peak alpha frequency in CFS/ME compared to matched controls. Findings were consistent with reduced efficiency of thalamo-cortical connections in CFS/ME patients. And this correlated with reduced ability to coordinate cognitive symptoms. There may be prognostic value to facilitate the evaluation of CFS/ME as part of the diagnostic regimen. The second presentation looked at cortical hypoactivation during resting EEG in those with CFS/ME, and suggested central nervous system pathology. Exact low resolution electromagnetic tomography (ELORETA) could be applied to the understanding of brain fog. There were elevated delta sources in CFS/ME, with the highest percentage of voxel activations mainly in the left hemisphere regions of interest. Implications of abnormal delta sources can include speech difficulties, as Broca’s area is involved, and a possible indication of limbic encephalitis. No patients with psychiatric comorbidity were included in these studies.

Meta-analysis of cognitive functioning

Susan Cockshell (Adelaide, Australia) had investigated cognitive functioning in CFS/ME, using meta-analysis of previous studies and using that information to study a group of those with CFS/ME. Out of 4000 abstracts, 50 reported cognitive symptoms. She then studied 50 patients and matched controls. The main cognitive deficit found in those with CFS/ME appears to be a slowing in information processing speed. All were motivated to perform well. After testing it took 2-3 days for the CFS/ME patients to recover from the resultant fatigue.

Revision of the IACFS/ME physician's primer

This panel session highlighted the changes that have been made to the new edition of this manual for physicians. Most of the authoring committee were present and Ken Friedman (Vermont, USA) summarized the changes. Particular important changes included a section on the Severely Ill, and a comprehensive index.

There was much discussion from the floor including a plea from Dr Lily Chu (California, USA) to include more issues relating to mortality in the next revision.

The conference was summarized by Dr Anthony Komaroff and that summary is available on line.

Immunology workshop

Eight professional workshops were then held throughout the first day. I attended the immunology workshop outlined below:

Dr Dan Peterson chaired this and introduced the session with a brief discussion about our body defences, such as the skin, mucus membranes, stomach enzymes, bacterial toxins in GI tract, phagocytes and natural killer (NK) cells. He explained the innate and adaptive immune systems which interact via the cytokines. A number of presentations by immunology experts then followed.

1. Sonya Marshall-Gradisnik (Gold Coast, Australia) who gave an overview of her work and the establishment of the $150million building attached to Griffith University—the National Centre for Neuro-immunology and Emerging Diseases. She discussed the role of NK-cells, residing in the immune system. They influence the adaptive immune response and kill abnormal cells. An envelope in the cell contains granzymes, which pass through a protein via perforin pores. The abnormal cell is lysed through a cell-death pathway. LAMP (membrane proteins) encapsulate granzymes and perforin. NK-cells bind to target cells. Chemokine receptors (KIRs) sneak out infected cells. There are 2 types of KIRs (killer immunoglobulin-like receptors): inhibitory and activating. MicroRNAs control the function of the NK-cells. There are two NK phenotypes—“ dim” and “bright”.

The current status of CFS/ME is that there is no diagnostic test, pathology is unknown but there is consistency of NK-cell lysis. A snapshot analysis of moderately ill CFS/ME patients was done looking at lytic proteins, to see if lysis and phenotypes are consistent over time. NK-cells are found to be down in function over time, and there is a significant reduction in “bright” over time. The question was asked “Do lytic proteins play a role in CFS/ME?” Granzyme B decreases over time. Impaired degranulation is suggested. There was significant reduction in lysis in the severely ill groups. There were significant differences between severely ill and controls in NK phenotypes (CD158b+ and CD158a/h+) with reduced activation. A number of microRNAs were significantly reduced on NK cells, which influence efficiency.

2. Sharni Hardcastle (Gold Coast, Australia) looked at their severe cohort. And the adaptive immune system. There were alterations in T-regulatory cells and increased B-cell activation. There were some cytotoxic cross-over cells. In the severely ill patients there was an increase in plasma dendritic cells, increased naïve and plasma B-cells, decrease in transitory and regulating B-cells and a decrease in ɣɗ1 phenotypes. Regulatory NKT-cells were increased in the severe patients. CD8a and CD4 were changed in the severely ill.

3. Nancy Klimas talked about cytotoxic T-cells and the immune system in CFS/ME. This is part of the acquired system. NK-cells evolve first and the acquired immune system develops over time. 5% of the immune system is in the blood, the rest is everywhere else, particularly in the gut. The cells need to be close together (e.g., in lymph nodes) to be efficient. There are more glial cells (white blood cells) than neurons in the brain. There is duality of the immune system: a) humoral (NK-cells) and b) cell-mediated (T-cells). T cells only recognize antigen associated with MHC (major histocompatibility complex ) molecules on the cell. This is very specific. Perforin and granzymes poke holes in the cells leading to death. Networks of communication may get severed. Ways to reconnect need to be modelled. Perforin has been found to be down in T-cells.

Biomarkers can be treatment targets. E.g., Neuropeptide-Y connects the immune system and the nervous system. IN CFS/ME there is high NPY and low CD-26.

4. Paula Waziry (Miami, USA) discussed gene regulation. There are variable symptoms in CFS/ME. Viral reactivation may occur due to genetic, environmental and epigenetic effects on gene expression. PBMCs are involved (B and T). Mononuclear cells have a nucleus! And everything is regulated at many levels by gene expression. Data shows decreased levels of human microRNAs in CFS/ME. In EBV there may be impaired NPC function, but interferon will “undo” the reaction.

