Solve ME/CFS Initiative’s 2nd Annual Discovery Forum, held on October 14th in Washington DC, brought together leaders from across industry, academia, federal agencies, and biotech companies to tackle the most pressing issues confronting ME/CFS. In this interview, Dr. Zaher Nahle discusses ME/CFS science and policy with Dr. Maureen Hanson, founder and director of the Center for Enervating Neuroimmune Disease at Cornell University and member of the Solve ME/CFS Initiative’s Research Advisory Council.
Genome-Epigenome Interactions Associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Abstract:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an example of a complex disease of unknown etiology. Multiple studies point to disruptions in immune functioning in ME/CFS patients as well as with specific genetic polymorphisms and alterations of the DNA methylome in lymphocytes. However, the association between DNA methylation and genetic background in relation to the ME/CFS is currently unknown.
In this study we explored this association by characterizing the genomic (~4.3 million SNPs) and epigenomic (~480 thousand CpG loci) variability between populations of ME/CFS patients and healthy controls. We found significant associations of methylation states in T-lymphocytes at several CpG loci and regions with ME/CFS phenotype. These methylation anomalies are in close proximity to genes involved with immune function and cellular metabolism.
Finally, we found significant correlations of genotypes with methylation phenotypes associated with ME/CFS. The findings from this study highlight the role of epigenetic and genetic interactions in complex diseases, and suggest several genetic and epigenetic elements potentially involved in the mechanisms of disease in ME/CFS.
Source: Santiago Herrera, Wilfred C. de Vega, David Ashbrook, Suzanne D. Vernon, Patrick O. McGowan. Genome-Epigenome Interactions Associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. bioRxiv preprint first posted online Dec. 22, 2017; doi: http://dx.doi.org/10.1101/237958. (Full article)
Hemispherx Successfully Completes Commercial Scale Demonstration Batch of Ampligen® at Contract Manufacturer
NEW BRUNSWICK, N.J., Dec. 20, 2017 (GLOBE NEWSWIRE) — Hemispherx Biopharma (NYSE American:HEB) said, its Contract Manufacturing Organization (CMO) for Ampligen® has completed a commercial scale demonstration/engineering manufacturing run, along with the re-qualifications of analytical methods that were agreed upon during a previous successful Pre-Approval Inspection (PAI) as necessary prior to the production of commercial lots of Ampligen®.
This accomplishment, in addition to completing all qualification operations to address new equipment and new container closure/vial components, allows the manufacture of current Good Manufacturing Practice (cGMP) clinical product in March 2018 following a scheduled shut down of the CMO for its bi-annual maintenance program. Completion of the demonstration/engineering manufacturing run provides confidence that the clinical product will meet the stringent quality control release and stability testing prior to release and should be available to patients by the end of the second quarter 2018. The manufacture of a second clinical lot of Ampligen® is being scheduled to assure maintenance of the clinical supply inventory.
- Ampligen® has been approved in Argentina for severely debilitated Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients. Hemispherx recently reported that discussions are underway with the U.S. FDA on the next steps regarding a New Drug Application (NDA) for Ampligen® in ME/CFS, which afflicts more than one million people in this country, according to the Centers for Disease Control (CDC). Ampligen® is the only drug to have completed a Phase 3 clinical trial in the U.S. in ME/CFS.
- Earlier this year Hemispherx began supplying Ampligen® for pancreatic cancer patients in an Early Access Program (EAP) in the Netherlands. In addition, work is underway at two leading U.S. cancer centers to define Ampligen®’s potential role in enhancing the effectiveness of PD-1 and PD-L1 checkpoint inhibitors in the fast-growing field of immuno-oncology.
Efficacy and safety of noophen in the treatment of chronic fatigue syndrome in patients with cerebrovascular insufficiency
Abstract:
AIM: To assess the efficacy and safety of noophen in the treatment of chronic fatigue syndrome in patients with cerebrovascular insufficiency.
MATERIAL AND METHODS: Fifty-three patients with cerebrovascular disease, who complain about persistent fatigue, were randomized into two groups. Patients of the main group (n=33) received standard therapy and noophen, patients of the control group (n=20) received only standard therapy. Treatment efficacy was assessed using MFI-20, HADS-A, LSEQ. In addition, cognitive functioning was evaluated using Schulte test.
