Dr. Rosamund Vallings
  • Home
  • About Ros
  • About CFS
    • What is CFS?
    • Who is at risk?
    • Diagnosis
    • Management
  • Information
    • CFS/ME and Covid-19 >
      • CFS and Covid-19 - Articles
    • Books
    • Upcoming Events
    • Handouts
    • Reports
    • Links
    • Abstracts
    • News Items
    • Obituaries
    • Articles

Abstracts from 1 December 2022

1/12/2022

0 Comments

 
The of Hyperactivated Platelets and Fibrinaloid Microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
 
Jean M. Nunes , Arneaux Kruger, Amy Proal,Douglas B. Kell, Etheresia Pretorius
 1,3,*
1
Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7602, South Africa
2
Pharmaceuticals 2022, 15(8), 931; https://doi.org/10.3390/ph15080931
Received: 27 June 2022 / Revised: 20 July 2022 / Accepted: 23 July 2022 / Published: 27 July 2022
(This article belongs to the Special Issue Anticoagulants and Antiplatelet Drugs)Abstract  We have previously demonstrated that platelet-poor plasma (PPP) obtained from patients with Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is characterized by a hypercoagulable state and contains hyperactivated platelets and considerable numbers of already-formed amyloid fibrin(ogen) or fibrinaloid microclots. Due to the substantial overlap in symptoms and etiology between Long COVID/PASC and ME/CFS, we investigated whether coagulopathies reflected in Long COVID/PASC—hypercoagulability, platelet hyperactivation, and fibrinaloid microclot formation—were present in individuals with ME/CFS and gender- and age-matched healthy controls. ME/CFS samples showed significant hypercoagulability as judged by thromboelastography of both whole blood and platelet- plasma. The area of plasma images containing fibrinaloid microclots was commonly more than 10-fold greater in untreated PPP from individuals with ME/CFS than in that of healthy controls. A similar difference was found when the plasma samples were treated with thrombin. Using labelled PAC-1, which recognizes glycoprotein IIb/IIIa, and CD62P, which binds P-selectin, we observed hyperactivation of platelets in ME/CFS hematocrit samples. Using a quantitative scoring system, the ME/CFS platelets were found to have a mean spreading score of 2.72 ± 1.24 vs. 1.00 (activation with     formation) for healthy controls. We conclude that ME/CFS is accompanied by substantial and measurable changes in coagulability, platelet hyperactivation, and fibrinaloid microclot formation. However, the fibrinaloid microclot load was not as great as was previously noted in Long COVID/PASC. Fibrinaloid microclots, in particular, may contribute to many ME/CFS symptoms, such as fatigue, seen in patients with ME/CFS, via the (temporary) blockage of microcapillaries and hence ischemia. Furthermore, fibrinaloid microclots might damage the endothelium. The discovery of these biomarkers represents an important development in ME/CFS research. It also points to possible uses for treatment strategies using known drugs and/or nutraceuticals that target systemic vascular pathology and endothelial inflammation.

Serum of Post-COVID-19 Syndrome Patients with or without ME/CFS Differentially Affects Endothelial Cell Function In Vitroby Lavinia Flaskamp     Constanze Roubal   Franziska Sotzny   Claudia Kedor  Sandra Bauer   ,
Carmen Scheibenbogen   and  Martina Seifert
Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, 13353 Berlin, Germany
Cells 2022, 11(15), 2376; https://doi.org/10.3390/cells11152376
Received: 8 July 2022 / Revised: 28 July 2022 / Accepted: 29 July 2022 / Published: 2 August 2022
Abstract
A proportion of COVID-19 reconvalescent patients develop post-COVID-19 syndrome (PCS) including a subgroup fulfilling diagnostic criteria of Myalgic encephalomyelitis/Chronic Fatigue Syndrome (PCS/CFS). Recently, endothelial dysfunction (ED) has been demonstrated in these patients, but the mechanisms remain elusive. Therefore, we investigated the effects of patients’ sera on endothelia cells (ECs) in vitro. PCS (n = 17), PCS/CFS (n = 13), and healthy controls (HC, n = 14) were screened for serum anti-endothelial cell autoantibodies (AECAs) and dysregulated cytokines. Serum-treated ECs were analysed for the induction of activation markers and the release of small molecules by flow cytometry. Moreover, the angiogenic potential of sera was measured in a tube formation assay. While only marginal differences between patient groups were observed for serum cytokines, AECA binding to ECs was significantly increased in PCS/CFS patients. Surprisingly, PCS and PCS/CFS sera reduced surface levels of several EC activation markers. PCS sera enhanced the release of molecules associated with vascular remodelling and significantly promoted angiogenesis in vitro compared to the PCS/CFS and HC groups. Additionally, sera from both patient cohorts induced the release of molecules involved in inhibition of nitric oxide-mediated endothelial relaxation. Overall, PCS and PCS/CFS patients′ sera differed in their AECA content and their functional effects on ECs, i.e., secretion profiles and angiogenic potential. We hypothesise a pro-angiogenic effect of PCS sera as a compensatory mechanism to ED which is absent in PCS/CFS patients.
Keywords: 
endothelial cells; angiogenesis; endothelial dysfunction; post-COVID syndrome; myalgic encephalomyelitis/chronic fatigue syndrome; autoantibodies

 
30% of Adults With COVID Have Symptoms Lasting 3 MonthsAaron Gould Sheinin
November 30, 2022
WEBMED
Nearly 3 of every 10 U.S. adults who have had COVID-19 said that their symptoms lasted at least 3 months, according to a new Census Bureau report.
The report, called the Household Pulse Survey, was based on responses collected from Nov. 2-14. Nearly 36 million adults – 29.1% – said their symptoms lasted at least a quarter of the year. In Mississippi, more than 42% of adults said they had extended symptoms, the most of any state, while only 22% of adults in Maine said the same, the lowest of any state.
Those numbers are actually down slightly from Oct. 5-17, when 29.6% of U.S. adults said they'd had long COVID symptoms. The same percentages were seen in September, while from July 27 to Aug. 8, the percentage of adults with long COVID symptoms was 33.2%.
In the same survey, nearly 15% of all adults said they had ever experienced long COVID of any duration during the Nov. 2-Nov. 14 survey period.
It’s estimated that more than a third of people who have had COVID-19 also have neurological complications such as brain fog that persist or develop 3 months after infection. And two-thirds of people with long COVID still have neurological symptoms after 6 months, some studies show.
Recent data reveals long COVID is keeping 2 million to 4 million Americans out of work, and the virus is still killing nearly 400 people in the U.S. every day.
Sources     .S. Census Bureau: "Household Pulse Survey."
 
Am J Respir Crit Care Med. 2022 Jan 1; 205(1): 126–129.
Published online 2021 Oct 19. doi: 10.1164/rccm.202108-1903LE PMCID: PMC8865580
PMID: 34665688
Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome
Esther de Boer, 1 , 2 Irina Petrache, 1 , 2 ,* Nir M. Goldstein, 1 J. Tod Olin, 1 Rebecca C. Keith, 1 , 2 Brian Modena, 1 Michael P. Mohning, 1 , 2 Zulma X. Yunt, 1 , 2 Inigo San-Millán, 2 , 3 , ‡ and Jeffrey J. Swigris 1 , 2 , ‡
To the Editor:  After acute infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many individuals experience a range of symptoms including dyspnea, exercise intolerance, and chest pain commonly referred to as “post–COVID-19 syndrome” or as post-acute sequelae of SARS-CoV-2 infection (PASC) (1). Exertional dyspnea and physical activity intolerance in PASC can be debilitating despite mild acute coronavirus disease (COVID-19) and normal resting pulmonary physiology and cardiac function (2). There is an urgent need to understand the pathogenesis of PASC and find effective treatments. The cardiopulmonary exercise test (CPET) is commonly used to investigate unexplained exertional dyspnea; as such, it could provide insight into mechanisms of PASC. CPET data can be used to calculate rates of β-oxidation of fatty acids (FATox) and of lactate clearance, providing insight into mitochondrial function (3). Fit individuals have better mitochondrial function and a higher rate of FATox during exercise than less fit individuals (4). Our results suggest that patients with PASC have significant impairment in fat β-oxidation and increased blood lactate accumulation during exercise, regardless of previous comorbidities.
In this study, we investigated whether patients with PASC had compromised mitochondrial function during graded exercise. Data were obtained via retrospective review of the electronic medical record from a cohort of 50 subjects with PASC (n = 50, age = 50 ± 15 yr, 35 female) that were consecutively referred to and willing to complete CPET in the Pulmonary Physiology Laboratory at National Jewish Health between June 2020 and April 2021 (Table 1). No subject was excluded. Patients were assessed on a cycle ergometer (Vmax 29; SensorMedics Corp) using a continuous ramp protocol to exhaustion. Cardiovascular, ventilatory, metabolic, and gas exchange data were collected using a metabolic cart (Ultima Cardio2 System; Med graphics) per standard protocol (5). For calculations of total FATox and carbohydrate oxidation (CHOox), we used the stoichiometric equations by Frayn and colleagues: FATox [g/min]  = 1.67 × V˙o2 [L/min] – 1.67 × V˙co2 [L/min] and CHOox [g/min] = 4.55 × V˙o2 [L/min] – 3.21 × V˙co2 [L/min] (6). Patient data were compared with results from two published cohorts that included subjects tested with CPET in Denver, Colorado (i.e., the same altitude as our cohort). The characteristics of these cohorts have been previously described (3). Statistical analyses were performed in SPSS Statistics V.27 (IBM) and graphed with Prism V.9.1.0(221) (GraphPad Software). Our study was approved by The Biomedical Research Alliance of New York (BRANY) Institutional Review Board (IRB) study # 20-12-582-528.

Long-lasting Symptoms After an Acute COVID-19 Infection and Factors Associated With Their ResolutionOlivier Robineau, MD, PhD1,2; Marie Zins, MD, PhD3; Mathilde Touvier, MD, PhD4; et alEmmanuel Wiernik, PhD3; Cedric Lemogne, MD, PhD5; Xavier de Lamballerie, MD, PhD6; Hélène Blanché, PhD7; Jean-François Deleuze, PhD7; Paola Mariela Saba Villarroel, PhD6; Céline Dorival, PhD1; Jerome Nicol, PhD1; Roselyn Gomes-Rima, MPH8; Emmanuelle Correia, PhD8; Mireille Coeuret-Pellicer, MD, MPH3; Nathalie Druesne-Pecollo, PhD4; Younes Esseddik, PhD4; Céline Ribet, PhD3; Marcel Goldberg, MD, PhD3; Gianluca Severi, PhD8,9; Fabrice Carrat, MD, PhD1,10; for the Santé, Pratiques, Relations et Inégalités Sociales en Population Générale Pendant la Crise COVID-19–Sérologie (SAPRIS-SERO) Study Group
JAMA Netw Open. 2022;5(11):e2240985. doi:10.1001/jamanetworkopen.2022.40985
Key Points
Question  What is the duration of persistent symptoms after SARS-CoV-2 infection, and what factors are associated with their resolution?
Findings  This cross-sectional study nested in 3 French population-based cohorts found that approximately 10% of individuals with acute COVID-19 infection still had symptoms after 1 year of follow-up. The risk factors associated with the duration of these symptoms vary depending on their persistence.
Meaning  This study suggests that persistent symptoms after SARS-CoV-2 infection is a public health concern.
Abstract
Importance  Persistent symptoms after SARS-CoV-2 infection are an emerging public health problem. The duration of these symptoms remains poorly documented.
Objective  To describe the temporal dynamics of persistent symptoms after SARS-CoV-2 infection and the factors associated with their resolution.
Design, Setting, and Participants  This cross-sectional study involved 53 047 participants from 3 French adult population-based cohorts (CONSTANCES [Consultants des Centres d’Examens de Santé], E3N/E4N, and Nutrinet-Santé) who were included in a nationwide survey about SARS-CoV-2 infection. All participants were asked to complete self-administered questionnaires between April 1 and June 30, 2020. Variables included sociodemographic characteristics, comorbid conditions, COVID-19 diagnosis, and acute symptoms. Blood samples were obtained for serologic analysis between May 1 and November 30, 2020, from patients with SARS-CoV-2 infection defined as enzyme-linked immunosorbent assay immunoglobulin G antispike detection confirmed with a neutralization assay. A follow-up internet questionnaire was completed between June 1 and September 30, 2021, with details on persistent symptoms, their duration, and SARS-CoV-2 infection diagnosis by polymerase chain reaction.
Main Outcomes and Measures  Persistent symptoms were defined as symptoms occurring during the acute infection and lasting 2 or more months. Survival models for interval-censored data were used to estimate symptom duration from the acute episode. Multivariable adjusted hazard ratios (HRs) were estimated for age, sex, and comorbid conditions. Factors associated with the resolution of symptoms were assessed.
Results  A total of 3972 participants (2531 women [63.7%; 95% CI, 62.2%-65.2%]; mean [SD] age, 50.9 [12.7] years) had been infected with SARS-CoV-2. Of these 3972 participants, 2647 (66.6% [95% CI, 65.1%-68.1%]) reported at least 1 symptom during the acute phase. Of these 2647 participants, 861 (32.5% [95% CI, 30.8%-34.3%]) reported at least 1 persistent symptom lasting 2 or more months after the acute phase. After 1 year of follow-up, the estimated proportion of individuals with complete symptom resolution was 89.9% (95% CI, 88.7%-90.9%) with acute symptoms. Older age (>60 years; HR, 0.78; 95% CI, 0.68-0.90), female sex (HR, 0.64; 95% CI, 0.58-0.70), history of cancer (HR, 0.61; 95% CI, 0.47-0.79), history of tobacco consumption (HR, 0.80; 95% CI, 0.73-0.88), high body mass index (≥30: HR, 0.75; 95% CI, 0.63-0.89), and high number of symptoms during the acute phase (>4; HR, 0.43; 95% CI, 0.39-0.48) were associated with a slower resolution of symptoms.
Conclusions and Relevance  In this cross-sectional study, persistent symptoms were still present in 10.1% of infected individuals at 1 year after SARS-CoV-2 infection. Given the high level of cumulative incidence of COVID-19, the absolute prevalent number of people with persistent symptoms is a public health concern.