5. Konstance Knox (Wisconsin, USA) had looked at B-cell function and the pathogenesis of CFS/ME. B-cells are produced in the marrow and travel to lymphoid organs. They are part of the adaptive immune system. 2-5% of serum IgM/IgG is not directed at specific pathogens. They are naturally occurring antibodies. Work has been done on mice (Jay Levy).

Regulatory B-cells (0.5% of B-cells): a) secrete IL-10 (anti-inflammatory) which restores TH-1/TH-2 balance and b) secrete TGF-β1 which induces apoptosis. B-cells receive and present the antigen. She mentioned the rituxin studies. The drug is directed at CD20. She questioned whether there may be an increased risk of lymphoma in CFS/ME. The B-cell may be a very important component of CFS/ME.

6. David Baewer (Wisconsin, USA) Talked about the role of serology in the diagnosis of the herpes virus, and how to order diagnostic studies. There are limitations in serology in CFS/ME, but there is a body of literature and a need to rule out a herpes diagnosis in CFS/ME. There are billions of herpes viruses in our systems, and we will all have viral antibodies. Positive IgM equates to active infection leading to latency for life. Reactivation to IgM response is rare. Therefore IgM will be of little use. Immune dysregulation means tests are unreliable. Molecular testing for herpes is more reliable. Qualitative tests for virus DNA is 85% positive in the population. Virus replication needs to be tested using reverse transcriptase PCR. Late transcript viral RNA is more reliable. The virus actively transcribes active gene products. There may be a smouldering herpes infection going on.

7. Troy Querec (Atlanta, USA) discussed cytotoxicity in a multicenter trial looking at impaired NK-cells. e.g. CD107a functional assay. He stressed the point that shipping time decreases cell viability, and discussed methods of shipping. Impaired NK function is a promising biomarker. Functional assays are not always available. A pilot study is planned to assess design variables.

8. Isabel Barao-Sylvestre (Nevada, USA) had looked at NK-cells and cytokines. Cytokines are LMW proteins. There is no single organ source. Lymphokines come from lymphocytes, chemokines are functional, interleukins are messengers between leucocytes. There are chains of cytokine action. They are potentially useful markers. She talked about therapeutic antibodies being used in autoimmune diseases, and IgG subclasses, with deficiencies in some patients in CFS/ME.

9. Mary Ann Fletcher (Miami, USA) – was described as having much wisdom after 35 years of research into this illness. In 1990 she found reduced NK function with elevated pro-inflammatory cytokines. These findings have been confirmed around the world and are potential biomarkers. Age of sample, technique used, and identified diagnosis of the patient are all important factors. Their team is ready to go ahead.

10. Dennis Mangan (California, USA) is a communications expert, which seems apt in the field of immunology . He describes communication as having a sender and receiver with a message flowing between them. Modification and sensitization is possible.

11. Beth Unger (Atlanta, USA) describing herself as a “non-immunologist” summed up the workshop. She described it as a very complex situation. There needs to be very good laboratories. With a focus on methods, there are excellent prospects. A lab has the potential to do almost “anything” if it is deemed important enough. The immune system seems crucial to understanding this illness.

Poster presentations

89 posters were displayed and will be summarized later.

2014 Stanford ME/CFS Symposium: Advances in Clinical Care and Translational Research

By Rosamond Vallings
March 19, 2014

The day opened with a very good overview of the work being undertaken at Stanford: Â Jose Montoya; The Stanford ME/CFS initiative; a brief history of collaboration, innovation and discovery in the filed of infection-associated chronic diseases.

He talked of a large team working over 4 years. He described ME/CFS as a real illness affecting many lives.

He presented a case study initially of a patient who had HHV-6 in the blood and cerebrospinal fluid, treated with valganciclovir with a good response. The MRI had shown bright lesions in the right thalamus. Antivirals were again being considered after this patient relapsed later.

He then elaborated on the fact that there are subsets of this illness, and evolution of the illness over time. Stanford got involved as they came upon many patients face-to-face.

The Stanford Initiative is looking at the immune system, genes, neuroradiology, EEGs, cardiology and infectious diseases. He mentioned how some patients are bedridden and have extreme sensitivities. It is likely that there are infections triggering the illness or perpetuating it. Valganciclovir is helpful for HHV6 and EBV. But none of this is necessarily the full answer. Trials did demonstrate the effects of antiviral therapy, which also has an immunomodulatory effect. They are now looking at the effects of methylphenindate as a treatment plus a nutrient formula.

The underlying principles: much time and questions, a multidisciplinary team, clinical and translational research and methodology (double blinded, placebo controlled trials). There needs to be a candid and rigorous approach.

Their clinic has 600 patients currently and a waiting list of 300. They have a multidisciplinary team and have weekly meetings. 3 groups of trials are currently running: drug studies, longitudinal studies and case control studies—e.g., cytokine levels associated with severity. In this one, 13 cytokines are found to have an upward trend leading to many effects, and levels correlate with severity. In addition there are associations with autoimmune disease, and this may be consistent with an auto-immune process going on in ME/CFS. 2 cytokines are particularly higher in women: leptin and resistan. The LASSO method is used. TGFbeta correlates with duration of illness, is decreased and levels correlate with severity. This opens the door for treatment with antiinflammatory agents. Rest, good sleep and meditation are all options to be considered.

Beth Unger: Epidemiology of CFS–what have we learned?

She started by saying that there is often disagreement about terminology and definition, which can be confusing. I.e., Are CFS and ME synonyms or different?

