Fredrik Hoel, August Hoel, [...], and Karl J. Tronstad
JLI Insight - Published by American Soc for Clinical Investigation
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls. Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses. In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.
Keywords: Immunology, Metabolism
Keywords: Bioinformatics, Fatty acid oxidation, Intermediary metabolism
October 10, 2022
Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021
Global Burden of Disease Long COVID Collaborators
JAMA. Published online October 10, 2022. doi:10.1001/jama.2022.18931
Question Among individuals who had symptomatic SARS-CoV-2 infection in 2020 and 2021, what proportion experienced common self-reported Long COVID symptom clusters 3 months after initial infection?
Findings This observational analysis involved bayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. The modeled estimated proportion with at least 1 of the 3 self-reported Long COVID symptom clusters 3 months after symptomatic SARS-CoV-2 infection was 6.2%, including 3.7% for ongoing respiratory problems, 3.2% for persistent fatigue with bodily pain or mood swings, and 2.2% for cognitive problems after adjusting for health status before COVID-19.
Meaning This study presents modeled estimates of the proportion of individuals with at least 1 of the 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after symptomatic SARS-CoV-2 infection.
Importance Some individuals experience persistent symptoms after initial symptomatic SARS-CoV-2 infection (often referred to as Long COVID).
Objective To estimate the proportion of males and females with COVID-19, younger or older than 20 years of age, who had Long COVID symptoms in 2020 and 2021 and their Long COVID symptom duration.
Design, Setting, and Participants Bayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. Of the 54 studies, 44 were published and 10 were collaborating cohorts (conducted in Austria, the Faroe Islands, Germany, Iran, Italy, the Netherlands, Russia, Sweden, Switzerland, and the US). The participant data were derived from the 44 published studies (10 501 hospitalized individuals and 42 891 nonhospitalized individuals), the 10 collaborating cohort studies (10 526 and 1906), and the 2 US electronic medical record databases (250 928 and 846 046). Data collection spanned March 2020 to January 2022.
Exposures Symptomatic SARS-CoV-2 infection.
Main Outcomes and Measures Proportion of individuals with at least 1 of the 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after SARS-CoV-2 infection in 2020 and 2021, estimated separately for hospitalized and nonhospitalized individuals aged 20 years or older by sex and for both sexes of nonhospitalized individuals younger than 20 years of age.
Results A total of 1.2 million individuals who had symptomatic SARS-CoV-2 infection were included (mean age, 4-66 years; males, 26%-88%). In the modeled estimates, 6.2% (95% uncertainty interval [UI], 2.4%-13.3%) of individuals who had symptomatic SARS-CoV-2 infection experienced at least 1 of the 3 Long COVID symptom clusters in 2020 and 2021, including 3.2% (95% UI, 0.6%-10.0%) for persistent fatigue with bodily pain or mood swings, 3.7% (95% UI, 0.9%-9.6%) for ongoing respiratory problems, and 2.2% (95% UI, 0.3%-7.6%) for cognitive problems after adjusting for health status before COVID-19, comprising an estimated 51.0% (95% UI, 16.9%-92.4%), 60.4% (95% UI, 18.9%-89.1%), and 35.4% (95% UI, 9.4%-75.1%), respectively, of Long COVID cases. The Long COVID symptom clusters were more common in women aged 20 years or older (10.6% [95% UI, 4.3%-22.2%]) 3 months after symptomatic SARS-CoV-2 infection than in men aged 20 years or older (5.4% [95% UI, 2.2%-11.7%]). Both sexes younger than 20 years of age were estimated to be affected in 2.8% (95% UI, 0.9%-7.0%) of symptomatic SARS-CoV-2 infections. The estimated mean Long COVID symptom cluster duration was 9.0 months (95% UI, 7.0-12.0 months) among hospitalized individuals and 4.0 months (95% UI, 3.6-4.6 months) among nonhospitalized individuals. Among individuals with Long COVID symptoms 3 months after symptomatic SARS-CoV-2 infection, an estimated 15.1% (95% UI, 10.3%-21.1%) continued to experience symptoms at 12 months.
Conclusions and Relevance This study presents modeled estimates of the proportion of individuals with at least 1 of 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after symptomatic SARS-CoV-2 infection.
Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults
A Systematic Review and Meta-analysis
Matthew S. Durstenfeld, MD, MAS1,2; Kaiwen Sun, MD1; Peggy Tahir, MLIS, MA3; et alMichael J. Peluso, MD, MHS, MPhil, DTMH1,4; Steven G. Deeks, MD1,4; Mandar A. Aras, MD, PhD1,5; Donald J. Grandis, MD1,5; Carlin S. Long, MD1,5; Alexis Beatty, MD1,5,6; Priscilla Y. Hsue, MD1,2
JAMA Netw Open. 2022;5(10):e2236057. doi:10.1001/jamanetworkopen.2022.36057
Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults
Question Is exercise capacity reduced more than 3 months after SARS-CoV-2 infection among those with long COVID-19 (LC) symptoms compared with recovered individuals without symptoms, and what patterns of limitations on cardiopulmonary exercise testing (CPET) are common?
