A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and ‘post-exertional malaise’, exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology.

Methods: To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group.

Results: A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < -0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation.

Conclusions: The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.

Source: Sweetman E, Kleffmann T, Edgar C, de Lange M, Vallings R, Tate W. A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction. J Transl Med. 2020 Sep 24;18(1):365. doi: 10.1186/s12967-020-02533-3. PMID: 32972442. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02533-3 (Full text)

Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe fatigue illness that occurs most commonly following a viral infection, but other physiological triggers are also implicated. It has a profound long-term impact on the life of the affected person. ME/CFS is diagnosed primarily by the exclusion of other fatigue illnesses, but the availability of multiple case definitions for ME/CFS has complicated diagnosis for clinicians.

There has been ongoing controversy over the nature of ME/CFS, but a recent detailed report from the Institute of Medicine (Academy of Sciences, USA) concluded that ME/CFS is a medical, not psychiatric illness. Importantly, aspects of the biological basis of the ongoing disease have been revealed over the last 2-3 years that promise new leads towards an effective clinical diagnostic test that may have a general application.

Our detailed molecular studies with a preclinical study of ME/CFS patients, along with the complementary research of others, have reported an elevation of inflammatory and immune processes, ongoing neuro-inflammation, and decreases in general metabolism and mitochondrial function for energy production in ME/CFS, which contribute to the ongoing remitting/relapsing etiology of the illness. These biological changes have generated potential molecular biomarkers for use in diagnostic ME/CFS testing.

Source: Sweetman E, Noble A, Edgar C, Mackay A, Helliwell A, Vallings R, Ryan M, Tate W. Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Diagnostics (Basel). 2019 Jul 10;9(3). pii: E73. doi: 10.3390/diagnostics9030073. https://www.mdpi.com/2075-4418/9/3/73 (Full article)

Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a poorly understood disease affecting 0.2%-2% of the global population. To gain insight into the pathophysiology of ME/CFS in New Zealand, we examined the transcriptomes of peripheral blood mononuclear cells by RNA-seq analysis in a small well-characterized patient group (10 patients), with age/gender-matched healthy controls (10 control subjects).

Twenty-seven gene transcripts were increased 1.5- to sixfold and six decreased three- to sixfold in the patient group ( P < 0.01). The top enhanced gene transcripts, IL8, NFΚBIA and TNFAIP3, are functionally related to inflammation, and significant changes were validated for IL8 and NFΚBIA by quantitative polymerase chain reaction (qPCR). Functional network analysis of the altered gene transcripts ( P < 0.01) detected interactions between the products related to inflammation, circadian clock function, metabolic dysregulation, cellular stress responses and mitochondrial function. Ingenuity pathway analysis ( P < 0.05) provided further insights into the dysfunctional physiology, highlighting stress and inflammation pathways.

This analysis provides novel insights into the molecular changes in ME/CFS and contributes to the understanding of the pathophysiological mechanisms of the disease.

Source: Sweetman E, Ryan M, Edgar C, MacKay A, Vallings R, Tate W. Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738418820402. doi: 10.1177/2058738418820402.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350121/ (Full article)

Cognition In Young People With ME/CFS

By Dr R. Vallings

One of the main reasons that young people with ME/CFS struggle with school is associated with cognition. Mental confusion, memory problems and difficulties with concentration are all described and may relate to abnormal neurological pathology, sluggish cerebral circulation and generalised fatigue.

Cognitive effort leads to fatigue in the same way that exercise will lead to muscle fatigue and post-exertional malaise. Headaches are frequently a prominent and persistent symptom, and they too will interfere with the student’s cognitive ability. There can be aggravation of symptoms associated with trying to focus and learn from a computer screen. Many will describe visual symptoms with blurring of text or eye fatigue.

A noisy classroom situation may not be conducive to mental effort, and students are often moving from room to room carrying heavy books, this all adding to the burden which the illness poses.

The young person may have problems with sleep, waking feeling unrefreshed, and again cognitive effort may thus be limited. He/she may arrive at school feeling already exhausted due to lack of restorative sleep and having to get up early, and then issues such as travelling, and the anxiety associated with what may lie ahead that day.

