Tag: 2021

ME/CFS: Past, Present and Future

Abstract:

This review raises a number of compelling issues related to the condition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Some historical perspective is necessary in order to highlight the nature of the controversy concerning its causation. Throughout history, a pattern tends to repeat itself when natural phenomena require explanation. Dogma usually arrives first, then it is eventually replaced by scientific understanding. The same pattern is unfolding in relation to ME/CFS, but supporters of the psychological dogma surrounding its causation remain stubbornly resistant, even in the face of compelling scientific evidence to the contrary. Acceptance of the latter is not just an academic issue; the route to proper understanding and treatment of ME/CFS is through further scientific research rather than psychological theorisation. Only then will a long-suffering patient group benefit.

Source: Weir, William, and Nigel Speight. 2021. “ME/CFS: Past, Present and Future” Healthcare 9, no. 8: 984. https://doi.org/10.3390/healthcare9080984 https://www.mdpi.com/2227-9032/9/8/984/htm (Full text)

Effect of Dietary Coenzyme Q10 Plus NADH Supplementation on Fatigue Perception and Health-Related Quality of Life in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem, and profoundly debilitating neuroimmune disease, probably of post-viral multifactorial etiology. Unfortunately, no accurate diagnostic or laboratory tests have been established, nor are any universally effective approved drugs currently available for its treatment. This study aimed to examine whether oral coenzyme Q10 and NADH (reduced form of nicotinamide adenine dinucleotide) co-supplementation could improve perceived fatigue, unrefreshing sleep, and health-related quality of life in ME/CFS patients.
A 12-week prospective, randomized, double-blind, placebo-controlled trial was conducted in 207 patients with ME/CFS, who were randomly allocated to one of two groups to receive either 200 mg of CoQ10 and 20 mg of NADH (n = 104) or matching placebo (n = 103) once daily. Endpoints were simultaneously evaluated at baseline, and then reassessed at 4- and 8-week treatment visits and four weeks after treatment cessation, using validated patient-reported outcome measures.
A significant reduction in cognitive fatigue perception and overall FIS-40 score (p < 0.001 and p = 0.022, respectively) and an improvement in HRQoL (health-related quality of life (SF-36)) (p < 0.05) from baseline were observed within the experimental group over time. Statistically significant differences were also shown for sleep duration at 4 weeks and habitual sleep efficiency at 8 weeks in follow-up visits from baseline within the experimental group (p = 0.018 and p = 0.038, respectively).
Overall, these findings support the use of CoQ10 plus NADH supplementation as a potentially safe therapeutic option for reducing perceived cognitive fatigue and improving the health-related quality of life in ME/CFS patients. Future interventions are needed to corroborate these clinical benefits and also explore the underlying pathomechanisms of CoQ10 and NADH administration in ME/CFS.
Source: Castro-Marrero J, Segundo MJ, Lacasa M, Martinez-Martinez A, Sentañes RS, Alegre-Martin J. Effect of Dietary Coenzyme Q10 Plus NADH Supplementation on Fatigue Perception and Health-Related Quality of Life in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients. 2021; 13(8):2658. https://doi.org/10.3390/nu13082658  https://www.mdpi.com/2072-6643/13/8/2658 (Full text)

Benefits of micronutrient supplementation on nutritional status, energy metabolism, and subjective wellbeing

Abstract:

The human body, particularly the brain, requires energy, stored in the form of adenosine triphosphate. Energy metabolism during cellular respiration is dependent on the presence of multiple micronutrients, which act as essential components, coenzymes, or precursors at every stage. An adequate supply of multiple micronutrients is vital for efficient energy production. However, micronutrient intakes below the recommended dietary allowance are common, even in industrialized countries. Intakes of vitamins A, D, E, folate, iron, zinc, and selenium are suboptimal across all age groups. Suboptimal micronutrient levels have been shown to contribute to low energy levels, physical and mental fatigue, and impaired cognitive performance and wellbeing – symptoms frequently present in the general population.

