Journal of Translational Medicine volume 23, Article number: 1048 (2025) Journal of Translational Medicine    Published: 08 October 2025
Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling
Ewan Hunter, Heba Alshaker, Oliver Bundock, Cicely Weston, Shekinah Bautista, Abel Gebregzabhar, Anya Virdi, Joseph Croxford, Ann Dring, Ryan Powell, Dominik Vugrinec, Caroline Kingdon, Carol Wilson, Sarah Dowrick, Jayne Green, Alexandre Akoulitchev & Dmitri Pchejetski 
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multifactorial disorder characterised by profound fatigue, post-exertional malaise, cognitive impairments, and autonomic dysfunction. Despite its significant impact on quality of life, ME/CFS lacks definitive diagnostic biomarkers, complicating diagnosis and management. Recent evidence highlights potential blood tests for ME/CFS biomarkers in immunological, genetic, metabolic, and bioenergetic domains. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression and cross-tissue exosome signalling. We have previously developed an epigenetic assay, EpiSwitch®, that employs an algorithm-based CCs analysis. Using EpiSwitch® technology, we have shown the presence of disease-specific CCs in peripheral blood mononuclear cells (PBMCs) of patients with amyotrophic lateral sclerosis (ALS), rheumatoid arthritis (RA), prostate and colorectal cancers, diffuse Large B-cell lymphoma and severe COVID-19. In a recent paper, we have identified a profile of systemic chromosome conformations in cancer patients reflective of the predisposition to respond to immune checkpoint inhibitors, PD-1/PD-L1 antagonists, with 85% accuracy. In this Retrospective case/control study (EPI-ME, Epigenetic Profiling Investigation in Myalgic Encephalomyelitis), we used whole blood samples retrospectively collected from n = 47 patients with severe ME/CFS and n = 61 age-matched healthy control patients to perform whole-genome 3D DNA screening for CCs correlating to ME/CFS diagnosis. We identified a 200-marker model for ME/CFS diagnosis (Episwitch®CFS test). First testing on the retrospective independent validation cohort demonstrated a strong systemic ME/CFS signal with a sensitivity of 92% and a specificity of 98%.Pathways analysis revealed several likely contributors to the pathology of ME/CFS, including interleukins, TNFα, neuroinflammatory pathways, toll-like receptor signalling and JAK/STAT. Comparison with pathways involved in the action of Rituximab and glatiramer acetate (Copaxone) (therapies with potential in ME/CFS treatment) identified IL2 as a shared pathway with clear patient clustering, indicating a possibility of a potential responder group for targeted treatment.

____________________________________________________________________
Explor Neuroprot Ther. 2025;5:1004116 DOI: https://doi.org/10.37349/ent.2025.1004116
Received: April 28, 2025 Accepted: July 25, 2025 Published: October 14, 2025
Academic Editor: Vijay K. Sharma, National University of Singapore, National University Hospital, Singapore
Abstract
Aim: Post-exertional malaise (PEM) has been a challenging construct to measure, particularly with self-report instruments, which have the benefits of being less expensive and less invasive than cardiopulmonary exercise tests. Existing PEM questionnaires have often been used for diagnostic purposes and less frequently as outcome measures. Few self-report PEM measures address comprehensive PEM domains, including types of triggers, duration of symptoms, delayed symptom onset, number of symptoms, frequency and severity of symptoms, as well as whether pacing or other strategies reduce or eliminate PEM. Without characterizing these features, salient aspects of PEM would be overlooked. However, efforts to assess all these domains can be time-consuming and potentially burdensome.
Methods: The current study offers investigators a brief but comprehensive instrument of critical PEM domains, called the DePaul Symptom Questionnaire (DSQ)-PEM-2, to assess PEM. Validation data were derived from a large sample of individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Results: The DSQ-PEM-2 was developed using an existing dataset of individuals with ME, CFS, or both ME and CFS, allowing comprehensive coverage of key PEM domains.
Conclusions: The DSQ-PEM-2 can be used either for diagnostic purposes or as an outcome measure. The instrument’s time frames for symptom manifestation can be adapted to suit a variety of research or clinical contexts. Future validation studies need to include a healthy control group.

____________________________________________________________________

Original Investigation
Effectiveness of Colchicine for the Treatment of Long COVID 
A Randomized Clinical Trial
Abhinav Bassi, MPH1; Niveditha Devasenapathy, PhD, MBBS, MSc1; Shani S. Thankachen, MPH1et al
JAMA Intern Med Published Online: October 20, 2025
doi:10.1001/jamainternmed.2025.5408
Key Points
Question  What is the effectiveness of 28-week oral colchicine therapy in improving functional outcomes among individuals with persistent symptoms after acute COVID-19 infection?
Findings  In this randomized clinical trial including 346 adults, there was no statistically significant difference in functional capacity, respiratory function, mental states, constitutional symptoms, or inflammatory markers at 52 weeks among those treated with colchicine or placebo.
Meaning  This trial provides evidence against colchicine monotherapy as a broadly effective treatment for long COVID.
Abstract
Importance  Long COVID is characterized by persistent symptoms after SARS-CoV-2 infection, with inflammation playing a key role in pathogenesis. Colchicine, an established anti-inflammatory agent, may reduce these symptoms by targeting inflammatory pathways.
Objective  To evaluate the superiority of colchicine over placebo in improving functional outcome at 52 weeks from baseline.
Design, Setting, and Participants  This double-blind, 1:1 randomized clinical trial recruited participants with confirmed SARS-CoV-2 infection and persistent symptoms from 8 hospitals in 6 states in India between January 2022 and July 2023. Individuals were eligible if they had functional limitation (Post–COVID-19 Functional Status scale grade 2 or more) and/or elevated inflammatory markers (high-sensitivity C-reactive protein >0.20 mg/dL and/or neutrophil to lymphocyte ratio >5). Outcomes were assessed at 12, 26, and 52 weeks after randomization. Data were analyzed from January to February 2025.
Interventions  Participants were randomly assigned to receive colchicine, 0.5 mg, once or twice daily, based on body weight, or placebo for 26 weeks.
Main Outcomes and Measures  The primary outcome was the change in distance walked during a 6-minute walk test from baseline to 52 weeks. Secondary outcomes included changes in inflammatory markers and patient-reported outcome measures, such as quality of life, anxiety, depression, fatigue, dyspnea, measured using validated instruments.
Results  Of 346 participants included in the modified intention-to-treat analysis, 209 (60.4%) were female, 137 (39.6%) were male, and the mean (SD) age was 46 (12) years. At 52 weeks, there was no difference in mean (SD) change in 6-minute walk test distance between the colchicine and placebo groups (colchicine, 35.5 [19.76] m; placebo, 29.96 [19.83] m; mean difference, 5.59 m; 95% CI, –9.00 to 20.18; P = .45). Similar null findings were seen across all predefined outcomes, except for a small, nonclinically relevant difference in the mean (SD) ratio of forced expiratory volume in 1 second to forced vital capacity (colchicine, −0.02 [0.03]; placebo, −0.06 [0.03]; mean difference, 0.04; 95% CI, 0.02 to 0.07; P = .001).
Conclusions and Relevance  In this randomized clinical trial, among adults with long COVID, colchicine did not improve functional capacity, respiratory function, or inflammatory markers. These findings underscore the need to explore alternative therapeutic approaches for long COVID.
Trial Registration  Clinical Trial Registry of India: CTRI/2021/11/038234
____________________________________________________________________

2025 Sep 19:2025.09.18.25335914. [Version 1] doi: 10.1101/2025.09.18.25335914
The genetic architecture of fibromyalgia across 2.5 million individuals
Isabel Kerrebijn  et al1,2, Author information
Copyright and License information
PMCID: PMC12458511  PMID: 41001472
The complete version history of this preprint is available at medRxiv.
Abstract
Fibromyalgia is a common and debilitating chronic pain syndrome of poorly understood etiology. Here, we conduct a multi-ancestry genome-wide association study meta-analysis across 2,563,755 individuals (54,629 cases and 2,509,126 controls) from 11 cohorts, identifying the first 26 risk loci for fibromyalgia. The strongest association was with a coding variant in HTT, the causal gene for Huntington’s disease. Gene prioritization implicated the HTT regulator GPR52, as well as diverse genes with neural roles, including CAMKV, DCC, DRD2/NCAM1, MDGA2, and CELF4. Fibromyalgia heritability was exclusively enriched within brain tissues and neural cell types. Fibromyalgia showed strong, positive genetic correlation with a wide range of chronic pain, psychiatric, and somatic disorders, including genetic correlations above 0.7 with low back pain, post-traumatic stress disorder and irritable bowel syndrome. Despite large sex differences in fibromyalgia prevalence, the genetic architecture of fibromyalgia was nearly identical between males and females. This work provides the first robust genetic evidence defining fibromyalgia as a central nervous system disorder, thereby establishing a biological framework for its complex pathophysiology and extensive clinical comorbidities.

____________________________________________________________________

The Off-Label Treatment That Helps Many With Fibromyalgia
Medscape Medical News      Laurie Tarkan    October 29, 2025
An unlikely, decades-old drug is gaining traction as a promising off-label treatment for fibromyalgia, driven by a handful of studies and a growing number of anecdotal reports.
Low-dose naltrexone (LDN), a medication originally developed to treat substance use disorders, is said to relieve the chronic pain, fatigue, and brain fog associated with the debilitating condition that afflicts millions of Americans but is difficult to treat.
“It helps over 70% of my patients,” said Scott Zashin, MD, a Dallas-based rheumatologist, and fellow of the American College of Rheumatology. “I’d say less than 10% need to stop it because of side effects.”
Used for decades at doses of 50-100 mg to treat opioid and alcohol use disorders, the drug at that high dose binds to opioid receptors, blocking opioids from attaching to the receptors, so people don’t get that feel-good sensation from booze or drugs.
Early researchers found an unexpected result: “We noticed that when people tapered down to lower doses, their pain would also get better,” said Arya Mohabbat, MD, assistant professor at the Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
Today the LDN trend is fueled primarily by success stories rather than large-scale trials.
One of those stories is Dan Kenyon, age 45, who says LDN reduced his pain by more than half. “It has helped even more with brain fog, fatigue, and sleep,” said Kenyon from Iowa, who was diagnosed in his early thirties after years of unexplained muscle soreness and fatigue.
Despite the word-of-mouth buzz, though, many doctors are not aware of it, don’t think there’s enough evidence to prescribe it, or don’t know how to prescribe it because it’s not marketed by pharmaceutical companies. Still others see LDN as a low-risk, low-cost treatment option for fibromyalgia and other chronic pain conditions — and blame lack of pharmaceutical investment for impeding its progress.
“Naltrexone is an old cheap generic medication,” said Mohabbat. “Just because you formulate it to a lower dose, it doesn’t change the patent, and they can’t charge a lot of money for it.”
How Patients in Pain Are Finding LDN
Looking back, Kenyon thinks the pain started when he was about 20. He had a physically demanding job in fire and water damage restoration, and his muscles would ache throughout the day, pain lingering into the next morning. Even after switching to less strenuous work — first running a retail store, then an online screen-printing business — his pain kept getting worse. Soon it was joined by depression and insomnia. “I got to a point where I just couldn’t motivate myself to work anymore, my sales slowed down, and I didn’t care,” Kenyon said.
At age 32, he saw a rheumatologist who diagnosed him with fibromyalgia. He tried gabapentin, but it gave him panic attacks and affected his balance. Weaning off it was so hard he was reluctant to try other medications.
Browsing an online message board, he read success stories of people on LDN. His rheumatologist said he hadn’t heard of naltrexone being used for chronic pain and wasn’t willing to prescribe it. So Kenyon dropped it.
“Things started getting more painful for me last fall, so it sparked my interest in it again,” Kenyon said. On Reddit, he learned how to get it prescribed online, purchased through a compounding pharmacy.
“I was nervous to try it but started with a very low dose and kept bumping it up every 6 or 7 days,” Kenyon said. It took about 3 months to get to 4.5 mg, which is considered an effective dose. It was working: “I have upwards of a 50% reduction in pain.”
Few Studies, Promising Results
Several studies back LDN for fibromyalgia, though most are small.
In 2013, a randomized controlled study of 31 women with fibromyalgia found that LDN offered an average 29% reduction in pain vs 18% for women on a placebo. An analysis of that data found that half the women on LDN were “much improved” or “very much improved” — compared with just 20%-30% of patients who find meaningful improvement on current fibromyalgia-approved medications, said study author Jarred Younger, PhD, director of the Neuroinflammation, Pain and Fatigue Laboratory at The University of Alabama at Birmingham.
A 2023 cohort study of LDN for pain conditions included 115 people, most having fibromyalgia. The study found that 65% reported a benefit in their pain and other symptoms. A review of nine studies found LDN effective in managing fibromyalgia symptoms, and so did a 2024 review of randomized controlled trials.
Further research shows pain improvements in other conditions, like Crohn’s disease and Long COVID.
To be sure, more research is needed. “We need a double blinded randomized trial for 12 months that looks at side effects and how people do functionally,” said Mohabbat.
“There’s still that question mark in the air,” said Younger. “Clearly it helps a lot of people, but without the study, a lot of physicians aren’t going to want to use it,” he said. But the buzz is growing. “LDN comes up in every medical conference.”
How LDN Works
LDN is thought to tamp down nerve inflammation responsible for many of the symptoms of fibromyalgia like pain, fatigue, malaise, brain fog, and flu-like symptoms. In fibromyalgia, glial cells, which support neurons, are activated, causing an inflammatory response. LDN blocks a receptor that activates glial cells, stopping the inflammatory cascade.
Like any medication, it doesn’t help everyone and won’t completely get rid of symptoms. But for those it helps, it can be life changing.
Jane Lamping, age 53, who lives in San Diego, was diagnosed with fibromyalgia in 2014, and has tried a long list of medications — among them Tramadol, Lyrica, Cymbalta, Fetzima, Mobic, gabapentin, Toradol injections. But she continued to have many flares, which left her unable to keep a job. Like many with fibromyalgia, Lamping had to carefully manage her exertion to try to prevent flares. In 2022, her doctor, who had been following the research on LDN, suggested she try it.
It reduced her pain, brain fog, and fatigue. “It has helped immensely. I do still get flares and pain cycles. But they are less frequent, and it has reduced the intensity as well,” she said. A bonus: It helped with her migraines.
A Crowd-Sourced Approach in the Absence of Robust Data
Kenyon, like many people, learned how to take LDN from online groups and shared it with his physician — a crucial step, Zashin said. “The window for optimally dosing naltrexone is very small and requires high accuracy,” said Younger. Like any medication, it carries potential risks.

____________________________________________________________________

    •    The first big GWAS FM study scored by finding many significant regions of the genes we are born with that appear to contribute to FM. That finding, as the authors said, puts FM on a “firm biological foundation”.

• The genes highlighted in the study affect things like interneuron excitability (pain processing/subclinical seizures), hippocampal functioning (memory impairment), the kynurenine pathway (pain and others), dopamine (motivation and cognition), sleep, natural killer cell functioning (!), neuroplasticity, excitatory neurotransmission, testosterone metabolism, cognitive issues, microglial activation, neuroinflammation, lipid and mitochondrial issues.
• The study, in other words, confirmed that people with FM have a genetic predisposition to many of the biological abnormalities studies have found.
• Like ME/CFS, the genes almost wholly pointed to the brain, and, in particular, in FM, to genes that affect pain and sensory processing. Genetic variants that affect similar areas of the brain were found in both ME/CFS and FM.
• Many genes found in FM have also been found to contribute to other illnesses. This suggested to the authors that the genetic architecture found in FM constitutes a kind of “transdiagnostic” genetic vulnerability that reaches far beyond FM itself. That “vulnerability profile”, they believe, affects core neurobiological systems such as central nervous system excitability, dopaminergic/serotonergic signaling, and neuroimmune stress.
• It’s also found in diseases like ME/CFS, chronic pain conditions, IBS, PTSD, depression, and more. A ChatGPT 5.0 analysis concluded that “DecodeME’s strongest loci for ME/CFS sit exactly where you’d expect such a vulnerability to live“.
• Two genes, in particular, offer new treatment pathways for FM. Drugs for them are not available right now, but are under development and being tested.

____________________________________________________________________

Mestinon has done it again. Another study has shown that in the short term, Mestinon can move the needle on two factors, energy production and strength, that are in short supply in ME/CFS.

• This study assessed handgrip strength, which turns out to be quite a proxy for overall health.
• Dozens (dozens!) of large studies have found that weaker grip strength is associated with a higher risk of death from any cause. It’s more strongly predictive of cardiovascular death than high blood pressure. Reduced handgrip strength has been linked to higher rates of heart attack, stroke, type II diabetes. The list goes on and on.
• Besides keeping us stronger, our muscles play a vital role in our metabolism by regulating glucose, and the myokines they produce affect the immune system, metabolism, and the brain.
• Because inflammation, insulin resistance, oxidative stress, hormonal problems, and poor mitochondrial health can all whack the muscles, people with these problems often have poor handgrip strength.
• Given that, it’s perhaps no surprise that several studies have not only found reduced handgrip strength in ME/CFS but that it’s correlated with ME/CFS severity, and the amount of post-exertional malaise and muscle pain people with ME/CFS experience.
• The small study involved two visits. The first was done to assess handgrip strength and orthostatic intolerance at baseline, and then again hour later. During the next visit, Mestinon was administered immediately after the first handgrip strength test to assess its impact on the second handgrip strength test conducted an hour later.
• Unfortunately, the study did not break up the results by gender. (Men have much higher handgrip strengths than women.) The mean baseline handgrip strength, though, was very low (16.5 kg), and it declined during the second test an hour later.
• After taking Mestinon, though, the ME/CFS patients’ handgrip strength not only did not decline but actually increased.
• This is the second short-term study to show that Mestinon increased energy production/strength. Systrom’s earlier study showed that Mestinon increased energy production during an invasive exercise test. Mestinon, then, has scored on two important factors in ME/CFS.
• Mestinon could be doing a number of things. It could be aiding muscle recruitment during exertion. (Reduced muscle recruitment during exertion could be causing everything from mitochondrial problems, orthostatic intolerance, and low preload.) By improving autonomic nervous system activity, it could be enhancing blood flows. By improving calcium handling in the cells, it could be enhancing mitochondrial activity.
• We should know more about Mestinon and ME/CFS soon. The Open Medicine Foundation’s LIFT trial with David Systrom will not only be assessing how effective Mestinon and low dose naltrexone are, it’ll be digging deep into their pathophysiology to understand how these drugs are helping, which kinds of patients they are helping, and what pathways to focus on.

____________________________________________________________________

Circulating Levels of SMPDL3B Define Metabolic Endophenotypes and Subclinical Kidney Alterations in Myalgic Encephalomyelitis
Bita Rostami-Afshari   Wesam Elremaly,Neil R. McGregor,Katherine Jin Kai Huang
 Christopher W. Armstrong,Anita Franco,Christian Godbout,Mohamed Elbakry,Rim Abdelli
  And Alain Moreau
The Open Medicine Foundation ME/CFS Collaborative Research Centre, Bio21 Molecular Science and Biochemistry Institute, University of Melbourne, Melbourne, VIC 3010, Australia
Int. J. Mol. Sci. 2025, 26(18), 8882; https://doi.org/10.3390/ijms26188882
Abstract
Myalgic Encephalomyelitis (ME) is a complex, multisystem disorder with poorly understood pathophysiological mechanisms. SMPDL3B, a membrane-associated protein expressed in renal podocytes, is essential for lipid raft integrity and glomerular barrier function. We hypothesize that reduced membrane-bound SMPDL3B may contribute to podocyte dysfunction and impaired renal physiology in ME. To investigate this, we quantified soluble SMPDL3B in plasma and urine as a surrogate marker of membrane-bound SMPDL3B status and assessed renal clearance and plasma metabolomic profiles. In a cross-sectional study of 56 ME patients and 16 matched healthy controls, ME patients exhibited significantly lower urine-to-plasma ratios of soluble SMPDL3B and reduced renal clearance, suggesting podocyte-related abnormalities. Plasma metabolomics revealed dysregulation of metabolites associated with renal impairment, including succinic acid, benzoic acid, phenyllactic acid, 1,5-anhydroglucitol, histidine, and citrate. In ME patients, plasma SMPDL3B levels inversely correlated with 1,5-anhydroglucitol concentrations and renal clearance. Multivariable modeling identified the urine-to-plasma SMPDL3B ratio as an independent predictor of clearance. Female ME patients showed more pronounced SMPDL3B alterations, reduced clearance, and greater symptom severity. Non-linear associations between soluble SMPDL3B and lipid species further suggest systemic metabolic remodeling. These findings support soluble SMPDL3B as a potential non-invasive biomarker of renal-podocyte involvement in ME, highlighting sex-specific differences that may inform future therapeutic strategies.
Keywords: 
SMPDL3B; myalgic encephalomyelitis; renal clearance; metabolomics; 1,5-anhydroglucitol; sex differences; urinary biomarkers; glomerular barrier; lipid metabolism
____________________________________________________________________

NPJ Metab Health Dis. 2025 Sep 3;3(1):34.  doi: 10.1038/s44324-025-00079-w
Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS
Xiaoyu Che # 1 2, Amit Ranjan # 3, Cheng Guo 3, Keming Zhang 3, Rochelle Goldsmith 4, Susan Levine 5, Kegan J Moneghetti 6, Yali Zhai 3, Liner Ge 7, Nischay Mishra 3 8, Mady Hornig 9, Lucinda Bateman 10, Nancy G Klimas 11, Jose G Montoya 12, Daniel L Peterson 13, Sabra L Klein 14, Oliver Fiehn 15, Anthony L Komaroff 16, W Ian Lipkin 17 18 19
Affiliations Expand:PMID: 40903540  - PMCID: PMC12408823
DOI: 10.1038/s44324-025-00079-w
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue, post-exertional malaise (PEM), and cognitive dysfunction. ME/CFS patients often report a prodrome consistent with infection. We present a multi-omics analysis based on plasma metabolomic and proteomic profiling, and immune responses to microbial stimulation, before and after exercise. We report evidence of an exaggerated innate immune response after exposure to microbial antigens; impaired energy production involving the citric acid cycle, beta-oxidation of fatty acids, and urea cycle energy production from amino acids; systemic inflammation linked to lipid abnormalities; disrupted extracellular matrix homeostasis with release of endogenous ligands that promote inflammation; reduced cell-cell adhesion and associated gut dysbiosis; complement activation; redox imbalance reflected by disturbances in copper-dependent antioxidant pathways; and dysregulation of tryptophan-serotonin-kynurenine pathways. Many abnormalities were worse following exercise and correlated with the intensity of symptoms. Our findings may inform development of targeted therapeutic interventions for ME/CFS and PEM.
© 2025. The Author(s).
PubMed Disclaimer
Conflict of interest statement
Competing interests: The authors declare no competing interests.

A Non-Opioid Drug for Fibromyalgia Soon to Hit the US Market
For the first time in 15 years, a drug has been approved for fibromyalgia in the U.S.
On August 15th, the FDA approved Tonmya for use in fibromyalgia (FM). It’s been a long wait – 15 years – since the last drug was approved for FM. I felt like pinching myself. Health Rising has been following the Tonmya (formerly TNX-102) saga for at least five years.
Tonmya seemed as dead as a duck at some points, and over that time, we’ve seen drugs come and go, but somehow, little Tonix Pharmaceuticals hung on through thick and thin and managed to produce a winner when others could not.
Fifteen years is a long dry spell for a disease afflicting approximately ten million people in the U.S. Seth Lederman, Tonix’s CEO, and the driver behind the drug, pointed out in our talk that the lack of drug approvals is not the FDA’s fault. The FDA is eager to approve new pain drugs that meet its standards, but drug companies are largely not stepping up to the plate.
That’s too bad. With the last 3 FDA-approved drugs (Lyrica-2007, Cymbalta-2008, and Savella-2009) producing “strikingly modest” effects, FM patients are surely ready to try a new approach. One large study reported that “only a minority of fibromyalgia patients continue taking medications for more than a short period of time due to either lack of efficacy, side effects, or both.” Even though long-term opioid use carries substantial risks and is not a good solution for many, Lederman noted that their research indicates that many doctors have turned to them, not the FDA-approved drugs, to treat fibromyalgia patients.
Getting a drug approved by the FDA, particularly if you’re a small drug company, is not for the faint of heart. Check out some recent examples in the FM and ME/CFS fields.
Tomnya reduces pain by helping people with fibromyalgia achieve deeper sleep.
It took 15 years, but a 4th drug called Tonmya has been approved to treat fibromyalgia in the U.S. With the three other FDA-approved drugs (Lyrica, Cymbalta, and Savella) producing “strikingly modest” results and most patients choosing not to continue with them, the FM community was past due for a new treatment option.

• Tonix Pharmaceuticals is a small drug company, and its achievement was remarkable given the travails it went through and the inability of other drug companies (one very large) to bring their FM drugs to market.
• Tonix had to endure two failed major trials – one because the dose was too small and one because of the COVID pandemic, but persisted, and with the last two trials coming in with good numbers, the drug was approved on August 15th.
• Tonmya is nothing like the past FDA-approved drugs (an anticonvulsant and two antidepressants with pain-reducing qualities). An updated, sublingual form of Flexeril (cyclobenzaprine), which is primarily used as a muscle relaxant, Tonmya is being used by Tonix as a sleep drug.
• Tomnya shoots the drug straight into the body, thereby increasing its bioavailability and efficiency, and bypassing the toxicity problems that were relegating Flexeril to short-term use.
• Tonmya is different from other sleep drugs in that it blocks four receptors associated with increased alertness. Its goal is not to reduce insomnia but to enhance deep sleep in FM.
• It’s not a miracle drug. It will not take your fibromyalgia away, and not everyone with fibromyalgia benefits. Studies in over 1000 people with FM show, though, that Tonmya consistently produces “clinically meaningful”; i.e., clearly noticeable improvements in pain, fatigue, and sleep in the fibromyalgia population at large.
• Side effects are minimal with a very small percentage of participants reporting fatigue, and others reporting temporary sensations such as tingling in the mouth when the dose is taken.
• Tonix will become available in the US in the 4th quarter of this year. Costs and insurance coverage are not yet available. Tonix is only approved in the US but the company hopes to become available in other countries over time.
• Pain specialists were happy to see a new treatment approach become available. Citing the limited and poor treatment options available, Philip Mease, M.D., Director of Rheumatology Research at the Providence Swedish Medical Center, said “Tonmya is a novel treatment approach that targets nonrestorative sleep that… can impact core symptoms, specifically pain.”

_________________________________________________________________________
New Blood Test Shows Over 90% Accuracy for Lyme Disease
Edited by Patricia McKnight
August 22, 2025
A groundbreaking new blood test for Lyme disease is showing remarkable results, with over 90% accuracy across all disease stages, as presented at the 2025 Association for Diagnostics & Laboratory Medicine meeting.
Currently, diagnosing Lyme disease presents significant challenges; while some patients develop a characteristic rash, about 30% don't show this symptom, making early detection difficult.
LymeSeek is an innovative test that simultaneously detects 10 different antigens and uses deep learning algorithms to analyze responses, delivering unprecedented sensitivity and specificity.
The results are impressive: In very early stages, LymeSeek achieved 100% accuracy compared to just 37% with standard testing. Even in posttreatment cases after 6 months, it identified 97% of cases while standard testing caught less than half.
The test is now moving toward FDA clinical trials, potentially revolutionizing how we diagnose and treat Lyme disease across all stages.
This content was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. 
Medscape Medical News © 2025 WebMD, LLC
Cite this: New Blood Test Shows Over 90% Accuracy for Lyme Disease - Medscape - August 22, 2025.
_________________________________________________________________________

Artificial Intelligence Arrives in Long COVID Diagnostic and Treatment Fight

• Solarina Ho       August 26, 2025
• As healthcare systems continue to grapple with identifying and managing long COVID, artificial intelligence (AI) is showing promise as an important tool that could one day expand scientists’ understanding and even lead to new diagnostics for the condition. 
• Three recent studies demonstrated how machine learning and AI algorithms can be leveraged to process vast amounts of complex clinical notes, hospital data, and patient data. All three highlighted how AI could potentially tackle different aspects of long COVID and advance how clinicians identify, track, predict, and treat it.
• Because of the way the SARS-CoV-2 virus binds to human cells, long COVID complications can develop almost anywhere, experts said — from the brain to the heart to the gastrointestinal system — causing upwards of more than 200 symptoms. Many of these symptoms can also be caused by other diseases and conditions, making diagnosis and treatment challenging.
• “That’s hard from a medical point of view, because that’s not typical of how we think of most illnesses that we deal with,” said Fahad Razak, MD, internist at St. Michael’s Hospital and Canada Research Chair in Healthcare Data and Analytics at the University of Toronto in Toronto, Ontario, Canada.
• “Probably all of our data underestimates the real population-level burden of how many people are affected by [long COVID], and I think many people suffer in silence,” he said.
• Three Studies, Three AI Applications
• In a study published in Med, scientists at Mass General Brigham developed a type of AI tool called precision phenotyping to analyze millions of data points from the electronic health records of nearly 300,000 patients across 14 hospitals and 20 community health centers in Massachusetts. The technique identifies and tracks symptoms and conditions linked to COVID-19 to distinguish them from other illnesses.
• Scientists said the tool was nearly 3% more accurate than current diagnostic methods for long COVID. It allows for very detailed and precise analysis of information that could help with the challenging task of diagnosis, ensuring patients receive appropriate care. It is an example of AI’s ability to synthesize, curate, and sift through enormous volumes of information.
• The system only considers long COVID if the symptoms cannot be explained by anything else in the patient’s medical history. After exhausting all other possibilities, the tool flagged about 22.8% of cases as long COVID.
• “It’s been really, really challenging to define and diagnose long COVID. One of the reasons is because its symptoms are very heterogeneous, overlapping with many things,” said co-author Hossein Estiri, PhD, head of AI research at the Center for AI and Biomedical Informatics of the Learning Healthcare System at Mass General Brigham and associate professor of medicine at Harvard Medical School, Boston.
• “The more we can find innovative ways of using AI to address these complex, evolving phenotypes, the better,” he said.
• The algorithm is already public and is packaged in a software tool that can be implemented in different institutions across the US and internationally, according to Estiri, adding that the center is looking for more institutions to participate. At this stage, it is helping to advance research designed to better understand the condition through larger sample sizes and flag potential patients to enroll in future studies or clinical trials.
• “One of the most difficult things about long COVID is that it can affect almost any organ system, and in many ways, it’s a mimicker of many other illnesses that we have to deal with,” said Razak, who was also the scientific director of the Ontario COVID-19 Science Advisory Table and coauthored dozens of papers that shaped the policy, public health, and clinical response to the pandemic. “This is an interesting example where AI could do something much more efficiently than any of us, individually, clinically could do.”
• Data Sharing for Local Decision-Making
• At the University of Pennsylvania’s Perelman School of Medicine, Philadelphia, researchers used a machine learning technique called latent transfer learning to gain a clearer picture of the specific healthcare burdens of long COVID among pediatric patients in different hospitals. The technique, which boosts statistical precision by analyzing information across hospitals, tracked the electronic health records of 432,165 young patients from eight pediatric hospital systems.
• According to a study published in Patterns, researchers found that many patients fell into one of four subgroups: those with mental health conditions like anxiety, depression, and ADHD; those with atopic/allergic conditions, including asthma; those with noncomplex chronic conditions; and those with complex chronic conditions like multisystem disorders. The technique also identified the type of care patients required and the impact these patient groups had on hospitals.
• Long COVID is less common in children than in adults. But it involves a unique and understudied patient population group that is growing, gaining weight, and developing their mental and cognitive understanding of the world, explained co-author of the study, Yong Chen, PhD, professor of biostatistics in the Department of Biostatistics, Epidemiology, and Informatics with the Perelman School of Medicine.
• “The number one message we try to pass is the awareness and the complexity of pediatric long COVID,” said Chen. “It’s extremely complicated in terms of the subtype of long COVID for children and adolescents for the reason that they are highly entangled by their developmental age.” A COVID infection has a nontrivial impact on the digestive system, for example, so how would outcomes be measured without being confounded by a child’s natural growth? Chen explained.
• The transfer learning approach is much more precise because it adaptively incorporates data from other hospitals while accounting for differences in patient populations, hospital staffing, and equipment. Chen and his colleagues advocate for hospitals and health systems to work together and share data to facilitate more personalized care and improve responses to future public health crises.
• “You could start to triage your patients into better categories and different follow-up and management approaches,” said Razak. “The ability to identify that based on complex, many millions of data points of information would greatly enhance clinical care.”
• Predicting Long COVID
• In a much smaller and more limited study, researchers in Italy used three different machine learning approaches to predict with up to 94% accuracy which patients would eventually develop pulmonary long COVID. Clinical data collected early in the pandemic from patients with COVID-19 hospitalized across four different Italian hospitals were analyzed. The different AI methods used in the study illustrated effective strategies for predicting long COVID, the scientists said, even when the patient sample size was small.
• Researchers said these approaches could help healthcare professionals identify which patients were more susceptible to developing long COVID and provide support to mitigate the condition’s long-term impact. It would allow doctors to identify high-risk patients early, allowing a more tailored approach to care and management strategies, and help healthcare providers allocate resources more efficiently.
• Coming to a Hospital Near You?
• Electronic health records make these kinds of insights not only possible but also easy to deploy and almost immediately useful.
• “20 years ago, this information would have been largely unactionable, because most of the healthcare encounters would have been largely pen and paper, handwritten information that cannot be extracted out to use for analytics,” said Razak.
• “What these papers are harnessing is the many billions of dollars of investments that have already occurred within the Canadian and the US healthcare systems to largely digitize the system,” he said.
• Yet experts agree there are important ethical and feasibility constraints in medical AI that need to be addressed before AI can be used broadly in clinical settings.
• “There’s governance, privacy, cost, and technical barriers that I would say are all solvable, but they would take resources and will to do it,” said Razak. He noted that even at St. Michael’s Hospital, where he works — “one of the most data-advanced hospitals in Canada” — there is only one algorithm implemented in its clinical practice.
• Still, these findings are promising and intriguing from a research perspective, and these algorithms may one day help clinicians directly in decision-making on patient care.
• “Could they be implemented in the health system? I think they could be implemented pretty quickly,” said Razak. “Would clinicians know what to do with them to change the way they’re managing clinical care? No, not yet.”
• Medscape Medical News © 2025 WebMD, LLC
  Cite this: Artificial Intelligence Arrives in Long COVID Diagnostic and Treatment Fight - Medscape - August 26, 2025.

_________________________________________________________________________

International Journal of Molecular Sciences
Precision Medicine Study of Post-Exertional Malaise Epigenetic Changes in Myalgic Encephalomyelitis/Chronic Fatigue Patients During Exercise
Sayan Sharma 1,† , Lynette D. Hodges 2,† , Katie Peppercorn 3 , Jemma Davis 3, Christina D. Edgar 3,Euan J. Rodger 1 , Aniruddha Chatterjee 1,* and Warren P. Tate 1,*
1 Department of Pathology and Molecular Medicine, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand; [email protected] (S.S.); [email protected] (E.J.R.)
2 School of Sport, Exercise and Nutrition, College of Health, Massey University, Palmerston North 4410, New Zealand; [email protected]
3 Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand; [email protected] (K.P.); [email protected] (J.D.); [email protected] (C.D.E.)
* Correspondence: [email protected] (A.C.); [email protected] (W.P.T.)
† These authors contributed equally to this work.
Abstract
Post-exertional malaise (PEM) is a defining symptom of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), yet its molecular underpinnings remain elusive. This study investigated the temporal–longitudinal DNA methylation changes associated with PEM using a structured two-day maximum repeated effort cardiopulmonary exercise testing (CPET) protocol involving pre- and two post-exercise blood samplings from five ME/CFS patients. Cardiopulmonary measurements revealed complex heterogeneous profiles among the patients compared to typical healthy controls, and VO2 peak indicated all patients had poor normative fitness. The switch to anaerobic metabolism occurred at a lower workload in some patients on Day Two of the test. Reduced Representation Bisulphite Sequencing followed by analysis with Differential Methylation Analysis Packageversion 2 (DMAP2) identified differentially methylated fragments (DMFs) present in the DNA genomes of all five ME/CFS patients through the exercise test compared with ‘before exercise’. With further filtering for >10% methylation differences, there were early DMFs (0–24 h after first exercise test) and late DMFs between (24–48 h after the second exercise test), as well as DMFs that changed gradually (between 0 and 48 h). Of these, 98% were ME/CFS-specific, compared with the two healthy controls accompanying the longitudinal study. Principal component analysis illustrated the three distinct clusters at the 0 h, 24 h, and 48 h timepoints, but with heterogeneity among the patients within the clusters, highlighting dynamic methylation responses to exertion in individual patients. There were 24 ME/CFS-specific DMFs at gene promoter fragments that
revealed distinct patterns of temporal methylation across the timepoints. Functional enrichment of ME-specific DMFs revealed pathways involved in endothelial function, morphogenesis, inflammation, and immune regulation. These findings uncovered temporally dynamic epigenetic changes in stress/immune functions in ME/CFS during PEM and suggest molecular signatures with potential for diagnosis and of mechanistic significance.
Keywords: ME/CFS; CPET; epigenetics; DNA methylation; post-exertional malaise
Int.

_________________________________________________________________________

Nature  npj metabolic health and disease  Open access  Published: 03 September 2025
Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS
Xiaoyu Che, Amit Ranjan, Cheng Guo, Keming Zhang, Rochelle Goldsmith, Susan Levine, Kegan J. Moneghetti, Yali Zhai, Liner Ge, Nischay Mishra, Mady Hornig, Lucinda Bateman, Nancy G. Klimas, Jose G. Montoya, Daniel L. Peterson, Sabra L. Klein, Oliver Fiehn, Anthony L. Komaroff & W. Ian Lipkin 
npj Metabolic Health and Disease volume 3, Article number: 34 (2025) Cite this article
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue, post-exertional malaise (PEM), and cognitive dysfunction. ME/CFS patients often report a prodrome consistent with infection. We present a multi-omics analysis based on plasma metabolomic and proteomic profiling, and immune responses to microbial stimulation, before and after exercise. We report evidence of an exaggerated innate immune response after exposure to microbial antigens; impaired energy production involving the citric acid cycle, beta-oxidation of fatty acids, and urea cycle energy production from amino acids; systemic inflammation linked to lipid abnormalities; disrupted extracellular matrix homeostasis with release of endogenous ligands that promote inflammation; reduced cell-cell adhesion and associated gut dysbiosis; complement activation; redox imbalance reflected by disturbances in copper-dependent antioxidant pathways; and dysregulation of tryptophan-serotonin-kynurenine pathways. Many abnormalities were worse following exercise and correlated with the intensity of symptoms. Our findings may inform development of targeted therapeutic interventions for ME/CFS and PEM.

_________________________________________________________________________


 J.Psychopharmacol  .2025 Sep 16:2698811251368371.  doi: 10.1177/02698811251368371. Online ahead of print.
Solriamfetol improves daily fatigue symptoms in adults with myalgic encephalomyelitis/chronic fatigue syndrome after 8 weeks of treatment
Joel L Young 1 2 3, Richard N Powell 2, Anna Powell 2, Lisa L M Welling 4, Lauren Granata 2, Jaime Saal 1 2
Affiliations Expand
PMID: 40958377   DOI: 10.1177/02698811251368371
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term illness with no treatment options that address the disease directly. Solriamfetol is a selective dual norepinephrine-dopamine reuptake inhibitor that promotes wakefulness in obstructive sleep apnea and narcolepsy.
Aims: This study evaluated the efficacy and safety of solriamfetol for fatigue symptoms in adults with ME/CFS over 8 weeks of treatment.
Methods: This was a phase 4, double-blind, randomized, placebo-controlled trial of solriamfetol in adults with ME/CFS. Eligible participants (N = 38) were randomly assigned to receive 75 mg (titrated to 150 mg as needed) solriamfetol or placebo. Participants completed a battery of assessments at weekly visits. The primary outcome was Fatigue Symptom Inventory (FSI) scores, and the secondary outcome measure was Behavioral Rating Inventory of Executive Function for Adults (BRIEF-A), at Weeks 6 and 8. T-tests assessed the differences in mean change from baseline between solriamfetol and placebo. Adverse events were monitored throughout the study.
Results: At Week 8 (p = 0.039), but not Week 6 (p = 0.270), solriamfetol improved FSI severity compared to placebo. On the BRIEF-A global executive composite, solriamfetol improved more than placebo at Week 8 (p = 0.012), driven by improved metacognition index (p = 0.004), but not behavioral regulation index (p = 0.574). Solriamfetol was well tolerated, with most common AEs being sleep loss and headaches.
Conclusions: Solriamfetol demonstrated good safety and efficacy in improving fatigue and executive functioning in patients with ME/CFS. As a dual norepinephrine-dopamine reuptake inhibitor and wakefulness-promoting factors, solriamfetol has the potential to improve fatigue symptoms of ME/CFS.
Clinical trial number: NCT04622293.
Keywords: Chronic fatigue syndrome; myalgic encephalomyelitis; solriamfetol; wakefulness.
PubMed Disclaimer

_________________________________________________________________________

SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis
Gepubliceerd op 3 september 2025
Rostami-Afshari, Elremaly, Franco, Elbakry, Akoume, Boufaied, Moezzi, Leveau, Rompré, Godbout, Mella, Fluge & Moreau
Abstract
Background
Sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B) is emerging as a potential biomarker and therapeutic target in myalgic encephalomyelitis (ME), a complex multisystem disorder characterized by immune dysfunction, metabolic disturbances, and persistent fatigue. This study investigates the role of SMPDL3B in ME pathophysiology and explores its clinical relevance.
Methods
A case–control study was conducted in two independent cohorts: a Canadian cohort (249 ME patients, 63 controls) and a Norwegian replication cohort (141 ME patients). Plasma and membrane-bound SMPDL3B levels were quantified using ELISA and flow cytometry. Gene expression of SMPDL3B and PLCXD1, encoding phosphatidylinositol-specific phospholipase C (PI-PLC), was analyzed by qPCR. The effects of dipeptidyl peptidase-4 (DPP-4) inhibitors—vildagliptin, saxagliptin, and linagliptin—on modulation of membrane-bound and soluble SMPDL3B were assessed in vitro by qPCR, flow cytometry and ELISA.
Results
ME patients exhibited significantly elevated plasma SMPDL3B levels, which correlated with symptom severity. Flow cytometry revealed a reduction in membrane-bound SMPDL3B in monocytes, accompanied by increased PLCXD1 expression and elevated plasma levels of PI-PLC and SMPDL3B. These findings suggest that immune dysregulation in ME may be linked to enhanced cleavage of membrane-bound SMPDL3B by PI-PLC. Sex-specific differences were observed, with female ME patients displaying higher plasma SMPDL3B levels, an effect influenced by estrogen. In vitro, estradiol upregulated SMPDL3B expression, indicating hormonal regulation. Vildagliptin and saxagliptin were tested for their potential to inhibit PI-PLC activity independently of their role as DPP-4 inhibitors, and restored membrane-bound SMPDL3B while reduced its soluble form.
Conclusions
SMPDL3B emerges as a key biomarker for ME severity and immune dysregulation, with its activity influenced by hormonal and PI-PLC regulation. The ability of vildagliptin and saxagliptin to preserve membrane-bound SMPDL3B and reduce its soluble form via PI-PLC inhibition suggests a novel therapeutic strategy. These findings warrant clinical trials to evaluate their potential in mitigating immune dysfunction and symptom burden in ME.
Source: Journal of Translational Medicine, open access

_________________________________________________________________________

Meta-analysis of natural killer cell cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome
Gepubliceerd op 15 september 2025
Baraniuk, Eaton-Fitch, Marshall-Gradisnik
Reduced natural killer (NK) cell cytotoxicity is the most consistent immune finding in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Meta-analysis of the published literature determined the effect size of the decrement in ME/CFS.
Databases were screened for papers comparing NK cell cytotoxicity in ME/CFS and healthy controls. A total of 28 papers and 55 effector:target cell ratio (E:T) data points were collected.
Cytotoxicity in ME/CFS was significantly reduced to about half of healthy control levels, with an overall Hedges’ g of 0.96 (0.75–1.18).
Heterogeneity was high but was explained by the range of E:T ratios, different methods, and potential outliers.
Frozen and shipped cells do not retain sufficient cytotoxicity. Whole blood 51Cr assays have the largest effect size, but extrapolating without showing the raw data reduced the information that can be gained. Purified NK cells with E:T of 25:1 and detection by fluorescent cytometry using Annexin V for early and late apoptosis was a reasonable non-radioactive alternative. Hedges’ g and thresholds for ME/CFS and HC % cytotoxicity at various E:T values and different cell sources and methods provide guidelines to diagnose ME/CFS in future studies.
Fresh specimens or new methods will be necessary for NK cell cytotoxicity to become a routine clinical laboratory test for diagnosis. Technical problems related to the assay methods are a limitation that may be overcome by innovative engineering.
Future studies should report NK cell cytotoxicity with subjective common data elements to understand behavioral correlations and investigate interactions with dysfunction of metabolomics, mitochondria, and brain cell function using magnetic resonance imaging (153) in order to gain a better understanding of integrated disease pathophysiology and symptom generation.
NK cells represent a model system to understand molecular mechanisms of disease in ME/CFS and for testing potential drugs in vitro for efficacy before human clinical trials. The effect sizes calculated here may allow improved design for future studies of deficient NK cell cytotoxicity in ME/CFS.
The outcomes confirm reproducible NK cell dysfunction in ME/CFS and will guide studies using the NK cell model system for pathomechanistic investigations.
NK cells from ME/CFS subjects have significantly lower cytotoxicity than control subjects. The reduction in K562 cell killing by fresh NK cells remains one of the most promising potential biomarkers for ME/CFS.
Source: Frontiers, open access
_________________________________________________________________________