Too much exercise, standing for long periods, heat and poor nutrition can all compromise cognition. The student will be motivated to keep up with peers, and push him/herself mentally, physically and socially beyond the comfort zone, and suffer the consequences cognitively.

The teacher may have minimal understanding of the illness and its sequelae, and even the efforts of parents to explain can be brushed aside as “fussiness”. Attention span may be very short and the labels of laziness, attention deficit or learning disorders can be appended inappropriately.

Those with ME/CFS are usually highly motivated to achieve and will be disappointed by failures and lack of encouragement. Ridicule is often reported.

Parents and medical personnel need to communicate with the teachers to enhance their understanding of ME/CFS. To ensure that the student has the best possible opportunities to achieve appropriate education and a feeling of success. This will mean allowing the student to work at their own pace with adequate rest periods.

Management of the Cognitive Difficulties by the Primary Care Physician

Once a firm diagnosis has been made, the young person will feel relieved that there is an explanation for their problems, particularly those experienced by attempts to participate in regular schooling.

Parents need to be involved in this discussion, which should be addressed principally to the patient, so that he/she is also involved in decision making, and feels part of the team approach. Only the young person knows how they feel, and should be encouraged to verbalise their fears and needs. Teenagers will often need opportunity for discussion without a parent present.

Many young people fear getting behind their peers academically. There is a fear of never being able to catch up and consequently losing friends who move on. There needs to be encouragement to participate in ongoing education, however minimally, but without undue pressure.

This may mean limited attendance at school, or if available, correspondence education or home-schooling. The student can then work at their own pace. They should be encouraged to work for short periods with adequate rest periods, recognising when they are ready to rest. Some sort of structure for the days is helpful.

This may be difficult, if at home with parents needing to work. Particular difficulties need to be discussed, such as aggravation from computer screens, and difficulty focusing on written text (sometimes a ruler placed across the page can help with maintaining focus). Aggravating factors such as noise, bright lights, temperature and unpleasant odours may need to be adjusted. Snacks and drinks need to be available and allowed.

If well enough, some gentle outdoor exercise during breaks between cognitive effort should be suggested, and for younger children playing with siblings or friends after school or at weekends should be encouraged.

Focus on symptom control is important, and this may be achieved with attention to sleep difficulties and efficient pain management. Learning good relaxation strategies with the use of music, visualisation, and teaching self hypnosis all have a role. Having their own private space means that these things are more likely to be done, and rest will be undisturbed. Regular snacking with plenty of salt can help overcome symptoms associated with orthostatic intolerance.

Medication such as very low-dose tricyclics or melatonin to help with sleep may be useful. Some young people benefit from use of stimulants such as methylphenidate, but there is a risk of a false sense of wellbeing, leading to overdoing things. If the child is depressed or unduly anxious, this should be addressed and there should be opportunity to talk things through privately with a trusted professional, who has understanding of this illness.

The young person needs to understand the issues that can aggravate cognition, such as overdoing things mentally and physically, learning m to pace carefully, and avoiding situations which have proved detrimental. Planning time carefully and incorporating rewards can all help to ensure a better outcome.

Attention to achieving a regular body clock will mean that a good routine that fits in with family and school is possible. Standing for long periods, getting overheated or dehydrated and not eating adequately should all be avoided.

Above all there needs to be a sense of achievement, (however small), progress and normality if at all possible. Only the young person him/herself know how they really feel, and gaining a sense of control over this illness, rather than letting the illness control them entirely will achieve a growing sense of personal achievement and freedom from stress.

Reprinted with permission from Meeting Place – Autumn 2016 – Number 123: The official quarterly journal of ANZEMS Inc.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease that affects children and adolescents as well as adults. The etiology has not been established. While many pediatricians and other health-care providers are aware of ME/CFS, they often lack essential knowledge that is necessary for diagnosis and treatment. Many young patients experience symptoms for years before receiving a diagnosis.

This primer, written by the International Writing Group for Pediatric ME/CFS, provides information necessary to understand, diagnose, and manage the symptoms of ME/CFS in children and adolescents. ME/CFS is characterized by overwhelming fatigue with a substantial loss of physical and mental stamina. Cardinal features are malaise and a worsening of symptoms following minimal physical or mental exertion. These post-exertional symptoms can persist for hours, days, or weeks and are not relieved by rest or sleep.