There is consensus that the illness is characterized by severe fatigue unrelieved by rest, and accompanied by additional symptoms, such as post-exertional malaise and cognitive difficulty, etc. There may be other comorbid conditions. The key issue is the vicious circle of sleep, pain and fatigue leading to cognitive difficulties.

The areas of disagreement in the definitions seem to be duration, number of symptoms, exclusion conditions and whether post-exertional malaise is acquired or part of the disease. Most studies are based on the 1994 Fukuda definition and this is widely used. The findings can be extrapolated to other definitions. 80% of patients do have post-exertional malaise. Case definitions are inadequate to explain the actual experience of the illness. Patients and caregivers do however speak eloquently.

Epidemiology looks at demographics, prevalence, significance, prognosis and risk factors.

Prevalence: The highest prevalence is in the 40-50 year old age group. More females than males are affected. It does occur in children. Prevalence may be higher in some racial groups and the socially disadvantaged. Most CFS patients are ill for more than 5 years. 50% seek medical care.

When finding out how common the illness is, it depends where you look and how you ask. A meta-analysis of 14 adult studies showed a different picture with self-report of 3.2% and clinical assessment at 0.76%. Prevalence is likely about 0.31% in the USA, which equates to about 1 million sufferers. In teens the rate is between 0.4% and 2.4%. it is not rare.

Significance: Functional impairment is equivalent to that in MS, HIV, cancer, diabetes and lung disease. There is frequently inability to attend school. There is decreased working memory and motor speed. Various domains of the SF36 generate generally low scores. For fatigue, sleep and pain, the PROMIST scores are worse compared to other illnesses.

Economic burden: In the USA, $9-37billion is lost in productivity, (equivalent to 19% reduction in earnings) and $9-14billion in medical costs.

Barriers to healthcare utilization: Over half the patients had at least one barrier. These included: accessibility, negative illness beliefs, the healthcare system itself.

Prognosis: Presentation of the illness may be sudden or gradual, and symptoms wax and wane. Good clinical management leads to increased wellbeing and functional improvement. The likelihood of recovery decreases with the severity of the illness. Recovery is more likely in children.

Associated factors: Infection, stressors, genetics. Work is usually done using case definitions as there is no biomarker. It is important to identify subgroups.

Future directions include: a multi-site study of CFS/ME and exploring the use of national surveys.

Jarred Younger–Daily fluctuations in cytokines in CFS/ME

This is a novel way of looking at the immune system. i.e—tracking symptom variability comparing good days and bad days and cytokine levels. We need to be able to track something in the blood, and this could be a potential target for new drugs. Cytokine levels may correlate with symptoms. Fluctuating levels may influence symptoms. There are now free programmes/apps to track symptoms over 25 days. Blood is then needed for 25 consecutive days, but with tiny needles and skilled phlebotomists, this need not be too difficult. Classic cytokines and chemokines can be measured.

His team had looked at 3 women with fibromyalgia, and found that leptin levels correlated in all three with symptoms. They then looked at 10 women with CFS/ME, and found that leptin levels correlated with fatigue in 6 of the 10. Comparing with 10 healthy women there was minimal correlation. A network analysis of all cytokines relating to fatigue was done, and leptin was the only one that significantly correlated.

Leptin was three times higher in females than males. It comes from the white fat tissue and is increased in stress and is very "inflammatory."

The microglia are the primary defence in the CNS. Firing leads to a pro-inflammatory state, which makes a person feel ill – this is a normal "sickness response." Microglia can be primed by aging, genetics etc and this can lead to over-expression. The astrocytes take over once the microglia are activated. Leptin crosses the blood-brain barrier and primes the microglia (lowers the threshold). If hit by TNFalpha, leptin increases the vulnerability of the microglia.

He then asked the question "What next?"—leptin antagonists—there are many possibilities, but this is not applicable yet. But cardiac hormones and some antihypertensives do have anti-leptin effects. He noted too that leptin suppresses the appetite. Leptin levels decrease with avoidance of stress.

Modulators of leptin include: naltrexone, minomycin, dextromethorphan, rimfampicin, ceftrixone. A number of natural compounds have the potential too such a tumeric, reservatrol and stinging nettle, but none have been tested.

A biobank is needed, so that more analyses can be done. He noted that leptin can be measured in saliva.

Amit Kaushal—Gene expression findings in CFS/ME

The approach by the Davis Lab was to look at phenotypes and gene expression. 200 patients and 400 healthy controls were assessed. MFI (20 scale) was used with 20 questions. This showed that the phenotypes of the patients were different from the controls. There was much variability in the CFS group—fatigue was far greater than in the controls. Looking at gene expression, whole blood was used looking at RNA activation, microarray overview etc. 47,000 genes can be measured simultaneously in patients versus controls. False positives are possible.

When looking at the sickest patients versus the healthiest of the controls there were more significant genes. There were a large number of genes showing significant different expression between patients and controls. Diseases with systemic inflammation were more highly correlated.

Limitations in the studies are whether there is significance of blood markers. But if there is a signal, the signal should be chased. He concluded that CFS/ME is a heterogeneous disease phenotypically, and there is genomic evidence for a chronic inflammatory state. The inflammation is associated with core intracellular components.

Mehdi Skhiri—Cardiovascular Aging in CFS/ME

He talked about 3 studies:

1. Small heart syndrome (Japan)—56 cases, 38 controls. There was significant difference between the CFS patients and controls using chest xray and echo, with patients having a smaller heart. However in the CFS group, only those with a low cardiac index were included, but this did not apply to controls.

2. Impaired cardiac function in CFS measured by MRI tagging—12 patients, 10 controls. The cardiac index (equivalent to output) was lower in CFS. Left ventricular volume was down, there were reduced cavity volumes, and reduced stroke volume and cardiac output. This correlated with a markedly reduced blood volume.