Findings In this systematic review and meta-analysis of 38 studies comprising 2160 participants, exercise capacity was reduced by 4.9 mL/kg/min among individuals with symptoms consistent with LC compared with individuals without symptoms more than 3 months after SARS-CoV-2 infection. Findings among individuals with exertional intolerance suggest that deconditioning, dysfunctional breathing, chronotropic incompetence, and abnormal peripheral oxygen extraction and/or use may contribute to reduced exercise capacity.
Meaning These findings suggest that CPET may provide insight into the mechanisms for reduced exercise capacity among individuals with LC.
Importance Reduced exercise capacity is commonly reported among individuals with COVID-19 symptoms more than 3 months after SARS-CoV-2 infection (long COVID-19 [LC]). Cardiopulmonary exercise testing (CPET) is the criterion standard to measure exercise capacity and identify patterns of exertional intolerance.
Objectives To estimate the difference in exercise capacity among individuals with and without LC symptoms and characterize physiological patterns of limitations to elucidate possible mechanisms of LC.
Data Sources A search of PubMed, EMBASE, Web of Science, preprint servers, conference abstracts, and cited references was performed on December 20, 2021, and again on May 24, 2022. A preprint search of medrxiv.org, biorxiv.org, and researchsquare.com was performed on June 9, 2022.
Study Selection Studies of adults with SARS-CoV-2 infection more than 3 months earlier that included CPET-measured peak oxygen consumption (V̇o2) were screened independently by 2 blinded reviewers; 72 (2%) were selected for full-text review, and 35 (1%) met the inclusion criteria. An additional 3 studies were identified from preprint servers.
Data Extraction and Synthesis Data extraction was performed by 2 independent reviewers according to the PRISMA reporting guideline. Data were pooled using random-effects models.
Main Outcomes and Measures Difference in peak V̇o2 (in mL/kg/min) among individuals with and without persistent COVID-19 symptoms more than 3 months after SARS-CoV-2 infection.
Results A total of 38 studies were identified that performed CPET on 2160 individuals 3 to 18 months after SARS-CoV-2 infection, including 1228 with symptoms consistent with LC. Most studies were case series of individuals with LC or cross-sectional assessments within posthospitalization cohorts. Based on a meta-analysis of 9 studies including 464 individuals with LC symptoms and 359 without symptoms, the mean peak V̇o2 was −4.9 (95% CI, −6.4 to −3.4) mL/kg/min among those with symptoms with a low degree of certainty. Deconditioning and peripheral limitations (abnormal oxygen extraction) were common, but dysfunctional breathing and chronotropic incompetence were also described. The existing literature was limited by small sample sizes, selection bias, confounding, and varying symptom definitions and CPET interpretations, resulting in high risk of bias and heterogeneity.
Conclusions and Relevance The findings of this systematic review and meta-analysis study suggest that exercise capacity was reduced more than 3 months after SARS-CoV-2 infection among individuals with symptoms consistent with LC compared with individuals without LC symptoms, with low confidence. Potential mechanisms for exertional intolerance other than deconditioning include altered autonomic function (eg, chronotropic incompetence, dysfunctional breathing), endothelial dysfunction, and muscular or mitochondrial pathology.
AIM ImmunoTech Announces FDA Clearance of IND Application to Evaluate Ampligen in Phase 2 Clinical Study for the Treatment of Post-COVID Conditions
Company expects to commence patient enrollment and dosing in Q1 2023 October 12, 2022 08:45 ET | Source: AIM ImmunoTech Inc.
OCALA, Fla, Oct. 12, 2022 (GLOBE NEWSWIRE) -- AIM ImmunoTech Inc. (NYSE: American AIM) (“AIM” or the “Company”), an immuno-pharma company focused on the research and development of therapeutics to treat multiple types of cancers, immune disorders, and viral diseases, including COVID-19, the disease caused by the SARS-CoV-2 virus, today announced its Investigational New Drug (IND) application filed with the U.S. Food and Drug Administration (FDA) may proceed to initiate a Phase 2 study evaluating its investigational drug, Ampligen, as a therapeutic for patients with post-COVID conditions (“AMP-518”). AIM has pending patent applications for compositions and methods for treating post-COVID conditions with a composition comprising Ampligen.
“We are very pleased to be able to proceed with our Phase 2 study and are prepared to advance Ampligen as a potential therapeutic for the treatment of myalgic encephalomyelitis/chronic fatigue (ME/CFS)-like post-COVID conditions, an exploding area of significant unmet medical need,” commented Thomas K. Equels, MS JD, Chief Executive Officer of AIM. “Post-COVID-19 Disabling Fatigue, along with other debilitating post-COVID conditions such as ‘Brain Fog’, continue to affect tens of millions of people worldwide. Based on the preliminary uncontrolled clinical data flowing from our AMP-511 study and the antiviral activity we have seen to date, we believe Ampligen has the potential to be an effective treatment option and an important solution for patients and physicians. We are deeply grateful for the FDA’s regulatory guidance related to this important clinical trial and with the IND clearance now in hand, our team is working to get the study up and running as quickly and efficiently as possible. We expect to commence enrollment in early 2023.”