Other symptoms include cognitive problems, unrefreshing or disturbed sleep, generalized or localized pain, lightheadedness, and additional symptoms in multiple organ systems. While some young patients can attend school, on a full or part-time basis, many others are wheelchair dependent, housebound, or bedbound.

Prevalence estimates for pediatric ME/CFS vary from 0.1 to 0.5%. Because there is no diagnostic test for ME/CFS, diagnosis is purely clinical, based on the history and the exclusion of other fatiguing illnesses by physical examination and medical testing. Co-existing medical conditions including orthostatic intolerance (OI) are common.

Successful management is based on determining the optimum balance of rest and activity to help prevent post-exertional symptom worsening. Medications are helpful to treat pain, insomnia, OI and other symptoms. The published literature on ME/CFS and specifically that describing the diagnosis and management of pediatric ME/CFS is very limited. Where published studies are lacking, recommendations are based on the clinical observations and practices of the authors.

Source: Rowe PC, Underhill RA, Friedman KJ, Gurwitt A, Medow MS, Schwartz MS, Speight N, Stewart JM, Vallings R, Rowe KS. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer. Front Pediatr. 2017 Jun 19;5:121. doi: 10.3389/fped.2017.00121. eCollection 2017. http://journal.frontiersin.org/article/10.3389/fped.2017.00121/full

Myalgic encephalomyelitis: International Consensus Criteria

Abstract:

The label ‘chronic fatigue syndrome’ (CFS) has persisted for many years because of the lack of knowledge of the aetiological agents and the disease process. In view of more recent research and clinical experience that strongly point to widespread inflammation and multisystemic neuropathology, it is more appropriate and correct to use the term ‘myalgic encephalomyelitis’ (ME) because it indicates an underlying pathophysiology. It is also consistent with the neurological classification of ME in the World Health Organization’s International Classification of Diseases (ICD G93.3).

Consequently, an International Consensus Panel consisting of clinicians, researchers, teaching faculty and an independent patient advocate was formed with the purpose of developing criteria based on current knowledge. Thirteen countries and a wide range of specialties were represented. Collectively, members have approximately 400 years of both clinical and teaching experience, authored hundreds of peer-reviewed publications, diagnosed or treated approximately 50 000 patients with ME, and several members coauthored previous criteria. The expertise and experience of the panel members as well as PubMed and other medical sources were utilized in a progression of suggestions/drafts/reviews/revisions.

The authors, free of any sponsoring organization, achieved 100% consensus through a Delphi-type process. The scope of this paper is limited to criteria of ME and their application. Accordingly, the criteria reflect the complex symptomatology. Operational notes enhance clarity and specificity by providing guidance in the expression and interpretation of symptoms. Clinical and research application guidelines promote optimal recognition of ME by primary physicians and other healthcare providers, improve the consistency of diagnoses in adult and paediatric patients internationally and facilitate clearer identification of patients for research studies.

© 2011 The Association for the Publication of the Journal of Internal Medicine.

Comment in: A controversial consensus–comment on article by Broderick et al. [J Intern Med. 2012]

 

Source: Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles AC, Speight N, Vallings R, Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisbik S, Mena I, Mikovits JA, Miwa K, Murovska M, Pall ML, Stevens S. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011 Oct;270(4):327-38. doi: 10.1111/j.1365-2796.2011.02428.x. Epub 2011 Aug 22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427890/ (Full article)

 

A case of chronic fatigue syndrome triggered by influenza H1N1 (swine influenza)

Abstract:

This case report describes an adolescent boy who was diagnosed as suffering from chronic fatigue syndrome 5 months after infection with H1N1 influenza.

 

Source: Vallings R. A case of chronic fatigue syndrome triggered by influenza H1N1 (swine influenza) .J Clin Pathol. 2010 Feb;63(2):184-5. doi: 10.1136/jcp.2009.071944. Epub 2009 Oct 26. https://www.ncbi.nlm.nih.gov/pubmed/19858526