Tag: review

Tetrahydrobiopterin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Friend or Foe?

Abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a chronic multisystem disease characterized by severe muscle fatigue, pain, dizziness, and brain fog. The two most common symptoms are post-exertional malaise (PEM) and orthostatic intolerance (OI). ME/CFS patients with OI (ME+OI) suffer from dizziness or faintness due to a sudden drop in blood pressure while maintaining an upright posture. Clinical research has demonstrated that patients with OI display severe cardiovascular abnormalities resulting in reduced effective blood flow in the cerebral blood vessels. However, despite intense investigation, it is not known why the effective cerebral blood flow is reduced in OI patients. Based on our recent findings, we observed that tetrahydrobiopterin (BH4) metabolism was highly dysregulated in ME+OI patients. In the current review article, we attempted to summarize our recent findings on BH4 metabolism to shed light on the molecular mechanisms of OI.

Source: Rahman AFMT, Benko A, Bulbule S, Gottschalk CG, Arnold LA, Roy A. Tetrahydrobiopterin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Friend or Foe? Biomolecules. 2025 Jan 10;15(1):102. doi: 10.3390/biom15010102. PMID: 39858496; PMCID: PMC11763651. https://pmc.ncbi.nlm.nih.gov/articles/PMC11763651/ (Full text)

Machine learning and multi-omics in precision medicine for ME/CFS

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and multifaceted disorder that defies simplistic characterisation. Traditional approaches to diagnosing and treating ME/CFS have often fallen short due to the condition’s heterogeneity and the lack of validated biomarkers. The growing field of precision medicine offers a promising approach which focuses on the genetic and molecular underpinnings of individual patients.

In this review, we explore how machine learning and multi-omics (genomics, transcriptomics, proteomics, and metabolomics) can transform precision medicine in ME/CFS research and healthcare. We provide an overview on machine learning concepts for analysing large-scale biological data, highlight key advancements in multi-omics biomarker discovery, data quality and integration strategies, while reflecting on ME/CFS case study examples. We also highlight several priorities, including the critical need for applying robust computational tools and collaborative data-sharing initiatives in the endeavour to unravel the biological intricacies of ME/CFS.

Source: Huang K, Lidbury BA, Thomas N, Gooley PR, Armstrong CW. Machine learning and multi-omics in precision medicine for ME/CFS. J Transl Med. 2025 Jan 14;23(1):68. doi: 10.1186/s12967-024-05915-z. PMID: 39810236. Huang K, Lidbury BA, Thomas N, Gooley PR, Armstrong CW. Machine learning and multi-omics in precision medicine for ME/CFS. J Transl Med. 2025 Jan 14;23(1):68. doi: 10.1186/s12967-024-05915-z. PMID: 39810236. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05915-z (Full text)

Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence

Abstract:

Background: Recent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessive sodium and calcium overload in skeletal muscles of ME/CFS patients to cause mitochondrial damage. Since then, experimental evidence has been provided that supports this concept.

Methods: We collect, summarize and discuss the current state of knowledge for the key role of skeletal muscle pathophysiology. We try to explain which risk factors and mechanisms are responsible for a subgroup of patients with post COVID syndrome (PCS) to develop ME/CFS (PC-ME/CFS).

