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

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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.

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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.

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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.
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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.
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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.

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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.
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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.”

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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. 

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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
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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.
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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.

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.

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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.

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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.
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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.

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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.

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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.

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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.

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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.
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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.

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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.
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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.
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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.
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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.

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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
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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.

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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.

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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

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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.

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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.

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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.
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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.
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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.
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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.

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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.

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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
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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).

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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).

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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 .

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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.
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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.

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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

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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.

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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.

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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.

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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."

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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.

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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.
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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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
 
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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."
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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.

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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.

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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.

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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.

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‘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.

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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.

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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.

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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.

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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.

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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

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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

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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.
 
 
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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.
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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

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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.

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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.

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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.
 
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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."

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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.
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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.
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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. 

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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. 

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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.

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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.
 
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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.

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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.
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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

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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.

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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.

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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.
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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.

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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.
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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.

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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.

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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.

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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."

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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

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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.

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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.

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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.

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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.

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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.

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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. 

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• 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.

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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.
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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.

WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome
Ping-yuan Wang, Jin Ma, Young-Chae Kim https://orcid.org/0000-0002-5130-4413, +10, and Paul M. Hwang  
Edited by Se-Jin Lee, University of Connecticut School of Medicine, Farmington, CT; received February 17, 2023; accepted June 27, 2023
August 14, 2023  120 (34) e2302738120  https://doi.org/10.1073/pnas.2302738120
Vol. 120 | No. 34  Significance
Chronic fatigue is a debilitating symptom that affects many individuals, but its mechanism remains poorly understood. This study shows that endoplamic reticulum (ER) stress–induced WASF3 protein localizes to mitochondria and disrupts respiratory supercomplex assembly, leading to decreased oxygen consumption and exercise endurance. Alleviating ER stress decreases WASF3 and restores mitochondrial function, indicating that WASF3 can impair skeletal muscle bioenergetics and may be targetable for treating fatigue symptoms.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging. A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies. We report that overexpression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress. Increased expression of WASF3 in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue. Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation. In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID.
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The plasma metabolome of long COVID patients two years after infection
Yamilé López-Hernández, Joel Monárrez-Espino, David Alejandro, García López, Jiamin Zheng, Juan Carlos Borrego, Claudia Torres-Calzada, José Pedro Elizalde-Díaz, Rupasri Mandal, Mark Berjanskii, Eduardo Martínez-Martínez, Jesús Adrián López & David S. Wishart 
Scientific Reports volume 13, Article number: 12420 (2023) Cite this article
Abstract

One of the major challenges currently faced by global health systems is the prolonged COVID-19 syndrome (also known as “long COVID”) which has emerged as a consequence of the SARS-CoV-2 epidemic. It is estimated that at least 30% of patients who have had COVID-19 will develop long COVID. In this study, our goal was to assess the plasma metabolome in a total of 100 samples collected from healthy controls, COVID-19 patients, and long COVID patients recruited in Mexico between 2020 and 2022. A targeted metabolomics approach using a combination of LC–MS/MS and FIA MS/MS was performed to quantify 108 metabolites. IL-17 and leptin were measured in long COVID patients by immunoenzymatic assay. The comparison of paired COVID-19/long COVID-19 samples revealed 53 metabolites that were statistically different. Compared to controls, 27 metabolites remained dysregulated even after two years. Post-COVID-19 patients displayed a heterogeneous metabolic profile. Lactic acid, lactate/pyruvate ratio, ornithine/citrulline ratio, and arginine were identified as the most relevant metabolites for distinguishing patients with more complicated long COVID evolution. Additionally, IL-17 levels were significantly increased in these patients. Mitochondrial dysfunction, redox state imbalance, impaired energy metabolism, and chronic immune dysregulation are likely to be the main hallmarks of long COVID even two years after acute COVID-19 infection.

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MEDICAL NEWS (UNIVADIS)
New Treatment Option for Long-term InsomniaRob Hicks   |   18 September 2023
The National Institute for Health and Care Excellence (NICE) has recommended  daridorexant (QUVIVIQ, Idorsia) as a new treatment option for long-term insomnia but underscored the importance of keeping the duration of treatment as brief as possible. 
Long-term insomnia — also known as chronic insomnia or insomnia disorder — is defined as dissatisfaction with quantity or quality of sleep for 3 nights or more per week for at least 3 months with an effect on daytime functioning. The condition — thought to affect around 7% of the UK adult population —has both night-time symptoms as well as a negative impact on physical health, daytime functioning, and overall wellbeing. Furthermore, suboptimal management of the condition is associated with decreased workplace productivity, and an increased risk of workplace accidents, falls, and costly workplace errors.
Lisa Artis, deputy CEO of The Sleep Charity UK, said: "While we all may experience short periods of sleeplessness, people living with chronic insomnia are persistently deprived of the restorative sleep they need, which can have a major impact on their overall health and wellbeing."
The standard first treatment for insomnia is sleep hygiene advice plus cognitive behavioural therapy for insomnia (CBTi). However, access to CBTi varies across England, and there are difficulties accessing CBTi, NICE alerted. "Even when CBTi was available, people with insomnia were often not aware of it," the regulator pointed out.
_______________________________________________________________________________Tackling Overactive WakefulnessA key component of the wake and sleep signalling process is the orexin system — made up of orexin A and orexin B neuropeptides, and receptors OX1R and OX2R — which helps promote wakefulness. 
This system stimulates targeted neurons in the wake system leading to the release of several chemicals — serotonin, histamine, acetylcholine, norepinephrine — to promote wakefulness. Under normal circumstances, orexin levels rise throughout the day as wakefulness is promoted, and then fall at night. 
Overactivity of the wake system is an important driver of insomnia. Daridorexant works by selectively blocking only the activation of orexin receptors, thereby decreasing the brain's "overactive wakefulness".
Daridorexant is taken orally once a night, around half an hour before bed. The list price per pack for the 50mg or the 25mg dose is £1.40 per day.
Evidence presented to an appraisal committee showed a reduction in insomnia with daridorexant compared with placebo over a 12-month period, and that the drug was effective in improving symptoms related to long-term insomnia, reducing the total number of minutes that a person was awake after initially falling asleep, and the time it took for the person to fall asleep after going to bed. After 12 months' treatment, daridorexant was not associated with physical signs of dependency, tolerance, or rebound insomnia after its discontinuation.
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Daridorexant Recommended as Second LineIn final draft guidance, NICE said that daridorexant would be offered as a second-line treatment option for long-term insomnia, but only if CBTi had been tried but had not worked, or if CBTi was not available or was unsuitable. It is estimated that just over 20,000 people in England could receive the treatment in the next year.
"There is some uncertainty about its longer-term benefit compared with placebo beyond 12 months, and [about] cost-effectiveness modelling assumptions," cautioned NICE. However, it emphasised that "even accounting for this uncertainty", the cost-effectiveness estimates for daridorexant compared with 'no treatment' was within the range it normally considered to be an acceptable use of NHS resources. 
Dr David O'Regan, consultant in psychiatry and sleep medicine, said that the decision by the regulator represented a "significant breakthrough" for chronic insomnia patients. "While other treatment options for insomnia are available, these may not be suitable for long-term use, effective for all patients, or specifically licensed for the treatment of chronic insomnia," he explained. 
The regulator stressed that the "length of treatment should be as short as possible", and that treatment with the drug should be assessed within 3 months of starting and should be stopped in people whose long-term insomnia had not responded adequately. If treatment was continued, assessment of whether it was still working should be made at regular intervals.
NICE said that as a new medicinal product containing a new active substance, daridorexant was subject to additional monitoring, and it was therefore important to report on the Yellow Card system any suspected adverse events.
Final NICE guidance is due to be published on 18 October, 2023.
For more news, follow Medscape on  Facebook, Twitter, Instagram, and YouTube 
References  Disclaimer 
Daridorexant for treating long-term insomnia
National Institute for Health and Care Excellence

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Infectious Diseases     October 6, 2023
Autoimmune and Autoinflammatory Connective Tissue Disorders Following COVID-19Sung Ha Lim, MD1; Hyun Jeong Ju, MD, PhD2; Ju Hee Han, MD3; et alJi Hae Lee, MD, PhD2; Won-Soo Lee, MD, PhD1; Jung Min Bae, MD, PhD2; Solam Lee, MD, PhD1,4
JAMA Netw Open. 2023;6(10):e2336120. doi:10.1001/jamanetworkopen.2023.36120
Key Points
Question  Is COVID-19 associated with an increased risk of autoimmune and autoinflammatory disorders?
Findings  This cohort study including 354 527 individuals with COVID-19 and 6 134 940 controls identified a significant elevation in the risk of multiple incident autoimmune and autoinflammatory disorders subsequent to COVID-19. Notably, certain disease risks exhibited a positive association with the severity of COVID-19.
Meaning  These findings suggest that autoimmune and autoinflammatory connective tissue disorders may manifest as post–COVID-19 sequelae, highlighting the potential long-term health ramifications associated with COVID-19; long-term management should include evaluating the development of such disorders in patients who had COVID-19.
Abstract
Importance  Multiple cases of autoimmune and autoinflammatory diseases after COVID-19 have been reported. However, their incidences and risks have rarely been quantified.
Objective  To investigate the incidences and risks of autoimmune and autoinflammatory connective tissue disorders after COVID-19.
Design, Setting, and Participants  This was a retrospective population-based study conducted between October 8, 2020, and December 31, 2021, that used nationwide data from the Korea Disease Control and Prevention Agency COVID-19 National Health Insurance Service cohort and included individuals who received a diagnosis of COVID-19 via polymerase chain reaction testing and a control group with no evidence of COVID-19 identified from National Health Insurance Service of Korea cohort. Data analysis was conducted from September 2022 to August 2023.
Exposures  Receipt of diagnosis of COVID-19.
Main Outcomes and Measures  The primary outcomes were the incidence and risk of autoimmune and autoinflammatory connective tissue disorders following
COVID-19. A total of 32 covariates, including demographics, socioeconomic statuses, lifestyle factors, and comorbidity profiles, were balanced through inverse probability weighting. The incidences and risks of autoimmune and autoinflammatory connective tissue disorders were compared between the groups using multivariable Cox proportional hazard analyses.
Results  A total of 354 527 individuals with COVID-19 (mean [SD] age, 52.24 [15.55] years; 179 041 women [50.50%]) and 6 134 940 controls (mean [SD] age, 52.05 [15.63] years; 3 074 573 women [50.12%]) were included. The risks of alopecia areata (adjusted hazard ratio [aHR], 1.12; 95% CI, 1.05-1.19), alopecia totalis (aHR, 1.74; 95% CI, 1.39-2.17), antineutrophil cytoplasmic antibody–associated vasculitis (aHR, 2.76; 95% CI, 1.64-4.65), Crohn disease (aHR, 1.68; 95% CI, 1.31-2.15), and sarcoidosis (aHR, 1.59; 95% CI, 1.00-2.52) were higher in the COVID-19 group. The risks of alopecia totalis, psoriasis, vitiligo, vasculitis, Crohn disease, ulcerative colitis, rheumatoid arthritis, adult-onset Still disease, Sjögren syndrome, ankylosing spondylitis, and sarcoidosis were associated with the severity of COVID-19.
Conclusions and Relevance  In this retrospective cohort study, COVID-19 was associated with a substantial risk for autoimmune and autoinflammatory connective tissue disorders, indicating that long-term management of patients with COVID-19 should include evaluation for such disorders.

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Autoimmunity Reviews Volume 19, Issue 6, June 2020, 102527
A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors
Klaus Wirth a, Carmen Scheibenbogen b
https://doi.org/10.1016/j.autrev.2020.102527
Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiology of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system.
We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ß2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia.
Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ß2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiology of ME/CFS without an autoimmune pathogenesis.
 
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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,  Valter Silva Monteiro, Julio Silva, Kathy Kamath, Minlu Zhang, Abhilash Dhal, Isabel M. Ott, Gabrielee Valle, Mario Peña-Hernández, Tianyang Mao, Bornali Bhattacharjee, Takehiro Takahashi, Carolina Lucas, Eric Song, Dayna McCarthy, Akiko Iwasaki 

• Nature (2023)     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.

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Serotonin reduction in post-acute sequelae of viral infectionArticle in Cell   Andrea C. Wong, Ashwarya S. Devason, Iboro C. Umana,Sara Cherry,Christoph A. Thaiss,Maayan Levy Published:October 16, 2023DOI:https://doi.org/10.1016/j.cell.2023.09.013
HighlightsLong COVID is associated with reduced circulating serotonin levels
Serotonin depletion is driven by viral RNA-induced type I interferons (IFNs)
IFNs reduce serotonin through diminished tryptophan uptake and hypercoagulability
Peripheral serotonin deficiency impairs cognition via reduced vagal signaling
SummaryPost-acute sequelae of COVID-19 (PASC, “Long COVID”) pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.
 
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Long COVID Linked With Viral Persistence, Serotonin DeclineEmily Harris
JAMA. Published online November 1, 2023. doi:10.1001/jama.2023.21170
A study linking viral infection with reduced levels of serotonin, a neurotransmitter involved in learning, memory, and mood, has proposed a new potential mechanism underlying post–COVID-19 condition. Also known as long COVID, the condition involves symptoms such as fatigue, memory loss, and cognitive impairment.
Using results from human participants, mice, and organoid cultures, the researchers found that long COVID was tied with a decline in serotonin. A viral reservoir in the gut appeared to trigger inflammation that decreased intestinal absorption of tryptophan, serotonin’s precursor molecule.
Serotonin activity supports vagus nerve function, among other roles. In the study, serotonin loss was associated with lower nerve activity. Dysfunction in the vagus nerve was linked with characteristic long COVID symptoms such as memory loss and hippocampal dysfunction.
“Clinicians treating patients with long COVID have been relying on personal reports from those patients to determine if their symptoms are improving,” Sara Cherry, PhD, an author of the study published in Cell, said in a statement. “Now, our research shows that there are biomarkers we may be able to use to match patients to treatments or clinical trials.”
Published Online: November 1, 2023. doi:10.1001/jama.2023.21170

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Brain Behav Immun Health  . 2023 Apr 27:30:100627.  doi: 10.1016/j.bbih.2023.100627.  2023 Jul.
Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndromeMelanie Uhde 1, Alyssa C Indart 1, Peter H R Green 1 2, Robert H Yolken 3, Dane B Cook 4, Sanjay K Shukla 5, Suzanne D Vernon 6, Armin Alaedini 1 7 2 8
PMID: 37396339   PMCID: PMC10308215   DOI: 10.1016/j.bbih.2023.100627
AbstractThe etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear. Relying on data from two independent pairs of ME/CFS and control cohorts, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium in ME/CFS. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.
Keywords: Acute-phase innate immune response; Antibody; B cell; Citrate; Glucose; Gut epithelial barrier; IL-10; Immunoregulation; Inflammation; Metabolism; Microbial translocation; Microbiota; Myalgic encephalomyelitis/chronic fatigue syndrome; TLR4.
© 2023 Published by Elsevier Inc.

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 Medscape Medical News
Nirmatrelvir-Ritonavir Ineffective at Reducing Most Post-COVID Condition     Becky Ellis  October 30, 2023 
TOPLINE:
Nirmatrelvir-ritonavir doesn't reduce the incidence of most post-COVID conditions, according to a new study. Thromboembolic events are the exception.
 
METHODOLOGYA retrospective study of 9593 veterans older than 65 years examined the impact of nirmatrelvir-ritonavir in comparison with no treatment on post-COVID-19 conditions (PCCs).Researchers coded 31 conditions, including those that fell into cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, and endocrine categories.
The incidence of PCCs was analyzed 31 to 180 days after treatment.
 
TAKEAWAY:The combined incidence of venous thromboembolism and pulmonary embolism was reduced among patients given nirmatrelvir-ritonavir.
No statistically significant reduction of other conditions was found.
Results differ from the conclusions of a smaller study that found that the incidence of 10 of 13 PCCs was lower.
 
IN PRACTICE:"Our results suggest that considerations about PCCs may not be an important factor in COVID-19 treatment decisions," the authors write.
SOURCE:The study was funded by the US Department of Veterans Affairs and was published online in Annals of Internal Medicine on October 30. George Ioannou, MD, director of hepatology at the VA Puget Sound Health Care System in Seattle, led the study.

LIMITATIONS:A large number of outcomes were observed, so it's possible that the association between treatment with nirmatrelvir-ritonavir and reduced incidence of thromboembolic events occurred by chance.
Data on COVID-19 treatments and PCCs may be incomplete. The long-term effects of PCCs may not have been fully captured by the International Classification of Diseases, 10th Revision, which was used for diagnosis codes.
Electronic health records did not accurately capture the symptom burden or the date symptoms began. Patients in the treatment arm may have had more symptoms than matched control persons who were not treated.
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Postacute sequelae of COVID-19 at 2 yearsBenjamin Bowe, Yan Xie & Ziyad Al-Aly 
Nature Medicine volume 29, pages2347–2357 (2023) 
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to postacute sequelae in multiple organ systems, but evidence is mostly limited to the first year postinfection. We built a cohort of 138,818 individuals with SARS-CoV-2 infection and 5,985,227 noninfected control group from the US Department of Veterans Affairs and followed them for 2 years to estimate the risks of death and 80 prespecified postacute sequelae of COVID-19 (PASC) according to care setting during the acute phase of infection. The increased risk of death was not significant beyond 6 months after infection among nonhospitalized but remained significantly elevated through the 2 years in hospitalized individuals. Within the 80 prespecified sequelae, 69% and 35% of them became not significant at 2 years after infection among nonhospitalized and hospitalized individuals, respectively. Cumulatively at 2 years, PASC contributed 80.4 (95% confidence interval (CI): 71.6–89.6) and 642.8 (95% CI: 596.9–689.3) disability-adjusted life years (DALYs) per 1,000 persons among nonhospitalized and hospitalized individuals; 25.3% (18.9–31.0%) and 21.3% (18.2–24.5%) of the cumulative 2-year DALYs in nonhospitalized and hospitalized were from the second year. In sum, while risks of many sequelae declined 2 years after infection, the substantial cumulative burden of health loss due to PASC calls for attention to the care needs of people with long-term health effects due to SARS-CoV-2 infection.

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Characterising the evolving SARS-CoV-2 seroprevalence in urban and rural Malawi between February 2021 and April 2022: a population-based cohort studyLouis Banda, Antonia Ho,Stephen Kasenda ,Annie Chauma Mwale, AbenaS Amoah,Amelia Crampin *   Published:October 27, 2023DOI:https://doi.org/10.1016/j.ijid.2023.10.020
HighlightsThis was a longitudinal SARS-CoV-2 serosurvey in an urban & rural cohort in Malawi
Post-Omicron SARS-CoV-2 seroprevalence was very high (rural: 89%; urban: 94%)
Most SARS-CoV-2 infections were subclinical; few required healthcare attendants
Seroconversion risk varied by location & age across the successive infection waves
Hybrid immunity was associated with higher seroprevalence and antibody titresAbstractObjectivesTo investigate the changing SARS-CoV-2 seroprevalence and associated health and sociodemographic factors in Malawi between February 2021 and April 2022.
Methods
Four three-monthly serosurveys were conducted within a longitudinal population-based cohort in rural Karonga District and urban Lilongwe, testing for SARS-CoV-2 S1 IgG antibodies using an enzyme-linked immunosorbent assay. Population seroprevalence was estimated in all and unvaccinated participants. Bayesian mixed effects logistic models estimated the odds of seropositivity in the first survey, and of seroconversion between surveys, adjusting for age, sex, occupation, location, and assay sensitivity/specificity.
Results
Of 2005 participants (Karonga,n=1005;Lilongwe,n=1000), 55.8% were female and median age was 22.7 years. Between Surveys 1-4, population-weighted SARS-CoV-2 seroprevalence increased from 26.3% to 89.2% and 46.4% to 93.9% in Karonga and Lilongwe, respectively. At Survey 4, seroprevalence did not differ by COVID-19 vaccination status in adults, except for those aged 30+ in Karonga (unvaccinated:87.4%,95% credible interval 79.3-93.0%; 2 doses:98.1%,94.8-99.5%). Location and age were associated with seroconversion risk. Individuals with hybrid immunity had higher SARS-CoV-2 seropositivity and antibody titres, than those infected.
Conclusions
High SARS-CoV-2 seroprevalence combined with low morbidity and mortality indicate that universal vaccination is unnecessary at this stage of the pandemic, supporting change in national policy to target at-risk groups.

