Transient clinical improvement and immune modulation following recombinant Zoster vaccination in a patient with ME/CFS

Abstract:

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder associated with immune dysregulation yet lacks definitive biomarkers or effective therapies. Acute immune perturbations may transiently modulate disease manifestations.

Methods: We report the case of a female patient in her 60s with severe, long-standing ME/CFS who experienced changes in symptom following administration of recombinant zoster vaccine (RZV; Shingrix). Peripheral blood mononuclear cells were analyzed pre- and post-vaccination using flow cytometry, with comparison to a female healthy control. Plasma galectin-9 (Gal-9) levels were quantified by ELISA.

Results: Both RZV doses were associated with rapid, transient remission of symptoms, including improved sleep, cognition, pain, mobility, and respiratory function, followed by relapse. Immunologically, pre-vaccination profiling revealed elevated monocytes, increased CD71+ erythroid cells, and features of T cell exhaustion marked by Gal-9/PD-1 co-expression and impaired cytokine responses. Post-vaccination, monocyte frequency decreased, Gal-9+/PD-1+ T cells were reduced, and NK cell degranulation improved, indicating partial restoration of immune function.

Conclusion: This case demonstrates that immune stimulation via RZV may transiently reverse immune dysfunction and improve clinical symptoms in ME/CFS. These findings support a role for reversible immune exhaustion in disease pathogenesis and highlight potential avenues for biomarker development and therapeutic intervention.

Source: Bigleri A, Alimo ET, Abouda A, Osman M, Cohen Tervaert JW, Elahi S. Transient clinical improvement and immune modulation following recombinant Zoster vaccination in a patient with ME/CFS. Brain Behav Immun Health. 2026 Oct 13;58:101388. doi: 10.1016/j.bbih.2026.101388. PMID: 42927120; PMCID: PMC13694728. https://pmc.ncbi.nlm.nih.gov/articles/PMC13694728/ (Full text)

“The Poison Ivy Treatment” – An Intriguing CFS Case Study by Dr. Bell

by Dr. David S Bell, MD, FAAP*
February 2, 2011

This ME/CFS patient case history is one of 10 that Dr. David Bell included in his book Faces of CFS – Case Histories of Chronic Fatigue Syndrome, published in August, 2000.* Each case illustrates a different aspect of the illness that he observed in managing patients affected by the ‘Lyndonville Outbreak’ in New York, and none remains more fresh or intriguing than this one.

Reprinted with the kind permission of ProHealth: 2/2/11

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“This minor test is one of hundreds that prove to me that CFS is real and can be studied.” – David S Bell

I had been treating patients in my Lyndonville clinic for 10 years when, one day, I happened to pick up the chart of a patient whose name was unfamiliar to me. He was awaiting me in my examining room.

I quickly learned that Edwin Maxwell was the man who owned the beautiful farm on the Stillwell road. I had admired this farm every time I passed it on my way to the nearby hospital. The old barns were always maintained with care. I had come to expect an orderly procession of snowdrops, tulips and lilies on tended patches of lawn every spring and summer. I could see that a lovely stream ran through the rear of the property, which looked like a European forest – tidy, but natural, as wonderfully wild as anything could be and still be called a farm.

I also knew whoever tended this farm had a certain mysterious wisdom. If hay had just been cut on the Maxwell farm on a summer day, you could count on three sunny days to follow. Even the weather seemed to respect this farmer; his sixth sense was more reliable than any TV forecast.

I observed, as well, that there was no rush, no great urgency, to this farmer’s life. He tended his fields with patience, as if he knew that the earth would unfold its crops the way life unfolds its secrets – all in due time.

I liked the 45-year-old Edwin Maxwell immediately. He began our conversation by letting me know he was Dr. Wilson’s patient and would remain Dr. Wilson’s patient. He wanted to talk to me about this new disease I was studying, however, because he knew something about it.

He allowed as how he had every intention of paying for his visit, but he wanted me to understand that he was there to tell me something about CFS, not to be treated.