3. Evidence of diminished cardiac function. The study involved sedentary and non-sedentary controls and mild and severe CFS patients. 12 lead ECG was used. Cardiac index was down in patients who also had a possibly 15% decreased blood volume.

Problems noted: no data on vascular pathology, no study without some bias, cardiovascular matching is not easy to achieve.

A further phenotyping study was presented, with 82 patients. Exclusion included, obesity, athletes, Ehlers danlos, any cardiac condition and those unable to exercise. Results showed: cardiac remodeling in patients, with smaller cavities (because of different levels of fitness), no clear differences between L and R ventricular function and no signs of early cardiovascular aging or increased risks.

Michael Zeineh—MRI findings in CFS/ME

He is a neuro-radiologist. He had looked at 14 CFS patients and 15 controls. He outlined his 3T imaging protocol, looking at volume, grey/white matter and perfusion. Grey matter in CFS was similar to controls, white matter was lower in CFS than controls, and the thalamic volume was slightly down in CFS compared to controls. He also looked at cortical thickness, which thins in dementia. The cortex was thicker in 5 regions in patients and the differences were more noticeable in younger patients. There are many tracts in the brain, and these are affected by handedness. There was no difference in Arterial Spin Labelling perfusion, but there was increased cortical thickening along the endpoints of both arcuate tracts. In patients there was increased phosphatidic acid in the arcuate and inferior longitudinal fasciculus.

Marcie and Mark Zinn—EEG/LORETA (low-resolution brain electromagnetic tomography) studies suggesting cortical pathology in ME/CFS

They looked at 50 patients and 50 controls, using a standard EEG. Peak frequency is associated with cognitive function. The CFS patients showed reduced PAFs over 58% of the cortex, This was significant, and suggests brain pathology. They then looked at the effects of fatigue, and this predicted the PAFs well. The implications are that there are interruptions in goal-directed behaviour. This leads to mental status changes (cognitive problems) affecting alertness and attention, memory and temporal organisation of behaviour. These findings could help confirm the diagnosis, monitor disease progression and monitor treatment response.

They then determined whether LORETA can be applied to the understanding of cognitive impairment in CFS, and to examine the underlying neurological underpinning of CFS. CFS patients had widespread delta sources mainly in the left frontal lobes. Axial slices showed depth and abnormalities.

The implications mean disruptions in transmission of information. This includes: destabilisation of ascending arousal system mechanisms, inhibition of faster brain rhythms—thus more basic generalised functional processing takes place, deficits in language production and syntax, pathophysiological CNS conditions: grey/white matter lesions etc. There are also lower beta-2 sources in CFS, primary motor deficits, sensory ataxia and pain sensation disturbances. Speech deficits occur as a result of abnormalities around Broca's area. There may be behavioural effects such as apathy. All this is a possible indicator of limbic encephalomyelitis.

The implications are that there is central fatigue and brain fog with no psychiatric comorbidity. In summary there is hypoactivation in CFS and LORETA shows this link.

Anthony Komaroff—Medical care of ME/CFS patients

An overview of management of patients with this illness was presented. Age range is 5 – 65 years. 65% patients are female. It affects all socio-economic groups, but is more common in Afro-Americans and Latinos. 50% patients are "shut-in" or bedridden much of the time. Average duration of illness is 14 years (4-36 year range). Post-exertional malaise (PEM) is characteristic and not seen in any other illness. Cognitive impairment is common. The SF-36 shows low scores in all areas. 10% patients achieve full remission, 23% end up with an alternative diagnosis.

This is not depression, as SSRIs do not fix it. There are abnormalities in the HPA, and neurological and immunological abnormalities are not seen in depression. However with psychological assessment, 50% patients have a diagnosis of depression after onset. Prolactin is often elevated in CFS, and decreased in depression.

Abnormalities found include: neuro-endocrine dysfunction, cognitive deficit, autonomic dysfunction, abnormalities on MRI,Spect and EEG, lactate abnormalities in the CSF, striking differences in immune system. There is evidence of abnormal energy metabolism. Infectious agents implicated include HHV6 in 90-95% patients (the receptor is the complement receptor).

Treatment options discussed:

  • CBT helps patients cope with the illness and reduces symptoms.
  • Gradual exercise plan which should be gentle to avoid PEM
  • Trazadone for sleep
  • Rituximab—as possible autoimmune disease

Final words were that case definitions may encompass several different subsets or other illnesses.

Jose Montoya–Circulating cytokines in ME/CFS patients reveal a novel inflammatory and autoimmune profile

Flu-like symptlms are ongoing, but conventional markers are seldom elevated. There is an associated TH-2 shift. He presented a controlled study of 197 cases and 300 controls. MFI20 and FSS scores were measured to assess severity, followed by statistical analysis. Included was the LASSO technique, and also "random forest". In the results, patients and controls were well matched. The CFS patients almost all had PEM. 26 cytokines were found to decline with age. 4 had differences between males and females: Leptin. IL-1alpha, ENA78 and resistan.

15 cytokines behaved differently in CFS compared to controls. 13 out of the 15 were significant differences, and these were the pro-inflammatory cytokines. Mild cases tend to fall below the controls, severe cases tend to fall above the controls.

Activation of B-cells suggests the possibility of autoimmune disease.

IL-17 is associated with psoriasis, IBD, Arthritis and MS. Leptin and resistan are associated with female sex. Lowered TGF-beta is associated with duration of illness—it is a powerful anti-inflammatory cytokine, whose capacity gets lost. The body thus feels inflamed.