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Long-term Prognosis at 1.5 years after Infection with Wild-type strain of SARS-CoV-2 and Alpha, Delta, as well as Omicron Variants
Jane Agergaard, Jesper Damsgaard Gunst, Berit Schiøttz-Christensen, Lars Østergaard, Christian Wejse     Published:October 29, 2023DOI:https://doi.org/10.1016/j.ijid.2023.10.022
Highlights
Trajectory of long COVID in SARS-CoV-2 wild-type, Alpha, Delta, and Omicron
Similar patterns of symptoms and severity of long COVID across all four variants
No clinically significant decline in median severity up to 1.5 years after infection
More than 50% of long COVID patients failed to improve using any outcome measure
Patients infected with Omicron may experience severe non-improving long COVID
 
Abstract
Objectives
Knowledge is limited on how changing SARS-CoV-2 variants may translate into different characteristics and affect prognosis of patients with long COVID, especially following Omicron variants. We compared long-term prognosis of patients in a Danish Post COVID Clinic infected with wild-type strain, Alpha, Delta, or Omicron variants as well as the pre-Omicron compared to the Omicron period.
 
Methods
At enrollment a Post COVID symptom Questionnaire (PCQ), and standard health scores, were registered, and repeated four times until 1.5 years after infection. PCQ was the primary outcome to assess severity of long COVID, and delta PCQ to assess failure to improve.
Results
A total of 806 patients were enrolled. Patients infected with Omicron and Delta variants presented with more severe long COVID (median PCQ 43 in Delta vs 38 in wild-type, P=0.003) and health scores (EQ5D-index was 0.70 in Omicron vs 0.76 in wild-type, P=0.009 and 0.78 pre-Omicron, P=0.006). At 1.5 year after infection patients had no clinically meaningful decline in severity of long COVID, and 57% (245/429) of patients failed to improve 1.5 years after infection, with no differences between variants.
Conclusions
More than half of patients referred to a Post COVID Clinic failed to improve in long COVID severity 1.5 years after infection regardless of variants of SARS-CoV-2.

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 Medscape Medical News
Inside a Long COVID Clinic's Fight to Meet Crushing Patient NeedsSolarina Ho        November 17, 2023
Janna Friedly was thrilled, hopeful — and relieved — by the email that had landed in her inbox: After years of fighting an uphill battle to treat patients with long COVID, her Seattle clinic, one of the first and longest-running facilities in the US, was finally getting a much-needed financial boost from the US Department of Health and Human Services.
The multimillion-dollar grant, which came through in September, was going to help Friedly and her colleagues at the University of Washington's Post-COVID Rehabilitation and Recovery Care at Harborview Medical Center meet some of the crushing demands of long COVID care.
"This entire year has been really filled with patients that have been trying to get access to the clinic for a year. And they're still struggling," said Friedly, MD, MPH, chair of the Department of Rehabilitation Medicine at the University of Washington School of Medicine and executive director at Harborview.
The tremendous demand and backlog had prompted the clinic in January 2023 to severely limit referrals to King County and the university. It was a hard decision that meant the rest of Washington, Wyoming, Alaska, Montana and Idaho — the five-state "WWAMI" region the clinic served — lost access to critical post-COVID healthcare.
At Harborview, there is now hope. The grant money will allow Friedly and her colleagues to make meaningful headway on their ambitious goals. But they are also realistic about the formidable task ahead.
Their circumstances are hardly unique. Clinics across the country are facing daunting challenges — amid dire patient needs, insufficient funding from state and federal health agencies has led to significant hurdles in patient care, especially for vulnerable and underserved communities, according to interviews and surveys with more than a dozen long COVID clinics, doctors, advocates, and patients. At the same time, a lack of training and education on long COVID within the broader medical community is hurting patients.
The grant announcement of a million dollars a year for up to 5 years per clinic — awarded to nine established multidisciplinary centers across the US through the Agency for Healthcare Research and Quality (AHRQ) of HHS — provides considerable relief.
But how far can $5 million stretch, given that long COVID is so complex, the needs of patients are so great, and the resources clinics have to manage them are so limited?

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SARS-CoV-2 Reinfection is Preceded by Unique Biomarkers and Related to Initial Infection Timing and Severity: an N3C RECOVER EHR-Based Cohort Study View ORCID ProfileEmily Hadley,  View ORCID ProfileYun Jae Yoo,  View ORCID ProfileSaaya Patel,  View ORCID ProfileAndrea Zhou,  View ORCID ProfileBryan Laraway,  View ORCID ProfileRachel Wong,  View ORCID ProfileAlexander Preiss,  View ORCID ProfileRob Chew, Hannah Davis,  View ORCID ProfileChristopher G Chute,  View ORCID ProfileEmily R Pfaff,  View ORCID ProfileJohanna Loomba,  View ORCID ProfileMelissa Haendel,  View ORCID ProfileElaine Hill,  View ORCID ProfileRichard Moffitt, the N3C and RECOVER consortia the N3C and RECOVER consortia
doi: https://doi.org/10.1101/2023.01.03.22284042
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.    00001401819.
AbstractAlthough the COVID-19 pandemic has persisted for over 2 years, reinfections with SARS-CoV-2 are not well understood. We use the electronic health record (EHR)-based study cohort from the National COVID Cohort Collaborative (N3C) as part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative to characterize reinfection, understand development of Long COVID after reinfection, and compare severity of reinfection with initial infection. We validate previous findings of reinfection incidence (5.9%), the occurrence of most reinfections during the Omicron epoch, and evidence of multiple reinfections. We present novel findings that Long COVID diagnoses occur closer to the index date for infection or reinfection in the Omicron BA epoch. We report lower albumin levels leading up to reinfection and a statistically significant association of severity between first infection and reinfection (chi-squared value: 9446.2, p-value: 0) with a medium effect size (Cramer’s V: 0.18, DoF = 4).
 
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Complement dysregulation is a predictive and therapeutically amenable feature of long COVID
Kirsten Baillie, Helen E Davies, Samuel B K Keat, Kristin Ladell, Kelly L Miners, Samantha A Jones, Ermioni Mellou,  View ORCID ProfileErik J M Toonen,  View ORCID ProfileDavid A Price, B Paul Morgan, Wioleta M Zelek
doi: https://doi.org/10.1101/2023.10.26.23297597
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.     003040347
ABSTRACTBackground Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is a hallmark of acute COVID-19 but has not been investigated as a potential determinant of long COVID.
Methods We quantified a series of complement proteins, including markers of activation and regulation, in plasma samples from healthy convalescent individuals with a confirmed history of infection with SARS-CoV-2 and age/ethnicity/gender/infection/vaccine-matched patients with long COVID.
Findings Markers of classical (C1s-C1INH complex), alternative (Ba, iC3b), and terminal pathway (C5a, TCC) activation were significantly elevated in patients with long COVID. These markers in combination had a receiver operating characteristic predictive power of 0.794. Other complement proteins and regulators were also quantitatively different between healthy convalescent individuals and patients with long COVID. Generalized linear modeling further revealed that a clinically tractable combination of just four of these markers, namely the activation fragments iC3b, TCC, Ba, and C5a, had a predictive power of 0.785.
Conclusions These findings suggest that complement biomarkers could facilitate the diagnosis of long COVID and further suggest that currently available inhibitors of complement activation could be used to treat long COVID.
Funding This work was funded by the National Institute for Health Research (COV-LT2-0041), the PolyBio Research Foundation, and the UK Dementia Research Institute.

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Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Postacute Sequelae of SARS-CoV-2

• Phillip Joseph, MD, Inderjit Singh, MD,Rudolf Oliveira, MD, PhD,
• Kristine Madsen, MS,Aaron B. Waxman, MD, PhD,David M. Systrom, MD 

Published:April 11, 2023DOI:https://doi.org/10.1016/j.chest.2023.03.049
Topic ImportancePostacute sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from COVID-19. Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood.
Review FindingsEarly studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms.
SummaryThis review illustrates exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.

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Front. Neurosci., 26 June 2023      Sec. Autonomic Neuroscience
Volume 17 - 2023 | https://doi.org/10.3389/fnins.2023.1203514
Fatigue: Physiology and Pathology
Cognitive impairment in post-acute sequelae of COVID-19 and short duration myalgic encephalomyelitis patients is mediated by orthostatic hemodynamic changes
Heather Day1 Brayden Yellman2 Sarah Hammer2 Candace Rond2 Jennifer Bell2 Saeed Abbaszadeh2 Greg Stoddard1 Derya Unutmaz3 Lucinda Bateman2 Suzanne D. Vernon2*

• 1School of Medicine, The University of Utah, Salt Lake City, UT, United States
• 2Bateman Horne Center, Salt Lake City, UT, United States
• 3Jackson Laboratory for Genomic Medicine, School of Medicine, University of Connecticut, Farmington, CT, United States

Introduction: Cognitive impairment is experienced by people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of COVID-19 (PASC). Patients report difficulty remembering, concentrating, and making decisions. Our objective was to determine whether orthostatic hemodynamic changes were causally linked to cognitive impairment in these diseases.
Methods: This prospective, observational cohort study enrolled PASC, ME/CFS, and healthy controls. All participants underwent clinical evaluation and assessment that included brief cognitive testing before and after an orthostatic challenge. Cognitive testing measured cognitive efficiency which is defined as the speed and accuracy of subject’s total correct responses per minute. General linear mixed models were used to analyze hemodynamics and cognitive efficiency during the orthostatic challenge. Additionally, mediation analysis was used to determine if hemodynamic instability induced during the orthostatic challenge mediated the relationship between disease status and cognitive impairment.
Results: Of the 276 participants enrolled, 256 were included in this study (34 PASC, 71 < 4 year duration ME/CFS, 69 > 10 year ME/CFS duration, and 82 healthy controls). Compared to healthy controls, the disease cohorts had significantly lower cognitive efficiency scores immediately following the orthostatic challenge. Cognitive efficiency remained low for the >10 year ME/CFS 2 and 7 days after orthostatic challenge. Narrow pulse pressure less than 25% of systolic pressure occurred at 4 and 5 min into the orthostatic challenge for the PASC and ME/CFS cohorts, respectively. Abnormally narrow pulse pressure was associated with slowed information processing in PASC patients compared to healthy controls (−1.5, p = 0.04). Furthermore, increased heart rate during the orthostatic challenge was associated with a decreased procedural reaction time in PASC and < 4 year ME/CFS patients who were 40 to 65 years of age.
Discussion: For PASC patients, both their disease state and hemodynamic changes during orthostatic challenge were associated with slower reaction time and decreased response accuracy during cognitive testing. Reduced cognitive efficiency in <4 year ME/CFS patients was associated with higher heart rate in response to orthostatic stress. Hemodynamic changes did not correlate with cognitive impairment for >10 year ME/CFS patients, but cognitive impairment remained. These findings underscore the need for early diagnosis to mitigate direct hemodynamic and other physiological effects on symptoms of cognitive impairment.

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CONCISE REVIEW FOR CLINICIANS| VOLUME 98, ISSUE 10, P1544-1551, OCTOBER 2023
Diagnosis and Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Stephanie L. Grach, MD, MS Jaime Seltzer, MS Tony Y. Chon, MD Ravindra Ganesh, MD, MBBS         https://doi.org/10.1016/j.mayocp.2023.07.032
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic neurologic disease often preceded by infection. There has been increased interest in ME/CFS recently because of its significant overlap with the post-COVID syndrome (long COVID or post-acute sequelae of COVID), with several studies estimating that half of patients with post-COVID syndrome fulfill ME/CFS criteria. Our concise review describes a generalist approach to ME/CFS, including diagnosis, evaluation, and management strategies.

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Post-acute sequelae of SARS-CoV-2 (PASC) in nursing home residents: A retrospective cohort studySophie E. Clark MD, Liza Bautista MD, Karen Neeb MSN, CNP, Ana Montoya MD, MPH, Kristen E. Gibson MPH, Julia Mantey MPH, MUP, Mohammed Kabeto MS
First published: 10 November 2023  https://doi.org/10.1111/jgs.18678
Presentation: poster presentation at American Geriatric Society, Long Beach CA, May 2023.
AbstractBackgroundPost-acute sequelae of SARS-CoV-2 (PASC) describes a syndrome of physical and cognitive decline that persists after acute symptoms of infection resolve. Few studies have explored PASC among nursing home (NH) residents.
MethodsA retrospective cohort study was conducted at two NHs in Michigan. COVID-positive patients were identified from March 21, 2020 to October 26, 2021. The comparison group were patients who lived at the same NH but who were never infected during the study period. Minimum Data Set was used to examine trajectories of functional dependence (Activity of Daily Living [ADL] composite score) and cognitive function (Brief Interview for Mental Status [BIMS]). Linear mixed-effects models were constructed to estimate short-term change in function and cognition immediately following diagnosis and over time for an additional 12 months, compared to pre-COVID and non-COVID trajectories and adjusting for sex, age, and dementia status.
ResultsWe identified 171 residents (90 COVID-19 positive, 81 non-COVID) with 719 observations for our analyses. Cohort characteristics included: 108 (63%) ≥ 80 yrs.; 121 (71%) female; 160 (94%) non-Hispanic white; median of 3 comorbidities (IQR 2–4), with no significant differences in characteristics between groups. COVID-19 infection affected the trajectory of ADL recovery for the first 9 months following infection, characterized by an immediate post-infection decrease in functional status post-infection (−0.60 points, p = 0.002) followed by improvement toward the expected functional trajectory sans infection (0.04 points per month following infection, p = 0.271).ConclusionsNH residents experienced a significant functional decline that persisted for 9 months following acute infection. Further research is needed to determine whether increased rehabilitation services after COVID-19 may help mitigate this decline.

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Naltrexone 6 mg once daily versus placebo in woNaltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial: a randomised, double-blind, placebo-controlled trialKarin Due Bruun, MD ,Prof Robin Christensen, PhD,Prof Henrik Bjarke Vaegter, PhD,Morten Rune Blichfeldt-Eckhardt, PhD Lars Bye-Møllert al. 
https://doi.org/10.1016/S2665-9913(23)00278-3
SummaryBackgroundLow-dose naltrexone is used to treat fibromyalgia despite minimal evidence for its efficacy. This trial aimed to investigate whether 12-week treatment with 6 mg low-dose naltrexone was superior to placebo for reducing pain in women with fibromyalgia.
MethodsWe did a single-centre, randomised, double-blind, placebo-controlled trial in Denmark. We enrolled women aged 18–64 years who were diagnosed with fibromyalgia. Participants were randomly assigned 1:1 to receive low-dose naltrexone (6 mg) or an identical-appearing placebo, using a computerised algorithm with no stratifications applied. Participants, investigators, outcome assessors, and statistical analysts were all masked to treatment allocation. The primary outcome was change in pain intensity on an 11-point numeric rating scale from baseline to week 12, in the intention-to-treat population. Safety was assessed in participants in the intention-to-treat population who received at least one dose of their allocated intervention. This trial was registered with ClincalTrials.gov (NCT04270877) and EudraCT (2019-000702-30).
FindingsWe screened 158 participants for eligibility from Jan 6, 2021, to Dec 27, 2022, and 99 patients were randomly assigned to low-dose naltrexone (n=49) or placebo (n=50). The mean age was 50·6 years (SD 8·8), one (1%) of 99 participants was Arctic Asian and 98 (99%) were White. No participants were lost to follow-up. The mean change in pain intensity was –1·3 points (95% CI –1·7 to –0·8) in the low-dose naltrexone group and –0·9 (–1·4 to –0·5) in the placebo group, corresponding to a between-group difference of –0·34 (–0·95 to 0·27; p=0·27, Cohen's d 0·23). Discontinuations due to adverse events were four (8%) of 49 in the low-dose naltrexone group and three (6%) of 50 in the placebo group. 41 (84%) of 49 patients in the low-dose naltrexone group had an adverse event versus 43 (86%) of 50 in the placebo group. One serious adverse event occurred in the placebo group and no deaths occurred.
InterpretationThis study did not show that treatment with low-dose naltrexone was superior to placebo in relieving pain. Our results indicate that low-dose naltrexone might improve memory problems associated with fibromyalgia, and we suggest that future trials investigate this further.
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults: United States, 2021–2022
NCHS Data Brief No. 488, December 2023
Anjel Vahratian, Ph.D., M.P.H., Jin-Mann S. Lin, Ph.D., Jeanne Bertolli, Ph.D., M.P.H., and Elizabeth R. Unger, Ph.D., M.D.
Key findings
Data from the National Health Interview Survey

• In 2021–2022, 1.3% of adults had myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
• The percentage of adults who had ME/CFS increased with age through ages 60–69 and then declined among those age 70 and older.
• White non-Hispanic (1.5%) adults were more likely to have ME/CFS compared with Asian non-Hispanic (0.7%) and Hispanic (0.8%) adults.
• Adults with a family income less than 100% of the federal poverty level (2.0%) were more likely to have ME/CFS, followed by those at 100–199% (1.7%), and those at or above 200% (1.1%).
• The percentage of adults who had ME/CFS increased with increasing rurality of their place of residence.

 
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem illness characterized by activity-limiting fatigue, worsening of symptoms after activity, and other symptoms (1). It affects all age, sex, and racial and ethnic groups and costs the U.S. economy about $18–$51 billion annually (2–5). This report describes the percentage of adults who had ME/CFS at the time of interview by selected demographic and geographic characteristics based on data from the 2021–2022 National Health Interview Survey (NHIS).

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December 28, 2023  Post–COVID-19 Condition in Children 6 and 12 Months After Infection
Frederick Dun-Dery, PhD, MPhil1; Jianling Xie, MD, MPH2; Kathleen Winston, MSc3; et alBrett Burstein, MDCM, PhD, MPH4,5; Jocelyn Gravel, MD, MSc6; Jason Emsley, MSc, MD, PhD7; Vikram Sabhaney, MD8; Roger Zemek, MD9,10; Simon Berthelot, MD, MSc11; Darcy Beer, MD12; April Kam, MD, MScPH13; Gabrielle Freire, MDCM, MHSc14; Ahmed Mater, MD15; Robert Porter, MD, MSc16; Naveen Poonai, MD, MSc17,18,19; Anne Moffatt, MD20; Andrew Dixon, MD21; Marina I. Salvadori, MD22,23; Stephen B. Freedman, MDCM, MSc24; for the Pediatric Emergency Research Canada (PERC) COVID Study Group
JAMA Netw Open. 2023;6(12):e2349613. doi:10.1001/jamanetworkopen.2023.49613
Key Points
Question  What proportion of children meet the post–COVID-19 condition (PCC) symptom definition at 6 and 12 months following SARS-CoV-2 testing in pediatric emergency departments?
Findings  In this cohort study, at 6 and 12 months, a statistically greater number of children with SARS-CoV-2 positive tests compared with those with negative tests met the PCC symptom and quality of life change definition. However, the absolute risk differences were very small (0.42% and 0.51% at 6 and 12 months, respectively).
Meaning  Although there is an increased prevalence of symptoms consistent with the PCC definition that reduce quality of life among SARS-CoV-2 infected children, very few infected children develop PCC.
Abstract
Importance  There is a need to understand the long-term outcomes among children infected with SARS-CoV-2.
Objective  To quantify the prevalence of post–COVID-19 condition (PCC) among children tested for SARS-CoV-2 infection in pediatric emergency departments (EDs).
Design, Setting, and Participants  Multicenter, prospective cohort study at 14 Canadian tertiary pediatric EDs that are members of the Pediatric Emergency Research Canada network with 90-day, 6-month, and 12-month follow-up. Participants were children younger than 18 years who were tested for SARS-CoV-2 infection between August 2020 and February 2022. Data were analyzed from May to November 2023.
Exposure  The presence of SARS-CoV-2 infection at or within 14 days of the index ED visit.
Main Outcomes and Measures  Presence of symptoms and QoL reductions that meet the PCC definition. This includes any symptom with onset within 3 months of infection that is ongoing at the time of follow-up and affects everyday functioning. The outcome was quantified at 6 and 12 months following the index ED visit.
Results  Among the 5147 children at 6 months (1152 with SARS-CoV-2 positive tests and 3995 with negative tests) and 5563 children at 12 months (1192 with SARS-CoV-2 positive tests and 4371 with negative tests) who had sufficient data regarding the primary outcome to enable PCC classification, the median (IQR) age
was 2.0 (0.9-5.0) years, and 2956 of 5563 (53.1%) were male. At 6-month follow-up, symptoms and QoL changes consistent with the PCC definition were present in 6 of 1152 children with positive SARS-CoV-2 tests (0.52%) and 4 of 3995 children with negative SARS-CoV-2 tests (0.10%; absolute risk difference, 0.42%; 95% CI, 0.02% to 0.94%). The PCC definition was met at 12 months by 8 of 1192 children with positive SARS-CoV-2 tests (0.67%) and 7 of 4371 children with negative SARS-CoV-2 tests (0.16%; absolute risk difference, 0.51%; 95% CI, 0.06 to 1.08%). At 12 months, the median (IQR) PedsQL Generic Core Scale scores were 98.4 (90.0-100) among children with positive SARS-CoV-2 tests and 98.8 (91.7-100) among children with negative SARS-CoV-2 tests (difference, −0.3; 95% CI, −1.5 to 0.8; P = .56). Among the 8 children with SARS-CoV-2 positive tests and PCC at 12-month follow-up, children reported respiratory (7 of 8 patients [88%]), systemic (3 of 8 patients [38%]), and neurologic (1 of 8 patients [13%]) symptoms.
Conclusions and Relevance  In this cohort study of children tested for SARS-CoV-2 infection in Canadian pediatric EDs, although children infected with SARS-CoV-2 reported increased chronic symptoms, few of these children developed PCC, and overall QoL did not differ from children with negative SARS-CoV-2 tests.