I settled back in my chair and waited. By then – the autumn of 1988 – there had been so much publicity about CFS that literally hundreds of people, some of them writing to me or calling me from the four corners of the earth, had already offered me their theories about what was causing CFS.

These theories of causation ranged from discarded plutonium at the nearby West Valley nuclear processing plant, to PCB’s in the salmon of Lake Ontario, to yeast in the intestinal tracts of sufferers. Then, as now, I listened to every one of these ideas with honest interest.

I continue to believe that, someday, someone would come up with the correct answer. Nevertheless, even then, these theories were growing pretty thin, sometimes bordering on the weird.

Edwin continued by stating that he, too, suffered from the disease I was studying. He was not looking for confirmation from me; in fact, his expression brooked no argument. He explained that he had been comparing notes on his symptoms with a number of his friends and neighbors who had CFS and were my patients.

I confess I was surprised: Most people with CFS show up in my clinic in a state of perplexed misery, wondering if I can tell them what is causing their joint pain and headaches and exhaustion. Edwin, in contrast, seemed to have a rare intellectual grasp on the disease.

When I tentatively asked him to tell me about his symptoms, he explained that the fatigue was the worst.

Three years before, he said, he could lift six, maybe seven, wagons of hay bales if he had to, and feed them onto the conveyor belt to the barn loft. He could plow and roll 17 acres of land in one day. Had for years – until three years ago. He added that he suffered from scratchy, sore throats. He had muscle pain, but he also pointed out that there was no reason, at his age, to have muscle pain. Hell, his father was still baling hay at 70.

He reported with obvious chagrin that he needed to wear sunglasses while he worked, even though he had always disliked sun glasses; they were something city people took to the beach.

So Edwin Maxwell could have CFS, I mused. Okay – now what? I waited.

“This spring,” Edwin said, “I had a lot of fields to plant in a short time.” He was choosing his words carefully. “The winters are okay, because it’s easy to cut the days down and get the extra rest. But not in the spring. There is so much to be done after the geese leave.”

Lyndonville happens to be on the migration pathway of Canadian geese. These great birds descend on the land for four to six weeks in the early spring, and when the fields begin to dry out from the winter snow, the geese head across the lake toward Canada. It is a time of great excitement in Lyndonville. The days begin lengthening in earnest now, and the geese are incredibly noisy.
You don’t even mind being woken at five in the morning by two thousand geese in the back cornfield. They leave when the ground begins to dry, the beginning of the plowing season.

“I remembered that the spring before,” Edwin continued, “I got poison ivy on my arm while cutting some brush in the back of the house. The poison ivy was nasty, but I noticed that the fatigue was better.

“I didn’t think much more about it. Then, this spring, just before plowing, I decided to pull up some poison ivy roots and rub them on my arms. Afterward, the itching was horrible, but my fatigue got better for about two full weeks. I could work just like before I got this disease, and I got all my planting done in time. But I noticed that as the poison ivy wore off, the fatigue came back.”

Edwin Maxwell was a careful observer of not only nature, but of himself, I realized. He asked for nothing in return. He was imparting some information to me, in case I was interested.

I was interested. New concepts about CFS either fit, or they did not fit, based on the selective “principles” I have developed over years of observation, principles framed by my experience. I realized immediately I had just heard a new “principle.”

Edwin’s revelation meant that the fatigue in CFS was not fixed; it could be variable. It could come and go, and was just a symptom; perhaps not even a necessary symptom. Theoretically, you could have CFS without being tired!

Consider the implications: if you were shot, or had a broken bone, little would be changed if you also acquired poison ivy; neither would exposure to the weed impact on your tuberculosis or your depression or your radiation sickness.

Poison ivy was an allergic response generated by the immune system, and localized at the point of exposure. Edwin was suggesting that this immune response – a sharp blip in the day to day functioning of the immune system, resulting from exposure to an allergen – might somehow diminish the fatigue in so-called “chronic fatigue syndrome.”

I had already discovered that among my CFS patients who were children, particularly, at least half had early childhood histories of either asthma, or allergies to various common substances.

