A new study from Bulgaria with intriguing blood biomarker data, well-supported hypotheses, and stellar arguments about the importance of longitudinal data and cohort selection.

Treg and Oxidative Stress Biomarker Profiles in Long COVID and MECFS. (MPDI IJMS). https://doi.org/10.3390/ijms27219422

Abbreviated abstract in r/science (where it found me) https://www.reddit.com/r/science/s/Rn9szgTkqD

> Chronic immune dysregulation is the possible pathophysiological mechanism in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long coronavirus infectious disease (long COVID, LC). However, a detailed characterization of regulatory and effector T-cell subsets in these conditions remains limited. To assess and compare T-cell subsets in relation to serum biomarkers of chronic activation and oxidative/nitrosative stress in an attempt to differentiate between LC and ME/CFS patients. Peripheral blood mononuclear cells (PMNC) from LC patients (n= 89), ME/CFS patients (n = 125), and healthy controls (HC, n = 80) were analyzed using multiparameter flow cytometry.

> The immune-serum biomarkers distinguishing LC, ME/CFS, and HC comprised Th17, CD15s+CD161−eTreg, and CD161+ Treg. The five-marker signature retained significance after adjustment for age, BMI, and sex.

> In spite of shared biomarkers of oxidative stress and T-cell response dysregulation, our results support the hypothesis that LC and ME/CFS differ in the extent of cellular damage and the exhaustion of compensatory mechanisms

This article belongs to the IJMS Special Issue Molecular Pathologies and Treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome—2nd Edition.

There are pockets of researchers out there working with great care who have a handle on both the pathophysiology and the structural / methodological issues with moving the field forward.

I’ll put some excerpts below.

“Planned Phase 2a trial will evaluate whether PP-007 can improve oxygen delivery and shorten recovery from post-exertional malaise, a debilitating hallmark of ME/CFS. ChronicleBio’s AI-powered precision medicine platform will identify patients most likely to respond to treatment.”

PP-007 (or Sanguinate) is modified hemoglobin from cows that has two functions: it deliver oxygen to tissue and carries carbon monoxide (CO). CO can be toxic but the idea is that controlled delivery of very small amounts to tissue can reduce inflammation and improve blood flow

Some potential good news for the commonly POTS comorbid folks among us:

Regeneron announces that Baloncibart reduced orthostatic heart rate and improved orthostatic symptoms in a Phase 2 trial for POTS.

“Baloncibart is a monoclonal antibody that blocks NPR1 and increases blood volume, thereby easing POTS symptoms.

The Phase 2 trial was 1:1:1 randomized, double blinded and included 82 patients, 150mg Baloncibart (n=27), 450mg Baloncibart (n=27) and placebo (n=28). Primary endpoint was the change in heart rate from lying down to standing (DeltaHR) at day 8.

Baloncibart 450mg reduced DeltaHR at day 8 with a least-squares (LS) mean difference of -11.4 bpm (p=0.0007) and at day 29 with LS mean difference of -7.4 bpm (p=0.0124). Baloncibart 150 mg reduced DeltaHR versus placebo at day 8 with LS mean difference of -9.5 bpm (p=0.0045).

Furthermore did Baloncibart 450mg improve orthostatic symptoms, physical tunctioning, and activities of daily living versus placebo at day 29, as measured by the LWPQ.”

An interesting study found by accident that people sick with FM, ME and MS often belong to a generic subtype that has a change in TSPO receptors.

Why is that important?

That’s a common tracer site used to measure neuroinflammation. Meaning the neuroinflammation in patients might be invisible to PET scans leading to false negatives. And there seems to be correlation with symptoms as well.

“Results

In the present study individuals with fibromyalgia, (ME/CFS), or multiple sclerosis were more likely to have a mixed- or low-affinity genotypes compared to healthy controls. Presence of the low or mixed genotypes were also associated with greater self-reported fatigue severity and depressive symptoms.”

Some more news from the Bezisterim trial just got released after they’ve done more analysis. Seems there’s two subtypes that respond particularly well:

High inflammatory subtypes

&

Low white blood cell count patients

Won’t you look at that, CDC researchers lobbying for better research and treatment of post infectious conditions. Especially those without biomarker.