Oved Amitay, PhD, President and CEO of the advocacy organization Solve M.E. added, “Post-COVID conditions continue to present as a serious public health crisis and there remains an ongoing struggle for patients to access safe and effective therapeutics. To address this unmet need, it is critical that we apply existing knowledge, such as studies done previously in ME/CFS. In the AMP-516 study in people with ME/CFS, Ampligen has demonstrated an encouraging safety profile and was well tolerated, and data in post-COVID from the AMP-511 study shows a similar profile. Additionally, the data published in the PLOS ONE paper from a subgroup analysis in the AMP-516 study showed a response rate greater than 50%, a statistically significant response in people who were treated closer to the onset of their disease. I am therefore hopeful about the potential of Ampligen for post-COVID conditions given the possibility of an earlier intervention and believe that this study is an important step in addressing the needs of people with these post-infection debilitating symptoms.”
The planned Phase 2 study is a two-arm, randomized, double-blind, placebo-controlled, multicenter study to evaluate efficacy and safety of Ampligen in patients experiencing the post-COVID condition of fatigue. The primary outcome measure of the study is change from baseline to week 13 in PROMIS® Fatigue Score. Other study outcomes include: change from baseline to week 6 in PROMIS® Fatigue Score; change from baseline to week 6 and 13 in distance traveled during a 6-minute walk test; proportion of subjects with minimal clinically important difference, defined as at least 54 meters, in the Six-Minute Walk Test at the end of 12-week treatment phase; change from baseline to week 6 and 13 in PROMIS® Cognitive Function Score; change from baseline to week 6 and 13 in PROMIS® Sleep Disturbance Score; and change from baseline to week 6 and 13 in 36-Item Short Form Survey.
Approximately 80 subjects between the ages of 18 to 60 years old are expected to be enrolled across up to 10 centers in the United States. Patients will be randomized 1:1 to receive twice weekly IV infusions of Ampligen or placebo for 12 weeks with a follow up phase of 2 weeks. The Company expects to commence patient enrollment and dosing in the AMP-518 study in Q1 2023.
Mol Cell Neurosci. 2022 May;120:103731. doi: 10.1016/j.mcn.2022.103731. Epub 2022 Apr 26.
Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE)
Gunnar Gottschalk 1, Daniel Peterson 2, Konstance Knox 3, Marco Maynard 4, Ryan J Whelan 4, Avik Roy 5 PMID: 35487443
Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a multisystem illness characterized by extreme muscle fatigue associated with pain, neurocognitive impairment, and chronic inflammation. Despite intense investigation, the molecular mechanism of this disease is still unknown. Here we demonstrate that autophagy-related protein ATG13 is strongly upregulated in the serum of ME/CFS patients, indicative of impairment in the metabolic events of autophagy. A Thioflavin T-based protein aggregation assay, array screening for autophagy-related factors, densitometric analyses, and confirmation with ELISA revealed that the level of ATG13 was strongly elevated in serum samples of ME/CFS patients compared to age-matched controls. Moreover, our microglia-based oxidative stress response experiments indicated that serum samples of ME/CFS patients evoke the production of reactive oxygen species (ROS) and nitric oxide in human HMC3 microglial cells, whereas neutralization of ATG13 strongly diminishes the production of ROS and NO, suggesting that ATG13 plays a role in the observed stress response in microglial cells. Finally, an in vitro ligand binding assay provided evidence that ATG13 employs the Receptor for Advanced Glycation End-products (RAGE) to stimulate ROS in microglial cells. Collectively, our results suggest that an impairment of autophagy following the release of ATG13 into serum could be a pathological signal in ME/CFS.
Keywords: ATG13; Autophagy; ME/CFS; Microglia: RAGE; NO; ROS.
Published by Elsevier Inc.
Addiction Drug Shows Promise Lifting Long COVID Brain Fog, Fatigue
By Julie Steenhuysen
October 18, 2022
CHICAGO (Reuters) - Lauren Nichols, a 34-year-old logistics expert for the U.S. Department of Transportation in Boston, has been suffering from impaired thinking and focus, fatigue, seizures, headache and pain since her COVID-19 infection in the spring of 2020.
Last June, her doctor suggested low doses of naltrexone, a generic drug typically used to treat alcohol and opioid addiction. After more than two years of living in "a thick, foggy cloud," she said, "I can actually think clearly." Researchers chasing long COVID cures are eager to learn whether the drug can offer similar benefits to millions suffering from pain, fatigue and brain fog months after a coronavirus infection. The drug has been used with some success to treat a similar complex, post-infectious syndrome marked by cognitive deficits and overwhelming fatigue called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Drawing on its use in ME/CFS and a handful of long COVID pilot studies, there are now at least four clinical trials planned to test naltrexone in hundreds of patients with long COVID, according to a Reuters review of Clinicaltrials.gov and interviews with 12 ME/CFS and long COVID researchers. It is also on the short list of treatments to be tested in the U.S. National Institutes of Health's $1 billion RECOVER Initiative, which aims to uncover underlying causes and find treatments for long COVID, advisers to the trial told Reuters.