When supplemented in combination in well-conducted trials, multiple micronutrients ± coenzyme Q10 reduced oxidative stress in chronic fatigue syndrome; in healthy people they increased cerebral blood-flow hemodynamic response, energy expenditure, and fat oxidation; reduced mental and physical fatigue; improved the speed and accuracy of cognitive function during demanding tasks; and reduced stress. The results from these clinical trials suggest that even in industrialized countries, where adults might be assumed to have a healthy, balanced diet, there is a rationale to supplement with multiple micronutrients, including coenzyme Q10, to improve nutritional status, support energy metabolism, and improve subjective wellbeing.

Source: Maggini S, Óvári V, Ferreres Giménez I, Pueyo Alamán MG. Benefits of micronutrient supplementation on nutritional status, energy metabolism, and subjective wellbeing. Nutr Hosp. 2021 Jul 28. English. doi: 10.20960/nh.03788. Epub ahead of print. PMID: 34323089.

Chronic fatigue syndrome and long covid: individualisation, not compartmentalisation

Newman’s investigation of chronic fatigue syndrome and long covid supports the development of specialised multidisciplinary support for patients with long covid.1 But compartmentalisation of a problem like chronic fatigue syndrome can sometimes miss the point.

Dysregulated systems, by their nature, cannot be manipulated into functionality, so the clinical modelling of a system disturbance is often best undertaken by a clinician with dedicated expertise in multisystem assessment who can pull the “hard” and “soft” data together.

Specialised teams, such as the fatigue clinic at the Royal London Hospital for Integrated Medicine, routinely individualise chronic fatigue syndrome cases to a high level of detail. In the absence of objective data, the use of advanced and holistic history taking can explore the factors that perpetuate the clinical state.

The “forensic” part of the inquiry searches for the symptomatic features of pathophysiological change, hypothalamic dysregulation, or ongoing immunological disturbance. The physical and functional inquiry is then contextualised by an empathic and holistic psychosocial survey.

Each patient has a unique combination of perpetuating factors in chronic fatigue syndrome and long covid, so treatment approaches should also be individualised to a high degree. This level of individualisation is not always possible using a compartmentalised method of assessment.

Source: Malcolm R S. Chronic fatigue syndrome and long covid: individualisation, not compartmentalisation. BMJ 2021; 374 :n1863 doi:10.1136/bmj.n1863 https://www.bmj.com/content/374/bmj.n1863

The reification of the clinical diagnosis of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) as an immune and oxidative stress disorder: construction of a data-driven nomothethic network and exposure of ME/CFS subgroups

Abstract:

The approach towards myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) remains in a permanent state of crisis with fierce competition between the psychosocial school, which attributes ME/CFS to the perception of effort, and the medical approach (Maes and Twisk, BMC Med, 2010,8,35). The aim of this paper is to review how to construct a nomothetic model of ME/CFS using Partial Least Squares (PLS) path analysis and ensembling causome (bacterial translocation as assessed with IgM/IgA responses to LPS), protectome (lowered coenzyme Q10), adverse outcome pathways (AOP) including increased lysozyme, CD38+ T cell activation, cell-mediated immune activation (CMI), and IgM responses to oxidative specific epitopes and NO-adducts (IgM OSENO).

Using PLS, we trained, tested and validated this knowledge- and data-driven causal ME/CFS model, which showed adequate convergence, construct and replicability validity. This bottom-up explicit data model of ME/CFS objectivates the descriptive narratives of the ME/CFS phenome, using causome-protectome-AOP data, whereby the abstract concept ME/CFS is translated into pathways, thereby securing the reification of the ME/CFS phenome.