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Long COVID: New Info on Who Is Most Likely to Get ItSolarina Ho  December 27, 2023   Medscape Medical news.
The COVID-10 pandemic may no longer be a global public health emergency, but millions continue to struggle with the aftermath: Long COVID. New research and clinical anecdotes suggest that certain individuals are more likely to be afflicted by the condition, nearly 4 years after the virus emerged. 
People with a history of allergies, anxiety or depression, arthritis, and autoimmune diseases and women are among those who appear more vulnerable to developing long COVID, said doctors who specialize in treating the condition.
Many patients with long COVID struggle with debilitating fatigue, brain fog, and cognitive impairment. The condition is also characterized by a catalog of other symptoms that may be difficult to recognize as long COVID, experts said. That's especially true when patients may not mention seemingly unrelated information, such as underlying health conditions that might make them more vulnerable. This makes screening for certain conditions and investigating every symptom especially important. 
The severity of a patient's initial infection is not the only determining factor for developing long COVID, experts said.
"Don't judge the person based on how sick they were initially," said Mark Bayley, MD, medical director of the Toronto Rehabilitation Institute at University Health Network and a professor with the Temerty Faculty of Medicine at the University of Toronto. "You have to evaluate every symptom as best you can to make sure you're not missing anything else." 
Someone who only had a bad cough or felt really unwell for just a few days and recovered but started feeling rotten again later — "that's the person that we are seeing for long COVID," said Bayley. 
While patients who become severely sick and require hospitalization have a higher risk of developing long COVID, this group size is small compared with the much larger number of people infected overall. As a result, despite the lower risk, those who only become mild to moderately sick make up the vast majority of patients in long COVID clinics. 
A small Northwestern Medicine study found that 41% of patients with long COVID never tested positive for COVID-19 but were found to have antibodies that indicated exposure to the virus. 
Doctors treating patients with long COVID should consider several risk factors, specialists said. They include:

• A history of asthma, eczema, or allergies
• Signs of autonomic nervous system dysfunction
• Preexisting immune system issues
• Chronic infections
• Diabetes
• Being slightly overweight
• A preexisting history of anxiety or depression
• Joint hypermobility (being "double-jointed" with pain and other symptoms)

L

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Long COVID in Nursing Home Residents Manifests as Functional DeclineEmily Harris
JAMA. 2024;331(1):15. doi:10.1001/jama.2023.24682
People living in nursing homes tended to need more help with activities of daily living, such as bathing and dressing, for months following infection with SARS-CoV-2 compared with their peers who were not infected, a retrospective cohort study found. Nursing home residents also experienced modest declines in cognition after COVID-19 infection.
The findings were based on data from 171 residents, most of whom were aged 80 years or older. About 94% of participants were White individuals. In addition, all participants had multiple comorbidities, with more than half living with dementia.
The nursing home residents who had COVID-19 experienced improvements in both their functional status and cognition within 1 year after their illness. Moreover, most residents were unvaccinated at the time of their diagnoses, which occurred between March 2020 and October 2021. The results might therefore reflect the highest rates of long COVID early in the pandemic before widespread vaccination, the researchers wrote in the Journal of the American Geriatrics Society.
Published Online: December 13, 2023. doi:10.1001/jama.2023.24682
 

Medical News in Brief
August 2, 2023
Orexin Agonist Effective but Not Safe in Narcolepsy Trial
Emily Harris
JAMA. Published online August 2, 2023. doi:10.1001/jama.2023.13621
A new treatment for narcolepsy improved people’s ability to stay awake and reduced their weekly episodes of cataplexy, or sudden muscle weakness, compared with placebo, according to results from an 8-week clinical trial that included 73 participants. Currently, people with narcolepsy manage their condition with multiple medications that often do not control all their symptoms.
All participants had narcolepsy type 1, a condition defined by cataplexy symptoms and loss of neurons that produce orexin—a neuropeptide also known as hypocretin that binds to receptors in the brain to help people stay awake and alert. The drug used in the study was an orexin agonist.
The trial was terminated, however, because 8 participants experienced drug-induced liver damage. “Despite the halt in the development of [the drug], there is a strong rationale to pursue the use of orexin agonists for the treatment of narcolepsy type 1 and perhaps other disorders of hypersomnolence or circadian dislocation,” the author of a linked editorial wrote in the New England Journal of Medicine.
Published Online: August 2, 2023. doi:10.1001/jama.2023.13621

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Front. Psychol., 27 February 2023
Sec. Neuropsychology
Volume 14 - 2023 | https://doi.org/10.3389/fpsyg.2023.1127193
The Conners Continuous Performance Test CPT3™: Is it a reliable marker to predict neurocognitive dysfunction in Myalgic encephalomyelitis/chronic fatigue syndrome
Judith Fernández-Quirós1,2* Marcos Lacasa-Cazcarra3 Jose Alegre-Martín1 Ramón Sanmartín-Sentañes1 Miriam Almirall1 Patricia Launois-Obregón1 Jesús Castro-Marrero1 Amanda Rodríguez-Urrutia2,4,5,6 Jose A. Navarro-Sanchis2,4 J. Antoni Ramos-Quiroga2,4,5,6

• 1Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Unit, Division of Rheumatology, Vall d’Hebron Hospital Research Institute Universitat Autònoma de Barcelona, Barcelona, Spain
• 2Department of Mental Health, Hospital Universitari Vall d’Hebron, Barcelona, Spain
• 3e-Health Center, Universitat Oberta de Catalunya, Barcelona, Spain
• 4Group of Psychiatry, Mental Health and Addictions, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
• 5Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain
• 6Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

Introduction: The main objective is to delimit the cognitive dysfunction associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in adult patients by applying the Continuous Performance Test (CPT3™). Additionally, provide empirical evidence on the usefulness of this computerized neuropsychological test to assess ME/CFS.
Method: The final sample (n = 225; 158 Patients/67 Healthy controls) were recruited in a Central Sensitization Syndromes (CSS) specialized unit in a tertiary hospital. All participants were administered this neuropsychological test.
Results: There were significant differences between ME/CFS and healthy controls in all the main measures of CPT3™. Mainly, patients had a worse indicator of inattentiveness, sustained attention, vigilance, impulsivity, slow reaction time, and more atypical T-scores, which is associated with a likelihood of having a disorder characterized by attention deficits, such as Attention Deficit Hyperactivity Disorder (ADHD). In addition, relevant correlations were obtained between the CPT3™ variables in the patient’s group. The most discriminative indicators of ME/CFS patients were Variability and Hit Reaction Time, both measures of response speed.
Conclusion: The CPT3™ is a helpful tool to discriminate neurocognitive impairments from attention and response speed in ME/CFS patients, and it could be used as a marker of ME/CFS severity for diagnosing or monitoring this disease.
Fernández-Quirós, ✉ [email protected]

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A Mixed Methods System for the Assessment of Post Exertional Malaise in Encephalomyelitis/Chronic Fatigue Syndrome
Barbara Stussman, Brice Calco, Gina Norato, Angelique Gavin, Snigdha Chigurupati, Avindra Nath, Brian Walitt      doi: https://doi.org/10.1101/2023.04.24.23288821This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
AbstractBackground A central feature of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is post exertional malaise (PEM), which is an acute worsening of symptoms
after a physical, emotional and/or mental exertion. PEM is also a feature of Long
COVID. Dynamic measures of PEM have historically included scaled questionnaires which have not been validated in ME/CFS. To enhance our understanding of PEM and how best to measure it, we conducted semi-structured qualitative interviews (QIs) at the same intervals as Visual Analog Scale (VAS) measures after a Cardiopulmonary Exercise Test (CPET).
Methods Ten ME/CFS and nine healthy volunteers participated in a CPET. For each participant, PEM symptom VAS (7 symptoms) and semi-structured QIs were administered at six timepoints over 72 hours before and after a single CPET. QI data were used to plot the severity of PEM at each time point and identify the self-described most bothersome symptom for each patient. QI data were used to determine the symptom trajectory and peak of PEM. Performance of QI and VAS data were compared to each other using Spearman correlations.
Results QIs documented that each ME/CFS volunteer had a unique PEM experience, with differences noted in the onset, severity, trajectory over time, and most bothersome symptom. No healthy volunteers experienced PEM. Scaled QI data were able to identify PEM peaks and trajectories, even when VAS scales were unable to do so due to known ceiling and floor effects. QI and VAS fatigue data corresponded well prior to exercise (baseline, r=0.7) but poorly at peak PEM (r=0.28) and with the change from baseline to peak (r=0.20). When the most bothersome symptom identified from QIs was used, these correlations improved (r=.0.77, 0.42. and 0.54 respectively) and reduced the observed VAS scale ceiling and floor effects.
Conclusion QIs were able to capture changes in PEM severity and symptom quality over time in all the ME/CFS volunteers, even when VAS scales failed to do so. Information collected from QIs also improved the performance of VAS. Measurement of PEM can be improved by using a quantitative-qualitative mixed model approach.
Disclaimer This research/work/investigator was supported (in part) by the Division of Intramural Research of the National Institutes of Health, NINDS. The content is solely the responsibility of the author(s) and does not necessarily represent the official views of the National Institutes of Health.
 
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Acute Encephalomyelitis in a 52-year-old Male Post Messenger Ribonucleic Acid Severe Acute Respiratory Syndrome Coronavirus 2  vaccination   - A Case Report
Pamela Lamisi Alebna; Muhammad Ahmad Shahid; Timothy Brannan; Ting Shen; Valentin Marian
J Med Case Reports. 2023;17(202) 
Abstract and IntroductionBackground: Acute disseminated encephalomyelitis is a well-known, but rare, side effect of some vaccines, or symptom following a febrile illness.
Case: A 69-year-old, otherwise healthy Hispanic male presented with acute fever, confusion, and later progressive weakness after receiving the first dose of the mRNA-1273 (Moderna) severe acute respiratory syndrome coronavirus 2 vaccine. Considering the progressive deterioration of the patient, despite being on multiple immunosuppressive agents, a brain biopsy was obtained, which revealed nonspecific meningoencephalitis.
Conclusion: In this case, we highlight the need for a regulatory framework to assist clinicians and patients with coverage of treatment for acute disseminated encephalomyelitis. The use of intravenous immunoglobulin in conjunction with glucocorticoids seems to be an effective treatment option.

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May 31, 2023

Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms
Joeffre Braga, BSc1,2,3; Mariel Lepra, BSc1,2,3; Stephen J. Kish, PhD1,2,3,4; et alPablo. M. Rusjan, PhD5,6; Zahra Nasser1; Natasha Verhoeff, BHSc1; Neil Vasdev, PhD1,2,4; Michael Bagby, PhD2,7; Isabelle Boileau, PhD1,2,3,4; M. Ishrat Husain, MBBS, MD1,2,3,4; Nathan Kolla, MD, PhD1,2,3,4,8; Armando Garcia, BSc1,2; Thomas Chao, PhD9; Romina Mizrahi, PhD5,6; Khunsa Faiz, MD10; Erica L. Vieira, PhD1,2; Jeffrey H. Meyer, MD, PhD1,2,3,4
JAMA Psychiatry. 2023;80(8):787-795. doi:10.1001/jamapsychiatry.2023.1321
Key Points
Question  Is translocator protein distribution volume (TSPO VT), an index of gliosis (an inflammatory change), measured by positron emission tomography, elevated in the brain after acute COVID-19 infection with sequelae of depressive and cognitive symptoms?
Findings  In this case-control study, TSPO VT was elevated in 20 participants with persistent depressive and cognitive symptoms after initially mild to moderate COVID-19 infection when compared with 20 healthy controls, more prominently in the ventral striatum and dorsal putamen. The TSPO VT in the dorsal putamen of COVID-19 cases negatively correlated with motor speed.
Meaning  These findings suggest that gliosis, especially in the ventral striatum and dorsal putamen, may reflect injury, ongoing inflammation, or both and provide directions for further therapeutic development.
Abstract
Importance  Persistent depressive symptoms, often accompanied by cognitive symptoms, commonly occur after COVID-19 illness (hereinafter termed COVID-DC, DC for depressive and/or cognitive symptoms). In patients with COVID-DC, gliosis, an inflammatory change, was suspected, but measurements of gliosis had not been studied in the brain for this condition.
Objective  To determine whether translocator protein total distribution volume (TSPO VT), a marker of gliosis that is quantifiable with positron emission tomography (PET), is elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of persons with COVID-DC.
Design, Setting, and Participants  This case-control study conducted at a tertiary care psychiatric hospital in Canada from April 1, 2021, to June 30, 2022, compared TSPO VT of specific brain regions in 20 participants with COVID-DC with that in 20 healthy controls. The TSPO VT was measured with fluorine F 18–labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) PET.
Main Outcomes and Measures  The TSPO VT was measured in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus. Symptoms were measured with neuropsychological and psychological tests, prioritizing outcomes related to striatal function.
Results  The study population included 40 participants (mean [SD] age, 32.9 [12.3] years). The TSPO VT across the regions of interest was greater in persons with COVID-DC (mean [SD] age, 32.7 [11.4] years; 12 [60%] women) compared with healthy control participants (mean [SD] age, 33.3 [13.9] years; 11 [55%] women): mean (SD) difference, 1.51 (4.47); 95% CI, 0.04-2.98; 1.51 divided by 9.20 (17%). The difference was most prominent in the ventral striatum (mean [SD] difference, 1.97 [4.88]; 95% CI, 0.36-3.58; 1.97 divided by 8.87 [22%]) and dorsal putamen (mean difference, 1.70 [4.25]; 95% CI, 0.34-3.06; 1.70 divided by 8.37 [20%]). Motor speed on the finger-tapping test negatively correlated with dorsal putamen TSPO VT (r, −0.53; 95% CI, −0.79 to −0.09), and the 10 persons with the slowest speed among those with COVID-DC had higher dorsal putamen TSPO VT than healthy persons by 2.3 (2.30 divided by 8.37 [27%]; SD, 2.46; 95% CI, 0.92-3.68).
Conclusions and Relevance  In this case-control study, TSPO VT was higher in patients with COVID-DC. Greater TSPO VT is evidence for an inflammatory change of elevated gliosis in the brain of an individual with COVID-DC. Gliosis may be consequent to inflammation, injury, or both, particularly in the ventral striatum and dorsal putamen, which may explain some persistent depressive and cognitive symptoms, including slowed motor speed, low motivation or energy, and anhedonia, after initially mild to moderate COVID-19 illness.
 
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Editorial  May 31, 2023
Does Microglial Activation Lead to Cognitive Changes After COVID-19 Infection?
Alexander Gerhard, MD1,2,3
JAMA Psychiatry. 2023;80(8):767. doi:10.1001/jamapsychiatry.2023.0664
One of the many issues we have yet to understand in relation to the COVID-19 pandemic is the mechanism by which the infection can cause long-lasting neuropsychiatric symptoms, particularly cognitive symptoms and depression as part of the postacute period, referred to as post–COVID-19 condition (also known as long COVID). Since as many as 20% of individuals might experience cognitive impairment 12 or more weeks following COVID-19 diagnosis,1 it is paramount to understand the underlying pathophysiology in order to develop potential therapeutic avenues. Microglial activation as part of the neuroinflammatory response of the brain can occur as an answer to a direct insult to the brain (this includes viral infection) but can also occur following respiratory inflammation and might play an important role in the development of cognitive problems after COVID-19 infection.2
Braga et al3 present elegant work on this matter. They have examined the in vivo neuroinflammatory changes in patients with persistent depressive and cognitive symptoms after COVID-19 infection using positron emission tomography (PET) and the ligand [18F]FEPPA for the translocator protein 18 kDa (TSPO), which is expressed by activated microglia as part of the neuroinflammatory response of the brain.
They found an increased expression of TSPO in patients with persistent neurocognitive symptoms after COVID-19 infection compared to healthy control individuals, especially in the ventral striatum and dorsal putamen. TSPO binding in the dorsal putamen of individuals with post–COVID-19 conditions negatively correlated with speed in motor tasks.
These findings indicate that microglial activation was associated with the development of neurocognitive symptoms after COVID-19 infection and the imaging technique the authors used has the advantage that it allows the imaging of this part of the neuroinflammatory process in vivo. The authors conclude that increased microglial activation in the ventral striatal and dorsal putamen reflects a possible mechanism to explain persistent depressive cognitive symptoms after COVID-19 infection.
The work by Braga et al3 has important pilot character, as it elucidates a possible mechanism behind neurocognitive symptoms after COVID-19 infection. One could speculate that suppression of microglial activation might lead to improvement of these symptoms. While this is an important piece in the jigsaw puzzle of neuroinflammation in chronic neurological disease, it is important to keep in mind that we still lack understanding of the complex picture for several reasons.
1.    Although the PET technique Braga and colleagues3 applied has been used with their own and other TSPO tracers for more than 25 years, particularly in the investigation of neurodegenerative disorders and their association with neuroinflammatory changes, it has a number of limitations—mainly the fact that the PET signal is particularly noisy and is not restricted to microglial cells.4,5
2.    TSPO expression is only one part of the complex neuroinflammatory response of the brain (however, it is the only one we can currently relatively reliably image in vivo in patients). Our PET techniques do not currently allow us to distinguish between different states of microglial activation.
3.    To target neuroinflammatory changes therapeutically, we will need a much more detailed understanding of microglial activation at different time points of neurological disorders. Not surprisingly, relatively simplistic attempts to suppress microglial activation have so far not resulted in clinical meaningful results.6
Future work aiming to understand the potential neuroinflammatory basis of cognitive symptoms and mood changes after COVID-19 infection will therefore need to concentrate on additional targets other than TSPO. Furthermore, longitudinal imaging (PET) studies should be carried out, allowing us to establish the correlation between the time course of central inflammatory changes and clinical parameters and, in turn, with peripheral inflammatory changes. Combining these lines of investigation might ultimately allow us to modulate neuroinflammatory changes after COVID-19 and other neuropsychiatric disorders in a way that is beneficial to patients.
Corresponding Author: Alexander Gerhard, MD, Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, 27 Palatine Rd, M20 3LJ Manchester, United Kingdom ([email protected]).
Published Online: May 31, 2023. doi:10.1001/jamapsychiatry.2023.0664

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Gene    Volume 877, 15 August 2023, 147568Research paper

A unique circular RNA expression pattern in the peripheral blood of myalgic encephalomyelitis/chronic fatigue syndrome patients
Yuning Cheng a, Si-Mei Xu a, Konii Takenaka a, Grace Lindner a, Ashton Curry-Hyde a, Michael Janitz a b
https://doi.org/10.1016/j.gene.2023.147568Get rights and content   
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with obscure aetiology. The underdiagnosis rate of ME/CFS is high due to the lack of diagnostic criteria based on objective markers. In recent years, circRNAs have emerged as potential genetic biomarkers for neurological diseases, including Parkinson’s disease and Alzheimer’s disease, making them likely to have the same prospect of being biomarkers in ME/CFS. However, despite the extensive amount of research that has been performed on the transcriptomes of ME/CFS patients, all of them are solely focused on linear RNAs, and the profiling of circRNAs in ME/CFS has been completely omitted. In this study, we investigated the expression profiles of circRNAs, comparing ME/CFS patients and controls before and after two sessions of cardiopulmonary exercise longitudinally.
In patients with ME/CFS, the number of detected circRNAs was higher compared to healthy controls, indicating potential differences in circRNA expression associated with the disease. Additionally, healthy controls showed an increase in the number of circRNAs following exercise testing, while no similar pattern was evident in ME/CFS patients, further highlighting physiological differences between the two groups. A lack of correlation was observed between differentially expressed circRNAs and their corresponding coding genes in terms of expression and function, suggesting the potential of circRNAs as independent biomarkers in ME/CFS. Specifically, 14 circRNAs were highly expressed in ME/CFS patients but absent in controls throughout the exercise study, indicating a unique molecular signature specific to ME/CFS patients and providing potential diagnostic biomarkers for the disease. Significant enrichment of protein and gene regulative pathways were detected in relation to five of these 14 circRNAs based on their predicted miRNA target genes. Overall, this is the first study to describe the circRNA expression profile in peripheral blood of ME/CFS patients, providing valuable insights into the molecular mechanisms underlying the disease.