Patient-reported treatment outcomes in ME/CFS and long COVID
Gepubliceerd op 10 september 2025
Eckey, Peng Li, Morrison, Bergquist, Davis, Wenzhong Xiao
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are persistent multisystem illnesses affecting many patients. With no known effective FDA-approved treatments for either condition, patient-reported outcomes of treatments may prove helpful in identifying management strategies that can improve patient care and generate new avenues for research.
Here, we present the results of an ME/CFS and long COVID treatment survey with responses from 3,925 patients. We assess the experiences of these patients with more than 150 treatments in conjunction with their demographics, symptoms, and comorbidities.
Treatments with the greatest perceived benefits are identified. Patients with each condition who participated in the study shared similar symptom profiles, including all the core symptoms of ME/CFS, e.g., 89.7% of ME/CFS and 79.4% of long COVID reported postexertional malaise (PEM).
Furthermore, treatment responses between these two patient groups were significantly correlated (R2 = 0.68). Patient subgroups, characterized by distinct symptom profiles and comorbidities, exhibited increased responses to specific treatments, e.g., a POTS-dominant cluster benefiting from autonomic modulators and a cognitive-dysfunction cluster from CNS stimulants.
This study underscores the symptomatic and therapeutic similarities between ME/CFS and long COVID and highlights the commonalities and nuanced complexities of infection-associated chronic diseases and related conditions.
While this study does not provide recommendations for specific therapies, in the absence of approved treatments, insights from patient-reported experiences provide urgently needed real-world evidence for developing targeted patient care therapies and future clinical trials.
Source: PNAS, open access

_________________________________________________________________________


Steroid dynamics in myalgic encephalomyelitis / chronic fatigue syndrome: a case-control study using ultra performance supercritical fluid chromatography tandem mass spectrometry
Gepubliceerd op 24 september 2025
Thomas, Ubhayasekera, Armstrong, Huang & Bergquist
Abstract
Background
Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a multisystem disorder characterised by unrelenting fatigue, post-exertional malaise, and dysfunction across immune, nervous, metabolism, and endocrine systems. Given the broad role of steroid hormones in regulating these systems, this study investigated differences in the steroid metabolome and network dynamics between ME/CFS patients and matched controls.
Methods
Blood plasma steroid levels were quantified using Ultra-Performance Supercritical Fluid Chromatography- Tandem Mass Spectrometry (UPSFC-MS/MS) in ME/CFS patients (n = 24) and age and gender matched controls (n = 24). Group comparisons of absolute steroid concentrations were performed using Mann-Whitney U tests. Partial Spearman correlation networks were evaluated to examine direct associations between steroids within each group, and centrality metrics were used to evaluate structural differences. Steroid-steroid ratios were analysed to reflect biochemical relationships. Multivariate analysis with Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) was also conducted.
Results
No significant group differences in absolute steroid concentrations were observed following FDR correction. However, network analysis revealed a marked reduction in direct steroid-steroid relationships in ME/CFS, with controls exhibiting 52 significant partial correlations, while the ME/CFS group retained only one (cortisol – corticosterone). Centrality analysis further revealed a shift in network structure, with cortisone emerging as highly central in ME/CFS (degree = 7, betweenness = 16.7), despite being peripheral in controls, and progesterone showing reduced integration in ME/CFS (degree = 3 vs. 12, eigenvector = 0.40 vs. 0.93). Steroid-steroid ratio analysis revealed a higher cortisol-to-pregnanolone ratio and a lower pregnanolone-to-progesterone ratio in ME/CFS, although these findings did not remain significant after FDR correction. OPLS-DA indicated a modest relationship between steroid levels and group classification (R²Y = 22.8%), but negative Q² values suggested poor predictive power.
Conclusions
Despite no significant differences in absolute steroid levels, network analysis revealed profound disruptions in steroid-steroid relationships in ME/CFS compared to controls, suggesting disrupted steroid homeostasis. Collectively the results suggest dysregulation of HPA axis function and progestogen pathways, as demonstrated by altered partial correlations, centrality profiles, and steroid ratios. These findings illustrate the importance of hormone network dynamics in ME/CFS pathophysiology and underscores the need for more research into steroid metabolism.
Source: Journal of Translational Medicine, open access

A causal link between autoantibodies and neurological symptoms in long COVID
Keyla Santos Guedes de Sa 1,2,*, Julio Silva 1,2,*, Rafael Bayarri-Olmos 1,2,*, Ryan Brinda 1,2, Robert Alec Rath Constable 1,2, Patricia A Colom Diaz 1,2, Dong-il Kwon 1,2,3, Gisele Rodrigues 1,2, Li Wenxue 2,4, Christopher Baker 1,2, Bornali Bhattacharjee 1,2, Jamie Wood 5, Laura Tabacof 5, Yansheng Liu 2,4, David Putrino 5,†, Tamas L Horvath 6,†, Akiko Iwasaki 1,2,3,†
Author information    Copyright and License information
PMCID: PMC11213106  PMID: 38947091
The complete version history of this preprint is available at medRxiv.
Summary
Acute SARS-CoV-2 infection triggers1 the generation of diverse and functional autoantibodies (AABs), even after mild cases. Persistently elevated autoantibodies have been found in some individuals with long COVID (LC). Using a >21,000 human protein array, we identified diverse AAB targets in LC patients that correlated with their symptoms. Elevated AABs to proteins in the nervous system were found in LC patients with neurocognitive and neurological symptoms. Purified Immunoglobulin G (IgG) samples from these individuals reacted with human pons tissue and were cross-reactive with mouse sciatic nerves, spinal cord, and meninges. Antibody reactivity to sciatic nerves and meninges correlated with patient-reported headache and disorientation. Passive transfer of IgG from patients to mice led to increased sensitivity and pain, mirroring patient-reported symptoms. Similarly, mice injected with IgG showed loss of balance and coordination, reflecting donor-reported dizziness. Our findings suggest that targeting AABs could benefit some LC patients.
Keywords: Autoantibodies, Long COVID, Chronic Pain, SARS-CoV-2

_________________________________________________________________________

Published: 22 April 2025

Unequal access to diagnosis of myalgic encephalomyelitis in England
Gemma Louise Samms & Chris P. Ponting 
BMC Public Health volume 25, Article number: 1417 (2025)  
Abstract
Background
People with Myalgic Encephalomyelitis (ME/CFS; sometimes referred to as chronic fatigue syndrome) experience poor health-related quality of life and only rarely recover. ME/CFS has no curative treatment, and no single diagnostic test. Public health and policy decisions relevant to ME/CFS require knowledge of its prevalence and barriers to diagnosis. However, people with ME/CFS report lengthy diagnostic delays and prevalence estimates vary greatly due to uneven diagnosis and misdiagnosis. Factors that influence diagnosis could be revealed by stratifying a single population by gender, age and ethnicity.
Methods
Hospital Episode Statistics data, routinely collected by the NHS in England, was downloaded from the Feasibility Self-Service of NHS DigiTrials. This was used to stratify individuals with the ICD-10 code that best reflects ME/CFS symptoms (G93.3) according to age, self-reported gender and ethnicity, General Practice and NHS England Integrated Care Board (ICB).
Results
In all, 100,055 people in England had been diagnosed with ME/CFS (ICD-10:G93.3) between April 1 1989 and October 7 2023, 0.16% of all registered patients. Of these, 79,445 were females and 20,590 males, a female-to-male ratio of 3.88:1. Female relative to male prevalence peaked at about 6-to-1 in individuals’ fourth and fifth decades of life. Prevalence varied widely across the 42 ICBs: 0.086%-0.82% for females and 0.024%-0.21% for males. White individuals were approximately fivefold more likely to be diagnosed with ME/CFS than others; Black, Asian or Chinese ethnicities are associated with particularly low rates of ME/CFS diagnoses. This ethnicity bias is stronger than for other common diseases. Among active English GP practices, 176 (3%) had no registered ME/CFS patients. Eight ICBs (19%) each contained fewer than 8 other-than-white individuals with a G93.3 code despite their registers containing a total of 293,770 other-than-white patients.
Conclusion
Other-than-white ethnic groups, older females (> 60y), older males (> 80y), and people living in areas of multiple deprivation are disproportionately undiagnosed with ME/CFS. Lifetime prevalence of ME/CFS for English females and males may be as high as 0.92% and 0.25%, respectively, or approximately 404,000 UK individuals overall (0.6%). This improved estimate of ME/CFS prevalence allows more accurate assessment of the socioeconomic and disease burden imposed by ME/CFS.

​_________________________________________________________________________

Indistinguishable mitochondrial phenotypes after exposure of healthy myoblasts to myalgic encephalomyelitis or control serum
Audrey A. Ryback,   Charles Hillier,  Camila M Loureiro,  Chris P Ponting,   Caroline F Dalton
doi: https://doi.org/10.1101/2025.06.03.657595
This article is a preprint and has not been certified by peer review 
Abstract
Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome is a disease of uncertain aetiology that affects up to 400,000 individuals in the UK. Exposure of cultured cells to the sera of people with ME has been proposed to cause phenotypic changes in these cells in vitro when compared to sera from healthy controls. ME serum factors causing these changes could inform the development of diagnostic tests. In this study, we performed a large-scale, pre-registered replication of an experiment from Fluge et al (2016) that reported an increase in maximal respiratory capacity in healthy myoblasts after treatment with serum from people with ME compared to serum from healthy controls. We replicated the original experiment with a larger sample size, using sera from 67 people with ME and 53 controls to treat healthy cultured myoblasts, and generated results from over 1,700 mitochondrial stress tests performed with a Seahorse Bioanalyser. We observed no significant differences between treatment with ME or healthy control sera for our primary outcome of interest, oxygen consumption rate at maximal respiratory capacity. Results from our study provide strong evidence against the hypothesis that ME blood factors differentially affect healthy myoblast mitochondrial phenotypes in vitro.
Competing Interest Statement
The authors have declared no competing interest.
Funder Information Declared
Action for ME, https://ror.org/0569v7v35, Clare Francis Research Fellowship
bioRxiv and medRxiv thank the following for their generous financial support:
The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam.
Posted June 06, 2025.

​_________________________________________________________________________

Precision phenotyping for curating research cohorts of patients with unexplained post-acute sequelae of COVID-19
Authors: Azhir A, Hügel J, Tian J, Cheng J, Basset IV, Bell DS, … Estiri H (Massachusetts General Hospital, USA)
Name and Date of Publication: Med. 14 March 2025
Link: https://doi.org/10.1016/j.medj.2024.10.009
Easy Read Overview: Scientists studied health records to create a better tool for finding and predicting long COVID (PASC) symptoms, which current methods often miss or get wrong. Their new algorithm works more accurately across different ages, genders, and ethnic groups, even spotting rare symptoms like hearing loss and diabetic issues. It can help doctors diagnose long COVID more fairly and correctly, and the tool is free for use in any healthcare system.
Current diagnostic codes for post-acute sequelae of SARS-CoV-2 (PASC) are often inaccurate, biased across demographics, and underestimate their true prevalence. Similarly, the criteria to predict those most at risk of developing post-acute sequelae of SARS-CoV-2 (PASC) are inadequate. The authors conducted a retrospective longitudinal case-control study to develop a more accurate precision phenotyping algorithm. This tool aims to not only improve diagnosis but also predict the onset, affected systems, and duration of PASC across different demographic groups.
The study analysed the electronic health records (EHR) of three groups: 85,364 confirmed COVID-19 patients (at least one year post-infection), 170,497 post-pandemic individuals without COVID-19, and 39,817 pre-pandemic controls. A Sequential Pattern Mining algorithm, based on WHO’s PASC definition and Clinical Classifications Software, was used to sift through this data. The outputs were independently reviewed and refined.
Compared to the International Classification of Diseases U09.9 diagnosis code, the new algorithm achieved 79.9% diagnostic precision—an improvement of 2.7%—and more accurately estimated community prevalence. It effectively excluded false positives (due to pre-existing conditions) and identified false negatives (conditions misdiagnosed, but linked to prior COVID-19). The breadth of data allowed the algorithm to detect rarer sequelae beyond common symptoms like fatigue or sleep issues, including vision and hearing loss, diabetic complications, and sexual dysfunction.
The algorithm also provided a more balanced demographic analysis, which allowed for better analysis of which sequelae are more common based on age, gender, and ethnicity. For example, those under 45 were more likely to develop gynaecological, dermatological, or psychiatric sequelae; women had higher odds of PASC in certain organs; Asian and Hispanic patients had lower PASC risk; while Black patients faced higher risk regardless of age or health status.
The authors emphasise that their algorithm aligns with the National Academies of Sciences, Engineering, and Medicine’s (NASEM) newly proposed broad definition of PASC as an infection-associated chronic condition (IACC). They have made their tools and data publicly available for integration into any healthcare system.
_________________________________________________________________________

Comparative Study Between Cognitive Phenotypes of Myalgic Encephalomyelitis /Chronic Fatigue Syndrome and Multiple Sclerosis
Authors: Sebaiti MA, Oubaya N, Gounden Y, Samson C, Lechapt E, Wahab A … & Authier F-J (Paris-East Creteil University, France)
Name and Date of Publication: Diagnostics. 17 February, 2025
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC11854609/pdf/diagnostics-15-00487.pdf
Easy Read Overview: This study compared thinking and memory problems in people with ME/CFS and multiple sclerosis (MS). It found that both groups had trouble with memory and attention, but people with ME/CFS had more difficulty remembering new information. The results suggest that special brain training could help people with ME/CFS improve their thinking skills.
ME/CFS involves a range of disabling symptoms, with cognitive impairments being one of the most commonly reported. The aim of this study was to identify a specific cognitive profile unique to ME/CFS. Multiple sclerosis (MS) was used as a comparison group due to the overlapping symptoms of pain, cognitive impairment and fatigue.
A retrospective analysis of patient data from the Henri Mondor Hospital in France was undertaken. Data from 40 participants with ME/CFS (Fukuda criteria), and 40 participants with MS (relapsing-remitting) were included in this study. All participants had completed a screening of cognitive function and neuropsychological tests. Neuropsychological tests assessed short and long-term memory, visual and auditory processing, processing speed, executive function, working memory, and planning ability. All participants completed the tests in the same order.
The authors found that both ME/CFS and MS participant groups showed deficits in episodic memory retrieval, visual selective attention, and reading speed. ME/CFS participants were also found to have a lower performance in consolidation processes than MS participants. In both groups, performance on the cognitive tests was not related to levels of fatigue, pain and depression.
The authors conclude that this study highlights the similarities and differences in cognitive profiles of ME/CFS and MS patients. The impairment in consolidation processes shown by ME/CFS participants helps define a specific cognitive phenotype for ME/CFS, especially as this was not correlated with pain, fatigue or depression. The authors suggest that future research, especially with functional imaging, may identify the neurobiological mechanism causing this. The authors also propose that this research can be used to assist the management of ME/CFS, by considering implementing cognitive training with a focus on verbal learning strategies and working memory exercises.
_________________________________________________________________________

Untargeted metabolomics and quantitative analysis of tryptophan metabolites in myalgic encephalomyelitis patients and healthy volunteers: A comparative study using high-resolution mass spectrometry
Authors: Abujrais S, Vallianatou T, and Bergquist J (Uppsala University, Sweden)
Name and Date of Publication: ACS Chemical Neuroscience. September 20, 2024
Link: https://doi.org/10.1021/acschemneuro.4c00444
Easy Read Overview: Researchers studied people with ME/CFS and found changes in how their bodies process tryptophan, a substance important for energy, mood, and the immune system. They found that different patients had different changes, but some common chemical differences were seen in all ME/CFS patients. These results may help doctors find better ways to diagnose and treat ME/CFS in the future.
The tryptophan metabolic pathway has received attention in ME/CFS research due to its involvement in immune function, neurotransmission and energy production. These authors used untargeted metabolomics – scanning a biological sample for a wide range of chemical compounds, without choosing them in advance – as well as targeted analysis of tryptophan and its metabolites, to gain a better understanding of the altered metabolic pathways underlying ME/CFS.
Plasma samples were obtained from  19 patients from Stora Sköndal in Stockholm (ME-SK), and 19 patients from Gottfries Clinic (ME-GC), as well as 24 healthy controls (HC). The 38 ME/CFS patients met three diagnosis criteria – Canadian Consensus Criteria, International Consensus Criteria, and Institute of Medicine (IOM) criteria. A pooled plasma sample was created for quality control (QC). Liquid chromatography-high-resolution mass spectrometry (LC-HRMS) was used for both targeted and untargeted analysis.
Analysis found significant differences between the two ME/CFS cohorts, suggesting the metabolic impact of ME/CFS can vary widely, however, 30 common significantly altered metabolites were identified. The untargeted analysis found dysregulation of quinolinic acid and indoleacetic acid (tryptophan metabolic products), L-adrenaline and S-adenosyl-L-homocysteine (SAH), and the vitamin B3, the arginine-proline and the aspartate-asparagine pathways.
The targeted analysis of tryptophan metabolites and related compounds also identified differences between ME-SK and ME-GC, as well as between ME/CFS and HC. The analysis found significantly altered levels of hypoxanthine, a biomarker for hypoxia, indicative of reduced oxygen extraction in ME/CFS; nicotinamide and riboflavin, which are important in energy production; and phenylalanine, involved in neurotransmission. Significant alteration were also observed in metabolites within the serotonin pathway, which is involved in mood and sleep regulation, and in the kynurenine pathway, which is associated with neurotransmission, inflammation and immune response (with alteration of 3-hydroxyanthranilic acid (3HAA) posing significant health implications). Differences in some metabolites between sex and/or age indicated potential age-related changes, as well as biological differences between male and female ME/CFS presentation.
This study identified several potential biomarkers, as well as potential targets for the treatment of ME/CFS. The authors recommend that further studies, particularly into the kynurenine pathway, use similar sample sizes and analytic methods to avoid discrepancies and to examine the effect of medications, as well as the menstrual cycle, on the metabolites.

_________________________________________________________________________

ME/Chronic fatigue syndrome: The mysterious illness trapping people in their bodies
Authors: Madden-Smith Z
Name and Date of Publication: Re: News. May 12, 2025
Link: https://youtu.be/DsOAq6cs564?si=1Z0kkbLvX9FjAO40
This New Zealand video news story explores the impact of severe ME/CFS on those who live with the condition as well as their carers. It highlights the difficulty getting access to sufficient care in New Zealand and one mother’s solution in setting up a shared care system.
“Someone who is so physically unwell is being treated so poorly, as if they can just snap out of it. I don’t think I can think of another condition that would be treated this way. It just blows my mind,” said researcher Dr Anna Brooks.
“I just don’t think we’ve got to grips with this situation. Why is this not an emergency?” says ME/CFS educator Rose Silvester.
The video runs for 16 minutes and includes some music that may be difficult for some to tolerate.
_________________________________________________________________________

My wife has largely been bedbound for decades. Then our child joined her in isolation
Authors: McCluskey P
Name and Date of Publication: SBS News. 20 May 2025
Link: https://www.sbs.com.au/news/insight/article/toll-of-being-bedbound-with-me-cfs-chronic-fatigue-syndrome/dew0m9ikt
Peter McCluskey is carer for his wife and daughter, who both live with ME/CFS. In this article, he writes about his experience.
“The hardest part of being an ME/CFS carer is witnessing relentless suffering.
The quality of life for those with severe ME/CFS is often compared to that of late-stage cancer. But with this syndrome, the suffering is unending.
I effectively have a front row seat to a misery show that just goes on and on.
Equally challenging is communicating with some health professionals, who dismiss or downplay the illness, leaving carers and patients feeling invalidated and hopeless.
This deepens the isolation of managing this illness alone, amplifying the emotional toll on carers who must constantly advocate against disbelief while supporting their loved ones.”

_________________________________________________________________________

Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest
Braeden T. Charlton ,  Anouk Slaghekke ,  Brent Appelman , Moritz Eggelbusch , Jelle Y. Huijts , Wendy Noort , Paul W. Hendrickse ,  Frank W. Bloemers , elle J. Posthuma ,  Paul van Amstel ,  Richie P. Goulding ,  Hans Degens ,  Richard T. Jaspers ,  Michele van Vugt , Rob CI Wüst
doi:https://doi.org/10.1101/2025.05.02.25326885
This article is a preprint and has not been peer-reviewed This is new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
Abstract
Patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suffer from a reduced exercise capacity, skeletal muscle abnormalities and post-exertional malaise (PEM), where worse symptoms with cognitive or physical exertion. PEM often results in avoidance of physical activity, resulting in a lower aerobic fitness, which may contribute to skeletal muscle abnormalities. Here, we compared whole-body exercise responses and skeletal muscle adaptations after strict 60-day bed rest in healthy people with those in patients with long COVID and ME/CFS, and healthy age- and sex-matched controls. Bed rest altered the respiratory and cardiovascular responses to (sub)maximal exercise, while patients demonstrated respiratory alterations only at submaximal exercise. Bed rest caused muscle atrophy, and the reduced oxidative phosphorylation related to reductions in maximal oxygen uptake. Patients with long COVID and ME/CFS did not have muscle atrophy, but had fewer capillaries and a more glycolytic fibers, none of which were associated with maximal oxygen uptake. While the whole-body aerobic capacity is similar following bed rest compared to patients, the skeletal muscle characteristics differed, suggesting that physical inactivity alone does not explain the lower exercise capacity in long COVID and ME/CFS.
    •    Systrom at the CDC: The ME/CFS Mitochondrial Drug Trial Fails Plus More

• The failure of the mitochondrial drug trial was unfortunate, but the data gained during the trial could help explain a lot about key problems such as fatty acid metabolism in ME/CFS. 
• While the Astellas drug failed, the recent one-off Mestinon study succeeded in increasing energy production (VO2 max) during exercise in ME/CFS patients, apparently by affecting blood flows. In fact, three of the five drugs Systrom reported he uses in ME/CFS affect blood flows in one way or the other. 
• Preload failure – the inability to return normal amounts of blood back to the heart – is the signature invasive exercise finding in ME/CFS – and is also commonly found in POTS and people with small fiber neuropathy. 
• Preload failure is also accompanied by problems with oxygen extraction by the mitochondria and/or right/left shunting of blood away from the muscles. In one, mitochondrial failure is the cause; in the other, blood vessel problems are – and the treatments for each are completely different. 
• While it’s not clear that shunting is present in ME/CFS and long COVID, a fibromyalgia study found evidence that more blood than usual was being shunted into the hands of FM patients and was getting stuck there. Since the hands serve as reservoirs of blood for the rest of the body, getting blood stuck in the hands could negatively affect the blood flows needed for exercise, concentration, etc. 
• While attempts to link small fiber neuropathy to the exercise problems in ME/CFS have thus far failed, more extensive assessments of the small nerve fibers are underway and could yield different results. 
• A trend towards excessive activation of the TRAIL inflammatory pathway, and inflammatory activity, in general, was upregulated in ME/CFS during exercise. Interestingly, Nancy Klimas’s supercomputer studies plucked out a drug called etanercept that knocks down the end of the TRAIL pathway line – a powerful inflammatory cytokine called TNF-a. A case report of a severe long-COVID patient found that drug to be helpful. 

_________________________________________________________________________


medRxiv
 [Preprint]. 2025 Apr 17:2025.04.16.25325949. [Version 1] doi: 10.1101/2025.04.16.25325949
Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection
Silvia Lucena Lage 1,*,†, Katherine Bricker-Holt 1,†, Joseph M Rocco 1, Adam Rupert 2, Frank X Donovan 3, Yevgeniya A Abramzon 3, Settara C Chandrasekharappa 3, Colton McNinch 4, Logan Cook 1, Eduardo Pinheiro Amaral 5, Gabriel Rosenfeld 4, Thomas Dalhuisen 6, Avery Eun 6, Rebecca Hoh 6, Emily Fehrman 6, Jeffrey N Martin 7, Steven G Deeks 6, Timothy J Henrich 6, Michael J Peluso 6, Irini Sereti 1,*
Copyright and License information     PMCID: PMC12047922  PMID: 40321289
The complete version history of this preprint is available at medRxiv.
Abstract
SARS-CoV-2 can cause a variety of post-acute sequelae including Long COVID19 (LC), a complex, multisystem disease characterized by a broad range of symptoms including fatigue, cognitive impairment, and post-exertional malaise. The pathogenesis of LC is incompletely understood. In this study, we performed comprehensive cellular and transcriptional immunometabolic profiling within a cohort that included SARS-CoV-2-naïve controls (NC, N=30) and individuals with prior COVID-19 (~4-months) who fully recovered (RC, N=38) or went on to experience Long COVID symptoms (N=58). Compared to the naïve controls, those with prior COVID-19 demonstrated profound metabolic and immune alterations at the proteomic, cellular, and epigenetic level. Specifically, there was an enrichment in immature monocytes with sustained inflammasome activation and oxidative stress, elevated arachidonic acid levels, decreased tryptophan, and variation in the frequency and phenotype of peripheral T-cells. Those with LC had increased CD8 T-cell senescence and a distinct transcriptional profile within CD4 and CD8 T-cells and monocytes by single cell RNA sequencing. Our findings support a profound and persistent immunometabolic dysfunction that follows SARS-CoV-2 which may form the pathophysiologic substrate for LC. Our findings suggest that trials of therapeutics that help restore immune and metabolic homeostasis may be warranted to prevent, reduce, or resolve LC symptoms.
Keywords: post-acute sequelae of SARS-CoV-2, COVID-19, Long COVID, inflammation, metabolism, immunosenescence
_________________________________________________________________________

Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest
 View ORCID ProfileBraeden T. Charlton , View ORCID ProfileAnouk Slaghekke , View ORCID ProfileBrent Appelman , View ORCID ProfileMoritz Eggelbusch , Jelle Y. Huijts , View ORCID ProfileWendy Noort , View ORCID ProfilePaul W. Hendrickse , View ORCID ProfileFrank W. Bloemers , View ORCID ProfileJelle J. Posthuma , View ORCID ProfilePaul van Amstel , View ORCID ProfileRichie P. Goulding , View ORCID ProfileHans Degens , View ORCID ProfileRichard T. Jaspers , View ORCID ProfileMichele van Vugt , View ORCID ProfileRob CI Wüst
doi:https://doi.org/10.1101/2025.05.02.25326885
This article is a pre-print.  It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
Abstract
Patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suffer from a reduced exercise capacity, skeletal muscle abnormalities and post-exertional malaise (PEM), where worse symptoms with cognitive or physical exertion. PEM often results in avoidance of physical activity, resulting in a lower aerobic fitness, which may contribute to skeletal muscle abnormalities. Here, we compared whole-body exercise responses and skeletal muscle adaptations after strict 60-day bed rest in healthy people with those in patients with long COVID and ME/CFS, and healthy age- and sex-matched controls. Bed rest altered the respiratory and cardiovascular responses to (sub)maximal exercise, while patients demonstrated respiratory alterations only at submaximal exercise. Bed rest caused muscle atrophy, and the reduced oxidative phosphorylation related to reductions in maximal oxygen uptake. Patients with long COVID and ME/CFS did not have muscle atrophy, but had fewer capillaries and a more glycolytic fibers, none of which were associated with maximal oxygen uptake. While the whole-body aerobic capacity is similar following bed rest compared to patients, the skeletal muscle characteristics differed, suggesting that physical inactivity alone does not explain the lower exercise capacity in long COVID and ME/CFS.
_________________________________________________________________________

Resource   19 June 2025  Open access    Transparent process
Replicated blood-based biomarkers for myalgic encephalomyelitis not explicable by inactivity
Sjoerd Viktor Beentjes https://orcid.org/0000-0002-7998-4262 [email protected], Artur Miralles Méharon https://orcid.org/0009-0006-7977-3955, Julia Kaczmarczyk, Amanda Cassar, Gemma Louise Samms, Nima S Hejazi, Ava Khamseh https://orcid.org/0000-0001-5203-2205 [email protected], and Chris P Ponting https://orcid.org/0000-0003-0202-7816 [email protected]Author Information
EMBO Mol Med  (2025)  https://doi.org/10.1038/s44321-025-00258-8
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a common female-biased disease. ME/CFS diagnosis is hindered by the absence of biomarkers that are unaffected by patients’ low physical activity level. Our analysis used semi-parametric efficient estimators, an initial Super Learner fit followed by a one-step correction, three mediators, and natural direct and indirect estimands, to decompose the average effect of ME/CFS status on molecular and cellular traits. For this, we used UK Biobank data for up to 1455 ME/CFS cases and 131,303 controls. Hundreds of traits differed significantly between cases and controls, including 116 significant for both female and male cohorts. These were indicative of chronic inflammation, insulin resistance and liver disease. Nine of 14 traits were replicated in the smaller All-of-Us cohort. Results cannot be explained by restricted activity: via an activity mediator, ME/CFS status significantly affected only 1 of 3237 traits. Individuals with post-exertional malaise show stronger biomarker differences. Single traits could not cleanly distinguish cases from controls. Nevertheless, these results keep alive the future ambition of a blood-based biomarker panel for accurate ME/CFS diagnosis.

Doctoral Thesis: Characterising the Electrophysiological Properties of Cells in Health and Disease
July 2, 2025
Dr Krista Clarke is a post-doctoral researcher at the University of Surrey, and was co-funded by ME Research UK and the ME Association to assess the electrical properties of white blood cells in ME/CFS. Krista's thesis has now been published.
Abstract
Dielectrophoresis Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome SARS-CoV-2 PBMC COVID-19 Chondrocyte Diagnosis
Biological cells possess intrinsic electrophysiological properties which are fundamental to cellular function. Changes in cell elctrophysiology can act as a biomarker, for example to indicate transition from healthy to diseased cell states, changes in cell function, or cell differentiation. This thesis presents three studies which used dielectrophoresis (DEPtech 3DEP) and ζ-potential analysis (two fast, label-free, high-throughput, non-invasive, and low-cost tools) to examine the electrophysiological properties of two cell types, peripheral blood mononuclear cells (PBMCs) and chondrocytes, for novel medical applications.
The first study investigated the electrophysiological properties of PBMCs in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); a debilitating disease of unknown pathophysiology with no reliable, validated, and quantitative diagnostic test. The dielectric and ζ-potential response of PBMCs to 1.5-hour hyperosmotic challenge differentiated ME/CFS donors from healthy controls with 81.80% sensitivity and 85.70% specificity. This shows potential as a quantitative diagnostic biomarker
The second study examined whether the electrophysiological properties of PBMCs could act as a correlate of protection to SARS-CoV-2. Cytoplasmic conductivity in unchallenged PBMCs was significantly reduced in donors who had received three SARS-CoV-2 vaccine doses compared with unmatched COVID-19 naïve donors. Stimulation with the receptor binding domain of the SARS-CoV-2 spike protein resulted in significant differences in normalised values of membrane conductance in third-dose vaccinated donors, from COVID-19 naïve and second-dose donors.
The third study investigated chondrocytes, which are used extensively in cell-based cartilage-repair therapies. Chondrocytes rapidly dedifferentiate and become fibroblastic during monolayer cell culture – decreasing the success of reimplantation surgery. Significant changes in chondrocyte electrophysiological properties were observed over time in culture, laying the foundations for the identification of an electrophysiological biomarker that correlates with chondrocytic phenotype, to improve re-implantation outcome.
These studies demonstrate novel applications of dielectrophoresis and ζ-potential analysis – to quantitatively diagnose ME/CFS, identify changes in PBMCs following COVID-exposure, and changes in chondrocyte electrophysiology during dedifferentiation.

______________________________________________________________________

Original Investigation Infectious Diseases
Sex Differences in Long COVID
Dimpy P. Shah, MD, PhD1; Tanayott Thaweethai, PhD2,3; Elizabeth W. Karlson, MD, MS4; et al
JAMA Netw Open     Published Online: January 22, 2025
2025;8;(1):e2455430. doi:10.1001/jamanetworkopen.2024.55430
Key Points
Question  Does the risk of long COVID, or post-COVID condition, differ by sex?
Findings  In this cohort study of 12 276 individuals, females had a significantly higher risk of long COVID compared with males after adjusting for sociodemographic and clinical risk factors. The sex-based difference in long COVID risk was age, pregnancy, and menopause dependent, with the highest risk among females aged 40 to 55 years.
Meaning  These findings highlight the importance of evaluating differences in risk of long COVID after SARS-CoV-2 infection in males and females and of comparing biological mechanisms that may underlie sexually dimorphic long COVID trajectories.
Abstract
Importance  A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain.
Objective  To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection.
Design, Setting, and Participants  This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)–Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection.
Exposure  Self-reported sex (male, female) assigned at birth.
Main Outcomes and Measures  Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity.
Results  Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants.
Conclusions and Relevance  In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.

______________________________________________________________________

Review  Infection         2025 Feb;53(1):1-13.
 doi: 10.1007/s15010-024-02386-8. Epub 2024 Sep 6.
Towards an understanding of physical activity-induced post-exertional malaise: Insights into microvascular alterations and immunometabolic interactions in post-COVID condition and myalgic encephalomyelitis/chronic fatigue syndrome
Simon Haunhorst 1 2, Diana Dudziak 3, Carmen Scheibenbogen 4, Martina Seifert 4 5, Franziska Sotzny 4, Carsten Finke 6, Uta Behrends 7 8 9, Konrad Aden 10 11, Stefan Schreiber 11, Dirk Brockmann 12, Paul Burggraf 13, Wilhelm Bloch 14, Claudia Ellert 15 16, Anuradha Ramoji 17 18, Juergen Popp 17 18, Philipp Reuken 19, Martin Walter 20 21, Andreas Stallmach 19, Christian Puta 22 23 24
PMID: 39240417    PMCID: PMC11825644      DOI: 10.1007/s15010-024-02386-8
Abstract
Background: A considerable number of patients who contracted SARS-CoV-2 are affected by persistent multi-systemic symptoms, referred to as Post-COVID Condition (PCC). Post-exertional malaise (PEM) has been recognized as one of the most frequent manifestations of PCC and is a diagnostic criterion of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Yet, its underlying pathomechanisms remain poorly elucidated.
Purpose and methods: In this review, we describe current evidence indicating that key pathophysiological features of PCC and ME/CFS are involved in physical activity-induced PEM.
Results: Upon physical activity, affected patients exhibit a reduced systemic oxygen extraction and oxidative phosphorylation capacity. Accumulating evidence suggests that these are mediated by dysfunctions in mitochondrial capacities and microcirculation that are maintained by latent immune activation, conjointly impairing peripheral bioenergetics. Aggravating deficits in tissue perfusion and oxygen utilization during activities cause exertional intolerance that are frequently accompanied by tachycardia, dyspnea, early cessation of activity and elicit downstream metabolic effects. The accumulation of molecules such as lactate, reactive oxygen species or prostaglandins might trigger local and systemic immune activation. Subsequent intensification of bioenergetic inflexibilities, muscular ionic disturbances and modulation of central nervous system functions can lead to an exacerbation of existing pathologies and symptoms.
Keywords: ME/CFS; Physical activity; Post COVID condition; Post-exertional malaise; SARS-CoV-2.

______________________________________________________________________

Home | JAMA Pediatrics | New Online      Original Investigation
Characterizing Long COVID Symptoms During Early Childhood
Rachel S. Gross, MD, MS1; Tanayott Thaweethai, PhD2,3; Amy L. Salisbury, PhD4; et al
Published Online: May 27, 2025
2025;179;(7):781-792. doi:10.1001/jamapediatrics.2025.1066
Key Points
Question  Which prolonged symptoms in early childhood are associated with SARS-CoV-2 infection?
Findings  In the Researching COVID to Enhance Recovery (RECOVER)–Pediatrics cohort study including 472 infants/toddlers and 539 preschool-aged children, prolonged symptoms were identified that were more common in young children with infection history than those without. Infants/toddlers (0-2 years) with infection history were more likely to experience trouble sleeping, fussiness, poor appetite, stuffy nose, and cough, and preschool-aged children (3-5 years) were more likely to experience dry cough and daytime tiredness/sleepiness or low energy; empirically derived indices for long COVID research were developed from these symptoms.
Meaning  Results of this cohort study suggest that symptom patterns were distinguishable across infants/toddlers and preschool-aged children, and from previously studied older children and adults.
Abstract
Importance  Recent studies have identified characteristic symptom patterns of long COVID (LC) in adults and children older than 5 years. However, LC remains poorly characterized in early childhood. This knowledge gap limits efforts to identify, care for, and prevent LC in this vulnerable population.
Objectives  To identify symptoms that had the greatest difference in frequency comparing children with a history of SARS-CoV-2 infection to those without, to identify differences in the types of symptoms by age group (infants/toddlers [0-2 years] vs preschool-aged children [3-5 years]), and to derive an index that can be used in research studies to identify young children with LC.
Design, Setting, and Participants  This was a multisite longitudinal cohort study with enrollment from over 30 US health care and community settings, including infants, toddlers, and preschool-aged children with and without SARS-CoV-2 infection history. Study data were analyzed from May to December 2024.
Exposure  SARS-CoV-2 infection.
Main Outcomes and Measures  LC and 41 symptoms among infants/toddlers and 75 symptoms among preschool-aged children.
Results  The study included 472 infants/toddlers (mean [SD] age, 12 [9] months; 278 infected with SARS-CoV-2; 194 uninfected; 234 male [50%]; 73 Black or African American [16%]; 198 Hispanic, Latino, or Spanish [43%]; 242 White [52%]) and 539 preschool-aged children (mean [SD] age, 48 [10] months; 399 infected with SARS-CoV-2; 140 uninfected; 277 female [51%]; 70 Black or African American [13%]; 210 Hispanic, Latino, or Spanish [39%]; 287 White [54%]). The median (IQR) time between first infections and completion of symptom surveys was 318 (198-494) days for infants/toddlers and 520 (330-844) days for preschool-aged children. A research index was derived for each age group based on symptoms most associated with infection history. The index is calculated by summing scores assigned to each prolonged symptom that was present, where higher scores indicate greater magnitude of association with history of SARS-CoV-2 infection: poor appetite (5 points), trouble sleeping (3.5 points), wet cough (3.5 points), dry cough (3 points), and stuffy nose (0.5 points) for infants/toddlers, and daytime tiredness/sleepiness/low energy (6.5 points) and dry cough (3 points) for preschool-aged children. Among infants/toddlers with infection, 40 of 278 (14%) were classified as having probable LC by having an index of at least 4 points. Among preschool-aged children, 61 of 399 (15%) were classified as having probable LC by having an index of at least 3 points. Participants with higher indices often had poorer overall health, lower quality of life, and perceived delays in developmental milestones.
Conclusions and Relevance  This cohort study identified symptom patterns and derived research indices that were distinct between the 2 age groups and differed from those previously identified in older ages, demonstrating the need to characterize LC separately across age ranges.

______________________________________________________________________

Original Investigation Infectious Diseases
Sex Differences in Long COVID
Dimpy P. Shah, MD, PhD1; Tanayott Thaweethai, PhD2,3; Elizabeth W. Karlson, MD, MS4; et al
JAMA Netw Open     Published Online: January 22, 2025
2025;8;(1):e2455430. doi:10.1001/jamanetworkopen.2024.55430
Question  Does the risk of long COVID, or post-COVID condition, differ by sex?
Findings  In this cohort study of 12 276 individuals, females had a significantly higher risk of long COVID compared with males after adjusting for sociodemographic and clinical risk factors. The sex-based difference in long COVID risk was age, pregnancy, and menopause dependent, with the highest risk among females aged 40 to 55 years.
Meaning  These findings highlight the importance of evaluating differences in risk of long COVID after SARS-CoV-2 infection in males and females and of comparing biological mechanisms that may underlie sexually dimorphic long COVID trajectories.
Abstract
Importance  A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain.
Objective  To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection.
Design, Setting, and Participants  This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)–Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection.
Exposure  Self-reported sex (male, female) assigned at birth.
Main Outcomes and Measures  Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity.
Results  Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants.
Conclusions and Relevance  In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.

______________________________________________________________________

The Role of T-Cell Exhaustion as a Driver in the Development of Post-Acute Infection Syndromes: A Literature Review
Willem Gielen1, Mahican Gielen1, Nigel McCracken2, Peter Derek Christian Leutscher1
Abstract
This literature review summarizes recent studies on T cell exhaustion and its role in post-acute infection syndromes (PAIS), including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID. It synthesizes the current evidence on how persistent immune dysfunction contributes to the chronic symptoms seen in these conditions. T cell exhaustion, marked by continuous antigen exposure, diminished effector function, and increased expression of inhibitory receptors such as PD-1, CTLA-4, TIM-3, and TIGIT, is increasingly recognized as a key factor in the pathogenesis of PAIS. Clinical and molecular studies have revealed altered T cell populations, impaired proliferative responses, and metabolic dysregulation in affected patients. Persistent viral antigens are implicated in maintaining this exhausted state, whereas neuroimmune interactions and autoimmune processes may further sustain symptomatology. Although this review did not employ a formal systematic methodology, it integrated findings from multiple studies to provide a comprehensive overview of the field. Challenges remain regarding standardized diagnostic criteria and biomarkers; however, advances in immune exhaustion markers present the potential for improved diagnosis and targeted treatments. Emerging therapeutic approaches include immune checkpoint modulation, metabolic interventions, antiviral therapy, and immunomodulation. Further research is needed to clarify the mechanisms, validate the biomarkers, and develop effective clinical interventions. Recognizing T cell exhaustion as a central mechanism offers a foundation for advancing our understanding and management of PAIS.
Correspondence: [email protected] — Qeios will forward to the authors

______________________________________________________________________

Patient-reported treatment outcomes in ME/CFS and long COVID
Martha Eckey, Peng Li, Braxton Morrison, +2 , and Wenzhong Xiao [email protected]Authors Info & Affiliations
Contributed by Ronald Davis; received December 24, 2024; accepted April 7, 2025; reviewed by Lucinda Bateman and Lewis E. Kazis
July 8, 2025     122 (28) e2426874122   https://doi.org/10.1073/pnas.2426874122
Significance
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are debilitating conditions that currently lack FDA-approved treatments. This study analyzes patient-reported outcomes from over 3,900 individuals, identifying treatments perceived as beneficial and uncovering symptom-based patient subgroups with distinct responses to therapies. Notably, there is significant overlap in the symptom profiles and treatment responses between ME/CFS and long COVID, suggesting that they may share underlying mechanisms. These findings offer valuable real-world insights for patients and their healthcare providers and help identify promising candidates for clinical trials, addressing an urgent need for effective therapies in these chronic illnesses.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are persistent multisystem illnesses affecting many patients. With no known effective FDA-approved treatments for either condition, patient-reported outcomes of treatments may prove helpful in identifying management strategies that can improve patient care and generate new avenues for research. Here, we present the results of an ME/CFS and long COVID treatment survey with responses from 3,925 patients. We assess the experiences of these patients with more than 150 treatments in conjunction with their demographics, symptoms, and comorbidities. Treatments with the greatest perceived benefits are identified. Patients with each condition who participated in the study shared similar symptom profiles, including all the core symptoms of ME/CFS, e.g., 89.7% of ME/CFS and 79.4% of long COVID reported postexertional malaise (PEM). Furthermore, treatment responses between these two patient groups were significantly correlated (R2 = 0.68). Patient subgroups, characterized by distinct symptom profiles and comorbidities, exhibited increased responses to specific treatments, e.g., a POTS-dominant cluster benefiting from autonomic modulators and a cognitive-dysfunction cluster from CNS stimulants. This study underscores the symptomatic and therapeutic similarities between ME/CFS and long COVID and highlights the commonalities and nuanced complexities of infection-associated chronic diseases and related conditions. While this study does not provide recommendations for specific therapies, in the absence of approved treatments, insights from patient-reported experiences provide urgently needed real-world evidence for developing targeted patient care therapies and future clinical trials.

______________________________________________________________________

Defective peripheral B cell tolerance leads to dysregulated B cell responses in Fibromyalgia Syndrome
Rachael Bashford-Rogers, Alexander Long, Antonio Choi Chiu, Orthi Onupom, and 8 more
This is a preprint; it has not been peer reviewed by a journal.
https://doi.org/10.21203/rs.3.rs-6836742/v1
This work is licensed under a CC BY 4.0 License
Abstract
Fibromyalgia syndrome (FMS) is a chronic pain disorder characterised by widespread musculoskeletal pain, fatigue, and cognitive dysfunction, with no definitive biomarkers or mechanism-based treatments. Emerging evidence suggests that immune dysregulation may contribute to the FMS pathogenesis, particularly involving B cells, which have been implicated in autoantibody production and neuronal sensitisation. However, whether peripheral B cell tolerance, a critical safeguard against autoimmunity, is compromised in FMS remains unknown. Here, we combined high-resolution B cell receptor (BCR) repertoire sequencing, deep immunophenotyping, and functional assays in a well-characterised FMS cohort to uncover profound defects in peripheral B cell tolerance. We reveal significant defects in peripheral B cell tolerance in FMS, including: (1) impaired naïve B cell anergy, marked by elevated CD21, CD22, and CD24 expression; (2) exaggerated proliferative responses and rapid CD24 downregulation upon stimulation; and (3) altered BCR selection patterns, with increased IGHV6-1/IGHJ6 usage, skewed class switching toward IGHA1, and enhanced clonal expansion. These features closely resemble immune pathology profiles observed in classical autoimmune diseases. These findings redefine FMS as a disorder of immune dysregulation, with defective B cell tolerance contributing to disease mechanisms. The convergence of interferon-driven B cell activation, clonal expansion, and autoantibody production suggests shared pathways with classical autoimmune diseases. Our study provides a foundation for mechanism-based diagnostics and targeted immunomodulatory therapies, offering new avenues for intervention in this debilitating condition.