 
Post–COVID-19 Symptoms 2 Years After SARS-CoV-2 Infection Among Hospitalized vs Nonhospitalized PatientsCésar Fernández-de-las-Peñas, PT, PhD1; Jorge Rodríguez-Jiménez, PT, MSc1; Ignacio Cancela-Cilleruelo, PT, MSc1; et alAngel Guerrero-Peral, MD, PhD2,3; José D. Martín-Guerrero, PhD4; David García-Azorín, MD, PhD2; Ana Cornejo-Mazzuchelli, MD5; Valentín Hernández-Barrera, PhD6; Oscar J. Pellicer-Valero, PhD4
JAMA Netw Open. 2022;5(11):e2242106. doi:10.1001/jamanetworkopen.2022.42106
Key Points
Question  What is the prevalence of post–COVID-19 symptoms among hospitalized and nonhospitalized patients 2 years after acute infection?
Findings  This cross-sectional study found that the proportion of patients with at least 1 post–COVID-19 symptom 2 years after acute infection was 59.7% for hospitalized patients and 67.5% for those not requiring hospitalization. No significant differences in post–COVID-19 symptoms were seen between hospitalized and nonhospitalized patients.
Meaning  Similar rates of post–COVID-19 symptoms between hospitalized and nonhospitalized patients suggest that, among all patients who contract COVID-19, these sequelae deserve attention.
Abstract
Importance  Identification of long-term post–COVID-19 symptoms among hospitalized and nonhospitalized patients is needed.
Objective  To compare the presence of post–COVID-19 symptoms 2 years after acute SARS-CoV-2 infection between hospitalized and nonhospitalized patients.
Design, Setting, and Participants  A cross-sectional cohort study was conducted at 2 urban hospitals and general practitioner centers from March 20 to April 30, 2020, among 360 hospitalized patients and 308 nonhospitalized patients with acute SARS-CoV-2 infection during the first wave of the pandemic. Follow-up was conducted 2 years later.
Main Outcomes and Measures  Participants were scheduled for a telephone interview 2 years after acute infection. The presence of post–COVID-19 symptoms was systematically assessed, with particular attention to symptoms starting after infection. Hospitalization and clinical data were collected from medical records. Between-group comparisons and multivariate logistic regressions were conducted.
Results  A total of 360 hospitalized patients (162 women [45.0%]; mean [SD] age, 60.7 [16.1] years) and 308 nonhospitalized patients (183 women [59.4%]; mean [SD] age, 56.7 [14.7] years) were included. Dyspnea was more prevalent at the onset of illness among hospitalized than among nonhospitalized patients (112 [31.1%] vs 36 [11.7%]; P < .001), whereas anosmia was more prevalent among nonhospitalized than among hospitalized patients (66 [21.4%] vs 36 [10.0%]; P = .003). Hospitalized patients were assessed at a mean (SD) of 23.8 (0.6) months after hospital discharge, and nonhospitalized patients were assessed at a mean (SD) of 23.4 (0.7) months after the onset of symptoms. The number of patients who exhibited at least 1 post–COVID-19 symptom 2 years after infection was 215 (59.7%) among hospitalized patients and 208 (67.5%) among nonhospitalized patients (P = .01). Among hospitalized and nonhospitalized patients, fatigue (161 [44.7%] vs 147 [47.7%]), pain (129 [35.8%] vs 92 [29.9%]), and memory loss (72 [20.0%] vs 49 [15.9%]) were the most prevalent post–COVID-19 symptoms 2 years after SARS-CoV-2 infection. No significant differences in post–COVID-19 symptoms were observed between hospitalized and nonhospitalized patients. The number of preexisting medical comorbidities was associated with post–COVID-19 fatigue (odds ratio [OR], 1.93; 95% CI, 1.09-3.42; P = .02) and dyspnea (OR, 1.91; 95% CI, 1.04-3.48; P = .03) among hospitalized patients. The number of preexisting medical comorbidities (OR, 3.75; 95% CI, 1.67-8.42; P = .001) and the number of symptoms at the onset of illness (OR, 3.84; 95% CI, 1.33-11.05; P = .01) were associated with post–COVID-19 fatigue among nonhospitalized patients.
Conclusions and Relevance  This cross-sectional study suggested the presence of at least 1 post–COVID-19 symptom in 59.7% of hospitalized patients and 67.5% of nonhospitalized patients 2 years after infection. Small differences in symptoms at onset of COVID-19 were identified between hospitalized and nonhospitalized patients. Post–COVID-19 symptoms were similar between hospitalized and nonhospitalized patients; however, lack of inclusion of uninfected controls limits the ability to assess the association of SARS-CoV-2 infection with overall and specific post–COVID-19 symptoms 2 years after acute infection. Future studies should include uninfected control populations.
 

Neuromodulation  . 2022 Nov 23;S1094-7159(22)01332-0. doi: 0.1016/j.neurom.2022.10.044. 
The Analgesic Effect of Transcranial Direct Current Stimulation in Fibromyalgia: A Systematic Review, Meta-Analysis, and Meta-Regression of Potential Influencers of Clinical EffectPaulo E P Teixeira 1, Kevin Pacheco-Barrios 2, Luis Castelo Branco 3, Paulo S de Melo 3, Anna Marduy 3, Wolnei Caumo 4, Stefania Papatheodorou 5, Julie Keysor 6, Felipe Fregni 7
PMID: 36435660
Abstract
Background: There is tentative evidence to support the analgesic effect of transcranial direct current stimulation (tDCS) in fibromyalgia (FM), with large variability in the effect size (ES) encountered in different clinical trials. Understanding the source of the variability and exploring how it relates to the clinical results could characterize effective neuromodulation protocols and ultimately guide care in FM pain. The primary objective of this study was to determine the effect of tDCS in FM pain as compared with sham tDCS. The secondary objective was to explore the relationship of methodology, population, and intervention factors and the analgesic effect of tDCS in FM.Materials and methods: For the primary objective, a systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized clinical trials (RCTs) investigating tDCS as an intervention for FM pain were searched in MEDLINE, Embase, and the Web Of Science. Studies were excluded if they used cross-over designs or if they did not use tDCS as an intervention for pain or did not measure clinical pain. Analysis for the main outcome was performed using a random-effects model. Risk of bias and evidence certainty were assessed for all studies using Cochrane Risk of Bias and Grading of Recommendations Assessment, Development, and Evaluation tools. For the secondary objective, a meta-regression was conducted to explore methodology, population, and intervention factors potentially related to the ES.
Results: Sixteen RCTs were included. Six studies presented a high risk of bias. Significant reduction in pain scores were found for FM (standardized mean difference = 1.22, 95% CI = 0.80-1.65, p < 0.001). Subgroup analysis considering tDCS as a neural target revealed no differences between common neural sites. Meta-regression revealed that the duration of the tDCS protocol in weeks was the only factor associated with the ES, in which protocols that lasted four weeks or longer reported larger ES than shorter protocols.
Conclusions: Results suggest an analgesic effect of tDCS in FM. tDCS protocols that last four weeks or more may be associated with larger ESs. Definite conclusions are inadequate given the large heterogeneity and limited quality of evidence of the included studies.

EDUCATION AND CLINICAL PRACTICE: ORIGINAL RESEARCH| VOLUME 162, ISSUE 5, P1116-1126, NOVEMBER 01, 2022
Neurovascular Dysregulation and Acute Exercise Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
A Randomized, Placebo-Controlled Trial of Pyridostigmine  
Phillip Joseph, MD Rosa Pari, MD Sarah Miller, BS Wenzhong Xiao, PhD  Aaron B. Waxman, MD, PhD  David M. Systrom, MD 
Published:May 05, 2022DOI:https://doi.org/10.1016/j.chest.2022.04.146
BackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, postexertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS.Research QuestionDoes neurovascular dysregulation contribute to exercise intolerance in ME/CFS, and can its treatment improve exercise capacity?
Study Design and MethodsForty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60-mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 min later. The primary end point was the difference in peak exercise oxygen uptake (Vo2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange.
ResultsTwenty-three subjects were assigned to receive pyridostigmine and 22 to receive placebo. The peak Vo2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs –40.2 ± 21.3 mL/min; P < .05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, –105.2 to –2.0). Peak vs rest Vo2 (25.9 ± 15.3 mL/min vs –60.8 ± 25.6 mL/min; P < .01), cardiac output (–0.2 ± 0.6 L/min vs –1.9 ± 0.6 L/min; P < .05), and right atrial pressure (1.0 ± 0.5 mm Hg vs –0.6 ± 0.5 mm Hg; P < .05) were greater in the pyridostigmine group compared with placebo.
InterpretationPyridostigmine improves peak Vo2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise Vo2, cardiac output, and right atrial pressure following placebo may signal the onset of postexertional malaise. 

 
Int J Mol Sci. 2020 Feb 6;21(3):1074. doi: 10.3390/ijms21031074.
An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS PatientsDaniel Missailidis 1, Sarah J Annesley 1, Claire Y Allan 1, Oana Sanislav 1, Brett A Lidbury 2, Donald P Lewis, Paul R Fisher 1     PMID: 32041178  PMCID: PMC7036826
 
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or "PEM"), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition. Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolizing patient blood cells. We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays. As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and "proton leak" as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signaling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters, and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged. Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to "normal" in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated.
Keywords: Complex V; TORC1; chronic fatigue syndrome; mitochondria; myalgic encephalomyelitis; seahorse respirometry.

 
Published: 22 September 2022
Long-term neurologic outcomes of COVID-19
Evan Xu, Yan Xie & Ziyad Al-Aly 
Nature Medicine volume 28, pages2406–2415 (2022)
Abstract
The neurologic manifestations of acute COVID-19 are well characterized, but a comprehensive evaluation of postacute neurologic sequelae at 1 year has not been undertaken. Here we use the national healthcare databases of the US Department of Veterans Affairs to build a cohort of 154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls; we use inverse probability weighting to balance the cohorts, and estimate risks and burdens of incident neurologic disorders at 12 months following acute SARS-CoV-2 infection. Our results show that in the postacute phase of COVID-19, there was increased risk of an array of incident neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (for example, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain–Barré syndrome, and encephalitis or encephalopathy. We estimated that the hazard ratio of any neurologic sequela was 1.42 (95% confidence intervals 1.38, 1.47) and burden 70.69 (95% confidence intervals 63.54, 78.01) per 1,000 persons at 12 months. The risks and burdens were elevated even in people who did not require hospitalization during acute COVID-19. Limitations include a cohort comprising mostly White males. Taken together, our results provide evidence of increased risk of long-term neurologic disorders in people who had COVID-19.
 

 
CLINICAL SUMMARY IN MEDSCAPE:Long COVID: average prevalence of 45%, with highest rate in EuropeMiriam Davis, PhD   |   15 December 2022
Takeaway
  • A global meta-analysis of 194 studies finds a pooled prevalence of long COVID averaging 45% across hospitalised and nonhospitalised patients.
  • The pooled prevalence is highest in Europe, standing at 62.7%.
  • The most common self-reported symptoms are fatigue, breathlessness (dyspnoea), impaired sleep, and pain/discomfort.
Why this matters
  • This is the most comprehensive meta-analysis to date covering long COVID.
  • Findings underscore the importance of prioritising care for long COVID.
Study design
  • Meta-analysis of 194 studies with 735,006 participants after a search of MEDLINE, the Cochrane Library, Scopus, CINAHL, and the preprint server medRxiv.
  • Studies were included if they had ≥100 people with confirmed or self-reported COVID-19 symptoms at ≥28 days after the onset of infection.
  • The preponderance of studies was from Europe (n=106) or Asia (n=49).
  • Most studies reported on hospitalised patients (n=122), whereas 18 were of nonhospitalised and 54 were of combined hospitalised and nonhospitalised patients (mixed).
  • Results relying on patient-reported outcomes and clinical evaluations were evaluated descriptively, and a meta-analysis was performed to generate prevalence estimates.
  • Funding: None.
Key results
  • Average study follow-up time was 126 days.
  • Regardless of hospitalisation status, the average pooled prevalence of long COVID (defined by ≥1 unresolved symptom) was 45%.
  • Europe had the highest estimated pooled prevalence (62.7%; 95% CI, 56.5%-68.5%), whereas Asia had 40.9% (95% CI, 34.5%-47.7%) and North America had 38.9% (95% CI, 24.0%-56.3%). The difference between Europe and Asia was statistically significant.
  • The 5 most common symptoms among formerly hospitalised patients were fatigue (28.4%), pain/discomfort (27.9%), impaired sleep (23.5%), breathlessness (dyspnoea) (22.6%), and impaired usual activity (22.3%).
  • The most common laboratory findings among formerly hospitalised patients were abnormal CT patterns/X-rays (45.3%), ground glass opacification on lungs (41.1%), and impaired diffusion capacity for carbon monoxide (31.7%).
  • Meta-regression of "one or more symptoms" found no associations with age, sex, or average follow-up time, a finding that challenges previous meta-analyses reporting higher prevalence among females.
Limitations
  • Symptom reporting was obtained from wide-ranging self-report tools.
  • Data were collected over a wide range of follow-up periods (>28 days to 387 days).
  • All studies were observational, and only a small percentage had control/comparator groups.
Adv Rheumatol. 2020 Jun 29;60(1):34.  doi: 10.1186/s42358-020-00135-7.