Ian Lipkin–Microbial diagnostics and discovery in ME/CFS

He said they were still able to use the earlier XMRV samples. He explained how one started with a hunt for "possible" microbes and then moved onto the "probable" when one could consider treatment options, followed by the "confirmed" when one looked at drugs and vaccines. He told us how emerging diseases usually came from animal sources.

He explained how micro-array techniques moved onto unbiased sequencing. There are 24 million peptide micro-arrays needed to investigate the vertebrate organism. He discussed as an example Kawasaki Disease, an autoimmune condition in children. Often diseases are due to an immunological response to an environmental trigger.

He then went on to discuss the human microbiome—abnormalities of which can create gastrointestinal symptoms, which in children are sometimes predictors for autism. He is interested in this relation to autism. There may be reduced enzyme and transporter RNA. The organism suterella is increased in autism and there may be an antibiotic cause, and a lack of the gene affecting gastrointestinal metabolism.

He then talked about his involvement with the Chronic Fatigue Initiative, who are doing multiplex assays. He is working closely with Montoya looking at viruses. HHV-6 has been found in the plasma of 4 out of 6 cases. Looking for HHV-6 in PBMCs, 13% were positive in patients and 11% positive in controls. Annellovirus was found in 75% of the samples—this may not be useful, but negative findings are as important as positive.

Looking immunologically at CFS/ME IL-17 was elevated in the first 3 years and then decreased. Lower levels were found in the CFS/ME patients' cerebrospinal fluid. They are doing RNA sequencing looking at biomarkers in 100 cases compared to 100 controls. This equates to 117million reads divided into 3 "libraries". But there is a need to control for library effects, as the "library" construction reflected the results – ie processing may be different.

They are also looking for chemicals produced by bacteria which may have systemic effects. He confirmed that there was zero evidence now for XMRV. Contamination is always a problem and contaminants must be eliminated prior to any analysis.

Jose Montoya closed the symposium remarking that this had been a most successful and exciting day.

Oral Complications in Sjögren's Syndrome and Chronic Dry Mouth

By R. Sanderson

Dry mouth and various oral and dental complications are problematic for many people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), or Fibromyalgia (FM). Persistent dryness of the mouth could indicate an autoimmune illness like Sjögren's, linked to poorly functioning or damaged salivary glands, or be the result of side effects associated with many medications. Either way, it is a problem that warrants prompt medical or dental attention.

Dental caries, which refers to localized disease that causes decay and cavities in teeth, and oral problems have a tendency to progress much more rapidly when there is poor salivation and ongoing dryness. The goal of this article is to provide information about the serious and often devastating consequences of persistent dry mouth and treatments that can help to protect teeth and restore oral health.

Ed. Note: This article features information about oral complications, research highlights, and guidelines for people living with Sjögren's Syndrome and chronic dry mouth. Most of the information used in this article is based on a lecture given by Dr. Athena Papas for the Greater Boston Sjögren's Syndrome Support Group held on December 5, 2013 at Tufts Medical Center, Sackler Building, in Boston, MA. Additional data is included in order to provide some background information and more resources for our readers.

This material was researched and prepared by a layperson with ME/CFS and Sjögren's. Every effort has been made to accurately convey the information delivered by Dr. Papas and represent the research of other scientists brought up in this material. As always, consult with your health care provider for advice and further evaluation of new or worsening symptoms. Please see our Disclaimer

The first part of the article discusses issues around diagnosing Sjogren's Syndrome. If you suffer from dry mouth and are more interested in issues/treatments for this general condition, you may want to skip to the part of the article beginning with "How to minimize oral complications and maximize oral health and comfort."

Challenges of current diagnostic criteria and future screening methods

Athena Papas, DMD, PhD, is the Erling Johansen Professor of Research, the Co-Head of Geriatric Dentistry, and the Director of the Oral Medicine Department at Tufts University School of Dental Medicine. Dr. Papas has published numerous research papers based on her extensive clinical experience in Geriatric Dentistry, Sjögren's Syndrome, medically compromised patients, and xerostomia. At the December 2013 meeting, Dr. Papas discussed research updates and oral concerns and challenges of Sjögren's in her presentation titled, "Living with the Oral Complications of Sjögren's Syndrome."

Dr. Papas began her presentation with a short, educational video, "Does your patient have Sjögren's Syndrome?" released for dentists. The following is a brief description of Sjögren's taken from this video:

"Although hallmark symptoms are dry eyes and dry mouth, Sjögren's may also cause dysfunction of other organs such as kidneys, gastrointestinal system, blood vessels, lungs, liver, pancreas, and the central nervous system. Patients may also experience extreme fatigue and joint pain and about ten percent of patients develop lymphoma of their salivary glands. All instances of Sjögren's are systemic, affecting the entire body."

Sjögren's can exist alone, as a primary condition, or with another connective or autoimmune tissue disease such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and other conditions.

Early diagnosis of Sjögren's remains a challenge

Sjögren's is one of the most commonly under-diagnosed autoimmune diseases, often taking 5 to 8 years before a diagnosis is made.

While there are several techniques to assess salivary gland and ocular involvement, tests for certain autoantibodies in serum, and methods to demonstrate tissue changes, no single test is specific and sensitive enough to make a diagnosis.

Lack of international consensus regarding what defined positive evidence of the illness and ways to differentiate the two variants of the illness were some of the reasons for revision of the classification criteria for Sjögren's.

In April 2012, the latest version of the classification criteria was released by a group of international experts which included new details, rules and thresholds for tests and how these need to performed and interpreted. (Source: The Kelley's Textbook of Rheumatology, 9th edition).