______________________________________________________________________

Inflammation and Interferon Signatures in Peripheral B-Lymphocytes and Sera of Individuals With Fibromyalgia
Serena Fineschi 1 2, Joakim Klar 3, Kristin Ayoola Gustafsson 3, Kent Jonsson 2 4, Bo Karlsson 2, Niklas Dahl 3
Abstract
Fibromyalgia (FM) is an idiopathic chronic disease characterized by widespread musculoskeletal pain, hyperalgesia and allodynia, often accompanied by fatigue, cognitive dysfunction and other symptoms. Autoimmunity and neuroinflammatory mechanisms have been suggested to play important roles in the pathophysiology of FM supported by recently identified interferon signatures in affected individuals. However, the contribution of different components in the immune system, such as the B-lymphocytes, in the progression to FM are yet unknown. Furthermore, there is a great need for biomarkers that may improve diagnostics of FM. Herein, we investigated the gene expression profile in peripheral B-cells, as well as a panel of inflammatory serum proteins, in 30 FM patients and 23 healthy matched control individuals. RNA sequence analysis revealed 60 differentially expressed genes when comparing the two groups. The group of FM patients showed increased expression of twenty-five interferon-regulated genes, such as S100A8 and S100A9, VCAM, CD163, SERPINA1, ANXA1, and an increased interferon score. Furthermore, FM was associated with elevated levels of 19 inflammatory serum proteins, such as IL8, AXIN1, SIRT2 and STAMBP, that correlated with the FM severity score. Together, the results shows that FM is associated with an interferon signature in B-cells and increased levels of a set of inflammatory serum proteins. Our findings bring further support for immune activation in the pathogenesis of FM and highlight candidate biomarkers for diagnosis and intervention in the management of FM.
Keywords: B-lymphocytes; RNA sequencing; fatigue; fibromyalgia; fibromyalgia score; inflammation; inflammatory proteins; interferon signature.

______________________________________________________________________

Patient-reported treatment outcomes in ME/CFS and long COVID
Martha Eckey, Peng Li, Braxton Morrison, and Wenzhong Xiao [email protected]Authors Info & Affiliations
Contributed by Ronald Davis; received December 24, 2024; accepted April 7, 2025; reviewed by Lucinda Bateman and Lewis E. Kazis
July 8, 2025  122 (28) e2426874122  https://doi.org/10.1073/pnas.2426874122
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are debilitating conditions that currently lack FDA-approved treatments. This study analyzes patient-reported outcomes from over 3,900 individuals, identifying treatments perceived as beneficial and uncovering symptom-based patient subgroups with distinct responses to therapies. Notably, there is significant overlap in the symptom profiles and treatment responses between ME/CFS and long COVID, suggesting that they may share underlying mechanisms. These findings offer valuable real-world insights for patients and their healthcare providers and help identify promising candidates for clinical trials, addressing an urgent need for effective therapies in these chronic illnesses.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are persistent multisystem illnesses affecting many patients. With no known effective FDA-approved treatments for either condition, patient-reported outcomes of treatments may prove helpful in identifying management strategies that can improve patient care and generate new avenues for research. Here, we present the results of an ME/CFS and long COVID treatment survey with responses from 3,925 patients. We assess the experiences of these patients with more than 150 treatments in conjunction with their demographics, symptoms, and comorbidities. Treatments with the greatest perceived benefits are identified. Patients with each condition who participated in the study shared similar symptom profiles, including all the core symptoms of ME/CFS, e.g., 89.7% of ME/CFS and 79.4% of long COVID reported postexertional malaise (PEM). Furthermore, treatment responses between these two patient groups were significantly correlated (R2 = 0.68). Patient subgroups, characterized by distinct symptom profiles and comorbidities, exhibited increased responses to specific treatments, e.g., a POTS-dominant cluster benefiting from autonomic modulators and a cognitive-dysfunction cluster from CNS stimulants. This study underscores the symptomatic and therapeutic similarities between ME/CFS and long COVID and highlights the commonalities and nuanced complexities of infection-associated chronic diseases and related conditions. While this study does not provide recommendations for specific therapies, in the absence of approved treatments, insights from patient-reported experiences provide urgently needed real-world evidence for developing targeted patient care therapies and future clinical trials.

______________________________________________________________________

Long COVID Gene Variants: A Step Toward a Diagnostic Test?
Solarina Ho  July 23, 2025
A large-scale global study has identified genetic variants that are risk factors for long COVID, a discovery that helps researchers better understand the biological systems involving the disease and one small, early step toward the elusive goal of developing a long COVID diagnostic test.
International researchers with the Long COVID Host Genetics Initiative used data from 33 independent studies and 19 countries across North America, Europe, the Middle East, and Asia to analyze the genomes of nearly 16,000 patients with long COVID, representing populations from six genetic ancestries. Nearly 1.9 million controls were included in the genome-wide association study, a research method that scans complete sets of DNA to identify genetic variations associated with a specific trait or disease.
Genetic variants found in the FOXP4 gene had a statistically significant risk linked to long COVID, the study, published in Nature Genetics, found. The FOXP4 gene is known to impact lung function, and its expression levels were higher in those with long COVID than in controls. In addition, the risk variants had a consistent effect across different ancestries. 
The researchers also found a causal relationship between a SARS-CoV-2 infection and long COVID and an additional causal risk between infections severe enough to require hospitalization and long COVID. Researchers also analyzed possible connections between variants associated with long COVID and those linked to other diseases and conditions. 
Scientists said the overall findings provided evidence that was consistent with long COVID research that suggests both individual genetic variants and environmental risk factors contribute to disease risk. The findings also provide genetic proof linking abnormal lung physiology and the development of long COVID, the authors concluded; however, they noted that long COVID symptoms are not only limited to lung function and may include fatigue and cognitive dysfunction as well.
The study’s co-author, Hanna Ollila, PhD, with the Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland, underscored that the newly discovered genetic variants were not predictive for clinical tests or personal disease risk.
“The findings from our study, and from genome-wide association studies in general, tell about biological mechanisms behind a disease. This can then help to understand the disease better. For example, is it a disease neuronal, immune, metabolic, and so on?” said Ollila, who is also a researcher with the Department of Anesthesia and Center for Genomic Medicine at Massachusetts General Hospital, Boston. There are still many steps between these types of discoveries and the development of a diagnostic test, she explained, since these types of genetic variants do not function like high-impact variants such as the BRCA mutations in breast cancer.
“In other words, they do not strongly predict whether someone will develop long COVID at the individual level,” Ollila said. “Instead, they highlight the biological systems involved in the disease. In this case, our findings point to immune pathways related to lung function.”
Ollila explained that genetics can guide diagnostic development by pointing to underlying mechanisms, which may then help identify biomarkers in blood or other tissues. These biomarkers could eventually contribute to diagnostic tools, but it is a process that takes time and collaboration and often depends on progress across several fields of research including imaging and clinical phenotyping.
Researchers hope that when larger sample sizes become available for bigger studies, the analyses and understanding of the correlations will become more precise, bringing more understanding and clarity on genetic risk factors, biological mechanisms, and biomarkers that could someday help with disease diagnosis. 
“We are likely still several years away, and possibly even a decade or more, from having a clinically useful diagnostic test based on genetic or biological markers for long COVID,” said Ollila. “That said, progress is accelerating thanks to the growing number of well-characterized cohorts and international collaborations. While these genetic findings are not yet ready for clinical application, they are an important step toward understanding long COVID, its relationship with other diseases, and the disease mechanisms that modulate risk for long COVID.”
Andreas Goebel a,b,*PMCID: PMC12226001  PMID: 40612406

______________________________________________________________________

Either the majority or all patients with severe fibromyalgia syndrome harbour proalgetic serum-immunoglobulin G autoantibodies; their possible relevance for patients must now be established through clinical trials.
Keywords: Fibromyalgia syndrome, FMS, Autoimmunity, Passive transfer, immunoglobulin
Abstract
Assessments of serum-autoantibodies in fibromyalgia syndrome (FMS) date back to the 1980s and have yielded inconsistent results. Based on a new passive transfer paradigm, since 2021 causative involvement of immunoglobulin G–mediated autoimmunity in severe FMS has been demonstrated in several studies, which have included UK, Swedish, and Canadian patients. These findings open the path to the development of novel diagnostic and immune-therapeutic approaches. Autoantibody targets and downstream mechanisms and the molecular processes that translate infection-, toxicity-, or stress-triggers into the FMS immune response in genetically or otherwise vulnerable individuals require study. These results in FMS also suggest that other chronic pain conditions or nonpainful symptom-based disorders may similarly be caused by noninflammatory minimally destructive autoantibody-mediated autoimmunity, thus offering hope for large groups of patients.
1. Background
Abnormal serum autoantibody titres in fibromyalgia syndrome (FMS) have been investigated at least as far back as the 1980s when Dinerman et al.16 reported the possible existence of a FMS subgroup without rheumatological comorbidity but with seropositivity for antinuclear antibodies (ANAs). The authors suggested that this finding may indicate involvement of autoimmune mechanisms. Since then, small studies have identified raised titres of various autoantibodies, potentially indicating abnormal immune activation or autoimmunity, although other studies were negative, and no consistent patterns have emerged.1,4,5,7,10,13,17,20,28,29,31,33,37–41,45–47,49–51,57,60 This evidence indicates that FMS is sometimes associated with mildly raised titres of specific immunoglobulin G (IgG) autoantibodies; furthermore, antibody-positivity is occasionally associated with an retrospectively identified FMS subgroup. The underpinning conceptual framework for these studies has in most cases been that antibody-induced structural or inflammatory change in tissue will induce activation of nociceptive (damage-sensing) nerve fibres, causing pain.
2. Witebsky–Rose postulates
In 1957, Witebsky et al.58 outlined criteria that can be used to identify a disorder as autoimmune, modelled on the Koch's postulates for the identifications of infectious microbes. A revised version was published 35 years later by one of the original authors, Noel Rose, together with Constantin Bona48 reflecting on advanced understanding of autoimmune mechanisms. Rose and Bona proposed to categorise evidence for autoimmune involvement in disease into (1) direct proof, (2) indirect evidence, and (3) circumstantial evidence.
Very rare direct proof derives from human-to-human transfer of disease such as when a scientist self-injects with plasma from a sick patient, or when pathogenic IgG from a mother is transported across the blood–placental barrier into the unborn child's circulation during the third trimester. Any transfer of serum-IgG purified from patients to experimental animals, which causes the patient phenotype in the animals is considered an alternative form of direct evidence; the authors specifically highlighted the example of serum-IgG transfer from patients with pemphigus to neonatal mice causing typical skin blisters. Sometimes, direct evidence can also derive from in vitro techniques, such as when serum-antibodies purified from patients with paroxysmal cold hemoglobinemia lyse erythrocytes taken from suitable patients.
Methods producing indirect evidence include the immunisation of experimental animals with the pertinent autoantigen, ie, the molecular structure against which the autoimmune response is directed in the human. As with direct proof approaches, these indirect methods are considered successful if they trigger the development of the human phenotype in the animals. Examples for indirect evidence include classical experimental results in myasthenia gravis where immunisation of rabbits with acetylcholine receptors derived from eel causes profound muscle weakness.42 Such methods obviously require that the antigen is known.
Finally, circumstantial evidence involves a favourable patient response to immune suppression. Rose and Bona thought that any such evidence would not provide proof for autoimmune disease, however, should incentivise further research. Several novel immune treatment methods might, however, instead be classed as direct evidence if the Witebsky–Rose criteria were to be revised in the future. Immunoadsorption, which removes serum-antibodies by filtration,6 and treatment with FcRn receptor antagonists,14 a novel class of drugs which reduces serum-antibodies by increasing their metabolism, both specifically target antibodies rather than causing general immune suppression. Such novel treatment technologies have been shown effective in several autoantibody-associated disorders, including myasthenia gravis.27 They differ from immune-suppressive approaches with very broad immune modifying effects known at the time of publication of the Witebsky–Rose criteria.

______________________________________________________________________

Defective peripheral B cell tolerance leads to dysregulated B cell responses in Fibromyalgia Syndrome
Rachael Bashford-Rogers, Alexander Long, Antonio Choi Chiu, Orthi Onupom, and 8 more
This is a preprint; it has not been peer reviewed by a journal.
https://doi.org/10.21203/rs.3.rs-6836742/v1
This work is licensed under a CC BY 4.0 License
Abstract
Fibromyalgia syndrome (FMS) is a chronic pain disorder characterised by widespread musculoskeletal pain, fatigue, and cognitive dysfunction, with no definitive biomarkers or mechanism-based treatments. Emerging evidence suggests that immune dysregulation may contribute to the FMS pathogenesis, particularly involving B cells, which have been implicated in autoantibody production and neuronal sensitisation. However, whether peripheral B cell tolerance, a critical safeguard against autoimmunity, is compromised in FMS remains unknown. Here, we combined high-resolution B cell receptor (BCR) repertoire sequencing, deep immunophenotyping, and functional assays in a well-characterised FMS cohort to uncover profound defects in peripheral B cell tolerance. We reveal significant defects in peripheral B cell tolerance in FMS, including: (1) impaired naïve B cell anergy, marked by elevated CD21, CD22, and CD24 expression; (2) exaggerated proliferative responses and rapid CD24 downregulation upon stimulation; and (3) altered BCR selection patterns, with increased IGHV6-1/IGHJ6 usage, skewed class switching toward IGHA1, and enhanced clonal expansion. These features closely resemble immune pathology profiles observed in classical autoimmune diseases. These findings redefine FMS as a disorder of immune dysregulation, with defective B cell tolerance contributing to disease mechanisms. The convergence of interferon-driven B cell activation, clonal expansion, and autoantibody production suggests shared pathways with classical autoimmune diseases. Our study provides a foundation for mechanism-based diagnostics and targeted immunomodulatory therapies, offering new avenues for intervention in this debilitating condition.

______________________________________________________________________

The sensitising effect of IgG in fibromyalgia syndrome is mediated by Mrgprb2 in mast cells
Karla R. Sanchez, Jamie Burgess, Qin Zheng, Uazman Alam, Harvey Neiland, Richard Berwick, 
David Andersson, Samantha Korver, Anne Marshall, Andreas Goebel, Xinzhong Dong
doi: https://doi.org/10.1101/2025.05.15.652596
This article is a preprint and has not been certified by peer review 
Abstract
Fibromyalgia syndrome (FMS) is characterized by elevated levels of immunoglobulin G (IgG), altered bowel habits, and increased pain sensitivity, suggesting immune dysregulation, but the exact mechanism remains unclear. Here, we found that FMS-IgG binds to mast cells in a MRGPRX2/b2-dependent manner, leading to mast cell recruitment and IL-6 secretion. Transferring serum-IgG from FMS patients to mice induced FMS-like symptoms and increased skin mast cells, indicating that FMS-IgG acts through mast cell activation. The ablation of mice Mrgprb2 mast cells or deleting Mrgprb2 receptors prevented IgG-induced heightened sensitivity to mechanical and cold stimuli. Stimulating human LAD2 cells with FMS IgG elicited MRGPRX2-dependent IL-6 production. Consistent with mice findings, mast cell density and tryptase levels increased in human FMS skin samples compared to healthy controls. Taken together our results suggests that FMS IgG mediates hypersensitivity via activation of mast cells bearing the MRGPRX2 receptor and that these cells are a potential therapeutic target.
Competing Interest Statement
X.D. is the scientific founder of and consultant for Escient Pharmaceuticals, a pharmaceutical company developing drugs targeting Mrgprs. X.D. collaborates with GlaxoSmithKline (GSK) on Mrgpr-related projects unrelated to this manuscript. Other authors declare no competing interests.
Funder Information Declared
Howard Hughes Medical Institute, https://ror.org/006w34k90
Pain Relief Foundation, https://ror.org/0017mh436
Versus Arthritis, https://ror.org/02jkpm469, 22471
Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
bioRxiv and medRxiv thank the following for their generous financial support:
The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam.
Posted May 16, 2025.

______________________________________________________________________

Sec. Infectious Diseases: Pathogenesis and Therapy
Volume 12 - 2025 | https://doi.org/10.3389/fmed.2025.1607353
Plasma cell targeting with the anti-CD38 antibody daratumumab in myalgic encephalomyelitis/chronic fatigue syndrome—a clinical pilot study
Øystein Fluge1,2*Ingrid Gurvin Rekeland1Kari Sørland1Kine Alme1Kristin Risa1Ove Bruland3Karl Johan Tronstad4Olav Mella1
1The Cancer Clinic, Haukeland University Hospital, Bergen,2Institute of Clinical Sciences, University of Bergen, Bergen, Norway
Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) entails low quality of life for patients and massive societal costs. There is an urgent need for elucidation of disease mechanisms and for rational treatment. Our working hypothesis is that ME/CFS in a subgroup of patients is associated with functional autoantibodies emerging after an infection, and that plasma-cell depletion with transient reductions in serum immunoglobulins will have a beneficial effect on patients’ symptoms.

• Objective: To evaluate feasibility and toxicity of plasma-cell targeting treatment using the subcutaneous anti-CD38 antibody daratumumab (Darzalex®) in moderate to severe ME/CFS, and to assess the clinical course through 12–24 months follow-up after daratumumab intervention.
• Methods: We performed a prospective, open-label pilot trial (EudraCT 2022–000281-18). Ten female patients were enrolled. Following 12 weeks run-in, six patients received four daratumumab injections. The next four patients received four, followed by three additional injections from week 14.
• Results: All planned treatments were administered, and there were no serious adverse events. Four patients had no significant clinical changes. Six patients experienced marked improvement. For all 10 patients, mean SF-36 Physical Function (SF-36 PF) increased from 25.9 to 55.0 at 8–9 months (p = 0.002). DePaul Questionnaire-Short Form (DSQ-SF) symptom scores decreased from 72.3 to 43.1 (p = 0.002). In six responders, mean SF-36 PF increased from 32.2 to 78.3, and DSQ-SF score decreased from 71.1 to 24.3. Five of these six patients had major and sustained improvement with a mean SF-36 PF of 88 (range 80–95) toward end of follow-up. Mean steps per 24 h was 3,359 (range 1,493–6,277) at baseline. At 8–9 months, the mean number of steps was 5,862, and 7,392 in the six responders. All five patients with sustained improvement reached a mean step count above 10,000/24 h for some weeks, and above 15,000 on individual days. Relative reduction of serum IgG levels was 54% in six patients with clinical improvement, and 40% among four with no benefit. Low baseline NK-cell count in blood was significantly associated with lack of clinical response.
• Conclusion: Subcutaneous daratumumab in 10 ME/CFS patients was well tolerated. In six patients, treatment was associated with clinical improvement and concurrent transient reduction of serum IgG levels, indicating important pathomechanistic roles for long-lived plasma cells and functional autoantibodies. No definite conclusions should be drawn before a randomized study has been performed.
• Clinical trial registration: https://euclinicaltrials.eu, Identifier: 2022-000281-18.

______________________________________________________________________

Infectious diseases:  Mitochondrial function is impaired in long COVID patients
Jane Macnaughtan,K-Yin Chau, Ewen Brennan, Marco Toffoli, Antonella Spinazzola, Toby Hillman
Article: 2528167 | Received 25 Sep 2024, Accepted 28 Mar 2025, Published online: 12 Aug 2025 
https://doi.org/10.1080/07853890.2025.2528167 
Abstract
Background
The Long COVID syndrome is a major global health problem, affecting approximately 10–20% of individuals infected with SARS-CoV-2 virus with many remaining symptomatic beyond one year. Fatigue, reduced exercise tolerance and hyperlactataemia on minimal exertion have led to the suggestion of a bioenergetic defect. We hypothesised that mitochondrial dysfunction is a pathological feature in Long COVID cases and would correlate with clinical outcome.
Methods
This prospective, case-controlled, observational study recruited 27 participants with an established diagnosis of Long COVID syndrome from a single tertiary clinic together with 16 age-matched controls aged 25–65 years. Seahorse-based mitochondrial flux analysis and bioenergetics profile of isolated peripheral blood mononuclear cells (PBMCs) was performed and correlated with clinical phenotype.
Findings
Long COVID cases had an increased baseline and ATP-induced oxygen consumption rate with a significant attenuation in tetramethylrhodamine methyl ester perchlorate fluorescence response to oligomycin. Correlations were observed between mitochondrial function and autonomic health, quality of life and time from index infection. Sex-specific differences were also observed.
Interpretation
PBMCs from Long COVID subjects exhibit an exceptional and distinctive change in ATP synthase, as it contributes to the mitochondrial membrane potential rather than using it exclusively to generate ATP. The findings suggest that the enzyme runs both forward and reverse reactions, synthesising and hydrolysing ATP. The correlation of mitochondrial function with clinical phenotype in Long COVID may indicate a causal relationship and warrants further validation in larger scale studies.
Keywords:
ATP synthase, long COVID, mitochondrial dysfunction, peripheral blood mononuclear cells 

______________________________________________________________________

University if Edinburgh
Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome
DecodeME collaboration      Research output: Working paper › Preprint
Abstract
Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, poorly understood disease that has no effective treatments, and has long been underserved by scientific research and national health systems. It is a sex-biased disease towards females that is often triggered by an infection, and its hallmark symptom is post-exertional malaise. People with ME/CFS often report their symptoms being disbelieved. The biological mechanisms causing ME/CFS remain unclear. We recruited 21,620 ME/CFS cases and performed genome-wide association studies (GWAS) for up to 15,579 cases and 259,909 population controls with European genetic ancestry. In these GWAS, we discovered eight loci that are significantly associated with ME/CFS, including three near BTN2A2, OLFM4, and RABGAP1L genes that act in the response to viral or bacterial infection. Four of the eight loci (RABGAP1L, FBXL4, OLFM4, CA10) were associated at p < 0.05 with cases ascertained using post-exertional malaise and fatigue in the UK Biobank and the Netherlands biobank Lifelines. We found no evidence of sex-bias among discovered associations, and replicated in males two genetic signals (ARFGEF2, CA10) discovered in females. The ME/CFS association near CA10 colocalises with a known association to multisite chronic pain. We found no evidence that the eight ME/CFS genetic signals share common causal genetic variants with depression or anxiety. Our findings suggest that both immunological and neurological processes are involved in the genetic risk of ME/CFS.
Original language
English

Publication status
Published - 6 Aug 2025

______________________________________________________________________

An integrative review on the orexin system and hypothalamic dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: implications for precision medicine
             Noé López-Amador *

• Explor Neuroprot Ther. 2025;5:1004112 DOl: https://doi.org/10.37349/ent.2025.1004112
• Received: May 26, 2025 Accepted: July 22, 2025 Published: August 13, 2025
• Academic Editor: Janez Mavri, National Institute of Chemistry, Slovenia
• Abstract
• Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder affecting an estimated 0.4% to 2.5% of community populations. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and marked metabolic heterogeneity underscore its complex pathophysiology. The hypothalamic peptides hypocretin-1 and -2 (also known as orexin-A and orexin-B), synthesized by neurons in the lateral hypothalamus, regulate sleep-wake cycles, arousal, autonomic function, and energy homeostasis. This integrative review aimed to synthesize current evidence on hypothalamic orexinergic dysfunction in ME/CFS and assess its potential as a biomarker framework for stratification in precision medicine. The review followed Whittemore and Knafl’s five-stage methodology. Comprehensive searches were conducted across PubMed, Scopus, Web of Science, and OpenAlex up to April 2025, supplemented by manual screening of reference lists. Data extraction and synthesis were performed using constant comparison techniques to integrate quantitative outcomes with theoretical insights. Twenty-seven studies met the inclusion criteria, consistently reporting reduced orexin-A levels in individuals with ME/CFS and variable orexin-B responses indicative of biomarker potential. Neuroendocrine findings, including alterations in cortisol and adrenocorticotropic hormone levels, along with inflammatory profiles, confirmed the involvement of neuroimmune interactions. Multi-omics analyses further delineated distinct patient subtypes characterized by unique molecular signatures. Hypothalamic orexinergic dysfunction emerges as a central feature of ME/CFS, with orexin-B representing a promising candidate biomarker. The integration of orexin profiling with multi-omics data and machine learning strategies provides a viable pathway towards precision-medicine interventions for this heterogeneous condition.

______________________________________________________________________

Pain Med:. 2025 Jul 8:pnaf089. doi: 10.1093/pm/pnaf089. Online ahead of print
Pain Relief by Targeting Nonrestorative Sleep in Fibromyalgia: A Phase 3 Randomized Trial of Bedtime Sublingual Cyclobenzaprine
Seth Lederman 1, Lesley M Arnold 2, Ben Vaughn 3, Jean M Engels 1, Mary Kelley 1, Gregory M Sullivan 1
PMID: 40627411       DOI: 10.1093/pm/pnaf089
Abstract
Objective: Fibromyalgia is the prototypic nociplastic chronic pain syndrome, characterized by widespread pain, nonrestorative sleep, and fatigue. We evaluated efficacy and safety of bedtime TNX-102 SL (sublingual cyclobenzaprine) 5.6 mg for treatment of fibromyalgia.
Methods: This phase 3, double-blind, multicenter, placebo-controlled trial randomized patients 1:1 to once-nightly TNX-102 SL 2.8 mg for 2 weeks, followed by 5.6 mg for 12 weeks, or to matching placebo (NCT05273749). The primary endpoint was change from baseline at week 14 in weekly average of daily diary pain intensity scores. Secondary endpoints included Patient Global Impression of Change, Fibromyalgia Impact Questionnaire (Revised) Symptoms and Function domains, Patient-Reported Outcomes Measurement Information System instruments for Sleep Disturbance and Fatigue, and daily diary sleep quality scores.
Results: Overall, 81.0% (n = 187/231) and 79.6% (n = 179/225) of patients receiving TNX-102 SL and placebo completed the trial, respectively. Treatment with TNX-102 SL vs placebo was associated with significantly greater reductions in the primary pain endpoint (P < 0.001; mean [SE], -1.8 [0.12] vs -1.2 [0.12]) and in each of the 6 secondary endpoints (P ≤ 0.001; all). The most common systemic treatment-emergent adverse events (TEAEs) with TNX-102 SL and placebo were COVID-19 (4.3% vs 3.1%, respectively), headache (3.0% vs 1.8%), and somnolence (3.0% vs 1.3%); the most common TEAEs overall were local administration-site reactions including oral hypoesthesia (23.4% vs 0.4%), product taste abnormal (11.3% vs 0.9%), and oral paresthesia (6.9% vs 0.9%), which were transient and self-limited.
Conclusion: Bedtime TNX-102 SL treatment was associated with significant improvements in fibromyalgia symptoms and function and was well tolerated.
Keywords: Fibromyalgia; clinical trial; cyclobenzaprine; nociplastic pain; sleep.
© The Author(s) 2025. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.
PubMed Disclaimer
​

Medscape Medical News - February 20, 2025 12 123 
New Five-Type Index Provides Doctors Guide for Long COVID 
David Brzostowicki 
A new analysis of long COVID patients has identified five distinct subtypes that researchers say will help doctors diagnose the condition. The new five-type index, developed by federal researchers with the National Institutes of Health’s RECOVER COVID Initiative, identified the most common symptoms in 14,000 people with long COVID, with data from an additional 4000 people added to the updated 2024 index. By using the index, physicians and researchers can better understand the condition, which is difficult to treat and diagnose because no standard definitions or therapies have been developed. Doctors can use the index to offer more targeted care and help patients manage their symptoms more effectively. The index may also help researchers find more treatments for long COVID. Because long COVID can affect so many different parts of the body, it will take time to fully understand how to treat it, but studies like this are making progress in the right direction, experts said. 
This new index uses an updated point system, where points are allotted to each symptom in a list of the 44 most reported symptoms in people with likely long COVID based on how often they occur. Among people in the study with prior COVID infection, 2213 (18%) met the threshold for long COVID. The 44 most common symptoms were then distributed among five subtypes, with each representing a difference in impact on quality of life and overall health. The most common symptoms were fatigue (85.8%), postexertional malaise (87.4%), and postexertional soreness (75.0%) — where persistent fatigue and discomfort occur after physical or mental exertion — dizziness (65.8%), brain fog (63.8%), gastrointestinal symptoms (59.3%), and palpitations (58%). Advertisement For those with prior COVID infection, symptoms were more prevalent in all cases.
 Subtype 1 Those grouped into subtype 1 did not report a high incidence of impact on quality of life, physical health, or daily function. Only 21% of people in subtype 1 reported a “poor or fair quality of life.” A change in smell or taste — usually a symptom that’s bothersome but doesn’t seriously impact overall health — was most present in subtype 1, with 100% of people in subtype 1 reporting it. 2/22/25, 10:59 AM New Five-Type Index Provides Doctors Guide for Long COVID https://www.medscape.com/viewarticle/new-five-type-index-provides-doctors-guide-long-covid-2025a10004gd?ecd=WNL_mdpls_250221_mscpedit_f… 2/6 The only other symptoms in over 50% of people with subtype 1— which were 490 of the 2213 with prior COVID infection — were fatigue (66%), postexertional malaise (53%), and postexertional soreness (55%). Though these two symptoms can certainly impact quality of life, they became much more prevalent in other subtypes. 
Subtype 2 The prevalence of possibly debilitating symptoms like postexertional malaise (94%), fatigue (81%), and chronic cough (100%) rose dramatically in people grouped into subtype 2. Plus, 25% of people in subtype 2 reported a “poor or fair quality of life. Postexertional malaise, I think, is probably one of the most debilitating of the symptoms. When somebody comes in and tells me that they’re tired and I think they might have long COVID, the first thing I try to do is see if it is postexertional malaise vs just postinfectious fatigue,” said Lisa Sanders, MD, medical director of Yale’s Long Covid Multidisciplinary Care Center in New Haven, Connecticut. Postinfectious fatigue usually resolves much more quickly than postexertional malaise. The latter accounts for several symptoms as also associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a chronic illness that causes severe fatigue and makes it difficult for sufferers to perform routine, daily activities. “Postexertional malaise is an additive symptom of ME/CFS, and that can take a long time to resolve,” Sanders added. The similarity between these two symptoms highlights the importance that physicians must place in scrutinizing symptoms to a high degree when they suspect a patient of having long COVID, experts said. By doing so, clinicians can unveil the mask of overlapping symptoms between long COVID symptoms and symptoms of other illnesses. 
Subtype 3: About 37% of people grouped in subtype 3 reported a poor or fair quality of life, a significant rise from subtypes 1 and 2. 
Fatigue symptoms were reported by 92%, whereas 82% reported postexertional soreness, and 70% reported dizziness. Additionally, 100% of people in subtype 3 reported brain fog as a symptom. Sanders said these symptoms are also common in people with postural orthostatic tachycardia syndrome. This condition results from a reduced volume of blood returning to the heart after standing up, which leads to an abnormally fast heart rate. Palpitations and fainting can then occur. Brain fog can be especially debilitating in people who are used to multitasking. With brain fog, people accustomed to easily alternating between tasks or doing multiple tasks at once can only do one thing at a time. This can cause stress and an overload of thoughts, even precipitating a change in careers if severe enough. Though brain fog tends to resolve within 6-9 months after infection, it can last up to 18 months or more. Experts say doctors should always be on the lookout if a patient complains they have trouble concentrating or multitasking in the months after a COVID infection. A neurological exam and cognitive testing can identify abnormalities in brain function. 
Subtype 4: About 40% of people in the study grouped into subtype 4 reported a poor or fair quality of life, a modest increase from those with subtype 3. About 65% reported symptoms of brain fog and 92% reported palpitations. Dizziness was also prevalent at 71%, whereas 60% reported gastrointestinal issues, and 36% said they experienced fever, sweats, and chills. Nearly 700 of the 2213 people fell into this subtype group, by far the highest number. 
Subtype 5: A whopping 66% of people in subtype 5 reported a poor to fair quality of life. These people usually reported multisystem symptoms. In terms of prevalence rises across the spectrum of 44 common long COVID symptoms, 99% reported shortness of breath; 98%, postexertional soreness; 94%, dizziness; 92%, postexertional malaise; 80%, GI problems; 78%, weakness; and 69%, chest pain. A higher proportion of Hispanic and multiracial participants were classified as having subtype 5. Also, according to the study, “higher proportions of unvaccinated participants and those with SARS-CoV-2 infection before circulation of the Omicron variant were in subtype 5.” This suggests the severity of the Delta variant of COVID-19 be linked to some of the worst long COVID symptoms, but further study would have to be done to conclusively determine may be just a correlation.
 When Do Symptoms Resolve? According to Sanders, around 17 million Americans are thought to have long COVID. Although 90%-100% of people typically recover within 3 years, that still leaves possibly around 5% of those who don’t recover. “What people usually say is, ‘I got COVID, and I never quite recovered,” Sanders said. “Five percent of 17 million turns out to be a lot. It’s a lot of suffering,” she added. “I would say that the most common symptoms are fatigue, brain fog, anosmia or dysgeusia, and sleep disorders,” as evidenced by the high percentage of people in certain subtypes of the study reporting a poor quality of life.

______________________________________________________________________________

Research Article:  Stellate Ganglion Block reduces symptoms of SARS-CoV-2-induced ME/CFS: A prospective cohort pilot study
Deborah L. Duricka & Luke D. Liu
Received 16 Nov 2024, Accepted 16 Jan 2025, Published online: 06 Feb 2025 
https://doi.org/10.1080/21641846.2025.2455876
ABSTRACT
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition characterized by fatigue, orthostatic intolerance (OI), post-exertional malaise (PEM) and unrefreshing sleep. Our previous work has shown that modulating the autonomic nervous system can alleviate symptoms of Long COVID, which shares striking similarities with ME/CFS.
Objective
Determine the effect of stellate ganglion block (SGB) on symptoms of ME/CFS.
Methods
Subjects who met the WHO criteria for Long COVID and the Institute of Medicine criteria for ME/CFS were treated with sequential bilateral SGBs separated by 18–24 hours for three consecutive weeks (n = 10). At baseline, and at 2-weeks and 2-months post-treatment, we collected subjective assessments (SF-36 and DSQ2) of symptoms, objective assessments of orthostatic intolerance and cognitive performance, and saliva to measure morning cortisol. During the entire study period, a wearable device collected physiological data several nights a week to measure sleep parameters.
Results
DSQ2 measures of PEM, Unrefreshing Sleep, Cognitive Impairment, and OI improved significantly following treatment. SF-36 measures of Vitality, Physical Function, and Social Function improved significantly following treatment. Objective symptoms of POTS associated with infectious onset resolved following treatment. Objective measures of cognitive impairment were reduced following treatment, most notably in the areas of Immediate and Delayed Recognition. Morning cortisol and measures of sleep architecture did not change significantly following treatment.
Conclusions
Symptoms of ME/CFS were reduced after treatment with SGBs in this small prospective cohort pilot study. Given the lack of FDA-approved treatments for ME/CFS, replication of results in a large clinical trial is warranted.

______________________________________________________________________________

Oxidative Stress is a shared characteristic of ME/CFS and Long COVID
Vishnu Shankar, Julie Wilhelmy, Ellis J. Curtis, Basil Michael, Layla Cervantes, Vamsee A. Mallajosyula, Ronald W. Davis, Michael Snyder,  View ORCID ProfileShady Younis, William H. Robinson, Sadasivan Shankar, Paul S. Mischel, Hector Bonilla, Mark M. Davis
doi: https://doi.org/10.1101/2024.05.04.592477
This article is a preprint and has not been certified by peer review 
Abstract
More than 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition, wherein patients of all ages report fatigue, post-exertional malaise, and other symptoms resembling myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). With no current treatments or reliable diagnostic markers, there is an urgent need to define the molecular underpinnings of these conditions. By studying bioenergetic characteristics of peripheral blood lymphocytes in over 16 healthy controls, 15 ME/CFS, and 15 LC, we find both ME/CFS and LC donors exhibit signs of elevated oxidative stress, relative to healthy controls, especially in the memory subset. Using a combination of flow cytometry, bulk RNA-seq analysis, mass spectrometry, and systems chemistry analysis, we also observed aberrations in ROS clearance pathways including elevated glutathione levels, decreases in mitochondrial superoxide dismutase levels, and glutathione peroxidase 4 mediated lipid oxidative damage. Critically, these changes in redox pathways show striking sex-specific trends. While females diagnosed with ME/CFS exhibit higher total ROS and mitochondrial calcium levels, males with an ME/CFS diagnosis have normal ROS levels, but larger changes in lipid oxidative damage. Further analyses show that higher ROS levels correlates with hyperproliferation of T cells in females, consistent with the known role of elevated ROS levels in the initiation of proliferation. This hyperproliferation of T cells can be attenuated by metformin, suggesting this FDA-approved drug as a possible treatment, as also suggested by a recent clinical study of LC patients. Thus, we report that both ME/CFS and LC are mechanistically related and could be diagnosed with quantitative blood cell measurements. We also suggest that effective, patient tailored drugs might be discovered using standard lymphocyte stimulation assays.
______________________________________________________________________________

Original Investigation   December 18, 2024
2024 Update of the RECOVER-Adult Long COVID Research Index
Linda N. Geng, MD, PhD1; Kristine M. Erlandson, MD, MSc2; Mady Hornig, MA, MD3,4; et alRebecca Letts, BA5; Caitlin Selvaggi, MS6; Hassan Ashktorab, PhD7; Ornina Atieh, MD8; Logan Bartram, MD9; Hassan Brim, PhD7; Shari B. Brosnahan, MD, MSc10; Jeanette Brown, MD, PhD11; Mario Castro, MD12; Alexander Charney, MD, PhD9; Peter Chen, MD13,14; Steven G. Deeks, MD15; Nathaniel Erdmann, MD, PhD16; Valerie J. Flaherman, MD, MPH17; Maher A. Ghamloush, MD18; Paul Goepfert, MD16; Jason D. Goldman, MD, MPH19; Jenny E. Han, MD, MSc20; Rachel Hess, MD, MS21; Ellie Hirshberg, MD22; Susan E. Hoover, MD23; Stuart D. Katz, MD10; J. Daniel Kelly, MD, PhD15; Jonathan D. Klein, MD, MPH24,25; Jerry A. Krishnan, MD, PhD24,26; Joyce Lee-Iannotti, MD27; Emily B. Levitan, ScD28; Vincent C. Marconi, MD29,30,31; Torri D. Metz, MD, MS32; Matthew E. Modes, MD, MPP, MS33; Janko Ž. Nikolich, MD, PhD34; Richard M. Novak, MD24,26; Igho Ofotokun, MD, MSc29; Megumi J. Okumura, MD, MAS35; Sairam Parthasarathy, MD36; Thomas F. Patterson, MD37; Michael J. Peluso, MD15; Athena Poppas, MD38; Orlando Quintero Cardona, MD39; Jake Scott, MD39; Judd Shellito, MD40; Zaki A. Sherif, PhD7; Nora G. Singer, MD41; Barbara S. Taylor, MD37; Tanayott Thaweethai, PhD6,42; Monica Verduzco-Gutierrez, MD37; Juan Wisnivesky, MD, DrPH9; Grace A. McComsey, MD43; Leora I. Horwitz, MD, MHS10,44; Andrea S. Foulkes, ScD6,42,45; for the RECOVER Consortium
JAMA. 2025;333(8):694-700. doi:10.1001/jama.2024.24184
Podcast (12:18)
2024 Update on Long COVID Classification and Symptom List
Key Points
Question  How do updated data from nearly 4000 additional participants and expanded symptom questionnaires inform the prior research classification for long COVID (LC) or post–COVID-19 condition?
Findings  In this prospective, observational cohort study, data from 13 647 adults participating in the Researching COVID to Enhance Recovery (RECOVER-Adult) study were used to update the research index for classifying symptomatic LC and 5 symptom subtypes that differ in associated demographic features and quality of life.
Meaning  The 2024 LC research index may help researchers identify people with symptomatic LC and its symptom subtypes. Refinement of the index will be needed as research advances and the understanding of LC deepens.
Abstract
Importance  Classification of persons with long COVID (LC) or post–COVID-19 condition must encompass the complexity and heterogeneity of the condition. Iterative refinement of the classification index for research is needed to incorporate newly available data as the field rapidly evolves.
Objective  To update the 2023 research index for adults with LC using additional participant data from the Researching COVID to Enhance Recovery (RECOVER-Adult) study and an expanded symptom list based on input from patient communities.
Design, Setting, and Participants  Prospective, observational cohort study including adults 18 years or older with or without known prior SARS-CoV-2 infection who were enrolled at 83 sites in the US and Puerto Rico. Included participants had at least 1 study visit taking place 4.5 months after first SARS-CoV-2 infection or later, and not within 30 days of a reinfection. The study visits took place between October 2021 and March 2024.
Exposure  SARS-CoV-2 infection.
Main Outcomes and Measures
Presence of LC and participant-reported symptoms.
Results  A total of 13 647 participants (11 743 with known SARS-CoV-2 infection and 1904 without known prior SARS-CoV-2 infection; median age, 45 years [IQR, 34-69 years]; and 73% were female) were included. Using the least absolute shrinkage and selection operator analysis regression approach from the 2023 model, symptoms contributing to the updated 2024 index included postexertional malaise, fatigue, brain fog, dizziness, palpitations, change in smell or taste, thirst, chronic cough, chest pain, shortness of breath, and sleep apnea. For the 2024 LC research index, the optimal threshold to identify participants with highly symptomatic LC was a score of 11 or greater. The 2024 index classified 20% of participants with known prior SARS-CoV-2 infection and 4% of those without known prior SARS-CoV-2 infection as having likely LC (vs 21% and 5%, respectively, using the 2023 index) and 39% of participants with known prior SARS-CoV-2 infection as having possible LC, which is a new category for the 2024 model. Cluster analysis identified 5 LC subtypes that tracked quality-of-life measures.
Conclusions and Relevance  The 2024 LC research index for adults builds on the 2023 index with additional data and symptoms to help researchers classify symptomatic LC and its symptom subtypes. Continued future refinement of the index will be needed as the understanding of LC evolves.

______________________________________________________________________________

Comparative Study Between Cognitive Phenotypes of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Multiple Sclerosis
by Mehdi Aoun Sebaiti, Nadia Oubaya,Yannick Gounden,Chloé Samson,Emmanuele Lechapt,Abir Wahab,Alain Creange,Mathieu Hainselin, and François-Jérôme Authier
CRP-CPO, UR UPJV 7273, Université de Picardie Jules Verne, F-80025 Amiens, France
INSERM, IMRB, Université Paris Est Créteil, F-94010 Créteil, France
Néocortex (Spécialistes de la Neuropsychologie), F-94100 Saint-Maur-des-Fossés, France, Département de Santé Publique, AP-HP, Hôpital Henri-Mondor, F-94010 Créteil, France,AP-HP, Hôpital René Muret, F-93270 Sevran, France,Département de Pathologie, AP-HP, Hôpital Henri Mondor, F-94010 Créteil, France,Service de Neurologie, AP-HP, Hôpital Henri Mondor, F-94010 Créteil, France,UF Centre Expert de Pathologie Neuromusculaire, AP-HP, Hôpital Henri Mondor, F-94010 Créteil, France
Diagnostics 2025, 15(4), 487; https://doi.org/10.3390/diagnostics15040487
Submission received: 3 January 2025 / Revised: 6 February 2025 / Accepted: 12 February 2025 / Published: 17 February 2025
(This article belongs to the Special Issue Assessment and Diagnosis of Cognitive Disorders)
Abstract
Objective: Cognitive impairments are one of the most common and disabling symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here, we address the possibility of a specific cognitive profile inherent to ME/CFS. Due to the occurrence of cognitive deficits, fatigue, and pain in both pathologies, multiple sclerosis (MS) is a relevant comparison model. For this purpose, we carried out a comparative study between cognitive profiles of patients with ME/CFS and patients suffering from MS. Methods: In total, 40 ME/CFS and 40 MS patients were included. A complete screening of all cognitive functions was carried out through an extensive battery of tests routinely used in clinical practice. Results: ME/CFS and MS patients showed deficits in episodic memory retrieval, visual selective attention and reading speed. ME/CFS patients also elicited a lower level of performance than MS patients regarding consolidation. For both groups, levels of performance on these cognitive tests did not correlate with levels of fatigue, pain, and depression. Conclusions: This study highlighted both similarities and differences in the cognitive profiles of ME/CFS and MS patients. While both groups exhibited deficits in episodic memory retrieval, visual selective attention, and reading speed, ME/CFS patients showed distinct impairment in consolidation processes. These cognitive deficits were not correlated with fatigue, pain, or depression, reinforcing the hypothesis of intrinsic cognitive dysfunction in ME/CFS. These findings define a specific cognitive phenotype for ME/CFS, which could improve diagnostic accuracy and therapeutic strategies. Future research, particularly in functional imaging, may elucidate the neurobiological mechanisms underlying these impairments.