We found that 31.6% of the variance in the physiosomatic symptom dimension of ME/CFS was explained by the cumulative effects of CMI and CD38+ activation, IgM OSENO, IgA LPS, lysozyme (all positive) and coenzyme Q10 (inversely). Cluster analysis performed on the PLS-generated latent vector scores of all feature sets exposed three distinct immune groups of ME/CFS, namely one with increased lysozyme, one with increased CMI + CD38 activation + depressive symptoms, and another with increased bacterial translocation + autoimmune responses to OSENO

Source: Maes M, Kubera M, Stoyanova K, Leunis JC. The reification of the clinical diagnosis of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) as an immune and oxidative stress disorder: construction of a data-driven nomothethic network and exposure of ME/CFS subgroups. Curr Top Med Chem. 2021 Jul 27. doi: 10.2174/1568026621666210727170147. Epub ahead of print. PMID: 34315375. https://pubmed.ncbi.nlm.nih.gov/34315375/

Evaluating Routine Blood Tests According to Clinical Symptoms and Diagnostic Criteria in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

There is a lack of research regarding blood tests within individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and between patients and healthy controls. We aimed to compare results of routine blood tests between patients and healthy controls. Data from 149 patients diagnosed with ME/CFS based on clinical and psychiatric evaluation as well as on the DePaul Symptom Questionnaire, and data from 264 healthy controls recruited from blood donors were compared. One-way ANCOVA was conducted to examine differences between ME/CFS patients and healthy controls, adjusting for age and gender.

Patients had higher sedimentation rate (mean difference: 1.38, 95% CI: 0.045 to 2.714), leukocytes (mean difference: 0.59, 95% CI: 0.248 to 0.932), lymphocytes (mean difference: 0.27, 95% CI: 0.145 to 0.395), neutrophils (mean difference: 0.34, 95% CI: 0.0 89 to 0.591), monocytes (mean difference: 0.34, 95% CI: 0.309 to 0.371), ferritin (mean difference: 28.13, 95% CI: -1.41 to 57.672), vitamin B12 (mean difference: 83.43, 95% CI: 62.89 to 124.211), calcium (mean difference: 0.02, 95% CI: -0.02 to 0.06), alanine transaminase (mean difference: 3.30, 95% CI: -1.37 to -7.971), low-density lipoproteins (mean difference: 0.45, 95% CI: 0.104 to 0.796), and total proteins (mean difference: 1.53, 95% CI: -0.945 to 4.005) than control subjects. The patients had lower potassium levels (mean difference: 0.11, 95% CI: 0.056 to 0.164), creatinine (mean difference: 2.60, 95% CI: 0.126 to 5.074) and creatine kinase (CK) (mean difference: 37.57, 95% CI: -0.282 to 75.422) compared to the healthy controls. Lower CK and creatinine levels may suggest muscle damage and metabolic abnormalities in ME/CFS patients.

Source: Baklund IH, Dammen T, Moum TÅ, Kristiansen W, Duarte DS, Castro-Marrero J, Helland IB, Strand EB. Evaluating Routine Blood Tests According to Clinical Symptoms and Diagnostic Criteria in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Clin Med. 2021 Jul 14;10(14):3105. doi: 10.3390/jcm10143105. PMID: 34300271. https://pubmed.ncbi.nlm.nih.gov/34300271/

Shadow Burden of Undiagnosed Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) on Society: Retrospective and Prospective-In Light of COVID-19

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a poorly understood, complex, multisystem disorder, with severe fatigue not alleviated by rest, and other symptoms, which lead to substantial reductions in functional activity and quality of life. Due to the unclear aetiology, treatment of patients is complicated, but one of the initial problems is the insufficient diagnostic process. The increase in the number of undiagnosed ME/CFS patients became specifically relevant in the light of the COVID-19 pandemic. The aim of this research was to investigate the issues of undiagnosed potential ME/CFS patients, with a hypothetical forecast of the expansion of post-viral CFS as a consequence of COVID-19 and its burden on society.