Repetitive transcranial magnetic stimulation of the prefrontal cortex for fibromyalgia syndrome: a randomised controlled trial with 6-months follow upSuman Tanwar 1 2, Bhawna Mattoo 1, Uma Kumar 3, Renu Bhatia 4
Affiliations expand PMID: 32600394
Abstract
Objectives: Fibromyalgia Syndrome (FMS), is a chronic pain disorder with poorly understood pathophysiology. In recent years, repetitive transcranial magnetic stimulation (rTMS) has been recommended for pain relief in various chronic pain disorders. The objective of the present research was to study the effect of low frequency rTMS over the right dorsolateral prefrontal cortex (DLPFC) on pain status in FMS.
Methods: Ninety diagnosed cases of FMS were randomized into Sham-rTMS and Real-rTMS groups. Real rTMS (1 Hz/1200 pulses/8 trains/90% resting motor threshold) was delivered over the right DLPFC for 5 consecutive days/week for 4 weeks. Pain was assessed by subjective and objective methods along with oxidative stress markers. Patients were followed up for 6 months (post-rTMS;15 days, 3 months and 6 months).
Results: In Real-rTMS group, average pain ratings and associated symptoms showed significant improvement post rTMS. The beneficial effects of rTMS lasted up to 6 months in the follow-up phase. In Sham-rTMS group, no significant change in pain ratings was observed.
Conclusion: Right DLPFC rTMS can significantly reduce pain and associated symptoms of FMS probably through targeting spinal pain circuits and top-down pain modulation .
Trial registration: Ref No: CTRI/2013/12/004228.
Keywords: Chronic pain; Dorsolateral prefrontal cortex; Neuromodulation; Nociceptive flexion reflex; Non-invasive therapy; Oxidative stress.

 
Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study
  • Claire E. Hastie, David J. Lowe, Andrew McAuley, Andrew J. Winter, Nicholas L. Mills, Corri Black, Janet T. Scott, Catherine A. O’Donnell, David N. Blane, Susan Browne, Tracy R. Ibbotson & Jill P. Pell 
Nature Communications volume 13, Article number: 5663 (2022) Cite this article
Published: 12 October 2022
Abstract
With increasing numbers infected by SARS-CoV-2, understanding long-COVID is essential to inform health and social care support. A Scottish population cohort of 33,281 laboratory-confirmed SARS-CoV-2 infections and 62,957 never-infected individuals were followed-up via 6, 12 and 18-month questionnaires and linkage to hospitalization and death records. Of the 31,486 symptomatic infections,1,856 (6%) had not recovered and 13,350 (42%) only partially. No recovery was associated with hospitalized infection, age, female sex, deprivation, respiratory disease, depression and multimorbidity. Previous symptomatic infection was associated with poorer quality of life, impairment across all daily activities and 24 persistent symptoms including breathlessness (OR 3.43, 95% CI 3.29–3.58), palpitations (OR 2.51, OR 2.36–2.66), chest pain (OR 2.09, 95% CI 1.96–2.23), and confusion (OR 2.92, 95% CI 2.78–3.07). Asymptomatic infection was not associated with adverse outcomes. Vaccination was associated with reduced risk of seven symptoms. Here we describe the nature of long-COVID and the factors associated with it.

 
Transient receptor potential melastatin 3 dysfunction in post COVID-19 condition and myalgic encephalomyelitis/chronic fatigue syndrome patients
  • Etianne Martini Sasso, Katsuhiko Muraki, Natalie Eaton-Fitch, Peter Smith, Olivia Ly Lesslar, Gary Deed & Sonya Marshall-Gradisnik 
Molecular Medicine volume 28, Article number: 98 (2022)  
AbstractBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multisystemic condition associated with post-infectious onset, impaired natural killer (NK) cell cytotoxicity and impaired ion channel function, namely Transient Receptor Potential Melastatin 3 (TRPM3). Long-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has resulted in neurocognitive, immunological, gastrointestinal, and cardiovascular manifestations recently recognised as post coronavirus disease 2019 (COVID-19) condition. The symptomatology of ME/CFS overlaps significantly with post COVID-19; therefore, this research aimed to investigate TRPM3 ion channel function in post COVID-19 condition patients.
MethodsWhole-cell patch-clamp technique was used to measure TRPM3 ion channel activity in isolated NK cells of N = 5 ME/CFS patients, N = 5 post COVID-19 patients, and N = 5 healthy controls (HC). The TRPM3 agonist, pregnenolone sulfate (PregS) was used to activate TRPM3 function, while ononetin was used as a TRPM3 antagonist.
ResultsAs reported in previous research, PregS-induced TRPM3 currents were significantly reduced in ME/CFS patients compared with HC (p = 0.0048). PregS-induced TRPM3 amplitude was significantly reduced in post COVID-19 condition compared with HC (p = 0.0039). Importantly, no significant difference was reported in ME/CFS patients compared with post COVID-19 condition as PregS-induced TRPM3 currents of post COVID-19 condition patients were similar of ME/CFS patients currents (p > 0.9999). Isolated NK cells from post COVID-19 condition and ME/CFS patients were resistant to ononetin and differed significantly with HC (p < 0.0001).
ConclusionThe results of this investigation suggest that post COVID-19 condition patients may have impaired TRPM3 ion channel function and provide further evidence regarding the similarities between post COVID-19 condition and ME/CFS. Impaired TRPM3 channel activity in post COVID-19 condition patients suggest impaired ion mobilisation which may consequently impede cell function resulting in chronic post-infectious symptoms. Further investigation into TRPM3 function may elucidate the pathomechanism, provide a diagnostic and therapeutic target for post COVID-19 condition patients and commonalities with ME/CFS patients.

 
2022 Jun 1;13(3):698-711.
 doi: 10.14336/AD.2021.0824. eCollection 2022 Jun.
The Role of Kynurenine Pathway and NAD+ Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeMona Dehhaghi 1 2, Hamed Kazemi Shariat Panahi 1, Bahar Kavyani 1, Benjamin Heng 1 2, Vanessa Tan 1 2, Nady Braidy 3, Gilles J Guillemin 1 2         PMID: 35656104 PMCID: PMC9116917
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, complex, and highly debilitating long-term illness. People with ME/CFS are typically unable to carry out their routine activities. Key hallmarks of the disease are neurological and gastrointestinal impairments accompanied by pervasive malaise that is exacerbated after physical and/or mental activity. Currently, there is no validated cure of biomarker signature for this illness. Impaired tryptophan (TRYP) metabolism is thought to play significant role in the pathobiology of ME/CFS. TRYP is an important precursor for serotonin and the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+). TRYP has been associated with the development of some parts of the brain responsible for behavioural functions. The main catabolic route for TRYP is the kynurenine pathway (KP). The KP produces NAD+ and several neuroactive metabolites with neuroprotective (i.e., kynurenic acid (KYNA)) and neurotoxic (i.e., quinolinic acid (QUIN)) activities. Hyperactivation of the KP, whether compensatory or a driving mechanism of degeneration can limit the availability of NAD+ and exacerbate the symptoms of ME/CFS. This review discusses the potential association of altered KP metabolism in ME/CFS. The review also evaluates the role of the patient's gut microbiota on TRYP availability and KP activation. We propose that strategies aimed at raising the levels of NAD+ (e.g., using nicotinamide mononucleotide and nicotinamide riboside) may be a promising intervention to overcome symptoms of fatigue and to improve the quality of life in patients with ME/CFS. Future clinical trials should further assess the potential benefits of NAD+ supplements for reducing some of the clinical features of ME/CFS.
Keywords: Kynurenine pathway; NAD+; gut microbiota; myalgic encephalomyelitis/chronic fatigue syndrome; tryptophan.
Copyright: © 2022 Dehhaghi et al.

 
October 10, 2022
Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021Global Burden of Disease Long COVID Collaborators
JAMA. 2022;328(16):1604-1615. doi:10.1001/jama.2022.18931 COVID-19 Resource Center
Key Points
Question  Among individuals who had symptomatic SARS-CoV-2 infection in 2020 and 2021, what proportion experienced common self-reported Long COVID symptom clusters 3 months after initial infection?
Findings  This observational analysis involved bayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. The modeled estimated proportion with at least 1 of the 3 self-reported Long COVID symptom clusters 3 months after symptomatic SARS-CoV-2 infection was 6.2%, including 3.7% for ongoing respiratory problems, 3.2% for persistent fatigue with bodily pain or mood swings, and 2.2% for cognitive problems after adjusting for health status before COVID-19.
Meaning  This study presents modeled estimates of the proportion of individuals with at least 1 of the 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after symptomatic SARS-CoV-2 infection.
Abstract
Importance  Some individuals experience persistent symptoms after initial symptomatic SARS-CoV-2 infection (often referred to as Long COVID).
Objective  To estimate the proportion of males and females with COVID-19, younger or older than 20 years of age, who had Long COVID symptoms in 2020 and 2021 and their Long COVID symptom duration.
Design, Setting, and Participants  Bayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. Of the 54 studies, 44 were published and 10 were collaborating cohorts (conducted in Austria, the Faroe Islands, Germany, Iran, Italy, the Netherlands, Russia, Sweden, Switzerland, and the US). The participant data were derived from the 44 published studies (10 501 hospitalized individuals and 42 891 nonhospitalized individuals), the 10 collaborating cohort studies (10 526 and 1906), and the 2 US electronic medical record databases (250 928 and 846 046). Data collection spanned March 2020 to January 2022.
Exposures  Symptomatic SARS-CoV-2 infection.
Main Outcomes and Measures  Proportion of individuals with at least 1 of the 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after SARS-CoV-2 infection in 2020 and 2021, estimated separately for hospitalized and nonhospitalized individuals aged 20 years or older by sex and for both sexes of nonhospitalized individuals younger than 20 years of age.
Results  A total of 1.2 million individuals who had symptomatic SARS-CoV-2 infection were included (mean age, 4-66 years; males, 26%-88%). In the modeled estimates, 6.2% (95% uncertainty interval [UI], 2.4%-13.3%) of individuals who had symptomatic SARS-CoV-2 infection experienced at least 1 of the 3 Long COVID symptom clusters in 2020 and 2021, including 3.2% (95% UI, 0.6%-10.0%) for persistent fatigue with bodily pain or mood swings, 3.7% (95% UI, 0.9%-9.6%) for ongoing respiratory problems, and 2.2% (95% UI, 0.3%-7.6%) for cognitive problems after adjusting for health status before COVID-19, comprising an estimated 51.0% (95% UI, 16.9%-92.4%), 60.4% (95% UI, 18.9%-89.1%), and 35.4% (95% UI, 9.4%-75.1%), respectively, of Long COVID cases. The Long COVID symptom clusters were more common in women aged 20 years or older (10.6% [95% UI, 4.3%-22.2%]) 3 months after symptomatic SARS-CoV-2 infection than in men aged 20 years or older (5.4% [95% UI, 2.2%-11.7%]). Both sexes younger than 20 years of age were estimated to be affected in 2.8% (95% UI, 0.9%-7.0%) of symptomatic SARS-CoV-2 infections. The estimated mean Long COVID symptom cluster duration was 9.0 months (95% UI, 7.0-12.0 months) among hospitalized individuals and 4.0 months (95% UI, 3.6-4.6 months) among nonhospitalized individuals. Among individuals with Long COVID symptoms 3 months after symptomatic SARS-CoV-2 infection, an estimated 15.1% (95% UI, 10.3%-21.1%) continued to experience symptoms at 12 months.
Conclusions and Relevance  This study presents modeled estimates of the proportion of individuals with at least 1 of 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after symptomatic SARS-CoV-2 infection.