______________________________________________________________________________

February 24, 2025
COVID-19 Vaccination and Odds of Post–COVID-19 Condition Symptoms in Children Aged 5 to 17 Years
Anna R. Yousaf, MD1; Josephine Mak, MPH1; Lisa Gwynn, DO, MBA, MSPH2,3; et alKaren Lutrick, PhD4; Robin F. Bloodworth, PhD, MPH5; Ramona P. Rai, MPH5; Zuha Jeddy, MPH5; Lindsay B. LeClair, MS, MPH5; Laura J. Edwards, MPH5; Lauren E.W. Olsho, PhD5; Gabriella Newes-Adeyi, PhD, MPH5; Alexandra F. Dalton, PhD1; Alberto J. Caban-Martinez, DO, PhD, MPH3; Manjusha Gaglani, MBBS6; Sarang K. Yoon, DO, MOH7; Kurt T. Hegmann, MD, MPH7; Andrew L. Phillips, MD, MOH7; Jefferey L. Burgess, MD, MPH, MS8; Katherine D. Ellingson, PhD9; Patrick Rivers, PhD9; Jennifer K. Meece, PhD10; Leora R. Feldstein, PhD1; Harmony L. Tyner, MD, MPH11; Allison Naleway, PhD12; Angela P. Campbell, MD, MPH1; Amadea Britton, MD, SM1; Sharon Saydah, PhD1
Author Affiliations Article Information
JAMA Netw Open. 2025;8(2):e2459672. doi:10.1001/jamanetworkopen.2024.59672
Key Points
Question  Does COVID-19 mRNA vaccination reduce the occurrence of post–COVID-19 condition (PCC) following SARS-CoV-2 infection in children aged 5 to 17 years?
Findings  In this case-control study with 622 participants, vaccination was associated with a 57% decreased odds of 1 or more PCC symptoms and a 73% decreased odds of 2 or more PCC symptoms.
Meaning  The findings of this study suggest that mRNA COVID-19 vaccination may be a protective factor against PCC in children following SARS-CoV-2 infection.
Abstract
Importance  An estimated 1% to 3% of children with SARS-CoV-2 infection will develop post–COVID-19 condition (PCC).
Objective  To evaluate the odds of PCC among children with COVID-19 vaccination prior to SARS-CoV-2 infection compared with odds among unvaccinated children.
Design, Setting, and Participants  In this case-control study, children were enrolled in a multisite longitudinal pediatric cohort from July 27, 2021, to September 1, 2022, and followed up through May 2023. Analysis used a case (PCC reported)–control (no PCC reported) design and included children aged 5 to 17 years whose first real time–polymerase chain reaction (RT-PCR)–confirmed SARS-CoV-2 infection occurred during the study period, who were COVID-19 vaccine age-eligible at the time of infection, and who completed a PCC survey at least 60 days after infection. From December 1, 2022, to May 31, 2023, children had weekly SARS-CoV-2 testing and were surveyed regarding PCC (≥1 new or ongoing symptom lasting ≥1 month after infection).
Exposures  COVID-19 mRNA vaccination status at time of infection was the exposure of interest; participants were categorized as vaccinated (≥2-dose series completed ≥14 days before infection) or unvaccinated. Vaccination status was verified through vaccination cards or vaccine registry and/or medical records when available.
Main Outcome and Measures  Main outcomes were estimates of the odds of PCC symptoms. Multivariate logistic regression was performed to estimate the odds of PCC among vaccinated children compared with odds of PCC among unvaccinated children.
Results  A total of 622 participants were included, with 28 (5%) case participants and 594 (95%) control participants. Median (IQR) age was 10.0 (7.0-11.9) years for case participants and 10.3 (7.8-12.7) years for control participants (P = .37). Approximately half of both groups reported female sex (13 case participants [46%] and 287 control participants [48%]). Overall, 57% of case participants (16 children) and 77% of control participants (458 children) were vaccinated (P = .05). After adjusting for demographic characteristics, number of acute COVID-19 symptoms, and baseline health, COVID-19 vaccination was associated with protection against acute COVID-19 and may encourage increased pediatric uptake.

______________________________________________________________________________

Nature   - scientific reports  

• Published: 03 March 2025

Cerebrospinal fluid metabolomics, lipidomics and serine pathway dysfunction in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS)

• James N. Baraniuk 

Scientific Reports volume 15, Article number: 7381 (2025)
Abstract
We proposed that cerebrospinal fluid would provide objective evidence for disrupted brain metabolism in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS). The concept of postexertional malaise (PEM) with disabling symptom exacerbation after limited exertion that does not respond to rest is a diagnostic criterion for ME/CFS. We proposed that submaximal exercise provocation would cause additional metabolic perturbations. The metabolomic and lipidomic constituents of cerebrospinal fluid from separate nonexercise and postexercise cohorts of ME/CFS and sedentary control subjects were contrasted using targeted mass spectrometry (Biocrates) and frequentist multivariate general linear regression analysis with diagnosis, exercise, gender, age and body mass index as independent variables. ME/CFS diagnosis was associated with elevated serine but reduced 5-methyltetrahydrofolate (5MTHF). One carbon pathways were disrupted. Methylation of glycine led to elevated sarcosine but further methylation to dimethylglycine and choline was decreased. Creatine and purine intermediates were elevated. Transaconitate from the tricarboxylic acid cycle was elevated in ME/CFS along with essential aromatic amino acids, lysine, purine, pyrimidine and microbiome metabolites. Serine is a precursor of phospholipids and sphingomyelins that were also elevated in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. The findings differ from prior hypometabolic findings in ME/CFS plasma. 
The novel findings generate new hypotheses regarding serine-folate-glycine one carbon and serine-phospholipid metabolism, elevation of end products of catabolic pathways, shifts in folate, thiamine and other vitamins with exercise, and changes in sphingomyelins that may indicate myelin and white matter dysfunction in ME/CFS.

______________________________________________________________________________

Health services research          Original research
Understanding symptom clusters, diagnosis and healthcare experiences in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID: a cross-sectional survey in the UK
http://orcid.org/0000-0002-8829-2217
Maedeh Mansoubi, Thomas Richards,Martine Ainsworth-Wells, Russell Fleming,
http://orcid.org/0000-0002-3602-2231
Phaedra Leveridge   Charles Shepherd,
http://orcid.org/0000-0002-2933-5213  Helen Dawes 
Correspondence to Dr Maedeh Mansoubi; [email protected]
Abstract
Objectives This study aims to provide an in-depth analysis of the symptoms, coexisting conditions and service utilisation among people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. The major research questions include the clustering of symptoms, the relationship between key factors and diagnosis time, and the perceived impact of National Institute for Health and Care Excellence (NICE) guidelines on patient care.
Design Cross-sectional survey using secondary data analysis.
Setting Community-based primary care level across the UK, incorporating online survey participation.
Participants A total of 10 458 individuals responded to the survey, of which 8804 confirmed that they or a close friend/family member had ME/CFS or long COVID. The majority of respondents were female (83.4%), with participants from diverse regions of the UK.
Primary and secondary outcome measures Primary outcomes included prevalence and clustering of symptoms, time to diagnosis, and participant satisfaction with National Health Service (NHS) care, while secondary outcomes focused on symptom management strategies and the perceived effect of NICE guidelines.
Results Fatigue (88.2%), postexertional malaise (78.2%), cognitive dysfunction (88.4%), pain (87.6%) and sleep disturbances (88.2%) were the most commonly reported symptoms among participants with ME/CFS, with similar patterns observed in long COVID. Time to diagnosis for ME/CFS ranged widely, with 22.1% diagnosed within 1–2 years of symptom onset and 12.9% taking more than 10 years. Despite updated NICE guidelines, only 10.1% of participants reported a positive impact on care, and satisfaction with NHS services remained low (6.9% for ME/CFS and 14.4% for long COVID).
Conclusions ME/CFS and long COVID share overlapping but distinct symptom clusters, indicating common challenges in management. The findings highlight significant delays in diagnosis and low satisfaction with specialist services, suggesting a need for improved self-management resources and better-coordinated care across the NHS.
______________________________________________________________________________

A review of intravenous immunoglobulin in the treatment of neuroimmune conditions, acute COVID-19 infection, and post-acute sequelae of COVID-19 syndrome
Authors: Morse AB, Motovilov K, Brode MW, Tee MF, Melamed E (Univ of Texas, USA)
Publication: Brain, Behavior, and Immunity
Link: https://www.sciencedirect.com/science/article/abs/pii/S0889159124006482
Intravenous immunoglobulin (IVIG) is a versatile therapy used to treat over 100 medical conditions, particularly neuroimmune disorders such as Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and myasthenia gravis. IVIG works by neutralising cytokines, modulating autoantibodies, and inhibiting the complement system.
The number of IVIG products approved by the US Food and Drug Administration (FDA) has increased from 9 in 2018 to 40 by 2024, targeting 31 different conditions like autoimmune neuropathies, and multiple sclerosis. Mostly, these formulations consist of standard polyclonal IgG for general applications, hyperimmune variants for specific diseases, and animal-derived products for targeted conditions.
During the COVID-19 pandemic, IVIG emerged as a potential therapy for addressing immune dysregulation and inflammation associated with COVID-19, as well as its long-term effects, known as post-acute sequelae of SARS-CoV-2 (PASC).
In acute COVID-19 cases, IVIG is used to address hypogammaglobulinemia, cytokine storms, and endothelial damage. Early administration in severe cases has shown benefits in reducing ICU stays, ventilator dependence, and mortality, while later use is less effective. Meta-analyses suggest IVIG helps critically ill patients, especially when given before disease progression. However, inconsistent findings highlight the need for optimised dosing and patient stratification, as IVIG’s efficacy may depend on its ability to reduce inflammation and modulate immune activity.
Emerging evidence suggests that IVIG may be an effective treatment for PASC, affecting 5–30% of COVID-19 survivors. Small studies have reported improvements in symptoms like fatigue, pain, and cognitive dysfunction. Ongoing clinical trials, including a phase II randomised controlled trial comparing IVIG to methylprednisolone, are exploring factors such as timing, dosing, and patient subgroups. As understanding of PASC and its pathophysiology grows, IVIG could significantly help manage long-term COVID-19 symptoms.
IVIG has shown positive results for some ME/CFS patients, especially those affected by an acute viral infection. There are similarities between ME/CFS and PASC, with around 50% of PASC patients meeting ME/CFS criteria, including post-exertional malaise. Both conditions may have an unclear autoimmune component.
Given that IVIG has been successful in treating autoimmune diseases like GBS, CIDP, and MMN, the authors propose that IVIG may also benefit PASC and ME/CFS. The authors conclude that, in light of the lack of evidence-based treatments for these conditions and the high prevalence of PASC, IVIG could be an important therapeutic option, pending further research.

______________________________________________________________________________

Exploring the role of galectin-9 and artemin as biomarkers in long COVID with chronic fatigue syndrome: links to inflammation and cognitive function
Authors: Elahi S, Rezaeifar M, Osman M, Shahbaz S (University of Alberta, Canada)
Publication: Frontiers in immunology
Link: https://doi.org/10.3389/fimmu.2024.1443363
These authors propose that neurological symptoms observed in long COVID (LC) are likely due to blood-brain barrier disruption and systemic inflammation. Previous research by these authors identified elevated galectin-9 (Gal-9) and artemin (ARTN) levels in LC patients with ME/CFS symptoms. The author’s goal was to assess plasma concentrations of Gal-9 and ARTN as biomarkers to differentiate LC patients with ME/CFS symptoms, SARS-Cov-2 recovered individuals and healthy controls. In addition, the authors compared these plasma concentrations with those of HIV patients.
The discovery cohort involved 44 LC patients and 24 SARS-Cov2-recovered individuals, all vaccine-naive and infected with the original Wuhan strain. The validating cohort involved 34 LC patients and 34 SARS-Cov-2-recovered individuals with vaccine coverage of 67.3% and 73.5%, respectively, and infected with the Delta and/or Omicron variants. The authors also involved 63 HIV patients for comparison with LC patients, as previous research showed elevated levels of Gal-9 in this population. Finally, 25 healthy individuals, serologically negative for HIV, hepatitis C virus, and hepatitis B viruses, were enrolled as controls.
Receiver operating characteristic (ROC) curve analysis identified relevant cut-off values for plasma Gal-9 and ARTN to differentiate LC patients, SARS-Cov2 recovered individuals, and controls in the discovery cohort. Plasma Gal-9 and ARTN were effective biomarkers with high sensitivity and specificity in differentiating groups in the validation cohort. The elevated plasma levels of Gal-9 positively correlated with sCD14, I-FABP, and LPS-binding protein in LC patients. These results suggest a complex interplay between immunity, compromised gastrointestinal integrity, and metabolic pathways in LC. Gal-9 levels also showed a positive correlation with cognitive failure scores, suggesting a role in cognitive impairment in LC patients with ME/CFS. In comparison with LC patients, HIV patients – who also displayed elevated Gal-9 plasma levels – presented significantly lower levels of ARTN.
The authors conclude that Gal-9 and/or ARTN may be sensitive biomarkers to identify and stratify LC patients with ME/CFS. The correlations between Gal-9, inflammatory markers, immune activation, and cognitive impairment provide valuable insights for future research. These findings highlight the need for longitudinal studies involving larger cohorts.
______________________________________________________________________________

Characteristics and predictors of Long Covid in children: a 3-year prospective cohort study
Authors: Camporesi A, Morello R, La Rocca A, Zampino G, Vezzuli F, Munblit D …  Buonsenso D (Gemelli University Hospital, Italy)
Publication: eClinical Medicine
Link: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00394-8/fulltext
This study sought to provide evidence of the characteristics and predictors of long COVID in children. It also aimed to establish the role vaccines might have in the prevention of the development of long COVID, as well as the risk of developing long COVID or autoimmune disease following reinfection with SARS-CoV-2 virus.
Participants were aged 0-18 years, had been infected with SARS-CoV-2, and were recruited from a paediatric post-COVID clinic in Rome. Participants were assessed at 3, 6, 12, 18, 24 and 36 months after their initial infection. 1319 participants were originally included in this study; however some were lost to follow-up. Vaccination status, demographic information, and detailed symptom logs were all collected, as well as newly acquired infections. Participants were also assessed for long COVID, as defined by the World Health Organization definition.
Statistically significant risk factors for developing long COVID included being over 12 years old, having co-morbidities, being infected with original variants, and female sex. At the 18-month follow-up, age over 12 years and infection with original and alpha variants remained statistically significant risk factors. Vaccinations were found to be associated with a lower risk of long COVID at time points 3, 6, and 12 months for older children, as well as a lower risk of reinfection with the SARS-CoV-2 virus. Infection with the original variant was associated with a higher risk of new-onset autoimmune disease. At the end of the study, the majority of participants were reported to have recovered, with only 11 participants continuing to meet the definition of long COVID. Only one participant was diagnosed with long COVID following re-infection.
The authors conclude that this study demonstrates the long-lasting impact of long COVID on children, as well as providing demographic and clinical predictors of long COVID development. Vaccines were associated with a lower risk of long COVID, and subsequent infections had minimal burden on most participants. These results highlight the need for further research into paediatric long COVID, to improve diagnosis and treatment, as well as inform prevention and management of future pandemics.
______________________________________________________________________________

Identifying microRNAs possibly implicated in myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: a review
Authors: Tsamou M, Kremers FAC, Samaritakis KA, Roggen EL (ToxGenSolutions, The Netherlands)  
Publication: International Journal of Molecular Sciences
Link: https://doi.org/10.3390/ijms25179551
The authors conducted a literature review of studies into microRNAs (miRNAs) implicated in regulating purported pathophysiological mechanisms of ME/CFS and/or fibromyalgia. The scope of this review was limited to the 25 human studies published in English after 2010 that contained the keywords “miRNA”, “myalgic encephalomyelitis (ME)”, “chronic fatigue syndrome (CFS)”, and/or “fibromyalgia (FM)”.
miRNAs mentioned in two or more papers were noted and grouped according to the processes they regulate. The metabolic processes linked to the miRNAs included immunity and inflammation, central sensitisation or chronic widespread pain reception, reduction/oxidisation reactions and mitochondrial function, autophagy, vascular function, cell metabolism, hypothalamic-pituitary-adrenal (HPA) axis function, transient receptor potential (TRP) ion channels, and tryptophan metabolism.
The authors then broke these processes down further, using other current literature to list the specific mechanisms (such as dysfunctional CD8+ cytotoxic T cells affecting the immune system, and higher levels of arginine vasopressin causing sustained activation of the HPA axis) that have been found to be dysfunctional in ME/CFS and/or FM for each of these overarching processes. The miRNAs miR-29c, miR-99b, miR-128, miR-374b, and miR-766 were of particular interest for their roles in immune response, central sensitisation, oxidative stress, and mitochondrial dysfunction, as well as miR-23a, miR-103, miR-152, and miR-320 for their roles in the majority of processes involved in the pathophysiology of ME/CFS and/or FM.
The goal of this review was to consolidate data identifying aberrant miRNA as emerging biomarkers for ME/CFS and FM to bridge the gaps in the current understanding of complex, multisystemic illnesses. The authors hope that this approach could lead to earlier diagnosis and improved treatments.
______________________________________________________________________________

Long COVID patients show brain swelling linked to memory and concentration problems, study finds
Authors: Miles, J.  
Publication: ABC News
Link: https://www.abc.net.au/news/2025-02-11/long-covid-brain-swelling-memory-problems-research-queensland/104917572
This article reported on the recent publication of a brain imaging study by Australian researchers at the National Centre for Neuroimmunology and Emerging Diseases (NCNED) which found that an area of the brain known as the hippocampus is larger in people with long COVID and ME/CFS than in healthy people. Hippocampus size was also found to be related to symptom severity in long COVID and ME/CFS.
The researchers suggest that the increased hippocampus size could result from the development of new cells as a way to compensate for cognitive difficulties associated with these conditions or possibly due to the ongoing presence of a virus. The researchers also claim that an enlarged hippocampus has not been observed in other conditions and may be unique to long COVID and ME/CFS.
Patients and clinicians report that this result validates that the condition is not psychological. The researchers are hopeful that this research could lead to better treatments.

Medscape Medical News > Conference News > ACR 2024
Post-Exertional Malaise in Fatiguing Diseases: What to Know to Avoid Harmful Exercise    Miriam E. Tucker     December 20, 2024
Identifying the phenomenon of post-exertional malaise (PEM) in patients with fatiguing conditions is critical because it necessitates a far more cautious approach to exercise, experts said.
PEM is a defining feature of the condition myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and it is present in many people with long COVID. It is characterized by a worsening of fatigue and of other symptoms after previously tolerated physical or mental exertion, typically emerging 24-72 hours after the exertion and lasting days or weeks thereafter. The experience is often called a “crash.”
In a study presented at American College of Rheumatology (ACR) 2024 Annual Meeting, PEM was also identified in people with various rheumatologic conditions, ranging from 4% in those with osteoarthritis to 20% in those with fibromyalgia. The presence of PEM was also associated with worse pain, sleep, cognition, and other symptoms that are also characteristic of ME/CFS and many cases of long COVID.
“PEM assessment is becoming more important in those with long COVID, as we are assisting more of those with long durations of this condition…This is the first study we know of presenting PEM rates in a rheumatologic disease population,” Kaleb Michaud, PhD, director of FORWARD—The National Databank for Rheumatic Diseases and professor of rheumatology and immunology, University of Nebraska Medical Center, Omaha, Nebraska, said in his presentation of the data at the ACR meeting.
During the discussion period, study investigator Leonard H. Calabrese, DO, head of the Section of Clinical Immunology, Cleveland Clinic, Cleveland, commented, “PEM is seen with numerous post-acute infectious sequelae. It segregates with that population of patients who meet the diagnostic criteria for ME/CFS, of which 50%-70% of people will also meet criteria for fibromyalgia…This is a first step, but it has big ramifications regarding exercise.”
In an interview with Medscape Medical News, Calabrese said, “We recommend exercise to virtually everyone with fibromyalgia who doesn’t have ME/CFS,” but that the assessment tool used in the study, the 5-item DePaul Symptoms Questionnaire, isn’t adequate for assessing true PEM that would preclude exercise, despite being validated. “That instrument is inexact and lacks specificity…It just shows where the field is. We need better biomarkers.”
In Those With PEM, Exercise May Harm
Asked to comment, Brayden P. Yellman, MD, a rheumatologist at the Bateman Horne Center, Salt Lake City, Utah, told Medscape Medical News, “if there is an infection-associated chronic condition that meets criteria for what we would call ME/CFS or long COVID, and if there’s true post-exertional malaise, any graded exercise that ultimately leads to post-exertional malaise is harmful…There is a subset of people who have milder disease, who can sometimes do very mild exercise that does not trigger PEM, and they do see benefits over time very slowly with really carefully curated, carefully monitored exercise. But we have to be really careful.”
For the majority, however, the approach is to teach patients to pace their activities in order to avoid PEM, also referred to as staying within their “energy envelope.” Clinician resources are available on the Bateman Horne Center’s website.
This isn’t typically included in rheumatology training, Yellman noted. “Having completed an entire rheumatology fellowship and working in rheumatology, I was not taught at all about [then-termed] chronic fatigue syndrome. It was lumped under fibromyalgia. And of course, they teach about fibromyalgia because it’s a great mimic of a lot of inflammatory, rheumatological conditions, but the idea of [PEM], that pathognomonic feature that we see in infection-associated chronic conditions, was not once mentioned when I trained, in 2014 to 2016.”
Nonetheless, he added, “rheumatologists are definitely seeing this in their fibromyalgia patients and some of their other patients at a high rate, and I’m sure that they’re missing it, along with other comorbidities like orthostatic hypotension.”
Another expert asked to weigh in, Todd Davenport, PT, DPT, PhD, professor and chair of the Department of Physical Therapy at the University of the Pacific, Stockton, California, told Medscape Medical News, “Our experience is that the body’s responses to short bouts of exercise are abnormal, and graded exercise is unsuccessful and makes people worse…Clinicians should be particularly on the lookout for PEM in patients who are already reporting fatigue, such as with fibromyalgia and rheumatologic conditions that can have some diagnostic overlaps with ME/CFS, because you can get fooled into thinking that your well-meaning exercise program intended to help give them a little more juice during their daily activities actually might be harmful.”
There are several lines of evidence for abnormal responses to exercise in people with PEM, Davenport said. These include muscle worsening, cardiac preload failure and impaired systemic oxygen extraction, metabolic dysregulation, and abnormal immunologic and neurologic changes.
Several studies show impaired recovery after 2-day cardiopulmonary exercise testing, with the largest to date published in July 2024. Patients with PEM have also reported harm from prescribed exercise.
Yellman commented, “We think of PEM like an injury, where you need to recover. If you keep stacking injuries on top of it, that injury is never going to heal the same way again…We are still trying to understand the pathophysiology of ME/CFS in general, and of PEM. But if you think of it as a neuroinflammatory injury, and there’s some evidence suggesting neuroinflammation, you can kind of understand the approach of needing to heal and to recover.”
How Prevalent Is PEM in Rheumatologic Conditions?
For the study presented at the ACR meeting, data of people with confirmed rheumatic diseases were taken from the ongoing longitudinal US-based research database FORWARD. Participants completed biannual self-reported questionnaires during January-June 2024 that included the 5-item PEM subscale from the validated DePaul Symptoms Questionnaire.
Questions relate to frequency and severity of each of the five items: “Dead, heavy feeling after starting to exercise,” “next-day soreness or fatigue after nonstrenuous, everyday activities,” “mentally tired after the slightest effort,” “minimum exercise makes you physically tired,” and “physically drained or sick after mild activity.” Participants are asked to rate each item on a scale from 0 if not present to 1 (mild/a little of the time) up to 4 (very severe/all of the time).
A positive PEM result was defined as a frequency of at least two and simultaneous severity of at least two on any survey item. Additional questions asked about recent and previous SARS-CoV-2 infections, long COVID diagnoses, and comorbidities.
Of 1158 individuals who completed the PEM questionnaire, 7.5% overall met PEM criteria. By individual condition, the proportions were 4.4% with osteoarthritis, 7.4% with rheumatoid arthritis, 12.2% with systemic lupus erythematosus, 13.8% with fibromyalgia diagnosed by rheumatologists, and 20.3% with fibromyalgia based on the 2016 revised ACR criteria.
The overall PEM prevalence was 8.3% among those reporting ever having COVID-19 and 9.5% among those who had COVID-19 during July-December 2023. The PEM prevalence increased more dramatically with more severe COVID-19 — 17.2% among those who had been hospitalized for COVID-19, 22.0% of those ever diagnosed with long COVID, and 28.1% with a long COVID diagnosis in January 2024.
By diagnosis, 50% of individuals who met the ACR’s 2016 fibromyalgia criteria and currently had long COVID scored positively for PEM.
Measures of pain, fatigue, sleep, patient global assessment, activity score, polysymptomatic distress, disability, depression, anxiety, and other functional scores were all significantly worse among those scoring positive for PEM (P < .001), Michaud reported.
Better Tools Are Available
The developer of the DePaul questionnaire, Leonard Jason, PhD, director of the Center for Community Research and professor of psychology at DePaul College of Science and Health, Chicago, told Medscape Medical News that an updated 10-item screening tool specifically designed to screen for PEM adds some important elements missing from the 5-item version.
Here, patients are initially asked two questions: “Do you experience a worsening of your fatigue/energy related illness after engaging in minimal physical effort?” and “Do you experience a worsening of your fatigue/energy related illness after engaging in mental effort?” If they answer “yes” to either, the next question is “If you feel worse after activities, how long does this last?” Answers are coded from 0 to 6 (24 hours or more).
The fourth additional question then asks how quickly patients recover, while a fifth question asks whether the person is avoiding activity because it makes them feel worse (thereby potentially creating a false negative).
For those scoring positive on the 10-item screen, a more comprehensive measure could be used, such as this online screening tool, Jason said.
Yellman said that the Bateman Horne Center uses a “good day, bad day” questionnaire to tease out some of the same information. In addition, he noted that it’s important to capture the timeframe between the exertion and the onset of symptoms because PEM doesn’t start during or immediately after activity. “If somebody is mowing the lawn and they start feeling symptoms immediately, they’re probably, at least in ME/CFS, experiencing orthostatic intolerance. Post-exertional malaise occurs 12-72 hours later, when their function is severely reduced as compared to baseline.” 
And of course, Davenport noted, listening to patients is key. “Patients will tell you wildly unusual responses to activity before you even do the work of trying to figure out what the activity was. They’ll tell you things like they can’t think as well, that they have to be in bed for 3 days to a week to 2 weeks, depending on the level of exertion.”
Yellman, Davenport, and several other colleagues are currently working on a paper that will explain the differences between pacing and graded exercise, define PEM, and provide guidelines. They aim to submit it in time for publication early next year. In the meantime, the Bateman Horne Center’s website provides numerous resources for healthcare professionals and patients.

------------------------------------------------------------

Machine learning and multi-omics in precision medicine for ME/CFS - Huang, Lidbury, Thomas, Gooley & Armstrong
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: Journal of Translational Medicine, Open Access
​------------------------------------------------------------

Journal of General Internal Medicine  
Incidence and Prevalence of Post-COVID-19 Myalgic Encephalomyelitis: A Report from the Observational RECOVER-Adult Study
Original Research   Open access  Published: 13 January 2025 
Suzanne D. Vernon PhD, Tianyu Zheng MS, Hyungrok Do PhD, Vincent C. Marconi MD, Leonard A. Jason PhD, 
Benjamin H. Natelson MD, Zaki A. Sherif PhD, Hector Fabio Bonilla MD, Emily Taylor MA, Janet M. Mullington PhD, Hassan Ashktorab PhD, Adeyinka O. Laiyemo MD, Hassan Brim PhD, Thomas F. Patterson MD, Teresa T. Akintonwa BA, Anisha Sekar BA, Michael J. Peluso MD, Nikita Maniar MD, Lucinda Bateman MD, Leora I. Horwitz MD & Rachel Hess MD on behalf of the NIH Researching COVID to Enhance Recovery (RECOVER) Consortium
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may occur after infection. How often people develop ME/CFS after SARS-CoV-2 infection is unknown.
Objective
To determine the incidence and prevalence of post-COVID-19 ME/CFS among adults enrolled in the Researching COVID to Enhance Recovery (RECOVER-Adult) study.
Design, Setting, and Participants
RECOVER-Adult is a longitudinal observational cohort study conducted across the U.S. We included participants who had a study visit at least 6 months after infection and had no pre-existing ME/CFS, grouped as (1) acute infected, enrolled within 30 days of infection or enrolled as uninfected who became infected (n=4515); (2) post-acute infected, enrolled greater than 30 days after infection (n=7270); and (3) uninfected (1439).
Measurements
Incidence rate and prevalence of post-COVID-19 ME/CFS based on the 2015 Institute of Medicine ME/CFS clinical diagnostic criteria.
Results
The incidence rate of ME/CFS in participants followed from time of SARS-CoV-2 infection was 2.66 (95% CI 2.63–2.70) per 100 person-years while the rate in matched uninfected participants was 0.93 (95% CI 0.91–10.95) per 100 person-years: a hazard ratio of 4.93 (95% CI 3.62–6.71). The proportion of all RECOVER-Adult participants that met criteria for ME/CFS following SARS-CoV-2 infection was 4.5% (531 of 11,785) compared to 0.6% (9 of 1439) in uninfected participants. Post-exertional malaise was the most common ME/CFS symptom in infected participants (24.0%, 2830 of 11,785). Most participants with post-COVID-19 ME/CFS also met RECOVER criteria for long COVID (88.7%, 471 of 531).
Limitations
The ME/CFS clinical diagnostic criteria uses self-reported symptoms. Symptoms can wax and wane.
Conclusion
ME/CFS is a diagnosable sequela that develops at an increased rate following SARS-CoV-2 infection. RECOVER provides an unprecedented opportunity to study post-COVID-19 ME/CFS.

​------------------------------------------------------------

Articles       The Lancet  
Volume 49101161February 2025
Efficacy of repeated immunoadsorption in patients with post-COVID myalgic encephalomyelitis/chronic fatigue syndrome and elevated β2-adrenergic receptor autoantibodies: a prospective cohort study
Elisa Steina ∙ Cornelia Heindricha ∙ Kirsten Wittkea ∙ Claudia Kedora ∙ Rebekka Rusta,c ∙ Helma Freitaga∙ et al. 
Summary
Background
Since the pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the leading trigger for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Evidence indicates that autoimmunity plays an important pathophysiological role. We aimed to evaluate the effectiveness of IA treatment in post-COVID ME/CFS patients.
Methods
This pre-post study included 20 post-coronavirus disease 2019 (COVID) ME/CFS patients found to have elevated β2 adrenergic autoantibodies (β2 AR-AB) between October 2022 and October 2023. Patients, with a median disease duration of 22 months (IQR: 15–31), were treated with five immunoadsorption sessions at Charité - Universitätsmedizin Berlin, Germany. Seven were male and 13 female, with a median age of 40 years (IQR: 36–51). The primary end point was the change in the Short Form (36) Health Survey physical functioning domain (SF36 PF) from baseline to four weeks post immunoadsorption. Key symptoms were assessed via questionnaires over six months. Handgrip strength and EndoPAT® measurements were used to evaluate muscle fatigue and vascular dysfunction. Seven patients who worsened after an initial response received a second cycle.
Findings
The treatment was generally well tolerated, reducing total immunoglobulin G by 79% (CI: 73–84%) and β2 AR-AB by 77% (CI: 58–95%). Patients demonstrated a mean increase in the SF36 PF of 17.75 points (CI: 13.41–26.16), with the greatest improvement occurring between months two and three, and significant gains maintained through month six. 14/20 (70%) patients were categorized as responders with an increase in the SF36 PF of ≥ ten points. Further lasting improvements were reported in fatigue, post-exertional malaise, pain, cognitive, autonomic, and immunological symptoms. Female patients had increased repeat handgrip strength at month six.
Interpretation
Immunoadsorption may improve symptoms in post-COVID ME/CFS patients. The beneficial effects of IgG depletion suggest a significant role for autoantibodies and disturbed B-cell function in the condition's pathophysiology.
Funding
Funded by The Federal Ministry of Education and Research and the Weidenhammer Zöbele Research Foundation.

​------------------------------------------------------------

Women’s Immune Systems May Explain Increased Long COVID Diagnoses
Samantha Anderer
JAMA. 2025;333(3):194-195. doi:10.1001/jama.2024.25505
Women are more likely than men to experience post–COVID-19 condition, also known as long COVID, and a new study from Science Translational Medicine identified a possible explanation.
In an analysis of blood samples from 45 participants taken during and after SARS-CoV-2 infection, the authors identified sex-specific immune pathways in acute infection that were associated with subsequent development of long COVID. Females with long COVID displayed a decreased expression of transforming growth factor β1, whereas males who developed long COVID expressed more of the protein. Additionally, compared with those who recovered, women with long COVID expressed more of the RNA gene XIST, which plays a role in autoimmunity. Despite the sex-specific markers, there were some consistencies across sexes, such as increased expression of proinflammatory monocytes.
The results could help inform tailored therapeutic interventions for long COVID, the authors stated.
Published Online: December 20, 2024. doi:10.1001/jama.2024.25505

​------------------------------------------------------------

Original Investigation    Infectious Diseases     January 22, 2025
Sex Differences in Long COVID
Dimpy P. Shah, MD, PhD1; Tanayott Thaweethai, PhD2,3; Elizabeth W. Karlson, MD, MS4; et al for the RECOVER Consortium
JAMA Netw Open. 2025;8(1):e2455430. doi:10.1001/jamanetworkopen.2024.55430
Key Points
Question  Does the risk of long COVID, or post-COVID condition, differ by sex?
Findings  In this cohort study of 12 276 individuals, females had a significantly higher risk of long COVID compared with males after adjusting for sociodemographic and clinical risk factors. The sex-based difference in long COVID risk was age, pregnancy, and menopause dependent, with the highest risk among females aged 40 to 55 years.
Meaning  These findings highlight the importance of evaluating differences in risk of long COVID after SARS-CoV-2 infection in males and females and of comparing biological mechanisms that may underlie sexually dimorphic long COVID trajectories.
Abstract
Importance  A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain.
Objective  To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection.
Design, Setting, and Participants  This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)–Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection.
Exposure  Self-reported sex (male, female) assigned at birth.
Main Outcomes and Measures  Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity.
Results  Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants.
Conclusions and Relevance  In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.

​------------------------------------------------------------

Nature: Published: 17 January 2025
Association between chronic fatigue syndrome/myalgic encephalomyelitis and cardiovascular disease
Mawulorm K. I. Denu, Ritika Revoori, Cherita Eghan, Fredrick Larbi Kwapong, Andrew Hillman, Cornelius A. Normeshie, Kofi Poku Berko, Emily L. Aidoo & Maame Araba E. Buadu 
Scientific Reports volume 15, Article number: 2294 (2025) 101 Altmetric
Abstract
Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a medical condition characterized by severe and prolonged fatigue that is not relieved by rest or attributed to any underlying medical or psychological condition. Individuals with CFS/ME are considered to have an increased risk of a wide range of comorbid conditions, including cardiovascular disease (CVD). The association between CFS/ME and CVD is not fully understood. To determine the prevalence of CFS/ME in a sample population and examine its association with CVD. Weighted sample size data of 114,834 was analyzed from the 2021–2022 national health interview survey (NHIS). Information on sociodemographic factors, CVD risk factors, and history of CFS/ME and CVD were collected. Multivariable logistic regression model was used to determine the association between CFS/ME and CVD, adjusting for traditional CVD risk factors (age, sex, race, hypertension, diabetes, dyslipidemia, smoking, and body mass index (BMI). Median age of participants was 53 years, and majority of participants were female (53.9%). Prevalence of CFS/ME was 1.2%. A history of CFS/ME was significantly associated with CVD (aOR 3.26, 95%CI 2.85, 3.72, p-value: <0.001) after adjusting for traditional CVD risk factors. A history of CFS/ME was independently associated with CVD after adjusting for traditional CVD risk factors. Patients with CFS/ME need close evaluation for CVD. Further studies are needed to better understand the relationship between CFS/ME and CVD.

​------------------------------------------------------------

Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
March 2023  Medicina 59(3):571  DOI:10.3390/medicina59030571  License  CC BY 4.0
Authors:
Geoffrey E. Moore   Betsy A Keller  Ithaca College  Jared Stevens  Xiangling Mao  Weill Cornell Medicine
Abstract and Figures
Background and Objectives: 
Post-exertional malaise (PEM) is the hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but there has been little effort to quantitate the duration of PEM symptoms following a known exertional stressor. Using a Symptom Severity Scale (SSS) that includes nine common symptoms of ME/CFS, we sought to characterize the duration and severity of PEM symptoms following two cardiopulmonary exercise tests separated by 24 h (2-day CPET). 
Materials and Methods: Eighty persons with ME/CFS and 64 controls (CTL) underwent a 2-day CPET. ME/CFS subjects met the Canadian Clinical Criteria for diagnosis of ME/CFS; controls were healthy but not participating in regular physical activity. All subjects who met maximal effort criteria on both CPETs were included. SSS scores were obtained at baseline, immediately prior to both CPETs, the day after the second CPET, and every two days after the CPET-1 for 10 days. Results: There was a highly significant difference in judged recovery time (ME/CFS = 12.7 ± 1.2 d; CTL = 2.1 ± 0.2 d, mean ± s.e.m., Chi2 = 90.1, p < 0.0001). The range of ME/CFS patient recovery was 1–64 days, while the range in CTL was 1–10 days; one subject with ME/CFS had not recovered after one year and was not included in the analysis. Less than 10% of subjects with ME/CFS took more than three weeks to recover. There was no difference in recovery time based on the level of pre-test symptoms prior to CPET-1 (F = 1.12, p = 0.33). Mean SSS scores at baseline were significantly higher than at pre-CPET-1 (5.70 ± 0.16 vs. 4.02 ± 0.18, p < 0.0001). Pharmacokinetic models showed an extremely prolonged decay of the PEM response (Chi2 > 22, p < 0.0001) to the 2-day CPET. 
Conclusions: ME/CFS subjects took an average of about two weeks to recover from a 2-day CPET, whereas sedentary controls needed only two days. These data quantitate the prolonged recovery time in ME/CFS and improve the ability to obtain well-informed consent prior to doing exercise testing in persons with ME/CFS. Quantitative monitoring of PEM symptoms may provide a method to help manage PEM.
​------------------------------------------------------------

Nnature  scientific reports     Published: 28 January 2025
Novel brain SPECT imaging unravels abnormal cerebral perfusion in patients with postural orthostatic tachycardia syndrome and cognitive dysfunction
Marie-Claire Seeley, Howard O’Brien, Gemma Wilson, Clair Coat, Tess Smith, Kevin Hickson, Reynold Casse,  Amanda J. Page, Celine Gallagher & Dennis H. Lau 
Scientific Reports volume 15, Article number: 3487 (2025)  
Abstract
Cognitive dysfunction is frequently reported in individuals with postural orthostatic tachycardia syndrome (POTS), possibly resulting from reduced cerebral blood flow (CBF). We used brain SPECT, an accessible imaging modality that has not been systematically evaluated in this patient group. Retrospective review of participants from our registry was undertaken to identify those who had a brain SPECT performed for investigation of cognitive dysfunction. Abnormal CBF was taken as z-score > 2 standard deviations of healthy control reference values. Patient reported outcome measures (PROMs) such as autonomic, gastric and quality of life symptom scores were analyzed. From a total of 56 participants (mean 34.8 ± 10.7 years, 88% females), PROMs indicate: moderate to severe autonomic dysfunction in 75%; at least mild to moderate gastroparesis in 23%; low global health rating and utility scores. Abnormal CBF was seen in 61% but did not differ by POTS triggers. The regions with the lowest mean z-scores were the lateral prefrontal and sensorimotor cortices. Hierarchal regression analyses found number of brain regions with abnormal CBF, autonomic and gastric symptoms to account for 51% of variances in health utility. Cerebral hypoperfusion is prevalent in those with POTS and cognitive dysfunction even whilst supine, contributing to reduced quality of life.

​------------------------------------------------------------

The search for a blood-based biomarker for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS): from biochemistry to electrophysiology
Krista S. P. Clarke, Caroline C. Kingdon, Michael Pycraft Hughes, Eliana Mattos Lacerda, Rebecca Lewis, Emily J. Kruchek, Robert A. Dorey & Fatima H. Labeed 
Journal of Translational Medicine volume 23, Article number: 149 (2025) Cite this article
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown aetiology characterised by symptoms of post-exertional malaise (PEM) and fatigue leading to substantial impairment in functioning. Other key symptoms include cognitive impairment and unrefreshing sleep, with many experiencing pain. To date there is no complete understanding of the triggering pathomechanisms of disease, and no quantitative biomarker available with sufficient sensitivity, specificity, and adoptability to provide conclusive diagnosis. Clinicians thus eliminate differential diagnoses, and rely on subjective, unspecific, and disputed clinical diagnostic criteria—a process that often takes years with patients being misdiagnosed and receiving inappropriate and sometimes detrimental care. Without a quantitative biomarker, trivialisation, scepticism, marginalisation, and misunderstanding of ME/CFS continues despite the significant disability for many. One in four individuals are bed-bound for long periods of time, others have difficulties maintaining a job/attending school, incurring individual income losses of thousands, while few participate in social activities.
Main body
Recent studies have reported promising quantifiable differences in the biochemical and electrophysiological properties of blood cells, which separate ME/CFS and non-ME/CFS participants with high sensitivities and specificities—demonstrating potential development of an accessible and relatively non-invasive diagnostic biomarker. This includes profiling immune cells using Raman spectroscopy, measuring the electrical impedance of blood samples during hyperosmotic challenge using a nano-electronic assay, use of metabolomic assays, and certain techniques which assess mitochondrial dysfunction. However, for clinical application, the specificity of these biomarkers to ME/CFS needs to be explored in more disease controls, and their practicality/logistics considered. Differences in cytokine profiles in ME/CFS are also well documented, but finding a consistent, stable, and replicable cytokine profile may not be possible. Increasing evidence demonstrates acetylcholine receptor and transient receptor potential ion channel dysfunction in ME/CFS, though how these findings could translate to a diagnostic biomarker are yet to be explored.
Conclusion
Different biochemical and electrophysiological properties which differentiate ME/CFS have been identified across studies, holding promise as potential blood-based quantitative diagnostic biomarkers for ME/CFS. However, further research is required to determine their specificity to ME/CFS and adoptability for clinical use.

​------------------------------------------------------------

Original Investigation   Infectious Diseases    January 22, 2025
Sex Differences in Long COVID
Dimpy P. Shah, MD, PhD1; et al  ; for the RECOVER Consortium
JAMA Netw Open. 2025;8(1):e2455430. doi:10.1001/jamanetworkopen.2024.55430
Key Points
Question  Does the risk of long COVID, or post-COVID condition, differ by sex?
Findings  In this cohort study of 12 276 individuals, fe
Findings  In this cohort study of 12 276 individuals, females had a significantly higher risk of long COVID compared with males after adjusting for sociodemographic and clinical risk factors. The sex-based difference in long COVID risk was age, pregnancy, and menopause dependent, with the highest risk among females aged 40 to 55 years.
Meaning  These findings highlight the importance of evaluating differences in risk of long COVID after SARS-CoV-2 infection in males and females and of comparing biological mechanisms that may underlie sexually dimorphic long COVID trajectories.
Abstract
Importance  A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain.
Objective  To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection.
Design, Setting, and Participants  This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)–Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection.
Exposure  Self-reported sex (male, female) assigned at birth.
Main Outcomes and Measures  Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity.
Results  Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants.
Conclusions and Relevance  In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age,  pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.

​------------------------------------------------------------

Chronic fatigue syndrome: Outcry over Cochrane decision to abandon review of exercise therapy
BMJ 2025; 388 doi: https://doi.org/10.1136/bmj.r169 (Published 27 January 2025)Cite this as: BMJ 2025;388:r169
Jacqui Wise
A decision to cancel a planned update of a Cochrane systematic review of exercise therapy for chronic fatigue syndrome has met with anger from a group advising the review and the patient community.
The decision has reignited calls for the review,1 which includes studies only up to May 2014, to be withdrawn for being outdated and misleading.
The review recommends exercise therapy to treat myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), concluding that this “probably has a positive effect on fatigue in adults compared to usual care or passive therapies.”
However, this treatment approach is controversial and has been criticised by patient groups who say that it can make symptoms worse. Guidelines from the National Institute for Health and Care Excellence, published in 2021, specifically advise against graded exercise therapy.2 Guidelines from the US Centers for Disease Control and Prevention also state that exercise therapy is not a cure for ME/CFS and that standard exercise recommendations for healthy people can be harmful for people with ME/CFS.3
The Cochrane systematic review was modified slightly by its authors in 2019 to place more emphasis on the limited applicability of the evidence to definitions of ME/CFS used in the included studies, the long term effects of exercise on symptoms of fatigue, and the limitations of evidence on harms that may occur.

​------------------------------------------------------------

Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study
Kiran Thapaliya ,Sonya Marshall-Gradisnik,Natalie Eaton-Fitch,Markus Barth,Maira Inderyas,Leighton Barnden
 Published: January 13, 2025 Plos one    https://doi.org/10.1371/journal.pone.0316625
Abstract
Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients share similar symptoms including post-exertional malaise, neurocognitive impairment, and memory loss. The neurocognitive impairment in both conditions might be linked to alterations in the hippocampal subfields. Therefore, this study compared alterations in hippocampal subfields of 17 long COVID, 29 ME/CFS patients, and 15 healthy controls (HC). Structural MRI data was acquired with sub-millimeter isotropic resolution on a 7 Telsa MRI scanner and hippocampal subfield volumes were then estimated for each participant using FreeSurfer software. Our study found significantly larger volumes in the left hippocampal subfields of both long COVID and ME/CFS patients compared to HC. These included the left subiculum head (long COVID; p = 0.01, ME/CFS; p = 0.002,), presubiculum head (long COVID; p = 0.004, ME/CFS; p = 0.005), molecular layer hippocampus head (long COVID; p = 0.014, ME/CFS; p = 0.011), and whole hippocampal head (long COVID; p = 0.01, ME/CFS; p = 0.01). Notably, hippocampal subfield volumes were similar between long COVID and ME/CFS patients. Additionally, we found significant associations between hippocampal subfield volumes and severity measures of ‘Pain’, ‘Duration of illness’, ‘Severity of fatigue’, ‘Impaired concentration’, ‘Unrefreshing sleep’, and ‘Physical function’ in both conditions. These findings suggest that hippocampal alterations may contribute to the neurocognitive impairment experienced by long COVID and ME/CFS patients. Furthermore, our study highlights similarities between these two conditions.

Citation: Thapaliya K, Marshall-Gradisnik S, Eaton-Fitch N, Barth M, Inderyas M, Barnden L (2025) Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study. PLoS ONE 20(1): e0316625. https://doi.org/10.1371/journal.pone.0316625
Editor: Daichi Sone, Jikei University School of Medicine, JAPAN
Received: August 21, 2024; Accepted: December 11, 2024; Published: January 13, 2025
Copyright: © 2025 Thapaliya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are present within the manuscript. The datasets from this study are not publicly available due to confidentiality agreements but could be available on reasonable request. Any request should be submitted to Chair, Griffith University Human Research Ethics Committee, by the e-mail [email protected] or phone (+61) 07 3735 2069.
Funding: This research was funded by ME Research UK (SCIO Charity Number SC036942) with the financial support of The Fred and Joan Davies Bequest. Other funding bodies include The Stafford Fox Medical Research Foundation (489798), the National Health and Medical Research Council (1199502), Talei Stewart, Buxton Foundation (4676), Henty Community (4879), Henty Lions Club (4880), Blake Beckett Trust Foundation (4579), Alison Hunter Memorial Foundation (4570), and the Change for ME Charity (4575).
Competing interests: The authors have declared that no competing interests exist.