The new criteria was intended, in part, to help ensure uniformity in participants selected for research.

To meet the classification criteria, there must be objective evidence in 2 out of 3 tests. For example, one of these tests must show one or more sites of inflammation per 4 mm squared area of glandular tissue for a positive result, according to the National Institutes of Health's release of April 2012, "New classification criteria released for research on Sjögren's Syndrome."

Clinicians and researchers who treat Sjögren's patients find these criteria can only detect patients with an established disease, that is, when their glands have already become damaged.

Patients will typically need to consult with at least two clinical specialties for evaluation and testing before a diagnosis can be made. The high cost of diagnostic tests, risks and discomfort associated with some of the procedures, and amount of time required to complete the testing/diagnostic process causes significant delay in diagnosis.

Continued disagreement and proposed changes to the 2012 classification criteria has gotten in the way of research for new treatments. All of the aforementioned issues underscore the importance of finding new ways to diagnose Sjögren's at an early stage of the illness.

Turning to saliva as a diagnostic tool

Saliva is often described by researchers and doctors as a mirror of the body and its well-being. It contains valuable diagnostic biomarkers which can help to screen for periodontal and other oral diseases, various cancers, systemic illnesses, and other conditions.

Other benefits of saliva-based tests are that they are less invasive and are rapid and cost-effective ways to screen for illness or detect early signs of illness.

Saliva analysis has been used, in some capacity, over the past 20 years to evaluate various medical problems; however, the field of research specifically devoted to disease detection and surveillance is called salivary diagnostics.

An investment made by the National Institute of Dental and Craniofacial Research (NIDCR) in saliva analysis over ten years ago, has generated significant advancement in salivary diagnostics. The NIDCR research initiative funded salivary diagnostic technology development at several research centers across the United States.

This research has led to discovery and development of a "diagnostic toolbox"— identification of components in human saliva, with biomarker profiles which can be used in the diagnosis of disease. (Source: A Primer on Salivary Diagnostics, published by the American Dental Association).

The future of salivary diagnostics

One of pioneers in salivary diagnostics is David T.W. Wong, D.M.D., D.M.Sc., the Associate Dean of Research at the University of California-Los Angeles (UCLA). Dr. Wong is also the Director at the UCLA Center for Oral/Head & Neck Oncology Research and Director of the Dental Research Institute at UCLA. Dr. Wong and the UCLA Dental Research Institute group have been instrumental in the development of salivary diagnostic biomarker profiles, which include: proteome, transcriptome, microRNA, metabolome and microbe. The Wong Lab/UCLA has established a research base that can serve as the scientific foundation for future dental and biomedical studies.

The UCLA research group has also developed statistical and informatics tools for salivary biomarker detection and validation. A prototype of this technology is a portable, integrated system that can rapidly detect multiple salivary proteins and other substances. This is an example of "point-of-care" technology that can be used at a healthcare provider's office to analyze oral fluid samples for disease or early signs of disease, eventually leading to chairside screening. Before this becomes common practice, scientists need to further investigate the potential diagnostic value of saliva and develop reliable and feasible technologies with high detection sensitivity. The future use and integration of salivary diagnostic technology may strengthen interdisciplinary patient care by changing the role that dentists and dental practitioners will play in healthcare. (Sources: A Primer on Salivary Diagnostics, American Dental Association. Salivary Diagnostics, The Wong Lab/UCLA School of Dentistry, The Dental Research Institute website).

Potential salivary biomarkers for Sjögren's

Research at the Department of General Dentistry at Tufts University School of Dental Medicine, Boston, MA has focused on both biomarkers and treatment of Sjögren's.

Dr. Athena Papas and Dr. Mabi Singh, who both treat high risk patients at the Tufts Dry Mouth Clinic, were two of several researchers from the Tufts University School of Dental Medicine to partake in a multi-center research study on salivary biomarkers. The aim of this study was to determine if biomarkers that could be used for diagnosis of Sjögren's are present in saliva.

"Discovery of putative salivary biomarkers for Sjögren's Syndrome using high resolution mass spectrometry and bioinformatics," published in the Journal of Oral Science, January 2012, found a biomarker that is unique to Sjögren's. They describe this biomarker as a "proteolytic peptide originating from human basic salivary proline-rich protein 3 precursor."

The research group concluded that the salivary biomarkers which they discovered, using the methods of detection and analysis detailed in the study, have the potential of serving as diagnostic/prognostic tools for Sjögren's Syndrome. A link to the full text of this research paper is provided at the end of this article.

How to minimize oral complications and maximize oral health and comfort

Dr. Papas has served as the principal investigator of numerous clinical trials and co-investigator of many research studies. She also possesses clinical expertise in the oral healthcare of geriatric patients, patients who are medically compromised as well as those with Sjögren's Syndrome and chronic dry mouth. Her combined and extensive research and clinical knowledge is evident in Dr. Papas' appreciation for the difficulties and complications that patients experience with Sjögren's/chronic dry mouth.

Common causes of tooth decay, dental problems, and oral pain

Saliva is essential for oral health. Once patients lose their saliva, they are at risk of losing their teeth. The effect of persistent dryness in the mouth may not always be understood by healthcare providers. Some, simply lacking knowledge in how to properly care for dry mouth, have given patients very poor advice. It is so important, but often very difficult, for patients to receive expert assistance at the early stages of their dental and oral complications. Many arrive at the Tufts Dry Mouth Clinic with teeth so eroded or broken that only jagged pieces protrude from the gums—the alarming discovery is many of these patients had extensive dental work, but it was no longer working. Dr. Papas tried to explained how this could happen.

