Category: Treatment

Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, debilitating, and multi-faceted illness. Heterogenous onset and clinical presentation with additional comorbidities make it difficult to diagnose, characterize, and successfully treat. Current treatment guidelines focus on symptom management, but with no clear target or causative mechanism, remission rates are low, and fewer than 5% of patients return to their pre-morbid activity levels. Therefore, there is an urgent need to undertake robust clinical trials to identify effective treatments.
This review synthesizes insights from clinical trials exploring pharmacological interventions and dietary supplements targeting immunological, metabolic, gastrointestinal, neurological, and neuroendocrine dysfunction in ME/CFS patients which require further exploration. Additionally, the trialling of alternative interventions in ME/CFS based on reported efficacy in the treatment of illnesses with overlapping symptomology is also discussed. Finally, we provide important considerations and make recommendations, focusing on outcome measures, to ensure the execution of future high-quality clinical trials to establish clinical efficacy of evidence-based interventions that are needed for adoption in clinical practice.
Source: Seton KA, Espejo-Oltra JA, Giménez-Orenga K, Haagmans R, Ramadan DJ, Mehlsen J on behalf of the European ME Research Group for Early Career Researchers (Young EMERG). Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives. Journal of Clinical Medicine. 2024; 13(2):325. https://doi.org/10.3390/jcm13020325 https://www.mdpi.com/2077-0383/13/2/325 (Full text)

Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/anti-pathogen agent in a retrospective case series

Highlights:

• Both Long COVID and ME/CFS are characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα.

• In a small Long COVID and ME/CFS case series, patients’ immune deficiency and health improve during treatment period with a nebulized antioxidant, anti-pathogen and immune-modulatory pharmacological agent.

• This work provides evidence of a useful biomarker, CD8 T-cell dysfunction reminiscent of T cell exhaustion, that may assist diagnosis and have utility for tracking disease outcome during therapy, including response to a potential new treatment.

Abstract:

Background: Patients with post-acute sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (PASC, i.e., Long COVID) have a symptom complex highly analogous to many features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting they may share some aspects of pathogenesis in these similar disorders. ME/CFS is a complex disease affecting numerous organ systems and biological processes and is often preceded by an infection-like episode. It is postulated that the chronic manifestations of illness may result from an altered host response to infection or inability to resolve inflammation, as is being reported in Long COVID. The immunopathogenesis of both disorders is still poorly understood. Here, we show data that suggest Long COVID and ME/CFS may be due to an aberrant response to an immunological trigger-like infection, resulting in a dysregulated immune system with CD8 T-cell dysfunction reminiscent of some aspects of T-cell clonal exhaustion, a phenomenon associated with oxidative stress. As there is an urgent need for diagnostic tools and treatment strategies for these two related disabling disorders, here, in a retrospective case series, we have also identified a potential nebulized antioxidant/anti-pathogen treatment that has evidence of a good safety profile. This nebulized agent is comprised of five ingredients previously reported individually to relieve oxidative stress, attenuate NF-κB signaling, and/or to act directly to inhibit pathogens, including viruses. Administration of this treatment by nebulizer results in rapid access of small doses of well-studied antioxidants and agents with anti-pathogen potential to the lungs; components of this nebulized agent are also likely to be distributed systemically, with potential to enter the central nervous system.

Methods and Findings: We conducted an analysis of CD8 T-cell function and severity of symptoms by self-report questionnaires in ME/CFS, Long COVID and healthy controls. We developed a CD8 T-cell functional assay, assessing CD8 T-cell dysfunction by intracellular cytokine staining (ICS) in a group of ME/CFS (n = 12) and Long COVID patients (n = 8), comparing to healthy controls (HC) with similar age and sex (n = 10). Magnet-enriched fresh CD8 T-cells in both patient groups had a significantly diminished capacity to produce both cytokines, IFNγ or TNFα, after PMA stimulation when compared to HC. The symptom severity questionnaire showed similar symptom profiles for the two disorders. Fortuitously, through a retrospective case series, we were able to examine the ICS and questionnaire data of 4 ME/CFS and 4 Long COVID patients in conjunction with their treatment (3–15 months). In parallel with the treatment pursued electively by participants in this retrospective case series, there was an increase in CD8 T-cell IFNγ and TNFα production and a decrease in overall self-reported symptom severity score by 54%. No serious treatment-associated side effects or laboratory anomalies were noted in these patients.