Results: Mitochondrial dysfunction is a long-held assumption to explain cardinal symptoms of ME/CFS. However, mitochondrial dysfunction could not be convincingly shown in leukocytes. By contrast, recent studies provide strong evidence for mitochondrial dysfunction in skeletal muscle tissue in ME/CFS. An electron microscopy study could directly show damage of mitochondria in skeletal muscle of ME/CFS patients with a preferential subsarcolemmal localization but not in PCS. Another study shows signs of skeletal muscle damage and regeneration in biopsies taken one day after exercise in PC-ME/CFS. The simultaneous presence of necroses and signs of regeneration supports the concept of repeated damage. Other studies correlated diminished hand grip strength (HGS) with symptom severity and prognosis. A MRI study showed that intracellular sodium in muscles of ME/CFS patients is elevated and that levels correlate inversely with HGS. This finding corroborates our concept of sodium and consecutive calcium overload as cause of muscular and mitochondrial damage caused by enhanced proton-sodium exchange due to anaerobic metabolism and diminished activity of the sodium-potassium-ATPase. The histological investigations in ME/CFS exclude ischemia by microvascular obstruction, viral presence or immune myositis. The only known exercise-induced mechanism of damage left is sodium induced calcium overload. If ionic disturbance and mitochondrial dysfunction is severe enough the patient may be captured in a vicious circle. This energy deficit is the most likely cause of exertional intolerance and post exertional malaise and is further aggravated by exertion.

Conclusion: Based on this pathomechanism, future treatment approaches should focus on normalizing the cause of ionic disbalance. Current treatment strategies targeting hypoperfusion have the potential to improve the dysfunction of ion transporters.

Source: Scheibenbogen C, Wirth KJ. Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1):e13669. doi: 10.1002/jcsm.13669. PMID: 39727052; PMCID: PMC11671797. https://pmc.ncbi.nlm.nih.gov/articles/PMC11671797/ (Full text)

Chronic inflammatory response syndrome: a review of the evidence of clinical efficacy of treatment

Abstract:

Chronic Inflammatory Response Syndrome (CIRS) is an acquired medical condition characterized by innate immune dysregulation following respiratory exposure to water-damaged buildings (WDB). This chronic syndrome involves a range of symptoms that simultaneously affecting multiple organ systems. The purpose of this literature review was to search the published literature for successful treatments for chronic inflammatory response syndrome, an under-recognized, underdiagnosed, multisymptom multisystem illness that can affect up to 25% of the population, thus representing a silent epidemic.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a common misdiagnosis for CIRS, is an entity that has broader awareness within the medical community despite the absence of a defined etiology, biomarkers or a treatment protocol that reverses the underlying conditions. Therefore, the search also included treatments for ME/CFS and sick building syndrome (SBS). Thirteen articles referenced treatment for CIRS, and 22 articles referenced treatment for CFS.

The only treatment with documented clinical efficacy was the Shoemaker Protocol, which was described in 11 of the 13 articles. This treatment protocol exhibits superior outcomes compared with the treatment protocols for ME/CFS.

Source: Dooley M, Vukelic A, Jim L. Chronic inflammatory response syndrome: a review of the evidence of clinical efficacy of treatment. Ann Med Surg (Lond). 2024 Nov 8;86(12):7248-7254. doi: 10.1097/MS9.0000000000002718. PMID: 39649915; PMCID: PMC11623837. https://pmc.ncbi.nlm.nih.gov/articles/PMC11623837/ (Full text)

Qigong and Tai Chi for ME/CFS: A Systematic Review of Randomized Controlled Trials

Abstract:

Objective: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating illness with symptoms such as post-exertional malaise and cognitive dysfunction that can be challenging for patients to manage independently. Randomized controlled trials (RCTs) have examined mind-body and psychological approaches that teach patients coping skills for mitigating ME/CFS symptoms, including emerging literature on Qigong or Tai Chi instruction programs. This systematic review aims to summarize the characteristics of these trials and highlight potential areas for future optimization and refinement.

Methods: Ovid MEDLINE, Embase.com, Web of Science Core Collection, Cochrane CENTRAL, PsycINFO via Ovid, and ClinicalTrials.gov were searched in April 2023 using controlled vocabulary and keywords for the following eligibility criteria: Sample (ME/CFS), Design (RCT), Behavioral Intervention (mind-body or psychological interventions). Data extraction and reporting followed Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Results: “Qigong” and “Tai Chi” yielded 142 and 80 abstracts, respectively. Of the 222 abstracts, full texts were available for 5 RCTs of Qigong (k = 5; N = 481). Notably, no trials of Tai Chi utilized a randomized control design. Among the 5 Qigong RCTs, the publication range was from 2012 to 2023. Details regarding intervention components and effects were summarized. Qigong intervention sessions (median = 12, mode = 10, 12) tended to last between 1-2 hours and occur across 5-12 weeks (median = 7, mode = 5). The Qigong interventions were all delivered in groups and incorporated at-home practice. Daily practice was a requirement (k = 4) or an advisement (k = 1). Patient-reported outcomes suggest an emerging evidence base for diffuse benefits on physical and emotional health outcomes.