Saliva is what keeps the enamel of teeth hard. Low amount of saliva production or loss of saliva leaves tooth enamel much more vulnerable to a wide range of dental problems. It is the weakening and erosion of tooth enamel which leads to many devastating complications.

The following list is a summary of the recognized as well as lesser known causes of tooth decay, deterioration, and erosion:

Acid in foods and beverages can affect teeth by accelerating demineralization of teeth (i.e., removing vital minerals). Frequency of consumption also matters—it is better to drink an acidic beverage all at once, rather than to keep sipping on it.

Acid reflux, found in at least half of Sjögren's patients, can cause stomach acids to backflow into the mouth, eat away at enamel, and even get at the pulp. Indications of acid backflow are soreness at the back of the throat, shiny amalgams, or signs of the enamel becoming eaten away around the amalgam. This acid can sometimes be so severe that it has completely worn away a person's teeth.

Brushing too hard can wear the teeth down (referred to as toothbrush abrasion) and brushing immediately after consuming acidic foods or drinks can make matters worse, by stripping away enamel.

Dryness cause teeth to dry out; when teeth dry out, they are much more likely to crack. Dryness can be the result of an underlying disease, like Sjögren's, or as a side effect from many drugs. Every effort needs to be made towards restoring moisture to the mouth.

Failed dental work, even in patients who have undergone a lot of dental work, is greatly due to inadequate preventative care. Work done on teeth that are already weakened or in an unhealthy condition or in a mouth with chronic dryness will simply not hold!

Fillings falling out of teeth often happens in teeth that are not hard enough. In most cases, it is not the filling but the teeth which have changed or deteriorated. This problem points back to causes of failed dental work. Getting a root canal or getting a tooth crowned does not eliminate future problems nor the need to continue protective therapy. In fact, teeth that have been worked on require even more attention and ongoing fluoride treatments or preventative measures. A tiny gap can easily develop along the edge of a crown and allow debris or bacteria to seep in.

Inflammation can occur in salivary glands as well as in the gingival margins of the teeth. In Sjögren's, it usually does not go below the gum line, like in periodontal disease.

Thick saliva; the watery part of saliva is the first to go in Sjögren's. Advanced dryness caused by the lack of saliva or damaged glands in Sjögren's can be so profound that a wooden tongue depressor will remain stuck on a patient's tongue.

Tooth Decay, particularly in Sjögren's, often occurs at the gum line, especially as gums start to recede. The root is much more sensitive to decay than the crown of the tooth. When there is a lot of tooth decay along the gum line, the tooth can shear right off.

Triggers of oral pain, sensitivity, and burning sensations

- Candidiasis: As saliva decreases, the development of candidiasis increases. A significant percentage (60%) of Sjögren's patients have candidiasis, especially the erythematous variant. This will present as red, irritated oral tissues and a red, raw tongue. It causes a lot of soreness and sensitivity inside the mouth. It can also develop as cracks at the corners of the mouth.

- Burning tongue/burning mouth: The lack of lubrication in the mouth can make the tongue become dry and rough due to friction against teeth and causes burning sensations. An interesting finding is that women have more taste buds than men. This difference may point to early means of survival that women were born with as they were the ones to determine if plants or foods were safe to eat by tasting them for their bitterness. When nerve endings on all of these extra taste buds become dry, irritated or inflamed, the patient will experience a burning mouth.

Treatments that make a difference and reduce tooth decay

Dr. Papas reviewed many treatment options which can help to minimize oral complications and maximize overall comfort and well-being. While there are many over-the-counter products advertised for dry mouth, she cautioned these products are primarily for comfort. They can be used, but they will not treat or protect the mouth or teeth. Treatments that make a difference, many times a prescription product, will help to stimulate salivation, restore moisture, protect and restore tooth enamel, and prevent anticipated complications.

The most important treatments and techniques for patients to start with are listed below:

Fluoride toothpaste – prescription-strength: Daily use of prescription-strength fluoride toothpaste is recommended (brand name, Colgate PreviDent). Research has shown that Sjögren's /dry mouth patients had less tooth decay with regular use of fluoride (i.e., as toothpaste, oral rinses, treatments provided by the dentist).

Fluoride varnishes: New ways to deliver fluoride, as a clear film that gets brushed on by the dentist. Discuss this option with your dentist.

Brushing techniques: Be sure to brush your teeth correctly. Don't scrub. Power toothbrushes with sonic technology are recommended for Sjögren's /dry mouth patients. These are found to more thoroughly remove plaque from teeth and gums.

Night-time routine: This should include brushing teeth with a prescription-strength toothpaste, followed by an application of MI Paste™ over the teeth, and then going to sleep (without rinsing). This regimen serves as an overnight treatment that will help remineralize and protect teeth.

Remineralize teeth by using a topical cream like MI Paste™ that contains calcium and phosphate. Place a small dab on a fingertip and spread it over teeth. Note: MI Paste contains RECALDENT™, a special milk-derived protein which helps to release the active ingredients. It may not be suitable for people with milk protein allergies. It is usually provided or sold by a dentist or an oral specialist, although it is sold at several online stores. Discuss this treatment option with your dentist.

Increase salivation with use of sialogogues: Sialogogues are agents or drugs that help to increase/stimulate salivation. Two of the most commonly used systemic sialogogues are pilocarpine (brand name, Salagen) and cevimeline (brand name, Evoxac). These are prescription drugs and may cause side effects in some patients. Research has shown that patients who had used Salagen for 4 years had much less tooth decay.