Conclusions: Here, in this small study, we present two observations that appear potentially fundamental to the pathogenesis and treatment of Long COVID and ME/CFS. The first is that both disorders appear to be characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα. The second is that in a small retrospective Long COVID and ME/CFS case series, this immune dysfunction and patient health improved in parallel with treatment with an immunomodulatory, antioxidant pharmacological treatment with anticipated anti-pathogen activity. This work provides evidence of the potential utility of a biomarker, CD8 T-cell dysfunction, and suggests the potential for benefit from a new nebulized antioxidant/anti-pathogen treatment. These immune biomarker data may help build capacity for improved diagnosis and tracking of treatment outcomes during clinical trials for both Long COVID and ME/CFS while providing clues to new treatment avenues that suggest potential efficacy for both conditions.

Source: Gil, A., Hoag, G.E., Salerno, J.P., Hornig, M., Klimas, N., Selin, L.K. Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/antipathogen agent in a retrospective case series. Brain, Behavior, & Immunity – Health (2024), doi: https://doi.org/10.1016/j.bbih.2023.100720 https://www.sciencedirect.com/science/article/pii/S2666354623001345 (Full text)

Mitochondrial Dysfunction and Coenzyme Q10 Supplementation in Post-Viral Fatigue Syndrome: An Overview

Abstract:

Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown causes characterised by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS); fibromyalgia (FM); and more recently post-COVID-19 condition (long COVID). To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders.
Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. The accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and long COVID. To address this issue, this article aims to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, it aims to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS.
Source: Mantle D, Hargreaves IP, Domingo JC, Castro-Marrero J. Mitochondrial Dysfunction and Coenzyme Q10 Supplementation in Post-Viral Fatigue Syndrome: An Overview. International Journal of Molecular Sciences. 2024; 25(1):574. https://doi.org/10.3390/ijms25010574 https://www.mdpi.com/1422-0067/25/1/574 (Full text)

An international survey of experiences and attitudes towards transcutaneous auricular vagus nerve stimulation for people with Myalgic Encephalomyelitis/chronic fatigue syndrome

Abstract:

Background and objectives: Myalgic encephalomyelitis (ME) is a complex, multi-system neurological condition. Dysfunction of the autonomic nervous system is a primary feature in diagnostic criteria, and management may include attempts to stimulate the parasympathetic nervous system. Transcutaneous auricular vagus nerve stimulation is an intervention that has been researched in neurological disorders, e.g. epilepsy, depression. While little evidence exists for its use in ME, this survey aims to explore the experiences and attitudes of people with ME to this intervention.

Methods: A 31-question online survey was devised and released on ME websites, Twitter and Facebook pages. People with ME read the information sheet and followed an online link to the survey. The survey was open for four weeks and all answers were anonymous.

Results: 116 responses were received. 56% of respondents reported favourable effects. Benefits of transcutaneous auricular vagus nerve stimulation were identified in relation to post exertional malaise, pain, gut problems, urinary problems, mental health, and the ability to leave the house. 67.2% of respondents would recommend the intervention to other people with ME. However, 4.3% would not recommend it and 6% reported it made them worse. 8.6% received support in setting up the device from healthcare workers.

Conclusion: The survey highlights that many people with ME experience significant benefits from using transcutaneous auricular vagus nerve stimulation; however due to potential negative effects there is the need for formal intervention studies to clearly identify safe parameters.

Source: Karen Leslie, Nicola Clague-Baker, Mohammad Abdelfattah Atallah Madi, Dawn Wiley, Andrea Parker, Michelle Bull & Natalie Hilliard. (2023) An international survey of experiences and attitudes towards transcutaneous auricular vagus nerve stimulation for people with Myalgic Encephalomyelitis/chronic fatigue syndrome, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2023.2286029 https://www.tandfonline.com/doi/abs/10.1080/21641846.2023.2286029

Case report: Recurrent cervical spinal stenosis masquerading as myalgic encephalomyelitis/chronic fatigue syndrome with orthostatic intolerance

Abstract:

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic, multi-system disorder that is characterized by a substantial impairment in the activities that were well tolerated before the illness.