Methods: The theoretical research was founded on the estimation of classic factors presumably affecting the diagnostic scope of ME/CFS and their ascription to Latvian circumstances, as well as a literature review to assess the potential interaction between ME/CFS and COVID-19 as a new contributing agent. The empirical study design consisted of two parts: The first part was dedicated to a comparison of the self-reported data of ME/CFS patients with those of persons experiencing symptoms similar to ME/CFS, but without a diagnosis. This part envisaged the creation of an assumption of the ME/CFS shadow burden “status quo”, not addressing the impact of COVID-19. The second part aimed to investigate data from former COVID-19 patients’ surveys on the presence of ME/CFS symptoms, 6 months after being affected by COVID-19. Descriptive and analytical statistical methods were used to analyse the obtained data.

Results: The received data assumed that the previously obtained data on the ME/CFS prevalence of 0.8% in the Latvian population are appropriate, and the literature review reports a prevalence of 0.2-1.0% in developed countries. Regarding the reciprocity of ME/CFS and COVID-19, the literature review showed a lack of research in this field. The empirical results show quite similar self-esteem among ME/CFS patients and undiagnosed patients with longstanding disease experience, while former COVID-19 patients show a significantly lower severity of these problems. Notably, “psychological distress (anxiety)” and “episodic fatigue” are significantly predominant symptoms reported by former COVID-19 patients in comparison with ME/CFS patients and undiagnosed patients prior to the COVID-19 pandemic. The results of our analysis predict that the total amount of direct medical costs for undiagnosed patients (out-of-pocket payments) is more than EUR 15 million p.a. (in Latvia), and this may increase by at least 15% due to the consequences of COVID-19.

Conclusions: ME/CFS creates a significant shadow burden on society, even considering only the direct medical costs of undiagnosed patients-the number of whom in Latvia is probably at least five times higher than the number of discerned patients. Simultaneously, COVID-19 can induce long-lasting complications and chronic conditions, such as post-viral CFS, and increase this burden. The Latvian research data assume that ME/CFS patients are not a high-risk group for COVID-19; however, COVID-19 causes ME/CFS-relevant symptoms in patients. This increases the need for monitoring of patients for even longer after recovering from COVID-19’s symptoms, in order to prevent complications and the progression of chronic diseases. In the context of further epidemiological uncertainty, and the possibility of severe post-viral consequences, preventive measures are becoming significantly more important; an integrated diagnostic approach and appropriate treatment could reduce this burden in the future.

Source: Araja D, Berkis U, Lunga A, Murovska M. Shadow Burden of Undiagnosed Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) on Society: Retrospective and Prospective-In Light of COVID-19. J Clin Med. 2021 Jul 6;10(14):3017. doi: 10.3390/jcm10143017. PMID: 34300183. https://pubmed.ncbi.nlm.nih.gov/34300183/

Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank

Abstract:

The evidence of an association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and chronic herpesviruses infections remains inconclusive. Two reasons for the lack of consistent evidence are the large heterogeneity of the patients’ population with different disease triggers and the use of arbitrary cutoffs for defining seropositivity. In this work we re-analyzed previously published serological data related to 7 herpesvirus antigens. Patients with ME/CFS were subdivided into four subgroups related to the disease triggers: S0-42 patients who did not know their disease trigger; S1-43 patients who reported a non-infection trigger; S2-93 patients who reported an infection trigger, but that infection was not confirmed by a lab test; and S3-48 patients who reported an infection trigger and that infection was confirmed by a lab test.

In accordance with a sensitivity analysis, the data were compared to those from 99 healthy controls allowing the seropositivity cutoffs to vary within a wide range of possible values. We found a negative association between S1 and seropositivity to Epstein-Barr virus (VCA and EBNA1 antigens) and Varicella-Zoster virus using specific seropositivity cutoff. However, this association was not significant when controlling for multiple testing. We also found that S3 had a lower seroprevalence to the human cytomegalovirus when compared to healthy controls for all cutoffs used for seropositivity and after adjusting for multiple testing using the Benjamini-Hochberg procedure. However, this association did not reach statistical significance when using Benjamini-Yekutieli procedure. In summary, herpesviruses serology could distinguish subgroups of ME/CFS patients according to their disease trigger, but this finding could be eventually affected by the problem of multiple testing.