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Journal of Translational Medicine (2023) 21:398 
https://doi.org/10.1186/s12967-023-04226-z REVIEW Open Access © The Author(s) 2023. 
Comparison of serum acylcarnitine levels in patients with myalgic encephalomyelitis/ chronic fatigue syndrome and healthy controls: a systematic review and meta-analysis 
Ryuhei Jinushi1,2,3,4* , Sakue Masuda2 , Yuki Tanisaka1 , Sho Nishiguchi3 , Kento Shionoya2 , Ryo Sato1 , Kei Sugimoto1 , Takahiro Shin1 , Rie Shiomi1 , Akashi Fujita1 , Masafumi Mizuide1 and Shomei Ryozawa1 
Abstract 
Background Myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease (ME/CFS/ SEID) is a condition diagnosed primarily based on clinical symptoms, including prolonged fatigue and post-exertional malaise; however, there is no specifc test for the disease. Additionally, diagnosis can be challenging since healthcare professionals may lack sufcient knowledge about the disease. Prior studies have shown that patients with ME/CFS/ SEID have low serum acylcarnitine levels, which may serve as a surrogate test for patients suspected of having this disease. This systematic review and meta-analysis aimed to investigate the diferences in serum acylcarnitine levels between patients with ME/CFS/SEID and healthy controls. 
Methods This systematic review was conducted using PubMed and Ichushi-Web databases. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, we included all studies from the databases’ inception until February 17, 2023, that evaluated blood tests in both patients with ME/CFS/SEID and healthy control groups. The primary endpoint was the diference in serum acylcarnitine levels between the two groups. 
Results The electronic search identifed 276 studies. Among them, seven met the eligibility criteria. The serum acylcarnitine levels were analyzed in 403 patients with ME/CFS/SEID. The patient group had signifcantly lower serum acylcarnitine levels when compared with the control group, and the statistical heterogeneity was high. 
Conclusion The patient group had signifcantly lower serum acylcarnitine levels when compared with the control group. In the future, the measurement of serum acylcarnitine levels, in addition to clinical symptoms, may prove to be a valuable diagnostic tool for this condition. 

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Suppressed immune and metabolic resBrain, Behavior, & Immunity - HealthVolume 30, July 2023, 100627
Responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome
Melanie Uhde a 1, Alyssa C. Indart a 1, Peter H.R. Green a c, Robert H. Yolken d, Dane B. Cook e, Sanjay K. Shukla f, Suzanne D. Vernon g, Armin Alaedini a b c h
https://doi.org/10.1016/j.bbih.2023.100627Get rights and content
Highlights·       •
Elevation of FABP2, a marker of intestinal cell damage in ME/CFS.
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Absence of optimal acute-phase LBP and sCD14 anti-microbial responses in ME/CFS.
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Compensatory but inadequate B cell response to microbial translocation in ME/CFS.
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Enhanced IL-10 regulatory response may drive the observed immunosuppression.
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Glucose and citrate metabolic dysfunction in ME/CFS may link the IL-10 activation and suppressed anti-microbial responses.
AbstractThe etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear. Relying on data from two independent pairs of ME/CFS and control cohorts, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium in ME/CFS. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.

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Cognitive impairments and mental health of patients with post-COVID-19: A cross-sectional study
Eva Morawa a 1, Johannes Krehbiel a b 1, Andrea Borho a, Regina Herold a, Marietta Lieb a, Caterina Schug a, Yesim Erim a b
https://doi.org/10.1016/j.jpsychores.2023.111441Get rights and content
Abstract
 
Background
Persistent cognitive complaints belong to the most frequent symptoms after COVID-19. This study explored the neuropsychological profile, mental health and risk factors for cognitive impairment in post-COVID-19 patients.
MethodsThe patients were recruited consecutively in the Post COVID Center of the University Hospital of Erlangen between 12/2022 and 05/2023. They underwent an extensive neuropsychological assessment including the Verbal Learning Memory Test (VLMT), the digit span backwards from the Wechsler Memory Scale-Revised (WMS-R), the Trail Making Test (TMT) Part A and B, the d2 Test of Attention and the Regensburger Verbal Fluency Test (RWT). For each cognitive domain we calculated the frequency of age-adjusted scores below the measure-specific norms. Depressive symptoms were measured with the Patient-Health-Questionnaire-9 (PHQ-9). Logistic regression analyses were computed.
ResultsIn 110 patients (mean age: 42.5 ± 11.9 years; 68.2% women), the most frequent cognitive deficits were observed for verbal fluency, working speed, delayed recall and attention. In almost every cognitive domain high education levels were associated with a decreased risk for cognitive impairment. Higher age was a risk factor for working speed and delayed recall and a protective factor for verbal fluency. Clinically relevant depressive symptoms were associated with an elevated risk for an impairment regarding some cognitive functions.
ConclusionCognitive dysfunctions were common among the post-COVID-19 patients. Differentiated exploration of cognitive impairments is crucial for a proper characterization of the post-COVID syndrome. In future research parameters of cognitive impairment should be correlated to alterations in biological markers of the disease like markers of immunological and microcirculation change.

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A Systematic Review of Persistent Clinical Features After SARS-CoV-2 in the Pediatric Population
Li Jiang, MD, MPH; Xuan Li, BSc; Jia Nie, MS; Kun Tang, Dphil; Zulfiqar A. Bhutta, PhD, FRS
Address correspondence to Zulfiqar A. Bhutta, PhD, FRS, 686 Bay St, 11th Floor, Suite 11.9731, Centre for Global Child Health, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada. E-mail: [email protected]
Pediatrics (2023) 152 (2): e2022060351. https://doi.org/10.1542/peds.2022-060351
CONTEXT
Long-term health effects after coronavirus disease 2019 (COVID-19) have been increasingly reported but their prevalence and significance in the pediatric population remains uncertain.
OBJECTIVE
To present the prevalence and characteristics of the long-term clinical features of COVID-19 (long COVID) in the global pediatric population.
DATA SOURCES
PubMed, Embase, Web of Science, Cochrane Library, WHO COVID-19 database, google scholar, medRxiv, bioRxiv, and multiple national public health databases.
STUDY SELECTION
Published articles and preprints from December, 2019 to December, 2022 investigating the epidemiology and characteristics of persistent clinical features at least 3 months after COVID-19 in children and adolescents (0–19 years old) were included.
DATA EXTRACTION
Study characteristics and detailed description of long COVID were extracted into a predefined form.
RESULTS
Twenty seven cohorts and 4 cross-sectional studies met the inclusion criteria and involved over 15 000 pediatric participants. A total of more than 20 persistent symptoms and clinical features were reported among children and adolescents. 16.2% (95% confidence interval 8.5% to 28.6%) of the pediatric participants experienced 1 or more persistent symptom(s) at least 3 months post COVID-19. Female gender might be associated with developing certain long COVID symptoms.
LIMITATIONS
Included studies presented with great heterogeneity because of significant variations in the definition of “long COVID,” follow up duration, and method. There could be nonresponse and other potential bias.
CONCLUSIONS
Persistent clinical features beyond 3 months among children and adolescents with proven COVID-19 are common and the symptom spectrum is wide. High-quality, prospective studies with proper controls are necessary in the future.

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WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome
Ping-yuan Wang, Jin Ma, Young-Chae Kim https://orcid.org/0000-0002-5130-4413, +10, and Paul M. Hwang 
Edited by Se-Jin Lee, University of Connecticut School of Medicine, Farmington, CT; received February 17, 2023; accepted June 27, 2023
August 14, 2023  120 (34) e2302738120  https://doi.org/10.1073/pnas.2302738120
SignificanceChronic fatigue is a debilitating symptom that affects many individuals, but its mechanism remains poorly understood. This study shows that endoplamic reticulum (ER) stress–induced WASF3 protein localizes to mitochondria and disrupts respiratory supercomplex assembly, leading to decreased oxygen consumption and exercise endurance. Alleviating ER stress decreases WASF3 and restores mitochondrial function, indicating that WASF3 can impair skeletal muscle bioenergetics and may be targetable for treating fatigue symptoms.
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging. A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies. We report that overexpression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress. Increased expression of WASF3 in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue. Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation. In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID.

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SCIENCE: 14 AUG 2023  3:15 PM      BY CATHERINE OFFORD
A protein that disrupts cells’ energy centers may be a culprit in chronic fatigue syndrome
New study offers clues as to how exhaustion could arise in people with ME/CFS—and potentially related conditions such as LongCovidCovidPeople living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) struggle not only with extreme exhaustion and the cognitive problems known as brain fog, but with a profound lack of information about what causes their symptoms and how to treat them. Scientists have yet to pin down the biology underlying the condition, which affects up to 2.5 million people in the United States alone, according to some estimates.Now, researchers have identified a protein that’s present at unusually high levels in the muscles of people with ME/CFS and that disrupts cells’ ability to generate energy. The findings, reported today in the Proceedings of the National Academy of Sciences, could point to new therapeutics for this condition and for illnesses that share similar characteristics, such as Long Covid.
Akiko Iwasaki, an immunobiologist at Yale School of Medicine who was not involved in the work, praises the research as “very well done” but cautions that the suspect protein is likely “a piece of the puzzle, as opposed to explaining the whole disease.” The findings suggest it could act as one of several “middlemen” between whatever sparks the illness and symptoms such as fatigue, she says.


Paul Hwang, a physician-scientist at the National Heart, Lung, and Blood Institute (NHLBI), and his colleagues initially set out to study a 38-year-old woman with a cancer-promoting mutation in a gene called TP53. Unlike her brother and her father, who shared this mutation, the woman (referred to as S1 in the study) was experiencing extreme long-term fatigue, though she hadn’t received a formal ME/CFS diagnosis.
Hwang’s team examined tissue samples from her muscle, looking for abnormalities in biochemical pathways related to TP53. That search revealed high levels of a protein called WASF3. It’s known to play a role in a cell’s ability to move, Hwang says, but the team found a little-cited 2011 study of gene activity in ME/CFS patients that predicted it might contribute to that condition, too.
The NHLBI researchers wondered whether WASF3 was interacting with mitochondria, cellular compartments responsible for energy generation that have been suggested to malfunction in people with ME/CFS and Long Covid. Sure enough, by changing levels of WASF3 inside cultured cells from S1 as well as in other human and mouse cells, the team found  the protein could disrupt mitochondrial function. Specifically, high levels of WASF3 interfered with the assembly of mitochondrial proteins into molecular complexes that support normal energy production.
Hwang’s group next genetically engineered mice to produce elevated amounts of WASF3. These animals also had defects in their mitochondrial function and were only able to run about half as far on a treadmill as regular mice.
Curious as to whether these results might be relevant to people formally diagnosed with ME/CFS, the researchers compared muscle samples from 14 people living with the illness with those of 10 healthy individuals. They found higher average levels of WASF3—and lower levels of the associated mitochondrial protein complexes—in people with the condition.
“It’s extremely encouraging” to see this kind of detailed molecular approach applied to an understudied illness like ME/CFS, says Mady Hornig, a physician-scientist studying the condition at the Columbia University Mailman School of Public Health. Although the NHLBI researchers didn’t study Long Covid directly, their findings “stand to address a very common set of health issues that are very tightly tied to disability in [both] Long Covid and ME/CFS,” she says.
Hornig, who has had Long Covid since 2020, adds that further work could try to address whether WASF3 also affects brain function. Deficits in brain energy metabolism may explain the cognitive fatigue that many ME/CFS patients find most debilitating, she says.
It’s not clear what causes high WASF3 levels in the first place. Hwang suggests a role for endoplasmic reticulum (ER) stress—a dysfunction of membranes that help the cell fold up its proteins. Viruses can trigger ER stress, perhaps explaining why ME/CFS and related conditions often arise after infection. (S1 told Hwang her fatigue started after she caught mononucleosis as a teenager.)
Several of the lab’s experiments support Hwang’s proposal: Both S1 and the people with ME/CFS had biochemical signatures of ER stress in their muscles, and treating S1’s cells in a dish with a drug that blocks ER stress lowered WASF3 levels and restored mitochondrial function. On the flipside, using toxins to artificially induce ER stress in cultured cells or in mice caused a rise in WASF3 levels, Hwang says.  
But more work is needed to understand this link, says Pere Puigserver, a cell biologist at Harvard Medical School. ER stress can itself be prompted by mitochondrial dysfunction, making it hard to pin down the order of events leading to fatigue, he says. WASF3’s multiple cellular roles mean it might have other effects in people with ME/CFS, too, he adds.
Hwang acknowledges there are likely to be other pathways causing fatigue in ME/CFS and Long Covid, and that the drivers of illness might be different for different people. His group is now looking at drugs that could put the brakes on ER stress or reduce WASF3’s effects on mitochondria, with an eye toward designing a clinical study.


doi: 10.1126/science.adk3119
 
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November 2023; 10 (6)
SARS-CoV-2–Specific Immune Responses in Patients With Postviral Syndrome After Suspected COVID-19
Zachary S. Orban, Lavanya Visvabharathy, Gina S. Perez Giraldo, Millenia Jimenez,  View ORCID ProfileIgor J. Koralnik
First published August 23, 2023, 
DOI: https://doi.org/10.1212/NXI.0000000000200159
 
AbstractBackground and Objectives Millions of Americans were exposed to SARS-CoV-2 early in the pandemic but could not get diagnosed with COVID-19 due to testing limitations. Many have developed a postviral syndrome (PVS) including neurologic manifestations similar to those with postacute sequelae of SARS-CoV-2 infection (Neuro-PASC). Owing to those circumstances, proof of SARS-CoV-2 infection was not required for evaluation at Northwestern Medicine's Neuro COVID-19 clinic. We sought to investigate clinical and immunologic findings suggestive of SARS-CoV-2 exposure in patients with PVS.
Methods We measured SARS-CoV-2–specific humoral and cell-mediated immune responses against Nucleocapsid and Spike proteins in 29 patients with PVS after suspected COVID-19, 32 confirmed age-matched/sex-matched Neuro-PASC (NP) patients, and 18 unexposed healthy controls. Neurologic symptoms and signs, comorbidities, quality of life, and cognitive testing data collected during clinic visits were studied retrospectively.
Results Of 29 patients with PVS, 12 (41%) had detectable humoral or cellular immune responses consistent with prior exposure to SARS-CoV-2. Of 12 PVS responders (PVS+), 75% harbored anti-Nucleocapsid and 50% harbored anti-Spike responses. Patients with PVS+ had similar neurologic symptoms as patients with NP, but clinic evaluation occurred 5.3 months later from the time of symptom onset (10.7 vs 5.4 months; p = 0.0006). Patients with PVS+ and NP had similar subjective impairments in quality of life measures including cognitive function and fatigue. Patients with PVS+ had similar results in objective cognitive measures of processing speed, attention, and executive function and better results in working memory than patients with NP.
Discussion Antibody and T-cell assays showed evidence of prior SARS-CoV-2 exposure in approximately 40% of the PVS group. Three-quarters of patients with PVS+ had detectable anti-Nucleocapsid and one-half anti-Spike responses, highlighting the importance of multitargeted COVID-19 immunologic evaluation and the limitations of commercially available diagnostic tests. Despite their persistent symptoms, lack of COVID-19 diagnosis likely delayed clinical care in patients with PVS. Our data suggest that millions of Americans presenting with PVS resembling Neuro-PASC were indeed exposed to SARS-CoV-2 at the beginning of the pandemic, and they deserve the same access to care and inclusion in research studies as patients with NP with confirmed COVID-19 diagnosis.

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Volume 9, Issue 5, May 2023, e15595
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A preliminary survey among patients in Switzerland
Rea Tschopp a c d, Rahel S. König b, Protazy Rejmer e, Daniel H. Paris a c
https://doi.org/10.1016/j.heliyon.2023.e15595Get rights and content
AbstractMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multi-factorial systemic chronic debilitating disease of poorly understood etiology and limited systematic evidence. The questionnaire and interview-based survey included 169 ME/CFS patients from the Swiss ME/CFS association. The majority of patients were females (72.2%), single (55.7%) and without children (62.5%). Only one third were working (full/part-time). The mean onset of ME/CFS was 31.6 years of age with 15% of patients being symptomatic before their 18th birthday. In this cohort, patients had documented ME/CFS for a mean 13.7 years, whereby half (50.3%) stated their condition was progressively worsening. Triggering events and times of disease onset were recalled by 90% of the participants. An infectious disease was associated with a singular or part of multiple events by 72.9% and 80.6%, respectively. Prior to disease onset, a third of the patients reported respiratory infections; followed by gastro-intestinal infections (15.4%) and tick-borne diseases (16.2%). Viral infections were recalled by 77.8% of the respondents, with Epstein Barr Virus being the most commonly reported agent. Patients self-reported an average number of 13 different symptoms, all described specific triggers of symptoms exacerbation and 82.2% suffered from co-morbidities. This study collated clinically relevant information on ME/CFS patients in Switzerland, highlighting the extent of disease severity, the associated factors negatively affecting daily life activities and work status as well as potential socio-economic impact.

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ARTICLES| VOLUME 62, 102086, AUGUST 2023
The effects of COVID-19 on cognitive performance in a community-based cohort: a COVID symptom study biobank prospective cohort study
Nathan J. Cheetham,Rose Penfold,Valentina Giunchiglia,Vicky Bowyer,Carole H. Sudre, L Canas et al
Published:July 21, 2023DOI:https://doi.org/10.1016/j.eclinm.2023.102086
SummaryBackgroundCognitive impairment has been reported after many types of infection, including SARS-CoV-2. Whether deficits following SARS-CoV-2 improve over time is unclear. Studies to date have focused on hospitalised individuals with up to a year follow-up. The presence, magnitude, persistence and correlations of effects in community-based cases remain relatively unexplored.
MethodsCognitive performance (working memory, attention, reasoning, motor control) was assessed in a prospective cohort study of participants from the United Kingdom COVID Symptom Study Biobank between July 12, 2021 and August 27, 2021 (Round 1), and between April 28, 2022 and June 21, 2022 (Round 2). Participants, recruited from the COVID Symptom Study smartphone app, comprised individuals with and without SARS-CoV-2 infection and varying symptom duration. Effects of COVID-19 exposures on cognitive accuracy and reaction time scores were estimated using multivariable ordinary least squares linear regression models weighted for inverse probability of participation, adjusting for potential confounders and mediators. The role of ongoing symptoms after COVID-19 infection was examined stratifying for self-perceived recovery. Longitudinal analysis assessed change in cognitive performance between rounds.
Findings3335 individuals completed Round 1, of whom 1768 also completed Round 2. At Round 1, individuals with previous positive SARS-CoV-2 tests had lower cognitive accuracy (N = 1737, β = −0.14 standard deviations, SDs, 95% confidence intervals, CI: −0.21, −0.07) than negative controls. Deficits were largest for positive individuals with ≥12 weeks of symptoms (N = 495, β = −0.22 SDs, 95% CI: −0.35, −0.09). Effects were comparable to hospital presentation during illness (N = 281, β = −0.31 SDs, 95% CI: −0.44, −0.18), and 10 years age difference (60–70 years vs. 50–60 years, β = −0.21 SDs, 95% CI: −0.30, −0.13) in the whole study population. Stratification by self-reported recovery revealed that deficits were only detectable in SARS-CoV-2 positive individuals who did not feel recovered from COVID-19, whereas individuals who reported full recovery showed no deficits. Longitudinal analysis showed no evidence of cognitive change over time, suggesting that cognitive deficits for affected individuals persisted at almost 2 years since initial infection.
InterpretationCognitive deficits following SARS-CoV-2 infection were detectable nearly two years post infection, and largest for individuals with longer symptom durations, ongoing symptoms, and/or more severe infection. However, no such deficits were detected in individuals who reported full recovery from COVID-19. Further work is needed to monitor and develop understanding of recovery mechanisms for those with ongoing symptoms.

