Category: Overlapping Illnesses

Fibromyalgia, Chronic Fatigue Syndrome, and Multiple Sclerosis are associated with lower translocator protein binding affinity genotypes

Abstract:

Introduction: Neuroinflammation is a known pathophysiologic mechanism in multiple sclerosis and a proposed mechanism in fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Positron Emission Tomography (PET) imaging of the translocator protein (TSPO) has been widely used to measure neuroinflammation, though second-generation ligands are highly sensitive to a single nucleotide polymorphism, rs6971, resulting in high, mixed, and low affinity binders. It is unknown whether this polymorphism is associated with neuroinflammatory disorders.

Materials and methods: Eighty-six total participant genotypes for TSPO binding affinity were identified through Sanger sequencing (30 fibromyalgia, 21 ME/CFS, 11 multiple sclerosis, and 24 healthy controls). Associations between patient group and genotype were assessed with Fisher’s Exact test. Associations between genotype and symptom severity from self-report questionnaires were assessed with Kruskal-Wallis tests.

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.

Discussion: These findings should be confirmed in larger samples but suggest functional consequences of rs6971 polymorphism that may be related to the pathophysiology of pain and fatigue illnesses.

Source: Jones C, Younger J. Fibromyalgia, Chronic Fatigue Syndrome, and Multiple Sclerosis are associated with lower translocator protein binding affinity genotypes. medRxiv [Preprint]. 2026 Oct 21:2026.10.19.26365953. doi: 10.64898/2026.10.19.26365953. PMID: 42996068; PMCID: PMC13738865. https://pmc.ncbi.nlm.nih.gov/articles/PMC13738865/ (Full text)

More common than we thought: Hypermobile Ehlers-Danlos Syndrome, comorbidity burden, and long COVID risk in a national cohort

Abstract:

Hypermobile Ehlers-Danlos Syndrome (hEDS) is a complex, underdiagnosed connective tissue disorder characterized by widespread symptoms affecting multiple organ systems. Recent clinical observations suggest that individuals with hEDS may be at increased risk for persistent symptoms following COVID-19, commonly referred to as Long COVID.

Using data from over 19 million patients across the United States, we examined associations between hEDS, COVID-19 infection, Long COVID, and related chronic conditions. We identified just over 25,000 individuals with hEDS and estimated a prevalence of approximately 1 in 800, which is higher than previously recognized.

Despite similar rates of COVID-19 infection between patients with hEDS and matched controls, patients with hEDS were nearly three times more likely to develop Long COVID. This risk was concentrated among patients with hEDS who also had overlapping conditions commonly seen in post-viral syndromes, including autonomic dysfunction (POTS), immune dysregulation (MCAS), and chronic fatigue (ME/CFS). Patients with hEDS also exhibited higher odds of having additional risk factors for severe or prolonged illness, including chronic lung and autoimmune conditions, depression, and cerebrovascular disease.

A subgroup of patients received their hEDS diagnosis only after a COVID-19 or Long COVID diagnosis, and this subgroup was highly enriched for multimorbidity, particularly POTS and MCAS.

These findings establish hEDS as more prevalent than previously recognized and identify a substantially elevated, comorbidity-driven risk of Long COVID in this population. Improved screening, earlier diagnosis, and integrated care pathways are urgently needed to support this complex and underserved patient group.

Source: Pearson ML, Laraway BJ, Elias ER, Bilousova G, Haendel MA. More common than we thought: Hypermobile Ehlers-Danlos Syndrome, comorbidity burden, and long COVID risk in a national cohort. PLOS Digit Health. 2026 Nov 5;5(11):e0001707. doi: 10.1371/journal.pdig.0001707. PMID: 42986813; PMCID: PMC13739140. https://pmc.ncbi.nlm.nih.gov/articles/PMC13739140/ (Full text)

“Maureen’s Story”: Diagnosing a Case of Mold Toxicity

Reprinted with the kind permission of ProHealth: 9/14/11

Dr. Neil Nathan, a specialist in treatment of complex medical illnesses, practices with Gordan Medical Associates near Mendocino, CA.