In an earlier report, we had described three adult women who met criteria for ME/CFS and orthostatic intolerance, and had congenital or acquired cervical spinal stenosis. All three experienced substantial global improvements in their ME/CFS and orthostatic intolerance symptoms after recognition and surgical treatment of the cervical stenosis. After a several year period of improvement, one of the individuals in that series experienced a return of ME/CFS and orthostatic intolerance symptoms.

Main Symptoms and Clinical Findings: Radiologic investigation confirmed a recurrence of the ventral compression of the spinal cord due to a shift of the disc replacement implant at the involved cervical spinal level.

Therapeutic Intervention: Decompression of the spinal cord with removal of the implant and fusion at the original C5-C6 level was once again followed by a similar degree of improvement in function as had been observed after the first operation.

This recapitulation of the outcomes after surgical management of cervical stenosis provides further evidence in support of the hypothesis that cervical spinal stenosis can exacerbate pre-existing or cause new orthostatic intolerance and ME/CFS. Especially for those with refractory symptoms and neurological signs, surgical interventions may offer relief for selected patients with this complex condition.

Source: Charles C. Edwards III, Charles C. Edwards II, Scott Heinlein, Peter C. Rowe. Case report: Recurrent cervical spinal stenosis masquerading as myalgic encephalomyelitis/chronic fatigue syndrome with orthostatic intolerance. Frontiers in Neurology, Volume-14- 2023. https://www.frontiersin.org/articles/10.3389/fneur.2023.1284062/abstract

Senolytic drugs: from discovery to translation

Abstract:

Senolytics are a class of drugs that selectively clear senescent cells (SC). The first senolytic drugs Dasatinib, Quercetin, Fisetin and Navitoclax were discovered using a hypothesis-driven approach.

SC accumulate with ageing and at causal sites of multiple chronic disorders, including diseases accounting for the bulk of morbidity, mortality and health expenditures. The most deleterious SC are resistant to apoptosis and have up-regulation of anti-apoptotic pathways which defend SC against their own inflammatory senescence-associated secretory phenotype (SASP), allowing them to survive, despite killing neighbouring cells. Senolytics transiently disable these SCAPs, causing apoptosis of those SC with a tissue-destructive SASP.

Because SC take weeks to reaccumulate, senolytics can be administered intermittently – a ‘hit-and-run’ approach. In preclinical models, senolytics delay, prevent or alleviate frailty, cancers and cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, haematological, metabolic and skin disorders as well as complications of organ transplantation, radiation and cancer treatment.

As anticipated for agents targeting the fundamental ageing mechanisms that are ‘root cause’ contributors to multiple disorders, potential uses of senolytics are protean, potentially alleviating over 40 conditions in preclinical studies, opening a new route for treating age-related dysfunction and diseases. Early pilot trials of senolytics suggest they decrease senescent cells, reduce inflammation and alleviate frailty in humans.

Clinical trials for diabetes, idiopathic pulmonary fibrosis, Alzheimer’s disease, COVID-19, osteoarthritis, osteoporosis, eye diseases and bone marrow transplant and childhood cancer survivors are underway or beginning. Until such studies are done, it is too early for senolytics to be used outside of clinical trials.

Source: Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020 Nov;288(5):518-536. doi: 10.1111/joim.13141. Epub 2020 Aug 4. PMID: 32686219; PMCID: PMC7405395. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395/ (Full text)

Prevalence and Predictive Factors of Small Intestinal Bacterial Overgrowth in Patients With Chronic Fatigue Syndrome

Introduction: Chronic fatigue syndrome (CFS) is a poorly understood illness, characterized by fatigue and related symptoms including cognitive dysfunction, headaches, joint pains, and gastrointestinal distress. Irritable bowel syndrome (IBS) is common and present in approximately 60% patients with CFS while the prevalence of small intestinal bacterial overgrowth (SIBO) in IBS is approximately 40%. Our study aimed to 1) Determine the prevalence of SIBO in patients with CFS with and without IBS symptoms 2) Identify factors associated with increased risk of SIBO.

Methods: A retrospective chart review of 479 patients with CFS referred for hydrogen/methane breath testing. Clinical documentation was reviewed to identify positive breath test result diagnosing SIBO. Statistical analysis was conducted with 2-proportions z test and logistic regression analysis to identify predictive variables of SIBO diagnosis.