I knew that there were a number of papers already published in the medical literature connecting CFS to medical histories of “atopic” illness, also known as allergies. A history of allergies appeared to be a risk factor for acquiring CFS. In fact, it was one of my established “principles” of the disease that a complex, if poorly understood, relationship existed between having CFS and allergies.

Yet, Edwin was telling me that if you applied an allergen to a small patch of an arm – if you localized an allergic response, in other words – you could make the fatigue in CFS go away while the allergic response lasted.

It didn’t really matter to me whether this held true for anyone else in the world. If it was true for one person with CFS, then it provided an hypothesis that could be tested in other CFS patients. The key was to learn whether this phenomenon represented a fundamental physiologic mechanism of the disease, or was just an interesting fluke.

If consistently true of all CFS sufferers, then any theory of the cause of CFS would have to hold an explanation as to why a poison ivy attack gave Edwin Maxwell an energy boost.

Sometimes when you think a great deal about something, you get so used to your own thoughts that they begin to seem dull. It takes someone else’s ideas to wake you up again. Edwin watched me as I struggled mentally to fit these new pieces of the puzzle together. He could see that I was taking his comments seriously.

I was ready to accept that fatigue need not be present for someone to have CFS.

I knew several people who lived in families where one member or more was thoroughly debilitated with full-blown CFS, and who suffered from severe intellectual problems along with other symptoms highly suggestive of CFS, even though they lacked the accompanying exhaustion. In fact, they had no more
than ordinary fatigue.

Could you jettison fatigue from the definition of the disease? I think you could, although this view would be unlikely to be published in a medical journal, especially since, even today, members of the scientific establishment are unwilling to agree that any of the symptoms of CFS are “real” and not psychiatric in origin. To persuade this same community that you can have what they call “chronic fatigue syndrome” without having “fatigue” would be next to impossible.

Nevertheless, the variability of fatigue – the idea that some people could have the disease without being tired – had become for me a defining principle. In truth, if this principle proved true, then the margins of CFS would begin to blur with the margins of attention deficit disorder (ADD), and other learning disabilities, especially in children. That was the population in which I most commonly saw patients with all the symptoms of CFS, minus one: fatigue.

Edwin Maxwell’s story got me thinking more intensively about the cause of the fatigue in CFS. I was intrigued that a natural substance, one manufactured by the body, called interleukin, might be the culprit.

While it may seem naive to look for a single substance responsible for fatigue, it did not seem a hopeless task. Scientists have been experimenting with one type of interleukin, interleukin-2 (or IL-2), as a therapy for several kinds of cancer. What researchers inevitably find, however, is that it doesn’t take very much IL-2 to induce symptoms in cancer patients that are almost as bad as the cancer.

Amidst the numerous side effects that include confusion and mood changes, IL-2 also causes profound fatigue when it is administered as a drug therapy.

Some months before Edwin Maxwell’s visit to my clinic, I had published a scientific paper with a collaborator, internal medicine specialist Paul Cheney, in which we reported that children and adults with CFS had startlingly high levels of the receptor molecule for IL-2. These levels were so high that it implied that the chemical IL-2 could be causing the fatigue and other symptoms of the disease.(1)

I realized that Edwin – if he was willing – could help me test my nascent theory that measuring IL-2 levels might be a way to quantitate the fatigue in CFS in a laboratory. He was willing.

I told him we would take blood samples from him when he was exhausted and measure IL-2 receptor. Then, we would apply poison ivy to his arm and wait until the fatigue improved. When the poison ivy kicked in and the fatigue went away, we would draw more blood. I suggested we do this three times, to be sure of our results.

Edwin liked my idea. It made sense to him. One sunny afternoon at the end of July that summer, I drew blood from Edwin’s arm during a “normal” period when the farmer’s exhaustion was pretty severe. I asked him to maintain a kind of symptom severity journal, as well, which required him to rate the severity of fatigue and 11 other symptoms on a scale of one to ten, with ten being the worst.

After I drew his blood, Edwin himself rubbed poison ivy on his arm. A week later I met him in the emergency room where they kept a camera and photographed the rash on his arms. A few days later, Edwin’s fatigue had subsided substantially, and I drew another sample of blood. We waited for the good effects of the poison ivy to wear off. Then we repeated the entire process.