This information is excerpted with kind permission from his book On Hope and Healing for Those Who Have Fallen Through the Medical Cracks ©2010 Neil Nathan, MD, all rights reserved. These excerpts provide a general introduction to biotoxicity as one cause of unexplained illness; but a detailed discussion of biotoxicity’s many agents, symptoms, diagnosis, and treatment can be found in the book.

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Mold and Biotoxicity: There’s a Fungus Among Us

When it comes to understanding the different components of chronic illness, the concept of toxicity has received a good deal of recent attention. With the publication of Dr. Richie Shoemaker’s brilliant book, Mold Warriors, we now have some new tools to both evaluate and treat toxicity in its different forms.

It is fairly obvious that a microbe (bacteria, virus, fungus, parasite, or other infective agent) makes us sick by infecting us, and it is equally clear that treating these disease-causing microbes will make us better. But what is just becoming clear to us is that not only do these microbes make us sick by causing an infection, but some of these microbes can, in the process of being killed by our immune system, release toxins into our bodies that make us even sicker. Because these toxins are made by microbes, which are living biological systems, we call them biotoxins.

For most, the immune system recognizes these toxins and uses its defense mechanisms to destroy them. Unfortunately, about 25% of people are genetically unable to make an antibody to these toxins, and these patients may get progressively sicker as the toxins accumulate within their bodies.

What specific microbes are we talking about? The most common offenders are molds, especially the black mold Stachybotrys, but several other mold species such as Cladosporium and Fusarium can play a role in toxin formation. Harmful toxins can also be produced by certain viruses, especially those in the Herpes family, such as Epstein-Barr virus, which is the agent of mononucleosis; Cytomegalovirus; and Human Herpes Virus 6 (HHV-6), which is the agent of roseola infection.

A new and particularly toxic strain of HHV-6 has recently been discovered and has now been linked to chronic fatigue [ME/CFS] and fibromyalgia. Lyme bacteria can also produce these toxins, as can infections with the mycoplasmas, which are infective particles between viruses and bacteria in size. The atypical pneumonias (walking pneumonia) and Gulf War syndrome are examples of these infective agents.

Symptoms

So what are the symptoms of biotoxicity? Patients with this problem may experience a surprisingly wide range of symptoms related to many different organ systems. These symptoms sound a lot like fibromyalgia or chronic fatigue or depression. In children, it might appear like ADHD.

Diagnosis

The first order of business is to even consider the diagnosis.

Treatment

Several treatments for biotoxicity are currently in use. Dr. Shoemaker provides a combination of medications based on his testing. In its simplest form, this consists of using “Cholestyramine” the binding resin cholestyramine (trade name, Questran) or its cousin, Welchol.

Maureen’s Story

Maureen was a 28-year-old woman whom I saw for the first time in March of 2006. Her symptoms had begun three years previously, when she was working in a building with a very leaky roof.

She had also experienced several traumatic events at the same time, including a difficult divorce, which complicated both our evaluation and her perceptions about what may have triggered her illness.

In August of 2005, Maureen began to violently throw up on a daily basis, and this went on for months. She saw multiple physicians, including several gastrointestinal specialists, and underwent extensive testing, which showed no obvious cause for her symptoms.

She was diagnosed by various physicians as having bipolar disorder, irritable bowel syndrome, and hypochondriasis (meaning it was all in her head or psychosomatic).

Since her initial exposure to the mold, Maureen had gained 35 pounds and had developed sensitivities to all sorts of chemicals and perfumes (which we call multiple chemical sensitivities). This is actually a common event following untreated biotoxin exposure.

She continued to experience daily nausea and vomiting, regular headaches, and an inability to think clearly. She described her poor decision making in very simple terms: It’s like I’m inept.

She also reported blurred vision and bouts of chest tightness with wheezing.

When Maureen came to me, she had just lost her job of 14 years, at which she had been previously quite competent, and she was trying to live a normal life and raise her three children.