 
Patients With Mild COVID-19 at Risk of Some Post–COVID-19 Condition SymptomsHoward D. Larkinn   JAMA. Published online January 18, 2023. doi:10.1001/jama.2022.24498
COVID-19 Resource Center
Patients who were diagnosed with mild COVID-19 were up to 4.6 times more likely than uninfected patients to have some symptoms associated with post–COVID-19 condition (PCC) for 6 to 12 months, according to a study in The BMJ.
The study examined electronic health records from 1.9 million patients in a nationwide health care system in Israel who received polymerase chain reaction testing for SARS-CoV-2 over 19 months ending October 1, 2021. It compared outcomes of nearly 300 000 patients who tested positive with matched patients who tested negative.
The excess risks for infected patients were highest for altered senses of smell and taste, cognitive impairment, shortness of breath, weakness, and palpitations. Lower but significant excess risk was found for dizziness. The risk differences were higher 30 to 180 days after infection than 180 to 360 days after infection, and symptoms subsided among most patients with PPC within a year. The study’s findings were similar regardless of virus variants, age, and sex.
“This nationwide study suggests that patients with mild COVID-19 are at risk for a small number of health outcomes, most of which are resolved within a year from diagnosis,” the authors wrote.
Published Online: January 18, 2023. doi:10.1001/jama.2022.24498

 
Infectious Diseases  January 18, 2023
Persistent COVID-19 Symptoms at 6 Months After Onset and the Role of Vaccination Before or After SARS-CoV-2 InfectionStephanie A. Richard, PhD1,2; Simon D. Pollett, MBBS1,2; Anthony C. Fries, PhD3; et alCatherine M. Berjohn, MD, MPH1,4,5; Ryan C. Maves, MD1,4; Tahaniyat Lalani, MBBS1,2,6; Alfred G. Smith, MD6; Rupal M. Mody, MD7; Anuradha Ganesan, MBBS, MPH1,2,8; Rhonda E. Colombo, MD1,2,5,9; David A. Lindholm, MD5,10; Michael J. Morris, MD10; Nikhil Huprikar, MD5,8; Christopher J. Colombo, MD5,9; Cristian Madar, MD11; Milissa Jones, MD, MPH11,12; Derek T. Larson, DO5,13; Samantha E. Bazan, AN14; Katrin Mende, PhD1,2,10; David Saunders, MD5; Jeffrey Livezey, MD12; Charlotte A. Lanteri, MD1; Ann I. Scher, PhD; Celia Byrne, PhD; Jennifer Rusiecki, PhD; Evan Ewers, MD1,13; Nusrat J. Epsi, PhD1,2; Julia S. Rozman, BS1,2; Caroline English1,2; Mark P. Simons, PhD1; David R. Tribble, MD1,15; Brian K. Agan, MD1,2; Timothy H. Burgess, MD1; for the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases With Pandemic Potential (EPICC) COVID-19 Cohort Study Group
JAMA Netw Open. 2023;6(1):e2251360. doi:10.1001/jamanetworkopen.2022.51360
Key Points
Question  What factors are associated with persistent post–COVID-19 symptoms, and how do post–COVID-19 medical encounters change over time?
Findings  In this cohort study of 1832 US adults, the risk of reporting symptoms for 28 or more days after COVID-19 onset was significantly higher in participants who were unvaccinated at the time of infection and those who reported moderate or severe acute illness symptoms. At 6 months after onset, participants had significantly higher risk of pulmonary, diabetes, neurological, and mental health encounters vs preinfection baseline.
Meaning  The findings suggest that COVID-19 is associated with increased health care encounters through 6 months after infection; vaccination was associated with lower risk of long-term COVID-19 symptoms.
Abstract
Importance  Understanding the factors associated with post-COVID conditions is important for prevention.
Objective  To identify characteristics associated with persistent post–COVID-19 symptoms and to describe post–COVID-19 medical encounters.
Design, Setting, and Participants  This cohort study used data from the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases With Pandemic Potential (EPICC) study implemented in the US military health system (MHS); MHS beneficiaries aged 18 years or older who tested positive for SARS-CoV-2 from February 28, 2020, through December 31, 2021, were analyzed, with 1-year follow-up.
Exposures  SARS-CoV-2 infection.
Main Outcomes and Measures  The outcomes analyzed included survey-reported symptoms through 6 months after SARS-CoV-2 infection and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis categories reported in medical records 6 months following SARS-CoV-2 infection vs 3 months before infection.
Results  More than half of the 1832 participants in these analyses were aged 18 to 44 years (1226 [66.9%]; mean [SD] age, 40.5 [13.7] years), were male (1118 [61.0%]), were unvaccinated at the time of their infection (1413 [77.1%]), and had no comorbidities (1290 [70.4%]). A total of 728 participants (39.7%) had illness that lasted 28 days or longer (28-89 days: 364 [19.9%]; ≥90 days: 364 [19.9%]). Participants who were unvaccinated prior to infection (risk ratio [RR], 1.39; 95% CI, 1.04-1.85), reported moderate (RR, 1.80; 95% CI, 1.47-2.22) or severe (RR, 2.25; 95% CI, 1.80-2.81) initial illnesses, had more hospitalized days (RR per each day of hospitalization, 1.02; 95% CI, 1.00-1.03), and had a Charlson Comorbidity Index score of 5 or greater (RR, 1.55; 95% CI, 1.01-2.37) were more likely to report 28 or more days of symptoms. Among unvaccinated participants, postinfection vaccination was associated with a 41% lower risk of reporting symptoms at 6 months (RR, 0.59; 95% CI, 0.40-0.89). Participants had higher risk of pulmonary (RR, 2.00; 95% CI, 1.40-2.84), diabetes (RR, 1.46; 95% CI, 1.00-2.13), neurological (RR, 1.29; 95% CI, 1.02-1.64), and mental health–related medical encounters (RR, 1.28; 95% CI, 1.01-1.62) at 6 months after symptom onset than at baseline (before SARS-CoV-2 infection).
Conclusions and Relevance  In this cohort study, more severe acute illness, a higher Charlson Comorbidity Index score, and being unvaccinated were associated with a higher risk of reporting COVID-19 symptoms lasting 28 days or more. Participants with COVID-19 were more likely to seek medical care for diabetes, pulmonary, neurological, and mental health–related illness for at least 6 months after onset compared with their pre-COVID baseline health care use patterns. These findings may inform the risk-benefit ratio of COVID-19 vaccination policy.

 
Long Covid stigma: Estimating burden and validating scale in a UK-based sampleMarija Pantelic , Nida Ziauddeen,Mark Boyes,Margaret E. O’Hara,Claire Hastie,Nisreen A. Alwan 
Published: November 23, 2022 https://doi.org/10.1371/journal.pone.0277317
AbstractStigma can be experienced as perceived or actual disqualification from social and institutional acceptance on the basis of one or more physical, behavioural or other attributes deemed to be undesirable. Long Covid is a predominantly multisystem condition that occurs in people with a history of SARSCoV2 infection, often resulting in functional disability. This study aimed to develop and validate a Long Covid Stigma Scale (LCSS); and to quantify the burden of Long Covid stigma.
MethodsData from the follow-up of a co-produced community-based Long Covid online survey using convenience non-probability sampling was used. Thirteen questions on stigma were designed to develop the LCSS capturing three domains–enacted (overt experiences of discrimination), internalised (internalising negative associations with Long Covid and accepting them as self-applicable) and anticipated (expectation of bias/poor treatment by others) stigma. Confirmatory factor analysis tested whether LCSS consisted of the three hypothesised domains. Model fit was assessed and prevalence was calculated.
Results966 UK-based participants responded (888 for stigma questions), with mean age 48 years (SD: 10.7) and 85% female. Factor loadings for enacted stigma were 0.70–0.86, internalised 0.75–0.84, anticipated 0.58–0.87, and model fit was good. The prevalence of experiencing stigma at least ‘sometimes’ and ‘often/always’ was 95% and 76% respectively. Anticipated and internalised stigma were more frequently experienced than enacted stigma. Those who reported having a clinical diagnosis of Long Covid had higher stigma prevalence than those without.
ConclusionThis study establishes a scale to measure Long Covid stigma and highlights common experiences of stigma in people living with Long Covid.
 

Infectious Diseases  February 1, 2023
Reports of Guillain-Barré Syndrome After COVID-19 Vaccination in the United StatesWinston E. Abara, MD1; Julianne Gee, MPH1; Paige Marquez, MSPH1; et alJared Woo, MPH1; Tanya R. Myers, PhD1; Allison DeSantis, MPH1; Jane A. G. Baumblatt, MD2; Emily Jane Woo, MD, MPH2; Deborah Thompson, MD2; Narayan Nair, MD2; John R. Su, MD, PhD1; Tom T. Shimabukuro, MD, MPH, MBA1; David K. Shay, MD, MPH1
JAMA Netw Open. 2023;6(2):e2253845. doi:10.1001/jamanetworkopen.2022.53845
Key Points
Question  Are Ad26.COV2.S (Janssen), BNT162b2 (Pfizer-BioNTech), or mRNA-1273 (Moderna) COVID-19 vaccines associated with Guillain-Barré syndrome (GBS) within 21 or 42 days after vaccination?
Findings  This cohort study of 487 651 785 COVID-19 vaccine doses found that in observed-to-expected analyses, the observed number of GBS reports was higher than expected based on background rates within 21 and 42 days after vaccination for Ad26.COV2.S but not BNT162b2 or mRNA-1273. GBS reporting rates within 21 and 42 days of Ad26.COV2.S vaccination were 9 to 12 times higher than after BNT162b2 or mRNA-1273 vaccination.
Meaning  These findings suggest that Ad26.COV2.S vaccination was associated with GBS and that GBS after BNT162b2 and mRNA-1273 may represent background incidence.
Abstract
Importance  Because of historical associations between vaccines and Guillain-Barré syndrome (GBS), the condition was a prespecified adverse event of special interest for COVID-19 vaccine monitoring.
Objective  To evaluate GBS reports to the Vaccine Adverse Event Reporting System (VAERS) and compare reporting patterns within 21 and 42 days after vaccination with Ad26.COV2.S (Janssen), BNT162b2 (Pfizer-BioNTech), and mRNA-1273 (Moderna) COVID-19 vaccines.
Design, Setting, and Participants  This retrospective cohort study was conducted using US VAERS reports submitted during December 2020 to January 2022. GBS case reports verified as meeting the Brighton Collaboration case definition for GBS in US adults after COVID-19 vaccination were included.
Exposures  Receipt of the Ad26.COV2.S, BNT162b2, or mRNA-1273 COVID-19 vaccine.
Main Outcomes and Measures  Descriptive analyses of GBS case were conducted. GBS reporting rates within 21 and 42 days after Ad26.COV2.S, BNT162b2, or mRNA-1273 vaccination based on doses administered were calculated. Reporting rate ratios (RRRs) after receipt of Ad26.COV2.S vs BNT162b2 or mRNA-1273 within 21- and 42-day postvaccination intervals were calculated. Observed-to-expected (OE) ratios were estimated using published GBS background rates.
Results  Among 487 651 785 COVID-19 vaccine doses, 17 944 515 doses (3.7%) were Ad26.COV2.S, 266 859 784 doses (54.7%) were BNT162b2, and 202 847 486 doses (41.6%) were mRNA-1273. Of 295 verified reports of individuals with GBS identified after COVID-19 vaccination (12 Asian [4.1%], 18 Black [6.1%], and 193 White [65.4%]; 17 Hispanic [5.8%]; 169 males [57.3%]; median [IQR] age, 59.0 [46.0-68.0] years), 275 reports (93.2%) documented hospitalization. There were 209 and 253 reports of GBS that occurred within 21 days and 42 days of vaccination, respectively. Within 21 days of vaccination, GBS reporting rates per 1 000 000 doses were 3.29 for Ad26.COV.2, 0.29 for BNT162b2, and 0.35 for mRNA-1273 administered; within 42 days of vaccination, they were 4.07 for Ad26.COV.2, 0.34 for BNT162b2, and 0.44 for mRNA-1273. GBS was more frequently reported within 21 days after Ad26.COV2.S than after BNT162b2 (RRR = 11.40; 95% CI, 8.11-15.99) or mRNA-1273 (RRR = 9.26; 95% CI, 6.57-13.07) vaccination; similar findings were observed within 42 days after vaccination (BNT162b2: RRR = 12.06; 95% CI, 8.86-16.43; mRNA-1273: RRR = 9.27; 95% CI, 6.80-12.63). OE ratios were 3.79 (95% CI, 2.88-4.88) for 21-day and 2.34 (95% CI, 1.83-2.94) for 42-day intervals after Ad26.COV2.S vaccination and less than 1 (not significant) after BNT162b2 and mRNA-1273 vaccination within both postvaccination periods.
Conclusions and Relevance  This study found disproportionate reporting and imbalances after Ad26.COV2.S vaccination, suggesting that Ad26.COV2.S vaccination was associated with increased risk for GBS. No associations between mRNA COVID-19 vaccines and risk of GBS were observed.
 
Question  Are Ad26.COV2.S (Janssen), BNT162b2 (Pfizer-BioNTech), or mRNA-1273 (Moderna) COVID-19 vaccines associated with Guillain-Barré syndrome (GBS) within 21 or 42 days after vaccination?
Findings  This cohort study of 487 651 785 COVID-19 vaccine doses found that in observed-to-expected analyses, the observed number of GBS reports was higher than expected based on background rates within 21 and 42 days after vaccination for Ad26.COV2.S but not BNT162b2 or mRNA-1273. GBS reporting rates within 21 and 42 days of Ad26.COV2.S vaccination were 9 to 12 times higher than after BNT162b2 or mRNA-1273 vaccination.
Meaning  These findings suggest that Ad26.COV2.S vaccination was associated with GBS and that GBS after BNT162b2 and mRNA-1273 may represent background incidence.
 