Journal of Translational Medicine

• Published: 05 July 2024

Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations
Betsy Keller, Candace N. Receno, Carl J. Franconi, Sebastian Harenberg, Jared Stevens, Xiangling Mao, Staci R. Stevens, Geoff Moore, Susan Levine, John Chia, Dikoma Shungu & Maureen R. Hanson 
Journal of Translational Medicine volume 22, Article number: 627 (2024)  
Abstract
Background
Post-exertional malaise (PEM), the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), represents a constellation of abnormal responses to physical, cognitive, and/or emotional exertion including profound fatigue, cognitive dysfunction, and exertion intolerance, among numerous other maladies. Two sequential cardiopulmonary exercise tests (2-d CPET) provide objective evidence of abnormal responses to exertion in ME/CFS but validated only in studies with small sample sizes. Further, translation of results to impairment status and approaches to symptom reduction are lacking.

Methods    Participants with ME/CFS (Canadian Criteria; n = 84) and sedentary controls (CTL; n = 71) completed two CPETs on a cycle ergometer separated by 24 h. Two-way repeated measures ANOVA compared CPET measures at rest, ventilatory/anaerobic threshold (VAT), and peak effort between phenotypes and CPETs. Intraclass correlations described stability of CPET measures across tests, and relevant objective CPET data indicated impairment status. A subset of case–control pairs (n = 55) matched for aerobic capacity, age, and sex, were also analyzed.
Results    Unlike CTL, ME/CFS failed to reproduce CPET-1 measures during CPET-2 with significant declines at peak exertion in work, exercise time, V˙e, V˙O2, V˙CO2, V˙ T, HR, O2pulse, DBP, and RPP. Likewise, CPET-2 declines were observed at VAT for V˙e/V˙CO2, PetCO2, O2pulse, work, V˙O2 and SBP. Perception of effort (RPE) exceeded maximum effort criteria for ME/CFS and CTL on both CPETs. Results were similar in matched pairs. Intraclass correlations revealed greater stability in CPET variables across test days in CTL compared to ME/CFS owing to CPET-2 declines in ME/CFS. Lastly, CPET-2 data signaled more severe impairment status for ME/CFS compared to CPET-1.
Conclusions     Presently, this is the largest 2-d CPET study of ME/CFS to substantiate impaired recovery in ME/CFS following an exertional stressor. Abnormal post-exertional CPET responses persisted compared to CTL matched for aerobic capacity, indicating that fitness level does not predispose to exertion intolerance in ME/CFS. Moreover, contributions to exertion intolerance in ME/CFS by disrupted cardiac, pulmonary, and metabolic factors implicates autonomic nervous system dysregulation of blood flow and oxygen delivery for energy metabolism. The observable declines in post-exertional energy metabolism translate notably to a worsening of impairment status. Treatment considerations to address tangible reductions in physiological function are proffered.
Trial registration number: ClinicalTrials.gov, retrospectively registered, ID# NCT04026425, date of registration: 2019-07-17.

-------------------------------------------------------------
ARTICLES| VOLUME 74, 102719, AUGUST 2024
Pre-existing sleep disturbances and risk of COVID-19: a meta-analysis
Jiawei Zhou,,Xia LiTing Zhang,Ziyan Liu,Peng Li,Na Yu,et al.
Open AccessPublished:July 05, 2024DOI:https://doi.org/10.1016/j.eclinm.2024.102719
Summary
Background
Sleep disturbances are widespread but usually overlooked health risk factors for coronavirus disease 2019 (COVID-19). We aimed to investigate the influence of pre-existing sleep disturbances on the susceptibility, severity, and long-term effects of COVID-19.
Methods
We searched PubMed, Web of Science, and Embase for relevant articles from inception to October 27, 2023 and updated at May 8, 2024. Sleep disturbances included obstructive sleep apnea (OSA), insomnia, abnormal sleep duration, night-shift work, and any other sleep disturbances. Outcomes were COVID-19 susceptibility, hospitalization, mortality, and long COVID. The effect sizes were pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). This study is registered with PROSPERO (CRD42024503518).
Findings
A total of 48 observational studies (n = 8,664,026) were included. Pre-existing sleep disturbances increased the risk of COVID-19 susceptibility (OR = 1.12, 95% CI 1.07–1.18), hospitalization (OR = 1.25, 95% CI 1.15–1.36), mortality (OR = 1.45, 95% CI 1.19–1.78), and long COVID (OR = 1.36 95% CI 1.17–1.57). Subgroup analysis showed that younger individuals with sleep disturbances were associated with higher susceptibility and hospitalization and a lower risk of mortality than older individuals. Males with sleep disturbances were associated with higher mortality. For specific sleep disturbances, the susceptibility and hospitalization of COVID-19 were associated with OSA, abnormal sleep duration, and night-shift work; mortality of COVID-19 was linked to OSA; risk of long COVID was related to OSA, abnormal sleep duration and insomnia.
Interpretation
Pre-existing sleep disturbances, especially OSA, increased the risk of COVID-19 susceptibility, hospitalization, mortality, and long COVID. Age and sex played important roles in the effect of sleep disturbances on COVID-19.
Funding
The National Natural Science Foundation of China and the Key Laboratory of Respiratory Diseases of Liaoning Province.

-------------------------------------------------------------

Post–Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) After Infection During Pregnancy
Metz, Torri D.; Reeder, Harrison T.; Clifton, Rebecca G.; More                       July 11, 2024
OBJECTIVE:
To estimate the prevalence of post–acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) after infection with SARS-CoV-2 during pregnancy and to characterize associated risk factors.
METHODS:
In a multicenter cohort study (NIH RECOVER [Researching COVID to Enhance Recovery]-Pregnancy Cohort), individuals who were pregnant during their first SARS-CoV-2 infection were enrolled across the United States from December 2021 to September 2023, either within 30 days of their infection or at differential time points thereafter. The primary outcome was PASC , defined as score of 12 or higher based on symptoms and severity as previously published by the NIH RECOVER-Adult Cohort, at the first study visit at least 6 months after the participant's first SARS-CoV-2 infection. Risk factors for PASC were evaluated, including sociodemographic characteristics, clinical characteristics before SARS-CoV-2 infection (baseline comorbidities, trimester of infection, vaccination status), and acute infection severity (classified by need for oxygen therapy). Multivariable logistic regression models were fitted to estimate associations between these characteristics and presence of PASC.
RESULTS:
Of the 1,502 participants, 61.1% had their first SARS-CoV-2 infection on or after December 1, 2021 (ie, during Omicron variant dominance); 51.4% were fully vaccinated before infection; and 182 (12.1%) were enrolled within 30 days of their acute infection. The prevalence of PASC was 9.3% (95% CI, 7.9–10.9%) measured at a median of 10.3 months (interquartile range 6.1–21.5) after first infection. The most common symptoms among individuals with PASC were postexertional malaise (77.7%), fatigue (76.3%), and gastrointestinal symptoms (61.2%). In a multivariable model, the proportion PASC positive with vs without history of obesity (14.9% vs 7.5%, adjusted odds ratio [aOR] 1.65, 95% CI, 1.12–2.43), depression or anxiety disorder (14.4% vs 6.1%, aOR 2.64, 95% CI, 1.79–3.88) before first infection, economic hardship (self-reported difficulty covering expenses) (12.5% vs 6.9%, aOR 1.57, 95% CI, 1.05–2.34), and treatment with oxygen during acute SARS-CoV-2 infection (18.1% vs 8.7%, aOR 1.86, 95% CI, 1.00–3.44) were associated with increased prevalence of PASC.
CONCLUSION:
The prevalence of PASC at a median time of 10.3 months after SARS-CoV-2 infection during pregnancy was 9.3% in the NIH RECOVER-Pregnancy Cohort. The predominant symptoms were postexertional malaise, fatigue, and gastrointestinal symptoms. Several socioeconomic and clinical characteristics were associated with PASC after infection during pregnancy.

-------------------------------------------------------------

ARTICLES| VOLUME 59, 101946, MAY 2023
Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study
Lucy E.M. Finnigan,Mark Philip Cassar,Margaret James Koziel,Joel Pradines,Hanan Lamlum,Karim Azer,et al. 
Open AccessPublished:April 14, 2023DOI:https://doi.org/10.1016/j.eclinm.2023.101946
Summary:     Background
‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID.
Methods
Patients with fatigue-dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical-based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two-week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849.
Findings
Between December 15th 2021, and May 23th 2022, 60 participants were screened, and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious or led to treatment discontinuation.
Interpretation
Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there were significant improvements in fatigue-based symptoms among patients living with Long COVID following a four-week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID.
Funding
Axcella Therapeutics.

-------------------------------------------------------------

Original Investigation Public Health July 24, 2024
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After SARS-CoV-2 Infection
Elizabeth R. Unger, MD, PhD1; Jin-Mann S. Lin, PhD1; Lauren E. Wisk, PhD2; et alHuihui Yu, PhD3; Michelle L’Hommedieu, PhD2; Helen Lavretsky, MD, MS4; Juan Carlos C. Montoy, MD, PhD5; Michael A. Gottlieb, MD6; Kristin L. Rising, MD, MSHP7,8; Nicole L. Gentile, MD, PhD9,10,11; Michelle Santangelo, MS12; Arjun K. Venkatesh, MD, MBA, MHS3,13; Robert M. Rodriguez, MD5; Mandy J. Hill, DrPH, MPH14; Rachel E. Geyer, MPH10; Efrat R. Kean, MD7; Sharon Saydah, PhD15; Samuel A. McDonald, MD, MS16,17; Ryan Huebinger, MD14; Ahamed H. Idris, MD16; Jocelyn Dorney, MPH3; Bala Hota, MD, MPH18; Erica S. Spatz, MD, MHS3,19; Kari A. Stephens, PhD10,20; Robert A. Weinstein, MD12,21; Joann G. Elmore, MD, MPH2; for the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE) Group
JAMA Netw Open. 2024;7(7):e2423555. doi:10.1001/jamanetworkopen.2024.23555
Key Points
Question  Does prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)–like illness differ between individuals with an acute infection–like index illness who are COVID-19 positive or negative?
Findings  In this cohort study of 4378 participants, the weighted prevalence of ME/CFS-like illness was 4.5% or less at 3 to 12 months after the index illness in the COVID-19–positive and COVID-19–negative groups, with no significant differences in odds of ME/CFS-like illness.
Meaning  The findings suggest that ME/CFS-like illness following an acute infection–like index illness does not vary by COVID-19 test result.
Abstract
Importance  Chronic symptoms reported following an infection with SARS-CoV-2, such as cognitive problems, overlap with symptoms included in the definition of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Objective  To evaluate the prevalence of ME/CFS-like illness subsequent to acute SARS-CoV-2 infection, changes in ME/CFS symptoms through 12 months of follow-up, and the association of ME/CFS symptoms with SARS-CoV-2 test results at the acute infection–like index illness.
Design, Setting, and Participants  This prospective, multisite, longitudinal cohort study (Innovative Support for Patients with SARS-CoV-2 Infections Registry [INSPIRE]) enrolled participants from December 11, 2020, to August 29, 2022. Participants were adults aged 18 to 64 years with acute symptoms suggestive of SARS-CoV-2 infection who received a US Food and Drug Administration–approved SARS-CoV-2 test at the time of illness and did not die or withdraw from the study by 3 months. Follow-up surveys were collected through February 28, 2023.
Exposure  COVID-19 status (positive vs negative) at enrollment.
Main Outcome and Measures  The main outcome was the weighted proportion of participants with ME/CFS-like illness based on the 2015 Institute of Medicine clinical case definition using self-reported symptoms.
Results  A total of 4378 participants were included in the study. Most were female (3226 [68.1%]). Mean (SD) age was 37.8 (11.8) years. The survey completion rates ranged from 38.7% (3613 of 4738 participants) to 76.3% (1835 of 4738) and decreased over time. The weighted proportion of participants identified with ME/CFS-like illness did not change significantly at 3 through 12 months of follow-up and was similar in the COVID-19–positive (range, 2.8%-3.7%) and COVID-19–negative (range, 3.1%-4.5%) groups. Adjusted analyses revealed no significant difference in the odds of ME/CFS-like illness at any time point between COVID-19–positive and COVID-19–negative individuals (marginal odds ratio range, 0.84 [95% CI, 0.42-1.67] to 1.18 [95% CI, 0.55-2.51]).
Conclusions and Relevance  In this prospective cohort study, there was no evidence that the proportion of participants with ME/CFS-like illness differed between those infected with SARS-CoV-2 vs those without SARS-CoV-2 infection up to 12 months after infection. A 3% to 4% prevalence of ME/CFS-like illness after an acute infection–like index illness would impose a high societal burden given the millions of persons infected with SARS-CoV-2.
-------------------------------------------------------------

WebMD Health News

Long COVID Risk Has Dropped Since Start of Pandemic
Ralph Ellis   July 19, 2024
Your chances of developing long COVID have significantly decreased since the pandemic began, offering a glimmer of hope and a sign of progress in the ongoing battle against the virus.
That's according to a new study published in The New England Journal of Medicine. Researchers at Washington University in St. Louis, who conducted the study, said that the drop was caused by vaccinations and changes in the virus itself. 
"You can see a clear and significant difference in risk during the delta and omicron eras between the vaccinated and unvaccinated," Ziyad Al-Aly, MD, director of the Clinical Epidemiology Center at the VA St. Louis Health Care System and head of the research and development service, said in a statement. "So, if people think COVID is no big deal and decide to forgo vaccinations, they're essentially doubling their risk of developing long COVID."
Researchers analyzed the health records collected from March 1, 2020, through January 31, 2022, for 441,583 veterans who were infected with COVID-19 and 4.7 million veterans who were not infected.
Among unvaccinated people, long COVID was developed by 10.4% infected with the original strain of COVID, 9.5% infected with the Delta strain, and 7.7% infected with Omicron.
Among vaccinated people, long COVID occurred in 5.3% of those infected with the Delta strain and 3.5% of those infected with Omicron.
Al-Aly noted that among people infected with the Omicron strain, the chances of heart, brain, kidney, and lung problems declined while the risk of problems with metabolic function and the GI system increased.
"Each variant has its own fingerprint," Al-Aly said. "The original virus hit the respiratory system hard. Omicron targeted metabolic and GI issues. It's important because while the risk of long COVID is quantitatively lower, a person can be at a higher risk of developing an illness based on the part of the body that the COVID variant targets."
With long COVID, symptoms persist months or years after infection. Common symptoms include extreme fatigue, shortness of breath, loss of the sense of smell, and muscle aches.
According to the CDC's Household Pulse Survey, 18.4% of American adults say they've experienced long COVID at some point.
-------------------------------------------------------------

RESEARCH ARTICLE  NEUROIMMUNOLOGY
Infection and chronic disease activate a systemic brain-muscle signaling axis
SHUO YANG HTTPS://ORCID.ORG/0000-0002-7929-0244 , MEIJIE TIAN HTTPS://ORCID.ORG/0000-0003-0547-9447, YULONG DAI, RONG WANG, [...], AND AARON JOHNSON HTTPS://ORCID.ORG/0000-0002-2783-5636 +12 authors 
SCIENCE IMMUNOLOGY  12 Jul 2024  Vol 9, Issue 97  DOI: 10.1126/sciimmunol.adm7908 
Editor’s summary
Neuroinflammation can cause symptoms outside of the central nervous system (CNS), including muscle pain and fatigue, yet how inflammatory signals in the brain are communicated to muscle remains to be determined. Using multiple models of CNS stress in fruit flies, Yang et al. identified that reactive oxygen species accumulation in the brain promoted expression of Upd3, a Drosophila ortholog of interleukin-6 (IL-6). IL-6 activated JAK-STAT signaling in skeletal muscle, resulting in mitochondrial dysfunction–impaired motor function. This axis was also activated in mice after CNS stress and evident in humans with neuroinflammation. This work identifies a conserved brain-to-muscle signaling axis that regulates muscle performance, which may be a promising therapeutic target. —Hannah Isles
Abstract
Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that Escherichia coli infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-β (Aβ42) in the CNS. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.

-------------------------------------------------------------

Viruses:. 2024 Apr 8;16(4):572.  doi: 10.3390/v16040572.
Herpesvirus Infection of Endothelial Cells as a Systemic Pathological Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Jean M Nunes , Douglas B Kell , Etheresia Pretorius   Affiliations Expand  PMID: 38675914   PMCID: PMC11053605
Abstract
Understanding the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that a herpesvirus infection of endothelial cells (ECs) may underlie ME/CFS symptomatology. We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment-symptoms consistent with ME/CFS and Long COVID. This paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation. We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within the ECs of ME/CFS patients. This review offers conceptual advances by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research toward potentially unexplored avenues in understanding and treating this complex syndrome.
Keywords: endothelial cells; herpesvirus; myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
PubMed Disclaimer
Conflict of interest statement
The authors declare no conflicts of interest.

-------------------------------------------------------------

J Transl Med. 2024; 22: 630.   Published online 2024 Jul 5. doi: 10.1186/s12967-024-05412-3
PMCID: PMC11227206 PMID: 38970055
Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone
Matthias Löhn1 and Klaus Josef Wirth1,2  
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with a broad overlap of symptomatology with Post-COVID Syndrome (PCS). Despite the severity of symptoms and various neurological, cardiovascular, microvascular, and skeletal muscular findings, no biomarkers have been identified. The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development. TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment. We propose that TRPM3 dysfunction may have a broader involvement in ME/CFS pathophysiology, affecting other organs. This paper discusses TRPM3’s expression in various organs and its potential impact on ME/CFS symptoms, with a focus on small nerve fibers and the brain, where TRPM3 is involved in presynaptic GABA release.
Keywords: TRPM3 channel, Myalgic Encephalomyelitis/Chronic fatigue syndrome, ME/CFS, Post-COVID syndrome, Long-COVID, Exercise intolerance, GABA, Small fiber neuropathy, Naltrexone
-------------------------------------------------------------

J Transl Med  . 2024 Jul 5;22(1):630.  doi: 10.1186/s12967-024-05412-3.
Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone
Matthias Löhn 1, Klaus Josef Wirth 2 3
PMID: 38970055  PMCID: PMC11227206   DOI: 10.1186/s12967-024-05412-3
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with a broad overlap of symptomatology with Post-COVID Syndrome (PCS). Despite the severity of symptoms and various neurological, cardiovascular, microvascular, and skeletal muscular findings, no biomarkers have been identified. The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development. TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment. We propose that TRPM3 dysfunction may have a broader involvement in ME/CFS pathophysiology, affecting other organs. This paper discusses TRPM3's expression in various organs and its potential impact on ME/CFS symptoms, with a focus on small nerve fibers and the brain, where TRPM3 is involved in presynaptic GABA release.
Keywords: Exercise intolerance; GABA; Long-COVID; ME/CFS; Myalgic Encephalomyelitis/Chronic fatigue syndrome; Naltrexone; Post-COVID syndrome; Small fiber neuropathy; TRPM3 channel.
© 2024. The Author(s).

-------------------------------------------------------------

J Cereb Blood Flow Metab   . 2024 Aug 7:271678X241270528.
 doi: 10.1177/0271678X241270528. Online ahead of print.
Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI
Laura Schönberg 1 2, Abdalla Z Mohamed 1, Qiang Yu 1, Richard A Kwiatek 1, Peter Del Fante 1, Vince D Calhoun 3, Zack Y Shan 1
PMID: 39113421     DOI: 10.1177/0271678X241270528
Abstract
Neurological symptoms are central to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), yet its underlying neurophysiological mechanisms remain elusive. We examined a neglected aspect of task-based functional MRI, focusing on how blood oxygenation level-dependent (BOLD) signals alter during cognitive tasks in ME/CFS. This prospective observational study utilised MRI scans on ME/CFS participants and healthy controls (HCs) with sedentary lifestyles (ACTRN12622001095752). Participants completed two blocks of a Symbol Digit Modalities Test, with 30 trials per block split into two sets. The fMRI signal changes between blocks and sets were compared within and between groups. Thirty-four ME/CFS participants (38 years ± 10; 27 women) and 34 HCs (38 ± 10; 27 women), were evaluated. In the second task block, ME/CFS participants exhibited increased activation in the right postcentral gyrus, contrasting with decreased activation in multiple regions in HCs. These results were further confirmed by significantly higher bilateral dynamic changes (2nd vs 1st set) in the motor, sensory and cognitive cortex in ME/CFS compared to HCs and significant correlations between those changes in the left primary motor cortex with fatigue severities. BOLD adaptation, potentially improving energy economy, was absent in ME/CFS, which may provide an underlying neurophysiological process in ME/CFS.
Keywords: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); Symbol Digit Modalities Test (SDMT); fatigue severity; neurophysiological adaptation; task functional MRI (tfMRI).

-------------------------------------------------------------

ACS Chemical NeuroscienceExpand
Research ArticleSeptember 20, 2024
Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry
Sandy Abujrais,Theodosia Vallianatou,Jonas Bergquist*
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex illness characterized by severe and often disabling physical and mental fatigue. So far, scientists have not been able to fully pinpoint the biological cause of the illness and yet it affects millions of people worldwide. To gain a better understanding of ME/CFS, we compared the metabolic networks in the plasma of 38 ME/CFS patients to those of 24 healthy control participants. This involved an untargeted metabolomics approach in addition to the measurement of targeted substances including tryptophan and its metabolites, as well as tyrosine, phenylalanine, B vitamins, and hypoxanthine using liquid chromatography coupled to mass spectrometry. We observed significant alterations in several metabolic pathways, including the vitamin B3, arginine-proline, and aspartate-asparagine pathways, in the untargeted analysis. The targeted analysis revealed changes in the levels of 3-hydroxyanthranilic acid, 3-hydroxykynurenine, hypoxanthine, and phenylalanine in ME/CFS patients compared to the control group. These findings suggest potential alterations in immune system response and oxidative stress in ME/CFS patients.
This publication is licensed under   CC-BY 4.0 .

-------------------------------------------------------------

Original Investigation      Public Health     October 7, 2024
Post–COVID-19 Condition Fatigue Outcomes Among Danish Residents
Elisabeth O’Regan, MMedSc1; Lampros Spiliopoulos, MSc1; Ingrid Bech Svalgaard, MSc1; et alNete Munk Nielsen, MD, PhD1,2; Anna Irene Vedel Sørensen, PhD3; Peter Bager, PhD1; Poul Videbech, MD, PhD4,5; Steen Ethelberg, PhD3,6; Anders Koch, MD, MPH, PhD3,7; Anders Hviid, MSc, DMSC1,8
Author Affiliations Article Information
JAMA Netw Open. 2024;7(10):e2434863. doi:10.1001/jamanetworkopen.2024.34863
Key Points
Question  Is SARS-CoV-2 infection associated with self-reported fatigue and postexertional malaise over time?
Findings  In this population-based cohort study of 50 115 Danish participants, where most of the study population was vaccinated before testing for SARS-CoV-2, a 3% increase in self-reported fatigue and 2-fold increase in symptoms of postexertional malaise were found 2 to 18 months after infection, compared with noninfected controls. In the same period, persons hospitalized with acute SARS-CoV-2 infection experienced a 23% increase in fatigue.
Meaning  The burden of post–COVID-19 condition fatigue was highest among patients with more severe cases of infection and was long-lasting, suggesting that patients with severe acute infection may benefit from clinical follow-up for fatigue.
Abstract
Importance  Fatigue remains one of the most common and debilitating symptoms of post–COVID-19 condition; however, existing studies are limited to select populations and often lack noninfected controls. It also remains unclear to what extent severity of infection and psychiatric conditions, which are often linked to chronic fatigue, modify the risk of post–COVID-19 condition fatigue symptoms.
Objective  To evaluate the impact of SARS-CoV-2 infection on self-reported fatigue and postexertional malaise over time and to explore possible risk factors, such as the impact of acute SARS-CoV-2 hospitalization and preexisting psychiatric conditions on postacute fatigue.
Design, Setting, and Participants  In this cohort study, Danish residents aged 15 years and older were invited to participate in the EFTER-COVID survey, which used repeated, self-reported online questionnaires that collected information on fatigue (Fatigue Assessment Scale) and postexertional malaise scores (DePaul Symptom Questionnaire) after individuals’ index SARS-CoV-2 polymerase chain reaction test. Participants were included if they completed a baseline and at least 1 follow-up questionnaire 2 to 18 months after testing for SARS-CoV-2.
Exposure  Testing for SARS-CoV-2 infection.
Main Outcomes and Measures  The primary outcomes were fatigue and postexertional malaise 2 to 18 months after testing. Mixed-effects models were used to compare scores between SARS-CoV-2 test-positive and test-negative individuals (testing period April 2021 to February 2023).
Results  Of a total of 50 115 participants (median [IQR] age at test date, 57 [46-67] years; 29 774 female [59.4%]), 25 249 were test positive and 24 866 were test negative. Most participants were vaccinated with at least 2 doses (21 164 test-negative participants [85.1%] and 22 120 test-positive participants [87.6%]) before their SARS-CoV-2 index test and fatigue reporting. In the period 2 to 18 months after testing, SARS-CoV-2 infection was associated with a small but significant 3% increase in self-reported fatigue scores (score ratio [SR], 1.03; 95% CI, 1.03-1.04) and higher odds of self-reported postexertional malaise (odds ratio, 2.04; 95% CI, 1.81-2.30), compared with test-negative participants. In the same period, hospitalization with SARS-CoV-2 increased fatigue scores by 23% (SR, 1.23; 95% CI, 1.20-1.26) compared with test-negative participants. Preexisting psychiatric conditions did not significantly modify postacute fatigue scores.
Conclusions and Relevance  In this cohort study, SARS-CoV-2 infection was associated with a subtle increase in self-reported fatigue and postexertional malaise symptoms 2 to 18 months after mild infection. In contrast, individuals hospitalized with acute SARS-CoV-2 experienced a more substantial increase in postacute symptoms. Preexisting psychiatric conditions did not significantly modify the risk of postacute fatigue symptoms. The findings largely captured symptoms following first-time infections in a population where most had been vaccinated. Persons who experienced severe acute infection may benefit from clinical follow-up for fatigue.
Care for people with severe ME is “nonexistent,” says coroner in call to action
BMJ 2024; 387 doi: https://doi.org/10.1136/bmj.q2202 (Published 08 October 2024)
The complete lack of specialist care in England for patients with severe myalgic encephalomyelitis (ME or chronic fatigue syndrome) could cause deaths in future unless urgent action is taken, a coroner has warned.
The hard hitting prevention of future deaths (PFD) report by assistant coroner Deborah Archer on the death of Maeve Boothby O’Neill, 27, also highlighted the lack of research funding, training, and guidelines on treating the condition.
The report, thought to be the first such report on the death of a patient with ME, has been sent to the health and social care secretary, Wes Streeting, and health minister Andrew Gwynne; NHS England; the National Institute for Health and Care Excellence (NICE); the Medical Research Council; the National Institute for Health and Care Research; and the Medical Schools Council.
O’Neill, who was bedbound, died at home in October 2021 after three admissions to the Royal Devon and Exeter Hospital.
-------------------------------------------------------------

University of Cambridge: Ultra-powered MRI scans show damage to brain’s ‘control centre’ is behind long-lasting Covid-19 symptoms
October 9, 2024
Using ultra-high-resolution scanners that can see the living brain in fine detail, researchers from the Universities of Cambridge and Oxford were able to observe the damaging effects Covid-19 can have on the brain.
University of Cambridge
Extracts
The study team scanned the brains of 30 people who had been admitted to hospital with severe Covid-19 early in the pandemic, before vaccines were available. The researchers found that Covid-19 infection damages the region of the brainstem associated with breathlessness, fatigue and anxiety.
The powerful MRI scanners used for the study, known as 7-Tesla or 7T scanners, can measure inflammation in the brain. Their results, published in the journal Brain, will help scientists and clinicians understand the long-term effects of Covid-19 on the brain and the rest of the body. Although the study was started before the long-term effects of Covid were recognised, it will help to better understand this condition.
The brainstem, which connects the brain to the spinal cord, is the control centre for many basic life functions and reflexes. Clusters of nerve cells in the brainstem, known as nuclei, regulate and process essential bodily functions such as breathing, heart rate, pain and blood pressure.
The researchers say the results could aid in the understanding of other conditions associated with inflammation of the brainstem, like MS and dementia. The 7T scanners could also be used to monitor the effectiveness of different treatments for brain diseases.
What Long COVID investigators can learn from four decades of ME/ CFS research 
☆ Leonard A. Jason a , * Suzanne D. Vernon , Benjamin H. Natelson e b , Hector Bonilla , Monica Verduzco Gutierrez f c , Zaki A. Sherif , Lisa O’Brien g d , , Emily Taylor h , 
On behalf of the RECOVER consortium, by members of the Diagnostic Testing and Test Algorithms Subcommittee of the Commonalities with Other Post Viral Syndromes Task Force. We appreciate the edits and suggestions from Ben Z. Katz. a b c d e f g h DePaul University, USA Icahn School of Medicine at Mount Sina, USA Stanford University, USA Howard University, USA Bateman Horne Center, USA UT Health San Antonio, USA Utah Long Haulers, USA Solve/ME, USA ARTICLE INFO 
ABSTRACT Keywords: Long COVID ME/CFS Similarities Case Definition Four decades of research in the field of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) have yielded lessons that may be instructive for those devising criteria to better comprehend Post-Acute Sequelae of SARS CoV-2 Infection (PASC) and Long COVID. For instance, substantial effort has been devoted to defining classification systems, operationalizing methods, and developing instruments with adequate reliability and validity in the ME/CFS field. The current article provides guidelines for developing a case definition for Long COVID and discusses the significance of psychometric issues and criterion variance, including how to specify symptoms, and develop thresholds, subtypes, and exclusionary conditions. ME/CFS research could enhance our knowledge of Long COVID pathophysiology, early diagnosis, prognosis, and the identification of effective treatments. Four decades of ME/CFS research: what Long COVID researchers

Muscle abnormalities worsen after post-exertional malaise in long COVID
Brent Appelman, Braeden T. Charlton, Richie P. Goulding, Tom J. Berkhoff, Ellen A. Breedveld, Wendy Noort, Carla Offringa, Frank W. Bloemers, Michel van Weeghel, Bauke V. Schomakers, Pedro Coelho, Jelle J. Posthuma, Eleonora Aronica, W. Joost Wiersinga, Michèle van Vugt & Rob C. I. Wüst 
Nature Communications volume 15, Article number: 17 (2024) Cite this article
Abstract
A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.

--------------------------------------------------------------------
Brain Behav Immun Health. 2024 Mar; 36: 100733.
Published online 2024 Feb 1. doi: 10.1016/j.bbih.2024.100733
PMCID: PMC10862402  PMID: 38352659
Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19
Anar Isman,a Andy Nyquist,a,∗ Bailey Strecker,a Girish Harinath,a Virginia Lee,a Xingyu Zhang,b and Sajad Zalzalaa
Abstract
A subset of patients experiences persistent fatigue symptoms after COVID-19, and patients may develop long COVID, which is characterized by lasting systemic symptoms. No treatments for this condition have been validated and are urgently warranted. In this pilot study, we assessed whether treatment with low-dose naltrexone (LDN, 4.5 mg/day) and supplementation with NAD + through iontophoresis patches could improve fatigue symptoms and quality of life in 36 patients with persistent moderate/severe fatigue after COVID-19. We detected a significant increase from baseline in SF-36 survey scores after 12 weeks of treatment (mean total SF-36 score 36.5 [SD: 15.6] vs. 52.1 [24.8]; p < 0.0001), suggestive of improvement of quality of life. Furthermore, participants scored significantly lower on the Chalder fatigue scale after 12 weeks of treatment (baseline: 25.9 [4.6], 12 weeks: 17.4 [9.7]; p < 0.0001). We found a subset of 52 % of patients to be responders after 12 weeks of treatment. Treatment was generally safe, with mild adverse events previously reported for LDN, which could be managed with dose adjustments. The iontophoresis patches were associated with mild, short-lived skin irritation in 25 % of patients. Our data suggest treatment with LDN and NAD+ is safe and may be beneficial in a subset of patients with persistent fatigue after COVID-19. Larger randomized controlled trials will have to confirm our data and determine which patient subpopulations might benefit most from this strategy.
Keywords: COVID-19, Long COVID, Fatigue, Quality of life, Low dose naltrexone, NAD+, SF-36

--------------------------------------------------------------------

ARTICLE| VOLUME 5, ISSUE 1, 101373, JANUARY 16, 2024
Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation
Luyen Tien Vu ,Faraz Ahmed 7,Hongya Zhu 7,Maureen R. Hanson,Jennifer K. Grenier,Andrew Grimson 8,et al        DOI:https://doi.org/10.1016/j.xcrm.2023.101373
Highlights
The ME/CFS immune system is profiled by scRNA-seq at baseline and after provocation.
Monocyte dysregulation is prominent and dysregulation correlates with disease severity
Platelets are also dysregulated, but this dysregulation resolves after provocation
Summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and poorly understood disease. To understand immune dysregulation in ME/CFS, we use single-cell RNA sequencing (scRNA-seq) to examine immune cells in patient and control cohorts. Postexertional malaise (PEM), an exacerbation of symptoms following strenuous exercise, is a characteristic symptom of ME/CFS. To detect changes coincident with PEM, we applied scRNA-seq on the same cohorts following exercise. At baseline, ME/CFS patients display classical monocyte dysregulation suggestive of inappropriate differentiation and migration to tissue. We identify both diseased and more normal monocytes within patients, and the fraction of diseased cells correlates with disease severity. Comparing the transcriptome at baseline and postexercise challenge, we discover patterns indicative of improper platelet activation in patients, with minimal changes elsewhere in the immune system. Taken together, these data identify immunological defects present at baseline in patients and an additional layer of dysregulation in platelets.

--------------------------------------------------------------------

A phenomenological study on the lived experience of men with Chronic Fatigue Syndrome
Gracie Elizabeth Snellhttps://orcid.org/0000-0002-1472-8196[email protected], Catherine Heidi Seage https://orcid.org/0000-0002-8590-867X, and Jenny Mercer https://orcid.org/0000-0001-5917-0491View all authors and affiliations
Journal of Health Psychology   Volume 29, Issue 3
https://doi.org/10.1177/13591053231186385
Abstract
Whilst chronic fatigue syndrome (CFS) has been widely researched amongst women, studies investigating how men experience a CFS diagnosis is limited. This study utilised an interpretative phenomenological approach to interview five men who have a medical diagnosis of CFS. Six themes emerged to demonstrate the participants’ experiences prior to, during and after obtaining their CFS diagnosis. Findings revealed that participants were initially reluctant to accept their condition, confounded by their perception that symptoms compromised their sense of masculinity. They also felt that healthcare professionals had limited recognition of CFS leading them to seek social support and legitimisation from other sources. The struggle to come to terms with a different lifestyle and sense of masculinity prevailed. Such knowledge could be effectively utilised by researchers, practitioners and employers to facilitate an increased understanding of male accounts of the condition and more bespoke interventions where required.

--------------------------------------------------------------------

Unravelling shared mechanisms: insights from recent ME/CFS research to illuminate long COVID pathologies
Sarah J. Annesley  Daniel Missailidis  Benjamin Heng  Elisha K. Josev , Christopher W. Armstrong 7
Published:March 04, 2024DOI:https://doi.org/10.1016/j.molmed.2024.0

Highlights

• Approximately half of patients with long COVID (LC) fulfil the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The two conditions share clinical similarities and proposed disease pathologies, but it is still unclear whether they also share common molecular abnormalities.
• Most consistently altered pathologies in ME/CFS and LC include an increased reliance on alternatives to carbohydrates as substrates for energy production and altered gut microbiota, with a reduction in butyrate-synthesising bacteria.
• Therapeutic approaches targeted at the autoimmune response showed early promising results, but have not passed further clinical trials.
• ME/CFS and LC research has identified potential biomarkers, which need to be replicated and validated, with the most accurate and clinically practicable appearing to be measurements of RNAs for ME/CFS.

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic illness often triggered by an initiating acute event, mainly viral infections. The transition from acute to chronic disease remains unknown, but interest in this phenomenon has escalated since the COVID-19 pandemic and the post-COVID-19 illness, termed ‘long COVID’ (LC). Both ME/CFS and LC share many clinical similarities. Here, we present recent findings in ME/CFS research focussing on proposed disease pathologies shared with LC. Understanding these disease pathologies and how they influence each other is key to developing effective therapeutics and diagnostic tests. Given that ME/CFS typically has a longer disease duration compared with LC, with symptoms and pathologies evolving over time, ME/CFS may provide insights into the future progression of LC.

--------------------------------------------------------------------

Experts call for more research into long COVID, as study reveals high prevalence in WA
By Emily JB Smith, Rebecca Trigger, and Phoebe Pin   (U Tube)
Posted Wed 3 Apr 2024 at 10:15amWednesday 3 Apr 2024 at 10:15am, updated Thu 4 Apr 2024 at 12:06am

• In short: A study conducted in WA found nearly 20 per cent of COVID-19 patients experienced debilitating symptoms like fatigue and memory loss three months after infection.
• It indicated a higher prevalence of long-term symptoms in WA compared to earlier studies in Australia, the UK, and Canada.
• What's next? Authorities are being urged to develop more practical policies to assist people with long COVID.

Researchers say more support is needed for patients suffering from long-term illness associated with a COVID-19 infection, with new data showing a large number of West Australians have been left unable to work due to their crippling symptoms.
The Australian National University (ANU) study surveyed 11,000 people who tested positive to COVID during a significant outbreak of the Omicron variant in WA in 2022.
The study published in March found almost 20 per cent of those patients were still suffering symptoms of fatigue, memory loss and concentration difficulties three months after they first became sick.
Lead researcher Mulu Woldegiorgis said there was little pre-existing data available on the topic, but that the new research suggested there was a high rate of long-term COVID-19 symptoms in WA.
In their report, Dr Woldegiorgis and her colleagues acknowledged one of the limitations of the ANU survey was that it relied on subjective symptom descriptions from patients, and the reported impact of their symptoms on work or study was not independently verified.
Dr Woldegiorgis said it was important for patients' symptoms to be taken seriously.
"I think it's real and it needs more investigation," she said.
"When we see its impact on work or study, more than one in six of those who used to work before their infection were not able to fully return to work or study due to their ongoing symptoms."

--------------------------------------------------------------------

A body–brain circuit that regulates body inflammatory responses
Hao Jin, Mengtong Li, Eric Jeong, Felipe Castro-Martinez & Charles S. Zuker 
Nature (2024)Cite this article
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
Abstract
The body-brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function1,2, metabolism3 and nutritional state4-6. Here, we show that a peripheral immune insult powerfully activates the body-brain axis to regulate immune responses. We demonstrate that pro- and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body-to-brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords exceptional neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuro-immune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock.

--------------------------------------------------------------------

Front. Immunol., 18 January 2024 Sec. Viral Immunology
Volume 15 - 2024 | https://doi.org/10.3389/fimmu.2024.1341843
Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome
Suguru Saito1Shima Shahbaz1Xian Luo2Mohammed Osman3Desiree Redmond3Jan Willem Cohen Tervaert3Liang Li2,4Shokrollah Elahi1,5*†

• 1School of Dentistry, Division of Foundational Sciences, Edmonton, AB, Canada
• 2The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB, Canada
• 3Department of Medicine, Division of Rheumatology, Edmonton, AB, Canada
• 4Department of Chemistry, University of Alberta, Edmonton, AB, Canada
• 5Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

Introduction: A group of SARS-CoV-2 infected individuals present lingering symptoms, defined as long COVID (LC), that may last months or years post the onset of acute disease. A portion of LC patients have symptoms similar to myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), which results in a substantial reduction in their quality of life. A better understanding of the pathophysiology of LC, in particular, ME/CFS is urgently needed.
Methods: We identified and studied metabolites and soluble biomarkers in plasma from LC individuals mainly exhibiting ME/CFS compared to age-sex-matched recovered individuals (R) without LC, acute COVID-19 patients (A), and to SARS-CoV-2 unexposed healthy individuals (HC).
Results: Through these analyses, we identified alterations in several metabolomic pathways in LC vs other groups. Plasma metabolomics analysis showed that LC differed from the R and HC groups. Of note, the R group also exhibited a different metabolomic profile than HC. Moreover, we observed a significant elevation in the plasma pro-inflammatory biomarkers (e.g. IL-1α, IL-6, TNF-α, Flt-1, and sCD14) but the reduction in ATP in LC patients. Our results demonstrate that LC patients exhibit persistent metabolomic abnormalities 12 months after the acute COVID-19 disease. Of note, such metabolomic alterations can be observed in the R group 12 months after the acute disease. Hence, the metabolomic recovery period for infected individuals with SARS-CoV-2 might be long-lasting. In particular, we found a significant reduction in sarcosine and serine concentrations in LC patients, which was inversely correlated with depression, anxiety, and cognitive dysfunction scores.
Conclusion: Our study findings provide a comprehensive metabolomic knowledge base and other soluble biomarkers for a better understanding of the pathophysiology of LC and suggests sarcosine and serine supplementations might have potential therapeutic implications in LC patients. Finally, our study reveals that LC disproportionally affects females more than males, as evidenced by nearly 70% of our LC patients being female.
--------------------------------------------------------------------

Published: 03 January 2024
Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study
Al Ozonoff, Naresh Doni Jayavelu, Shanshan Liu, Esther Melamed, Carly E. Milliren, Jingjing Qi, Linda N. Geng, Grace A. McComsey, Charles B. Cairns, Lindsey R. Baden, Joanna Schaenman, Albert C. Shaw, Hady amaha, Vicki Seyfert-Margolis, Florian Krammer, Lindsey B. Rosen, Hanno Steen, Caitlin Syphurs, Ravi Dandekar, Casey P. Shannon, Rafick P. Sekaly, Lauren I. R. Ehrlich, David B. Corry, Farrah Kheradmand, IMPACC Network, Nadine Rouphael 
Nature Communications volume 15, Article number: 216 (2024)  
Abstract
Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.

--------------------------------------------------------------------

STATE-OF-THE-ART REVIEW| FEBRUARY 07 2024

Postacute Sequelae of SARS-CoV-2 in Children 
Suchitra Rao, MBBS, MSCS;Rachel S. Gross, MD, MS;Sindhu Mohandas, MD;Cheryl R. Stein, PhD;Abigail Case, MD;Benard Dreyer, MD;Nathan M. Pajor, MD;H. Timothy Bunnell, PhD;David Warburton, MD;E lizabeth Berg, MD;Jonathan B. Overdevest, MD;Mark Gorelik, MD;Joshua Milner, MD;Sejal Saxena, BA;Ravi Jhaveri, MD;John C. Wood, MD, PhD;Kyung E. Rhee, MD, MSc, MA;Rebecca Letts, BA;Christine Maughan, BS;  Nick Guthe, BA;Leah Castro-Baucom, MA;Melissa S. Stockwell, MD, MPH
Pediatrics (2024) 153 (3): e2023062570.
https://doi.org/10.1542/peds.2023-062570

The coronavirus disease 2019 (COVID-19) pandemic has caused significant medical, social, and economic impacts globally, both in the short and long term. Although most individuals recover within a few days or weeks from an acute infection, some experience longer lasting effects. Data regarding the postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) in children, or long COVID, are only just emerging in the literature. These symptoms and conditions may reflect persistent symptoms from acute infection (eg, cough, headaches, fatigue, and loss of taste and smell), new symptoms like dizziness, or exacerbation of underlying conditions. Children may develop conditions de novo, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune conditions and multisystem inflammatory syndrome in children. This state-of-the-art narrative review provides a summary of our current knowledge about PASC in children, including prevalence, epidemiology, risk factors, clinical characteristics, underlying mechanisms, and functional outcomes, as well as a conceptual framework for PASC based on the current National Institutes of Health definition. We highlight the pediatric components of the National Institutes of Health-funded Researching COVID to Enhance Recovery Initiative, which seeks to characterize the natural history, mechanisms, and long-term health effects of PASC in children and young adults to inform future treatment and prevention efforts. These initiatives include electronic health record cohorts, which offer rapid assessments at scale with geographical and demographic diversity, as well as longitudinal prospective observational cohorts, to estimate disease burden, illness trajectory, pathobiology, and clinical manifestations and outcomes.

--------------------------------------------------------------------

ORIGINAL RESEARCH article
Front. Pediatr., 18 January 2024
Sec. Children and Health
Volume 11 - 2023 | https://doi.org/10.3389/fped.2023.1266738
One-year follow-up of young people with ME/CFS following infectious mononucleosis by Epstein-Barr virus
Rafael Pricoco1 Paulina Meidel1 Tim Hofberger1 Hannah Zietemann1 Yvonne Mueller1 Katharina Wiehler1 Kaja Michel1 Johannes Paulick1 Ariane Leone1 Matthias Haegele1 Sandra Mayer-Huber1 Katrin Gerrer1 Kirstin Mittelstrass1 Carmen Scheibenbogen2 Herbert Renz-Polster3 Lorenz Mihatsch1*† Uta Behrends1,4,†

• 1MRI Chronic Fatigue Center for Young People (MCFC), Children’s Hospital, TUM School of Medicine, Technical University of Munich and Munich Municipal Hospital Schwabing, Munich, Germany
• 2Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin and Berlin Institute of Health (BIH), Berlin, Germany
• 3Mannheim Institute of Public Health, Social and Preventive Medicine, University Medicine Mannheim, Heidelberg, Germany
• 4German Center for Infection Research (partner site Munich), Munich, Germany

Background: Infectious mononucleosis after primary infection with Epstein-Barr virus (EBV-IM) has been linked to the development of myalgic encephalomyelitis/chronic fatigue-syndrome (ME/CFS) in children, adolescents, and young adults. Here, we present clinical phenotypes and follow-up data from a first German cohort of young people with ME/CFS following EBV-IM.
Methods: 12 adolescents and 13 young adults were diagnosed with IM-triggered ME/CFS at our specialized tertiary outpatient service by clinical criteria requiring post-exertional malaise (PEM) and a history of confirmed EBV primary infection as triggering event. Demographic information, laboratory findings, frequency and severity of symptoms, physical functioning, and health-related quality of life (HRQoL) were assessed and re-evaluated 6 and 12 months later.
Results: Young adults displayed more severe symptoms as well as worsening of fatigue, physical and mental functioning, and HRQoL throughout the study, compared to adolescents. After one year, 6/12 (54%) adolescents no longer met the diagnostic criteria for ME/CFS while all young adults continued to fulfill the Canadian consensus criteria. Improvement in adolescents was evident in physical functioning, symptom frequency and severity, and HRQoL, while young adults showed little improvement. EBV serology and EBV DNA load did not correlate with distinct clinical features of ME/CFS, and clinical chemistry showed no evidence of inflammation. Remarkably, the median time from symptom onset to ME/CFS diagnosis was 13.8 (IQR: 9.1–34.9) months.
Conclusions: ME/CFS following EBV-IM is a severely debilitating disease often diagnosed late and with limited responses to conventional medical care, especially in adults. Although adolescents may have a better prognosis, their condition can fluctuate and significantly impact their HRQoL. Our data emphasize that biomarkers and effective therapeutic options are also urgently needed to improve medical care and pave the way to recovery.