Conclusions: Qigong interventions are promising, yet relatively understudied, in improving ME/CFS symptom severity and frequency. Future trials must implement standardized eligibility criteria for ME/CFS history, integrate Qigong or Tai Chi with other empirically supported mind-body and psychological practices, and assess long-term resiliency outcomes relevant to ME/CFS survivorship.

Source: Markwart M, Felsenstein D, Mehta DH, Sethi S, Tsuchiyose E, Lydson M, Yeh GY, Hall DL. Qigong and Tai Chi for ME/CFS: A Systematic Review of Randomized Controlled Trials. Glob Adv Integr Med Health. 2024 Nov 7;13:27536130241275607. doi: 10.1177/27536130241275607. PMID: 39524182; PMCID: PMC11544658. https://pmc.ncbi.nlm.nih.gov/articles/PMC11544658/ (Full text)

A review of intravenous immunoglobulin in the treatment of neuroimmune conditions, acute COVID-19 infection, and post-acute sequelae of COVID-19 Syndrome

Abstract:

Intravenous immunoglobulin (IVIG) is an immunomodulatory therapy that has been studied in several neuroimmune conditions, such as Guillain-Barré Syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and multiple sclerosis. It has also been proposed as a potential treatment option for acute COVID-19 infection and post-acute sequelae of SARS-CoV-2 infection (PASC). IVIG is thought to function by providing the recipient with a pool of antibodies, which can, in turn, modulate immune responses through multiple mechanisms including neutralization of cytokines and autoantibodies, saturation of neonatal fragment crystallizable receptors, inhibition of complement activation, and regulation of T and B cell mediated inflammation.

In acute COVID-19, studies have shown that early administration of IVIG and plasmapheresis in severe cases can reduce the need for mechanical ventilation, shorten ICU and hospital stays, and lower mortality. Similarly, in PASC, while research is still in early stages, IVIG has been shown to alleviate persistent symptoms in small patient cohorts.

Furthermore, IVIG has shown benefits in another condition which has symptomatic overlap with PASC, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), though studies have yielded mixed results. It is important to note that IVIG can be associated with several potential adverse effects, such as anaphylaxis, headaches, thrombosis, liver enzyme elevations and renal complications. In addition, the high cost of IVIG can be a deterrent for payers and patients.

This review provides a comprehensive update on the use of IVIG in multiple neuroimmune conditions, ME/CFS, acute COVID-19, and PASC, as well as covers its history, production, pricing, and mechanisms of action. We also identify key areas of future research, including the need to optimize the use of Ig product dosing, timing, and patient selection across conditions, particularly in the context of COVID-19 and PASC.

Source: Morse BA, Motovilov K, Michael Brode W, Michael Tee F, Melamed E. A review of intravenous immunoglobulin in the treatment of neuroimmune conditions, acute COVID-19 infection, and post-acute sequelae of COVID-19 Syndrome. Brain Behav Immun. 2024 Oct 8:S0889-1591(24)00648-2. doi: 10.1016/j.bbi.2024.10.006. Epub ahead of print. PMID: 39389388. https://www.sciencedirect.com/science/article/abs/pii/S0889159124006482

Autoimmunity’s enigmatic role: exploring the connection with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complicated, heterogeneous condition distinguished by post-exertional neuroimmune exhaustion and multisystem symptoms. Its complexity poses challenges for physicians, researchers and those inflicted by its presence. Due to conflicting evidence and limiting consensus, the association and contribution autoimmunity serves in the pathophysiology or aetiology of ME/CFS is yet to be confirmed. This systematic review synthesises the currently available data to clarify the role autoimmunity has in the pathogenesis of ME/CFS and explore the therapeutic limitations.