RESULTS AND CONCLUSION: Treatment with noophen resulted in the marked decrease in the total intensity of fatigue measured with MFI-20. The decrease in fatigue intensity by 30-50% was observed in 3/4 of patients of the main group. Noophen reduced all components of fatigue syndrome, including a mental component, and improved motivation. The reduction of the mental fatigue component was combined with the improvement of cognitive functioning assessed with Schulte test. Therefore, the effect of noophen on motivation and mental fatigue component can promote cognitive training in patients with cerebrovascular insufficiency.
Source: Vorob’eva OV, Rusaya VV. Efficacy and safety of noophen in the treatment of chronic fatigue syndrome in patients with cerebrovascular insufficiency. [Article in Russian; Abstract available in Russian from the publisher] Zh Nevrol Psikhiatr Im S S Korsakova. 2017;117(11):31-36. doi: 10.17116/jnevro201711711131-36. https://www.ncbi.nlm.nih.gov/pubmed/29265084
Differing case definitions point to the need for an accurate diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome
Excerpt:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterised by unexplained and persistent or recurrent incapacitating fatigue accompanied by a variety of symptoms and substantial reductions in previous levels of occupational, educational, social and/or personal activity [1, 2]. Given the absence of biomarkers for diagnosis, ME/CFS is defined by a combination of symptoms, most of which are non-specific and common to a number of diseases and conditions.
Over 20 case definitions have been proposed, leading to large variations in sensitivity and specificity of diagnosis. These diverse sets of diagnostic criteria and distinct ways in which they have been applied pose significant problems, as research results may vary considerably according to which definition is used. A particular problem occurs when overly inclusive criteria are used, since their lack of specificity may lead to considerable selection bias [3, 4]. Unfortunately, many studies, clinical trials in particular, have used broad case definitions such as the Oxford criteria [5], which requires little more than the presence of persistent significant fatigue for over 6 months and the exclusion of conditions that could explain symptoms, for a diagnosis to be made.
This problem has been highlighted by the Agency for Healthcare Research and Quality (AHRQ) review of evidence for the NIH Pathways to Prevention Workshop [4], which showed significant changes to the interpretation of evidence for treatment, when studies using broad case definitions, such as the Oxford criteria, are excluded from the analysis. The implications for clinical practice suggest that fit-for-all management approaches to ME/CFS, although more applicable to those who fit such broadly inclusive criteria, may be inadequate for patients who fulfil better targeted case definitions.
For patients selected using more restrictive definitions, cognitive behavioural therapy (CBT), graded exercise therapy (GET) and other forms of non-drug management approaches to ME/CFS, are most appropriate as adjunct therapies rather than restorative treatments, when provided by therapists with a good understanding of ME/CFS. These forms of behavioural intervention have been shown to support the well-being and rehabilitation of those suffering from many chronic and disabling conditions [6]. However, it is very important that the use of behaviourally based management strategies does not deter researchers, physicians, and other health professionals from the overarching goal of investigating the causes and pathophysiology of ME/CFS in various sub-groups and the development of specific treatments.
Source: Luis Nacul, PhD, Caroline C. Kingdon, MS, Erinna W Bowman, MSc, Hayley Curran, MS, and Eliana M Lacerda, PhD. Differing case definitions point to the need for an accurate diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome.Fatigue. Author manuscript; available in PMC 2017 Dec 14. Published in final edited form as: Fatigue. 2017; 5(1): 1–4. Published online 2017 Jan 8. doi: 10.1080/21641846.2017.1273863 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730342/ (Full article)
Autonomic Nervous System Functioning Related to Nocturnal Sleep in Patients With Chronic Fatigue Syndrome Compared to Tired Controls
Abstract:
STUDY OBJECTIVES: Autonomic nervous system (ANS) dysfunction is common in chronic fatigue syndrome (CFS). One of the main complaints in CFS is unrefreshing sleep. We aimed to study the nocturnal cardiac ANS in different sleep stages in patients filling the 2015 Institute of Medicine CFS diagnostic criteria.
METHODS: In this case series study, the nocturnal heart rate variability and blood pressure (BP) variables in polysomnography were studied in groups of patients with CFS (n = 8) and tired controls (n = 8) aged 16-49 years. Five of the patients with CFS and controls were female. The heart rate variability and BP parameters and heart rate were studied in all sleep stages and wake.