Results: 479 patients with CFS referred for glucose or lactulose breath testing were identified. Three hundred sixty-seven of those patients completed a breath test with available result: 152(41%) SIBO+ (mean age (SD) 50 (17)), 164(45%) SIBO- (mean age SD 46 (15)), and 78(21%) equivocal results. In CFS patients with conclusive breath test result, 48% tested positive for SIBO, and the diagnosis of IBS was present in 186/316 (59%). There was no difference in the prevalence of IBS between the SIBO+ vs SIBO-group [98/152 (64%) vs 88/164 (53%), P < 0.05]. Using multiple logistic regression analysis, age, unknown race, and IBS diagnosis all significantly predicted increased odds of having a positive breath test (Table 1). Conversely, PPI use was associated with decreased odds of a positive breath test. Due to the high prevalence of IBS in our cohort and the association between IBS and SIBO, an analysis was performed excluding patients with IBS diagnosis. When excluding patients with IBS, unknown race and TCA use were associated with increased odds of positive breath test, while diarrhea, hypothyroidism, PPI, and naltrexone use were associated with decreased odds (P< 0.05).

Conclusion: SIBO is highly prevalent in patients with CFS referred for breath testing. Older age and comorbid IBS diagnosis predict increased odds of positive breath test. Surprisingly, PPI use predicted decreased odds despite its prior implication as a possible risk factor for SIBO. Further studies are needed to explore the underlying mechanism causing the overlap between CFS, IBS and SIBO which may provide insights into potential therapies for CFS.

Source: Karhu, Elisa MD, MS; Neshatian, Leila MD, MS; Fass, Ofer MD; Sonu, Irene MD; Nguyen, Linda Anh MD. S1821 Prevalence and Predictive Factors of Small Intestinal Bacterial Overgrowth in Patients With Chronic Fatigue Syndrome. The American Journal of Gastroenterology 118(10S):p S1351-S1352, October 2023. | DOI: 10.14309/01.ajg.0000956924.26236.c4 https://journals.lww.com/ajg/fulltext/2023/10001/s1821_prevalence_and_predictive_factors_of_small.2162.aspx

Patient perspectives of recovery from myalgic encephalomyelitis/chronic fatigue syndrome: An interpretive description study

Abstract:

Aims and objectives: Myalgic encephalomyelitis (ME), also called chronic fatigue syndrome (CFS), is characterised by persistent fatigue, postexertional malaise, and cognitive dysfunction. It is a complex, long-term, and debilitating illness without widely effective treatments. This study describes the treatment choices and experiences of ME/CFS patients who have experienced variable levels of recovery.

Method: Interpretive description study consisting of semi-structured qualitative interviews with 33 people who met the US Centers for Disease Control (2015) diagnostic criteria for ME/CFS and report recovery or symptom improvement.

Results: Twenty-six participants endorsed partial recovery, and seven reported full recovery from ME/CFS. Participants reported expending significant time and energy to identify, implement, and adapt therapeutic interventions, often without the guidance of a medical practitioner. They formulated individualised treatment plans reflecting their understanding of their illness and personal resources. Most fully recovered participants attributed their success to mind-body approaches.

Conclusion: Patients with ME/CFS describe independently constructing and managing treatment plans, due to a lack of health system support. Stigmatised and dismissive responses from clinicians precipitated disengagement from the medical system and prompted use of other forms of treatment.

Source: Hasan Z, Kuyvenhoven C, Chowdhury M, Amoudi L, Zeraatkar D, Busse JW, Sadik M, Vanstone M. Patient perspectives of recovery from myalgic encephalomyelitis/chronic fatigue syndrome: An interpretive description study. J Eval Clin Pract. 2023 Nov 6. doi: 10.1111/jep.13938. Epub ahead of print. PMID: 37927138. https://onlinelibrary.wiley.com/doi/10.1111/jep.13938 (Full text)

Successful treatment of myalgic encephalomyelitis/chronic fatigue syndrome using hydrogen gas: four case reports