Methods: This systematic review was conducted in accordance with the PRISMA and Cochrane guidelines. Full-text articles containing the primary key terms “Autoimmunity/Autoimmune” and “ME/CFS” were included provided their suitability to the inclusion and exclusion criteria.

Results: Ten publications investigating the role of autoimmunity in ME/CFS were examined. One investigated the role of cytokine signalling; Three investigated the genetic nature of autoimmunity in ME/CFS patients; One examined the immune lineage of ME/CFS patients; Six investigated the presence and role of autoantibodies in ME/CFS patients.

Conclusion: The findings generated from this systematic review highlight inconsistent and insufficient evidence to classify ME/CFS as an autoimmune disease. Additionally, it further emphasises the complexity of ME/CFS and highlights the challenges in distinguishing autoreactivity from deregulatory processes. Future research is urgently needed to advance the development of diagnostic and treatment strategies.

Source: Batham J, Dwyer J, Eaton-Fitch N, Marshall-Gradisnik S. Autoimmunity’s enigmatic role: exploring the connection with myalgic encephalomyelitis/chronic fatigue syndrome. BMC Immunol. 2024 Oct 1;25(1):62. doi: 10.1186/s12865-024-00657-5. PMID: 39354352. https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-024-00657-5 (Full text)

The persistence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) after SARS-CoV-2 infection: A systematic review and meta-analysis

Highlights:

  • SARS-CoV-2 can trigger Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
  • 51% of Long COVID-19 patients have Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
  • Long COVID-19 is a new name for an old disease.

Abstract:

Objectives: Long COVID-19 (LC) patients experience a number of chronic idiopathic symptoms that are highly similar to those of post-viral Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We have therefore performed a systematic review and meta-analysis to determine the proportion of LC patients that satisfy ME/CFS diagnostic criteria.

Methods: Clinical studies published between January 2020 to May 2023 were identified using the PubMed, Web of Science, Embase and CINAHL databases. Publication inclusion/exclusion criteria were formulated using the global CoCoPop framework. Data were pooled using a random-effects model with a restricted maximum-likelihood estimator. Study quality was assessed using the Joanna Briggs Institute critical assessment tool.

Results: We identified 13 eligible studies that reported a total of 1,973 LC patients. Our meta-analysis indicated that 51% (95% CI, 42%-60%) of LC patients satisfied ME/CFS diagnostic criteria with fatigue, sleep disruption, and muscle/joint pain being the most common symptoms. Importantly, LC patients also experienced the ME/CFS hallmark symptom, post-exertional malaise.

Conclusions: Our study not only demonstrates that LC patients exhibit similar symptom clusters to ME/CFS, but that approximately half of LC patients satisfy a diagnosis of ME/CFS. Our findings suggest that current ME/CFS criteria could be adapted to the identification of a subset of LC patients that may facilitate the standardized diagnosis, management and the recruitment for clinical studies in the future.

Source: Ankush Dehlia, Mark A. Guthridge. The persistence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) after SARS-CoV-2 infection: A systematic review and meta-analysis. Journal of Infection, 2024, 106297, ISSN 0163-4453, https://doi.org/10.1016/j.jinf.2024.106297.
https://www.sciencedirect.com/science/article/pii/S0163445324002317 (Full text)

Adrenergic dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A systematic review and meta-analysis

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are comorbid disorders with overlapping symptoms. Research highlights autonomic dysfunction compared to healthy individuals, particularly involving the sympathetic branch. While past reviews focused on neurophysiological assessments, this systematic review summarises biological adrenergic markers, offering deeper insights into the observed sympathetic dysfunction in ME/CFS and FM aiming to identify targetable pathophysiological mechanisms.