Source: Domingues TD, Grabowska AD, Lee JS, Ameijeiras-Alonso J, Westermeier F, Scheibenbogen C, Cliff JM, Nacul L, Lacerda EM, Mouriño H, Sepúlveda N. Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank. Front Med (Lausanne). 2021 Jul 5;8:686736. doi: 10.3389/fmed.2021.686736. PMID: 34291062; PMCID: PMC8287507. https://pubmed.ncbi.nlm.nih.gov/34291062/

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: When Suffering Is Multiplied

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness defined predominantly by symptoms. Routine laboratory test results often are normal, raising the question of whether there are any underlying objective abnormalities. In the past 20 years, however, new research technologies have uncovered a series of biological abnormalities in people with ME/CFS. Unfortunately, many physicians remain unaware of this, and some tell patients that “there is nothing wrong” with them. This skepticism delegitimizes, and thereby multiplies, the patients’ suffering.

Source: Komaroff AL. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: When Suffering Is Multiplied. Healthcare. 2021; 9(7):919. https://doi.org/10.3390/healthcare9070919 https://www.mdpi.com/2227-9032/9/7/919/htm

The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP 2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious multifactorial disorder. The origin remains ambiguous, however reduced natural killer (NK) cell cytotoxicity is a consistent immunological feature of ME/CFS. Impaired transient receptor potential melastatin 3 (TRPM3), a phosphatidylinositol dependent channel, and impaired calcium mobilisation have been implicated in ME/CFS pathology. This investigation aimed to examine the localisation of TRPM3 at the NK cell plasma membrane and co-localisation with phosphatidylinositol 4,5-bisphosphate (PIP2). The effect of IL-2 priming and treatment using pregnenolone sulfate (PregS) and ononetin on TRPM3 co-localisation and NK cell cytotoxicity in ME/CFS patients and healthy controls (HC) was also investigated.

Methods: NK cells were isolated from 15 ME/CFS patients and 15 age- and sex-matched HC. Immunofluorescent technique was used to determine co-localisation of TRPM3 with the NK cell membrane and with PIP2 of ME/CFS patients and HC. Flow cytometry was used to determine NK cell cytotoxicity. Following IL-2 stimulation and treatment with PregS and ononetin changes in co-localisation and NK cell cytotoxicity were measured.

Results: Overnight treatment of NK cells with PregS and ononetin resulted in reduced co-localisation of TRPM3 with PIP2 and actin in HC. Co-localisation of TRPM3 with PIP2 in NK cells was significantly reduced in ME/CFS patients compared with HC following priming with IL-2. A significant increase in co-localisation of TRPM3 with PIP2 was reported following overnight treatment with ononetin within ME/CFS patients and between groups. Baseline NK cell cytotoxicity was significantly reduced in ME/CFS patients; however, no changes were observed following overnight incubation with IL-2, PregS and ononetin between HC and ME/CFS patients. IL-2 stimulation significantly enhanced NK cell cytotoxicity in HC and ME/CFS patients.

Conclusion: Significant changes in co-localisation suggest PIP2-dependent TRPM3 function may be impaired in ME/CFS patients. Stimulation of NK cells with IL-2 significantly enhanced cytotoxic function in ME/CFS patients demonstrating normal function compared with HC. A crosstalk exists between IL-2 and TRPM3 intracellular signalling pathways which are dependent on Ca2+ influx and PIP2. While IL-2R responds to IL-2 binding in vitro, Ca2+ dysregulation and impaired intracellular signalling pathways impede NK cell function in ME/CFS patients.

Source: Eaton-Fitch N, Cabanas H, du Preez S, Staines D, Marshall-Gradisnik S. The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl Med. 2021 Jul 15;19(1):306. doi: 10.1186/s12967-021-02974-4. PMID: 34266470.  https://pubmed.ncbi.nlm.nih.gov/34266470/