“Infection-associated chronic conditions and illnesses (IACCI) encompass several debilitating syndromes with overlapping symptoms that have been identified and documented for decades, […]

In contrast, syndromes that lack objective tests, even when following a recognized infection, such as myalgic encephalomyelitis/chronic fatigue syndrome, post-treatment Lyme disease syndrome, and dysautonomia, are underrecognized and often stigmatized. The COVID-19 pandemic and subsequent recognition of Long COVID as the newest example of IACCI offer new opportunities to address all aspects of IACCI.”

"Our findings suggest that knowledge gaps, absent or limited transportability, and insufficiently adapted healthcare services restricted access to necessary care, and could even make healthcare itself a risk for deterioration. Family/Lay caregivers frequently assumed coordinative, nursing, and medical responsibilities in the absence of accessible professional support.

Improving provision for this population requires models designed around the functional capacities and individual needs of people with severe and very severe ME/CFS, including home-based and outreach care, telemedicine, multidisciplinary coordination, adapted routine and emergency care, and ME/CFS-specific professional education.”

Basic knowledge to most patients but always very important to objectively capture these realities imo

Seems NAKO PAIS, a genetic sequencing project will get a whopping 27 million in funding to profile 20.000 post infectious patients versus 25.000 healthy controls. They plan to do whole genome sequencing as well as profiling antibodies to relevant infectious diseases.

No official press announcement yet but you can find this data on the website of the German center for research, technology and space exploration.

was looking for statistics on M.E. rates in long covid patients - would somebody be able to explain to me the discrepancy in the results of these two studies?

"Long COVID neuropathy: The role of mast cells"

Zachary L Morcos, Theoharis C Theoharides

Abstract

Postacute sequelae of SARS-CoV-2 infection (PASC), or Long COVID, is estimated to affect over 60 million individuals globally, with almost half of COVID-19 survivors experiencing persistent symptoms such as neuropathic pain, fatigue, and autonomic dysfunction. Despite its prevalence, the pathophysiology of PASC remains poorly understood. This narrative review highlights activation of mast cells (MCs), the unique tissue immune cells as a central contributor to neuropathic manifestations in PASC. Mast cell locations near nerves and vessels allows them to regulate neuroimmune and neurovascular processes. Mast cell activation mirrors patterns seen in small-fiber neuropathy and myalgic encephalomyelitis/chronic fatigue syndrome, suggesting a shared immune-mediated etiology. The SARS-CoV-2 spike protein has been shown to activate MCs via angiotensin-converting enzyme 2 and toll-like receptor 4, triggering release of pro-inflammatory and neurotoxic mediators, including interleukin-1β, interleukin-6, tumor necrosis factor alpha, histamine, and tryptase. Such mediators sensitize peripheral nerves, disrupt the blood-brain barrier, and recruit microglia, ultimately contributing to small-fiber injury, neuroinflammation, and dysautonomia. Emerging reports suggest benefit from MC-directed treatments although responses remain variable. Understanding the role of MCs in PASC may offer a plausible mechanism of pathogenesis and guide targeted therapies. Future studies are needed to validate these findings and improve PASC patient outcomes.

PubMed: https://pubmed.ncbi.nlm.nih.gov/41790576/
DOI: https://doi.org/10.1093/jnen/nlag016

Full text is paywalled but I found it on sci-hub.

"A 62 EV-miRNA signature provides insight into the interconnected neuro-systemic pathways disrupted in ME/CFS, particularly those governing neuronal connectivity and cellular scaffolding. Within this candidate EV-miRNA signature, the top-ranked miRNAs—miR-21-5p, let-7f-5p, miR-26b-5p, and miR-20a-5p—emerge as potential candidate biomarkers whose specific elevation was not shared by HC. These findings establish a valuable framework for targeted diagnosis and enhance our understanding of the molecular pathways involved in synaptic and structural alterations in ME/CFS."