0 Comments

Abstracts from 1 October 2022

10/10/2022

0 Comments

 
A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome
Fredrik Hoel, August Hoel, [...], and Karl J. Tronstad
JLI Insight - Published by American Soc for Clinical Investigation
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls. Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses. In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.
Keywords: Immunology, Metabolism
Keywords: Bioinformatics, Fatty acid oxidation, Intermediary metabolism
_______________________________________________________________________________

October 10, 2022
Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021
Global Burden of Disease Long COVID Collaborators
JAMA. Published online October 10, 2022. doi:10.1001/jama.2022.18931
Key Points
Question  Among individuals who had symptomatic SARS-CoV-2 infection in 2020 and 2021, what proportion experienced common self-reported Long COVID symptom clusters 3 months after initial infection?
Findings  This observational analysis involved bayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. The modeled estimated proportion with at least 1 of the 3 self-reported Long COVID symptom clusters 3 months after symptomatic SARS-CoV-2 infection was 6.2%, including 3.7% for ongoing respiratory problems, 3.2% for persistent fatigue with bodily pain or mood swings, and 2.2% for cognitive problems after adjusting for health status before COVID-19.
Meaning  This study presents modeled estimates of the proportion of individuals with at least 1 of the 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after symptomatic SARS-CoV-2 infection.
Abstract
Importance  Some individuals experience persistent symptoms after initial symptomatic SARS-CoV-2 infection (often referred to as Long COVID).
Objective  To estimate the proportion of males and females with COVID-19, younger or older than 20 years of age, who had Long COVID symptoms in 2020 and 2021 and their Long COVID symptom duration.
Design, Setting, and Participants  Bayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. Of the 54 studies, 44 were published and 10 were collaborating cohorts (conducted in Austria, the Faroe Islands, Germany, Iran, Italy, the Netherlands, Russia, Sweden, Switzerland, and the US). The participant data were derived from the 44 published studies (10 501 hospitalized individuals and 42 891 nonhospitalized individuals), the 10 collaborating cohort studies (10 526 and 1906), and the 2 US electronic medical record databases (250 928 and 846 046). Data collection spanned March 2020 to January 2022.
Exposures  Symptomatic SARS-CoV-2 infection.
Main Outcomes and Measures  Proportion of individuals with at least 1 of the 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after SARS-CoV-2 infection in 2020 and 2021, estimated separately for hospitalized and nonhospitalized individuals aged 20 years or older by sex and for both sexes of nonhospitalized individuals younger than 20 years of age.
Results  A total of 1.2 million individuals who had symptomatic SARS-CoV-2 infection were included (mean age, 4-66 years; males, 26%-88%). In the modeled estimates, 6.2% (95% uncertainty interval [UI], 2.4%-13.3%) of individuals who had symptomatic SARS-CoV-2 infection experienced at least 1 of the 3 Long COVID symptom clusters in 2020 and 2021, including 3.2% (95% UI, 0.6%-10.0%) for persistent fatigue with bodily pain or mood swings, 3.7% (95% UI, 0.9%-9.6%) for ongoing respiratory problems, and 2.2% (95% UI, 0.3%-7.6%) for cognitive problems after adjusting for health status before COVID-19, comprising an estimated 51.0% (95% UI, 16.9%-92.4%), 60.4% (95% UI, 18.9%-89.1%), and 35.4% (95% UI, 9.4%-75.1%), respectively, of Long COVID cases. The Long COVID symptom clusters were more common in women aged 20 years or older (10.6% [95% UI, 4.3%-22.2%]) 3 months after symptomatic SARS-CoV-2 infection than in men aged 20 years or older (5.4% [95% UI, 2.2%-11.7%]). Both sexes younger than 20 years of age were estimated to be affected in 2.8% (95% UI, 0.9%-7.0%) of symptomatic SARS-CoV-2 infections. The estimated mean Long COVID symptom cluster duration was 9.0 months (95% UI, 7.0-12.0 months) among hospitalized individuals and 4.0 months (95% UI, 3.6-4.6 months) among nonhospitalized individuals. Among individuals with Long COVID symptoms 3 months after symptomatic SARS-CoV-2 infection, an estimated 15.1% (95% UI, 10.3%-21.1%) continued to experience symptoms at 12 months.
Conclusions and Relevance  This study presents modeled estimates of the proportion of individuals with at least 1 of 3 self-reported Long COVID symptom clusters (persistent fatigue with bodily pain or mood swings; cognitive problems; or ongoing respiratory problems) 3 months after symptomatic SARS-CoV-2 infection.
​_______________________________________________________________________________

Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults
A Systematic Review and Meta-analysis
Matthew S. Durstenfeld, MD, MAS1,2; Kaiwen Sun, MD1; Peggy Tahir, MLIS, MA3; et alMichael J. Peluso, MD, MHS, MPhil, DTMH1,4; Steven G. Deeks, MD1,4; Mandar A. Aras, MD, PhD1,5; Donald J. Grandis, MD1,5; Carlin S. Long, MD1,5; Alexis Beatty, MD1,5,6; Priscilla Y. Hsue, MD1,2
JAMA Netw Open. 2022;5(10):e2236057. doi:10.1001/jamanetworkopen.2022.36057
Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults 
Key Points
Question  Is exercise capacity reduced more than 3 months after SARS-CoV-2 infection among those with long COVID-19 (LC) symptoms compared with recovered individuals without symptoms, and what patterns of limitations on cardiopulmonary exercise testing (CPET) are common?
Findings  In this systematic review and meta-analysis of 38 studies comprising 2160 participants, exercise capacity was reduced by 4.9 mL/kg/min among individuals with symptoms consistent with LC compared with individuals without symptoms more than 3 months after SARS-CoV-2 infection. Findings among individuals with exertional intolerance suggest that deconditioning, dysfunctional breathing, chronotropic incompetence, and abnormal peripheral oxygen extraction and/or use may contribute to reduced exercise capacity.
Meaning  These findings suggest that CPET may provide insight into the mechanisms for reduced exercise capacity among individuals with LC.
Abstract
Importance  Reduced exercise capacity is commonly reported among individuals with COVID-19 symptoms more than 3 months after SARS-CoV-2 infection (long COVID-19 [LC]). Cardiopulmonary exercise testing (CPET) is the criterion standard to measure exercise capacity and identify patterns of exertional intolerance.
Objectives  To estimate the difference in exercise capacity among individuals with and without LC symptoms and characterize physiological patterns of limitations to elucidate possible mechanisms of LC.
Data Sources  A search of PubMed, EMBASE, Web of Science, preprint servers, conference abstracts, and cited references was performed on December 20, 2021, and again on May 24, 2022. A preprint search of medrxiv.org, biorxiv.org, and researchsquare.com was performed on June 9, 2022.
Study Selection  Studies of adults with SARS-CoV-2 infection more than 3 months earlier that included CPET-measured peak oxygen consumption (V̇o2) were screened independently by 2 blinded reviewers; 72 (2%) were selected for full-text review, and 35 (1%) met the inclusion criteria. An additional 3 studies were identified from preprint servers.
Data Extraction and Synthesis  Data extraction was performed by 2 independent reviewers according to the PRISMA reporting guideline. Data were pooled using random-effects models.
Main Outcomes and Measures  Difference in peak V̇o2 (in mL/kg/min) among individuals with and without persistent COVID-19 symptoms more than 3 months after SARS-CoV-2 infection.
Results  A total of 38 studies were identified that performed CPET on 2160 individuals 3 to 18 months after SARS-CoV-2 infection, including 1228 with symptoms consistent with LC. Most studies were case series of individuals with LC or cross-sectional assessments within posthospitalization cohorts. Based on a meta-analysis of 9 studies including 464 individuals with LC symptoms and 359 without symptoms, the mean peak V̇o2 was −4.9 (95% CI, −6.4 to −3.4) mL/kg/min among those with symptoms with a low degree of certainty. Deconditioning and peripheral limitations (abnormal oxygen extraction) were common, but dysfunctional breathing and chronotropic incompetence were also described. The existing literature was limited by small sample sizes, selection bias, confounding, and varying symptom definitions and CPET interpretations, resulting in high risk of bias and heterogeneity.
Conclusions and Relevance  The findings of this systematic review and meta-analysis study suggest that exercise capacity was reduced more than 3 months after SARS-CoV-2 infection among individuals with symptoms consistent with LC compared with individuals without LC symptoms, with low confidence. Potential mechanisms for exertional intolerance other than deconditioning include altered autonomic function (eg, chronotropic incompetence, dysfunctional breathing), endothelial dysfunction, and muscular or mitochondrial pathology.
​_______________________________________________________________________________

AIM ImmunoTech Announces FDA Clearance of IND Application to Evaluate Ampligen in Phase 2 Clinical Study for the Treatment of Post-COVID Conditions
Company expects to commence patient enrollment and dosing in Q1 2023  October 12, 2022 08:45 ET | Source: AIM ImmunoTech Inc.
OCALA, Fla, Oct. 12, 2022 (GLOBE NEWSWIRE) -- AIM ImmunoTech Inc. (NYSE: American AIM) (“AIM” or the “Company”), an immuno-pharma company focused on the research and development of therapeutics to treat multiple types of cancers, immune disorders, and viral diseases, including COVID-19, the disease caused by the SARS-CoV-2 virus, today announced its Investigational New Drug (IND) application filed with the U.S. Food and Drug Administration (FDA) may proceed to initiate a Phase 2 study evaluating its investigational drug, Ampligen, as a therapeutic for patients with post-COVID conditions (“AMP-518”). AIM has pending patent applications for compositions and methods for treating post-COVID conditions with a composition comprising Ampligen.
“We are very pleased to be able to proceed with our Phase 2 study and are prepared to advance Ampligen as a potential therapeutic for the treatment of myalgic encephalomyelitis/chronic fatigue (ME/CFS)-like post-COVID conditions, an exploding area of significant unmet medical need,” commented Thomas K. Equels, MS JD, Chief Executive Officer of AIM. “Post-COVID-19 Disabling Fatigue, along with other debilitating post-COVID conditions such as ‘Brain Fog’, continue to affect tens of millions of people worldwide. Based on the preliminary uncontrolled clinical data flowing from our AMP-511 study and the antiviral activity we have seen to date, we believe Ampligen has the potential to be an effective treatment option and an important solution for patients and physicians. We are deeply grateful for the FDA’s regulatory guidance related to this important clinical trial and with the IND clearance now in hand, our team is working to get the study up and running as quickly and efficiently as possible. We expect to commence enrollment in early 2023.”
Oved Amitay, PhD, President and CEO of the advocacy organization Solve M.E. added, “Post-COVID conditions continue to present as a serious public health crisis and there remains an ongoing struggle for patients to access safe and effective therapeutics. To address this unmet need, it is critical that we apply existing knowledge, such as studies done previously in ME/CFS. In the AMP-516 study in people with ME/CFS, Ampligen has demonstrated an encouraging safety profile and was well tolerated, and data in post-COVID from the AMP-511 study shows a similar profile. Additionally, the data published in the PLOS ONE paper from a subgroup analysis in the AMP-516 study showed a response rate greater than 50%, a statistically significant response in people who were treated closer to the onset of their disease. I am therefore hopeful about the potential of Ampligen for post-COVID conditions given the possibility of an earlier intervention and believe that this study is an important step in addressing the needs of people with these post-infection debilitating symptoms.”
The planned Phase 2 study is a two-arm, randomized, double-blind, placebo-controlled, multicenter study to evaluate efficacy and safety of Ampligen in patients experiencing the post-COVID condition of fatigue. The primary outcome measure of the study is change from baseline to week 13 in PROMIS® Fatigue Score. Other study outcomes include: change from baseline to week 6 in PROMIS® Fatigue Score; change from baseline to week 6 and 13 in distance traveled during a 6-minute walk test; proportion of subjects with minimal clinically important difference, defined as at least 54 meters, in the Six-Minute Walk Test at the end of 12-week treatment phase; change from baseline to week 6 and 13 in PROMIS® Cognitive Function Score; change from baseline to week 6 and 13 in PROMIS® Sleep Disturbance Score; and change from baseline to week 6 and 13 in 36-Item Short Form Survey.
Approximately 80 subjects between the ages of 18 to 60 years old are expected to be enrolled across up to 10 centers in the United States. Patients will be randomized 1:1 to receive twice weekly IV infusions of Ampligen or placebo for 12 weeks with a follow up phase of 2 weeks. The Company expects to commence patient enrollment and dosing in the AMP-518 study in Q1 2023.
Mol Cell Neurosci. 2022 May;120:103731. doi: 10.1016/j.mcn.2022.103731. Epub 2022 Apr 26.
​_______________________________________________________________________________

Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE)
Gunnar Gottschalk 1, Daniel Peterson 2, Konstance Knox 3, Marco Maynard 4, Ryan J Whelan 4, Avik Roy 5  PMID: 35487443
Abstract
Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a multisystem illness characterized by extreme muscle fatigue associated with pain, neurocognitive impairment, and chronic inflammation. Despite intense investigation, the molecular mechanism of this disease is still unknown. Here we demonstrate that autophagy-related protein ATG13 is strongly upregulated in the serum of ME/CFS patients, indicative of impairment in the metabolic events of autophagy. A Thioflavin T-based protein aggregation assay, array screening for autophagy-related factors, densitometric analyses, and confirmation with ELISA revealed that the level of ATG13 was strongly elevated in serum samples of ME/CFS patients compared to age-matched controls. Moreover, our microglia-based oxidative stress response experiments indicated that serum samples of ME/CFS patients evoke the production of reactive oxygen species (ROS) and nitric oxide in human HMC3 microglial cells, whereas neutralization of ATG13 strongly diminishes the production of ROS and NO, suggesting that ATG13 plays a role in the observed stress response in microglial cells. Finally, an in vitro ligand binding assay provided evidence that ATG13 employs the Receptor for Advanced Glycation End-products (RAGE) to stimulate ROS in microglial cells. Collectively, our results suggest that an impairment of autophagy following the release of ATG13 into serum could be a pathological signal in ME/CFS.
Keywords: ATG13; Autophagy; ME/CFS; Microglia: RAGE; NO; ROS.
Published by Elsevier Inc.
​_______________________________________________________________________________

Addiction Drug Shows Promise Lifting Long COVID Brain Fog, Fatigue
By Julie Steenhuysen
October 18, 2022
Reuters
CHICAGO (Reuters) - Lauren Nichols, a 34-year-old logistics expert for the U.S. Department of Transportation in Boston, has been suffering from impaired thinking and focus, fatigue, seizures, headache and pain since her COVID-19 infection in the spring of 2020.
Last June, her doctor suggested low doses of naltrexone, a generic drug typically used to treat alcohol and opioid addiction. After more than two years of living in "a thick, foggy cloud," she said, "I can actually think clearly." Researchers chasing long COVID cures are eager to learn whether the drug can offer similar benefits to millions suffering from pain, fatigue and brain fog months after a coronavirus infection. The drug has been used with some success to treat a similar complex, post-infectious syndrome marked by cognitive deficits and overwhelming fatigue called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Drawing on its use in ME/CFS and a handful of long COVID pilot studies, there are now at least four clinical trials planned to test naltrexone in hundreds of patients with long COVID, according to a Reuters review of Clinicaltrials.gov and interviews with 12 ME/CFS and long COVID researchers. It is also on the short list of treatments to be tested in the U.S. National Institutes of Health's $1 billion RECOVER Initiative, which aims to uncover underlying causes and find treatments for long COVID, advisers to the trial told Reuters.
Unlike treatments aimed at addressing specific symptoms caused by COVID damage to organs, such as the lungs, low-dose naltrexone (LDN) may reverse some of the underlying pathology driving symptoms, they said.
Naltrexone has anti-inflammatory properties and has been used at low doses for years to treat conditions such as fibromyalgia, Crohn's disease and multiple sclerosis, said Dr. Jarred Younger, director of the Neuro-inflammation, Pain and Fatigue Laboratory at the University of Alabama at Birmingham.
At 50 milligrams - 10 times the low dose - naltrexone is approved to treat opioid and alcohol addiction. Several generic manufacturers sell 50mg pills, but low-dose naltrexone must be purchased through a compounding pharmacy.
Younger, author of a scientific review of the drug as a novel anti-inflammatory, in September submitted a grant application to study LDN for long COVID. "It should be at the top of everyone's list for clinical trials," he said.
Still, the drug is unlikely to help all patients with long COVID, a collection of some 200 symptoms ranging from pain and heart palpitations to insomnia and cognitive impairment. One 218-patient ME/CFS study found 74% had improvements in sleep, reduced pain and neurological disturbances.
"It's not a panacea," said Jaime Seltzer, a Stanford researcher and head of scientific outreach for the advocacy group MEAction. "These people weren't cured, but they were helped."
12
'HUMAN AGAIN' Dr. Jack Lambert, an infectious disease expert at University College Dublin School of Medicine, had used LDN to treat pain and fatigue associated with chronic Lyme disease.
During the pandemic, Lambert recommended LDN to colleagues treating patients with lingering symptoms after bouts of COVID.
It worked so well that he ran a pilot study among 38 long COVID patients. They reported improvements in energy, pain, concentration, insomnia and overall recovery from COVID-19 after two months, according to findings published in July.
Lambert, who is planning a larger trial to confirm those results, said he believes LDN may repair damage of the disease rather than mask its symptoms.
Other planned LDN trials include one by the University of British Columbia in Vancouver and a pilot study by Ann Arbor, Michigan-based startup AgelessRx. That study of 36 volunteers should have results by year-end, said company co-founder Sajad Zalzala. Scientists are still working on explaining the mechanism for how LDN might work. Experiments by Dr. Sonya Marshall-Gradisnik of the National Centre for Neuroimmunology and Emerging Diseases in Australia suggest ME/CFS and long COVID symptoms arise from a significant reduction in function of natural killer cells in the immune system. In laboratory experiments, LDN may have helped restore their normal function, a theory that must still be confirmed. Others believe infections trigger immune cells in the central nervous system called microglia to produce cytokines, inflammatory molecules that cause fatigue and other symptoms associated with ME/CFS and long COVID. Younger believes naltrexone calms these hypersensitized immune cells.
Dr. Zach Porterfield, a virologist at the University of Kentucky who co-chairs a RECOVER task force looking at commonalities with other post-infectious syndromes, said it has recommended LDN be included in RECOVER's treatment trials. Other therapies under consideration, sources said, were antivirals, such as Pfizer Inc's Paxlovid, anti-clotting agents, steroids and nutritional supplements. RECOVER officials said they have received dozens of proposals and could not comment on which drugs will be tested until trials are finalized. Dr. Hector Bonilla, co-director of the Stanford Post-Acute COVID-19 Clinic and a RECOVER adviser, has used LDN in 500 ME/CFS patients, with about half reporting benefits.
He studied LDN in 18 long COVID patients, with 11 showing improvements, and said he believes larger, formal trials could determine whether LDN offers a true benefit. Nichols, a patient adviser to RECOVER, was "ecstatic" when she learned LDN was being considered for the government-funded trials. While LDN has not fixed all her COVID-related problems, Nichols can now work all day without breaks and have a social life at home. "It has made me feel like a human again."
(Reporting by Julie Steenhuysen in Chicago; Editing by Caroline Humer and Bill Berkrot)
​_______________________________________________________________________________

Phenotypic characteristics of peripheral immune cells of Myalgic encephalomyelitis/chronic fatigue syndrome via transmission electron microscopy: A pilot study
  • FFereshteh Jahanbani  ,Rajan D. Maynard ,Justin Cyril Sing, Shaghayegh Jahanbani, John J. Perrino, Damek V. Spacek, Ronald W. Davis, Michael P. Snyder x
  • Published: August 9, 2022  https://doi.org/10.1371/journal.pone.0272703  PLOS one
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic multi-systemic disease characterized by extreme fatigue that is not improved by rest, and worsens after exertion, whether physical or mental. Previous studies have shown ME/CFS-associated alterations in the immune system and mitochondria. We used transmission electron microscopy (TEM) to investigate the morphology and ultrastructure of unstimulated and stimulated ME/CFS immune cells and their intracellular organelles, including mitochondria. PBMCs from four participants were studied: a pair of identical twins discordant for moderate ME/CFS, as well as two age- and gender- matched unrelated subjects—one with an extremely severe form of ME/CFS and the other healthy. TEM analysis of CD3/CD28-stimulated T cells suggested a significant increase in the levels of apoptotic and necrotic cell death in T cells from ME/CFS patients (over 2-fold). Stimulated Tcells of ME/CFS patients also had higher numbers of swollen mitochondria. We also found a large increase in intracellular giant lipid droplet-like organelles in the stimulated PBMCs from the extremely severe ME/CFS patient potentially indicative of a lipid storage disorder. Lastly, we observed a slight increase in platelet aggregation in stimulated cells, suggestive of a possible role of platelet activity in ME/CFS pathophysiology and disease severity. These results indicate extensive morphological alterations in the cellular and mitochondrial phenotypes of ME/CFS patients’ immune cells and suggest new insights into ME/CFS biology. 
​_______________________________________________________________________________

No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Marthe Ueland, Riad Hajdarevic, Olav Mella, Elin B. Strand, Daisy D. Sosa, Ola D. Saugstad, Øystein Fluge, Benedicte A. Lie & Marte K. Viken 
Translational Psychiatry volume 12, Article number: 277 (2022) Published: 11 July 2022
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with a variety of symptoms such as post-exertional malaise, fatigue, and pain, but where aetiology and pathogenesis are unknown. An increasing number of studies have implicated the involvement of the immune system in ME/CFS. Furthermore, a hereditary component is suggested by the reported increased risk for disease in relatives, and genetic association studies are being performed to identify potential risk variants. We recently reported an association with the immunologically important human leucocyte antigen (HLA) genes HLA-C and HLA-DQB1 in ME/CFS. Furthermore, a genome-wide genetic association study in 42 ME/CFS patients reported significant association signals with two variants in the T cell receptor alpha (TRA) locus (P value <5 × 10−8). As the T cell receptors interact with the HLA molecules, we aimed to replicate the previously reported findings in the TRA locus using a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK biobank (2105 cases and 4786 controls). We investigated numerous SNPs in the TRA locus, including the two previously ME/CFS-associated variants, rs11157573 and rs17255510. No associations were observed in the Norwegian cohort, and there was no significant association with the two previously reported SNPs in any of the cohorts. However, other SNPs showed signs of association (P value <0.05) in the UK Biobank cohort and meta-analyses of Norwegian and UK biobank cohorts, but none survived correction for multiple testing. Hence, our research did not identify any reliable associations with variants in the TRA locus.
​_______________________________________________________________________________

Journal of Translational Medicine (2022) 20:273 https://doi.org/10.1186/s12967-022-03460-1 
RESEARCH Combination of whole body cryotherapy with static stretching exercises reduces fatigue and improves functioning of the autonomic nervous system in Chronic Fatigue Syndrome 
Sławomir Kujawski1* , Joanna Słomko1 , Beata R. Godlewska2 , Agnieszka CudnochJędrzejewska3 , Modra Murovska4 , Julia L. Newton5 , Łukasz Sokołowski1 and Paweł Zalewski1,3
 Abstract 
Background: The aim of this study was to explore the tolerability and efect of static stretching (SS) and whole body cryotherapy (WBC) upon fatigue, daytime sleepiness, cognitive functioning and objective and subjective autonomic nervous system functioning in those with Chronic Fatigue Syndrome (CFS) compared to a control population. 
Methods: Thirty-two CFS and eighteen healthy controls (HC) participated in 2 weeks of a SS+WBC programme. This programme was composed of fve sessions per week, 10 sessions in total. 
Results: A significant decrease in fatigue was noted in the CFS group in response to SS+WBC. Some domains of cognitive functioning (speed of processing visual information and set-shifting) also improved in response to SS+WBC in both CFS and HC groups. Our study has confrmed that WBC is well tolerated by those with CFS and leads to symp tomatic improvements associated with changes in cardiovascular and autonomic function. 
Conclusions: Given the preliminary data showing the benefcial efect of cryotherapy, its relative ease of application, good tolerability, and proven safety, therapy with cold exposure appears to be an approach worth attention. Further studies of cryotherapy as a potential treatment in CFS is important in the light of the lack of efective therapeutic options for these common and often disabling symptoms
​_______________________________________________________________________________

Activity monitoring and patient-reported outcome measures in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients
Ingrid G. Rekeland , Kari Sørland, Ove Bruland, Kristin Risa, Kine Alme, Olav Dahl, Karl J. Tronstad, Olav Mella, Øystein Fluge 
Published: September 19, 2022  https://doi.org/10.1371/journal.pone.0274472  PLOS one
Abstract
Introduction
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with no validated specific and sensitive biomarker, and no standard approved treatment. In this observational study with no intervention, participants used a Fitbit activity tracker. The aims were to explore natural symptom variation, feasibility of continuous activity monitoring, and to compare activity data with patient reported outcome measures (PROMs).
Materials and methods
In this pilot study, 27 patients with mild to severe ME/CFS, of mean age 42.3 years, used the Fitbit Charge 3 continuously for six months. Patients wore a SenseWear activity bracelet for 7 days at baseline, at 3 and 6 months. At baseline and follow-up they completed the Short Form 36 Health Survey (SF-36) and the DePaul Symptom Questionnaire–Short Form (DSQ-SF).
Results
The mean number of steps per day decreased with increasing ME/CFS severity; mild 5566, moderate 4991 and severe 1998. The day-by-day variation was mean 47% (range 25%–79%). Mean steps per day increased from the first to the second three-month period, 4341 vs 4781 steps, p = 0.022. The maximum differences in outcome measures between 4-week periods (highest vs lowest), were more evident in a group of eight patients with milder disease (baseline SF-36 PF > 50 or DSQ-SF < 55) as compared to 19 patients with higher symptom burden (SF-36 PF < 50 and DSQ-SF > 55), for SF-36 PF raw scores: 16.9 vs 3.4 points, and for steps per day: 958 versus 479 steps. The correlations between steps per day and self-reported SF-36 Physical function, SF-36 Social function, and DSQ-SF were significant. Fitbit recorded significantly higher number of steps than SenseWear. Resting heart rates were stable during six months.
Conclusion
Continuous activity registration with Fitbit Charge 3 trackers is feasible and useful in studies with ME/CFS patients to monitor steps and resting heart rate, in addition to self-reported outcome measures.
​_______________________________________________________________________________