Unlike treatments aimed at addressing specific symptoms caused by COVID damage to organs, such as the lungs, low-dose naltrexone (LDN) may reverse some of the underlying pathology driving symptoms, they said.
Naltrexone has anti-inflammatory properties and has been used at low doses for years to treat conditions such as fibromyalgia, Crohn's disease and multiple sclerosis, said Dr. Jarred Younger, director of the Neuro-inflammation, Pain and Fatigue Laboratory at the University of Alabama at Birmingham.
At 50 milligrams - 10 times the low dose - naltrexone is approved to treat opioid and alcohol addiction. Several generic manufacturers sell 50mg pills, but low-dose naltrexone must be purchased through a compounding pharmacy.
Younger, author of a scientific review of the drug as a novel anti-inflammatory, in September submitted a grant application to study LDN for long COVID. "It should be at the top of everyone's list for clinical trials," he said.
Still, the drug is unlikely to help all patients with long COVID, a collection of some 200 symptoms ranging from pain and heart palpitations to insomnia and cognitive impairment. One 218-patient ME/CFS study found 74% had improvements in sleep, reduced pain and neurological disturbances.
"It's not a panacea," said Jaime Seltzer, a Stanford researcher and head of scientific outreach for the advocacy group MEAction. "These people weren't cured, but they were helped."
'HUMAN AGAIN' Dr. Jack Lambert, an infectious disease expert at University College Dublin School of Medicine, had used LDN to treat pain and fatigue associated with chronic Lyme disease.
During the pandemic, Lambert recommended LDN to colleagues treating patients with lingering symptoms after bouts of COVID.
It worked so well that he ran a pilot study among 38 long COVID patients. They reported improvements in energy, pain, concentration, insomnia and overall recovery from COVID-19 after two months, according to findings published in July.
Lambert, who is planning a larger trial to confirm those results, said he believes LDN may repair damage of the disease rather than mask its symptoms.
Other planned LDN trials include one by the University of British Columbia in Vancouver and a pilot study by Ann Arbor, Michigan-based startup AgelessRx. That study of 36 volunteers should have results by year-end, said company co-founder Sajad Zalzala. Scientists are still working on explaining the mechanism for how LDN might work. Experiments by Dr. Sonya Marshall-Gradisnik of the National Centre for Neuroimmunology and Emerging Diseases in Australia suggest ME/CFS and long COVID symptoms arise from a significant reduction in function of natural killer cells in the immune system. In laboratory experiments, LDN may have helped restore their normal function, a theory that must still be confirmed. Others believe infections trigger immune cells in the central nervous system called microglia to produce cytokines, inflammatory molecules that cause fatigue and other symptoms associated with ME/CFS and long COVID. Younger believes naltrexone calms these hypersensitized immune cells.
Dr. Zach Porterfield, a virologist at the University of Kentucky who co-chairs a RECOVER task force looking at commonalities with other post-infectious syndromes, said it has recommended LDN be included in RECOVER's treatment trials. Other therapies under consideration, sources said, were antivirals, such as Pfizer Inc's Paxlovid, anti-clotting agents, steroids and nutritional supplements. RECOVER officials said they have received dozens of proposals and could not comment on which drugs will be tested until trials are finalized. Dr. Hector Bonilla, co-director of the Stanford Post-Acute COVID-19 Clinic and a RECOVER adviser, has used LDN in 500 ME/CFS patients, with about half reporting benefits.
He studied LDN in 18 long COVID patients, with 11 showing improvements, and said he believes larger, formal trials could determine whether LDN offers a true benefit. Nichols, a patient adviser to RECOVER, was "ecstatic" when she learned LDN was being considered for the government-funded trials. While LDN has not fixed all her COVID-related problems, Nichols can now work all day without breaks and have a social life at home. "It has made me feel like a human again."