A few months old but I dont think we’ve discussed this here before. Relatively small sample size but interesting nonetheless

„Methods

Circulating EVs from ME/CFS (n = 6), ICF (n = 6), and depression (n = 8) patients were analyzed using flow cytometry, nano-tracking analysis, and comprehensive miRNA analysis. Differentially expressed miRNAs were analyzed using KEGG pathway enrichment to identify ME/CFS-specific signatures. Key candidate biomarkers were further validated in an additional healthy control (HC) cohort (n = 4).“

"Cognitive impairment, often described as “brain fog,” is a disabling feature of chronic fatigue syndrome (ME/CFS), but its underlying mechanism remains unclear. This study shows that stress-inducible Wiskott–Aldrich syndrome protein family member 3 (WASF3), previously linked to mitochondrial dysfunction in skeletal muscle of patients with ME/CFS, also suppresses oxidative metabolism in the brain. Increased WASF3 shifted hippocampal metabolism toward a hypometabolic state and impaired learning. Conversely, reduced WASF3 enhanced oxidative metabolic markers and protected cognitive function during cellular stress. These findings identify WASF3 as a mediator linking endoplasmic reticulum (ER) stress to brain bioenergetic dysfunction and suggest that targeting ER stress-WASF3 signaling may alleviate cognitive symptoms in ME/CFS and related postviral fatigue disorders more broadly."

Interesting Pretorius Pre Print:

“Homocysteine (Hcy) is a non-proteinogenic, sulphur-containing amino acid generated during methionine metabolism, that can be converted to a thiolactone that will react with the e-amino groups of protein lysine residues causing widespread dysfunction.

Hyperhomocysteinaemia can arise from genetic causes or through an inadequacy of certain B vitamins. We here develop and evidence the hypothesis that raised homocysteine (Hcy), its conversion to homocysteine thiolactone (HTL), and the consequent N-homocysteinylation of proteins contribute to at least a subset of the manifestations of LC and ME/CFS. This has both testable predictions and therapeutic consequences”

This randomized controlled trial studied whether low-dose naltrexone (LDN) improves fatigue in people with Long COVID.

• Participants: 160 adults, treated for 16 weeks with LDN (1–4.5 mg daily) or placebo.

• Results: LDN did not significantly improve fatigue compared with placebo.

• Other outcomes: No significant differences in pain, overall symptoms, daily steps, or quality of life.

• Safety: Most adverse events were mild or moderate, but severe adverse events were slightly more frequent with LDN.

• Conclusion: The study does not support routine use of LDN for post-COVID fatigue.

Important: This is a preprint that has not yet undergone peer review. The findings apply to the doses and 16-week treatment period studied.

Here you can look at mor comments about this paper: https://s4me.info/threads/low-dose-naltrexone-for-post-covid-fatigue-syndrome-a-randomized-controlled-trial-2026-naik-nacul.53290/

Results are in for "Low-dose prednisolone and B vitamins for post-COVID-19 syndrome in Germany: the PreVitaCOV randomised clinical trial" (Phase 3 trial)

Results: "This trial showed a statistically significant short-term reduction in symptom severity in the five dimensions of the PROMIS score in patients with post-COVID with low-dose prednisolone. However, the effect did not reach the prespecified threshold for clinical relevance."

The cohort was defined as: “adult patients with a documented SARS-CoV-2 infection at least 12 weeks before study inclusion and presenting with at least one of the symptoms—fatigue, dyspnoea, cognitive impairment, anxiety or depression—developed during or after infection were considered eligible.”

I really personally wish we wouldn’t run big trials like these with cohorts mixing people who “only” experience anxiety alongside the most severe and complex cases. We’ll never know if the statistically but not clinically significant effect wouldn’t have looked more convincing if they had required for example at least two of the above criteria fulfilled in all patients or subgrouped for severity like Bezisterim did

A new multi omics study on 119 PASC patients compared to 100 acutely ill covid patients and 44 controls seems to have yielded some interesting results:

“PASC status was associated with failure to regain a healthy baseline molecular status in these patients and aberrations in multiple biological pathways, including sphingolipids, chromatin-associated processes, and others”

Additionally:

“A machine learning algorithm trained on patients’ data produced 9 top entities allowing PASC diagnosis with a mean precision-recall area under the curve (AUC) of 0.97”