We did not get to the third trial because by then Edwin had begun to dread the effects of the poison ivy as much as he had grown to dread the fatigue. He begged off, and I respectfully complied with his wishes. I already thought him very brave to offer himself up to medical science as he had done.

Also, the emergency ward staff was beginning to look at me in a funny way because I kept photographing the poison ivy someone was giving himself. Ah, science……

Ours was never anything more than an informal experiment, one that ended somewhat prematurely, but its results were provocative.

Just as Edwin had reported, his fatigue, as well as his other symptoms, were diminished when he was suffering from acute poison ivy. Somehow, this classic allergic response mitigated his most debilitating symptoms: fatigue, compromised intellectual capabilities, and physical pain.

However, the results failed to confirm beyond all doubt my theory about the relationship between IL-2 levels in the blood and fatigue. The results did suggest that fatigue severity was not just a coincidence, the normal ups and downs of CFS symptoms. It was intriguing to speculate that this relationship could even be someday turned into an effective treatment of the symptoms.

Unfortunately, the options are not that good. Edwin preferred the regular CFS symptoms to severe poison ivy symptoms. Maybe it’s not such a great treatment.

Medical science is cumbersome. Hints, such as the hints produced by this experiment, cannot be published in medical journals without real proof. And to conduct a proper experiment takes a great deal of time, money and paperwork, all of which are in short supply for the clinician. But the most frustrating part is the inability of clinicians to communicate to those able to do real experiments that CFS is real and must be taken seriously.

Two weeks ago I attended a neurology conference and CFS was dismissed by the lecturer as a minor psychosomatic nuisance for which there were no tests. The real problem is that academics and governmental public health personnel refuse to put aside their biases and look for the proofs. They seem content to criticize experiments like Edwin’s as incomplete. And of course they are correct.

But Edwin’s poison ivy treatment was over 10 years ago [now more than 20], and still nothing has come from it. This minor test is one of hundreds that prove to me that CFS is real and can be studied. From a scientific perspective, the relationship between the debilitating symptoms of CFS and allergic response is fascinating. I have been naive to think that it would be fascinating for others.

The misperception that CFS is psychosomatic comes only from scientists’ inability to look beyond their psychosomatic biases and look for the proofs.

Edwin doesn’t care, and in this respect he is unique. He gets on with his life, tends the springtime garden with care, manages to get the hay in every summer. He is able to accept the presence of symptoms as he accepts hail which damages the apple crop. And he is lucky, his symptoms are relatively mild and he can ration his time. If he worked in a factory assembly line with rigid hours, he would not be as lucky.

I rarely see Edwin now. Sometimes, while driving by his beautiful farm on the Stillwell road on my way to the hospital, I wave to him in the flower bed, or when he is putting the tractor into the barn. He is busy getting on with the business at hand, he doesn’t have time to feel sick.

– Dr. David S Bell, MD, Lyndonville, New York, August 15, 2000
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1. Citation: “Interleukin-2 and the Chronic Fatigue Syndrome,”  Annals of Internal Medicine, Feb 15, 1989, by Paul R. Cheney, MD, PhD; Susan E. Dorman; David S. Bell, MD.

* This article is excerpted with kind permission from Dr. Bell’s classic book Faces of CFS – Case Histories of Chronic Fatigue Syndrome; © David S Bell, MD, 2000.

Genetic Insights into Circulating Complement Proteins in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Potential Inflammatory Subgroup

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-system illness with heterogeneity that complicates identifying the pathophysiology, biomarkers, and therapeutic targets. Evidence indicates the importance of immune dysregulation, including the complement system, in ME/CFS. This study investigates the contribution of genetic drivers to potential dysregulation of the complement pathway in ME/CFS.