(Reporting by Julie Steenhuysen in Chicago; Editing by Caroline Humer and Bill Berkrot)
Phenotypic characteristics of peripheral immune cells of Myalgic encephalomyelitis/chronic fatigue syndrome via transmission electron microscopy: A pilot study
- FFereshteh Jahanbani ,Rajan D. Maynard ,Justin Cyril Sing, Shaghayegh Jahanbani, John J. Perrino, Damek V. Spacek, Ronald W. Davis, Michael P. Snyder x
- Published: August 9, 2022 https://doi.org/10.1371/journal.pone.0272703 PLOS one
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic multi-systemic disease characterized by extreme fatigue that is not improved by rest, and worsens after exertion, whether physical or mental. Previous studies have shown ME/CFS-associated alterations in the immune system and mitochondria. We used transmission electron microscopy (TEM) to investigate the morphology and ultrastructure of unstimulated and stimulated ME/CFS immune cells and their intracellular organelles, including mitochondria. PBMCs from four participants were studied: a pair of identical twins discordant for moderate ME/CFS, as well as two age- and gender- matched unrelated subjects—one with an extremely severe form of ME/CFS and the other healthy. TEM analysis of CD3/CD28-stimulated T cells suggested a significant increase in the levels of apoptotic and necrotic cell death in T cells from ME/CFS patients (over 2-fold). Stimulated Tcells of ME/CFS patients also had higher numbers of swollen mitochondria. We also found a large increase in intracellular giant lipid droplet-like organelles in the stimulated PBMCs from the extremely severe ME/CFS patient potentially indicative of a lipid storage disorder. Lastly, we observed a slight increase in platelet aggregation in stimulated cells, suggestive of a possible role of platelet activity in ME/CFS pathophysiology and disease severity. These results indicate extensive morphological alterations in the cellular and mitochondrial phenotypes of ME/CFS patients’ immune cells and suggest new insights into ME/CFS biology.
No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Marthe Ueland, Riad Hajdarevic, Olav Mella, Elin B. Strand, Daisy D. Sosa, Ola D. Saugstad, Øystein Fluge, Benedicte A. Lie & Marte K. Viken
Translational Psychiatry volume 12, Article number: 277 (2022) Published: 11 July 2022
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with a variety of symptoms such as post-exertional malaise, fatigue, and pain, but where aetiology and pathogenesis are unknown. An increasing number of studies have implicated the involvement of the immune system in ME/CFS. Furthermore, a hereditary component is suggested by the reported increased risk for disease in relatives, and genetic association studies are being performed to identify potential risk variants. We recently reported an association with the immunologically important human leucocyte antigen (HLA) genes HLA-C and HLA-DQB1 in ME/CFS. Furthermore, a genome-wide genetic association study in 42 ME/CFS patients reported significant association signals with two variants in the T cell receptor alpha (TRA) locus (P value <5 × 10−8). As the T cell receptors interact with the HLA molecules, we aimed to replicate the previously reported findings in the TRA locus using a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK biobank (2105 cases and 4786 controls). We investigated numerous SNPs in the TRA locus, including the two previously ME/CFS-associated variants, rs11157573 and rs17255510. No associations were observed in the Norwegian cohort, and there was no significant association with the two previously reported SNPs in any of the cohorts. However, other SNPs showed signs of association (P value <0.05) in the UK Biobank cohort and meta-analyses of Norwegian and UK biobank cohorts, but none survived correction for multiple testing. Hence, our research did not identify any reliable associations with variants in the TRA locus.
Journal of Translational Medicine (2022) 20:273 https://doi.org/10.1186/s12967-022-03460-1
RESEARCH Combination of whole body cryotherapy with static stretching exercises reduces fatigue and improves functioning of the autonomic nervous system in Chronic Fatigue Syndrome
Sławomir Kujawski1* , Joanna Słomko1 , Beata R. Godlewska2 , Agnieszka CudnochJędrzejewska3 , Modra Murovska4 , Julia L. Newton5 , Łukasz Sokołowski1 and Paweł Zalewski1,3
Background: The aim of this study was to explore the tolerability and efect of static stretching (SS) and whole body cryotherapy (WBC) upon fatigue, daytime sleepiness, cognitive functioning and objective and subjective autonomic nervous system functioning in those with Chronic Fatigue Syndrome (CFS) compared to a control population.
Methods: Thirty-two CFS and eighteen healthy controls (HC) participated in 2 weeks of a SS+WBC programme. This programme was composed of fve sessions per week, 10 sessions in total.
Results: A significant decrease in fatigue was noted in the CFS group in response to SS+WBC. Some domains of cognitive functioning (speed of processing visual information and set-shifting) also improved in response to SS+WBC in both CFS and HC groups. Our study has confrmed that WBC is well tolerated by those with CFS and leads to symp tomatic improvements associated with changes in cardiovascular and autonomic function.
Conclusions: Given the preliminary data showing the benefcial efect of cryotherapy, its relative ease of application, good tolerability, and proven safety, therapy with cold exposure appears to be an approach worth attention. Further studies of cryotherapy as a potential treatment in CFS is important in the light of the lack of efective therapeutic options for these common and often disabling symptoms
Activity monitoring and patient-reported outcome measures in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients
Ingrid G. Rekeland , Kari Sørland, Ove Bruland, Kristin Risa, Kine Alme, Olav Dahl, Karl J. Tronstad, Olav Mella, Øystein Fluge
Published: September 19, 2022 https://doi.org/10.1371/journal.pone.0274472 PLOS one
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with no validated specific and sensitive biomarker, and no standard approved treatment. In this observational study with no intervention, participants used a Fitbit activity tracker. The aims were to explore natural symptom variation, feasibility of continuous activity monitoring, and to compare activity data with patient reported outcome measures (PROMs).