--------------------------------------------------------------------

2024 Jan;13(1):e12403. doi: 10.1002/jev2.12403.
Dysregulation of extracellular vesicle protein cargo in female myalgic encephalomyelitis/chronic fatigue syndrome cases and sedentary controls in response to maximal exercise
Ludovic Giloteaux 1, Katherine A Glass 1, Arnaud Germain 1, Carl J Franconi 1, Sheng Zhang 2, Maureen R Hanson 1
PMID: 38173127     PMCID: PMC10764978    DOI: 10.1002/jev2.12403
Abstract
In healthy individuals, physical exercise improves cardiovascular health and muscle strength, alleviates fatigue and reduces the risk of chronic diseases. Although exercise is suggested as a lifestyle intervention to manage various chronic illnesses, it negatively affects people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), who suffer from exercise intolerance. We hypothesized that altered extracellular vesicle (EV) signalling in ME/CFS patients after an exercise challenge may contribute to their prolonged and exacerbated negative response to exertion (post-exertional malaise). EVs were isolated by size exclusion chromatography from the plasma of 18 female ME/CFS patients and 17 age- and BMI-matched female sedentary controls at three time points: before, 15 min, and 24 h after a maximal cardiopulmonary exercise test. EVs were characterized using nanoparticle tracking analysis and their protein cargo was quantified using Tandem Mass Tag-based (TMT) proteomics. The results show that exercise affects the EV proteome in ME/CFS patients differently than in healthy individuals and that changes in EV proteins after exercise are strongly correlated with symptom severity in ME/CFS. Differentially abundant proteins in ME/CFS patients versus controls were involved in many pathways and systems, including coagulation processes, muscle contraction (both smooth and skeletal muscle), cytoskeletal proteins, the immune system and brain signalling.
Keywords: ME/CFS; chronic fatigue syndrome; exercise; extracellular vesicle cargo; myalgic encephalomyelitis; proteomics.
© 2024 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.

--------------------------------------------------------------------

Exp Physiol   . 2024 Jun 14.   doi: 10.1113/EP091986. Online ahead of print.
Cell-free DNA kinetics in response to muscle-damaging exercise: A drop jump study
Ema Juškevičiūtė 1 2, Elmo Neuberger 2, Nerijus Eimantas 1, Kirsten Heinkel 2, Perikles Simon 2, Marius Brazaitis 1
PMID: 38875105   DOI: 10.1113/EP091986
Abstract
A significant increase in circulating cell-free DNA (cfDNA) occurs with physical exercise, which depends on the type of exertion and the duration. The aims of this study were as follows: (1) to investigate the time course of cfDNA and conventional markers of muscle damage from immediately after to 96 h after muscle-damaging exercise; and (2) to investigate the relationship between cfDNA and indicators of primary (low-frequency fatigue and maximal voluntary isometric contraction) and secondary (creatine kinase and delayed-onset muscle soreness) muscle damage in young healthy males. Fourteen participants (age, 22 ± 2 years; weight, 84.4 ± 11.2 kg; height, 184.0 ± 7.4 cm) performed 50 intermittent drop jumps at 20 s intervals. We measured cfDNA and creatine kinase concentrations, maximal voluntary isometric contraction torque, low-frequency fatigue and delayed-onset muscle soreness before and at several time points up to 96 h after exercise. Plasma cfDNA levels increased from immediately postexercise until 72 h postexercise (P < 0.01). Elevation of postexercise cfDNA was correlated with both more pronounced low-frequency fatigue (r = -0.52, P = 3.4 × 10-11) and delayed-onset muscle soreness (r = 0.32, P = 0.00019). Levels of cfDNA change in response to severe primary and secondary muscle damage after exercise. Levels of cfDNA exhibit a stronger correlation with variables related to primary muscle damage than to secondary muscle damage, suggesting that cfDNA is a more sensitive marker of acute loss of muscle function than of secondary inflammation or damaged muscle fibres.
Keywords: blood markers; cell‐free DNA; eccentric exercise; muscle damage.
© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

--------------------------------------------------------------------

Published: 04 January 2024
Muscle abnormalities worsen after post-exertional malaise in long COVID
Brent Appelman, Braeden T. Charlton, Richie P. Goulding, Tom J. Kerkhoff, Ellen A. Breedveld, Wendy Noort, Carla Offringa, Frank W. Bloemers, Michel van Weeghel, Bauke V. Schomakers, Pedro Coelho, Jelle J. Posthuma, Eleonora Aronica, W. Joost Wiersinga, Michèle van Vugt & Rob C. I. Wüst 
Nature Communications volume 15, Article number: 17 (2024)  
Abstract
A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.

--------------------------------------------------------------------

Successful Subcutaneous Immunoglobulin Therapy in a Case Series of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
GEPUBLICEERD OP 24 juni 2024     Sjogren, Bragée, Britton
Abstract
Purpose
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains an enigma with no curable treatment options at hand. Although patients with ME/CFS are a heterogeneous group, a large proportion of patients present with an infection-driven symptomatology, making them potential responders to immunologic treatments, such as immunoglobulin (IG).
Previous studies on IG treatment in patients with ME/CFS have not been consistent but have described beneficial effects in subgroups of patients.
Methods
Here we present data on a series of cases (n = 17) with infection-related ME/CFS (as defined by disease history and ongoing recurrent infections) treated with subcutaneous low-dose IG (0.06 g/kg/mo) over 5 weeks with continuous monitoring of symptoms.
Findings
Patients were predominantly female (65%) with mild-to-moderate disease severity (82%) and with poor self-reported quality of life (median, 25 on a 0-100 scale) and working ability (median, 5 on a 0-100 scale) before treatment. After 5 weeks of treatment with low-dose IG, significant improvements in symptoms, quality of life, and working ability were noted (all P < 0.05). Among the 7 patients who reported the highest benefit of the treatment, quality of life increased by 35 units (on a 0-100 scale), with 1 patient reporting complete elimination of ME/CFS symptoms. No serious side effects were detected with the treatment.
Implications
In this limited-sized case series, we found pronounced beneficial effects of low-dose IG in a large proportion of patients with infection-related ME/CFS. Further well-controlled studies are needed to verify the potential benefits of IG treatment in patients with ME/CFS with infection-driven symptomatology.

--------------------------------------------------------------------

Source: Clinical Therapeutics, open access
Ageing Res Rev. 2024 Jun 28:102400. doi: 10.1016/j.arr.2024.102400. Online ahead of print.
Long COVID as a Disease of Accelerated Biological Aging: An Opportunity to Translate Geroscience Interventions
Areez Shafqat 1, Mary Clare Masters 2, Utkarsh Tripathi 3, Tamara Tchkonia 4, James L Kirkland 5, Shahrukh K Hashmi 6
PMID: 38945306    DOI: 10.1016/j.arr.2024.102400
Abstract
It has been four years since long COVID-the protracted consequences that survivors of COVID-19 face-was first described. Yet, this entity continues to devastate the quality of life of an increasing number of COVID-19 survivors without any approved therapy. Furthermore, there remains a paucity of clinical trials addressing the biological root causes of this disease. Notably, the symptoms of long COVID-including but not limited to exercise intolerance, cognitive impairment, orthostasis, and functional decline-are typically seen with advancing age. Leveraging this similarity, we posit that Geroscience-which aims to target the biological drivers of aging to prevent age-associated conditions as a group-could offer promising therapeutic avenues for long COVID. Bearing this in mind, this review presents a framework for studying long COVID as a state of effectively accelerated biological aging. Thus, we comprehensively review here the role of biological hallmarks of aging in long COVID, identifying research gaps and proposing directions for future preclinical and clinical studies.
Keywords: Cellular Senescence; Dysbiosis; Geroscience; Inflammation; Long COVID; Mitochondrial Dysfunction.
Copyright © 2024 Elsevier B.V. All rights reserved.

Cortex     Volume 173, April 2024, Pages 161-174
Behavioural Neurology
Enhanced motor network engagement during reward gain anticipation in fibromyalgia
Su Hyoun Park, Andrew M. Michael, Anne . Baker, Carina Lei, Katherine T. Martucci 
Abstract
Reward motivation is essential in shaping human behavior and cognition. Both reward motivation and reward brain circuits are altered in chronic pain conditions, including fibromyalgia. In this study of fibromyalgia patients, we used a data-driven independent component analysis (ICA) approach to investigate how brain networks contribute to altered reward processing. From females with fibromyalgia (N = 24) and female healthy controls (N = 24), we acquired fMRI data while participants performed a monetary incentive delay (MID) reward task. After analyzing the task-based fMRI data using ICA to identify networks, we analyzed 3 networks of interest: motor network (left), value-driven attention network, and basal ganglia network. Then, we evaluated correlation coefficients between each network timecourse versus a task-based timecourse which modeled gain anticipation. Compared to controls, the fibromyalgia cohort demonstrated significantly stronger correlation between the left motor network timecourse and the gain anticipation timecourse, indicating the left motor network was more engaged with gain anticipation in fibromyalgia. In an exploratory analysis, we compared motor network engagement during early versus late phases of gain anticipation. Across cohorts, greater motor network engagement (i.e., stronger correlation between network and gain anticipation) occurred during the late timepoint, which reflected enhanced motor preparation immediately prior to response. Consistent with the main results, patients exhibited greater engagement of the motor network during both early and late phases compared with healthy controls. Visual-attention and basal ganglia networks revealed similar engagement in the task across groups. As indicated by post-hoc analyses, motor network engagement was positively related to anxiety and negatively related to reward responsiveness. In summary, we identified enhanced reward-task related engagement of the motor network in fibromyalgia using a novel data-driven ICA approach. Enhanced motor network engagement in fibromyalgia may relate to impaired reward motivation, heightened anxiety, and possibly to altered motor processing, such as restricted movement or dysregulated motor planning.
___________________________________________________________________________
 
Clin Neurophysiol. 2023 Jan; 145: 81–88.
Published online 2022 Nov 11. doi: 10.1016/j.clinph.2022.10.017
PMCID: PMC9650483  PMID: 36455453
Co-ultramicronized palmitoylethanolamide/luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome
Viviana Versace,a,⁎,1 Paola Ortelli,a,1 Sabrina Dezi,a Davide Ferrazzoli,a Alessia Alibardi,a Ilenia Bonini,a Michael Engl,b Roberto Maestri,c Martina Assogna,d Valentina Ajello,e Elke Pucks-Faes,f Leopold Saltuari,a Luca Sebastianelli,a Markus Kofler,f,2 and Giacomo Kochd,g,2
Abstract
 
Objective
Transcranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABAB-ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI).
Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI.
 
MethodsThirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700 mg + 70 mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity.
 
Results
Patients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected.
 
Conclusions
Eight weeks of treatment with PEA-LUT restore GABAB activity and cortical plasticity in long Covid patients.
 
Significance
This study confirms altered physiology of the motor cortex in long COVID-19 syndrome and indicates PEA-LUT as a candidate for the treatment of this post-viral condition.
Keywords: Palmitoylethanolamide, Long Covid, Transcranial magnetic stimulation, Long-interval intracortical inhibition, LTP-like cortical plasticity
 
___________________________________________________________________________
 
COVID Virus Can Remain in the Body Over a Year
Ralph Ellis
March 11, 2024 - Medscape
Scientists at the University of California San Francisco have discovered that remnants of the COVID-19 virus can linger in blood and tissue for more than a year after a person is first infected.
In their research on long COVID, the scientists found COVID antigens in the blood for up to 14 months after infection and in tissue samples for more than 2 years after infection.
"These two studies provide some of the strongest evidence so far that COVID antigens can persist in some people, even though we think they have normal immune responses," Michael Peluso, MD, an infectious disease researcher in the UCSF School of Medicine, who led both studies, said in a statement.
Scientists don't know what causes long COVID, in which symptoms of the illness persist months or years after recovery. The most common symptoms are extreme fatigue, shortness of breath, loss of smell, and muscle aches.
The UCSF research team examined blood samples from 171 infected people and found the COVID "spike" protein was still present up to 14 months after infection in some people. The antigens were found more often in people who were hospitalized with COVID or who reported being very sick but were not hospitalized.
Researchers next looked at the UCSF Long COVID Tissue Bank, which contains samples donated by patients with and without long COVID.
They found portions of viral RNA in the tissue up to 2 years after people were infected, though there was no evidence of reinfection. Those viral fragments were found in connective tissue where immune cells are, suggesting that the fragments caused the immune system to attack, according to the researchers.
The UCSF team is running clinical trials to find out if monoclonal antibodies or antiviral drugs can remove the virus.
The findings were presented in Denver this week at the Conference on Retroviruses and Opportunistic Infections.
SOURCES:
EurekAlert: "COVID-19 virus can stay in the body more than a year after infection."
University of California San Francisco: "First Tissue Bank May Help Solve Mystery of Long COVID Misery."
 40

___________________________________________________________________________

Expert Opin Ther Targets. 2017 Aug;21(8):817-826. 
doi: 10.1080/14728222.2017.1353603. Epub 2017 Jul 12.
Sleep disturbances and severe stress as glial activators: key targets for treating central sensitization in chronic pain patients?Jo Nijs 1 2 3, Marco L Loggia 4, Andrea Polli 1 2, Maarten Moens 5 6, Eva Huysmans 1 2, Lisa Goudman 1 2 5, Mira Meeus 1 7 8, Luc Vanderweeën 1 2 9, Kelly Ickmans 1 3, Daniel Clauw 10
PMID: 28685641 DOI: 10.1080/14728222.2017.1353603
AbstractThe mechanism of sensitization of the central nervous system partly explains the chronic pain experience in many patients, but the etiological mechanisms of this central nervous system dysfunction are poorly understood. Recently, an increasing number of studies suggest that aberrant glial activation takes part in the establishment and/or maintenance of central sensitization. Areas covered: This review focused on preclinical work and mostly on the neurobiochemistry studied in animals, with limited human studies available. Glial overactivation results in a low-grade neuroinflammatory state, characterized by high levels of BDNF, IL-1β, TNF-α, which in turn increases the excitability of the central nervous system neurons through mechanisms like long-term potentiation and increased synaptic efficiency. Aberrant glial activity in chronic pain might have been triggered by severe stress exposure, and/or sleeping disturbances, each of which are established initiating factors for chronic pain development. Expert opinion: Potential treatment avenues include several pharmacological options for diminishing glial activity, as well as conservative interventions like sleep management, stress management and exercise therapy. Pharmacological options include propentofylline, minocycline, β -adrenergic receptor antagonists, and cannabidiol. Before translating these findings from basic science to clinical settings, more human studies exploring the outlined mechanisms in chronic pain patients are needed.

___________________________________________________________________________
 
Worsening symptoms is associated with larger cerebral blood flow abnormalities during tilt-testing in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Authors: van Campen CMC, Rowe PC & Visser FC (Stichting CardioZorg, The Netherlands). Publication:  Medicina
Link: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00323-1/fulltext
Previous studies have found that ME/CFS patients experience abnormal reduction in cerebral blood flow (CBF) during tilt testing. Studies have not previously examined the relationship between ME/CFS symptom severity and CBF reduction. The authors sought to examine whether there was a correlation between the severity of symptoms and the degree of CBF reduction during tilt testing.
110 ME/CFS patients (International Consensus Criteria (ICC)) were selected from the authors’ existing database. Patients had completed tilt testing and assessments of ME/CFS symptomology on the same day, and again at a subsequent follow-up. In addition, the authors combined the data from of two previous studies, which included 219 participants whose symptom severity had been defined by the ICC.
The authors found that of the 110 patients from their database, 71 were retested due to worsening symptoms. Within this group, the ICC disease severity changed, with a significant number of patients experiencing a more severe ICC disease rating, from 51% mild, 45% moderate and 4% severe at the initial visit, to 1% mild, 72% moderate and 27% severe at follow-up. In this group, the CBF reduction also changed, from 19% at the first test, to 31% at the follow-up. Of the 39 patients with stable disease, the severity of disease distribution and CBF reduction did not differ significantly between the initial visit and follow-up. When looking at the combined data from the two previous studies, the authors found that patients with mild, moderate, and severe disease experienced CBF reductions of 25%, 29%, and 33% respectively.
The authors conclude that there is a strong association between ME/CFS disease severity and percentage CBF reduction during tilt testing, with a more severe disease rating being associated with a larger reduction in CBF. The authors propose that this objective measure of confirming worsening symptoms may help to guide treatment and measure the effectiveness of therapies.

___________________________________________________________________________

Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post‐acute COVID‐19 syndrome with and without postural orthostatic tachycardia syndrome: a multi‐omic profiling study
Authors: Mahdi A, Zhao A, Fredengren E, Fedorowski A, Braunschweig F, Nygren‐Bonnier M, … Ståhlberg M (Karolinska University Hospital, Sweden)
Publication: Scientific Reports   Link:https://doi.org/10.1038/s41598-023-47539-1
An estimated 30% of severely affected post-acute COVID-19 syndrome (PACS) patients experience postural orthostatic tachycardia syndrome (POTS) and present with microvascular endothelial dysfunction. To unravel the unknown pathological mechanisms underlying PACS with POTS, the authors applied an unbiased multi-omic approach to participants’ plasma to analyse cardio-metabolic proteins, pro-inflammatory cytokines/chemokines, and sphingolipids.
A total of 42 non-hospitalised patients with PACS (diagnosed according to the WHO definition) were recruited from the post-acute COVID-19 clinic at Karolinska University Hospital in Sweden. On average, participants had been unwell for 18 months. Participants were divided into 2 groups depending on the presence (PACS+POTS, 20 individuals) or absence (PACS-POTS, 22 individuals) of POTS, defined as (1) a persistent rise in heart rate of more than 30 beats/min, or (2) a heart rate inferior to 120 beats/min within 10 min of the tilt-up test. PACS patients were matched with 21 healthy individuals (healthy controls). There were no significant differences in symptom scores between the two PACS groups. Women were more represented than men in all groups.
Differential expression analysis of 700 plasma proteins showed that PACS patients had a clearly dysregulated plasma proteome with around 200 dysregulated proteins when compared to healthy controls. There were no significant differences in dysregulated proteins between the two PACS groups.
Gene ontology enrichment analysis revealed many significantly altered pathways in both PACS groups compared with healthy controls, including haemostasis, inflammation, amino acid metabolism, and apoptosis. Differential expression analysis of 36 cytokines showed similar cytokine dysregulation in both PACS groups, with 11 up-regulated cytokines compared to healthy controls. Differential expression analysis of 88 plasma sphingolipids showed 16 and 19 dysregulated lipids in PACS+POTS and PACS-POTS respectively, compared to healthy controls. Nevertheless, the authors found no significant difference in proteins, cytokines, or sphingolipids between PACS+POTS and PACS-POTS groups. Principal component analysis also failed to differentiate between these groups.
Collectively, this study suggests that the pro-inflammatory, proliferative and pro-coagulative state in PACS represents an important phenotype in the pathophysiology. Therefore, the resolution of inflammation and micro clots, combined with haemostasis correction, might alleviate PACS burden. The absence of distinctions between participants with and without POTS suggests that POTS may not be associated with the dysregulation of plasma proteins, cytokines, and sphingolipids observed in PACS.

___________________________________________________________________________

Catalytic antibodies may contribute to demyelination in myalgic encephalomyelitis/chronic fatigue syndromeAuthors: Jensen MA, Dafoe ML, Wilhelmy J, Cervantes L, Okumu AN, Kipp L, … Davis RW (Stanford University, USA)
Publication: Biochemistry     Link: https://doi.org/10.1071/AH23106 
Multiple sclerosis (MS) is an autoimmune inflammatory disease affecting the central nervous system (CNS), characterised by symptoms of pain and impaired nerve communication from the demyelination caused by catalytic antibodies (antibodies with enzyme-like behaviour (Abzs)). There are considerable overlaps between MS and ME/CFS. MRI and PET studies have found physical abnormalities in the brain of ME/CFS patients, and ME/CFS shares symptoms of pain and impaired nerve communication that may be caused by the digestion of myelin basic protein (MBP). The aim of this study was to examine the role of Abzs in ME/CFS. 
Total plasma antibodies (Abs) were collected from 19 patients with ME/CFS (diagnosed using the Canadian Consensus Criteria), 19 healthy controls (HC), and 3 patients with MS to be used as an expected metric comparison. Samples were analysed to identify catalytic antibodies.
When added to bovine brain MBP substrate, 47% of ME/CFS Abs showed digestion, compared to 5% of HC. The authors suggest that those with ME/CFS whose Abs did not cleave MBP may have symptoms unrelated to myelin breakdown or that, similar to MS, there may be patterns of remission and relapse. The Abzs were shown to have serine protease-like activity. Three additional substrates (casein, a-lactalbumin, and lysozyme) were used to determine that breakdown was myelin-specific, not random proteolysis. Purification and size-exclusion assays proved that there was no protease involvement in the MBP breakdown. When the MS drug, glatiramer acetate (GA) was added to ME/CFS Abs + MBP assays, the breakdown of MBP was significantly reduced. GA was shown to be Abzs-specific and did not cause inhibition of general serine protease enzyme activity. Fractionated GA demonstrated the higher molecular weight fragments having greater potency.
The concentration of GA used in these assays far exceeds the general dosage used in MS (and thus what is proposed for usage in myelin-associated ME/CFS). However, demyelination has a long-term cumulative effect, and treatment with GA often takes 6 to 9 months before effects become apparent. As such, the authors believe that the higher dosage used in these assays accounts for these longer-term effects. The authors recommend that a prospective study be undertaken over a long period of time to discover whether there is a similar relapsing-remission pattern in ME/CFS as seen in MS.

___________________________________________________________________________

‘We have no services for you...so you have to make the best out of it’: A qualitative study of myalgic encephalomyelitis/chronic fatigue syndrome patients’Authors:Melby, L. & das Nair, R. (SINTEF, Norway)  Publication:Health Expectations
Link: https://www.abc.net.au/news/2023-12-08/dave-clark-on-living-with-chronic-fatigue-syndrome/103071294
The authors of this study sought to gain a comprehensive understanding of Norwegian ME/CFS patients’ experiences of dissatisfaction with healthcare services and to explore the reasons for this dissatisfaction.
The authors used in-depth interviews conducted in participants’ homes, lasting between 40 and 150 minutes, to gain an understanding of participants’ encounters with healthcare services as well as to assess participants’ reasons for satisfaction or dissatisfaction with these healthcare services. In total, 48 participants from 24 households in Norway participated in the interviews. This number included 37 individuals diagnosed with ME/CFS (25 females, 12 males, age range 10-59), in addition to family and household members.
The authors identified four key reasons why ME/CFS patients and their families experienced dissatisfaction with healthcare services. The first was nonexistent services, which involved study participants feeling as though they received a lack of practical help and information, or they were told effective treatment was not a possibility after receiving their ME/CFS diagnosis. The second reason was non-personalised services, where participants received healthcare services that were not adapted to their needs, resulting in these services being viewed as inappropriate or damaging. The third was slow services, where ME/CFS patients and their families believed they received services too late in their ME/CFS trajectory for these services to be useful. The fourth was inappropriate services, where participants believed the healthcare services they received, did not address their ME/CFS, and they felt sicker than they had previously.
The authors concluded that dissatisfaction with healthcare services that Norwegian ME/CFS patients and their families experienced may stem from a variety of factors including systemic issues such as bureaucracy within the healthcare industry, inadequate knowledge of ME/CFS leading to a lack of precise recommendations and uncertainty amongst healthcare professionals, poor personalisation and flexibility from healthcare services, healthcare providers’ disbelief in ME/CFS as a medical condition, and a lack of patient involvement in the design of healthcare services.
The authors note the importance of highlighting ME/CFS patients’ negative healthcare experiences in order to improve future services. The authors suggest that future research should investigate how ME/CFS patients can be involved in healthcare service design to help improve healthcare services.

___________________________________________________________________________

Is Low Cortisol a Marker of Long COVID?Armin Alaedini, PhD Stafford Lightman, PhD Gary P. Wormser, MD
Published:March 21, 2024DOI:https://doi.org/10.1016/j.amjmed.2024.03.013
Cortisol is the primary glucocorticoid hormone produced by the adrenal glands, playing a critical role in multiple physiological processes, including metabolism, immune response regulation, cardiovascular regulation, and the body's stress response
. The secretion of cortisol is closely regulated by the hypothalamus-pituitary-adrenal (HPA) axis. The process is initiated by the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which stimulates the production of adrenocorticotropic hormone (ACTH) by the pituitary gland. In turn, ACTH prompts the adrenal glands to release cortisol
. Cortisol measurements have been used extensively in research to investigate the hormone's relationship with various physiological disruptions and health conditions, including mental health disorders, immune system dysfunction, and metabolic disorders
. However, it is essential to recognize the potential pitfalls in the assessment and interpretation of cortisol levels in translational research, as overlooking them can foster misinformation and confusion regarding potential clinical or diagnostic relevance of the findings.
In two recent studies (Klein et al. in 2023 and Fleischer et al. in 2024 ), researchers reported on the analysis of hormonal and other markers in blood samples from individuals with post-acute sequelae of SARS CoV-2 infection (PASC)—commonly known as long COVID (LC). Long COVID is associated with a range of persistent symptoms, including fatigue, pain, and brain fog that can be debilitating. Notably, the most compelling and statistically significant finding of the Klein et al. study revolved around the levels of cortisol, which were reported to be much lower in long COVID patients than in controls without long COVID . The authors of the study concluded that “[s]erum cortisol was the most significant predictor of LC status in the model, and cortisol alone achieved an AUC.of 0.96” 
. The findings have been widely publicized in the media, engendering speculation regarding their therapeutic and biomarker potential in long COVID.. On the other hand, a more recent study by Fleischer et al. found no significant difference or trends in the cortisol levels in a comparison of post-COVID-19 patients, with and without persistent symptoms, apparently contradicting the results reported in the earlier study. While the cortisol assessments in both of these two studies  may represent remarkable and consequential findings in the context of long COVID, unfortunately, they are impacted by significant limitations and concerns regarding how the cortisol levels were assessed and interpreted.
The levels of cortisol in the body are very dynamic, following a distinct circadian pattern throughout the day. Levels typically increase in the first half hour after awakening by up to 60%, in what has been called the cortisol awakening response, followed by a sharp drop over the next few hours, reaching their lowest point in the evening.. Underlying this circadian rhythm, cortisol also exhibits ultradian fluctuations in a pulsatile pattern with several peaks and troughs throughout the day that change in amplitude.. Because of these fluctuations and the wide and rapid changes in circulating levels, reliable and reproducible evaluation of cortisol secretion is not trivial. Such assessment cannot be based on only a single measurement, but rather requires the collection of multiple blood, saliva, or urine samples throughout the day. Any single measurement would also ideally need to account for the time elapsed since awakening and not necessarily just the time of day. In assessing the difference in cortisol output between groups, multiple measurements in blood or saliva samples are usually used to analyze the change from baseline, the size of the cortisol awakening response, or the elevation and slopepe of the diurnal curve Surprisingly, none of these approaches was taken in either of the two cited studies of cortisol levels in long COVID. Both studies conducted a single measurement in blood plasma or serum, taking note of the time of day, but not the time since awakening, for the sample collection. More importantly, no attempt was made to take serial samples to overcome the problem associated with the very rapid changes occurring due to ultradian rhythmicity. Considering the dramatic ultradian and diurnal cortisol oscillations, meaningful interpretation of the reported cortisol levels in these two studies is simply not possible. The issue is further compounded by the potential association of long COVID with sleep disturbances , including earlier than average awakening times, which could significantly shift the cortisol diurnal curve, giving the appearance of uniformly lower circulating levels during the daytime. The additional finding that the time of sample collection was not a significant predictor of cortisol levels in the study by Klein et al. adds weight to existing concerns about the validity of the reported results and the conclusions regarding the value of blood cortisol concentration as a potential biomarker of long COVID.
Given the presence of persistent fatigue as a hallmark symptom of long COVID, the evaluation of HPA axis function through the assessment of cortisol output is a logical approach. However, considering the available data and the major methodological shortcomings noted in the two published studies, it is clear that neither the utility of cortisol as a biomarker nor the therapeutic role of corticosteroids in treating long COVID can be justified at this juncture. The issues raised here underscore the need for further rigorous and comprehensive investigations into the relationship between cortisol response and long COVID, taking special note of the cortisol diurnal pattern, potential confounding factors impacting this pattern, and the utilization of well-documented and established methods of assessing cortisol levels
. The recent availability of new techniques to measure cortisol levels sequentially across the full 24 hours, including during sleep should provide the methodology needed for obtaining reliable and accurate data on HPA axis function in long COVID and other conditions.

___________________________________________________________________________
 
Redox Biol. 2023 Sep:65:102796. doi: 10.1016/j.redox.2023.102796. Epub 2023 Jul 3.
Autoantibodies to selenoprotein P in chronic fatigue syndrome suggest selenium transport impairment and acquired resistance to thyroid hormoneQian Sun 1, Elisa Oltra 2, D A Janneke Dijck-Brouwer 3, Thilo Samson Chillon 4, Petra Seemann 5, Sabrina Asaad 4, Kamil Demircan 4, José Andrés Espejo-Oltra 2, Teresa Sánchez-Fito 2, Eva Martín-Martínez 6, Waldemar B Minich 4, Frits A J Muskiet 3, Lutz Schomburg 7
PMID: 37423160 PMCID: PMC10338150 DOI: 10.1016/j.redox.2023.102796
AbstractChronic Fatigue Syndrome (CFS) presents with symptoms of hypothyroidism, including mental and physical fatigue, poor sleep, depression, and anxiety. However, thyroid hormone (TH) profiles of elevated thyrotropin and low thyroxine (T4) are not consistently observed. Recently, autoantibodies to the Se transporter SELENOP (SELENOP-aAb) have been identified in Hashimoto's thyroiditis and shown to impair selenoprotein expression. We hypothesized that SELENOP-aAb are prevalent in CFS, and associate with reduced selenoprotein expression and impaired TH deiodination. Se status and SELENOP-aAb prevalence was compared by combining European CFS patients (n = 167) and healthy controls (n = 545) from different sources. The biomarkers total Se, glutathione peroxidase (GPx3) and SELENOP showed linear correlations across the samples without reaching saturation, indicative of Se deficiency. SELENOP-aAb prevalence was 9.6-15.6% in CFS versus 0.9-2.0% in controls, depending on cut-off for positivity. The linear correlation between Se and GPx3 activity was absent in SELENOP-aAb positive patients, suggesting impaired Se supply of kidney. A subgroup of paired control (n = 119) and CSF (n = 111) patients had been characterized for TH and biochemical parameters before. Within this subgroup, SELENOP-aAb positive patients displayed particularly low deiodinase activity (SPINA-GD index), free T3 levels, total T3 to total T4 (TT3/TT4) and free T3 to free T4 (FT3/FT4) ratios. In 24 h urine, iodine concentrations were significantly lower in SELENOP-aAb positive than in SELENOP-aAb negative patients or controls (median (IQR); 43.2 (16.0) vs. 58.9 (45.2) vs. 89.0 (54.9) μg/L). The data indicate that SELENOP-aAb associate with low deiodination rate and reduced activation of TH to active T3. We conclude that a subset of CFS patients express SELENOP-aAb that disturb Se transport and reduce selenoprotein expression in target tissues. Hereby, TH activation decreases as an acquired condition not reflected by thyrotropin and T4 in blood. This hypothesis opens new diagnostic and therapeutic options for SELENOP-aAb positive CFS, but requires clinical evidence from intervention trials.

___________________________________________________________________________
 
Investigating the Human Intestinal DNA Virome and Predicting Disease-Associated Virus–Host Interactions in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Shen-Yuan Hsieh 1 , George M. Savva 2 , Andrea Telatin 1 , Sumeet K. Tiwari 1 , Mohammad A. Tariq 1,† , Fiona Newberry 1,‡, Katharine A. Seton 1 , Catherine Booth 2 , Amolak S. Bansal 3 , Thomas Wileman 1,4 , Evelien M. Adriaenssens 1 and Simon R. Carding 1,4, Food, Microbiome, and Health Research Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK; [email protected] (S.-Y.H.); [email protected] (A.T.); [email protected] (S.K.T.); [email protected] (M.A.T.); [email protected] (F.N.); [email protected] (K.A.S.); [email protected] (T.W.) 2 
Core Science Resources, Quadram Institute Bioscience, Norwich NR4 7UQ, UK; [email protected] (G.M.S.); [email protected] (C.B.) 3 Spire St. Anthony’s Hospital, Surrey SM3 9DW, UK; [email protected] 4 Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK * 
Correspondence: [email protected] † Present affiliation: Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, UK. ‡ Present affiliation: Department of Biosciences, School of Science & Technology, Nottingham Trent University, Nottingham NG11 8NS, UK.
 Abstract: Understanding how the human virome, and which of its constituents, contributes to health or disease states is reliant on obtaining comprehensive virome profiles. By combining DNA viromes from isolated virus-like particles (VLPs) and whole metagenomes from the same faecal sample of a small cohort of healthy individuals and patients with severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we have obtained a more inclusive profile of the human intestinal DNA virome. Key features are the identification of a core virome comprising tailed phages of the class Caudoviricetes, and a greater diversity of DNA viruses including extracellular phages and integrated prophages. Using an in silico approach, we predicted interactions between members of the Anaerotruncus genus and unique viruses present in ME/CFS microbiomes. This study therefore provides a framework and rationale for studies of larger cohorts of patients to further investigate disease-associated interactions between the intestinal virome and the bacteriome.

___________________________________________________________________________
 
LANCET: ARTICLES| VOLUME 24, ISSUE 3, P256-265, MARCH 2024
A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled trial
Raphaela I Lau, MSc ,Qi Su, PhD ,Ivan S F Lau, MBBCh, Jessica Y L Ching, PhDProf Martin C S Wong, MD,Louis H S Lau, MBChB,et al.
Published:December 07, 2023DOI:https://doi.org/10.1016/S1473-3099(23)00685-0
SummaryBackgroundPost-acute COVID-19 syndrome (PACS) affects over 65 million individuals worldwide but treatment options are scarce. We aimed to assess a synbiotic preparation (SIM01) for the alleviation of PACS symptoms.
MethodsIn this randomised, double-blind, placebo-controlled trial at a tertiary referral centre in Hong Kong, patients with PACS according to the US Centers for Disease Control and Prevention criteria were randomly assigned (1:1) by random permuted blocks to receive SIM01 (10 billion colony-forming units in sachets twice daily) or placebo orally for 6 months. Inclusion criterion was the presence of at least one of 14 PACS symptoms for 4 weeks or more after confirmed SARS-CoV-2 infection, including fatigue, memory loss, difficulty in concentration, insomnia, mood disturbance, hair loss, shortness of breath, coughing, inability to exercise, chest pain, muscle pain, joint pain, gastrointestinal upset, or general unwellness. Individuals were excluded if they were immunocompromised, were pregnant or breastfeeding, were unable to receive oral fluids, or if they had received gastrointestinal surgery in the 30 days before randomisation. Participants, care providers, and investigators were masked to group assignment. The primary outcome was alleviation of PACS symptoms by 6 months, assessed by an interviewer-administered 14-item questionnaire in the intention-to-treat population. Forward stepwise multivariable logistical regression was performed to identify predictors of symptom alleviation. The trial is registered with ClinicalTrials.gov, NCT04950803.
FindingsBetween June 25, 2021, and Aug 12, 2022, 463 patients were randomly assigned to receive SIM01 (n=232) or placebo (n=231). At 6 months, significantly higher proportions of the SIM01 group had alleviation of fatigue (OR 2·273, 95% CI 1·520–3·397, p=0·0001), memory loss (1·967, 1·271–3·044, p=0·0024), difficulty in concentration (2·644, 1·687–4·143, p<0·0001), gastrointestinal upset (1·995, 1·304–3·051, p=0·0014), and general unwellness (2·360, 1·428–3·900, p=0·0008) compared with the placebo group. Adverse event rates were similar between groups during treatment (SIM01 22 [10%] of 232 vs placebo 25 [11%] of 231; p=0·63). Treatment with SIM01, infection with omicron variants, vaccination before COVID-19, and mild acute COVID-19, were predictors of symptom alleviation (p<0·0036).
InterpretationTreatment with SIM01 alleviates multiple symptoms of PACS. Our findings have implications on the management of PACS through gut microbiome modulation. Further studies are warranted to explore the beneficial effects of SIM01 in other chronic or post-infection conditions.

___________________________________________________________________________

Article https://doi.org/10.1038/s41467-023-44432-3 
Muscle abnormalities worsen after postexertional malaise in long COVID
Brent Appelman 1,2,15, Braeden T. Charlton 3,4,15, Richie P. Goulding3,4, Tom J. Kerkhoff 3,4,5,6, Ellen A. Breedveld 3,4, Wendy Noort3,4, Carla Offringa3,4, Frank W. Bloemers4,7, Michel van Weeghel 8 , Bauke V. Schomakers8 , Pedro Coelho9,10,11, Jelle J. Posthuma7,12, Eleonora Aronica 11, W. Joost Wiersinga 1,2,13, Michèle van Vugt2,14,15 & Rob C. I. Wüst 3,4,15
 A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. 
With this longitudinal casecontrol study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exerciseinduced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of postexertional malaise. 
This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases. Chronic sequelae after acute infections contribute to debilitating conditions that affect millions worldwide1–5 . After an acute SARS-CoV-2 infection, a subgroup of patients suffers from post-acute sequelae of COVID-19 (PASC), also called long COVID1,6–10. The most reported symptoms of long COVID include limited exercise tolerance and postexertional malaise, representing the worsening of symptoms after mental or physical exertion1,8,10. Current, yet unproven hypotheses explaining exercise tolerance and post-exertional malaise in long COVID include mitochondrial dysfunction, amyloid-containing deposit accumulation in blood vessels causing local hypoxia, systemic and local inflammation, disturbed immunological responses, hormonal imbalance, and viral persistence11–18. The extent to which the underlying physiology of impaired exercise capacity can be separated from factors related to the onset of post-exertional malaise remains unclear, largely due to indirect assessment of the underlying biomedical and psychological parameters, the cross-sectional nature of most studies, and patient heterogeneity. In this study, we systematically induced post-exertional malaise in a cohort of 25 well-defined patients with long COVID and controls. We obtained blood and skeletal muscle biopsies before and after a maximal exercise test (Supplemental Fig. 1) with the aim to study the biological factors contributing to the limited exercise capacity and postexertional malaise in long COVID. Results were compared with those obtained from 21 age- and sex-matched controls who fully recovered from a mild SARS-CoV-2 infection (Table 1). We characterized Long COVID based on the criteria established by the World Health Organization, and an important inclusion criterion was the presence of postexertional malaise19. Both groups were healthy and socially active prior to the initial PCR-proven SARS-CoV-2 infection. No participants were hospitalized due to SARS-CoV-2 infection. Fatigue questionnaires and accelerometer data confirmed the impact of long COVID on daily life (Supplemental Fig. 2). We show that skeletal muscle structure is associated with a lower exercise capacity in patients and that local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of postexertional malaise. 
Results Limited exercise capacity in long COVID
Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article

___________________________________________________________________________
 
Original Investigation Physical Medicine and Rehabilitation    April 4, 2024
Functional Limitations and Exercise Intolerance in Patients With Post-COVID ConditionA Randomized Crossover Clinical TrialAndrea Tryfonos, PhD1,2; Kaveh Pourhamidi, MD, PhD3; Gustav Jörnåker, MSc1; et alMartin Engvall, MD1,4; Lisa Eriksson, MSc1; Sara Elhallos, BSc1; Nicole Asplund1; Mirko Mandić, PhD1; Patrik Sundblad, MD, PhD1,4; Atif Sepic, MSc3; Eric Rullman, MD, PhD1,4; Lars Hyllienmark, MD, PhD3; Helene Rundqvist, PhD1,4; Tommy R. Lundberg, PhD1,4; Thomas Gustafsson, MD, PhD1,4
JAMA Netw Open. 2024;7(4):e244386. doi:10.1001/jamanetworkopen.2024.4386
Key Points
Question  Do nonhospitalized patients experiencing post-COVID condition (PCC) have exaggerated postexercise symptoms after high-intensity interval training (HIIT), moderate-intensity continuous training (MICT), and strength training (ST)?
Findings  In this randomized crossover clinical trial of 31 patients with PCC and 31 matched control participants, the exercise response was largely comparable between groups, with no profound symptom exacerbation. Patients with PCC reported more muscle pain after HIIT and concentration problems after MICT and had lower aerobic capacity and less muscle strength; 62% showed myopathic signs.
Meaning  The findings suggest that cautious exercise rehabilitation should be recommended to prevent further deconditioning among patients with PCC.
Abstract
Importance  Many patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration.
Objective  To assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC.
Design, Setting, and Participants  In this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited.
Interventions  After comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise.
Main Outcomes and Measures  The primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC.
Results  Thirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: −6.8 mL/kg/min; 95% CI, −10.7 to −2.9 mL/kg/min; P < .001) and less isometric knee extension muscle strength (mean difference: −37 Nm; 95% CI, −67 to −7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, −26.5 minutes/d; 95% CI, −42.0 to −11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing.
Conclusions and Relevance  In this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC.
Trial Registration  ClinicalTrials.gov Identifier: NCT05445830

___________________________________________________________________________

Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeMichael Anthony Jensen,Miranda Lee Dafoe,Julie Wilhelmy,Layla Cervantes,Anna N Okumu,Lucas Kipp,Mohsen Nemat-Gorgani, and Ronald Wayne Davis
Biochemistry 2024, 63, 1, 9–18  Publication Date:November 27, 2023 https://doi.org/10.1021/acs.biochem.3c00433
Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY-NC-ND 4.0.
Abstract
Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatiguesyndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP). We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness. In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP. Furthermore, we found that aprotinin, which is a specific serine protease inhibitor, specifically prevents breakdown of MBP while the other classes of protease inhibitors had no effect. This coincides with the published literature describing catalytic antibodies as having serine protease-like activity. Postpandemic research has also provided several reports of demyelination in COVID-19. Because COVID-19 has been described as a trigger for ME/CFS, demyelination could play a bigger role in patient symptoms for those recently diagnosed with ME/CFS. Therefore, by studying proteolytic antibodies in ME/CFS, their target substrates, and inhibitors, a new mechanism of action could lead to better treatment and a possible cure for the disease.This publication is licensed under
CC-BY-NC-ND 4.0.
 