Increase salivation by chewing: Chewing gum can also help to stimulate production of saliva. Xylitol gum is preferred because it helps to generate moisture in the mouth. Too much xylitol can cause diarrhea; therefore, the recommended consumption is no more 8 pieces per day.

Improve salivation by massaging glands: See massage techniques to relieve painful or swollen salivary glands, described in detail, at the end of this list.

Chlorhexidine: an antimicrobial oral rinse, available by prescription (brand name, Peridex, Periogard) is used to treat swollen or infected gums.

Anti-inflammatories, like Celebrex, have been shown to reduce inflammation in periodontal disease. A short course may help Sjögren's/dry mouth during a flare.

Omega 3 fatty acids can help to reduce inflammation and improve salivation.

Lubricate the inside of your mouth with extra virgin olive oil or vitamin E capsules.

Increase dental cleanings/exams plus fluoride treatments—ideally, four times per year to effectively manage and care for Sjögren's /chronic dry mouth.

Check for early signs of lymphoma, very important to do in Sjögren's as lymphoma is detected in about 10% of patients— don't ignore little things—a warning by Dr. Papas.

Dental implants, consider implants if all else fails. There have been 200 implants done at the Tufts Dental Specialty Clinic with a 97% success rate. Implants can also serve as a base for dentures.

Massage techniques to relieve painful or swollen salivary glands

The parotid glands are located in the upper part of each cheek, close to the ear, and secretions from the glands have to pass through a complex pattern of ductwork. The parotid glands are encapsulated and have a thick fibrous coating. These glands can become obstructed with a mucus plug or stones in the ducts and cause swelling, pain and damage to the ducts.

Therefore, it is very important to keep the flow of saliva moving and good way to encourage flow of saliva is by massaging the glands.

For parotid glands, place two fingers behind the ear and slide them forward along cheek, while applying gentle pressure.

For the submandibular/sublingual glands, place two fingers under the jaw and slide them forward, along the edge of the jaw line to promote flow of saliva into floor of the mouth.

These are self-applied massage techniques that can help to keep saliva flowing. Warm compresses can be used to soothe painful glands.

 A promising treatment for dry mouth is in the pipeline

Dr. Papas ended her presentation with encouraging news about her work with Dr. Howard Green, at Harvard Medical School, who had developed artificial skin for severely burned patients. They have conceived a treatment plan for a moisturizing agent that would be delivered by way of a mucoadhesive film (attached to the mucosa) into the oral cavity. They have asked the Forsyth Institute in Cambridge, MA to help them create this product, and it has shown an interest in it.


"A Primer on Salivary Diagnostics", American Dental Association, 2009. 

"New classification criteria released for research on Sjögren's Syndrome," National Institutes of Health's New & Events, Release of April 11, 2012: http://www.nih.gov/news/health/apr2012/nidcr-11.htm.

Shiboski SC et al, "American College of Rheumatology classification criteria for Sjögren's syndrome: A data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance Cohort", Arthritis Care & Research 64, no. 4 (2012): 475–487, doi: 10.1002/acr.21591. Full text of this article (Wiley Online Library) as PDF: http://onlinelibrary.wiley.com/doi/10.1002/acr.21591/pdf.

Spielmann N and Wong DT, "Saliva: diagnostics and therapeutic perspectives," Oral Disease 17, no. 4 (2011): 345–354, doi:10.1111/j.1601-0825.2010.01773.x. Full text of article as NIH Public Access Author Manuscript: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056919/

St. Clair, EW. "Sjögren's Syndrome," in The Kelley's Textbook of Rheumatology, 9th ed. Gary S. Firestein, M.D., et al (Philadelphia: Elsevier/Saunders, 2012), Ch. 73.

Zoukhri D  et al, "Discovery of putative salivary biomarkers for Sjögren's syndrome using high resolution mass spectrometry and bioinformatics," Journal of Oral Science 54, no. 1 (2012). Full text of this article: https://www.jstage.jst.go.jp/article/josnusd/54/1/54_1_61/_pdf.


For additional information on salivary diagnostics/salivaomics

Dr. David T. Wong extends an invitation to anyone who would like to explore more of research done by the UCLA School of Dentistry, Dental Research Institute to visit their website, Salivary Diagnostics

A chart that illustrates the scientific development of salivary diagnostic toolboxes can be seen at: Salivaomics Knowledge Base (The Wong Lab, at the UCLA School of Dentistry, Dental Research Institute).

Listen to an informative Podcast by the American Association for Clinical Chemistry, September 2012 issue, that features Dr. David T. Wong. In this 15 minute interview, Dr. Wong reviews one of his recent research papers and explains how the evaluation of RNA in saliva has the potential of becoming an emerging diagnostic technology in disease detection: "The Human Salivary RNA Transcriptome Revealed by Massively Parallel Sequencing." The link for this podcast can also be accessed on the Home page of The Wong Lab /UCLA Dental Research website.


Notice about names

The Massachusetts ME/CFS & FM Association would like to clarify the use of the various acronyms for Chronic Fatigue Syndrome (CFS), Chronic Fatigue & Immune Dysfunction Syndrome (CFIDS) and  Myalgic Encephalomyelitis (ME) on this site. When we generate our own articles on the illness, we will refer to it as ME/CFS, the term now generally used in the United States. When we are reporting on someone else’s report, we will use the term they use. The National Institutes of Health (NIH) and other federal agencies, including the CDC, are currently using ME/CFS. 

Massachusetts ME/CFS & FM Association changed its name in July, 2018, to reflect this consensus.