Biochem J  . 2022 Aug 31;479(16):1653-1708. doi: 10.1042/BCJ20220154.
The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications
Douglas B Kell 1 2 3, Etheresia Pretorius 1 3 PMID: 36043493 PMCID: PMC9484810
Abstract
Ischaemia-reperfusion (I-R) injury, initiated via bursts of reactive oxygen species produced during the reoxygenation phase following hypoxia, is well known in a variety of acute circumstances. We argue here that I-R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, our chief focus and most proximally, Long COVID. Ischaemia may be initiated via fibrin amyloid microclot blockage of capillaries, for instance as exercise is started; reperfusion is a necessary corollary when it finishes. We rehearse the mechanistic evidence for these occurrences here, in terms of their manifestation as oxidative stress, hyperinflammation, mast cell activation, the production of marker metabolites and related activities. Such microclot-based phenomena can explain both the breathlessness/fatigue and the post-exertional malaise that may be observed in these conditions, as well as many other observables. The recognition of these processes implies, mechanistically, that therapeutic benefit is potentially to be had from antioxidants, from anti-inflammatories, from iron chelators, and via suitable, safe fibrinolytics, and/or anti-clotting agents. We review the considerable existing evidence that is consistent with this, and with the biochemical mechanisms involved.
Keywords: Long COVID; amyloid microclots; ischaemia–reperfusion injury.
​_______________________________________________________________________________

RECOVER program takes first steps in advancing toward clinical trials to better understand Long COVID The NIH 
RECOVER initiative is preparing several clinical trials to evaluate treatments to improve symptoms related to post-acute sequelae of SARS-CoV-2 infection (PASC) or Long COVID. A trial protocol recently posted to ClinicalTrials.gov is in the final stages of development and approvals, and is expected to begin enrolling participants in early 2023. This trial is one of several that will test a variety of treatments for Long COVID. The causes of Long COVID are not well understood, and there are many different symptoms of Long COVID. Each trial will examine a treatment that targets one of five specific clusters of symptoms and their potential causes. The identification of the symptom clusters of focus began with patients. Through RECOVER study questionnaires, surveys, and discussions with people who have Long COVID, these were considered most burdensome, most important to address, and the priorities for trial protocols under development. The symptom clusters include: • Viral persistence: When the COVID-19 virus stays in some people’s bodies. • Autonomic dysfunction: Changes in ability to regulate heart rate, body temperature, breathing, digestion, and sensation. • Sleep disturbances: Changes to sleep patterns or ability to sleep. • Cognitive Dysfunction: Trouble thinking clearly or brain fog. • Exercise intolerance/fatigue: Changes in a person’s activity and/or energy level. The goal of these trials is to reduce the patient burden of illness due to Long COVID. The protocols for each trial were developed with patients and experts in these symptom areas. RECOVER researchers will also continue to engage patients, caregivers, and community representatives to better understand the impact of Long COVID on different groups. As an important complement to the therapeutic trials, RECOVER continues to conduct several longitudinal observational cohort studies and related sub-studies, more than 40 pathobiology studies, evaluation of potential PASC biomarkers, and analyses of more than 60 million electronic health records. The understanding of symptoms that patients are experiencing and their underlying biologic causes – as emerging from these studies – is informing the selection of clinical endpoints and other aspects of clinical trial design. More information about the clinical trials will be posted on recoverCOVID.org as it becomes available.
​_______________________________________________________________________________

Post–COVID-19 Symptoms 2 Years After SARS-CoV-2 Infection Among Hospitalized vs Nonhospitalized Patients
César Fernández-de-las-Peñas, PT, PhD1; Jorge Rodríguez-Jiménez, PT, MSc1; Ignacio Cancela-Cilleruelo, PT, MSc1; et alAngel Guerrero-Peral, MD, PhD2,3; José D. Martín-Guerrero, PhD4; David García-Azorín, MD, PhD2; Ana Cornejo-Mazzuchelli, MD5; Valentín Hernández-Barrera, PhD6; Oscar J. Pellicer-Valero, PhD4
JAMA Netw Open. 2022;5(11):e2242106. doi:10.1001/jamanetworkopen.2022.42106
Key Points
Question  What is the prevalence of post–COVID-19 symptoms among hospitalized and nonhospitalized patients 2 years after acute infection?
Findings  This cross-sectional study found that the proportion of patients with at least 1 post–COVID-19 symptom 2 years after acute infection was 59.7% for hospitalized patients and 67.5% for those not requiring hospitalization. No significant differences in post–COVID-19 symptoms were seen between hospitalized and nonhospitalized patients.
Meaning  Similar rates of post–COVID-19 symptoms between hospitalized and nonhospitalized patients suggest that, among all patients who contract COVID-19, these sequelae deserve attention.
Abstract
Importance  Identification of long-term post–COVID-19 symptoms among hospitalized and nonhospitalized patients is needed.
Objective  To compare the presence of post–COVID-19 symptoms 2 years after acute SARS-CoV-2 infection between hospitalized and nonhospitalized patients.
Design, Setting, and Participants  A cross-sectional cohort study was conducted at 2 urban hospitals and general practitioner centers from March 20 to April 30, 2020, among 360 hospitalized patients and 308 nonhospitalized patients with acute SARS-CoV-2 infection during the first wave of the pandemic. Follow-up was conducted 2 years later.
Main Outcomes and Measures  Participants were scheduled for a telephone interview 2 years after acute infection. The presence of post–COVID-19 symptoms was systematically assessed, with particular attention to symptoms starting after infection. Hospitalization and clinical data were collected from medical records. Between-group comparisons and multivariate logistic regressions were conducted.
Results  A total of 360 hospitalized patients (162 women [45.0%]; mean [SD] age, 60.7 [16.1] years) and 308 nonhospitalized patients (183 women [59.4%]; mean [SD] age, 56.7 [14.7] years) were included. Dyspnea was more prevalent at the onset of illness among hospitalized than among nonhospitalized patients (112 [31.1%] vs 36 [11.7%]; P < .001), whereas anosmia was more prevalent among nonhospitalized than among hospitalized patients (66 [21.4%] vs 36 [10.0%]; P = .003). Hospitalized patients were assessed at a mean (SD) of 23.8 (0.6) months after hospital discharge, and nonhospitalized patients were assessed at a mean (SD) of 23.4 (0.7) months after the onset of symptoms. The number of patients who exhibited at least 1 post–COVID-19 symptom 2 years after infection was 215 (59.7%) among hospitalized patients and 208 (67.5%) among nonhospitalized patients (P = .01). Among hospitalized and nonhospitalized patients, fatigue (161 [44.7%] vs 147 [47.7%]), pain (129 [35.8%] vs 92 [29.9%]), and memory loss (72 [20.0%] vs 49 [15.9%]) were the most prevalent post–COVID-19 symptoms 2 years after SARS-CoV-2 infection. No significant differences in post–COVID-19 symptoms were observed between hospitalized and nonhospitalized patients. The number of preexisting medical comorbidities was associated with post–COVID-19 fatigue (odds ratio [OR], 1.93; 95% CI, 1.09-3.42; P = .02) and dyspnea (OR, 1.91; 95% CI, 1.04-3.48; P = .03) among hospitalized patients. The number of preexisting medical comorbidities (OR, 3.75; 95% CI, 1.67-8.42; P = .001) and the number of symptoms at the onset of illness (OR, 3.84; 95% CI, 1.33-11.05; P = .01) were associated with post–COVID-19 fatigue among nonhospitalized patients.
Conclusions and Relevance  This cross-sectional study suggested the presence of at least 1 post–COVID-19 symptom in 59.7% of hospitalized patients and 67.5% of nonhospitalized patients 2 years after infection. Small differences in symptoms at onset of COVID-19 were identified between hospitalized and nonhospitalized patients. Post–COVID-19 symptoms were similar between hospitalized and nonhospitalized patients; however, lack of inclusion of uninfected controls limits the ability to assess the association of SARS-CoV-2 infection with overall and specific post–COVID-19 symptoms 2 years after acute infection. Future studies should include uninfected control populations.
​_______________________________________________________________________________

Front. Immunol., 20 October 2022 Sec. Viral Immunology https://doi.org/10.3389/fimmu.2022.949787
Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome
Eirini Apostolou1*, Muhammad Rizwan1, Petros Moustardas1, Per Sjögren2,3, Bo Christer Bertilson2,3, Björn Bragée2,3, Olli Polo3 and Anders Rosén1*
Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease considered to be triggered by viral infections in a majority of cases. Symptoms overlap largely with those of post-acute sequelae of COVID-19/long-COVID implying common pathogenetic mechanisms. SARS-CoV-2 infection is risk factor for sustained latent virus reactivation that may account for the symptoms of post-viral fatigue syndromes. The aim of this study was first to investigate whether patients with ME/CFS and healthy donors (HDs) differed in their antibody response to mild/asymptomatic SARS-CoV-2 infection. Secondly, to analyze whether COVID-19 imposes latent virus reactivation in the cohorts.
Methods: Anti-SARS-CoV-2 antibodies were analyzed in plasma and saliva from non-vaccinated ME/CFS (n=95) and HDs (n=110) using soluble multiplex immunoassay. Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva.
Results: At 3-6 months after mild/asymptomatic SARS-CoV-2 infection, virus-specific antibodies in saliva were substantially induced signifying a strong reactivation of latent viruses (EBV, HHV6 and HERV-K) in both cohorts. In patients with ME/CFS, antibody responses were significantly stronger, in particular EBV-encoded nuclear antigen-1 (EBNA1) IgG were elevated in patients with ME/CFS, but not in HDs. EBV-VCA IgG was also elevated at baseline prior to SARS-infection in patients compared to HDs.
Conclusion: Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. SARS-CoV-2 infection even in its mild/asymptomatic form is a potent trigger for reactivation of latent herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K), as detected by antibody fingerprints locally in the oral mucosa (saliva samples). This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma.
​_______________________________________________________________________________

COVID-19 Affects Brain 6 Months After Symptoms, Research Finds
Jay Croft  November 22, 2022  -Medscape

Scientists have found that COVID-19 causes brain "abnormalities" even six months after symptoms are gone, according to an upcoming report to the Radiological Society of North America.
They found changes to the brain stem and front lobe in areas of the brain associated with fatigue, insomnia, anxiety, depression, headaches, and cognitive issues.
About 20% of adults will have long-term effects from COVID-19, according to the CDC. Neurological symptoms associated with long COVID include poor concentration, headaches, and sleep problems. Long COVID can also cause changes to the heart, lungs, and other organs, the RSNA says.
In this study, researchers used a special MRI to detect and monitor neurological conditions such as microbleeds, vascular malformations, brain tumors, and stroke.
"Group-level studies have not previously focused on COVID-19 changes in magnetic susceptibility of the brain despite several case reports signaling such abnormalities," said study co-author Sapna S. Mishra, a Ph.D. candidate at the Indian Institute of Technology in Delhi, in SciTechDaily. "Our study highlights this new aspect of the neurological effects of COVID-19 and reports significant abnormalities in COVID survivors."
Scientists compared imaging of 46 patients who had recovered from COVID and 30 who had been healthy. The images were taken within six months of recovery.
"Changes in susceptibility values of brain regions may be indicative of local compositional changes," Mishra said. "Susceptibilities may reflect the presence of abnormal quantities of paramagnetic compounds, whereas lower susceptibility could be caused by abnormalities like calcification or lack of paramagnetic molecules containing iron."
The researchers will conduct similar studies on the same group of participants to see if the COVID-19 affects continue over time.
Credits:
Lead Image: Science Photo Library/Getty Images
WebMD Health News © 2022 
Cite this: COVID-19 Affects Brain 6 Months After Symptoms, Research Finds - Medscape - Nov 22, 2022.