We used protein quantitative trait loci (pQTL) analyses, adjusted for covariates using linear and logistic regression, to identify genetic variants significantly associated with plasma complement protein levels in a study sample identified from the general population (50 ME/CFS and 121 non-fatigued). ME/CFS patients carrying certain pQTLs exhibited dysregulation of the alternative complement pathway, which defined an inflammatory subgroup with a high C3/low Bb profile and established a genetic link to dysregulation of the alternative complement pathway. Six of the significant pQTLs were also associated with fatigue-related phenotypes in the UK Biobank, four of which were complement-associated, providing some validation in an independent population.

Our findings highlight a mechanism by which risk alleles contribute to ME/CFS heterogeneity, providing evidence of a genetic basis for complement dysregulation in a subset of patients. This approach could identify pathway-focused subgroups in ME/CFS and related illnesses to inform personalized approaches to diagnosis and treatment.

Source: Maya J, Unger ER, Lin JS, Rajeevan MS. Genetic Insights into Circulating Complement Proteins in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Potential Inflammatory Subgroup. Int J Mol Sci. 2026 Feb 5;27(3):1574. doi: 10.3390/ijms27031574. PMID: 41683992. https://www.mdpi.com/1422-0067/27/3/1574 (Full text)

The origin of autoimmune diseases: is there a role for ancestral HLA-II haplotypes in immune hyperactivity

Abstract:

The prevalence of autoimmune diseases in contemporary human populations poses a challenge for both medicine and evolutionary biology. This review explores how the ancestral human leukocyte antigen class II (HLA-II) haplotypes DR2-DQ6, DR4-DQ8 and DR3-DQ2 could play a central role in susceptibility to these diseases.

We propose that these haplotypes, selected in historical contexts of high infectious pressure, may have been maintained because of their ability to elicit strong T-cell responses against pathogens; however, that antigenic promiscuity may be associated with an increased tendency toward immune hyperreactivity in modern environments. This hyperreactivity, involving proinflammatory cytokines including interferon-gamma (IFN-γ), could contribute to the breakdown of tolerance and the emergence of autoimmunity and related clinical phenomena (e.g., Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome and post-vaccination syndromes), although the evidence for the latter remains limited.

Finally, we discuss how chronic infections, immunotherapies, vaccination, obesity and chronic physical stressors may exacerbate this susceptibility and consider the therapeutic implications of integrating HLA-II profiling into clinical practice.

Source: Ruiz-Pablos M, Paiva B, Zabaleta A. The origin of autoimmune diseases: is there a role for ancestral HLA-II haplotypes in immune hyperactivity. Front Immunol. 2025 Dec 4;16:1710571. doi: 10.3389/fimmu.2025.1710571. PMID: 41425584; PMCID: PMC12711860. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1710571/full (Full text)

Immunoglobulin G complexes from post-infectious ME/CFS, including post-COVID ME/CFS disrupt cellular energetics and alter inflammatory marker secretion

Highlights:

  • This study addresses a critical gap in understanding the role of autoimmunity in ME/CFS and PASC, two debilitating conditions with overlapping features and few effective treatments.
  • By demonstrating that IgG antibodies from ME/CFS patients can directly alter mitochondrial structure and function in human endothelial cells, specifically inducing mitochondrial fragmentation and metabolic reprogramming, this study provides a mechanistic link between autoantibodies and endothelial cell dysfunction.
  • Furthermore, proteomic analyses reveal unique immune complex signatures in ME/CFS and PASC, highlighting disease-specific IgG activity and supporting the idea of antibody-mediated metabolic dysregulation.
  • These insights are especially important because they establish a foundation for novel, targeted therapies that modulate antibody activity or protect mitochondrial function.

Abstract:

Background: Autoimmunity is a key clinical feature in both post-infectious Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of COVID (PASC). Passive transfer of immunoglobulins from patients’ sera into mice induces some clinical features of PASC. However, the physiological effects of immunoglobulins on cellular alterations remain elusive. In this study, we tested the potential effects of immunoglobulins from ME/CFS patients on endothelial cell dysfunction.