But she could hardly function.

Her energy level was very low, and she reported difficulty staying asleep and waking up unrefreshed each morning. She described joint pains in her neck, shoulder, and upper back, and she displayed the classical irritable bowel symptoms of gas bloating, distention and diarrhea alternating with constipation.

When I tested her vision with the Functional Acuity Contrast Test (FACT),a test of ability to detect contrasts that can indicate poor retinal function and has been closely related to biotoxicity], the results strongly suggested biotoxin exposure.

Her DHEA test was a little low, as was her progesterone level. I started her on natural progesterone cream, ¼ tsp daily, applied to her skin. I also put her on a small dose of DHEA.

And we started cholestyramine in the form of Questran Light, one scoop mixed with water three times daily, which is the best immediate treatment for mold toxicity.

When Maureen returned in April, just six weeks later, she reported that she was already 80% better. Her energy was markedly improved despite the fact that she was still living in her home, which had obvious mold exposure.

She had a new job, was successfully working again, but noticed that when she missed even a single day of her Questran, she became lethargic again.

She planned to remediate her home to clean up the mold, and she was thrilled that she had her life back; she was no longer plagued by nausea, vomiting, chest pain, and joint pain.

She was so impressed with her improvement in just a short period of time, that she bought a copy of Mold Warriors to give to her family physician, who had essentially told her she was a hypochondriac.

Her physician refused to even look at the book or to take Maureen’s story seriously.

It has been my experience that most of our mold-toxic patients have had a similar experience to Maureen’s. Their symptoms are usually misunderstood as representing psychological imbalances, particularly depression, but they do not respond well to antidepressant and anti-anxiety medications. That should be the tip-off that we need to look deeper for a cause of these symptoms.

Recalling that only 25% of patients are genetically unable to make the antibodies they need to these toxins, these patients may live in a home with others who have no symptoms or work in a mold-laden environment where others are not sick.

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* Neil Nathan, MD, is perhaps best known to ProHealth readers for his recent trial of “A simplified Methylation Protocol for Treatment of ME/CFS and Fibromyalgia,” conducted in collaboration with Drs. Amy Yasko, Rich Van Konynenburg, and Jacob Teitelbaum.

Note: This information has not been reviewed by the FDA. It is general information and is not meant to take the place of a physician’s attention or to prevent, diagnose, treat or cure any illness, condition or disease. It is very important that you make no change in your healthcare plan or health support regimen without researching and discussing it in collaboration with your professional healthcare team.

Post-acute infection: before we forget it again

Abstract:

Long COVID did not invent the post-acute phase of infection; it made it impossible to ignore. Acute infections are still often framed as time-limited events that end in recovery, deterioration or death, but this view fails to capture patients who remain biologically and clinically unwell after the acute infection has passed. The problem extends beyond SARS-CoV-2. Post-acute morbidity has been described after influenza, Epstein-Barr virus infection, Q fever, sepsis, and other infections, yet definitions, coding systems, and clinical pathways remain fragmented.

We argue that post-acute infection should not be organized only by the initiating pathogen. Such pathogen-centric labels may be clinically tidy, but they risk producing heterogeneous cohorts, diluted biomarker signals, and disease-specific silos that obscure shared mechanisms of incomplete recovery. Instead, the field needs a second axis: the host-recovery state.

Persistent inflammation, immune remodelling, loss of tolerance, antigenic stimulation, endothelial dysfunction, mitochondrial impairment, and tissue injury may represent overlapping immunometabolic failure modes across infections. Defining these states over time could help transform post-acute infection from a residual clinical label into a mechanism-informed framework for research, biomarkers, and care.