And as always glad to see something on the subject published in a nature journal

Scientists used so called PUFAs (polyunsaturated fatty acids) and their metabolism as a marker of the bodies inflammation management during and after SARS-Cov2 infection. What they found was that this mechanism supposed to resolve inflammation after infection was dysregulated from the acute phase onwards in individuals who later developed LC

Persistently activated virus-specific CD8 T cells indicate antigen-driven immune aberrations in long COVID

Mark M. Painter, David B. Reeg, Naomi R. Douek, Sophie L. Gray-Gaillard, ... Akiko Iwasaki, Timothy J. Henrich, Steven G. Deeks, Michael J. Peluso, E. John Wherry

Abstract

Long COVID (LC) affects millions of people worldwide, yet its driving mechanisms remain incompletely defined and no treatment has been approved. Persistence of SARS-CoV-2 and reactivation of herpesviruses have been implicated in LC, but direct detection of these viral antigens in blood and tissues has been challenging.

T cells are exquisitely sensitive to viral antigens, survey organs throughout the body, and can be readily sampled in peripheral blood. Using high-dimensional spectral flow cytometry and single-cell sequencing approaches with multiplexed peptide/HLA tetramers, we profiled virus-specific T cells from hundreds of people with LC and recovered controls.

We identified a subset of people with LC that maintained elevated activation of CD8 T cells targeting SARS-CoV-2 spike and/or lytic antigens from Epstein-Barr virus, but not other viral specificities. Spike-specific cells in LC expressed genes linked to TCR stimulation, terminal effector differentiation, and exhaustion and demonstrated reduced functionality upon cognate peptide stimulation ex vivo.

Thus, T cells from a subset of people with LC are likely chronically stimulated by persistent SARS-CoV-2 antigens. These findings establish the use of T cells as biosensors of persisting antigen in LC and other disease settings and may help develop new therapeutic strategies for LC.

https://www.biorxiv.org/content/10.64898/2026.10.14.759221v1

Some positive news: Felipe Correa da Silva, the leading researcher behind the post mortem brain autopsy and tissue analysis in ME/CFS, announced that he won a new Dutch grant called "Off Road." It is intended for curiosity-driven, high risk, high reward ideas and provides up to €100.000 in funding.

“For people living with ME/CFS, cognitive symptoms can be one of the most disabling features of the disease. With RememberME, I will explore whether hippocampal synaptic alterations are a potential mechanism for cognitive symptoms in ME/CFS.

Beyond investigating a potential biological explanation for these symptoms, I will also explore what human postmortem brain tissue can reveal about the cellular architecture underlying communication between brain regions. I hope this work can complement neuroimaging studies by providing a cellular perspective on the brain networks implicated in ME/CFS. We also plan to extend this framework to other brain regions very soon, in close collaboration with Prof. Sonya Marshall-Gradisnikl and her team - dr. Natalie Eaton-Fitch and dr. Etianne Martini Sasso.”

The recordings from the recent Prime symposium have now been uploaded on the Action for ME YouTube channel.

Link to the program, for easy overview of topics and speakers: https://www.actionforme.org.uk/wp-content/uploads/2026/09/PRIME-2026-Symposium-Programme-v4.pdf

Interested in seeing the theories behind the women/men split seen in MECFS.

The good folks over at the ME/CFS Science Blog have applied another studies methodology of analysis to the Decode ME genetic dataset. This time one that basically links genetic data to specific brain cell types, the image above shows the results. Glutaminergic excitory neurons most easily manage to cross the significance cutoff but the more nebulous medium spiny neuron also shows up again approaching significance.

https://s4me.info/threads/a-comparative-atlas-of-single-cell-chromatin-accessibility-in-the-human-brain-li-et-al-2023.53034/#post-728476

More discussion and data can be found over here ⬆️

A team of Charité Berlin researchers studied 49 Long
COVID patients receiving head and neck lymphatic drainage.

Brain fog, concentration, headaches and fatigue improved, raising questions about the brain's waste clearance system.

Controlled trials are needed as we’ve seen big placebo effects/natural remission in other cohorts