Abstracts from August 1st

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.