Materials and methods
In this pilot study, 27 patients with mild to severe ME/CFS, of mean age 42.3 years, used the Fitbit Charge 3 continuously for six months. Patients wore a SenseWear activity bracelet for 7 days at baseline, at 3 and 6 months. At baseline and follow-up they completed the Short Form 36 Health Survey (SF-36) and the DePaul Symptom Questionnaire–Short Form (DSQ-SF).
The mean number of steps per day decreased with increasing ME/CFS severity; mild 5566, moderate 4991 and severe 1998. The day-by-day variation was mean 47% (range 25%–79%). Mean steps per day increased from the first to the second three-month period, 4341 vs 4781 steps, p = 0.022. The maximum differences in outcome measures between 4-week periods (highest vs lowest), were more evident in a group of eight patients with milder disease (baseline SF-36 PF > 50 or DSQ-SF < 55) as compared to 19 patients with higher symptom burden (SF-36 PF < 50 and DSQ-SF > 55), for SF-36 PF raw scores: 16.9 vs 3.4 points, and for steps per day: 958 versus 479 steps. The correlations between steps per day and self-reported SF-36 Physical function, SF-36 Social function, and DSQ-SF were significant. Fitbit recorded significantly higher number of steps than SenseWear. Resting heart rates were stable during six months.
Continuous activity registration with Fitbit Charge 3 trackers is feasible and useful in studies with ME/CFS patients to monitor steps and resting heart rate, in addition to self-reported outcome measures.
Biochem J . 2022 Aug 31;479(16):1653-1708. doi: 10.1042/BCJ20220154.
The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications
Douglas B Kell 1 2 3, Etheresia Pretorius 1 3 PMID: 36043493 PMCID: PMC9484810
Ischaemia-reperfusion (I-R) injury, initiated via bursts of reactive oxygen species produced during the reoxygenation phase following hypoxia, is well known in a variety of acute circumstances. We argue here that I-R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, our chief focus and most proximally, Long COVID. Ischaemia may be initiated via fibrin amyloid microclot blockage of capillaries, for instance as exercise is started; reperfusion is a necessary corollary when it finishes. We rehearse the mechanistic evidence for these occurrences here, in terms of their manifestation as oxidative stress, hyperinflammation, mast cell activation, the production of marker metabolites and related activities. Such microclot-based phenomena can explain both the breathlessness/fatigue and the post-exertional malaise that may be observed in these conditions, as well as many other observables. The recognition of these processes implies, mechanistically, that therapeutic benefit is potentially to be had from antioxidants, from anti-inflammatories, from iron chelators, and via suitable, safe fibrinolytics, and/or anti-clotting agents. We review the considerable existing evidence that is consistent with this, and with the biochemical mechanisms involved.
Keywords: Long COVID; amyloid microclots; ischaemia–reperfusion injury.
RECOVER program takes first steps in advancing toward clinical trials to better understand Long COVID The NIH
RECOVER initiative is preparing several clinical trials to evaluate treatments to improve symptoms related to post-acute sequelae of SARS-CoV-2 infection (PASC) or Long COVID. A trial protocol recently posted to ClinicalTrials.gov is in the final stages of development and approvals, and is expected to begin enrolling participants in early 2023. This trial is one of several that will test a variety of treatments for Long COVID. The causes of Long COVID are not well understood, and there are many different symptoms of Long COVID. Each trial will examine a treatment that targets one of five specific clusters of symptoms and their potential causes. The identification of the symptom clusters of focus began with patients. Through RECOVER study questionnaires, surveys, and discussions with people who have Long COVID, these were considered most burdensome, most important to address, and the priorities for trial protocols under development. The symptom clusters include: • Viral persistence: When the COVID-19 virus stays in some people’s bodies. • Autonomic dysfunction: Changes in ability to regulate heart rate, body temperature, breathing, digestion, and sensation. • Sleep disturbances: Changes to sleep patterns or ability to sleep. • Cognitive Dysfunction: Trouble thinking clearly or brain fog. • Exercise intolerance/fatigue: Changes in a person’s activity and/or energy level. The goal of these trials is to reduce the patient burden of illness due to Long COVID. The protocols for each trial were developed with patients and experts in these symptom areas. RECOVER researchers will also continue to engage patients, caregivers, and community representatives to better understand the impact of Long COVID on different groups. As an important complement to the therapeutic trials, RECOVER continues to conduct several longitudinal observational cohort studies and related sub-studies, more than 40 pathobiology studies, evaluation of potential PASC biomarkers, and analyses of more than 60 million electronic health records. The understanding of symptoms that patients are experiencing and their underlying biologic causes – as emerging from these studies – is informing the selection of clinical endpoints and other aspects of clinical trial design. More information about the clinical trials will be posted on recoverCOVID.org as it becomes available.