 
___________________________________________________________________________
 
Persistent complement dysregulation with signs of thromboinflammation in active Long CovidCARLO CERVIA-HASLER HTTPS://ORCID.ORG/0000-0001-7120-8739, SARAH C. BRÜNINGK HTTPS://ORCID.ORG/0000-0003-3176-1032, TOBIAS HOCH HTTPS://ORCID.ORG/0000-0003-0319-6064, BOWEN FAN, GIULIA MUZIO HTTPS://ORCID.ORG/0000-0001-5999-2030, RYAN C. THOMPSON HTTPS://ORCID.ORG/0000-0002-0450-8181, LAURA CEGLAREK HTTPS://ORCID.ORG/0009-0005-7117-0335, ROMAN MELEDIN HTTPS://ORCID.ORG/0000-0001-6921-825X, PATRICK WESTERMANN HTTPS://ORCID.ORG/0000-0003-2894-6140, [...], AND ONUR BOYMAN HTTPS://ORCID.ORG/0000-0001-8279-5545 +18 authors
SCIENCE 19 Jan 2024 Vol 383, Issue 6680 DOI: 10.1126/science.adg7942
Editor’s summarySome individuals can endure persistent, debilitating symptoms for many months after an initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the factors underpinning these health issues, called Long Covid, are poorly understood. Comparing the blood of patients with confirmed SARS-CoV-2 infection with that of uninfected controls, Cervia-Hasler et al. found that patients experiencing Long COVID exhibited changes to blood serum proteins indicating activation of the immune system’s complement cascade, altered coagulation, and tissue injury (see the Perspective by Ruf). At the cellular level, Long Covid was linked to aggregates comprising monocytes and platelets. These findings provide a resource of potential biomarkers for diagnosis and may inform directions for treatments. —Sarah H. Ross
Structured Abstract  INTRODUCTIONAcute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes various clinical phenotypes, ranging from asymptomatic to life-threatening COVID-19. About 5% of all infected individuals do not recover from acute disease but develop long-term complications, called Long Covid. Current hypotheses on factors contributing to Long Covid include tissue damage, viral reservoirs, autoimmunity, and persistent inflammation. There are currently no diagnostic tests or therapeutic solutions for affected patients.
RATIONALEWe followed 39 healthy controls and 113 COVID-19 patients for up to 1 year after initial confirmation of acute SARS-CoV-2 infection to identify biomarkers associated with Long Covid. At 6-month follow-up, 40 patients had Long Covid symptoms. Repeated clinical assessments were paired with blood draws, resulting in a total of 268 longitudinal blood samples. We measured >6500 proteins in serum by proteomics. Top candidate biomarkers were identified using computational tools and further evaluated experimentally.
RESULTSLong Covid patients exhibited increased complement activation during acute disease, which also persisted at 6-month follow-up. The complement system is part of the innate immune system and contributes to immunity and homeostasis by targeting pathogens and damaged cells, among other functions. Interestingly, blood complement levels normalized in Long Covid patients recovering before their 6-month follow-up. The complement system can be activated by various triggers, resulting in formation of the terminal complement complex (TCC), made of the complement components C5b-9. These complexes can integrate into cell membranes and induce cell activation or lysis. Long Covid patients showed imbalanced TCC formation, marked by increased soluble C5bC6 complexes and decreased levels of C7-containing TCC formations that can incorporate into cell membranes. This suggested increased membrane insertion of TCCs in Long Covid patients, contributing to tissue damage. Accordingly, Long Covid patients showed elevated tissue injury markers in blood and a thromboinflammatory signature, characterized by markers of endothelial activation, such as von Willebrand factor (vWF), and red blood cell lysis. Low antithrombin III levels in Long Covid patients were accompanied by signs of increased cleavage by thrombin, a driver of TCC formation. Furthermore, Long Covid patients had elevated platelet activation markers and monocyte–platelet aggregates at 6-month follow-up, particularly in cases where Long Covid persisted for 12 months or more. These patients also showed signs of antibody-mediated activation of the classical complement pathway, which was associated with increased anti-CMV (cytomegalovirus, also known as human herpesvirus 5) and anti-EBV (Epstein-Barr virus) immunoglobulin G (IgG) antibody levels.
CONCLUSIONOur data suggest that active Long Covid is accompanied by a blood protein signature marked by increased complement activation and thromboinflammation, including activated platelets and markers of red blood cell lysis. Tissue injury may also be complement-mediated and, in turn, activate the complement system. Moreover, complement activation may be driven by antigen–antibody complexes, involving autoantibodies and antibodies against herpesviruses, as well as cross-talk with a dysregulated coagulation system. In addition to offering a basis for new diagnostic solutions, our work provides support for clinical research on complement modulators for patients suffering from Long Covid.
___________________________________________________________________________

Original Investigation Physical Medicine and Rehabilitation April 4, 2024
Functional Limitations and Exercise Intolerance in Patients With Post-COVID Condition  A Randomized Crossover Clinical TrialAndrea Tryfonos, PhD1,2; Kaveh Pourhamidi, MD, PhD3; Gustav Jörnåker, MSc1; et alMartin Engvall, MD1,4; Lisa Eriksson, MSc1; Sara Elhallos, BSc1; Nicole Asplund1; Mirko Mandić, PhD1; Patrik Sundblad, MD, PhD1,4; Atif Sepic, MSc3; Eric Rullman, MD, PhD1,4; Lars Hyllienmark, MD, PhD3; Helene Rundqvist, PhD1,4; Tommy R. Lundberg, PhD1,4; Thomas Gustafsson, MD, PhD1,4
JAMA Netw Open. 2024;7(4):e244386. doi:10.1001/jamanetworkopen.2024.4386
Key Points
Question  Do nonhospitalized patients experiencing post-COVID condition (PCC) have exaggerated postexercise symptoms after high-intensity interval training (HIIT), moderate-intensity continuous training (MICT), and strength training (ST)?
Findings  In this randomized crossover clinical trial of 31 patients with PCC and 31 matched control participants, the exercise response was largely comparable between groups, with no profound symptom exacerbation. Patients with PCC reported more muscle pain after HIIT and concentration problems after MICT and had lower aerobic capacity and less muscle strength; 62% showed myopathic signs.
Meaning  The findings suggest that cautious exercise rehabilitation should be recommended to prevent further deconditioning among patients with PCC.
Abstract
Importance  Many patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration.
Objective  To assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC.
Design, Setting, and Participants  In this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited.
Interventions  After comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise.
Main Outcomes and Measures  The primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC.
Results  Thirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: −6.8 mL/kg/min; 95% CI, −10.7 to −2.9 mL/kg/min; P < .001) and less isometric knee extension muscle strength (mean difference: −37 Nm; 95% CI, −67 to −7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, −26.5 minutes/d; 95% CI, −42.0 to −11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing.
Conclusions and Relevance  In this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC.
Trial Registration  ClinicalTrials.gov Identifier: NCT05445830

___________________________________________________________________________

ARTICLE Vol 5 Issue 1, 101373, Jan 16,2024
Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation
Highlights   COVID-19 disease severity is associated with demographic and clinical risk factorsPopulation-level variables can confound severity and outcome models
Shifting standards of care, testing practices, and sampling skew outcome metrics
SummarySevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with enhanced transmissibility and immune escape have emerged periodically throughout the coronavirus disease 2019 (COVID-19) pandemic, but the impact of these variants on disease severity has remained unclear. In this single-center, retrospective cohort study, we examined the association between SARS-CoV-2 clade and patient outcome over a two-year period in Chicago, Illinois. Between March 2020 and March 2022, 14,252 residual diagnostic specimens were collected from SARS-CoV-2-positive inpatients and outpatients alongside linked clinical and demographic metadata, of which 2,114 were processed for viral whole-genome sequencing. When controlling for patient demographics and vaccination status, several viral clades were associated with risk for hospitalization, but this association was negated by the inclusion of population-level confounders, including case count, sampling bias, and shifting standards of care. These data highlight the importance of integrating non-virological factors into disease severity and outcome models for the accurate assessment of patient risk.

___________________________________________________________________________

A phenomenological study on the lived experience of men with Chronic Fatigue SyndromeGracie Elizabeth Snell https://orcid.org/0000-0002-1472-8196 [email protected], Catherine Heidi Seage https://orcid.org/0000-0002-8590-867X, and Jenny Mercer 
Journal of Health Psychology       Volume 29, Issue 3     https://doi.org/10.1177/13591053231186385
AbstractWhilst chronic fatigue syndrome (CFS) has been widely researched amongst women, studies investigating how men experience a CFS diagnosis is limited. This study utilised an interpretative phenomenological approach to interview five men who have a medical diagnosis of CFS. Six themes emerged to demonstrate the participants’ experiences prior to, during and after obtaining their CFS diagnosis. Findings revealed that participants were initially reluctant to accept their condition, confounded by their perception that symptoms compromised their sense of masculinity. They also felt that healthcare professionals had limited recognition of CFS leading them to seek social support and legitimisation from other sources. The struggle to come to terms with a different lifestyle and sense of masculinity prevailed. Such knowledge could be effectively utilised by researchers, practitioners and employers to facilitate an increased understanding of male accounts of the condition and more bespoke interventions where required.

___________________________________________________________________________
 
Experts call for more research into long COVID, as study reveals high prevalence in WA
Authors: Smith EJB, Trigger R, Pin P
Publication: ABC News 
Link: https://www.abc.net.au/news/2024-04-03/research-finds-long-covid-rates-high-in-wa/103647042
 
An Australian National University (ANU) study of 11,000 people in Western Australia who had tested positive for COVID-19 during a 2022 Omicron outbreak found that almost 20% had persistent symptoms three months after initially becoming sick. Researchers say that this suggests that the rate of long COVID is high in WA and urges more research into the condition.
 
Dr Michael Livingston, a rural GP in WA’s Wheatbelt, said that people should not be complacent about COVID-19 prevention. He suggested that the government should develop a “clean air” policy, and fit air filters into spaces like offices and schools to minimise transmission.
 
___________________________________________________________________________
 
Proc Natl Acad Sci U S A. 2023 Sep 12; 120(37): e2304722120.
Published online 2023 Sep 5. doi: 10.1073/pnas.2304722120
PMCID: PMC10500270   PMID: 37669378
Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection
Anoop T. Ambikan,# a , 1 Nazif Elaldi,# b , 1 Sara Svensson-Akusjärvi, a Binnur Bagci, c Ayse Nur Pektas, d Roger Hewson, e , f Gokhan Bagci, g Mehmet Arasli, h Sofia Appelberg, i Adil Mardinoglu, j , k Vikas Sood, a , l Ákos Végvári, m Rui Benfeitas, a Soham Gupta, a Ilhan Cetin, n Ali Mirazimi, i , o , p and Ujjwal Neogi a , 2
SIGNIFICANCE
Our study identified a dysregulation and hyperactivity of the critical metabolic process of the central carbon and energy metabolism, and metabolic flux related to the amino acid metabolism during the acute progressive phases of infection can promote the exhausted phenotype upon recovery leading to postviral fatigue syndrome in CCHFV (Crimean-Congo hemorrhagic fever virus) infection.
Keywords: Crimean-Congo hemorrhagic fever virus, genome-scale metabolic models, post viral fatigue
 

Covid Has Caused Thousands of US Deaths: New CDC Data
Medscape Medical News     Lisa Rapaport   January 03, 2024
While COVID has now claimed more than 1 million lives in the United States alone, these aren't the only fatalities caused at least in part by the virus. A small but growing number of Americans are surviving acute infections only to succumb months later to the lingering health problems caused by long COVID.
Much of the attention on long COVID has centered on the sometimes debilitating symptoms that strike people with the condition, with no formal diagnostic tests or standard treatments available, and the effect it has on quality of life. But new figures from the US Centers for Disease Control and Prevention (CDC) show that long COVID can also be deadly.
More than 5000 Americans have died from long COVID since the start of the pandemic, according to new estimates from the CDC.
This total, based on death certificate data collected by the CDC, includes a preliminary tally of 1491 long COVID deaths in 2023 in addition to 3544 fatalities previously reported from January 2020 through June 2022.
Guidance issued in 2023 on how to formally report long COVID as a cause of death on death certificates should help get a more accurate count of these fatalities going forward, said Robert Anderson, PhD, chief mortality statistician for the CDC.
"We hope that the guidance will help cause of death certifiers be more aware of the impact of long COVID and more likely to report long COVID as a cause of death when appropriate," Anderson said. "That said, we do not expect that this guidance will have a dramatic impact on the trend."
There's no standard definition or diagnostic test for long COVID. It's typically diagnosed when people have symptoms at least 3 months after an acute infection that weren't present before they got sick. As of the end of last year, about 7% of American adults had experienced long COVID at some point, the CDC estimated in September 2023.
The new death tally indicates long COVID remains a significant public health threat and is likely to grow in the years ahead, even though the pandemic may no longer be considered a global health crisis, experts said.
For example, the death certificate figures indicate:

• COVID-19 was the third leading cause of American deaths in 2020 and 2021, and the fourth leading cause of death in the United States in 2023.
• Nearly 1% of the more than one million deaths related to COVID-19 since the start of the pandemic have been attributed to long COVID, according to data released by the CDC.
• The proportion of COVID-related deaths from long COVID peaked in June 2021 at 1.2% and again in April 2022 at 3.8%, according to the CDC. Both of these peaks coincided with periods of declining fatalities from acute infections.

"I do expect that deaths associated with long COVID will make up an increasingly larger proportion of total deaths associated with COVID-19," said Mark Czeisler, PhD, a researcher at Harvard Medical School who has studied long COVID fatalities. 
Months and even years after an acute infection, long COVID can contribute to serious and potentially life-threatening conditions that impact nearly every major system in the body, according to the CDC guidelines for identifying the condition on death certificates. 
This means long COVID may often be listed as an underlying cause of death when people with this condition die of issues related to their heart, lungs, brain or kidneys, the CDC guidelines noted.
The risk for long COVID fatalities remains elevated for at least 6 months for people with milder acute infections and for at least 2 years in severe cases that require hospitalization, some previous research suggested.
As happens with other acute infections, certain people are more at risk for fatal case of long COVID. Age, race, and ethnicity have all been cited as risk factors by researchers who have been tracking the condition since the start of the pandemic.
Half of long COVID fatalities from July 2021 to June 2022 occurred in people aged 65 years and older, and another 23% were recorded among people aged 50-64 years old, according a report from CDC.
Long COVID death rates also varied by race and ethnicity, from a high of 14.1 cases per million among America Indian and Alaskan natives to a low of 1.5 cases per million among Asian people, the CDC found. Death rates per million were 6.7 for White individuals, 6.4 for Black people, and 4.7 for Hispanic people.
The disproportionate share of Black and Hispanic people who developed and died from severe acute infections may have left fewer survivors to develop long COVID, limiting long COVID fatalities among these groups, the CDC report concluded.
It's also possible that long COVID fatalities were undercounted in these populations because they faced challenges accessing healthcare or seeing providers who could recognize the hallmark symptoms of long COVID.
It's also difficult to distinguish between how many deaths related to the virus ultimately occur as a result of long COVID rather than acute infections. That's because it may depend on a variety of factors, including how consistently medical examiners follow the CDC guidelines, said Ziyad Al-Aly, MD, chief of research at the Veterans Affairs, St. Louis Health Care System and a senior clinical epidemiologist at Washington University in St. Louis.
"Long COVID remains massively underdiagnosed, and death in people with long COVID is misattributed to other things," Al-Aly said.
An accurate test for long COVID could help lead to a more accurate count of these fatalities, Czeisler said. Some preliminary research suggests that it might one day be possible to diagnose long COVID with a blood test.
"The timeline for such a test and the extent to which it would be widely applied is uncertain," Czeisler noted, "though that would certainly be a gamechanger."

________________________________________________________________________
Muscle abnormalities worsen after post-exertional malaise in long COVIDNature Communications volume 15, Article number: 17 (2024 
 
  Brent Appelman, ·  Braeden T. Charlton, ·  Richie P. Goulding, ·  Tom J. Kerkhoff, ·  Ellen A. Breedveld, ·  Wendy Noort, ·  Carla Offringa, ·  Frank W. Bloemers, ·  Michel van Weeghel, ·  Bauke V. Schomakers, ·  Pedro Coelho, ·  Jelle J. Posthuma, ·  Eleonora Aronica, ·  W. Joost Wiersinga, ·  Michèle van Vugt & ·  Rob C. I. Wüst 
Abstract
A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.
________________________________________________________________________
 
Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Postacute Sequelae of SARS-CoV-2 - More in Common Than Not?Authors: Joseph P, Singh I, Oliviera R, Capone CA, Mullen MP, Cook DB, … Systrom DM (Harvard Medical School, Boston, USA)
Publication: Chest Journal
Link: https://doi.org/10.1016/j.chest.2023.03.049
The aim of this review was to examine the capacity of invasive and noninvasive cardiopulmonary tests (iCPETs and niCPETs) to assess ME/CFS and post-acute sequelae of COVID-19 (PASC); the commonalities between both conditions, including small fiber neuropathies (SFN), dyspnea, and mitochondrial dysfunction; how symptoms in children differed to adults; and future directions. niCPET studies found that inefficient breathing in ME/CFS patients led to lower peak oxygen uptake (VO2) than in controls. Serial niCPETS (24 hours apart) assessed recovery and PEM, showing further VO2 reduction, lowered levels of exercise tolerance, and earlier anabolic thresholds (AT) in ME/CFS patients. Behavioural and psychological studies found worsened brain function, pain levels, metabolite and immune activity, and further changes to the gut microbiome. Some papers described chronotropic incompetence in both ME/CFS and PASC, but this was not shown in other larger studies.
________________________________________________________________________
 
Cognitive impairment in post-acute sequelae of COVID-19 and short duration myalgic encephalomyelitis patients is mediated by orthostatic hemodynamic changesAuthors: Day H, Yellman B, Hammer S, Rond C, Bell J, Abbaszadeh S, … Vernon SD (Bateman Horne Centre, United States)
Publication: Frontiers in Neuroscience
Link: https://www.frontiersin.org/articles/10.3389/fnins.2023.1203514/full
Many patients with ME/CFS and post-acute sequelae of COVID-19 (PASC) experience cognitive impairment. This can include trouble with concentration, remembering and decision making. This study sought to determine whether orthostatic haemodynamic changes were associated to cognitive impairment in ME/CFS and PASC.
This study utilised a prospective, observational cohort method, and included 256 participants, in three groups: ME/CFS (140 participants, Institute of Medicine criteria), PASC (34 participants) and healthy controls (82 participants). The ME/CFS group was further divided into two subgroups: illness duration less than four years (71 participants) and illness duration greater than 10 years (69 participants). Participants completed clinical evaluation and assessment, including cognitive efficiency measurements (speed and accuracy of responses). Participants completed a cognitive test before, immediately after, and two and seven days after the orthostatic challenge. The orthostatic challenge was a 10-minute NASA lean test, measuring blood pressure and heart rate, and extrapolating pulse pressure and peripheral perfusion.
The authors found that ME/CFS and PASC participants had significantly lower cognitive efficiency scores immediately after the orthostatic challenge, when compared to healthy controls. In ME/CFS participants with disease duration of greater than 10 years, these scores remained low at two and seven days following the orthostatic challenge. Narrow pulse pressure was observed in PASC and ME/CFS participants, and in PASC participants this was associated with slowed information processing compared to healthy controls. Increased heart rate and decreased procedural reaction was observed during the orthostatic challenge in PASC and some ME/CFS participants with disease duration of less than four years.
PASC participants were seen to experience haemodynamic changes during orthostatic challenge that were associated with slowed reaction time and reduced response accuracy. ME/CFS participants with disease duration of less than 4 years experienced reduced cognitive efficiency associated with elevated heart rate in response to orthostatic challenge. ME/CFS participants with disease duration of greater than 10 years experienced cognitive impairment, but this was not correlated with haemodynamic changes associated with orthostatic challenge. The authors suggest that these findings highlight the necessity of early diagnosis to reduce the impact of haemodynamic and other physiological effects on cognitive impairment symptoms. 

________________________________________________________________________

Diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndromeAuthors: Grach SL, Seltzer J, Chon TY, & Ganesh R (Mayo Clinic, United States)
Publication: Mayo Clinic Proceedings
Link: https://www.mayoclinicproceedings.org/article/S0025-6196(23)00402-0/fulltext
There has been an increased interest in ME/CFS as up to 50% of patients with post-COVID syndrome go on to fulfil the criteria for ME/CFS. This review sought to describe a generalist approach to the diagnosis and management of ME/CFS.
Epidemiology/Etiology
·       ME/CFS affects all ages, genders, races and socioeconomic backgrounds. Presentation may differ in men compared to women, potentially resulting in underdiagnosis in men. 
·       Up to 80% of ME/CFS cases are preceded by an infection, most commonly viral, or by multiple smaller events followed by a final trigger causing clear onset.
Diagnosis
·       ME/CFS is a diagnosis based on the presence of particular signs and symptoms, not a diagnosis of exclusion. The US Centres for Disease Control and Prevention recommend the 2015 Institute of Medicine ME/CFS diagnostic criteria.   
·       The lack of diagnostic biomarkers, similarity to other diseases, and reduced clinician awareness of ME/CFS contribute to delayed diagnosis – approximately one third of ME/CFS patients waited at least 5 years for their diagnosis. 
·       Although ME/CFS is present across a spectrum of mild (approximately 25% of ME/CFS patients), moderate (50%) to severe and very severe (25%), the IOM criteria require a 50% decrease in pre-illness capacity in order to be diagnosed.
Practical considerations in diagnosis
·       Patient history: patients often report a wide range of symptoms, it is necessary to determine whether symptoms fulfil the ME/CFS diagnostic criteria. Post-exertional malaise (PEM) is a defining characteristic of ME/CFS. 
·       Risk factors for ME/CFS: female sex, age 10-19 or 30-39, infection (especially viral), preexisting or family history of autoimmune disease, neurologic or other multisystem chronic disease.
Co-morbidities
·       75-80% of ME/CFS patients report at least one other disease. The most commonly seen co-morbid diseases/disorders include hypermobile Ehlers-Danlos Syndrome, postural orthostatic tachycardia syndrome and other autonomic disorders, and mast cell activation syndrome.
General management
·       Managing energy expenditure and avoiding PEM through effective pacing may lead to improvements in functional ability over time and improved quality of life. Identifying the heart rate threshold that triggers PEM and staying below this level may assist self-management. 
·       Pacing does not involve systematic increases in activity, and is not curative. 
·       Graded exercise therapy has not been proven to be effective for ME/CFS. 
·       Pharmacological medications or supplements may assist with symptom management. Patients are often sensitive to medications and may need to be started on a low dose, with gradual increase in dose over time. 

________________________________________________________________________

PLoS One  . 2022 Mar 15;17(3):e0265315.  doi: 10.1371/journal.pone.0265315. eCollection 2022.
Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Multi-site Clinical Assessment of ME/CFS (MCAM) sub-studyDane B Cook 1 2, Stephanie VanRiper 1 2, Ryan J Dougherty 3, Jacob B Lindheimer 1 2 4, Michael J Falvo 5 6, Yang Chen 7, Jin-Mann S Lin 7, Elizabeth R Unger 7; MCAM Study Group
PMID: 35290404 PMCID: PMC8923458 DOI: 10.1371/journal.pone.0265315
AbstractBackground: Cardiopulmonary exercise testing has demonstrated clinical utility in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, to what extent exercise responses are independent of, or confounded by, aerobic fitness remains unclear.
Purpose: To characterize and compare exercise responses in ME/CFS and controls with and without matching for aerobic fitness.
Methods: As part of the Multi-site Clinical Assessment of ME/CFS (MCAM) study, 403 participants (n = 214 ME/CFS; n = 189 controls), across six ME/CFS clinics, completed ramped cycle ergometry to volitional exhaustion. Metabolic, heart rate (HR), and ratings of perceived exertion (RPE) were measured. Ventilatory equivalent ([Formula: see text], [Formula: see text]), metrics of ventilatory efficiency, and chronotropic incompetence (CI) were calculated. Exercise variables were compared using Hedges' g effect size with 95% confidence intervals. Differences in cardiopulmonary and perceptual features during exercise were analyzed using linear mixed effects models with repeated measures for relative exercise intensity (20-100% peak [Formula: see text]). Subgroup analyses were conducted for 198 participants (99 ME/CFS; 99 controls) matched for age (±5 years) and peak [Formula: see text] (~1 ml/kg/min-1).
Results: Ninety percent of tests (n = 194 ME/CFS, n = 169 controls) met standard criteria for peak effort. ME/CFS responses during exercise (20-100% peak [Formula: see text]) were significantly lower for ventilation, breathing frequency, HR, measures of efficiency, and CI and significantly higher for [Formula: see text], [Formula: see text] and RPE (p<0.05adjusted). For the fitness-matched subgroup, differences remained for breathing frequency, [Formula: see text], [Formula: see text], and RPE (p<0.05adjusted), and higher tidal volumes were identified for ME/CFS (p<0.05adjusted). Exercise responses at the gas exchange threshold, peak, and for measures of ventilatory efficiency (e.g., [Formula: see text]) were generally reflective of those seen throughout exercise (i.e., 20-100%).
Conclusion: Compared to fitness-matched controls, cardiopulmonary responses to exercise in ME/CFS are characterized by inefficient exercise ventilation and augmented perception of effort. These data highlight the importance of distinguishing confounding fitness effects to identify responses that may be more specifically associated with ME/CFS.

________________________________________________________________________

Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohortFranziska Legler h https://doi.org/10.1016/j.eclinm.2023.102146
Summary
BackgroundPost-COVID-19 syndrome (PCS) is characterised by a wide range of symptoms, primarily fatigue and exertion intolerance. While disease courses in the early months post-infection have been well-described, the long-term health consequences for patients with PCS with disabling fatigue remain unclear.
MethodsIn this prospective observational cohort study, we evaluated symptom severity and various biomarkers, including hand grip strength (HGS), cardiovascular function, and laboratory parameters, in 106 patients with PCS with moderate to severe fatigue and exertion intolerance at three time points after infection (3–8, 9–16, and 17–20 months). The study was conducted at the Charité’s Fatigue Centre and the Charité’s outpatient clinic for neuroimmunology at Berlin, Germany from July 16, 2020, to February 18, 2022. A subset of patients (PCS-ME/CFS) met the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome according to the Canadian Consensus Criteria (CCC). The aim was to determine differences in the disease course between the two patient groups (i.e., PCS vs PCS-ME/CFS) and identify correlating biomarkers.
FindingsPatients with PCS-ME/CFS reported persistently high severity of most symptoms up to 20 months after infection, while patients with PCS showed overall health improvement. Although fatigue and post-exertional malaise (PEM), hallmarks of post-infectious fatigue syndromes, were still evident in both groups, they remained more pronounced in PCS-ME/CFS. Inflammatory biomarkers decreased in both groups, but not antinuclear antibodies. Lower HGS at onset correlated with symptom persistence, particularly in patients with PCS-ME/CFS.
InterpretationOur findings suggest that PCS can persist beyond 20 months post-infection and encompass the full scope of post-infectious ME/CFS as defined by the CCC. Sub-classifying patients with PCS based on the CCC can assist in the management and monitoring of patients with PCS-ME/CFS due to their persistently higher symptom severity.
 
________________________________________________________________________

Distinguishing features of long COVID identified through immune profilingJon Klein, Jamie Wood, Jillian R. Jaycox, Rahul M. Dhodapkar, Peiwen Lu, Jeff R. Gehlhausen, Alexandra Tabachnikova, Kerrie Greene, Laura Tabacof, Amyn A. Malik, Valter Silva Monteiro, Julio Silva, Kathy Kamath, Abhilash Dhal, Isabel Ott, Gabrielee Valle, Mario Peña-Hernández, Tianyang Mao, Takehiro Takahashi, Carolina Lucas, Eric Song, Dayna McCarthy, Akiko Iwasaki 
Nature volume 623, pages139–148 Published: 25 September 2023

Abstract
Post-acute infection syndromes may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2,3,4. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein–Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.

________________________________________________________________________

The economic burden of myalgic encephalomyelitis/chronic fatigue syndrome in AustraliaTing Zhao A , Ingrid A. Cox   A , Hasnat Ahmad A , Julie A. Campbell A , Martin Hensher A , Andrew J Palmer A , Ryan M. Kelly B , Melissa J. Rogerson B , Karen Wills A and Barbara de Graaff A *
* Correspondence to: [email protected]
 
Australian Health Review 47(6) 707-715 https://doi.org/10.1071/AH23106
Submitted: 13 July 2023  Accepted: 7 November 2023  Published: 28 November 2023
© 2023 The Author(s) (or their employer(s)). Published by CSIRO Publishing on behalf of AHHA.
Abstract
Objective
This study aimed to estimate costs of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to patients, government and Australian society.
Methods
Australian ME/CFS patients and their carers were recruited using convenience sampling. Patients completed an online retrospective cost diary, providing ME/CFS-related direct medical, non-medical and indirect costs. Informal care costs were collected directly from carers. Data from the Pharmaceutical Benefits Scheme and Medicare Benefits Schedule were linked to participant survey data. Annual per patient and total societal costs were estimated, broken down by category and presented in 2021 AUD. Factors associated with higher costs were investigated using generalised linear models.
Results
One hundred and seventy five patients (mean age 49 years s.d. 14, 79.4% female) completed the cost diary. Estimated total annual societal costs of ME/CFS in Australia ranged between $1.38 and $10.09 billion, with average annual total costs of $63 400/patient. Three-quarters of these costs were due to indirect costs ($46 731). Disability severity was the key factor associated with higher costs, particularly for indirect costs (being 2.27-fold higher for severe disability than no/mild disability).
Conclusions
ME/CFS poses a significant economic burden in Australia, owing mainly to high indirect and informal care costs.
________________________________________________________________________

Why Are Women More Likely to Get Long COVID?
Tinker Ready     January 19, 2024  Medscape
Annette Gillaspie, a nurse in a small Oregon hospital, hoped she would be back working with patients by now. She contracted COVID-19 on the job early in the pandemic and ended up with long COVID.
After recovering a bit, her fatigue and dizziness returned, and today she is still working a desk job. She has also experienced more severe menstrual periods than before she had COVID.
"Being a female with long COVID definitely does add to the roller-coaster effect of symptoms," Gillaspie said.
Long COVID affects nearly twice as many women as men, with 6.6% of women reporting long COVID compared with 4% of men, according to a recent Census Bureau survey reported by the Centers for Disease Control and Prevention (CDC). Researchers are trying to determine why, what causes the gender disparity, and how best to treat it.
Scientists are also starting to look at the impact of long COVID on female reproductive health, including menstruation, pregnancy, and menopause.
Sex differences are common in infection-associated illnesses, said Beth Pollack, a research scientist specializing in long COVID in the Massachusetts Institute of Technology's Department of Biological Engineering, Cambridge, Massachusetts. "It informs research priorities and the lens with which we understand long COVID."
For example, reproductive health issues for women, such as puberty, pregnancy, and menopause, can alter the course of illness in a subset of women in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS), a condition that can cause dizziness and worse.
"This suggests that sex hormones may play key roles in immune responses to infections," Pollack said.
ME/CFS and a Possible Link to Long COVID in Women
Some of the research into long COVID is being led by teams studying infection-associated chronic illnesses like ME/CFS.
The problem: Advocates say ME/CFS has been under-researched. Poorly understood for years, the condition is one of a handful of chronic illnesses linked to infections, including Lyme disease and now long COVID. Perhaps not coincidently, they are more likely to affect women.
Many of the research findings about long COVID mirror data that emerged in past ME/CFS research, said Jaime Seltzer, the scientific director at #MEAction, Santa Monica, California, an advocacy group. One point in particular: ME/CFS strikes women about twice as much as men, according to the CDC.
Seltzer said the response to long COVID could be much further ahead if the research community acknowledged the work done over the years on ME/CFS. Many of the potential biomarkers and risk factors emerging for long COVID were also suspected in ME/CFS, but not thoroughly studied, she said.
She also said not enough work has been done to unravel the links between gender and these chronic conditions.
"We're stuck in this Groundhog Day situation," she said. "There isn't any research, so we can't say anything definitively."
Some New Research, Some New Clues
Scientists like Pollack are slowly making inroads. She was lead author on a 2023 review investigating the impact of long COVID on female reproductive health. The paper highlights long COVID links to ME/CFS, POTS, and Ehlers-Danlos syndrome (EDS), as well as a resulting laundry list of female reproductive health issues. The hope is physicians will examine how the menstrual cycle, pregnancy, and menopause affect symptoms and illness progression of long COVID.
The Tal Research group at MIT (where Pollack works) has also added long COVID to the list of infection-associated illnesses it studies. The lab is conducting a large study looking into both Lyme disease and long COVID. The goals are to identify biomarkers that can predict who will not recover and to advance available treatments.
Another MIT program, "SEXX + Immunity" holds seminars and networking sessions for scientists looking into the role of female and male biology in immune responses to infection.
Barriers to Progress Remain
On the clinical side, female patients with long COVID also have to deal with a historical bias that still lurks in medicine when it comes to women's health, said Alba Azola, MD, an assistant professor of physical medicine at Johns Hopkins Medicine, Baltimore, Maryland.
Azola said she has discovered clinical descriptions of ME/CFE in the literature archives that describe it as "neurasthenia" and dismiss it as psychological.
Patients say that it is still happening, and while it may not be so blunt, "you can read between the lines," Azola said.
Azola, who has worked with long-COVID patients and is now seeing people with ME/CFS, said the symptoms of infection-associated chronic illness can mimic menopause, and many of her patients received that misdiagnosis. She recommends that doctors rule out long COVID for women with multiple symptoms before attributing symptoms to menopause.
Seeing that some long-COVID patients were developing ME/CFS, staff at the Bateman Horne Center in Salt Lake City, Utah, set up a program for the condition in 2021. They were already treating patients with ME/CFS and what they call "multi-symptom chronic complex diseases."
Jennifer Bell, a certified nurse practitioner at the center, said she has not seen any patients with ovarian failure but plenty with reproductive health issues.
"There definitely is a hormonal connection, but I don't think there's a good understanding about what is happening," she said.
Most of her patients are female, and the more serious patients tend to go through a worsening of their symptoms in the week prior to getting a period, she said.
One thing Bell said she's noticed in the past year is an increase in patients with EDS, which is also more common in women.
Like long COVID, many of the conditions traditionally treated at the center have no cure. But Bell said the center has developed an expertise in treating post-exertional malaise, a common symptom of long COVID, and keeps up with the literature for treatments to try, like the combination of guanfacine and the antioxidant N-acetyl cysteine to treat brain fog, an approach developed at Yale.
"It's a very challenging illness to treat," Bell said.
Since the emergence of long COVID, researchers have warned that symptoms vary so much from person to person that treatment will need to be targeted.
Pollack of MIT agrees and sees a big role for personalized medicine.
We need to "identify phenotypes within and across these overlapping and co-occurring illnesses so that we can identify the right therapeutics for each person," she said.
As for Annette Gillaspie, she still hopes her long COVID will subside so she can get out from behind the desk and return to her normal nursing duties.
"I just got to a point where I realized I'm likely never going to be able to do my job," she said. "It was incredibly heart breaking, but it's the reality of long COVID, and I know I'm not the only one to have to step away from a job I loved."
Medscape Medical News © 2024 WebMD, LLC

________________________________________________________________________
 
The effectiveness of COVID-19 vaccines to  cohort study of data from the UK, Spain, and EstoniaMartí Català, PhD Núria Mercadé-Besora, BA Raio Kolde, PhD Nhung T H Trinh, PhD Elena Roel, PhDEdward Burn, PhD et al.
Published:January 11, 2024DOI:https://doi.org/10.1016/S2213-2600(23)00414-9
SummaryBackgroundAlthough vaccines have proved effective to prevent severe COVID-19, their effect on preventing long-term symptoms is not yet fully understood. We aimed to evaluate the overall effect of vaccination to prevent long COVID symptoms and assess comparative effectiveness of the most used vaccines (ChAdOx1 and BNT162b2).
MethodsWe conducted a staggered cohort study using primary care records from the UK (Clinical Practice Research Datalink [CPRD] GOLD and AURUM), Catalonia, Spain (Information System for Research in Primary Care [SIDIAP]), and national health insurance claims from Estonia (CORIVA database). All adults who were registered for at least 180 days as of Jan 4, 2021 (the UK), Feb 20, 2021 (Spain), and Jan 28, 2021 (Estonia) comprised the source population. Vaccination status was used as a time-varying exposure, staggered by vaccine rollout period. Vaccinated people were further classified by vaccine brand according to their first dose received. The primary outcome definition of long COVID was defined as having at least one of 25 WHO-listed symptoms between 90 and 365 days after the date of a PCR-positive test or clinical diagnosis of COVID-19, with no history of that symptom 180 days before SARS-Cov-2 infection. Propensity score overlap weighting was applied separately for each cohort to minimise confounding. Sub-distribution hazard ratios (sHRs) were calculated to estimate vaccine effectiveness against long COVID, and empirically calibrated using negative control outcomes. Random effects meta-analyses across staggered cohorts were conducted to pool overall effect estimates.
FindingsA total of 1 618 395 (CPRD GOLD), 5 729 800 (CPRD AURUM), 2 744 821 (SIDIAP), and 77 603 (CORIVA) vaccinated people and 1 640 371 (CPRD GOLD), 5 860 564 (CPRD AURUM), 2 588 518 (SIDIAP), and 302 267 (CORIVA) unvaccinated people were included. Compared with unvaccinated people, overall HRs for long COVID symptoms in people vaccinated with a first dose of any COVID-19 vaccine were 0·54 (95% CI 0·44–0·67) in CPRD GOLD, 0·48 (0·34–0·68) in CPRD AURUM, 0·71 (0·55–0·91) in SIDIAP, and 0·59 (0·40–0·87) in CORIVA. A slightly stronger preventative effect was seen for the first dose of BNT162b2 than for ChAdOx1 (sHR 0·85 [0·60–1·20] in CPRD GOLD and 0·84 [0·74–0·94] in CPRD AURUM).
InterpretationVaccination against COVID-19 consistently reduced the risk of long COVID symptoms, which highlights the importance of vaccination to prevent persistent COVID-19 symptoms, particularly in adults.

 ________________________________________________________________________

Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID View ORCID ProfileConnor B Grady, Bornali Bhattacharjee, Julio Silva, Jillian Jaycox, Lik Wee Lee, Valter Silva Monteiro, Mitsuaki Sawano, Daisy Massey, César Caraballo, Jeff R. Gehlhausen, Alexandra Tabachnikova, Tianyang Mao, Carolina Lucas, Mario A. Peña-Hernandez, Lan Xu, Tiffany J. Tzeng, Takehiro Takahashi, Jeph Herrin, Diana Berrent Güthe, Athena Akrami, Gina Assaf, Hannah Davis, Karen Harris, Lisa McCorkell, Wade L Schulz, Daniel Grffin, Hannah Wei, Aaron M Ring, Leying Guan, Charles Dela Cruz, Akiko Iwasaki,  View ORCID ProfileHarlan M Krumholz
doi: https://doi.org/10.1101/2024.01.11.24300929
This article is a preprint and has not been peer-reviewed    It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
000020126
AbstractBackground Long COVID contributes to the global burden of disease. Proposed root cause hypotheses include the persistence of SARS-CoV-2 viral reservoir, autoimmunity, and reactivation of latent herpesviruses. Patients have reported various changes in Long COVID symptoms after COVID-19 vaccinations, leaving uncertainty about whether vaccine-induced immune responses may alleviate or worsen disease pathology.
Methods In this prospective study, we evaluated changes in symptoms and immune responses after COVID-19 vaccination in 16 vaccine-naïve individuals with Long COVID. Surveys were administered before vaccination and then at 2, 6, and 12 weeks after receiving the first vaccine dose of the primary series. Simultaneously, SARS-CoV-2-reactive TCR enrichment, SARS-CoV-2-specific antibody responses, antibody responses to other viral and self-antigens, and circulating cytokines were quantified before vaccination and at 6 and 12 weeks after vaccination.
Results Self-report at 12 weeks post-vaccination indicated 10 out of 16 participants had improved health, 3 had no change, 1 had worse health, and 2 reported marginal changes. Significant elevation in SARS-CoV-2-specific TCRs and Spike protein-specific IgG were observed 6 and 12 weeks after vaccination. No changes in reactivities were observed against herpes viruses and self-antigens. Within this dataset, higher baseline sIL-6R was associated with symptom improvement, and the two top features associated with non-improvement were high IFN-β and CNTF, among soluble analytes.
Conclusions Our study showed that in this small sample, vaccination improved the health or resulted in no change to the health of most participants, though few experienced worsening. Vaccination was associated with increased SARS-CoV-2 Spike protein-specific IgG and T cell expansion in most individuals with Long COVID. Symptom improvement was observed in those with baseline elevated sIL-6R, while elevated interferon and neuropeptide levels were associated with a lack of improvement.
Plain language summary The impact of the COVID-19 vaccine on vaccine-naïve individuals suffering from Long COVID is uncertain. This study assessed the experience and immune signatures of 16 unvaccinated participants with Long COVID. A total of 10 participants had improved health status after vaccination, and one person reported only worsening health. As expected, vaccination increased immune cells and antibodies against the viral spike protein. Immune signatures may prove to be predictors of health status after vaccination. However, given the small number of participants, these initial findings need further validation.

________________________________________________________________________

Five Bold Predictions for Long COVID in 2024Sara Novak  January 25, 2024  Medscape Medical News
With a number of large-scale clinical trials underway and researchers on the hunt for new therapies, long COVID scientists are hopeful that this is the year patients — and doctors who care for them — will finally see improvements in treating their symptoms.
Here are five bold predictions — all based on encouraging research — that could happen in 2024. At the very least, they are promising signs of progress against a debilitating and frustrating disease.
#1: We'll gain a better understanding of each long COVID phenotype
This past year, a wide breadth of research began showing that long COVID can be defined by a number of different disease phenotypes that present a range of symptoms.
Researchers identified four clinical phenotypes: Chronic fatigue-like syndrome, headache, and memory loss; respiratory syndrome, which includes cough and difficulty breathing; chronic pain; and neurosensorial syndrome, which causes an altered sense of taste and smell.
Identifying specific diagnostic criteria for each phenotype would lead to better health outcomes for patients instead of treating them as if it were a "one-size-fits-all disease," said Nisha Viswanathan, MD, director of the long COVID program at UCLA Health, Los Angeles, California.
Ultimately, she hopes that this year her patients will receive treatments based on the type of long COVID they're personally experiencing, and the symptoms they have, leading to improved health outcomes and more rapid relief.
"Many new medications are focused on different pathways of long COVID, and the challenge becomes which drug is the right drug for each treatment," said Viswanathan.
#2: Monoclonal antibodies may change the game
We're starting to have a better understanding that what's been called "viral persistence" as a main cause of long COVID may potentially be treated with monoclonal antibodies. These are antibodies produced by cloning unique white blood cells to target the circulating spike proteins in the blood that hang out in viral reservoirs and cause the immune system to react as if it's still fighting acute COVID-19.
Smaller-scale studies have already shown promising results. A January 2024 study published in The American Journal of Emergency Medicine followed three patients who completely recovered from long COVID after taking monoclonal antibodies. "Remission occurred despite dissimilar past histories, sex, age, and illness duration," wrote the study authors.
Larger clinical trials are underway at the University of California, San Francisco, California, to test targeted monoclonal antibodies. If the results of the larger study show that monoclonal antibodies are beneficial, then it could be a game changer for a large swath of patients around the world, said David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City.
"The idea is that the downstream damage caused by viral persistence will resolve itself once you wipe out the virus," said Putrino.
#3: Paxlovid could prove effective for long COVID
The US Food and Drug Administration granted approval for Paxlovid last May for the treatment of mild to moderate COVID-19 in adults at a high risk for severe disease. The medication is made up of two drugs packaged together. The first, nirmatrelvir, works by blocking a key enzyme required for virus replication. The second, ritonavir, is an antiviral that's been used in patients with HIV and helps boost levels of antivirals in the body.
In a large-scale trial headed up by Putrino and his team, the oral antiviral is being studied for use in the post-viral stage in patients who test negative for acute COVID-19 but have persisting symptoms of long COVID.
Similar to monoclonal antibodies, the idea is to quell viral persistence. If patients have long COVID because they can't clear SAR-CoV-2 from their bodies, Paxlovid could help. But unlike monoclonal antibodies that quash the virus, Paxlovid stops the virus from replicating. It's a different mechanism with the same end goal.
It's been a controversial treatment because it's life-changing for some patients and ineffective for others. In addition, it can cause a range of side effects such as diarrhea, nausea, vomiting, and an impaired sense of taste. The goal of the trial is to see which patients with long COVID are most likely to benefit from the treatment.
#4: Anti-inflammatories like metformin could prove useful
Many of the inflammatory markers persistent in patients with long COVID were similarly present in patients with autoimmune diseases like rheumatoid arthritis, according to a July 2023 study published in JAMA.
The hope is that anti-inflammatory medications may be used to reduce inflammation causing long COVID symptoms. But drugs used to treat rheumatoid arthritis like abatacept and infliximabcan also have serious side effects, including increased risk for infection, flu-like symptoms, and burning of the skin.
"Powerful anti-inflammatories can change a number of pathways in the immune system," said Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, Ohio. Anti-inflammatories hold promise but, McComsey said, "some are more toxic with many side effects, so even if they work, there's still a question about who should take them."
Still, other anti-inflammatories that could work don't have as many side effects. For example, a study published in The Lancet Infectious Diseases found that the diabetes drug metformin reduced a patient's risk for long COVID up to 40% when the drug was taken during the acute stage.
Metformin, compared to other anti-inflammatories (also known as immune modulators), is an inexpensive and widely available drug with relatively few side effects compared with other medications.
#5: Serotonin levels — and selective serotonin reuptake inhibitors (SSRIs) — may be keys to unlocking long COVID
One of the most groundbreaking studies of the year came last November. A study published in the journal Cell found lower circulating serotonin levels in patents with long COVID than in those who did not have the condition. The study also found that the SSRI fluoxetine improved cognitive function in rat models infected with the virus.
Researchers found that the reduction in serotonin levels was partially caused by the body's inability to absorb tryptophan, an amino acid that's a precursor to serotonin. Overactivated blood platelets may also have played a role.
Michael Peluso, MD, an assistant research professor of infectious medicine at the UCSF School of Medicine, San Francisco, California, hopes to take the finding a step further, investigating whether increased serotonin levels in patients with long COVID will lead to improvements in symptoms.
"What we need now is a good clinical trial to see whether altering levels of serotonin in people with long COVID will lead to symptom relief," Peluso said last month in an interview with Medscape Medical News.
If patients show an improvement in symptoms, then the next step is looking into whether SSRIs boost serotonin levels in patients and, as a result, reduce their symptoms.
23
 132

________________________________________________________________________

Nature: A randomized open-label clinical trial on the effect of Amantadine on post Covid 19 fatigueJanuary 17, 2024  A A Harandi et al 2024     Scientific Reports
Abstract
Many COVID-19 survivors experience lingering post-COVID-19 symptoms, notably chronic fatigue persisting for months after the acute phase. Despite its prevalence, limited research has explored effective treatments for post-COVID-19 fatigue. This randomized controlled clinical trial assessed the impact of Amantadine on patients with post-COVID-19 fatigue. The intervention group received Amantadine for two weeks, while the control group received no treatment. Fatigue levels were assessed using the Visual Analog Fatigue Scale (VAFS) and Fatigue Severity Scale (FSS) questionnaires before and after the trial. At the study's onset, VAFS mean scores were 7.90 ± 0.60 in the intervention group and 7.34 ± 0.58 in the control group (P-value = 0.087). After two weeks, intervention group scores dropped to 3.37 ± 0.44, significantly lower than the control group's 5.97 ± 0.29 (P-value < 0.001). Similarly, FSS mean scores at the trial's commencement were 53.10 ± 5.96 in the intervention group and 50.38 ± 4.88 in the control group (P-value = 0.053). At the trial's end, intervention group scores decreased to 28.40 ± 2.42, markedly lower than the control group's 42.59 ± 1.50 (P-value < 0.001). In this study, we report the safety, tolerability, and substantial fatigue-relieving effects of Amantadine in post-COVID-19 fatigue. The intervention demonstrates a statistically significant reduction in fatigue levels, suggesting Amantadine's potential as an effective treatment for this persistent condition.
Discussion
Amantadine's effectiveness in relieving MS-related fatigue has been frequently shown, and its prescription is recommended by the German MS Society as well as in clinical practice guidelines published by NICE. Given the high incidence rate of post-COVID-19 fatigue and lack of treatment options, the satisfactory result obtained in our study with treatment with Amantadine is considerable. However, to our knowledge, there is no study investigating the effect of Amantadine on fatigue in post-COVID-19 patients to compare their results with ours.
Results
Our results showed a significant difference in the improvement of fatigue in patients receiving Amantadine compared to the control group. This improvement was evident in the FSS and the VAFS scores since the average of both reached less than half of the initial value after two weeks of treatment with Amantadine.
In conclusion, our study demonstrated that consuming Amantadine has a favorable effect on relieving post-COVID-19 fatigue. Our results reveal the safety and tolerability of two-weeks treatment with Amantadine in post-COVID-19 patients. We recommend well-designed double-blind, randomized studies with placebo and larger sample sizes to validate our results.