Source: Madsen HB, Desler C. Post-acute infection: before we forget it again. Clin Exp Immunol. 2026 Jan 6;220(1):uxag061. doi: 10.1093/cei/uxag061. PMID: 42931812; PMCID: PMC13701074. https://pmc.ncbi.nlm.nih.gov/articles/PMC13701074/ (Full text)

Overlapping Post-COVID Conditions: A Case of Myalgic Encephalomyelitis and Postural Orthostatic Tachycardia Syndrome Triggered by Sequential Epstein-Barr Virus (EBV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infections

Abstract:

The rise in post-infectious syndromes following COVID-19, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Postural Orthostatic Tachycardia Syndrome (POTS), has become increasingly common in clinical practice, representing an emerging clinical challenge. This case highlights a possible clinical scenario involving the interaction between sequential viral infections – such as the Epstein-Barr virus (EBV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) – in triggering overlapping chronic conditions. This report presents the case of a patient who developed ME/CFS and POTS following SARS-CoV-2 infection, with a prior history of EBV mononucleosis, and discusses the diagnostic, therapeutic, and pathophysiological implications.

A 48-year-old woman with a history of mononucleosis in childhood developed persistent and disabling symptoms after COVID-19 in January 2022. She presented with extreme fatigue, orthostatic intolerance, paresthesia, cognitive dysfunction, and multisystem symptoms. After extensive investigation, she was diagnosed with ME/CFS (early 2023) and POTS (later that year). Mast Cell Activation Syndrome (MCAS) was considered as a hypothesis during follow-up, but objective testing was not confirmatory. Management included pharmacological therapy (including low-dose naltrexone, duloxetine, and palmitoylethanolamide (PEA)), activity adjustments (pacing), and a multidisciplinary approach, with partial and fluctuating responses.

This case illustrates how viral infections such as EBV and SARS-CoV-2 may act as sequential triggers in an individual clinical trajectory compatible with the development of ME/CFS and POTS. The symptomatic overlap, the lack of readily available objective biomarkers in this patient, and the need for a predominantly clinical and functional diagnostic approach in her evaluation highlight the complexity of these conditions. This experience also underscores the importance of continued efforts in research, clinical training, and integrated care models to improve the management of patients presenting with post-COVID conditions (PCC).

Source: Mayrink Magalhães VR, Ribeiro Oliveira LA, Lourenço AJ, Ribeiro Camargos I, Da Silva LG, Filgueiras PS, De Souza Lima AE, Marques Contin SV, Costa M, Istilli P, Ferreira da Costa Gomes M, Pedretti CB, Correa PRL, Grenfell RF. Overlapping Post-COVID Conditions: A Case of Myalgic Encephalomyelitis and Postural Orthostatic Tachycardia Syndrome Triggered by Sequential Epstein-Barr Virus (EBV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infections. Cureus. 2026 Sep 24;18(9):e116844. doi: 10.7759/cureus.116844. PMID: 42927133; PMCID: PMC13695498. https://pmc.ncbi.nlm.nih.gov/articles/PMC13695498/ (Full text)

Explaining Fatigue and Post-Exertional Malaise in Long COVID and ME/CFS: From Skeletal Muscle To Exercise Immunology

Abstract:

The SARS-CoV-2 viral outbreak in 2020 resulted in a record number of global hospitalizations and deaths. Although most people recover from an initial COVID infection within 3 months, around 10% of people have symptoms that do not improve after 3 months, which is called long COVID. Other viruses and bacterial infections can also result in long-term symptoms, which is known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

One of the most common symptoms of long COVID or ME/CFS is post-exertional malaise, which is the worsening of symptoms or development of new symptoms after physical, mental or emotional stress. This can lead to patients leading less physically active lifestyles. Physical activity is known to be beneficial for overall health and wellbeing, mostly by increasing exercise capacity, which is a significant predictor in long-term health. Physical inactivity.