Methods: A systematic search was performed on PubMed, Web of Science, Embase and Scopus. Studies investigating peripheral biological markers of adrenergic function in patients with ME/CFS or FM compared to healthy controls at baseline were included. Meta-analyses were performed using R statistical software.

Results: This meta-analysis of 37 studies, encompassing 543 ME/CFS patients and 651 FM patients, compared with 747 and 447 healthy controls, respectively, revealed elevated adrenaline (SMD = .49 [.31-.67]; Z = 5.29, p < .01) and β1 adrenergic receptor expression (SMD = .79 [.06-1.52]; Z = 2.13; p = .03) in blood of ME/CFS patients at rest. Additionally, patients with ME/CFS had a greater increase in the expression of α2A adrenergic receptor (AR, SMD = .57 [.18-.97]; Z = 2.85, p < .01), β2 AR (SMD = .41 [.02-.81]; Z = 2.04; p = .04) and COMT (SMD = .42 [.03-.81]; Z = 2.11; p = .03) after exercise and an increased response of noradrenaline to an orthostatic test (SMD = .11 [-.47 to -.70]; Z = 2.10; p = .04), both found in blood. FM patients showed no significant differences at baseline but exhibited a diminished adrenaline response to exercise (SMD = -.79 [-1.27 to -.30]; Z = -3.14; p < .01).

Conclusion: This systematic review and meta-analysis revealed adrenergic dysfunction mainly in patients with ME/CFS. Higher baseline adrenaline levels and atypical responses to exercise in ME/CFS indicate that sympathetic dysfunction, underscored by adrenergic abnormalities, is more involved in the pathophysiology of ME/CFS rather than FM.

Source: Hendrix J, Fanning L, Wyns A, Ahmed I, Patil MS, Richter E, Van Campenhout J, Ickmans K, Mertens R, Nijs J, Godderis L, Polli A. Adrenergic dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A systematic review and meta-analysis. Eur J Clin Invest. 2024 Sep 25:e14318. doi: 10.1111/eci.14318. Epub ahead of print. PMID: 39319943. https://pubmed.ncbi.nlm.nih.gov/39319943/

Identifying microRNAs Possibly Implicated in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Review

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are chronic syndromes of unknown etiology, accompanied by numerous symptoms affecting neurological and physical conditions. Despite frequent revisions of the diagnostic criteria, clinical practice guidelines are often outdated, leading to underdiagnosis and ineffective treatment. Our aim was to identify microRNA (miRNA) biomarkers implicated in pathological mechanisms underlying these diseases.
A comprehensive literature review using publicly accessible databases was conducted. Interesting miRNAs were extracted from relevant publications on ME/CFS and/or FM, and were then linked to pathophysiological processes possibly manifesting these chronic diseases. Dysregulated miRNAs in ME/CFS and FM may serve as promising biomarkers for these diseases.
Key identified miRNAs, such as miR-29c, miR-99b, miR-128, miR-374b, and miR-766, were frequently mentioned for their roles in immune response, mitochondrial dysfunction, oxidative stress, and central sensitization, while miR-23a, miR-103, miR-152, and miR-320 were implicated in multiple crucial pathological processes for FM and/or ME/CFS.
In summary, both ME/CFS and FM seem to share many dysregulated biological or molecular processes, which may contribute to their commonly shared symptoms. This miRNA-based approach offers new angles for discovering molecular markers urgently needed for early diagnosis or therapeutics to tackle the pathology of these medically unexplained chronic diseases.
Source: Tsamou M, Kremers FAC, Samaritakis KA, Roggen EL. Identifying microRNAs Possibly Implicated in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Review. International Journal of Molecular Sciences. 2024; 25(17):9551. https://doi.org/10.3390/ijms25179551 https://www.mdpi.com/1422-0067/25/17/9551 (Full text)