________________________________________________________________________

News Medical: Long COVID and ME/CFS patients could benefit from a coordinated treatment strategyJanuary 23, 2024  News Medical Life Sciences
“Given the important clinical and pathological overlaps between ME/CFS and Long Covid co-ordinated research is something that the MEA has been calling for since May 2020 – when it became clear that Covid-19 was also triggering a post viral disease with symptoms that were identical to those found in ME/CFS
Sadly, it has taken over three years for many of the researchers involved in Long Covid research to accept that these overlaps occur
However the message is now getting through 
Hopefully, this will lead to a better understanding of what causes post viral disease and the development of effective forms of treatment aimed at the underlying disease process in both Long Covid and ME/CFS“
Dr Charles Shepherd,
Trustee and Hon. Medical Adviser to the ME Association.
________________________________________________________________________
 
Published: 12 December 2023
A pilot study on the immune cell proteome of long COVID patients shows changes to physiological pathways similar to those in myalgic encephalomyelitis/chronic fatigue syndromeKatie Peppercorn, Christina D. Edgar, Torsten Kleffmann & Warren P. Tate 
Scientific Reports volume 13, Article number: 22068 (2023)  
Abstract
Of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ~ 10% develop the chronic post-viral debilitating condition, long COVID (LC). Although LC is a heterogeneous condition, about half of cases have typical post-viral fatigue with onset and symptoms that are very similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A key question is whether these conditions are closely related. ME/CFS is a post-stressor fatigue condition that arises from multiple triggers. To investigate the pathophysiology of LC, a pilot study of patients (n = 6) and healthy controls (n = 5) has used quantitative proteomics to discover changes in peripheral blood mononuclear cell (PBMC) proteins. A principal component analysis separated all long COVID patients from healthy controls. Analysis of 3131 proteins identified 162 proteins differentially regulated, of which 37 were related to immune functions, and 21 to mitochondrial functions. Markov cluster analysis identified clusters involved in immune system processes, and two aspects of gene expression-spliceosome and transcription. These results were compared with an earlier dataset of 346 differentially regulated proteins in PBMC’s from ME/CFS patients (n = 9) analysed by the same methodology. There were overlapping protein clusters and enriched molecular pathways particularly in immune functions, suggesting the two conditions have similar immune pathophysiology as a prominent feature, and mitochondrial functions involved in energy production were affected in both conditions.

________________________________________________________________________


Sci.Rep. 2024; 14: 1343.
Published online 2024 Jan 16. doi: 10.1038/s41598-024-51904-z
PMCID: PMC10792128nnnnPMID: 38228731
A randomized open-label clinical trial on the effect of Amantadine on post Covid 19 fatigue
Ali Amini Harandi, 1 Hossein Pakdaman,1 Aida Medghalchi,1 Negin Kimia,1 Alireza Kazemian,1 Fatemeh Siavoshi,1 Siavash Shirzadeh Barough,1 Akram Esfandani,1 Mohammad Hossein Hosseini,1 and Seyed Ali Sobhanian2
Author information Article notes Copyright and License information PMC Disclaimer
Abstract
Many COVID-19 survivors experience lingering post-COVID-19 symptoms, notably chronic fatigue persisting for months after the acute phase. Despite its prevalence, limited research has explored effective treatments for post-COVID-19 fatigue. This randomized controlled clinical trial assessed the impact of Amantadine on patients with post-COVID-19 fatigue. The intervention group received Amantadine for two weeks, while the control group received no treatment. Fatigue levels were assessed using the Visual Analog Fatigue Scale (VAFS) and Fatigue Severity Scale (FSS) questionnaires before and after the trial. At the study's onset, VAFS mean scores were 7.90 ± 0.60 in the intervention group and 7.34 ± 0.58 in the control group (P-value = 0.087). After two weeks, intervention group scores dropped to 3.37 ± 0.44, significantly lower than the control group's 5.97 ± 0.29 (P-value < 0.001). Similarly, FSS mean scores at the trial's commencement were 53.10 ± 5.96 in the intervention group and 50.38 ± 4.88 in the control group (P-value = 0.053). At the trial's end, intervention group scores decreased to 28.40 ± 2.42, markedly lower than the control group's 42.59 ± 1.50 (P-value < 0.001). In this study, we report the safety, tolerability, and substantial fatigue-relieving effects of Amantadine in post-COVID-19 fatigue. The intervention demonstrates a statistically significant reduction in fatigue levels, suggesting Amantadine's potential as an effective treatment for this persistent condition.

________________________________________________________________________

New Tests May Finally Diagnose Long COVIDSara Novak  November 29, 2023 Medscape Medical News
 
One of the biggest challenges facing clinicians who treat long COVID is a lack of consensus when it comes to recognizing and diagnosing the condition. But a new study suggests testing for certain biomarkers may identify long COVID with accuracy approaching 80%. 
Effective diagnostic testing would be a game-changer in the long COVID fight, for it’s not just the fatigue, brain fog, heart palpitations, and other persistent symptoms that affect patients. Two out of three people with long COVID also suffer mental health challenges like depression and anxiety. Some patients say their symptoms are not taken seriously by their doctors. And as many as 12% of long COVID patients are unemployed because of the severity of their illness and their employers may be skeptical of their condition.
Quick, accurate diagnosis would eliminate all that. Now a new preprint study suggests that the elevation of certain immune system proteins are a commonality in long COVID patients and identifying them may be an accurate way to diagnose the condition.
Researchers at Cardiff University School of Medicine in Cardiff, Wales, United Kingdom, tracked 166 patients, 79 of whom had been diagnosed with long COVID and 87 who had not. All participants had recovered from a severe bout of acute COVID-19.
In an analysis of the blood plasma of the study participants, researchers found elevated levels of certain components. Four proteins in particular — Ba, iC3b, C5a, and TCC — predicted the presence of long COVID with 78.5% accuracy.
"I was gobsmacked by the results. We’re seeing a massive dysregulation in those four biomarkers," says study author Wioleta Zelek, PhD, a research fellow at Cardiff University. "It’s a combination that we showed was predictive of long COVID." 
The study revealed that long COVID was associated with inflammation of the immune system causing these complement proteins to remain dysregulated. Proteins like C3, C4, and C5 are important parts of the immune system because they recruit phagocytes, cells that attack and engulf bacteria and viruses at the site of infection to destroy pathogens like SARS-coV-2. 
In the case of long COVID, these proteins remain chronically elevated. While the symptoms of long COVID have seemed largely unrelated to one another, researchers point to elevated inflammation as a connecting factor that causes various systems in the body to go haywire.
"Anything that could help to better diagnose patients with long COVID is research we’re greatly appreciative of within the clinical community," said Nisha Viswanathan, MD, director of the University of California Los Angeles Long COVID program at UCLA Health in Los Angeles. 
Testing for biomarkers highlighted in the study, as well as others like serotonin and cortisol, may help doctors separate patients who have long COVID from patients who have similar symptoms caused by other conditions, said Viswanathan. For example, a recent study published in the journal Cell found lower serotonin levels in long COVID patients compared with patients who were diagnosed with acute COVID-19 but recovered from the condition.
 
Viswanathan cautions that the biomarker test does not answer all the questions about diagnosing long COVID. For example, Viswanathan said scientists don’t know whether complement dysregulation is caused by long COVID and not another underlying medical issue that patients had prior to infection, because "we don’t know where patients’ levels were prior to developing long COVID." For example, those with autoimmune issues are more likely to develop long COVID, which means their levels could have been elevated prior to a COVID infection.
It is increasingly likely, said Viswanathan, that long COVID is an umbrella term for a host of conditions that could be caused by different impacts of the virus. Other research has pointed to the different phenotypes of long COVID. For example, some are focused on cardiopulmonary issues and others on fatigue and gastrointestinal problems. 
"It looks like these different phenotypes have a different mechanism for disease," she said. This means that it’s less likely to be a one-size-fits-all condition and the next step in the research should be identifying which biomarker is aligned with which phenotype of the disease. 
Better diagnostics will open the door to better treatments, Zelek said. The more doctors understand about the mechanism causing immune dysregulation in long COVID patients, the more they can treat it with existing medications. Zelek’s lab has been studying certain medications like pegcetacoplan (C3 blocker), danicopan (anti-factor D), and iptacopan (anti-factor B) that can be used to break the body’s cycle of inflammation and reduce symptoms experienced in those with long COVID. 
These drugs are approved by the US Food and Drug Administration for the treatment of a rare blood disease called paroxysmal nocturnal hemoglobinuria. The C5 inhibitor zilucoplan has also been used in patients hospitalized with COVID-19 and researchers have found that the drug lowered serum C5 and interleukin-8 concentration in the blood, seeming to reduce certain aspects of the immune system’s inflammatory response to the virus. 
The Cardiff University research is one of the most detailed studies to highlight long COVID biomarkers to date, said infectious disease specialist Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, Ohio. The research needs to be duplicated in a larger study population that might include the other biomarkers like serotonin and cortisol to see if they’re related, she said. 
Researchers are learning more everyday about the various biomarkers that may be linked to long COVID, she added. This Cardiff study showed that a huge percentage of those patients had elevated levels of certain complements. The next step, said McComsey, "is to put all these puzzle pieces together" so that clinicians have a common diagnostic tool or tools that provide patients with some peace of mind in starting their road to recovery.

________________________________________________________________________
 
Why Are Women More Likely to Get Long COVID?Tinker Ready        Medscape medical news January 19, 2024
Annette Gillaspie, a nurse in a small Oregon hospital, hoped she would be back working with patients by now. She contracted COVID-19 on the job early in the pandemic and ended up with long COVID.  After recovering a bit, her fatigue and dizziness returned, and today she is still working a desk job. She has also experienced more severe menstrual periods than before she had COVID.  "Being a female with long COVID definitely does add to the roller-coaster effect of symptoms," Gillaspie said.
Long COVID affects nearly twice as many women as men, with 6.6% of women reporting long COVID compared with 4% of men, according to a recent Census Bureau survey reported by the Centers for Disease Control and Prevention (CDC). Researchers are trying to determine why, what causes the gender disparity, and how best to treat it.Scientists are also starting to look at the impact of long COVID on female reproductive health, including menstruation, pregnancy, and menopause.
Sex differences are common in infection-associated illnesses, said Beth Pollack, a research scientist specializing in long COVID in the Massachusetts Institute of Technology's Department of Biological Engineering, Cambridge, Massachusetts. "It informs research priorities and the lens with which we understand long COVID."  For example, reproductive health issues for women, such as puberty, pregnancy, and menopause, can alter the course of illness in a subset of women in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS), a condition that can cause dizziness and worse. "This suggests that sex hormones may play key roles in immune responses to infections," Pollack said.
ME/CFS and a Possible Link to Long COVID in Women
Some of the research into long COVID is being led by teams studying infection-associated chronic illnesses like ME/CFS.
The problem: Advocates say ME/CFS has been under-researched. Poorly understood for years, the condition is one of a handful of chronic illnesses linked to infections, including Lyme disease and now long COVID. Perhaps not coincidently, they are more likely to affect women.  Many of the research findings about long COVID mirror data that emerged in past ME/CFS research, said Jaime Seltzer, the scientific director at #MEAction, Santa Monica, California, an advocacy group. One point in particular: ME/CFS strikes women about twice as much as men, according to the CDC.
Seltzer said the response to long COVID could be much further ahead if the research community acknowledged the work done over the years on ME/CFS. Many of the potential biomarkers and risk factors emerging for long COVID were also suspected in ME/CFS, but not thoroughly studied, she said.  She also said not enough work has been done to unravel the links between gender and these chronic conditions. "We're stuck in this Groundhog Day situation," she said. "There isn't any research, so we can't say anything definitively."
 
Some New Research, Some New Clues
Scientists like Pollack are slowly making inroads. She was lead author on a 2023 review investigating the impact of long COVID on female reproductive health. The paper highlights long COVID links to ME/CFS, POTS, and Ehlers-Danlos syndrome (EDS), as well as a resulting laundry list of female reproductive health issues. The hope is physicians will examine how the menstrual cycle, pregnancy, and menopause affect symptoms and illness progression of long COVID.
The Tal Research group at MIT (where Pollack works) has also added long COVID to the list of infection-associated illnesses it studies. The lab is conducting a large study looking into both Lyme disease and long COVID. The goals are to identify biomarkers that can predict who will not recover and to advance available treatments.  Another MIT program, "SEXX + Immunity" holds seminars and networking sessions for scientists looking into the role of female and male biology in immune responses to infection.
Barriers to Progress Remain
On the clinical side, female patients with long COVID also have to deal with a historical bias that still lurks in medicine when it comes to women's health, said Alba Azola, MD, an assistant professor of physical medicine at Johns Hopkins Medicine, Baltimore, Maryland.  Azola said she has discovered clinical descriptions of ME/CFE in the literature archives that describe it as "neurasthenia" and dismiss it as psychological.  Patients say that it is still happening, and while it may not be so blunt, "you can read between the lines," Azola said.  Azola, who has worked with long-COVID patients and is now seeing people with ME/CFS, said the symptoms of infection-associated chronic illness can mimic menopause, and many of her patients received that misdiagnosis. She recommends that doctors rule out long COVID for women with multiple symptoms before attributing symptoms to menopause.
Seeing that some long-COVID patients were developing ME/CFS, staff at the Bateman Horne Center in Salt Lake City, Utah, set up a program for the condition in 2021. They were already treating patients with ME/CFS and what they call "multi-symptom chronic complex diseases."  Jennifer Bell, a certified nurse practitioner at the center, said she has not seen any patients with ovarian failure but plenty with reproductive health issues. "There definitely is a hormonal connection, but I don't think there's a good understanding about what is happening," she said. Most of her patients are female, and the more serious patients tend to go through a worsening of their symptoms in the week prior to getting a period, she said.  One thing Bell said she's noticed in the past year is an increase in patients with EDS, which is also more common in women.
Like long COVID, many of the conditions traditionally treated at the center have no cure. But Bell said the center has developed an expertise in treating post-exertional malaise, a common symptom of long COVID, and keeps up with the literature for treatments to try, like the combination of guanfacine and the antioxidant N-acetyl cysteine to treat brain fog, an approach developed at Yale.  "It's a very challenging illness to treat," Bell said.
Since the emergence of long COVID, researchers have warned that symptoms vary so much from person to person that treatment will need to be targeted.  Pollack of MIT agrees and sees a big role for personalized medicine.  We need to "identify phenotypes within and across these overlapping and co-occurring illnesses so that we can identify the right therapeutics for each person," she said.
As for Annette Gillaspie, she still hopes her long COVID will subside so she can get out from behind the desk and return to her normal nursing duties.  "I just got to a point where I realized I'm likely never going to be able to do my job," she said. "It was incredibly heart breaking, but it's the reality of long COVID, and I know I'm not the only one to have to step away from a job I loved."

________________________________________________________________________


Medicina (Kaunas). 2023 May; 59(5): 978.
Published online 2023 May 18. doi: 10.3390/medicina59050978PMCID: PMC10224216
PMID: 37241210
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators?
Klaus J. Wirth and Matthias Löhn*  Modra Murovska, Academic Editor
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is often associated with various other syndromes or conditions including mast cell activation (MCA), dysmenorrhea and endometriosis, postural tachycardia (POTS) and small fiber neuropathy (SFN). The causes of these syndromes and the reason for their frequent association are not yet fully understood. We previously published a comprehensive hypothesis of the ME/CFS pathophysiology that explains the majority of symptoms, findings and chronicity of the disease. We wondered whether some of the identified key pathomechanisms in ME/CFS are also operative in MCA, endometriosis and dysmenorrhea, POTS, decreased cerebral blood flow and SFN, and possibly may provide clues on their causes and frequent co-occurrence. Our analysis indeed provides strong arguments in favor of this assumption, and we conclude that the main pathomechanisms responsible for this association are excessive generation and spillover into the systemic circulation of inflammatory and vasoactive tissue mediators, dysfunctional β2AdR, and the mutual triggering of symptomatology and disease initiation. Overall, vascular dysfunction appears to be a strong common denominator in these linkages.
Keywords: ME/CFS, long COVID, MCA, endometriosis, dysmenorrhea, orthostatic intolerance, small fiber neuropathy, cerebral blood flow, brain fog, β2-adrenergic receptors

 ________________________________________________________________________

New Evidence Suggests Long COVID Could Be a Brain InjurySara Novak  February 08, 2024  Medscape Medical News
Brain fog is one of the most common, persistent complaints in patients with long COVID. It affects as many as 46% of patients who also deal with other cognitive concerns like memory loss and difficulty concentrating. 
Now, researchers believe they know why. A new study has found that these symptoms may be the result of a viral-borne brain injury that may cause cognitive and mental health issues that persist for years.
Researchers found that 351 patients hospitalized with severe COVID-19 had evidence of a long-term brain injury a year after contracting the SARS-CoV-2 virus. The findings were based on a series of cognitive tests, self-reported symptoms, brain scans, and biomarkers. 
Brain Deficits Equal to 20 Years of Brain AgingAs part of the preprint study, participants took a cognition test with their scores age-matched to those who had not suffered a serious bout of COVID-19. Then a blood sample was taken to look for specific biomarkers, showing that elevated levels of certain biomarkers were consistent with a brain injury. Using brain scans, researchers also found that certain regions of the brain associated with attention were reduced in volume.
Patients who participated in the study were "less accurate and slower" in their cognition, and suffered from at least one mental health condition, such as depression, anxiety, or posttraumatic stress disorder, according to researchers.
The brain deficits found in COVID-19 patients were equivalent to 20 years of brain aging and provided proof of what doctors have feared: that this virus can damage the brain and result in ongoing mental health issues. 
"We found global deficits across cognition," said lead study author Benedict Michael, PhD, director of the Infection Neuroscience Lab at the University of Liverpool in Liverpool, England. "The cognitive and memory problems that patients complained of were associated with neuroanatomical changes to the brain." 
Proof That Symptoms Aren't 'Figment' of Patients' ImaginationsCognitive deficits were common among all patients, but the researchers said they don't yet know whether the brain damage causes permanent cognitive decline. But the research provides patients who have been overlooked by some clinicians with proof that their conditions aren't a figment of their imaginations, said Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine's COVID Recovery Clinic. 
"Even though we're several years into this pandemic, there are still a lot of providers who don't believe that their patients are experiencing these residual symptoms," said Thompson, "That's why the use of biomarkers is important, because it provides an objective indication that the brain has been compromised in some way."
Some patients with long COVID have said that getting their doctors to believe they have a physical ailment has been a persistent problem throughout the pandemic and especially as it relates to the sometimes-vague collection of symptoms associated with brain fog. One study found that as many as 79% of study respondents reported negative interactions with their healthcare providers when they sought treatment for their long-COVID symptoms. 
How Do COVID-Related Brain Injuries Happen?Researchers are unsure what's causing these brain injuries, though they have identified some clues. Previous research has suggested that such injuries might be the result of a lack of oxygen to the brain, especially in patients who were hospitalized, like those in this study, and were put on ventilators.
Brain scans have previously shown atrophy to the brain's gray matter in COVID-19 patients, likely caused by inflammation from a heightened immune response rather than the virus itself. This inflammatory response seems to affect the central nervous system. As part of the new study, researchers found some neuroprotective effects of using steroids during hospitalization to reduce brain inflammation.
The results suggest that clinicians should overcome their skepticism and consider the possibility that their patients have suffered a brain injury and should be treated appropriately, said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine. "The old saying is that if it walks like a duck and talks like a duck, it's a duck," said Jackson. 
He contends that treatments used for patients who have brain injuries have also been shown to be effective in treating long COVID–related brain fog symptoms. These may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for the treatment of related mental health concerns.
A New Path ForwardTreating long-COVID brain fog like a brain injury can help patients get back to some semblance of normalcy, researchers said. "What we're seeing in terms of brain injury biomarkers and differences in brain scans correlates to real-life problems that these patients are dealing with on a daily basis," said Jackson. These include problems at work and in life with multitasking, remembering details, meeting deadlines, synthesizing large amounts of information, and maintaining focus on the task at hand, he said.
There's also a fear that even with treatment, the aging of the brain caused by the virus might have long-term repercussions and that this enduring injury may cause the early onset of dementia and Alzheimer's disease in those who were already vulnerable to it. One study, from the National Institute of Neurological Disorders and Stroke (NINDS), found that in those infected with COVID-19 who already had dementia, the virus "rapidly accelerated structural and functional brain deterioration." 
"We already know the role that neuroinflammation plays in the brains of patients with Alzheimer's disease," said Thompson. "If long COVID is involved in prolonged inflammation of the brain, it goes a long way in explaining the mechanism underlying [the study's reported] brain aging."
Still More to LearnIn some ways, this study raises nearly as many questions as it does answers. While it provides concrete evidence around the damage the virus is doing to the brains of patients who contracted severe COVID-19, researchers don't know about the impact on those who had less serious cases of the virus. 
For Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System, the concern is that some long-COVID patients may be suffering from cognitive deficits that are more subtle but still impacting their daily lives, and that they're not getting the help they need. 
What's more, said Al-Aly, it's unclear whether the impacts of the brain damage are permanent or how to stop them from worsening. Researchers and clinicians need a better understanding of the mechanism that allows this virus to enter the brain and do structural damage. If it's inflammation, will anti-inflammatory or antiviral medications work at preventing it? Will steroids help to offset the damage? "It's critical we find some answers," he said.
"SARS-CoV-2 isn't going anywhere. It will continue to infect the population, so if this is indeed a virus that damages the brain in the long term or permanently, we need to figure out what can be done to stop it," said Al-Aly.

________________________________________________________________________

Infectious Diseases  February 14, 2024
Cognitive Symptoms of Post–COVID-19 Condition and Daily FunctioningAbhishek Jaywant, PhD1; Faith M. Gunning, PhD1; Lauren E. Oberlin, PhD1; et alMauricio Santillana, PhD2,3; Katherine Ognyanova, PhD4; James N. Druckman, PhD5; Matthew A. Baum, PhD6; David Lazer, PhD7,8,9,10; Roy H. Perlis, MD, MSc11,12
JAMA Netw Open. 2024;7(2):e2356098. doi:10.1001/jamanetworkopen.2023.56098
Key Points
Question  How are post–COVID-19 condition self-reported cognitive symptoms associated with employment status, functional outcomes, and mood?
Findings  In this survey study including 14 767 individuals with post–COVID-19 condition surveyed in late 2022 to early 2023, 57% reported experiencing cognitive symptoms daily, compared with 27% with prior SARS-CoV-2 infection who did not develop post–COVID-19 condition. In those with post–COVID-19 condition, cognitive symptoms were associated with greater levels of depressive symptoms, greater reported functional impairment, and lesser likelihood of full-time employment.
Meaning  The findings of this study suggest that self-reported cognitive symptoms are prevalent in post–COVID-19 condition, often co-occur with depressive symptoms, and are associated with functional impairment.
Abstract
Importance  The frequent occurrence of cognitive symptoms in post–COVID-19 condition has been described, but the nature of these symptoms and their demographic and functional factors are not well characterized in generalizable populations.
Objective  To investigate the prevalence of self-reported cognitive symptoms in post–COVID-19 condition, in comparison with individuals with prior acute SARS-CoV-2 infection who did not develop post–COVID-19 condition, and their association with other individual features, including depressive symptoms and functional status.
Design, Setting, and Participants  Two waves of a 50-state nonprobability population-based internet survey conducted between December 22, 2022, and May 5, 2023. Participants included survey respondents aged 18 years and older.
Exposure  Post–COVID-19 condition, defined as self-report of symptoms attributed to COVID-19 beyond 2 months after the initial month of illness.
Main Outcomes and Measures  Seven items from the Neuro-QoL cognition battery assessing the frequency of cognitive symptoms in the past week and patient Health Questionnaire-9.
Results  The 14 767 individuals reporting test-confirmed COVID-19 illness at least 2 months before the survey had a mean (SD) age of 44.6 (16.3) years; 568 (3.8%) were Asian, 1484 (10.0%) were Black, 1408 (9.5%) were Hispanic, and 10 811 (73.2%) were White. A total of 10 037 respondents (68.0%) were women and 4730 (32.0%) were men. Of the 1683 individuals reporting post–COVID-19 condition, 955 (56.7%) reported at least 1 cognitive symptom experienced daily, compared with 3552 of 13 084 (27.1%) of those who did not report post–COVID-19 condition. More daily cognitive symptoms were associated with a greater likelihood of reporting at least moderate interference with functioning (unadjusted odds ratio [OR], 1.31 [95% CI, 1.25-1.36]; adjusted [AOR], 1.30 [95% CI, 1.25-1.36]), lesser likelihood of full-time employment (unadjusted OR, 0.95 [95% CI, 0.91-0.99]; AOR, 0.92 [95% CI, 0.88-0.96]) and greater severity of depressive symptoms (unadjusted coefficient, 1.40 [95% CI, 1.29-1.51]; adjusted coefficient 1.27 [95% CI, 1.17-1.38). After including depressive symptoms in regression models, associations were also found between cognitive symptoms and at least moderate interference with everyday functioning (AOR, 1.27 [95% CI, 1.21-1.33]) and between cognitive symptoms and lower odds of full-time employment (AOR, 0.92 [95% CI, 0.88-0.97]).
Conclusions and Relevance  The findings of this survey study of US adults suggest that cognitive symptoms are common among individuals with post–COVID-19 condition and associated with greater self-reported functional impairment, lesser likelihood of full-time employment, and greater depressive symptom severity. Screening for and addressing cognitive symptoms is an important component of the public health response to post–COVID-19 condition.

________________________________________________________________________

Original Investigation  March 23, 2023
Risk Factors Associated With Post−COVID-19 ConditionA Systematic Review and Meta-analysisVasiliki Tsampasian, MD, MSc1,2; Hussein Elghazaly, MBBS3; Rahul Chattopadhyay, MBBS, MSc1,4; et alMaciej Debski, MD, PhD1,2; Thin Kyi Phyu Naing, MBBS1,2; Pankaj Garg, PhD1,2; Allan Clark, PhD2; Eleana Ntatsaki, MD(Res), MA5,6; Vassilios S. Vassiliou, MBBS, PhD1,2
JAMA Intern Med. 2023;183(6):566-580. doi:10.1001/jamainternmed.2023.0750
COVID-19 Resource Center
Key Points
Question  Which individuals are at risk of developing post−COVID-19 condition (PCC)?
Findings  This systematic review and meta-analysis of 41 studies including 860 783 patients found that female sex, older age, higher body mass index, smoking, preexisting comorbidities, and previous hospitalization or ICU admission were risk factors significantly associated with developing PCC, and that SARS-CoV-2 vaccination with 2 doses was associated with lower risk of PCC.
Meanings  The findings of this systematic review and meta-analysis provide a profile of the characteristics associated with increased risk of developing PCC and suggest that vaccination may be protective against PCC.
Abstract
Importance  Post−COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support.
Objective  To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC.
Data sources  Medline and Embase databases were systematically searched from inception to December 5, 2022.
Study Selection  The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients.
Data Extraction and Synthesis  Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023.
Main Outcomes and Measures  The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19.
Results  The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76).
Conclusions and Relevance  This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination.

________________________________________________________________________

Opinion: Toward Solving the Long COVID PuzzleEric Topol  February 23, 2024  Medscape medical news
The following first appeared in the Substack of Eric Topol, MD, called Ground Truths.
In recent days, there were several important new reports that help explain the pathophysiology of long COVID. By coincidence, we published a Perspective in Science today to summarize the progress that has been made and the vital work that lies ahead.
Here, we'll summarize the new findings:
The Leaky Blood-Brain BarrierA systematic study of people with long COVID and controls, using MRI, brain-specific S100β protein, RNA-seq of white blood cells, endothelial cell response in culture provided new insights about the disrupted blood-brain barrier (BBB) in individuals with long COVID and symptoms of brain fog. They are well summarized by Prof Katerina Akassoglou from the Gladstone Institutes, who was not involved in the study and is a highly regarded scientist in the field of neurovascular inflammation: "This study is the first report of BBB disruption correlating with brain fog in patients with long COVID by dynamic contrast enhanced MRI. The MRI findings are in line with neuropathology reporting blood protein accumulation in brains from patients with COVID-19, and I expect that it will be the foundation for future studies at the blood–brain and immune interface for the discovery of mechanisms, biomarkers and therapies for neurological manifestations in long COVID."
The numbers of participants in each group was small, but the phenotyping was extraordinarily deep. Beyond the BBB, the notable findings were dysregulation of the clotting system and pro-inflammatory effects of endothelial cells.
Persistent Infections of SARS-CoV-2 as a Risk FactorFrom a large community surveillance project in the UK, 381 participants were found to have evidence of persistent infections of SARS-CoV-2 for 30 days or more. That was considerably higher than anticipated.
One percent to 3% had persistent infections for more than 30 days. In addition, 0.1%-0.5% had persistent infections for more than 60 days.
Serial assessment of viral loads indicated many of the people had rebounding high levels, indicating that there was likely actively replicating virus.
The risk for long COVID was increased by 55% in people with 12 weeks or more of persistent infection and by 24% in those with infection for 26 weeks or more.
Interferon Gamma as a Possible Biomarker for Diagnosis and TreatmentA new report assayed interferon gamma, part of the first line of defense of innate immunity to a SARS-CoV-2 infection. Individuals with long COVID had persistent elevation after the acute phase, and during follow-up serial assessment of this biomarker showed resolution among the participants with symptom resolution. This will need further assessment, but if replicated and extended, it might fulfill a major unmet need for both confirmation of diagnosis and a surrogate measure for treatments that are being assessed in prospective clinical trials, no less an objective metric for correlation with symptoms.
Myalgic Encephalomyelitis (ME/CFS) Deep PhenotypingThe 8-year, long-awaited NIH project results were published in a 70-page manuscript. Like the BBB study above, the number of participants studies was small but compensated by extensive characterization and suitable matched controls. With the considerable overlap of many of the symptoms of ME/CFS and long COVID, the results are notable: signs of persistent chronic antigen stimulation with immune system dysregulation (with T-cell exhaustion) along with multisystem disruption, some of which is central nervous system regulated, with specific regions of the brain implicated.
On a related note, The Economist had an article about postinfectious neurologic syndrome that occurs with COVID, ME/CFS, Lyme disease, and several other viruses. "Michelle Monje, a neuro-oncologist at Stanford School of Medicine, homed in on precisely how COVID-induced neurological damage might occur — particularly focusing on glial cells, as brain cells other than neurons are known."
Prof Monje has just recorded a new Ground Truths podcast on this topic, which will be posted very soon.
Two New Reports of Vaccination Protection vs Long COVIDFrom a study in the Annals of Epidemiology, Michiganders derived an important protective benefit against long COVID: Long COVID prevalence was 40%-60% lower among adults vaccinated (vs unvaccinated) prior to their COVID-19. This level of protection is consistent with many recent reports and has not been emphasized enough regarding an added benefit of booster shots. The data were previously reviewed on Ground Truths here.
And a new preprint report on protection in children and adolescents looked at different variants (Delta and Omicron) and cause and effect relationship for direct benefit of vaccination. More protection was found in teens than children, with the range of 60%-75%.
Our Science PerspectiveAnd finally, our essay in Science, in which we tried to encapsulate a lot of information on what has been learned so far and what is desperately needed to be done now. Ziyad Al-Aly put together a great thread that reviews the key points.
A Brief SummaryWe're making considerable headway on understanding what drives long COVID, along with the possibility of another biomarker candidate, which would be a big help as randomized clinical trials move forward. Clearly finding effective and safe treatments is an urgent matter and not enough is being done to pursue that yet, despite a long list of potential alluring interventions based on mechanistic insights. Hopefully that will get going now — it cannot happen soon enough.

________________________________________________________________________
 
Study IDs Immune Abnormality Possibly Causing Long COVIDTinker Ready  February 22, 2024 - Medscape
Swiss scientists have identified immune system abnormalities in patients with long COVID that might open the door to new diagnostic tests and treatments.
The researchers found that a group of proteins in the blood that are part of the body's immune response called the "complement system" are not working properly in patients with long COVID.
Blood samples turned up important differences between those who recovered from COVID and those who did not. These differences might be used as biomarkers to diagnose long COVID and might even point the way to new treatments for the condition, the researchers said.
By testing for 6500 blood proteins in about 300 patients, the Swiss researchers found that dysfunctional complement system proteins could possibly explain fatigue and "smoldering inflammation," said Onur Boyman, MD, a professor of immunology from University Hospital Zurich in Zurich, Switzerland.
Long COVID has been linked to hundreds of symptoms including brain fog, chronic fatigue, pain, and digestive issues. Various factors drive the condition and likely work with one another other, said David Putrino, PhD, from the Icahn School of Medicine at Mount Sinai in New York City. The Swiss study is useful because "we're trying to best understand how we can explain all of this far-reaching pathobiology," he said.
Testing Across ContinentsBoyman's team collected blood samples from people with COVID in Europe and New York and tracked them. They compared those who developed long COVID with those who did not. One protein that was most unique to patients with long COVID is a blood complement that activates the immune system, Boyman said. But in people with long COVID, the immune response stays activated after the virus is gone. He described the response as "smoldering inflammation" in multiple organs, including the lungs and the gastrointestinal system.
The complement system also plays a role in clearing the body of dead cells. If the cells "lie around too much," they can trigger an immune response, he said.
That may explain exercise intolerance in people with long COVID, Boyman said. Some people with long COVID have inflammation in the epithelium — the inner layer of their blood vessels. This would make it harder for the circulatory systems to recover from exercise, Boyman said.
"We think this regulated complement system is actually quite a central piece of the puzzle," he said.
The Microclot ConnectionThe findings also support past research linking blood clots to long COVID. He suggested that clinicians and researchers consider testing drugs that regulate or inhibit the complementary system as a treatment of long COVID. Boyman said they are currently used for rare immune diseases.
Resia Pretorius, PhD, a professor of physiological sciences at Stellenbosch University in Stellenbosch, South Africa, said scientists studying the role of microclots in patients with long COVID often see complementary proteins inside the clots, so it has already been associated with long COVID. But she likened this clotting process to a garbage can that "just rolls along and collects everything that gets in its way. I think they are actively driving inflammation and disease."
One factor complicating long COVID diagnosis and treatment is that it is a complex condition that involves multiple organ systems. That's why the latest research suggests an underlying driver for the multiple symptoms of long COVID, Putrino said.
"Not every person has every symptom; not every person has every organ system affected," Putrino said. "Whatever is happening is decided across the whole body."
Research Offers New DirectionThe Swiss paper contributes to the effort to identify systemic issues contributing to long COVID. It gives researchers one more thing to test for and link to specific, long COVID symptoms, opening the door to new treatments, Putrino said.
He doesn't think the study supports treating the complement dysfunction if researchers don't know what's driving it. It may be complicated by the body's failure to clear the virus completely, he said.
Pretorius recommended doctors test patients with long COVID for specific symptoms that may be treated using existing therapies. "If you think your patient had vascular pathology, you can test for it," she said.
Some patients have found certain supplements and over-the-counter products helpful, she said. Among them: Coenzyme Q 10 and clot-busters such as streptokinase and Nattokinase (though she noted some doctors may not be comfortable with supplements).
"It's the only thing we have until we've got trials," she said.
Putrino said more research is needed to identify potential root causes and symptoms. A common refrain, but the only thing that will lead to specific treatments.

________________________________________________________________________
 
Worsening Symptoms Is Associated with Larger Cerebral Blood Flow Abnormalities during Tilt-Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
C. (Linda) M. C. van Campen 1,* , Peter C. Rowe 2 and Frans C. Visser
 
Abstract: 
Background and Objectives: During tilt testing, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience an abnormal reduction in cerebral blood flow (CBF). The relationship between this CBF reduction and symptom severity has not been examined in detail. Our hypothesis was that ME/CFS severity is related to the degree of the CBF reduction during tilt testing. 
Materials and Methods: 
First, from our database, we selected ME/CFS patients who had undergone assessments of ME/CFS symptomatology and tilt tests on the same day, one at the first visit and the second during a follow-up. The change in symptomatology was related to the change in CBF during the tilt test. 
Second, we combined the data of two previously published studies (n = 219), where disease severity as defined by the 2011 international consensus criteria (ICC) was available but not published. 
Results: 71 patients were retested because of worsening symptoms. The ICC disease severity distribution (mild-moderate-severe) changed from 51/45/4% at visit-1 to 1/72/27% at follow-up (p < 0.0001). The %CBF reduction changed from initially 19% to 31% at followup (p < 0.0001). Of 39 patients with stable disease, the severity distribution was similar at visit-1 (36/51/13%) and at follow-up (33/49/18%), p = ns. The %CBF reduction remained unchanged: both 24%, p = ns. The combined data of the two previously published studies showed that patients with mild, moderate, and severe disease had %CBF reductions of 25, 29, and 33%, respectively (p < 0.0001). 
Conclusions: Disease severity and %CBF reduction during tilt testing are highly associated in ME/CFS: a more severe disease is related to a larger %CBF reduction. The data suggest a causal relationship where a larger CBF reduction leads to worsening symptoms. 

 ________________________________________________________________________

• Published: 19 November 2023 - Nature

Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post-acute COVID-19 syndrome with and without postural orthostatic tachycardia syndrome: a multi-omic profiling studyAli Mahdi, Allan Zhao, Emelie Fredengren, Artur Fedorowski, Frieder Braunschweig, Malin Nygren-Bonnier, Michael Runold, Judith Bruchfeld, Jannike Nickander, Qiaolin Deng, Antonio Checa, Liyew Desta, John Pernow & Marcus Ståhlberg 
Scientific Reports volume 13, Article number: 20230 (2023)  
AbstractPost-acute COVID-19 (PACS) are associated with cardiovascular dysfunction, especially postural orthostatic tachycardia syndrome (POTS). Patients with PACS, both in the absence or presence of POTS, exhibit a wide range of persisting symptoms long after the acute infection. Some of these symptoms may stem from alterations in cardiovascular homeostasis, but the exact mechanisms are poorly understood. The aim of this study was to provide a broad molecular characterization of patients with PACS with (PACS + POTS) and without (PACS-POTS) POTS compared to healthy subjects, including a broad proteomic characterization with a focus on plasma cardiometabolic proteins, quantification of cytokines/chemokines and determination of plasma sphingolipid levels. Twenty-one healthy subjects without a prior COVID-19 infection (mean age 43 years, 95% females), 20 non-hospitalized patients with PACS + POTS (mean age 39 years, 95% females) and 22 non-hospitalized patients with PACS-POTS (mean age 44 years, 100% females) were studied. PACS patients were non-hospitalized and recruited ≈18 months after the acute infection. Cardiometabolic proteomic analyses revealed a dysregulation of ≈200 out of 700 analyzed proteins in both PACS groups vs. healthy subjects with the majority (> 90%) being upregulated. There was a large overlap (> 90%) with no major differences between the PACS groups. Gene ontology enrichment analysis revealed alterations in hemostasis/coagulation, metabolism, immune responses, and angiogenesis in PACS vs. healthy controls. Furthermore, 11 out of 33 cytokines/chemokines were significantly upregulated both in PACS + POTS and PACS-POTS vs. healthy controls and none of the cytokines were downregulated. There were no differences in between the PACS groups in the cytokine levels. Lastly, 16 and 19 out of 88 sphingolipids were significantly dysregulated in PACS + POTS and PACS-POTS, respectively, compared to controls with no differences between the groups. Collectively, these observations suggest a clear and distinct dysregulation in the proteome, cytokines/chemokines, and sphingolipid levels in PACS patients compared to healthy subjects without any clear signature associated with POTS. This enhances our understanding and might pave the way for future experimental and clinical investigations to elucidate and/or target resolution of inflammation and micro-clots and restore the hemostasis and immunity in PACS.

________________________________________________________________________
 
Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

• Michael Anthony Jensen*Miranda Lee Dafoe,Julie Wilhelmy,Layla Cervantes,nna N Okumu,,Lucas Kipp, Nemat-Gorgani,, and Ronald Wayne Davis

·        
Cite this: Biochemistry 2024, 63, 1, 9–18  Publication Date:November 27, 2023
https://doi.org/10.1021/acs.biochem.3c00433
Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under 
CC-BY-NC-ND 4.0.
PDF (5 MB)
Abstract 
Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatiguesyndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP). We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness. In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP. Furthermore, we found that aprotinin, which is a specific serine protease inhibitor, specifically prevents breakdown of MBP while the other classes of protease inhibitors had no effect. This coincides with the published literature describing catalytic antibodies as having serine protease-like activity. Postpandemic research has also provided several reports of demyelination in COVID-19. Because COVID-19 has been described as a trigger for ME/CFS, demyelination could play a bigger role in patient symptoms for those recently diagnosed with ME/CFS. Therefore, by studying proteolytic antibodies in ME/CFS, their target substrates, and inhibitors, a new mechanism of action could lead to better treatment and a possible cure for the disease.
________________________________________________________________________
 
Persistent complement dysregulation with signs of thromboinflammation in active Long CovidCARLO CERVIA-HASLER HTTPS://ORCID.ORG/0000-0001-7120-8739, SARAH C. BRÜNINGK HTTPS://ORCID.ORG/0000-0003-3176-1032, TOBIAS HOCH HTTPS://ORCID.ORG/0000-0003-0319-6064, BOWEN FAN, GIULIA MUZIO HTTPS://ORCID.ORG/0000-0001-5999-2030, RYAN C. THOMPSON HTTPS://ORCID.ORG/0000-0002-0450-8181, LAURA CEGLAREK HTTPS://ORCID.ORG/0009-0005-7117-0335, ROMAN MELEDIN HTTPS://ORCID.ORG/0000-0001-6921-825X, PATRICK WESTERMANN HTTPS://ORCID.ORG/0000-0003-2894-6140, [...], AND ONUR BOYMAN HTTPS://ORCID.ORG/0000-0001-8279-5545 +18 
SCIENCE 19 Jan 2024 Vol 383, Issue 6680 DOI: 10.1126/science.adg7942
Editor’s summarySome individuals can endure persistent, debilitating symptoms for many months after an initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the factors underpinning these health issues, called Long Covid, are poorly understood. Comparing the blood of patients with confirmed SARS-CoV-2 infection with that of uninfected controls, Cervia-Hasler et al. found that patients experiencing Long COVID exhibited changes to blood serum proteins indicating activation of the immune system’s complement cascade, altered coagulation, and tissue injury (see the Perspective by Ruf). At the cellular level, Long Covid was linked to aggregates comprising monocytes and platelets. These findings provide a resource of potential biomarkers for diagnosis and may inform directions for treatments. —Sarah H. Ross
Structured AbstractINTRODUCTIONAcute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes various clinical phenotypes, ranging from asymptomatic to life-threatening COVID-19. About 5% of all infected individuals do not recover from acute disease but develop long-term complications, called Long Covid. Current hypotheses on factors contributing to Long Covid include tissue damage, viral reservoirs, autoimmunity, and persistent inflammation. There are currently no diagnostic tests or therapeutic solutions for affected patients.
RATIONALEWe followed 39 healthy controls and 113 COVID-19 patients for up to 1 year after initial confirmation of acute SARS-CoV-2 infection to identify biomarkers associated with Long Covid. At 6-month follow-up, 40 patients had Long Covid symptoms. Repeated clinical assessments were paired with blood draws, resulting in a total of 268 longitudinal blood samples. We measured >6500 proteins in serum by proteomics. Top candidate biomarkers were identified using computational tools and further evaluated experimentally.
RESULTSLong Covid patients exhibited increased complement activation during acute disease, which also persisted at 6-month follow-up. The complement system is part of the innate immune system and contributes to immunity and homeostasis by targeting pathogens and damaged cells, among other functions. Interestingly, blood complement levels normalized in Long Covid patients recovering before their 6-month follow-up. The complement system can be activated by various triggers, resulting in formation of the terminal complement complex (TCC), made of the complement components C5b-9. These complexes can integrate into cell membranes and induce cell activation or lysis. Long Covid patients showed imbalanced TCC formation, marked by increased soluble C5bC6 complexes and decreased levels of C7-containing TCC formations that can incorporate into cell membranes. This suggested increased membrane insertion of TCCs in Long Covid patients, contributing to tissue damage. Accordingly, Long Covid patients showed elevated tissue injury markers in blood and a thromboinflammatory signature, characterized by markers of endothelial activation, such as von Willebrand factor (vWF), and red blood cell lysis. Low antithrombin III levels in Long Covid patients were accompanied by signs of increased cleavage by thrombin, a driver of TCC formation. Furthermore, Long Covid patients had elevated platelet activation markers and monocyte–platelet aggregates at 6-month follow-up, particularly in cases where Long Covid persisted for 12 months or more. These patients also showed signs of antibody-mediated activation of the classical complement pathway, which was associated with increased anti-CMV (cytomegalovirus, also known as human herpesvirus 5) and anti-EBV (Epstein-Barr virus) immunoglobulin G (IgG) antibody levels.
CONCLUSIONOur data suggest that active Long Covid is accompanied by a blood protein signature marked by increased complement activation and thromboinflammation, including activated platelets and markers of red blood cell lysis. Tissue injury may also be complement-mediated and, in turn, activate the complement system. Moreover, complement activation may be driven by antigen–antibody complexes, involving autoantibodies and antibodies against herpesviruses, as well as cross-talk with a dysregulated coagulation system. In addition to offering a basis for new diagnostic solutions, our work provides support for clinical research on complement modulators for patients suffering from Long Covid.