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Published: 08 June 2023   The relevance of pacing strategies in managing symptoms of post-COVID-19 syndrome
Alaa Ghali, Valentin Lacombe, Camille Ravaiau, Estelle Delattre, Maria Ghali, Geoffrey Urbanski & Christian Lavigne 
Journal of Translational Medicine volume 21, article number: 375 (2023)  
AbstractBackgroundPost-COVID-19 syndrome (PCS) shares many features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). PCS represents a major health issue worldwide because it severely impacts patients’ work activities and their quality of life. In the absence of treatment for both conditions and given the beneficial effect of pacing strategies in ME/CFS, we conducted this study to assess the effectiveness of pacing in PCS patients.
MethodsWe retrospectively included patients meeting the World Health Organization definition of PCS who attended the Internal Medicine Department of Angers University Hospital, France between June 2020 and June 2022, and were followed up until December 2022. Pacing strategies were systematically proposed for all patients. Their medical records were reviewed and data related to baseline and follow-up assessments were collected. This included epidemiological characteristics, COVID-19 symptoms and associated conditions, fatigue features, perceived health status, employment activity, and the degree of pacing adherence assessed by the engagement in pacing subscale (EPS). Recovery was defined as the ability to return to work, and improvement was regarded as the reduction of the number and severity of symptoms.
ResultsA total of 86 patients were included and followed-up for a median time of 10 [6–13] months. Recovery and improvement rates were 33.7% and 23.3%, respectively. The EPS score was the only variable significantly associated with recovery on multivariate analysis (OR 40.43 [95% CI 6.22–262.6], p < 0.001). Patients who better adhered to pacing (high EPS scores) experienced significantly higher recovery and improvement rates (60–33.3% respectively) than those with low (5.5–5.5% respectively), or moderate (4.3–17.4% respectively) scores.
ConclusionOur findings demonstrated that pacing is effective in the management of patients with PCS, and that high levels of adherence to pacing are associated with better outcomes.

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ORIGINAL RESEARCH articleFront. Pediatr., 12 May 2023.Sec. Children and Health
Volume 11 - 2023 | https://doi.org/10.3389/fped.2023.1169447
Comparison of a 20 degree and 70 degree tilt test in adolescent myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients
C. (Linda) M. C. van Campen1* Peter C. Rowe2 Frans C. Visser1
Stichting CardioZorg, Hoofddorp, Netherlands    Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Introduction: During a standard 70-degree head-up tilt test, 90% of adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develop an abnormal reduction in cerebral blood flow (CBF). A 70-degree test might not be tolerated by young ME/CFS patients because of the high incidence of syncopal spells. This study examined whether a test at 20 degrees would be sufficient to provoke important reductions in CBF in young ME/CFS patients.
Methods: We analyzed 83 studies of adolescent ME/CFS patients. We assessed CBF using extracranial Doppler measurements of the internal carotid and vertebral arteries supine and during the tilt. We studied 42 adolescents during a 20 degree and 41 during a 70 degree test.
Results: At 20 degrees, no patients developed postural orthostatic tachycardia (POTS), compared to 32% at 70 degrees (p = 0.0002). The CBF reduction during the 20 degree tilt of −27(6)% was slightly less than during the reduction during a 70 degree test [−31(7)%; p = 0.003]. Seventeen adolescents had CBF measurements at both 20 and 70 degrees. The CBF reduction in these patients with both a 20 and 70 degrees test was significantly larger at 70 degrees than at 20 degrees (p < 0.0001).
Conclusions: A 20 degree tilt in young ME/CFS patients resulted in a CBF reduction comparable to that in adult patients during a 70 degree test. The lower tilt angle provoked less POTS, emphasizing the importance of using the 70 degree angle for that diagnosis. Further study is needed to explore whether CBF measurements during tilt provide an improved standard for classifying orthostatic intolerance.
 
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One in Five Doctors With Long COVID Can No Longer Work: Survey
Claire Sibonney  August 31, 2023
 
Crippling symptoms, lost careers, and eroded incomes: This is the harsh reality for doctors suffering with long COVID, according to the first major survey of physicians with the condition.
The survey, conducted by the British Medical Association (BMA) and the Long COVID Doctors for Action support group, sheds light on the lingering effects of long COVID on more than 600 chronically ill and disabled doctors with the condition. It also spotlights what they describe as a lack of medical and financial support from their government and employers at the National Health Service (NHS).
"We feel betrayed and abandoned," said Kelly Fearnley, MBChB, chair and co-founder of Long COVID Doctors for Action. "At a time of national crisis, when healthcare workers were asked to step up, we did. When the nation needed us, we stepped up. We put our lives on the line. We put our families' lives on the line. And now that we are injured after knowingly being unprotected and deliberately and repeatedly exposed to a level-three biohazard, we now find ourselves in this position."
Fearnley fell ill while working in a hospital's COVID ward in November 2020. She is one of an estimated two million people in the UK — including thousands of NHS employees — with long COVID. She hasn't been able to return to work in nearly 3 years.
Long COVID affects more than 65 million people worldwide. It is estimated that 1 in 10 people infected with the virus develop long-term symptoms. In the UK, healthcare and social care workers are seven times more likely to have had severe COVID-19 than other types of employees.
Doctors responding to the BMA survey reported a wide range of long COVID symptoms, including fatigue, headaches, muscular pain, nerve damage, joint pain, and respiratory problems.
Among the survey's key findings, 60% of doctors said long COVID has affected their ability to carry out day-to-day tasks on a regular basis. Almost 1 in 5 (18%) said they were no longer able to work, while fewer than 1 in 3 (31%) were working full time. This compares to more than half (57%) of respondents working full time before the onset of their COVID illness — a decline of 46%.
Nearly half (48%) of respondents said they have experienced some form of loss of earnings as a result of long COVID, and almost half of the doctors were never referred to an NHS long COVID clinic. The survey included the following first-person accounts from doctors living with the condition.

• One doctor said: "I nearly lost my life, my home, my partner and my career. I have received little support to help keep these. The impact on my mental health nearly cost [me] my life again."
• A senior consulting physician commented: "Life is absolutely miserable. Every day is a struggle. I wake up exhausted, the insomnia and night terrors are horrendous as I live through my worst fears every night. Any activity such as eating meals, washing etc will mean I have to go to bed for a few hours. I am unable to look after myself or my child, exercise or maintain social relationships. I have no financial security. Long COVID has totally destroyed my life."
• A salaried general practitioner said: "I can no longer work, finances are ruined. I didn't have employment protection so am now unemployed and penniless."

• Calls for action from the BMA include the following: Financial support for doctors and healthcare staff with long COVID;
• The recognition of long COVID as an occupational disease among healthcare workers, along with a definition of the condition that covers all of the debilitating disease's symptoms;
• Improved access to physical and mental health services to help comprehensive assessment, investigations, and treatment;
• Greater workplace protection for healthcare staff who risk their lives for others;
• Better support for long COVID sufferers to return to work safely if they can, including a flexible approach to the use of workplace adjustments.

"One would think, given the circumstances under which we fell ill and current workforce shortages, NHS employers would be eager to do everything to facilitate the return to work of people with long COVID," said Fearnley. "However, NHS employers are legally required to implement only 'reasonable adjustments,' and so things such as extended phased return or adjustments to shift patterns are not always being facilitated. Instead, an increasing number of employers are choosing to terminate contracts."
Raymond Agius, the BMA's occupational medicine committee co-chair, also put the blame on inadequate safety measures for doctors. Those inadequte measures persist to this day, inasmuch as UK hospitals have dropped masking requirements.
"During the COVID-19 pandemic, doctors were left exposed and unprotected at work," he said in a BMA press release. "They often did not have access to the right PPE.... Too many risk assessments of workplaces and especially of vulnerable doctors were not undertaken."
 
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Developing a Blood Cell-Based Diagnostic Test for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Peripheral Blood Mononuclear Cells
Jiabao Xu, Tiffany Lodge, Caroline Kingdon, James W. L. Strong, John Maclennan, Eliana Lacerda, Slawomir Kujawski, Pawel Zalewski, Wei E. Huang, Karl J. Morten
First published: 31 August 2023    https://doi.org/10.1002/advs.202302146
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by debilitating fatigue that profoundly impacts patients' lives. Diagnosis of ME/CFS remains challenging, with most patients relying on self-report, questionnaires, and subjective measures to receive a diagnosis, and many never receiving a clear diagnosis at all. In this study, a single-cell Raman platform and artificial intelligence are utilized to analyze blood cells from 98 human subjects, including 61 ME/CFS patients of varying disease severity and 37 healthy and disease controls. These results demonstrate that Raman profiles of blood cells can distinguish between healthy individuals, disease controls, and ME/CFS patients with high accuracy (91%), and can further differentiate between mild, moderate, and severe ME/CFS patients (84%). Additionally, specific Raman peaks that correlate with ME/CFS phenotypes and have the potential to provide insights into biological changes and support the development of new therapeutics are identified. This study presents a promising approach for aiding in the diagnosis and management of ME/CFS and can be extended to other unexplained chronic diseases such as long COVID and post-treatment Lyme disease syndrome, which share many of the same symptoms as ME/CFS.

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Research Letter  September 18, 2023
Post–COVID-19 Condition in Children
Lyndsey M. Hahn, PhD1,2; Emilie Manny, PhD1,2; Fabiana Mamede, PhD1; et alGurvinder Dhaliwal, BSc1,2; Joyce Chikuma, MSc1,2; Joan L. Robinson, MD1,2; Piush J. Mandhane, MD, PhD1,2
JAMA Pediatr. Published online September 18, 2023. doi:10.1001/jamapediatrics.2023.3239
Understanding of post–COVID-19 condition (PCC, or long COVID) in children remains limited, as studies vary in defining PCC and including limited prospective data before SARS-CoV-2 infection.1-3 The World Health Organization (WHO) defines PCC as “continuation or development of new symptoms 3 months after the
initial SARS-CoV-2 infection, with symptoms lasting for at least 2 months with no other explanation.”4 Symptoms must affect everyday functioning. Recent data suggest that PCC prevalence in children ranges from 1% to 70% in different study samples.1,5,6 We examined the incidence of PCC among school-aged children using a population-based sample that was recruited before SARS-CoV-2 infection. We hypothesized that children with more frequently reported symptoms before COVID-19 were likely to develop PCC.
Methods
Parents and children (aged 8-13 years) in Alberta, Canada, were recruited from the community between August 14, 2020, and March 12, 2021, and provided written consent or assented to participate in a longitudinal SARS-CoV-2 serological study. Baseline characteristics of the participants are described in the eTable in Supplement 1. The University of Alberta Research Ethics Board approved this cohort study, including the written consent and assent of participants. We followed the STROBE reporting guideline.
Parents prospectively reported their child’s symptoms every 2 weeks throughout the study duration (76 weeks). A child was considered to have PCC if any of the following was reported: a positive polymerase chain reaction (PCR) test result for SARS-CoV-2 infection, new symptoms that started within 3 months following a positive PCR result for COVID-19, and these symptoms persisting for a minimum of 8 weeks (4 reporting periods). Symptoms were considered resolved if children had a minimum of 4 weeks (2 reporting periods) without symptoms (weeks can be nonconsecutive). Kaplan-Meier survival analyses and Cox proportional hazards regression model were used to examine the association between symptoms before COVID-19 and time to resolution of symptoms after COVID-19. Multiple variable analysis also examined the implications of current or past health conditions reported at baseline for time to symptoms resolution. Children with COVID-19 before study recruitment were excluded from the survival analysis.
Two-sided P < .05 indicated statistical significance. Data analysis was performed with Stata 17.0 (StataCorp LLC).
Results
Of the 1026 children recruited, 513 were females (50.0%) and 511 were males (49.8%) at birth, with a mean (SD) age of 10.5 (2.1) years. Only 1 child (1/271 [0.4%]), after exclusions, met the WHO PCC definition (Figure 1). Symptoms had resolved for this child during the last 2 weeks of follow-up (final reporting period; 14 weeks’ postinfection follow-up).
Children were 77% less likely to have symptoms resolution after COVID-19 (hazard ratio [HR], 0.23; 95% CI, 0.08-0.60; P < .05) if they had symptoms reported every 2 weeks prior to infection. The most common post–COVID-19 symptoms included rhinitis (62%), sore throat (68%), headache (52%), cough (42%), fever (41%), and fatigue (35%). Each of these symptoms resolved within 10 weeks following a positive PCR test result (Figure 2). The more frequent presence of rhinitis (HR, 0.08; 95% CI, 0.01-0.42; P < .01), sore throat (HR, 0.08; 95% CI, 0.01-0.53; P < .05), headache (HR, 0.05; 95% CI, 0.01-0.27; P < .001), cough (HR, 0.00; 95% CI, 0.00-0.02; P < .001), fever (HR, 0.01; 95% CI, 0.00-0.13; P < .01), and fatigue (HR, 0.00; 95% CI, 0.00-0.09; P < .001) before COVID-19 infection was significantly associated with delayed resolution of each symptom after COVID-19. Neither current nor past health conditions were associated with symptoms after COVID-19.
Discussion
The incidence of PCC in this study was strikingly low (0.4%). Most children experienced a resolution of symptoms within 2 weeks of infection. Pre–COVID-19 symptoms were factors in post–COVID-19 symptoms.
Strengths of this study include use of pre–COVID-19 symptom data and longitudinal prospective collection of post–COVID-19 symptoms. Limitations include depending on parent-proxy symptom reporting and the narrow age range of participants. Additional research is required into the neurobehavioral sequelae of SARS-CoV-2 infection in school-aged children.
Accepted for Publication: June 22, 2023.
Published Online: September 18, 2023. doi:10.1001/jamapediatrics.2023.3239


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September 6, 2023
Some People Still Have Long COVID Symptoms After 2 Years
Emily Harris   JAMA. 2023;330(12):1127. doi:10.1001/jama.2023.16677
Although many symptoms of post–COVID-19 condition, or long COVID, resolve or improve with time, some people continue to experience symptoms after 2 years, according to a large study of US health care databases. Moreover, patients who were hospitalized with COVID-19 are more likely to have symptoms beyond year 2.
Out of an array of 80 prespecified postacute sequelae of COVID-19 across different organ systems, 65% of these symptoms remained elevated among hospitalized patients and 31% remained elevated among outpatients at year 2, the researchers reported in Nature Medicine.
The analysis used data from nearly 140 000 patients in the Veterans Health Administration databases who had been infected with SARS-CoV-2 and nearly 6 million patients who were not infected.
Published Online: September 6, 2023. doi:10.1001/jama.2023.16677

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Version 1. medRxiv. Preprint. 2023 Jul 31.
doi: 10.1101/2023.07.27.23293177  PMCID: PMC10418298  PMID: 37577714
This is a preprint.  It has not yet been peer reviewed by a journal.
Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to 2 Years Following COVID-19
Michael J. Peluso,1,* Dylan Ryder,2,* Robert Flavell,3,* Yingbing Wang,3 Jelena Levi,4 Brian H. LaFranchi,2 Tyler-Marie Deveau,2 Amanda M. Buck,2 Sadie E. Munter,2 Kofi A. Asare,2 Maya Aslam,3 Wally Koch,3 Gyula Szabo,5 Rebecca Hoh,1 Monika Deswal,1 Antonio Rodriguez,1 Melissa Buitrago,1 Viva Tai,1 Uttam Shrestha,3 Scott Lu,6 Sarah A. Goldberg,6 Thomas Dalhuisen,6 Matthew S. Durstenfeld,7 Priscilla Y. Hsue,7 J. Daniel Kelly,6 Nitasha Kumar,1 Jeffrey N. Martin,6 Aruna Gambir,4 Ma Somsouk,8 Youngho Seo,3 Steven G. Deeks,1 Zoltan G. Laszik,5 Henry F. VanBrocklin,3,^ and Timothy J. Henrich2,^
Abstract
The etiologic mechanisms of post-acute medical morbidities and unexplained symptoms (Long COVID) following SARS-CoV-2 infection are incompletely understood. There is growing evidence that viral persistence and immune dysregulation may play a major role. We performed whole-body positron emission tomography (PET) imaging in a cohort of 24 participants at time points ranging from 27 to 910 days following acute SARS-CoV-2 infection using a novel radiopharmaceutical agent, [18F]F-AraG, a highly selective tracer that allows for anatomical quantitation of activated T lymphocytes. Tracer uptake in the post-acute COVID group, which included those with and without Long COVID symptoms, was significantly higher compared to pre-pandemic controls in many anatomical regions, including the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. Although T cell activation tended to be higher in participants imaged closer to the time of the acute illness, tracer uptake was increased in participants imaged up to 2.5 years following SARS-CoV-2 infection. We observed that T cell activation in spinal cord and gut wall was associated with the presence of Long COVID symptoms. In addition, tracer uptake in lung tissue was higher in those with persistent pulmonary symptoms. Notably, increased T cell activation in these tissues was also observed in many individuals without Long COVID. Given the high [18F]F-AraG uptake detected in the gut, we obtained colorectal tissue for in situ hybridization SARS-CoV-2 RNA and immunohistochemical studies in a subset of participants with Long COVID symptoms. We identified cellular SARS-CoV-2 RNA in rectosigmoid lamina propria tissue in all these participants, ranging from 158 to 676 days following initial COVID-19 illness, suggesting that tissue viral persistence could be associated with long-term immunological perturbations.
Keywords: COVID-19, SARS-CoV-2, post-acute sequelae of SARS-CoV-2 (PASC), Long COVID, PET imaging, viral persistence, immune activation

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Nature  Published: 21 August 2023
 Postacute sequelae of COVID-19 at 2 years 
 Benjamin Bowe, Yan Xie & Ziyad Al-Aly 
Nature Medicine volume 29, pages2347–2357 (2023) 
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to postacute sequelae in multiple organ systems, but evidence is mostly limited to the first year postinfection. We built a cohort of 138,818 individuals with SARS-CoV-2 infection and 5,985,227 noninfected control group from the US Department of Veterans Affairs and followed them for 2 years to estimate the risks of death and 80 prespecified postacute sequelae of COVID-19 (PASC) according to care setting during the acute phase of infection. The increased risk of death was not significant beyond 6 months after infection among nonhospitalized but remained significantly elevated through the 2 years in hospitalized individuals. Within the 80 prespecified sequelae, 69% and 35% of them became not significant at 2 years after infection among nonhospitalized and hospitalized individuals, respectively. Cumulatively at 2 years, PASC contributed 80.4 (95% confidence interval (CI): 71.6–89.6) and 642.8 (95% CI: 596.9–689.3) disability-adjusted life years (DALYs) per 1,000 persons among nonhospitalized and hospitalized individuals; 25.3% (18.9–31.0%) and 21.3% (18.2–24.5%) of the cumulative 2-year DALYs in nonhospitalized and hospitalized were from the second year. In sum, while risks of many sequelae declined 2 years after infection, the substantial cumulative burden of health loss due to PASC calls for attention to the care needs of people with long-term health effects due to SARS-CoV-2 infection.

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People With Long COVID Have Specific Blood Biomarkers, Study Says       

Ralph Ellis  - September 26, 2023
From: Medscape's Long COVID Resource Center.
 