Post–COVID-19 Symptoms 2 Years After SARS-CoV-2 Infection Among Hospitalized vs Nonhospitalized Patients
César Fernández-de-las-Peñas, PT, PhD1; Jorge Rodríguez-Jiménez, PT, MSc1; Ignacio Cancela-Cilleruelo, PT, MSc1; et alAngel Guerrero-Peral, MD, PhD2,3; José D. Martín-Guerrero, PhD4; David García-Azorín, MD, PhD2; Ana Cornejo-Mazzuchelli, MD5; Valentín Hernández-Barrera, PhD6; Oscar J. Pellicer-Valero, PhD4
JAMA Netw Open. 2022;5(11):e2242106. doi:10.1001/jamanetworkopen.2022.42106
Question What is the prevalence of post–COVID-19 symptoms among hospitalized and nonhospitalized patients 2 years after acute infection?
Findings This cross-sectional study found that the proportion of patients with at least 1 post–COVID-19 symptom 2 years after acute infection was 59.7% for hospitalized patients and 67.5% for those not requiring hospitalization. No significant differences in post–COVID-19 symptoms were seen between hospitalized and nonhospitalized patients.
Meaning Similar rates of post–COVID-19 symptoms between hospitalized and nonhospitalized patients suggest that, among all patients who contract COVID-19, these sequelae deserve attention.
Importance Identification of long-term post–COVID-19 symptoms among hospitalized and nonhospitalized patients is needed.
Objective To compare the presence of post–COVID-19 symptoms 2 years after acute SARS-CoV-2 infection between hospitalized and nonhospitalized patients.
Design, Setting, and Participants A cross-sectional cohort study was conducted at 2 urban hospitals and general practitioner centers from March 20 to April 30, 2020, among 360 hospitalized patients and 308 nonhospitalized patients with acute SARS-CoV-2 infection during the first wave of the pandemic. Follow-up was conducted 2 years later.
Main Outcomes and Measures Participants were scheduled for a telephone interview 2 years after acute infection. The presence of post–COVID-19 symptoms was systematically assessed, with particular attention to symptoms starting after infection. Hospitalization and clinical data were collected from medical records. Between-group comparisons and multivariate logistic regressions were conducted.
Results A total of 360 hospitalized patients (162 women [45.0%]; mean [SD] age, 60.7 [16.1] years) and 308 nonhospitalized patients (183 women [59.4%]; mean [SD] age, 56.7 [14.7] years) were included. Dyspnea was more prevalent at the onset of illness among hospitalized than among nonhospitalized patients (112 [31.1%] vs 36 [11.7%]; P < .001), whereas anosmia was more prevalent among nonhospitalized than among hospitalized patients (66 [21.4%] vs 36 [10.0%]; P = .003). Hospitalized patients were assessed at a mean (SD) of 23.8 (0.6) months after hospital discharge, and nonhospitalized patients were assessed at a mean (SD) of 23.4 (0.7) months after the onset of symptoms. The number of patients who exhibited at least 1 post–COVID-19 symptom 2 years after infection was 215 (59.7%) among hospitalized patients and 208 (67.5%) among nonhospitalized patients (P = .01). Among hospitalized and nonhospitalized patients, fatigue (161 [44.7%] vs 147 [47.7%]), pain (129 [35.8%] vs 92 [29.9%]), and memory loss (72 [20.0%] vs 49 [15.9%]) were the most prevalent post–COVID-19 symptoms 2 years after SARS-CoV-2 infection. No significant differences in post–COVID-19 symptoms were observed between hospitalized and nonhospitalized patients. The number of preexisting medical comorbidities was associated with post–COVID-19 fatigue (odds ratio [OR], 1.93; 95% CI, 1.09-3.42; P = .02) and dyspnea (OR, 1.91; 95% CI, 1.04-3.48; P = .03) among hospitalized patients. The number of preexisting medical comorbidities (OR, 3.75; 95% CI, 1.67-8.42; P = .001) and the number of symptoms at the onset of illness (OR, 3.84; 95% CI, 1.33-11.05; P = .01) were associated with post–COVID-19 fatigue among nonhospitalized patients.
Conclusions and Relevance This cross-sectional study suggested the presence of at least 1 post–COVID-19 symptom in 59.7% of hospitalized patients and 67.5% of nonhospitalized patients 2 years after infection. Small differences in symptoms at onset of COVID-19 were identified between hospitalized and nonhospitalized patients. Post–COVID-19 symptoms were similar between hospitalized and nonhospitalized patients; however, lack of inclusion of uninfected controls limits the ability to assess the association of SARS-CoV-2 infection with overall and specific post–COVID-19 symptoms 2 years after acute infection. Future studies should include uninfected control populations.
Front. Immunol., 20 October 2022 Sec. Viral Immunology https://doi.org/10.3389/fimmu.2022.949787
Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome
Eirini Apostolou1*, Muhammad Rizwan1, Petros Moustardas1, Per Sjögren2,3, Bo Christer Bertilson2,3, Björn Bragée2,3, Olli Polo3 and Anders Rosén1*
Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease considered to be triggered by viral infections in a majority of cases. Symptoms overlap largely with those of post-acute sequelae of COVID-19/long-COVID implying common pathogenetic mechanisms. SARS-CoV-2 infection is risk factor for sustained latent virus reactivation that may account for the symptoms of post-viral fatigue syndromes. The aim of this study was first to investigate whether patients with ME/CFS and healthy donors (HDs) differed in their antibody response to mild/asymptomatic SARS-CoV-2 infection. Secondly, to analyze whether COVID-19 imposes latent virus reactivation in the cohorts.