Methods: We have isolated immunoglobulins from 106 individuals, including ME/CFS (n = 39), PCS-CFS (n = 15), MS (n = 20) patients, and healthy controls (n = 41). Protein composition of the isolated immune complexes was studied using mass spectrometry. The effect of isolated immune complexes on mitochondria was evaluated using confocal microscopy and a Seahorse XFe96 Extracellular Flux Analyzer, and the impact on inflammatory cytokine secretion was studied using a multiplex bead-based assay.

Results: Here, we demonstrate that IgG isolated from post-infectious ME/CFS patients selectively induces mitochondrial fragmentation in human endothelial cells and alters cellular energetics. This effect is lost upon cleavage of IgG into its Fab and Fc fragments. The digested Fab fragment from ME/CFS alone was able to alter the cellular energetics, resembling the effect of intact IgG. IgG from post-infectious ME/CFS, including post-COVID ME/CFS patients, induced distinct but separate cytokine secretion profiles in healthy PBMCs. Proteomics analysis of IgG-bound immune complexes revealed significant changes in immune complexes from ME/CFS patients, affecting extracellular matrix organization, whereas those from post-COVID ME/CFS patients pointed to alterations in hemostasis and blood clot regulation.

Conclusions: We demonstrate that IgGs from ME/CFS patients carry a chronic protective stress response that promotes mitochondrial adaptation via fragmentation, without altering mitochondrial ATP generation capacity in endothelial cells. Together, these results highlight a potential pathogenic role of IgG in post-infectious ME/CFS and point to novel therapeutic strategies targeting antibody-mediated metabolic dysregulation.

Source: Zheng Liu, Claudia Hollmann, Sharada Kalanidhi, Stephanie Lamer, Andreas Schlosser, Emils Edgars Basens, Georgy Nikolayshvili, Liba Sokolovska, Gabriela Riemekasten, Rebekka Rust, Judith Bellmann-Strobl, Friedemann Paul, Robert K. Naviaux, Zaiga Nora-Krukle, Franziska Sotzny, Carmen Scheibenbogen, Bhupesh K. Prusty. Immunoglobulin G complexes from post-infectious ME/CFS, including post-COVID ME/CFS disrupt cellular energetics and alter inflammatory marker secretion. Brain, Behavior, & Immunity – Health, Volume 52, 2026, 101187 ISSN 2666-3546,
https://doi.org/10.1016/j.bbih.2026.101187. https://www.sciencedirect.com/science/article/pii/S2666354626000207 (Full text)

Immunosenescence-Driven Hemodynamic Dysregulation and Cognitive Impairment in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Integrative Perspective

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder marked by persistent fatigue and cognitive impairments, often termed “brain fog.” Emerging evidence suggests that immunosenescence, age- or stress-related deterioration of immune function, plays a pivotal role in the pathogenesis of cognitive dysfunction in ME/CFS.

Immunosenescence induces chronic low-grade inflammation (inflammaging); alters T-, NK-, and B-cell function; and promotes the release of senescence-associated secretory phenotype (SASP) factors. These changes are proposed to cerebral blood flow (CBF) regulation, may impair endothelial nitric oxide production, and may contribute to blood-brain barrier (BBB) breakdown. Consequently, brain hypoperfusion and oxidative stress are associated with impaired neuronal energy metabolism and synaptic plasticity, particularly in memory-related networks such as the default mode and fronto-hippocampal systems. This results in reduced ATP availability, excitotoxicity, and neurotransmitter imbalance, contributing to cognitive decline.

The review proposes an “immune-vascular-cognitive axis” linking peripheral immune aging to central neural dysfunction. It further highlights therapeutic strategies-such as cytokine blockade, nitric oxide enhancement, immune modulation, and acupuncture-that may ameliorate neurovascular impairments and cognitive symptoms. Understanding this integrative mechanism may offer new pathways for targeted intervention in ME/CFS.