People with long COVID have specific biomarkers in their blood, a study published Monday in Nature said.
The findings may be a step toward creating blood tests to positively identify people with long COVID so specialized treatments can be employed, researchers said.
"This is a decisive step forward in the development of valid and reliable blood testing protocols for long COVID," said David Putrino, PhD., lead author and Professor of Rehabilitation and Human Performance and Director of the Abilities Research Center at Icahn Mount Sinai Health System.
Researchers from the Icahn School of Medicine at Mount Sinai and Yale School of Medicine looked at blood samples from about 270 people between January 2021 and June 2022. The people had never been infected with COVID, had fully recovered from an infection, or still showed symptoms at least four months after infection.
Using machine learning, the research teams were able to differentiate between people with and without long COVID with 96% accuracy based on distinctive features in the blood samples, according to a news release from Mount Sinai.
People with long COVID had abnormal T cell activity and low levels of the hormone cortisol. Cortisol helps people feel alert and awake, which would explain why people with long COVID often report fatigue, NBC News said in a report on the study.
"It was one of the findings that most definitively separated the folks with long Covid from the people without long Covid," Putrino told NBC News.
The study also found that long COVID appears to reactivate latent viruses including Epstein-Barr and mononucleosis, the study said.
The blood tests could allow doctors to come up with specialized treatments in people who report a wide variety of long COVID symptoms, Putrino said.
"There is no 'silver bullet' for treating long COVID, because it is an illness that infiltrates complex systems such as the immune and hormonal regulation," he said.
The CDC says about one in five Americans who had COVID still have long COVID. Symptoms include fatigue, brain fog, dizziness, digestive problems, and loss of smell and taste.
Sources:
Nature: "Distinguishing features of Long COVID identified through immune profiling”
Mount Sinai: "People with Long COVID Have Distinct Hormonal and Immune Differences From Those Without This Condition"

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Nature    2023 Sep 25. doi: 10.1038/s41586-023-06651-y. Online ahead of print.
Distinguishing features of Long COVID identified through immune profiling

Jon Klein # 1, Jamie Wood # 2, Jillian Jaycox # 1, Rahul M Dhodapkar # 1 3, Peiwen Lu # 1, Jeff R Gehlhausen # 1 4, Alexandra Tabachnikova # 1, Kerrie Greene 1, Laura Tabacof 2, Amyn A Malik 5, Valter Silva Monteiro 1, Julio Silva 1, Kathy Kamath 6, Minlu Zhang 6, Abhilash Dhal 6, Isabel M Ott 1, Gabrielee Valle 7, Mario Peña-Hernandez 1 8, Tianyang Mao 1, Bornali Bhattacharjee 1, Takehiro Takahashi 1, Carolina Lucas 1 9, Eric Song 1, Dayna Mccarthy 2, Erica Breyman 2, Jenna Tosto-Mancuso 2, Yile Dai 1, Emily Perotti 1, Koray Akduman 1, Tiffany J Tzeng 1, Lan Xu 1, Anna C Geraghty 10, Michelle Monje 10 11, Inci Yildirim 5 9 12 13, John Shon 6, Ruslan Medzhitov 1 11 9, Denyse Lutchmansingh 7, Jennifer D Possick 7, Naftali Kaminski 7, Saad B Omer 5 9 13 14, Harlan M Krumholz 9 15 16 17, Leying Guan 9 18, Charles S Dela Cruz 7 9, David van Dijk 19 20 21, Aaron M Ring 22 23, David Putrino 24 25, Akiko Iwasaki 26 27 28
PMID: 37748514m   DOI: 10.1038/s41586-023-06651-y
AbstractPost-acute infection syndromes (PAIS) may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a PAIS known as "Long COVID" (LC). Individuals with LC frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2-4; however, the biological processes associated with the development and persistence of these symptoms are unclear. Here, 273 individuals with or without LC were enrolled in a cross-sectional study that included multi-dimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with LC. Marked differences were noted in circulating myeloid and lymphocyte populations relative to matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with LC. Further, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with LC, particularly Epstein-Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with LC. Integration of immune phenotyping data into unbiased machine learning models identified key features most strongly associated with LC status. Collectively, these findings may help guide future studies into the pathobiology of LC and aid in developing relevant biomarkers.
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.

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Front Cell Neurosci  . 2022 May 9;16:888232. doi: 10.3389/fncel.2022.888232. eCollection 2022.
The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure
Herbert Renz-Polster 1, Marie-Eve Tremblay 2 3 4 5 6 7, Dorothee Bienzle 8, Joachim E Fischer 1
PMID: 35614970     PMCID: PMC9124899  DOI: 10.3389/fncel.2022.888232
AbstractAlthough myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking. Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated. Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia. From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features - post exertional malaise and decreased cerebral blood flow - are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.
Keywords: astrocytes; blood brain barrier; chronic fatigue syndrome; glia; microglia; myalgic encephalomyelitis; neuroinflammation; oligodendrocytes.
Copyright © 2022 Renz-Polster, Tremblay, Bienzle and Fischer.

J Med Virol  . 2020 Mar 4;92(12):3682-3688.  doi: 10.1002/jmv.25744. 
Cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6 infections in patients with myalgic еncephalomyelitis/chronic fatigue syndrome
Evelina Shikova 1 2, Valentina Reshkova 3, Аntoniya Kumanova 1, Sevdalina Raleva 1, Dora Alexandrova 2, Natasa Capo 4 5, Modra Murovska 6; European Network on ME/CFS (EUROMENE)  PMID: 32129496 PMCID: PMC7687071  DOI: 10.1002/jmv.25744
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystem chronic disease. The etiology and pathogenesis of ME/CFS are unknown. Infections of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus-6 (HHV-6) are suspected as etiological agents for ME/CFS. This study aims to estimate prevalence and type (active/latent) of EBV, CMV, and HHV-6 infections in Bulgarian ME/CFS patients. In the study were included 58 patients with ME/CFS and 50 healthy controls. Virus-specific antibodies were detected by enzyme-linked immunosorbent assay and viral genomic sequences in peripheral blood mononuclear cell (PBMCs) and plasma samples by nested polymerase chain reaction (PCR). We did not observe any significant differences in virus-specific immunoglobulin G and immunoglobulin M positivity rates between patients with ME/CFS and control group. In ME/CFS plasma samples, EBV DNA was found in 24.1%, CMV DNA in 3.4%, and HHV-6 DNA in 1.7% of samples. EBV DNA was detected in 4%, and CMV and HHV-6 DNA were not found in plasma samples of controls. The frequency of viral genome detection in PBMCs of patients and controls was 74% vs 78% for CMV, 81% vs 84% for EBV, and 82.8% vs 82% for HHV-6. The difference in frequency of EBV active infection in ME/CFS and control group was statistically significant (P = .0027). No ME/CFS and control individuals with active CMV and HHV-6 infection were observed. In conclusion, this study using both serological and PCR-based techniques for distinguishing between active and latent infection showed high rate of active EBV infection among patients with ME/CFS indicating that at least in a subset of cases, EBV is important factor for the development of disease.
Keywords: CMV; EBV; ELISA; HHV-6 infection; PCR; active infection; myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
© 2020 The Authors. Journal of Medical Virology published by Wiley Periodicals, Inc.
 
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Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms
Joeffre Braga, BSc1,2,3; Mariel Lepra, BSc1,2,3; Stephen J. Kish, PhD1,2,3,4; et alPablo. M. Rusjan, PhD5,6; Zahra Nasser1; Natasha Verhoeff, BHSc1; Neil Vasdev, PhD1,2,4; Michael Bagby, PhD2,7; Isabelle Boileau, PhD1,2,3,4; M. Ishrat Husain, MBBS, MD1,2,3,4; Nathan Kolla, MD, PhD1,2,3,4,8; Armando Garcia, BSc1,2; Thomas Chao, PhD9; Romina Mizrahi, PhD5,6; Khunsa Faiz, MD10; Erica L. Vieira, PhD1,2; Jeffrey H. Meyer, MD, PhD1,2,3,4
JAMA Psychiatry. Published online May 31, 2023. doi:10.1001/jamapsychiatry.2023.1321
Key Points
Question  Is translocator protein distribution volume (TSPO VT), an index of gliosis (an inflammatory change), measured by positron emission tomography, elevated in the brain after acute COVID-19 infection with sequelae of depressive and cognitive symptoms?
Findings  In this case-control study, TSPO VT was elevated in 20 participants with persistent depressive and cognitive symptoms after initially mild to moderate COVID-19 infection when compared with 20 healthy controls, more prominently in the ventral striatum and dorsal putamen. The TSPO VT in the dorsal putamen of COVID-19 cases negatively correlated with motor speed.
Meaning  These findings suggest that gliosis, especially in the ventral striatum and dorsal putamen, may reflect injury, ongoing inflammation, or both and provide directions for further therapeutic development.
Abstract
Importance  Persistent depressive symptoms, often accompanied by cognitive symptoms, commonly occur after COVID-19 illness (hereinafter termed COVID-DC, DC for depressive and/or cognitive symptoms). In patients with COVID-DC, gliosis, an inflammatory change, was suspected, but measurements of gliosis had not been studied in the brain for this condition.
Objective  To determine whether translocator protein total distribution volume (TSPO VT), a marker of gliosis that is quantifiable with positron emission tomography (PET), is elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of persons with COVID-DC.
Design, Setting, and Participants  This case-control study conducted at a tertiary care psychiatric hospital in Canada from April 1, 2021, to June 30, 2022, compared TSPO VT of specific brain regions in 20 participants with COVID-DC with that in 20 healthy controls. The TSPO VT was measured with fluorine F 18–labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) PET.
Main Outcomes and Measures  The TSPO VT was measured in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus. Symptoms were measured with neuropsychological and psychological tests, prioritizing outcomes related to striatal function.
Results  The study population included 40 participants (mean [SD] age, 32.9 [12.3] years). The TSPO VT across the regions of interest was greater in persons with COVID-DC (mean [SD] age, 32.7 [11.4] years; 12 [60%] women) compared with healthy control participants (mean [SD] age, 33.3 [13.9] years; 11 [55%] women): mean (SD) difference, 1.51 (4.47); 95% CI, 0.04-2.98; 1.51 divided by 9.20 (17%). The difference was most prominent in the ventral striatum (mean [SD] difference, 1.97 [4.88]; 95% CI, 0.36-3.58; 1.97 divided by 8.87 [22%]) and dorsal putamen (mean difference, 1.70 [4.25]; 95% CI, 0.34-3.06; 1.70 divided by 8.37 [20%]). Motor speed on the finger-tapping test negatively correlated with dorsal putamen TSPO VT (r, −0.53; 95% CI, −0.79 to −0.09), and the 10 persons with the slowest speed among those with COVID-DC had higher dorsal putamen TSPO VT than healthy persons by 2.3 (2.30 divided by 8.37 [27%]; SD, 2.46; 95% CI, 0.92-3.68).
Conclusions and Relevance  In this case-control study, TSPO VT was higher in patients with COVID-DC. Greater TSPO VT is evidence for an inflammatory change of elevated gliosis in the brain of an individual with COVID-DC. Gliosis may be consequent to inflammation, injury, or both, particularly in the ventral striatum and dorsal putamen, which may explain some persistent depressive and cognitive symptoms, including slowed motor speed, low motivation or energy, and anhedonia, after initially mild to moderate COVID-19 illness.

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Comparison of Medical and Mental Health Sequelae Following Hospitalization for COVID-19, Influenza, and Sepsis
Kieran L. Quinn, MD, PhD1,2,3,4,5; et al 
JAMA Intern Med. Published online June 20, 2023. doi:10.1001/jamainternmed.2023.2228
Key Points
Question  Is the risk of newly developing selected medical and mental health conditions greater within 1 year following hospitalization for severe COVID-19 compared with influenza or sepsis?
Findings  This population-based cohort study of 26 499 people hospitalized for COVID-19 compared with 17 516 historic controls with influenza, 282 473 historic controls with sepsis, and 52 878 people concurrently hospitalized with sepsis found that COVID-19 was associated with elevated 1-year risk of venous thromboembolism but not 12 other prespecified conditions.
Meaning  Apart from an elevated risk of venous thromboembolism, the burden of postacute conditions among those who survive hospitalization for COVID-19 may be comparable with other acute infections.
Abstract
Importance  People who survive hospitalization for COVID-19 are at risk for developing new cardiovascular, neurological, mental health, and inflammatory autoimmune conditions. It is unclear how posthospitalization risks for COVID-19 compare with those for other serious infectious illnesses.
Objective  To compare risks of incident cardiovascular, neurological, and mental health conditions and rheumatoid arthritis in 1 year following COVID-19 hospitalization against 3 comparator groups: prepandemic hospitalization for influenza and hospitalization for sepsis before and during the COVID-19 pandemic.
Design, Setting, and Participants  This population-based cohort study included all adults hospitalized for COVID-19 between April 1, 2020, and October 31, 2021, historical comparator groups of people hospitalized for influenza or sepsis, and a contemporary comparator group of people hospitalized for sepsis in Ontario, Canada.
Exposure  Hospitalization for COVID-19, influenza, or sepsis.
Main Outcome and Measures  New occurrence of 13 prespecified conditions, including cardiovascular, neurological, and mental health conditions and rheumatoid arthritis, within 1 year of hospitalization.
Results  Of 379 366 included adults (median [IQR] age, 75 [63-85] years; 54% female), there were 26 499 people who survived hospitalization for COVID-19, 299 989 historical controls (17 516 for influenza and 282 473 for sepsis), and 52 878 contemporary controls hospitalized for sepsis. Hospitalization for COVID-19 was associated with an increased 1-year risk of venous thromboembolic disease compared with influenza (adjusted hazard ratio, 1.77; 95% CI, 1.36-2.31) but with no increased risks of developing selected ischemic and nonischemic cerebrovascular and cardiovascular disorders, neurological disorders, rheumatoid arthritis, or mental health conditions compared with influenza or sepsis cohorts.
Conclusions and Relevance  In this cohort study, apart from an elevated risk of venous thromboembolism within 1 year, the burden of postacute medical and mental health conditions among those who survived hospitalization for COVID-19 was comparable with other acute infectious illnesses. This suggests that many of the postacute consequences of COVID-19 may be related to the severity of infectious illness necessitating hospitalization rather than being direct consequences of infection with SARS-CoV-2.

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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
Key Points
Question  Which individuals are at risk of developing post−COVID-19 condition?
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.

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2023 Feb; 24(3): 2698.Int J Mol Sci  Published online 2023 Jan31. doi: 10.3390/ijms24032698  PMCID: PMC9916639 PMID: 36769022
Stress-Induced Transcriptomic Changes in Females with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveal Disrupted Immune Signatures
Derek J. Van Booven,1 et al
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM), which is defined as a worsening of symptoms following even minor physical or mental exertion. Our study aimed to evaluate transcriptomic changes in ME/CFS female patients undergoing an exercise challenge intended to precipitate PEM. Our time points (baseline before exercise challenge, the point of maximal exertion, and after an exercise challenge) allowed for the exploration of the transcriptomic response to exercise and recovery in female patients with ME/CFS, as compared to healthy controls (HCs). Under maximal exertion, ME/CFS patients did not show significant changes in gene expression, while HCs demonstrated altered functional gene networks related to signaling and integral functions of their immune cells. During the recovery period (commonly during onset of PEM), female ME/CFS patients showed dysregulated immune signaling pathways and dysfunctional cellular responses to stress. The unique functional pathways identified provide a foundation for future research efforts into the disease, as well as for potential targeted treatment options.

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Orthostatic Intolerance and Chronotropic Incompetence in Patients With Myalgic Encephalomyelitis or Chronic Fatigue Syndrome
Circ Rep 2023; 5: 55–61 doi:10.1253/circrep.CR-22-0114
Kunihisa Miwa, MD, Ph
Background: Orthostatic intolerance markedly affects the day-to-day activities of patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome. Chronotropic incompetence (CI), defined as an impaired chronotropic response or reduced increases in heart rate during exercise and resulting in lower exercise capacity, may also be observed during orthostasis in patients with ME. 
Methods and Results: In this study, the recordings of 101 adult patients with ME (36 men, 65 women; mean [±SD] age 37±12 years) who underwent conventional active 10-min standing tests at least 3 times to determine the presence of CI were analyzed. Recordings were selected for 13 patients who experienced tests both with and without exhibiting postural orthostatic tachycardia syndrome (POTS; an increase in heart rate of ≥30beats/min or an actual heart rate of ≥120beats/min) while also both successfully completing and failing to complete 10-min standing on different occasions. Subjects in whom failure without POTS was observed in any test(s) while success was associated with POTS on other occasions were considered positive for CI during orthostasis. Of the 13 patients, 12 (92%) were CI positive, 5 (38%) of whom exclusively failed the tests without experiencing POTS. 
Conclusions: Some patients with ME were CI positive during standing tests, suggesting impaired sympathetic activation. The presence of POTS appears to be essential for maintaining orthostasis in these patients.

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Proteomics and cytokine analyses distinguish myalgic encephalomyelitis/chronic fatigue syndrome cases from controlsLudovic Giloteaux, Jiayi Li, Mady Hornig,W. Ian Lipkin, David Ruppert & Maureen R. Hanson 
Journal of Translational Medicine volume 21, Article number: 322 (2023)  
AbstractBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, heterogenous disease characterized by unexplained persistent fatigue and other features including cognitive impairment, myalgias, post-exertional malaise, and immune system dysfunction. Cytokines are present in plasma and encapsulated in extracellular vesicles (EVs), but there have been only a few reports of EV characteristics and cargo in ME/CFS. Several small studies have previously described plasma proteins or protein pathways that are associated with ME/CFS.
MethodsWe prepared extracellular vesicles (EVs) from frozen plasma samples from a cohort of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) cases and controls with prior published plasma cytokine and plasma proteomics data. The cytokine content of the plasma-derived extracellular vesicles was determined by a multiplex assay and differences between patients and controls were assessed. We then performed multi-omic statistical analyses that considered not only this new data, but extensive clinical data describing the health of the subjects.
ResultsME/CFS cases exhibited greater size and concentration of EVs in plasma. Assays of cytokine content in EVs revealed IL2 was significantly higher in cases. We observed numerous correlations among EV cytokines, among plasma cytokines, and among plasma proteins from mass spectrometry proteomics. Significant correlations between clinical data and protein levels suggest roles of particular proteins and pathways in the disease. For example, higher levels of the pro-inflammatory cytokines Granulocyte-Monocyte Colony-Stimulating Factor (CSF2) and Tumor Necrosis Factor (TNFα) were correlated with greater physical and fatigue symptoms in ME/CFS cases. Higher serine protease SERPINA5, which is involved in hemostasis, was correlated with higher SF-36 general health scores in ME/CFS. Machine learning classifiers were able to identify a list of 20 proteins that could discriminate between cases and controls, with XGBoost providing the best classification with 86.1% accuracy and a cross-validated AUROC value of 0.947. Random Forest distinguished cases from controls with 79.1% accuracy and an AUROC value of 0.891 using only 7 proteins.
ConclusionsThese findings add to the substantial number of objective differences in biomolecules that have been identified in individuals with ME/CFS. The observed correlations of proteins important in immune responses and hemostasis with clinical data further implicates a disturbance of these functions in ME/CFS.

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Queensland scientists push for new national treatment guidelines for chronic fatigue syndromeBy Janelle Miles
Posted Tue 13 Jun 2023 at 8:11amTuesday 13 Jun 2023 at 8:11am, updated Tue 13 Jun 2023 at 9:46amTuesday 13 Jun 2023 at 9:46am
 
Professor Sonya Marshall-Gradisnik says Australia's clinical guidelines for treating patients with ME/CFS are well out of date.(Supplied: Griffith University )
A meeting in Canberra today will push for new national guidelines to treat chronic fatigue syndrome.
Key points:

• It's estimated ME/CFS affects more than 240,000 Australians
• Symptoms include brain fog, memory loss, muscle and joint pain and post-exertional malaise
• Low-dose Naltrexone has been identified as a potential drug treatment for ME/CFS

Queensland scientists will provide up-to-date scientific data to support changes to existing protocols for patients with CFS, known medically as myalgic encephalomyelitis or ME/CFS.
They will join politicians, ME/CFS patient representatives and other researchers from across the country at Parliament House.
Griffith University's Sonya Marshall-Gradisnik, recognised as a world expert in ME/CFS, said Australia's treatment guidelines failed to reflect scientific advances in the pathology of the illness, conservatively estimated to affect 240,000 Australians.
The Royal Australian College of General Practitioners' guidelines for the treatment of chronic fatigue syndrome suggest graded exercise therapy and cognitive behavioural therapy.
"They're some 20 years out of date. There needs to be new clinical guidelines," Professor Marshall-Gradisnik said.
"The research that's been published in the last 20 years clearly outlines that myalgic encephalomyelitis, or chronic fatigue syndrome, is not a psychological or psychiatric illness.
"There is actual underlying pathology."
Professor Marshall-Gradisnik said other countries had withdrawn graded exercise therapy and cognitive behavioural therapy from their ME/CFS guidelines due to "the potential detrimental outcomes to patients".
Patients with ME/CFS can experience a range of symptoms including brain fog, confusion, difficulties with memory and concentration, sleep disturbances, heart problems, muscle and joint pain and intolerances to temperature, light and noise.
A distinguishing sign is post-exertional malaise, where even minor physical or mental activity makes symptoms worse.
Patients can be left bedridden and unable to work.
Potential treatment to be trialledProfessor Marshall-Gradisnik said her team at Griffith University's National Centre for Neuro-immunology and Emerging Diseases, had found dysfunction in the cells of patients with ME/CFS patients, which "align to the symptom presentation" of people with the condition.
"They can't bring calcium inside these cells. Calcium is important for all cell functions," she said.
The Griffith University research has identified low-dose Naltrexone as a potential drug treatment for ME/CFS, recognised as one of a suite of post-infectious diseases that often follow a viral illness.
Professor Marshall-Gradisnik said an Australian trial of Naltrexone in ME/CFS patients was expected to begin later this year.
She said participants would undergo magnetic resonance imaging scans of the brain to assess the affect of the drug on cellular dysfunction identified in ME/CFS.
Professor Marshall-Gradisnik is in Canberra for the meeting of the Parliamentary Friends of ME/CFS, which includes politicians from across the party divide.
"It's hoped the meeting will facilitate new ME/CFS guidelines so doctors across Australia have accurate and up-to-date advice," she said.