It is thought that many symptoms of long COVID and ME/CFS can be explained by lower physical activity of patients. However, people who are less physically active don’t experience post-exertional malaise, implying there are disease-specific changes. Many of the benefits that come from exercise come from a persons ability to adapt to an exercise session. Usually, exercise will create a short energy deficit, which then may result in small amounts of muscle damage. This then triggers a short-lived immune response, led first by neutrophils and macrophages, which result in activation of fibroadipogenic progenitor cells (FAP cells) and satellite cells (muscle stem cells). FAP cells and satellite cells communicate to repair damage to the muscle itself, while immune cells clear debris surrounding the muscle. In healthy situations, this creates a stronger, more resilient muscle. It is unknown whether these responses are still seen in long COVID or ME/CFS. The goal of this thesis then to 1) understand muscle changes in patients with long COVID and ME/CFS, 2) to better understand how these changes may relate to PEM, 3) to understand whether the muscle changes in patients are a result of physical inactivity.

Within the thesis, I find that patients with long COVID and ME/CFS have specific patterns of skeletal muscle that separate them from healthy individuals. This is highlighted by more fast-twitch fibre types, slow-twitch muscle atrophy, lower mitochondrial respiration that is separate from just mitochondrial loss, less metabolites related to oxidative capacity and antioxidation, less lipids that are required for cell membrane maintenance, and lower amounts of satellite cells and FAP cells.

Beyond this, I find that ME/CFS can be distinguished from long COVID by less capillaries, less slow-twitch fibres, less local immune cells, and lower amounts of several essential amino acids. As well, I find evidence that physical inactivity alone cannot explain long COVID and ME/CFS symptoms. Where all of long COVID, ME/CFS, and physical inactivity have lower whole-body aerobic capacity, physical inactivity causes a decrease in muscle fibre size, loss of mitochondria, increases in muscle lipotoxic lipids, and decreases in metabolites related to carnitine metabolism. These changes are not seen in either long COVID nor ME/CFS, and support the idea that long COVID and ME/CFS have disease specific muscle changes.

Overall, I find that the reduced whole-body capacity of long COVID and ME/CFS patients is not cause by physical inactivity, and is defined by reduced muscle oxidative ability. The lower amounts of local cells that would normally support exercise and damage responses are lower in both long COVID and ME/CFS, which partially explains the occurrence of PEM. This also suggests that patients experiencing PEM should not undertake normal rehabilitation, however it might be that more individually tailored, and severely monitored approaches may still be beneficial.
Source: Charlton, B. T. (2026). Explaining Fatigue and Post-Exertional Malaise in Long COVID and ME/CFS: From Skeletal Muscle To Exercise Immunology. [PhD-Thesis – Research and graduation internal, Vrije Universiteit Amsterdam]. https://doi.org/10.5463/thesis.1979 https://research.vu.nl/en/publications/explaining-fatigue-and-post-exertional-malaise-in-long-covid-and-/ https://research.vu.nl/ws/portalfiles/portal/517511531/aio01877%20braeden%20charltonfinal%20-%206acf4153820e1.pdf (Full text)

The Glymphatic–Meningeal Lymphatic System and Autophagy in ME/CFS and Long COVID: A Mechanistic Perspective

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of SARS-CoV-2 infection (Long COVID) are complex multisystem disorders affecting 60–400 million individuals globally. They are considered post-infectious illnesses and share similar biological mechanisms, including immune dysregulation, orthostatic intolerance and cognitive dysfunction, highlighting a substantial overlap between the two conditions. Persistent fatigue, sleep dysfunction, post-exertional malaise and brain fog are among some of their most common and debilitating symptoms.
Despite extensive research, they remain incurable, with no effective treatments, or simple diagnostic tests. They are increasingly understood as heterogeneous, multisystem diseases, involving neurological symptoms, with varying severities and diverse underlying biological abnormalities. More recently, the possibility of glymphatic dysfunction and autophagy impairment have been proposed as parts of the mechanistic features of the pathophysiology of these conditions, which are discussed more fully in the present perspective.
With the glymphatic and meningeal lymphatic systems being operationally integrated, we will try to delineate how the metabolic waste removal mechanism afforded by this system may work together with autophagy to maintain brain homeostasis. We will provide some of the established mechanistic features of toxicity of misfolded proteins, explore their role in causing glymphatic dysfunction and impairing autophagy, and discuss the potential for therapeutic interventions.
Source: Nemat-Gorgani M, Jensen MA, Davis RW. The Glymphatic–Meningeal Lymphatic System and Autophagy in ME/CFS and Long COVID: A Mechanistic Perspective. International Journal of Molecular Sciences. 2026; 27(20):9351. https://doi.org/10.3390/ijms27209351 https://www.mdpi.com/1422-0067/27/20/9351 (Full text)

