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
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.
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
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.
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