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue and malaise that persist for more than 6 months with neuropsychiatric symptoms, including slight fever, headache, weakness, impaired thinking, and depression.[1,2] The onset and severity of these symptoms vary and reduce the quality of life as well as social, occupational, and personal activities of those affected, with some becoming bedridden.[1,2] The number of ME/CFS patients in the United States is estimated to be between 836,000 and 2.5 million.[3]

Although it currently remains unclear whether there are objective and biological abnormalities in ME/CFS, recent neuroimaging, blood marker analyses, and energy metabolism and mitochondrial studies detected these abnormalities in ME/CFS patients.[4] ME/CFS may be caused by the activation of the immune system, both within and outside the brain, which induces the release of inflammatory cytokines. ME/CFS is presumed to cause abnormalities in the central and autonomic nervous systems, systemic energy metabolism, and immune system and also involve oxidative and nitrosative stress.[4,5,6] Dysfunctions in systemic energy metabolism may be related to abnormalities in the structure and function of mitochondria.[7,8,9,10]

Molecular hydrogen (H2) is a gaseous molecule that selectively scavenges reactive oxygen and nitrogen species with strong oxidizing power, namely, hydroxyl radicals (·OH) and peroxynitrite, respectively.[11,12] H2 easily crosses the blood-brain barrier and biological membranes, reaches mitochondria, and protects cells from ·OH-induced cell damage.[11,12] A recent literature review revealed that H2 attenuated acute or chronic fatigue in animals and healthy subjects.[13] We also reported that the anti-fatigue effects of H2 involved the protection of mitochondria, which may also ameliorate the pathogenesis of ME/CFS.[13] Therefore, we conducted this case study to test this hypothesis by examining the efficacy of H2 gas inhalation in four patients with ME/CFS.

Source: Hirano, Shin-ichi*; Ichikawa, Yusuke; Sato, Bunpei; Takefuji, Yoshiyasu; Satoh, Fumitake. Successful treatment of myalgic encephalomyelitis/chronic fatigue syndrome using hydrogen gas: four case reports. Medical Gas Research 14(2):p 84-86, June 2024. | DOI: 10.4103/2045-9912.385441 https://journals.lww.com/mgar/fulltext/2024/14020/successful_treatment_of_myalgic.7.aspx (Full text)

Exercise capacity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) treated with long-term pyridostigmine

Abstract:

Background: The pathophysiology underlying exertional intolerance in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains poorly understood. Previously, a single-dose of 60 mg pyridostigmine, a reversible acetylcholinesterase inhibitor, was found to acutely improve aerobic capacity (Joseph, P. et al. Chest 2022; 162:1116–26).

Aims: To build upon these prior findings, this study aimed to evaluate the long-term effect (>1 month) of pyridostigmine treatment on exercise intolerance in ME/CFS.

Methods: Between 2017-2022, patients who met the National Academy of Medicine criteria for ME/CFS, and had a minimum of two clinical, constant load, submaximal exercise tests (Shape Medical System, MN) were evaluated. Patients who began pyridostigmine after their baseline test were considered the treatment group. Measurements were taken at baseline (T0) and most recent follow-up (T1).

Results: At the follow-up evaluation (690 ± 547 days), the treatment group (n=37, dose range: 24-360mg/d) demonstrated a significant increase in oxygen uptake efficiency slope (OUES) (T0: 1.82 ± 0.56, T1: 1.98 ± 0.53; p=0.044) and pulmonary vascular capacitance (PVCAP) (T0: 486.19 ± 169.89 ml*mmHg, T1: 540.03 ± 170.59 ml*mmHg; p=0.040). These differences were not observed in the control group (n=16) OUES (T0: 1.62 ± 0.40, T1: 1.77 ± 0.47; p=0.268) and PVCAP (T0: 446.94 ± 144.80 ml*mmHg, T1: 465.81 ± 124.34 ml*mmHg; p=0.590).

Conclusion: Long-term treatment with pyridostigmine improved aerobic capacity in ME/CFS as demonstrated by an increase in OUES, mediated by improvements in central hemodynamics (PVCAP).

Source: Johanna Squires, Sarra Al-Zayer, David Systrom. Exercise capacity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) treated with long-term pyridostigmine. European Respiratory Journal Sep 2023, 62 (suppl 67) PA4639; DOI: 10.1183/13993003.congress-2023.PA4639 https://erj.ersjournals.com/content/62/suppl_67/PA4639