 
Guidance on “Long COVID” as a Disability Under the ADA, Section 504, and Section 1557
Although many people with COVID-19 get better within weeks, some people continue to experience symptoms that can last months after first being infected, or may have new or recurring symptoms at a later time.1   This can happen to anyone who has had COVID-19, even if the initial illness was mild.  People with this condition are sometimes called “long-haulers.”  This condition is known as “long COVID.”2
In light of the rise of long COVID as a persistent and significant health issue, the Office for Civil Rights of the Department of Health and Human Services and the Civil Rights Division of the Department of Justice have joined together to provide this guidance. 
This guidance explains that long COVID can be a disability under Titles II (state and local government) and III (public accommodations) of the Americans with Disabilities Act (ADA),3  Section 504 of the Rehabilitation Act of 1973 (Section 504),4  and Section 1557 of the Patient Protection and Affordable Care Act (Section 1557).5   Each of these federal laws protects people with disabilities from discrimination.6   This guidance also provides resources for additional information and best practices.  This document focuses solely on long COVID, and does not address when COVID-19 may meet the legal definition of disability.
The civil rights protections and responsibilities of these federal laws apply even during emergencies.7   They cannot be waived.
1.  What is long COVID and what are its symptoms?
According to the Centers for Disease Control and Prevention (CDC), people with long COVID have a range of new or ongoing symptoms that can last weeks or months after they are infected with the virus that causes COVID-19 and that can worsen with physical or mental activity.8
Examples of common symptoms of long COVID include:

• Tiredness or fatigue
• Difficulty thinking or concentrating (sometimes called “brain fog”)
• Shortness of breath or difficulty breathing
• Headache
• Dizziness on standing
• Fast-beating or pounding heart (known as heart palpitations)
• Chest pain
• Cough
• Joint or muscle pain
• Depression or anxiety
• Fever
• Loss of taste or smell

This list is not exhaustive.  Some people also experience damage to multiple organs including the heart, lungs, kidneys, skin, and brain.
2. Can long COVID be a disability under the ADA, Section 504, and Section 1557?
Yes, long COVID can be a disability under the ADA, Section 504, and Section 1557 if it substantially limits one or more major life activities.9   These laws and their related rules define a person with a disability as an individual with a physical or mental impairment that substantially limits one or more of the major life activities of such individual (“actual disability”); a person with a record of such an impairment (“record of”); or a person who is regarded as having such an impairment (“regarded as”).10   A person with long COVID has a disability if the person’s condition or any of its symptoms is a “physical or mental” impairment that “substantially limits” one or more major life activities.
This guidance addresses the “actual disability” part of the disability definition.  The definition also covers individuals with a “record of” a substantially limiting impairment or those “regarded as” having a physical impairment (whether substantially limiting or not). This document does not address the “record of” or “regarded as” parts of the disability definition, which may also be relevant to claims regarding long COVID.
a. Long COVID is a physical or mental impairment
A physical impairment includes any physiological disorder or condition affecting one or more body systems, including, among others, the neurological, respiratory, cardiovascular, and circulatory systems.  A mental impairment includes any mental or psychological disorder, such as an emotional or mental illness.11
Long COVID is a physiological condition affecting one or more body systems.  For example, some people with long COVID experience:

• Lung damage
• Heart damage, including inflammation of the heart muscle
• Kidney damage
• Neurological damage
• Damage to the circulatory system resulting in poor blood flow
• Lingering emotional illness and other mental health conditions

Accordingly, long COVID is a physical or mental impairment under the ADA, Section 504, and Section 1557.12
b. Long COVID can substantially limit one or more major life activities
“Major life activities” include a wide range of activities, such as caring for oneself, performing manual tasks, seeing, hearing, eating, sleeping, walking, standing, sitting, reaching, lifting, bending, speaking, breathing, learning, reading, concentrating, thinking, writing, communicating, interacting with others, and working.  The term also includes the operation of a major bodily function, such as the functions of the immune system, cardiovascular system, neurological system, circulatory system, or the operation of an organ.
The term “substantially limits” is construed broadly under these laws and should not demand extensive analysis.  The impairment does not need to prevent or significantly restrict an individual from performing a major life activity, and the limitations do not need to be severe, permanent, or long-term.  Whether an individual with long COVID is substantially limited in a major bodily function or other major life activity is determined without the benefit of any medication, treatment, or other measures used by the individual to lessen or compensate for symptoms.  Even if the impairment comes and goes, it is considered a disability if it would substantially limit a major life activity when the impairment is active.
Long COVID can substantially limit a major life activity.  The situations in which an individual with long COVID might be substantially limited in a major life activity are diverse.  Among possible examples, some include:

• A person with long COVID who has lung damage that causes shortness of breath, fatigue, and related effects is substantially limited in respiratory function, among other major life activities. 

• A person with long COVID who has symptoms of intestinal pain, vomiting, and nausea that have lingered for months is substantially limited in gastrointestinal function, among other major life activities.   

• A person with long COVID who experiences memory lapses and “brain fog” is substantially limited in brain function, concentrating, and/or thinking.

3. Is long COVID always a disability?
No.  An individualized assessment is necessary to determine whether a person’s long COVID condition or any of its symptoms substantially limits a major life activity.  The CDC and health experts are working to better understand long COVID. 
4. What rights do people whose long COVID qualifies as a disability have under the ADA, Section 504, and Section 1557?
People whose long COVID qualifies as a disability are entitled to the same protections from discrimination as any other person with a disability under the ADA, Section 504, and Section 1557.  Put simply, they are entitled to full and equal opportunities to participate in and enjoy all aspects of civic and commercial life. 
For example, this may mean that businesses or state or local governments will sometimes need to make changes to the way that they operate to accommodate a person’s long COVID-related limitations.  For people whose long COVID qualifies as a disability, these changes, or “reasonable modifications,” may include:

• Providing additional time on a test for a student who has difficulty concentrating
• Modifying procedures so a customer who finds it too tiring to stand in line can announce their presence and sit down without losing their place in line
• Providing refueling assistance at a gas station for a customer whose joint or muscle pain prevents them from pumping their own gas
• Modifying a policy to allow a person who experience dizziness when standing to be accompanied by their service animal that is trained to stabilize them

5. What federal resources are there for people with symptoms of long COVID?

• The Office for Civil Rights of the Department of Health and Human Services (HHS) has the following page on civil rights and COVID-19: https://www.hhs.gov/civil-rights/for-providers/civil-rights-covid19/index.html.
  • If you believe that an entity covered by HHS civil rights laws has violated your rights protected under these authorities, you may file a complaint at https://www.hhs.gov/ocr/complaints/index.html. 
• The Civil Rights Division of the Department of Justice has the following page on its ADA.gov website that discusses topics related to COVID-19 and the ADA:  https://www.ada.gov/emerg_prep.html.
  • If you believe that you or another person has been discriminated against by an entity covered by the ADA, you may file a complaint with the Disability Rights Section (DRS) in the Department of Justice.  Information about how to file a complaint is available at https://www.ada.gov/fact_on_complaint.htm. 
• CDC’s website has the following page on post-COVID conditions, which discusses long COVID: https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects.html.
• The Administration for Community Living’s document, “How ACL’s Disability and Aging Networks Can Help People with Long COVID,” provides information on resources and programs to assist people with long COVID.  This document is available at https://acl.gov/sites/default/files/COVID19/ACL_LongCOVID.pdf - PDF .
• While employment is outside of the scope of this guidance document, individuals who wish to learn more about COVID-19 and employment can visit the following Equal Employment Opportunity Commission page, which provides COVID-19 information and resources: www.eeoc.gov/coronavirus.
  • The EEOC’s main COVID-19 publication, What You Should Know about COVID-19 and the ADA, the Rehabilitation Act, and Other EEO Laws, is available at: https://www.eeoc.gov/wysk/what-you-should-know-about-covid-19-and-ada-rehabilitation-act-and-other-eeo-laws.
  • For information about filing an employment discrimination charge, see https://www.eeoc.gov/filing-charge-discrimination.

 
 
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Low Vitamin D Levels Are Associated With Long COVID Syndrome in COVID-19 Survivors Luigi di Filippo, Stefano Frara, Fabrizio Nannipieri, Alice Cotellessa, Massimo Locatelli, Patrizia Rovere Querini, Andrea GiustinaThe Journal of Clinical Endocrinology & Metabolism, dgad207, https://doi.org/10.1210/clinem/dgad207  Published:13 April 2023
AbstractLong COVID is an emerging syndrome affecting 50% to 70% of COVID-19 survivors that still lacks predicting factors.
 
Objective
Due to the extraskeletal effects of vitamin D, we retrospectively assessed the association between 25(OH) vitamin D levels and long COVID in COVID-19 survivors 6 months after hospitalization.
 
Methods
Long COVID was defined according to NICE guidelines. Fifty long COVID and 50 non–long-COVID subjects matched on a 1:1 basis were enrolled from an outpatient clinic post-COVID cohort seen from August to November 2020. Therapies/comorbidities affecting calcium/vitamin D/bone metabolism, and/or admission to the intensive care unit during hospitalization were exclusion criteria. 25(OH) Vitamin D was measured at hospital admission and 6 months after discharge.
 
Results
We observed lower 25(OH) vitamin D levels, evaluated at follow-up, in subjects with long COVID than those without (20.1 vs 23.2 ng/mL, P = .03). Regarding the affected health areas evaluated in the entire cohort, we observed lower 25(OH) vitamin D levels in those with neurocognitive symptoms at follow-up (n = 7) than those without (n = 93) (14.6 vs 20.6 ng/mL, P = .042). In patients presenting vitamin D deficiency (<20 ng/mL), both at admission and at follow-up (n = 42), those affected by long COVID (n = 22) presented lower 25(OH) vitamin D levels at follow-up than those not affected (n = 20) (12.7 vs 15.2 ng/mL, P = .041). In multiple regression analyses, lower 25(OH) vitamin D levels at follow-up were the only variable significantly associated with long COVID in our cohort (P = .008, OR 1.09, CI 1.01-1.16).
 
Conclusion
COVID-19 survivors with long COVID have lower 25(OH) vitamin D levels than matched patients without long COVID. Our data suggest that vitamin D levels should be evaluated in COVID-19 patients after hospital discharge. The role of vitamin D supplementation as a preventive strategy of COVID-19 sequelae should be tested in randomized controlled trials.

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Brain Behav Immun Health
. 2023 Apr 27;30:100627.  doi: 10.1016/j.bbih.2023.100627. eCollection 2023 Jul.
Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndromeMelanie Uhde 1, Alyssa C Indart 1, Peter H R Green 1 2, Robert H Yolken 3, Dane B Cook 4, Sanjay K Shukla 5, Suzanne D Vernon 6, Armin Alaedini 1 7 2 8
PMID: 37396339    PMCID: PMC10308215
Abstract
The etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear. Relying on data from two independent pairs of ME/CFS and control cohorts, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium in ME/CFS. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.
Keywords: Acute-phase innate immune response; Antibody; B cell; Citrate; Glucose; Gut epithelial barrier; IL-10; Immunoregulation; Inflammation; Metabolism; Microbial translocation; Microbiota; Myalgic encephalomyelitis/chronic fatigue syndrome; TLR4.
© 2023 Published by Elsevier Inc.

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Jama Research Letter Pediatrics
July 19, 2023
Incidence and Characteristics in Children with Post–COVID-19 Condition in SwedenMaria Bygdell, PhD1,2; Jenny M. Kindblom, PhD, MD1,3; Jari Martikainen, MSc4; et alHuiqi Li, PhD2; Fredrik Nyberg, PhD, MD2
JAMA Netw Open. 2023;6(7):e2324246. doi:10.1001/jamanetworkopen.2023.24246
Introduction
During the COVID-19 pandemic it has become increasingly clear that children have not been as severely affected as adults in the acute phase of the infection, with the exception of those affected by multisystem inflammatory syndrome in children (MIS-C).1,2 In accordance with adults, some children seem to be affected by persistent long-term symptoms of COVID-19, commonly referred to as post–COVID-19 condition (PCC).3 The frequency of PCC in the pediatric population is to a large extent unknown, and the occurrence in subgroups is not completely understood. The aim of this descriptive study was to describe the incidence of PCC in children and different subgroups of children using a unique population-based cohort with near-complete follow-up in high-quality Swedish registers.
Methods
We included all children ages 6 to 17 years residing in the 2 largest Swedish regions and retrieved information on both inpatient and outpatient care from specialists and primary health care clinicians using high-quality national or regional registers with near-complete coverage (eMethods in Supplement 1). The inclusion criterion was COVID-19 infection between January 31, 2020, and February 9, 2022. PCC was defined by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) code U09.9 (used in Sweden since October 20204,5) as the main or secondary diagnosis occurring 28 days or more after the COVID-19 infection. Follow-up ended at the earliest of: PCC diagnosis, emigration, death, or end of study (November 30, 2022). Incidence rate (per 100 person-years) and cumulative incidence are presented for the total cohort and according to subgroups. Data were analyzed with R Statistical Software version 4.2.2 (R Project for Statistical Computing).
Results
A total of 162 383 children (81 789 boys [50.4%], 80 594 girls [49.6%]), with a mean (SD) age of 12.0 (3.5) years at study start, had experienced a COVID-19 infection. Only a small proportion (529 [0.3%]) had been hospitalized due to COVID-19 and none of the children with PCC had been treated in intensive care. We found a PCC diagnosis in 326 children (0.2%) with COVID-19 (Figure). We observed numerically higher incidence rates of PCC cases among girls than boys (incidence rate per 100 person-years: 0.19; 95% CI, 0.16-0.22 vs 0.12; 95% CI, 0.10-0.14), older than younger children (age 12 to 17 years, 0.19; 95% CI, 0.17-0.22 vs 0.11; 95% CI, 0.09-0.14), with vs without comorbidities (any, 0.16; 95% CI, 0.14-0.18 vs none, 0.11; 95% CI, 0.07-0.15), and among hospitalized compared with nonhospitalized for acute COVID-19 (1.25; 95% CI, 0.62-2.23 vs 0.15; 95% CI, 0.13-0.17) (Table). Similar PCC occurrence was seen across categories of parental education. Children who had a diagnosis of MIS-C (63 children) showed an increased occurrence of PCC diagnosis compared with children without MIS-C. In addition, we observed a 6-fold higher occurrence of PCC if any of the parents had a PCC diagnosis (Table).
Discussion
In this population-based, well-powered cohort with uniquely comprehensive data regarding COVID-19 and PCC, only 0.2% children with COVID-19 had a subsequent diagnosis of PCC. Children with PCC were more often girls, older, had comorbidities, had been hospitalized for their COVID-19, or had a parent with a PCC diagnosis. The higher cumulative incidence of PCC among children with a parent with PCC may indicate that the etiology of PCC could involve genetic susceptibility, or that parental experience of long-term symptoms raises awareness of symptoms and facilitates navigation of the health care system. Moreover, the increased occurrence of PCC among hospitalized children is well in accordance with similar results regarding hospitalized adults.6 Because none of the children with PCC had been treated in intensive care, the diagnosis cannot be explained by misclassification of post–intensive care syndrome. The number of MIS-C cases in the study population was low and therefore the association of MIS-C with PCC needs to be evaluated further. A limitation with our study was that the PCC diagnosis code is not yet validated, and the strengths include the unique comprehensive data, the large population-based cohort, and the near-complete follow-up in high-quality registers.
In this descriptive study, PCC in children was rare. We observed a higher number of children with female sex, older age, hospitalization for COVID-19, and having a parent with PCC among cases with PCC.
Article Information:  Accepted for Publication: June 5, 2023.
Published: July 19, 2023. doi:10.1001/jamanetworkopen.2023.24246
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2023 Bygdell M et al. JAMA Network Open.
Corresponding Author: Maria Bygdell, PhD, Department of Internal and Clinical Nutrition, University of Gothenburg, Vita Stråket 11, 413 45 Gothenburg, Sweden ([email protected]).
Author Contributions: Drs Bygdell and Nyberg had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
 
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Development of a Definition of Postacute Sequelae of SARS-CoV-2 InfectionTanayott Thaweethai, PhD1,2; Sarah E. Jolley, MD, MS3; Elizabeth W. Karlson, MD, MS4; et alEmily B. Levitan, ScD5; Bruce Levy, MD2,4; Grace A. McComsey, MD6; Lisa McCorkell, MPP7; Girish N. Nadkarni, MD, MPH8; Sairam Parthasarathy, MD9; Upinder Singh, MD10; Tiffany A. Walker, MD11; Caitlin A. Selvaggi, MS1; Daniel J. Shinnick, MS1; Carolin C. M. Schulte, PhD1; Rachel Atchley-Challenner, PhD12; Leora I. Horwitz, MD13; Andrea S. Foulkes, ScD1,2; RECOVER Consortium 
JAMA. 2023;329(22):1934-1946. doi:10.1001/jama.2023.8823 COVID-19 Resource Center
Key Points
Question  What symptoms are differentially present in SARS-CoV-2–infected individuals 6 months or more after infection compared with uninfected individuals, and what symptom-based criteria can be used to identify postacute sequelae of SARS-CoV-2 infection (PASC) cases?
Findings  In this analysis of data from 9764 participants in the RECOVER adult cohort, a prospective longitudinal cohort study, 37 symptoms across multiple pathophysiological domains were identified as present more often in SARS-CoV-2–infected participants at 6 months or more after infection compared with uninfected participants. A preliminary rule for identifying PASC was derived based on a composite symptom score.
Meaning  A framework for identifying PASC cases based on symptoms is a first step to defining PASC as a new condition. These findings require iterative refinement that further incorporates clinical features to arrive at actionable definitions of PASC.
Abstract
Importance  SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.
Objective  To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.
Design, Setting, and Participants  Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.
Exposure  SARS-CoV-2 infection.
Main Outcomes and Measures  PASC and 44 participant-reported symptoms (with severity thresholds).
Results  A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.
Conclusions and Relevance  A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

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Brain Research Bulletin Available online 7 July 2023, 110702Chronic inflammation, neuroglia dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndromeMaia Chaves a, Olivia Braniff a, Angelina Angelova b, Yuru Deng c, Marie-Ève Tremblay a d e f g
https://doi.org/10.1016/j.brainresbull.2023.110702Get rights and content
Highlights  Plasmalogens (Pls) are lipids containing a vinyl-ether bond in their glycerol backbonePls have antioxidant properties and are important for curved membrane assemblies
Post-COVID-19 symptoms are highly prevalent and share several features with ME/CFS
Pls depletion is a shared biological hallmark of ME/CFS and acute COVID-19 syndrome
Pls replacement is a promising tool against neuroinflammation in these two conditions
Abstract
After five waves of COVID-19 outbreaks, it has been recognized that a significant portion of the affected individuals developed long-term debilitating symptoms marked by chronic fatigue, cognitive difficulties (“brain fog”), post-exertional malaise, and autonomic dysfunction. The onset, progression, and clinical presentation of this condition, generically named post-COVID-19 syndrome, overlap significantly with another enigmatic condition, referred to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Several pathobiological mechanisms have been proposed for ME/CFS, including redox imbalance, systemic and central nervous system inflammation, and mitochondrial dysfunction. Chronic inflammation and glial pathological reactivity are common hallmarks of several neurodegenerative and neuropsychiatric disorders and have been consistently associated with reduced central and peripheral levels of plasmalogens, one of the major phospholipid components of cell membranes with several homeostatic functions. Of great interest, recent evidence revealed a significant reduction of plasmalogens contents, biosynthesis, and metabolism in ME/CFS and acute COVID-19, with a strong association to symptom severity and other relevant clinical outcomes. These bioactive lipids have increasingly attracted attention due to their reduced levels representing a common pathophysiological manifestation between several disorders associated with aging and chronic inflammation. However, alterations in plasmalogen levels or their lipidic metabolism have not yet been examined in individuals suffering from post-COVID-19 symptoms. Here, we proposed a pathobiological model for post-COVID-19 and ME/CFS based on their common inflammation and dysfunctional glial reactivity, and highlighted the emerging implications of plasmalogen deficiency in the underlying mechanisms. Along with the promising outcomes of plasmalogen replacement therapy (PRT) for various neurodegenerative/neuropsychiatric disorders, we sought to propose PRT as a simple, effective, and safe strategy for the potential relief of the debilitating symptoms associated with ME/CFS and post-COVID-19 syndrome.