RESULTS: The amount of low-frequency oscillations of the electrocardiography R-R-intervals spectra (LF; predominantly reflects sympathetic activity) was higher for patients with CFS in all sleep stages compared to controls (P< .001). During wake, the amount of LF was lower for the patients with CFS (P< .05). The amount of high-frequency oscillations (HF; reflects parasympathetic activity) was lower in stage N3 sleep in the patients with CFS than for the controls (P< .0001), but, in total, HF was higher in patients with CFS (P< .001). Patients with CFS had higher overall nocturnal systolic and mean BP (P< .0001) and lower heart rate (P< .0001) than controls. No significant differences were found in sleep stage distributions.
CONCLUSIONS: The results suggest a nocturnal dysfunction of the cardiac ANS in CFS, presenting as lower parasympathetic tone in deep sleep and higher sympathetic tone asleep.
Source: Orjatsalo M, Alakuijala A, Partinen M. Autonomic Nervous System Functioning Related to Nocturnal Sleep in Patients With Chronic Fatigue Syndrome Compared to Tired Controls. J Clin Sleep Med. 2017 Dec 13. pii: jc-17-00330. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29246267
Tenuous link between chronic fatigue syndrome and pyruvate dehydrogenase deficiency
Abstract:
Researchers studying the energy metabolism of patients with chronic fatigue syndrome have reached the conclusion that these patients have impaired pyruvate dehydrogenase function, but their measurements are not consistent with the changes we see in patients with primary genetic pyruvate dehydrogenase deficiency.
A cross-sectional study published in December 2016 found a change in the pattern of amino acids in the plasma of patients with chronic fatigue syndrome. Gene expression in white blood cells and energy metabolism in muscle cells was also found to have changed (1). The authors interpret the results as an expression of functional inhibition of the enzyme pyruvate dehydrogenase, and they postulate dysregulation of the enzyme complex as a possible key factor in the pathogenesis associated with chronic fatigue syndrome.
The study received extensive media coverage (2, 3), and the link to pyruvate dehydrogenase is published without reservations as an established fact (4, 5). At our laboratory we are now receiving samples for metabolic screening from patients with suspected fatigue syndrome. On the basis of my own experience with biochemical diagnostic workup for pyruvate dehydrogenase deficiency, I would like to point out weaknesses in the study that should have prompted much greater caution in the conclusions.
Source: Bliksrud YT. Tenuous link between chronic fatigue syndrome and pyruvate dehydrogenase deficiency. Tidsskr Nor Laegeforen. 2017 Nov 28;137(23-24). doi: 10.4045/tidsskr.17.0948. Print 2017 Dec 12. [Article in English, Norwegian] http://tidsskriftet.no/en/2017/12/debatt/tenuous-link-between-chronic-fatigue-syndrome-and-pyruvate-dehydrogenase-deficiency (Full article)
Caring for people with severe myalgic encephalomyelitis: An interpretative phenomenological analysis of parents’ experiences
Abstract:
Experiences of parents who care for sons or daughters with severe myalgic encephalomyelitis are rarely discussed within the literature. Narratives of parent-carers in Lost Voices from a Hidden Illness were analyzed using interpretative phenomenological analysis. This study aimed to give voices to those who care for individuals with myalgic encephalomyelitis and are often stigmatized and inform future research supporting parent-carers. Results included themes of identity change, guilt, feeling like outsiders, uncertainty, changing perceptions of time, coping mechanisms, and improvement/symptom management. Findings could inform the development of carer-focused interventions and provide vital information to health professionals about parent-carers’ lived experience.
Source: Mihelicova M, Siegel Z, Evans M, Brown A, Jason L. Caring for people with severe myalgic encephalomyelitis: An interpretative phenomenological analysis of parents’ experiences. J Health Psychol. 2016 Dec;21(12):2824-2837. Epub 2015 Jun 10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675701/ (Full article)
Factors impacting the illness trajectory of post-infectious fatigue syndrome: a qualitative study of adults’ experiences
Abstract:
BACKGROUND: Post-infectious fatigue syndrome (PIFS), also known as post-viral fatigue syndrome, is a complex condition resulting in physical, cognitive, emotional, neurological, vocational and/or role performance disabilities in varying degrees that changes over time. The needs for health care resources are high, and costly, as is the economic burden on the affected individuals. Many factors may impact the trajectory, and frequently PIFS develops into a chronic condition. Health professionals lack understanding and knowledge, which results in delayed diagnosis, lack of recognition, appropriate treatment, support and practical help. The aim of our study was to explore, from the perspective of persons who had lived with PIFS for four years following an outbreak of Giardia l. induced enteritis, factors that may have impacted their illness trajectory and how these factors had played a role during different phases.