Source: Xu H, Luo Y, Wu X. Immunosenescence-Driven Hemodynamic Dysregulation and Cognitive Impairment in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Integrative Perspective. Compr Physiol. 2026 Feb;16(1):e70098. doi: 10.1002/cph4.70098. PMID: 41527963. https://pubmed.ncbi.nlm.nih.gov/41527963/

Comparable Immune Alterations and Inflammatory Signatures in ME/CFS and Long COVID

Abstract:

Background: Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME), is a debilitating condition characterized by persistent fatigue and multisystemic symptoms, such as cognitive impairment, musculoskeletal pain, and post-exertional malaise. Recently, parallels have been drawn between ME/CFS and Long COVID, a post-viral syndrome following infection with SARS-CoV-2, which shares many clinical features with CFS. Both conditions involve chronic immune activation, raising questions about their immunopathological overlap.

Objectives: This study aimed to compare immune biomarkers between patients with ME/CFS or Long COVID and healthy controls to explore shared immune dysfunction.

Methods: We analyzed lymphocyte subsets, cytokine profiles, psychological status and their correlations in 190 participants, 65 with CFS, 54 with Long COVID, and 70 healthy controls.

Results: When compared to healthy subjects, results in both conditions were marked by lower levels of lymphocytes (CFS-2.472 × 109/L, p = 0.006, LC-2.051 × 109/L, p = 0.009), CD8+ T cells (CFS-0.394 × 109/L, p = 0.001, LC-0.404 × 109/L, p = 0.001), and NK cells (CFS-0.205 × 109/L, p = 0.001, LC-0.180 × 109/L, p = 0.001), and higher levels of proinflammatory cytokines such as IL-6 (CFS-3.35 pg/mL, p = 0.050 LC-4.04 pg/mL, p = 0.001), TNF (CFS-2.64 pg/mL, p = 0.023, LC-2.50 pg/mL, p = 0.025), IL-4 (CFS-3.72 pg/mL, p = 0.041, LC-3.45 pg/mL, p = 0.048), and IL-10 (CFS-2.29 pg/mL, p = 0.039, LC-2.25 pg/mL, p = 0.018).

Conclusions: Notably, there were no significant differences between CFS and Long COVID patients in the tested biomarkers. These results demonstrate that ME/CFS and Long COVID display comparable immune and inflammatory profiles, with no significant biomarker differences observed between the two groups.

Source: Petrov S, Bozhkova M, Ivanovska M, Kalfova T, Dudova D, Nikolova R, Vaseva K, Todorova Y, Aleksova M, Nikolova M, Taskov H, Murdjeva M, Maes M. Comparable Immune Alterations and Inflammatory Signatures in ME/CFS and Long COVID. Biomedicines. 2025 Dec 8;13(12):3001. doi: 10.3390/biomedicines13123001. PMID: 41463013. https://www.mdpi.com/2227-9059/13/12/3001 (Full text)

Killer cell immunoglobulin-like receptor (KIR) alleles suggested to be associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease with unknown cause. Involvement of infection and immune dysregulation has been suggested, including changes in immune cell subsets and abnormal functions of natural killer (NK) cells.

The regulatory NK cell receptors, killer cell immunoglobulin-like receptors (KIR) have previously been investigated in small cohorts of ME/CFS patients with conflicting results regarding gene content. Here, we studied KIR genes also at the allelic level using high-resolution sequencing, in 418 ME/CFS patients and 473 healthy controls.

Human leukocyte antigen (HLA) class I genotype data were included for KIR ligand annotation. Our healthy control data represent KIR frequencies for a Norwegian population, which have not previously been reported. We found no association between ME/CFS and KIR gene content or copy number variations. However, our data suggested that specific KIR alleles at loci encoding inhibitory receptors were associated with ME/CFS, which was further supported by allelic haplotype analyses.

Three alleles were more frequent in patients, i.e. KIR3DL3*002 (OR = 1.43, 95 %CI (1.09-1.86), p = 0.009), KIR3DL1*020 (OR = 2.20, 95 %CI (1.19-4.06), p = 0.01) and KIR3DL2*009 (OR = 1.56, 95 %CI (1.09-2.23), p = 0.01), while two alleles had a reduced patient frequency, i.e. KIR3DL3*013 (OR = 0.60, 95 %CI (0.42-0.86), p = 0.005) and KIR3DL2*010 (OR = 0.46, 95 %CI (0.30-0.71), p = 0.0005). Our data support an involvement of NK cells in ME/CFS.