An insight into the long/post COVID care situation in Germany-a rapid scoping review

Abstract:

in English, German

Background: Long/post COVID and related conditions such as myalgic encephalomyelitis/chronic fatigue syndrome, postural orthostatic tachycardia syndrome and post-vaccination syndrome are associated with persistent functional impairments and are met with care structures in Germany that are difficult to navigate.

Objective: The rapid scoping review offers an insight into care structures, capacities, access, care pathways and gaps in care for these patient groups in the German healthcare system. It also takes into account patient and care provider perspectives.

Methods: The study follows the recommendations of the Joanna Briggs Institute and the PRISMA ScR checklist for conducting (rapid) scoping reviews. A MEDLINE search was conducted from 2020 onwards with predefined inclusion and exclusion criteria for evidence sources related to care in Germany.

Results: 44 evidence sources were included. General practitioners and paediatricians act as the first point of contact. Specialised outpatient clinics and rehabilitation facilities take on complex diagnostics and patient treatment. Care networks are rare. Navigating the healthcare system is characteris ed by information gaps, unclear responsibilities and long waiting times, so that those affected often organise their own care. Some report stigmatisation, misdiagnoses and stressful activation recommendations despite the risk of post exertional malaise.

Conclusion: Care is unevenly accessible, poorly coordinated and only limitedly evidence based. Shared knowledge and case databases, training, better diagnostic tools and robust efficacy studies are needed to improve access, management and safety of long/post COVID care.

Source: Ebster M, Gscheidle S, Lange S, Weijburg T, Arnold M. Ein Einblick in die Long/Post COVID-Versorgungslage in Deutschland – ein Rapid Scoping Review [An insight into the long/post COVID care situation in Germany-a rapid scoping review]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2026 Oct 16. German. doi: 10.1007/s00103-026-04313-8. Epub ahead of print. PMID: 42886231. https://link.springer.com/article/10.1007/s00103-026-04313-8 (Full text in German)

Post-acute sequelae of COVID-19 (PASC) are associated with distinct clinical phenotypes two years after SARS-CoV-2 infection: A data-driven approach

Abstract:

It is important to determine whether the persistent cognitive and fatigue complaints, as part of post-acute sequelae of COVID-19 (PASC), are associated with underlying patterns and specific symptoms clusters. Therefore, the aim of the present study was to investigate symptom clusters and clinical phenotypes in PASC.

We included n = 153 individuals (53 years old, 66% female, 2 years post SARS-CoV-2 infection) categorized into groups with (n = 88) and without (n = 65) PASC, defined by severe fatigue and concentration problems using validated cut-offs. Symptom clusters (i.e., component loadings and component scores) were identified using principal component analyses (PCA, eigenvalue[EV]>1.0), using clinical, somatic, coping and sleep factors, symptom severity, neuropsychological and physical tests (totalling 19 tests and questionnaires). We then used logistic regression techniques on (participant-level) component scores (standardized) to investigate associations with PASC. Finally, K-means clustering methods to identify clinical phenotypes. Analyses were adjusted for age, sex, education, nationality and time since infection.

PCA identified 5 components, explaining 70% of the variance. We labelled these components as follows: (1) PEM, ME/CFS and sleep symptoms, coping factors (EV = 7.0, 36.9% variance), (2) information-processing speed (EV = 2.5, 13.3%), (3) executive functioning (EV = 1.5, 8.0%, (4) physical performance (EV = 1.2, 6.5%), (5) somatic comorbidities and hospital admission (EV = 1.0, 5.5%). Logistic regression showed that only the first component scores (Odds ratio [95% confidence interval] = 97.1 [16.5-570.3], p < 0.001,), and none of the others (all p > 0.05), associated with PASC.