METHODS: In this retrospective exploratory qualitative study a group of 26 affected adults between 26 and 59 years old were selected for in-depth interviews. A maximum variation sample was recruited from a physician-diagnosed cohort of persons with PIFS enrolled at a tertiary outpatient fatigue clinic. The interviews were audio-recorded, transcribed verbatim and subjected to qualitative content analysis.
RESULTS: Unhelpful and helpful factors were associated with the healthcare system, health professionals and the affected persons were experienced as having an impact on the trajectory. External impacting factors which are related to the health care system, providers and the social security system are misdiagnosis, trivialization of symptoms, unhelpful advice, delayed diagnosis and lack of appropriate help. Internal impacting factors related to the affected individuals were lack of knowledge, overestimating functional capacity, assuming the condition will pass, ignoring body signals and denial. A model of impacting factors in each phase of the trajectory is presented.
CONCLUSION: Unmet needs may result in unnecessary disability and high societal and personal costs. Enhanced knowledge of impacting factors in each phase of the trajectory may contribute to more timely and tailored health care services and less use of health services. Increased functional capacity, improved health and ability to work or study may reduce the societal costs and the economic burden for the affected individuals
Source: Stormorken E, Jason LA, Kirkevold M. Factors impacting the illness trajectory of post-infectious fatigue syndrome: a qualitative study of adults’ experiences. BMC Public Health. 2017 Dec 13;17(1):952. doi: 10.1186/s12889-017-4968-2. (Full article)
Efficacy of acupoint catgut embedding combined with ginger-partitioned moxibustion on chronic fatigue syndrome of spleen-kidney yang deficiency syndrome and its effects on T lymphocyte subsets and activity of NK cell
Abstract:
OBJECTIVE: To observe the efficacy differences between acupoint catgut embedding combined with ginger-partitioned moxibustion and regular acupuncture on chronic fatigue syndrome (CFS) of spleen-kidney yang deficiency syndrome, and to explore its effects on T lymphocyte subsets and activity of NK cell.
METHODS: A total of 60 patients with CFS of spleen-kidney yang deficiency syndrome were randomly divided into a catgut embedding combined with ginger-partitioned moxibustion (CECGP) group and a regular acupuncture group, 30 cases in each one. The patients in the CECGP group were treated with acupoint catgut embedding combined with ginger-partitioned moxibustion; the acupoint catgut embedding was applied at Guanyuan (CV 4), Shenshu (BL 23), Pishu (BL 20), Zusanli (ST 36), Qihai (CV 6), once a week, while the ginger-partitioned moxibustion was applied at Guanyuan (CV 4), Qihai (CV 6) and Zusanli (ST 36), once every three days for consecutive one month. The patients in the regular acupuncture group were treated with regular acupuncture at Guanyuan (CV 4), Shenshu (BL 23), Pishu (BL 20), Zusanli (ST 36), Qihai (CV 6), once a day, 6 treatments per week (one day for rest) for consecutive one month. The clinical symptom scores, fatigue scale-14 (FS-14), fatigue assessment instrument (FAI), laboratory test results and total effective rate were compared between the two groups before and after treatment.
RESULTS: (1) After treatment, the clinical symptom scores, FS-14 and FAI were reduced in the two groups (all P<0.05); after treatment, the clinical symptom scores, FS-14 and FAI in the CECGP group were significantly lower than those in the regular acupuncture group (all P<0.05). (2) After treatment, the CD4+/CD8+, natural killer cell% (NK%), CD3+%, CD% were all increased in the two groups (all +4 P<0.05); the CD4+/CD8+, CD3+%, CD% in the CECGP group were significantly higher than those in the regular acupuncture group (all P<0.05). (3) After treatment, the total effective rate was 96.7% (29/30) in the CECGP group, which was similar to 93.3% (28/30) in the regular acupuncture group (P>0.05).
CONCLUSIONS: The acupoint catgut embedding combined with ginger-partitioned moxibustion, which could effectively relieve the symptoms, regulate T lymphocyte subsets and the activity of NK cell, is an effective method for CFS of spleen-kidney yang deficiency syndrome.
Source: Xia D, Chen P, Du P, Ding L, Liu A. [Efficacy of acupoint catgut embedding combined with ginger-partitioned moxibustion on chronic fatigue syndrome of spleen-kidney yang deficiency syndrome and its effects on T lymphocyte subsets and activity of NK cell]. Zhongguo Zhen Jiu. 2017 Aug 12;37(8):814-818. doi: 10.13703/j.0255-2930.2017.08.004. [Article in Chinese]