Source: Ramadan DJ, Kichula KM, Tao S, Porfilio T, Lande A, Fluge Ø, Mella O, Strand EB, Saugstad OD, Norman PJ, Lie BA, Viken MK. Killer cell immunoglobulin-like receptor (KIR) alleles suggested to be associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Brain Behav Immun. 2025 Aug 31:106098. doi: 10.1016/j.bbi.2025.106098. Epub ahead of print. PMID: 40897283. https://www.sciencedirect.com/science/article/pii/S0889159125003332 (Full text)

Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS

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 exposures 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 with 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 the tryptophan-serotonin-kynurenine pathways.

Many of these underlying abnormalities worsened following exercise in ME/CFS patients, but not in healthy subjects; many abnormalities reinforced each other and several were correlated with the intensity of symptoms. Our findings may inform targeted therapeutic interventions for ME/CFS and PEM.

Source: Che X, Ranjan A, Guo C, Zhang K, Goldsmith R, Levine S, Moneghetti KJ, Zhai Y, Ge L, Mishra N, Hornig M, Bateman L, Klimas NG, Montoya JG, Peterson DL, Klein SL, Fiehn O, Komaroff AL, Lipkin WI. Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS. medRxiv [Preprint]. 2025 Jul 24:2025.07.23.25332049. doi: 10.1101/2025.07.23.25332049. PMID: 40778181; PMCID: PMC12330418. https://pmc.ncbi.nlm.nih.gov/articles/PMC12330418/ (Full text available as PDF file)

Immune Signatures in Post-Acute Sequelae of COVID-19 (PASC) and Myalgia/Chronic Fatigue Syndrome (ME/CFS): Insights from the Fecal Microbiome and Serum Cytokine Profiles

Abstract:

While there are many postulates for the etiology of post-viral chronic fatigue and other symptomatology, little is known. We draw on our past experience of these syndromes to devise means which can expose the primary players of this malady in terms of a panoply participating biomolecules and the state of the stool microbiome.
Using databases established from a large dataset of patients at risk of colorectal cancer who were followed longitudinally over 3 decades, and a smaller database dedicated to building a Long PASC cohort (Post-Acute Sequelae of COVID-19), we were able to ascertain factors that predisposed patients to (and resulted in) significant changes in various biomarkers, i.e., the stool microbiome and serum cytokine levels, which we verified by collecting stool and serum samples.
There were significant changes in the stool microbiome with an inversion from the usual Bacillota and Bacteroidota species. Serum cytokines showed significant differences in MIP-1β versus TARC (CC chemokine ligand 17) in patients with either PASC or COVID-19 (p < 0.02); IL10 versus IL-12p70a (p < 0.02); IL-1b versus IL-6 (p < 0.01); MCP1 versus TARC (p < 0.03); IL-8 versus TARC (p < 0.002); and Eotaxin3 versus TARC (p < 0.004) in PASC. Some changes were seen solely in COVID-19, including MDC versus MIP-1α (p < 0.01); TNF-α versus IL-1-β (p < 0.06); MCP4 versus TARC (p < 0.0001). We also show correlates with chronic fatigue where an etiology was not identified.
These findings in patients with positive criteria for PASC show profound changes in the microbiome and serum cytokine expression. Patients with chronic fatigue without clear viral etiologies also have common associations, including a history of tonsillectomy, which evokes a likely immune etiology.
Source: Tobi, M., Chaudhari, D., Ryan, E. P., Rossi, N. F., Koka, O., Baxter, B., Tipton, M., Dutt, T. S., Tobi, Y., McVicker, B., & Angoa-Perez, M. (2025). Immune Signatures in Post-Acute Sequelae of COVID-19 (PASC) and Myalgia/Chronic Fatigue Syndrome (ME/CFS): Insights from the Fecal Microbiome and Serum Cytokine Profiles. Biomolecules, 15(7), 928. https://doi.org/10.3390/biom15070928 https://www.mdpi.com/2218-273X/15/7/928 (Full text)