Methods: Anti-SARS-CoV-2 antibodies were analyzed in plasma and saliva from non-vaccinated ME/CFS (n=95) and HDs (n=110) using soluble multiplex immunoassay. Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva.
Results: At 3-6 months after mild/asymptomatic SARS-CoV-2 infection, virus-specific antibodies in saliva were substantially induced signifying a strong reactivation of latent viruses (EBV, HHV6 and HERV-K) in both cohorts. In patients with ME/CFS, antibody responses were significantly stronger, in particular EBV-encoded nuclear antigen-1 (EBNA1) IgG were elevated in patients with ME/CFS, but not in HDs. EBV-VCA IgG was also elevated at baseline prior to SARS-infection in patients compared to HDs.
Conclusion: Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. SARS-CoV-2 infection even in its mild/asymptomatic form is a potent trigger for reactivation of latent herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K), as detected by antibody fingerprints locally in the oral mucosa (saliva samples). This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma.
COVID-19 Affects Brain 6 Months After Symptoms, Research Finds
Jay Croft November 22, 2022 -Medscape
Scientists have found that COVID-19 causes brain "abnormalities" even six months after symptoms are gone, according to an upcoming report to the Radiological Society of North America.
They found changes to the brain stem and front lobe in areas of the brain associated with fatigue, insomnia, anxiety, depression, headaches, and cognitive issues.
About 20% of adults will have long-term effects from COVID-19, according to the CDC. Neurological symptoms associated with long COVID include poor concentration, headaches, and sleep problems. Long COVID can also cause changes to the heart, lungs, and other organs, the RSNA says.
In this study, researchers used a special MRI to detect and monitor neurological conditions such as microbleeds, vascular malformations, brain tumors, and stroke.
"Group-level studies have not previously focused on COVID-19 changes in magnetic susceptibility of the brain despite several case reports signaling such abnormalities," said study co-author Sapna S. Mishra, a Ph.D. candidate at the Indian Institute of Technology in Delhi, in SciTechDaily. "Our study highlights this new aspect of the neurological effects of COVID-19 and reports significant abnormalities in COVID survivors."
Scientists compared imaging of 46 patients who had recovered from COVID and 30 who had been healthy. The images were taken within six months of recovery.
"Changes in susceptibility values of brain regions may be indicative of local compositional changes," Mishra said. "Susceptibilities may reflect the presence of abnormal quantities of paramagnetic compounds, whereas lower susceptibility could be caused by abnormalities like calcification or lack of paramagnetic molecules containing iron."
The researchers will conduct similar studies on the same group of participants to see if the COVID-19 affects continue over time.
Lead Image: Science Photo Library/Getty Images
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Cite this: COVID-19 Affects Brain 6 Months After Symptoms, Research Finds - Medscape - Nov 22, 2022.
Acupuncture and moxibustion for chronic fatigue syndrome: A systematic review and network meta-analysis
Fang, Yang MDa; Yue, Bo-Wen MDb,*; Ma, Han-Bo MDa; Yuan, Yi-Peng MDa
Medicine: August 05, 2022 - Volume 101 - Issue 31 - p e29310 doi: 10.1097/MD.0000000000029310
Background: Research into acupuncture and moxibustion and their application for chronic fatigue syndrome (CFS) has been growing, but the findings have been inconsistent.
To evaluate the existing randomized clinical trials (RCTs), compare the efficacy of acupuncture, moxibustion and other traditional Chinese medicine (TCM) treatments.
Three English-language databases (PubMed, Embase, Web of Science, and The Cochrane Library) and 4 Chinese-language biomedical databases (Chinese Biomedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang) were searched for RCTs published from database inception through August 2021.
RCTs include acupuncture, moxibustion, traditional Chinese herbal medicine, western medicine and no control.
Data extraction and synthesis:
Data were screened and extracted independently using predesigned forms. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias tool. We conducted a random-effects network meta-analysis within a frequentist framework. We assessed the certainty of evidence contributing to network estimates of the main outcomes with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.
Main outcomes and measures:
The primary outcomes were the overall response rate and FS-14 scale.
A total of 51 randomized controlled trials involving 3473 patients with CFS were included in this review. Forty one studies indicate low risk or unknown risk, and the GRADE scores of the combined results show low levels. Among the main indicators, traditional Chinese medicine therapies have excellent performance. However, the overall response rate is slightly different from the results obtained from the Fatigue Scale-14 total score. Moxibustion and traditional Chinese medicine (Odds ratios 48, 95% CrI 15–150) perform better in the total effective rate, while moxibustion plus acupuncture (MD 4.5, 95% CrI 3.0–5.9) is better in the FS-14 total score.
The effect of acupuncture and moxibustion in the treatment of CFS was significantly higher than that of other treatments. Traditional Chinese medicine should be used more widely in the treatment of CFS.