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MEDICAL NEWS
Long COVID Brain Fog 'Comparable to Ageing 10 Years'Rob Hicks   |   25 July 2023
The condition often referred to as 'brain fog' in people with long COVID could have a similar effect to ageing a decade, according to UK researchers, who called for more work to understand why this was the case and what could be done to help.
Cognitive impairment has been reported after many types of infection, including SARS-CoV-2, highlighted the team from King's College London (KCL), but it was unclear whether deficits following SARS-CoV-2 improve over time. They underlined that to date, studies had focused on hospitalised individuals with up to a year follow-up, but that the presence, magnitude, persistence, and correlations of effects in community-based cases remained "relatively unexplored".
The prospective cohort study, published in the journal eClinicalMedicine, set out to explore the impact of long COVID on thinking and memory skills. Researchers assessed cognitive performance — working memory, attention, reasoning, and motor control — of participants from the UK COVID Symptom Study Biobank in the first round between July and August, 2021, and the second, between April and June, 2022. Round one comprised 3335 individuals with and without SARS-CoV-2 infection and varying symptom duration, while data was available on 1768 individuals who also completed round two.
The effect of COVID-19 exposures on cognitive accuracy and reaction time scores were estimated, and the role of ongoing symptoms after SARS-CoV-2 infection was examined.
Claire Steves, professor of ageing and health at KCL, and a corresponding study author, said investigators "used sensitive tests to measure speed and accuracy across a range of brain challenges."
Decreased Cognitive AccuracyThe researchers found that at round 1, individuals with previous positive SARS-CoV-2 tests had lower cognitive accuracy than negative controls. 
Cognitive deficits were largest for individuals with "longer symptom durations, ongoing symptoms, and/or more severe infection", identified the researchers. Following SARS-CoV-2 infection, these deficits were detectable nearly 2 years post infection. However, no such deficits were detected in individuals who reported full recovery from COVID-19, the authors said.
"Deficits were largest for positive individuals with ≥12 weeks of symptoms," the researchers reported, with effects "comparable to hospital presentation during illness and 10 years age difference in the whole study population," they alerted.
Dr Nathan Cheetham, a senior postdoctoral data scientist at KCL, who led the research team, said: "This study shows the need to monitor those people whose brain function is most affected by COVID-19 to see how their cognitive symptoms continue to develop and provide support towards recovery."
Stratification by self-reported recovery revealed that deficits were only detectable in SARS-CoV-2 positive individuals who did not feel they had recovered from COVID-19, whereas individuals who reported full recovery showed no deficits.
Longitudinal analysis showed no evidence of cognitive change over time, which suggested that cognitive deficits for affected individuals "persisted" at almost 2 years since initial infection.
Professor Steves emphasised that the study showed that some individuals had "measurable changes" in cognitive function after COVID-19 going on for "nearly two years".
"The deficits in composite task accuracy scores were comparable in scale to the effect of presentation to hospital during illness, an increase in age of approximately 10 years, or exhibiting mild or moderate symptoms of psychological distress, but smaller than other effects such as lower educational attainment or above threshold fatigue level," according to the authors.
Lives "Continue to be Impacted by COVID-19"The researchers found "no evidence" of an effect of SARS-CoV-2 infection on average reaction time during tasks. This, they emphasised, was "reassuring" given the importance of processing speed within cognition and extensive relationships with outcomes such as frailty, dementia, and later mortality.
However, the scale of the deficits identified in the study may have "detrimental impacts" on quality-of-life and daily functioning at an individual level, as well as socio-economic impacts on society more broadly due to both a reduced capacity to work and an increased need for support, the authors cautioned.
They called for further work to monitor and develop understanding of recovery mechanisms for those with ongoing symptoms.
"The fact remains that two years on from their first infection, some people don't feel fully recovered and their lives continue to be impacted by the long-term effects of the coronavirus," commented Professor Steves, who said there was a need for "more work to understand why this is the case and what can be done to help".

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Gene  Volume 877, 15 August 2023, 147568
 
A unique circular RNA expression pattern in the peripheral blood of ME/chronic fatigue syndrome patients
Yuning Cheng a, SiMei Xu a, Konii Takenaka a, Grace Lindner a, Ashton Curry-Hyde a, Michael Janitz a b
https://doi.org/10.1016/j.gene.2023.147568
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with obscure aetiology. The underdiagnosis rate of ME/CFS is high due to the lack of diagnostic criteria based on objective markers. In recent years, circRNAs have emerged as potential genetic biomarkers for neurological diseases, including Parkinson’s disease and Alzheimer’s disease, making them likely to have the same prospect of being biomarkers in ME/CFS. However, despite the extensive amount of research that has been performed on the transcriptomes of ME/CFS patients, all of them are solely focused on linear RNAs, and the profiling of circRNAs in ME/CFS has been completely omitted. In this study, we investigated the expression profiles of circRNAs, comparing ME/CFS patients and controls before and after two sessions of cardiopulmonary exercise longitudinally.
In patients with ME/CFS, the number of detected circRNAs was higher compared to healthy controls, indicating potential differences in circRNA expression associated with the disease. Additionally, healthy controls showed an increase in the number of circRNAs following exercise testing, while no similar pattern was evident in ME/CFS patients, further highlighting physiological differences between the two groups. A lack of correlation was observed between differentially expressed circRNAs and their corresponding coding genes in terms of expression and function, suggesting the potential of circRNAs as independent biomarkers in ME/CFS. Specifically, 14 circRNAs were highly expressed in ME/CFS patients but absent in controls throughout the exercise study, indicating a unique molecular signature specific to ME/CFS patients and providing potential diagnostic biomarkers for the disease. Significant enrichment of protein and gene regulative pathways were detected in relation to five of these 14 circRNAs based on their predicted miRNA target genes. Overall, this is the first study to describe the circRNA expression profile in peripheral blood of ME/CFS patients, providing valuable insights into the molecular mechanisms underlying the disease.

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Journal of Translational Medicine 
Comparison of serum acylcarnitine levels in patients with myalgic encephalomyelitis/ chronic fatigue syndrome and healthy controls: a systematic review and meta-analysis
Ryuhei Jinushi1,2,3,4* , Sakue Masuda2 , Yuki Tanisaka1 , Sho Nishiguchi3 , Kento Shionoya2 , Ryo Sato1 , Kei Sugimoto1 , Takahiro Shin1 , Rie Shiomi1 , Akashi Fujita1 , Masafumi Mizuide1 and Shomei Ryozawa1 
Abstract 
Background Myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease (ME/CFS/ SEID) is a condition diagnosed primarily based on clinical symptoms, including prolonged fatigue and post-exertional malaise; however, there is no specifc test for the disease. Additionally, diagnosis can be challenging since healthcare professionals may lack sufcient knowledge about the disease. Prior studies have shown that patients with ME/CFS/ SEID have low serum acylcarnitine levels, which may serve as a surrogate test for patients suspected of having this disease. This systematic review and meta-analysis aimed to investigate the diferences in serum acylcarnitine levels between patients with ME/CFS/SEID and healthy controls.
 Methods This systematic review was conducted using PubMed and Ichushi-Web databases. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, we included all studies from the databases’ inception until February 17, 2023, that evaluated blood tests in both patients with ME/CFS/SEID and healthy control groups. The primary endpoint was the diference in serum acylcarnitine levels between the two groups. 
Results The electronic search identifed 276 studies. Among them, seven met the eligibility criteria. The serum acylcarnitine levels were analyzed in 403 patients with ME/CFS/SEID. The patient group had signifcantly lower serum acylcarnitine levels when compared with the control group, and the statistical heterogeneity was high. 
Conclusion The patient group had signifcantly lower serum acylcarnitine levels when compared with the control group. In the future, the measurement of serum acylcarnitine levels, in addition to clinical symptoms, may prove to be a valuable diagnostic tool for this condition.

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Brain, Behavior, & Immunity - Health  Volume 30, July 2023, 100627 
Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndromeMelanie Uhde a 1, Alyssa C. Indart a 1, Peter H.R. Green a c, Robert H. Yolken d, Dane B. Cook e, Sanjay K. Shukla f, Suzanne D. Vernon g, Armin Alaedini a b c h
https://doi.org/10.1016/j.bbih.2023.100627Get rights and content
Highlights·       •
Elevation of FABP2, a marker of intestinal cell damage in ME/CFS.
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Absence of optimal acute-phase LBP and sCD14 anti-microbial responses in ME/CFS.
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Compensatory but inadequate B cell response to microbial translocation in ME/CFS.
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Enhanced IL-10 regulatory response may drive the observed immunosuppression.
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Glucose and citrate metabolic dysfunction in ME/CFS may link the IL-10 activation and suppressed anti-microbial responses.
AbstractThe etiology and mechanism of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are poorly understood and no biomarkers have been established. Specifically, the relationship between the immunologic, metabolic, and gastrointestinal abnormalities associated with ME/CFS and their relevance to established symptoms of the condition remain unclear. Relying on data from two independent pairs of ME/CFS and control cohorts, one at rest and one undergoing an exercise challenge, we identify a state of suppressed acute-phase innate immune response to microbial translocation in conjunction with a compromised gut epithelium in ME/CFS. This immunosuppression, along with observed enhancement of compensatory antibody responses to counter the microbial translocation, was associated with and may be mediated by alterations in glucose and citrate metabolism and an IL-10 immunoregulatory response. Our findings provide novel insights into mechanistic pathways, biomarkers, and potential therapeutic targets in ME/CFS, including in the context of exertion, with relevance to both intestinal and extra-intestinal symptoms.

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 Long COVID 'Brain Fog' Confounds Doctors, but New Research Offers Hope   -  Sara Novak
July 03, 2023  Long COVID Resource Center.
Kate Whitley was petrified of COVID-19 from the beginning of the pandemic because she has Hashimoto disease, an autoimmune disorder that she knew put her at high risk for complications.
She was right to be worried. Two months after contracting the infection in September 2022, the 42-year-old Nashville resident was diagnosed with long COVID. For Whitley, the resulting brain fog has been the most challenging factor. She is the owner of a successful paper goods store, and she can't remember basic aspects of her job. She can't tolerate loud noises and gets so distracted that she has trouble remembering what she was doing.
Whitley doesn't like the term "brain fog" because it doesn't begin to describe the dramatic disruption to her life over the past 7 months.
"I just can't think anymore," she said. "It makes you realize that you're nothing without your brain. Sometimes I feel like a shell of my former self."
Brain fog is among the most common symptoms of long COVID, and also one of the most poorly understood. A reported 46% of those diagnosed with long COVID complain of brain fog or a loss of memory. Many clinicians agree that the term is vague and often doesn't truly represent the condition. That, in turn, makes it harder for doctors to diagnose and treat it. There are no standard tests for it, nor are there guidelines for symptom management or treatment.
"There's not a lot of imprecision in the term because it might mean different things to different patients," said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine and author of a new book, Clearing the Fog: From Surviving to Thriving With Long COVID ― A Practical Guide.
Jackson, who began treating Whitley in February 2023, said that it makes more sense to call brain fog a brain impairment or an acquired brain injury (ABI) because it doesn't occur gradually. COVID damages the brain and causes injury. For those with long COVID who were previously in the intensive care unit and may have undergone ventilation, hypoxic brain injury may result from the lack of oxygen to the brain.
Even among those with milder cases of acute COVID, there's some evidence that persistent neuro-inflammation in the brain caused by an activated immune system may also cause damage.
In both cases, the results can be debilitating. Whitley also has dysautonomia — a disorder of the autonomic nervous system that can cause dizziness, sweating, and headaches along with fatigue and heart palpitations.
She said that she's so forgetful that when she sees people socially, she's nervous of what she'll say. "I feel like I'm constantly sticking my foot in my mouth because I can't remember details of other people's lives," she said.
Although brain disorders such as Alzheimer's disease and other forms of dementia are marked by a slow decline, ABI occurs more suddenly and may include a loss of executive function and attention.
"With a brain injury, you're doing fine, and then some event happens (in this case COVID), and immediately after that, your cognitive function is different," said Jackson.
 
Additionally, ABI is an actual diagnosis, whereas brain fog is not.
"With a brain injury, there's a treatment pathway for cognitive rehabilitation," said Jackson.
Treatments may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for treatment of the mental and behavioral disorders that may result. Jackson said that while many patients aren't functioning cognitively or physically at 100%, they can make enough strides that they don't have to give up things such as driving and, in some cases, their jobs.
Other experts agree that long COVID may damage the brain. An April 2022 study published in the journal Nature found strong evidence that SARS-CoV-2 infection may cause brain-related abnormalities, for example, a reduction in gray matter in certain parts of the brain, including the prefrontal cortex, hypothalamus, and amygdala.
Additionally, white matter, which is found deeper in the brain and is responsible for the exchange of information between different parts of the brain, may also be at risk of damage as a result of the virus, according to a November 2022 study published in the journal SN Comprehensive Clinical Medicine.
Calling it a "fog" makes it easier for clinicians and the general public to dismiss its severity, said Tyler Reed Bell, PhD, a researcher who specializes in viruses that cause brain injury. He is a fellow in the Department of Psychiatry at the University of California, San Diego. Brain fog can make driving and returning to work especially dangerous. Because of difficulty focusing, patients are much more likely to make mistakes that cause accidents.
"The COVID virus is very invasive to the brain," Bell said.
Others contend this may be a rush to judgment. Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine's COVID Recovery Clinic, agrees that in more serious cases of COVID that cause a lack of oxygen to the brain, it's reasonable to call it a brain injury. But brain fog can also be associated with other long COVID symptoms, not just damage to the brain.
Chronic fatigue and poor sleep are both commonly reported symptoms of long COVID that negatively affect brain function, she said. Sleep disturbances, cardiac problems, dysautonomia, and emotional distress could also affect the way the brain functions post COVID. Finding the right treatment requires identifying all the factors contributing to cognitive impairment.
Part of the problem in treating long COVID brain fog is that diagnostic technology is not sensitive enough to detect inflammation that could be causing damage.
Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, Ohio, said her team is working on identifying biomarkers that could detect brain inflammation in a way similar to the manner researchers have identified biomarkers to help diagnose chronic fatigue syndrome. Additionally, a new study published last month in JAMA for the first time clearly defined 12 symptoms of long COVID, and brain fog was listed among them. All of this contributes to the development of clear diagnostic criteria.
"It will make a big difference once we have some consistency among clinicians in diagnosing the condition," said McComsey.
Whitley is thankful for the treatment that she's received thus far. She's seeing a cognitive rehabilitation therapist, who assesses her memory, cognition, and attention span and gives her tools to break up simple tasks, such as driving, so that they don't feel overwhelming. She's back behind the wheel and back to work.
But perhaps most importantly, Whitley joined a support group, led by Jackson, that includes other people experiencing the same symptoms she is. When she was at her darkest, they understood.
"Talking to other survivors has been the only solace in all this," Whitley said. "Together, we grieve all that's been lost."

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The effects of COVID-19 on cognitive performance in a community-based cohort: a COVID symptom study biobank prospective cohort studyNathan J. Cheetham  Rose Penfold  Valentina Giunchiglia  Vicky Bowyer  Carole H. Sudre  Liane S. Canas  et al.
Published:July 21, 2023DOI:https://doi.org/10.1016/j.eclinm.2023.102086
SummaryBackgroundCognitive impairment has been reported after many types of infection, including SARS-CoV-2. Whether deficits following SARS-CoV-2 improve over time is unclear. Studies to date have focused on hospitalised individuals with up to a year follow-up. The presence, magnitude, persistence and correlations of effects in community-based cases remain relatively unexplored.
MethodsCognitive performance (working memory, attention, reasoning, motor control) was assessed in a prospective cohort study of participants from the United Kingdom COVID Symptom Study Biobank between July 12, 2021 and August 27, 2021 (Round 1), and between April 28, 2022 and June 21, 2022 (Round 2). Participants, recruited from the COVID Symptom Study smartphone app, comprised individuals with and without SARS-CoV-2 infection and varying symptom duration. Effects of COVID-19 exposures on cognitive accuracy and reaction time scores were estimated using multivariable ordinary least squares linear regression models weighted for inverse probability of participation, adjusting for potential confounders and mediators. The role of ongoing symptoms after COVID-19 infection was examined stratifying for self-perceived recovery. Longitudinal analysis assessed change in cognitive performance between rounds.
Findings3335 individuals completed Round 1, of whom 1768 also completed Round 2. At Round 1, individuals with previous positive SARS-CoV-2 tests had lower cognitive accuracy (N = 1737, β = −0.14 standard deviations, SDs, 95% confidence intervals, CI: −0.21, −0.07) than negative controls. Deficits were largest for positive individuals with ≥12 weeks of symptoms (N = 495, β = −0.22 SDs, 95% CI: −0.35, −0.09). Effects were comparable to hospital presentation during illness (N = 281, β = −0.31 SDs, 95% CI: −0.44, −0.18), and 10 years age difference (60–70 years vs. 50–60 years, β = −0.21 SDs, 95% CI: −0.30, −0.13) in the whole study population. Stratification by self-reported recovery revealed that deficits were only detectable in SARS-CoV-2 positive individuals who did not feel recovered from COVID-19, whereas individuals who reported full recovery showed no deficits. Longitudinal analysis showed no evidence of cognitive change over time, suggesting that cognitive deficits for affected individuals persisted at almost 2 years since initial infection.
InterpretationCognitive deficits following SARS-CoV-2 infection were detectable nearly two years post infection, and largest for individuals with longer symptom durations, ongoing symptoms, and/or more severe infection. However, no such deficits were detected in individuals who reported full recovery from COVID-19. Further work is needed to monitor and develop understanding of recovery mechanisms for those with ongoing symptoms.

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CLINICAL SUMMARY FROM UNIVADISInfection Duration Linked to Long COVID-19Liz Scherer   |   29 July 2023
Key finding
Among healthcare workers, the likelihood of developing long COVID-19 (at least one symptom lasting longer than 4 weeks) appeared to increase proportionally to the duration of COVID-19 positivity, although adjusted analysis suggested that BNT162b2 vaccination (two doses plus a booster) reduced this probability, even during the Omicron wave.
The study was conducted by Italian researchers and appeared in the journal Clinical Infectious Diseases.
Implications
The longer COVID-19 symptoms last, the greater the risk for developing long COVID-19, especially in older female patients. Clinicians should continue to encourage patients to complete recommended BNT162b2 vaccination schedules to avert symptom severity, duration, and poor outcomes.
Results
Just over a third (34.1%) of the study cohort who had been previously infected with COVID-19 developed long COVID-19; the entire analysed cohort (n=1293) received three BNT162b2 vaccine doses. Compared with a reference group of all males with no allergy, infected during wave 1, unvaccinated and with a positivity for <10 days, vaccination and infection in wave 3 correlated with a lower probability of long COVID-19.
Conversely, self-reported positivity lasting 11-14 days increased long COVID-19 risk more than 2-fold, lasting 15-20 days increased more than 4-fold, and risk increased more than 5-fold when positivity lasted more than 21 days.
Only 14.5% of individuals with positivity lasting 10 days or fewer developed long COVID-19 vs 42.5% infected 15-21 days, and 56.2% for those infected more than 21 days. In a subgroup analysis and after adjustment, there was a 1.5-fold increased risk for long COVID-19 based on symptom duration, and vaccination with three doses decreased this risk by more than half.
Study design
Italian researchers conducted an observational study of 1293 fully vaccinated (two doses and one booster shot with BNT162b2) healthcare workers previously infected with SARS-CoV-2 and developing a COVID-19 infection during one of three waves in which the following variants were dominating: wave 1, wild-type; wave 2, Alpha variant; wave 3, Delta and Omicron variants.
The study goal was to determine the likelihood of developing long COVID-19 based on the duration of SARS-CoV-2 positivity. Long COVID-19 was defined as >1 symptoms lasting >4 weeks post-first COVID-19 infection.