Cluster analysis revealed two distinct clinical phenotypes among individuals with severe chronic fatigue: one marked by physical impairment and the other by diminished cognitive performance. Consistent with existing literature, we confirmed that PASC is a heterogeneous syndrome marked by extensive, interrelated symptoms. Notably, we identified specific cognitive and physical clinical phenotypes. These findings are important for future targeted diagnosis and treatment.

Source: Verfaillie SCJ, Verveen A, Visser D, Nieuwkerk P, Appelman B, Boellaard R, van Heugten CM, Horn J, Hulst HE, de Jong MD, Kuut TA, Maaden TV, van Os YMG, Prins M, Visser-Meily JMA, van Vugt M, van den Wijngaard CC, van Berckel BNM, Bosch JA, Tolboom N, Knoop H. Post-acute sequelae of COVID-19 (PASC) are associated with distinct clinical phenotypes two years after SARS-CoV-2 infection: A data-driven approach. PLoS One. 2026 Oct 15;21(10):e0359844. doi: 10.1371/journal.pone.0359844. PMID: 42879454; PMCID: PMC13671525. https://pmc.ncbi.nlm.nih.gov/articles/PMC13671525/ (Full text)

Exploratory clinical and immunological changes following Tixagevimab/Cilgavimab administration in immunodeficient patients with SARS-CoV-2-associated ME/CFS and persistent circulating spike protein

Abstract:

Background: Persistent circulating SARS-CoV-2 spike protein has been proposed as a potential contributor to long-COVID pathophysiology. Whether administration of spike-targeting monoclonal antibodies is followed by changes in spike protein concentrations, autonomic receptor autoantibodies, or clinical outcomes remains uncertain.

Methods: In this prospective, non-randomized observational study, 21 participants were enrolled. Ten immunodeficient patients with long-COVID-associated ME/CFS and detectable circulating spike protein received Tixagevimab/Cilgavimab for SARS-CoV-2 pre-exposure prophylaxis. One patient subsequently withdrew consent, leaving nine patients for paired baseline and 30-day follow-up analyses. Eleven healthy individuals with previous SARS-CoV-2 infection but without long COVID provided descriptive reference data and were not considered an efficacy control group.

Results: β1-adrenergic receptor autoantibody concentrations decreased from 26.8 ± 18.2 to 21.2 ± 14.7 U/ml (unadjusted p = 0.003). No statistically significant changes were observed for β2-adrenergic or M3/M4-muscarinic receptor autoantibodies. Median spike protein concentrations changed from 63 pg/ml (IQR 9-127) to 26 pg/ml (IQR 10-120; p = 0.63), with individual decreases observed in five of nine patients. None of the assessed clinical outcomes changed significantly at group level. Changes in spike protein concentrations were not significantly correlated with changes in the assessed autonomic receptor autoantibodies.

Conclusion: Tixagevimab/Cilgavimab administration was followed by a nominally significant within-patient reduction in β1-adrenergic receptor autoantibody concentrations, but not by conclusive changes in circulating spike protein or clinical outcomes. These findings are preliminary and hypothesis-generating. The small sample size, non-randomized design, brief 30-day follow-up, inclusion of only immunodeficient patients, and absence of an untreated disease-matched control group preclude conclusions regarding therapeutic efficacy.

Source: Seidel M, Anft M, Wiemers L, Seibert FS, Bertram S, Rosiewicz K, Stervbo U, Westhoff TH, Babel N. Exploratory clinical and immunological changes following Tixagevimab/Cilgavimab administration in immunodeficient patients with SARS-CoV-2-associated ME/CFS and persistent circulating spike protein. Immunol Lett. 2026 Oct 7:107247. doi: 10.1016/j.imlet.2026.107247. Epub ahead of print. PMID: 42843426. https://pubmed.ncbi.nlm.nih.gov/42843426/