​_______________________________________________________________________________

Acupuncture and moxibustion for chronic fatigue syndrome: A systematic review and network meta-analysis
Fang, Yang MDa; Yue, Bo-Wen MDb,*; Ma, Han-Bo MDa; Yuan, Yi-Peng MDa
Medicine: August 05, 2022 - Volume 101 - Issue 31 - p e29310 doi: 10.1097/MD.0000000000029310

Abstract
Background:   Research into acupuncture and moxibustion and their application for chronic fatigue syndrome (CFS) has been growing, but the findings have been inconsistent.
Objective: 
To evaluate the existing randomized clinical trials (RCTs), compare the efficacy of acupuncture, moxibustion and other traditional Chinese medicine (TCM) treatments.
Data sources: 
Three English-language databases (PubMed, Embase, Web of Science, and The Cochrane Library) and 4 Chinese-language biomedical databases (Chinese Biomedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang) were searched for RCTs published from database inception through August 2021.
Study selection: 
RCTs include acupuncture, moxibustion, traditional Chinese herbal medicine, western medicine and no control.
Data extraction and synthesis: 
Data were screened and extracted independently using predesigned forms. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias tool. We conducted a random-effects network meta-analysis within a frequentist framework. We assessed the certainty of evidence contributing to network estimates of the main outcomes with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.
Main outcomes and measures: 
The primary outcomes were the overall response rate and FS-14 scale.
Results: 
A total of 51 randomized controlled trials involving 3473 patients with CFS were included in this review. Forty one studies indicate low risk or unknown risk, and the GRADE scores of the combined results show low levels. Among the main indicators, traditional Chinese medicine therapies have excellent performance. However, the overall response rate is slightly different from the results obtained from the Fatigue Scale-14 total score. Moxibustion and traditional Chinese medicine (Odds ratios 48, 95% CrI 15–150) perform better in the total effective rate, while moxibustion plus acupuncture (MD 4.5, 95% CrI 3.0–5.9) is better in the FS-14 total score.
Conclusions: 
The effect of acupuncture and moxibustion in the treatment of CFS was significantly higher than that of other treatments. Traditional Chinese medicine should be used more widely in the treatment of CFS.
0 Comments

Abstracts from 5 August 2022

5/8/2022

0 Comments

 
Journal of Psychophysiology     Volume 175, May 2022, Pages 61-70
Blunted short-term autonomic cardiovascular reactivity to orthostatic and clinostatic challenges in fibromyalgia as an indicator of the severity of chronic pain
Author links open overlay panelAna M.Contreras-MerinoaDmitry M.DavydovbcCarmen M.Galvez-SánchezaGustavo A.Reyes del Pasoa 
https://doi.org/10.1016/j.ijpsycho.2022.03.001
Highlights
Fibromyalgia (FM) has been related to autonomic cardiovascular disturbances.
Short-term cardiovascular responses to gravitational stress were assessed in FM.
FM sufferers showed blunted cardiovascular responses in the first 30 s.
Cardiovascular reactivity correlated to pain, quality of life and affect in FM.
High temporal resolution measures are encouraged in postural stress research in FM.
Abstract
Fibromyalgia is a long-term pain disorder that has been related to autonomic dysfunctions and reduced cardiovascular reactivity. We aimed to assess the dynamic short-term cardiovascular responses to postural changes in fibromyalgia. Thirty-eight women with fibromyalgia and thirty-six healthy women underwent the “Chronic Pain Autonomic Stress Test”. Electrocardiogram, blood pressure and impedance cardiography were continuously recorded during active standing and lying down. Second-by-second values were derived over the first 30 s of each posture. Lower reactivity during the beginning of each position was observed in fibromyalgia sufferers compared to healthy women, with smaller responses seen during stand up in heart rate, blood pressure, cardiac output, total peripheral resistance, and pre-ejection period, and smaller changes during lying down in heart rate, cardiac output and total peripheral resistance. The magnitude of the autonomic adjustments to postural changes was inversely associated with the severity of clinical pain. These findings indicate an early impaired autonomic cardiovascular response to orthostatic and clinostatic challenges in fibromyalgia, suggesting less autonomic flexibility and adaptability to situational demands and challenges. Short-term second-by-second cardiovascular measures may be useful in the clinical assessment of fibromyalgia.
__________________________________________________________________________________
 
Front Cell Neuroscience . 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 FailureHerbert 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.

__________________________________________________________________________________

Medscape Medical News
Study: Long COVID Patients Have Immune System DifferencesKara Grant
August 11, 2022
Using immune profiling, a small but intense study found that people with long COVID have increased antibody responses to other non-COVID viruses, like Epstein-Barr Virus (EBV), as well as significantly lowered cortisol levels compared with people without long COVID.
The study — which is still a preprint, meaning it has yet to be peer-reviewed — looked at 215 people from Mount Sinai Hospital in New York City and Yale New Haven Hospital in Connecticut.
The 215 study participants were placed into four groups:
  • healthy individuals who haven't been previously infected with COVID-19
  • healthy, unvaccinated people who have had COVID
  • healthy, vaccinated people who have had COVID with no lingering symptoms
  • individuals who have had persistent symptoms following acute COVID infection
According to Yale immunology professor Akiko Iwasaki, PhD, and co-authors, an unexpected development in the group's research revealed that subsets of long COVID patients had antibody reactivity against non-COVID viruses, particularly Epstein-Barr Virus (EBV), a member of the herpes virus family.
The presence of EBV has been previously reported during severe COVID-19 infection in hospitalized patients. But the elevated immune responses to EBV found among patients in this study indicate a recent reactivation of this particular virus may be a common feature of long COVID.
The profiling conducted in the study found that the reactivation of EBV is not just incidental following a COVID-19 infection. In fact, the researchers write that these kinds of non-COVID viral pathogens "may alternatively mediate, aggravate, or exploit the persistent changes” in people with long COVID.
It's unclear, however, whether EBV reactivation may predispose those with long COVID to the development or worsening of autoimmune diseases, which has been reported among people with multiple sclerosis.
Additionally, one of the most striking findings was that participants with long COVID had significant decreases in levels of cortisol, the body's main stress hormone.
"Prior reports have associated low cortisol levels during the early phase of COVID-19 in patients that develop respiratory long COVID symptoms,” Iwasaki and colleagues write in the study. "Thus, our current finding of persistently decreased cortisol production in participants with long COVID more than a year following acute infection warrants expanded investigation.”
The authors note several important limitations to this study, primarily its small participant pool of 215 persons. While the individuals who participated were extensively immune profiled, the limited number hinders the study's ability to be broadly applicable to the general population.
 
__________________________________________________________________________________

medRxiv  . 2022 Jan 11;2021.06.14.21258895.  doi: 10.1101/2021.06.14.21258895. Preprint
Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeXiaoyu Che 1 2, Christopher R Brydges 3, Yuanzhi Yu 2, Adam Price 1, Shreyas Joshi 1, Ayan Roy 1, Bohyun Lee 1, Dinesh K Barupal 4, Aaron Cheng 1, Dana March Palmer 5, Susan Levine 6, Daniel L Peterson 7, Suzanne D Vernon 8, Lucinda Bateman 8, Mady Hornig 5, Jose G Montoya 9, Anthony L Komaroff 10, Oliver Fiehn 3, W Ian Lipkin 1
PMID: 35043127  PMCID: PMC8764736  DOI: 10.1101/2021.06.14.21258895
Update in·       Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Che X, Brydges CR, Yu Y, Price A, Joshi S, Roy A, Lee B, Barupal DK, Cheng A, Palmer DM, Levine S, Peterson DL, Vernon SD, Bateman L, Hornig M, Montoya JG, Komaroff AL, Fiehn O, Lipkin WI.Int J Mol Sci. 2022 Jul 18;23(14):7906. doi: 10.3390/ijms23147906.PMID: 35887252 
AbstractBackground: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.
Methods: Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.
Results: In ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).
Conclusion: Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.
One sentence summary: Plasma levels of plasmalogens are decreased in patients with myalgic encephalomyelitis/chronic fatigue syndrome suggesting peroxisome dysfunction.

__________________________________________________________________________________

Neurology  May 19, 2022
Comparison of Amitriptyline and US Food and Drug Administration–Approved Treatments for FibromyalgiaA Systematic Review and Network Meta-analysisHussein M. Farag, PharmD, MSc, PhD1; Ismaeel Yunusa, PharmD, PhD1,2; Hardik Goswami, BPharm, MSc, PhD1,3; et alIhtisham Sultan, PharmD1,4; Joanne A. Doucette, MSc, MSLIS1; Tewodros Eguale, MD, PhD1,5
JAMA Netw Open. 2022;5(5):e2212939. doi:10.1001/jamanetworkopen.2022.12939
Key Points
Question  What pharmacological treatments for adults with fibromyalgia are associated with the highest efficacy and acceptability?
Findings  In this systematic review and network meta-analysis of 36 randomized clinical trials (11 930 patients with fibromyalgia), duloxetine (120 mg) was associated with higher efficacy in treating pain and depression, while amitriptyline was associated with higher efficacy and acceptability in improving sleep, fatigue, and health-related quality of life outcomes.
Meaning  These findings suggest that with the heterogeneity of fibromyalgia symptoms, pharmacological treatments should be tailored to individual symptoms, including pain, sleep problems, depressed mood, fatigue, and health-related quality of life.
Abstract
Importance  Amitriptyline is an established medication used off-label for the treatment of fibromyalgia, but pregabalin, duloxetine, and milnacipran are the only pharmacological agents approved by the US Food and Drug Administration (FDA) to treat fibromyalgia.
Objective  To investigate the comparative effectiveness and acceptability associated with pharmacological treatment options for fibromyalgia.
Data Sources  Searches of PubMed/MEDLINE, Cochrane Library, Embase, and Clinicaltrials.gov were conducted on November 20, 2018, and updated on July 29, 2020.
Study Selection  Randomized clinical trials (RCTs) comparing amitriptyline or any FDA-approved doses of investigated drugs.
Data Extraction and Synthesis  This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Four independent reviewers extracted data using a standardized data extraction sheet and assessed quality of RCTs. A random-effects bayesian network meta-analysis (NMA) was conducted. Data were analyzed from August 2020 to January 2021.
Main Outcomes and Measures  Comparative effectiveness and acceptability (defined as discontinuation of treatment owing to adverse drug reactions) associated with amitriptyline (off-label), pregabalin, duloxetine, and milnacipran (on-label) in reducing fibromyalgia symptoms. The following doses were compared: 60-mg and 120-mg duloxetine; 150-mg, 300-mg, 450-mg, and 600-mg pregabalin; 100-mg and 200-mg milnacipran; and amitriptyline. Effect sizes are reported as standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes with 95% credible intervals (95% CrIs). Findings were considered statistically significant when the 95% CrI did not include the null value (0 for SMD and 1 for OR). Relative treatment ranking using the surface under the cumulative ranking curve (SUCRA) was also evaluated.
Results  A total of 36 studies (11 930 patients) were included. The mean (SD) age of patients was 48.4 (10.4) years, and 11 261 patients (94.4%) were women. Compared with placebo, amitriptyline was associated with reduced sleep disturbances (SMD, −0.97; 95% CrI, −1.10 to −0.83), fatigue (SMD, −0.64; 95% CrI, −0.75 to −0.53), and improved quality of life (SMD, −0.80; 95% CrI, −0.94 to −0.65). Duloxetine 120 mg was associated with the highest improvement in pain (SMD, −0.33; 95% CrI, −0.36 to −0.30) and depression (SMD, −0.25; 95% CrI, −0.32 to −0.17) vs placebo. All treatments were associated with inferior acceptability (higher dropout rate) than placebo, except amitriptyline (OR, 0.78; 95% CrI, 0.31 to 1.66). According to the SUCRA-based relative ranking of treatments, duloxetine 120 mg was associated with higher efficacy for treating pain and depression, while amitriptyline was associated with higher efficacy for improving sleep, fatigue, and overall quality of life.
Conclusions and Relevance  These findings suggest that clinicians should consider how treatments could be tailored to individual symptoms, weighing the benefits and acceptability, when prescribing medications to patients with fibromyalgia.

__________________________________________________________________________________

Published: 22 March 2022
Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)Milan Haffke, Helma Freitag, Gordon Rudolf, Martina Seifert, Wolfram Doehner, Nadja Scherbakov, Leif Hanitsch, Kirsten Wittke, Sandra Bauer, Frank Konietschke, Friedemann Paul, Judith Bellmann-Strobl, Claudia Kedor, Carmen Scheibenbogen & Franziska Sotzny 
Journal of Translational Medicine volume 20, Article number: 138 (2022)  
AbstractBackgroundFatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.
MethodsWe studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers.
ResultsFive of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs.
ConclusionA subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.

__________________________________________________________________________________

2022 Jun; 13(3): 698–711.Published online 2022 Jun 1. doi: 10.14336/AD.2021.0824
PMCID: PMC9116917  PMID: 35656104   Ageing and Disease
The Role of Kynurenine Pathway and NAD+ Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeMona Dehhaghi, 1 , 2 Hamed Kazemi Shariat Panahi, 1 Bahar Kavyani, 1 Benjamin Heng, 1 , 2 Vanessa Tan, 1 , 2 Nady Braidy, 3 and Gilles J. Guillemin 1 , 
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, complex, and highly debilitating long-term illness. People with ME/CFS are typically unable to carry out their routine activities. Key hallmarks of the disease are neurological and gastrointestinal impairments accompanied by pervasive malaise that is exacerbated after physical and/or mental activity. Currently, there is no validated cure of biomarker signature for this illness. Impaired tryptophan (TRYP) metabolism is thought to play significant role in the pathobiology of ME/CFS. TRYP is an important precursor for serotonin and the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+). TRYP has been associated with the development of some parts of the brain responsible for behavioural functions. The main catabolic route for TRYP is the kynurenine pathway (KP). The KP produces NAD+ and several neuroactive metabolites with neuroprotective (i.e., kynurenic acid (KYNA)) and neurotoxic (i.e., quinolinic acid (QUIN)) activities. Hyperactivation of the KP, whether compensatory or a driving mechanism of degeneration can limit the availability of NAD+ and exacerbate the symptoms of ME/CFS. This review discusses the potential association of altered KP metabolism in ME/CFS. The review also evaluates the role of the patient’s gut microbiota on TRYP availability and KP activation. We propose that strategies aimed at raising the levels of NAD+ (e.g., using nicotinamide mononucleotide and nicotinamide riboside) may be a promising intervention to overcome symptoms of fatigue and to improve the quality of life in patients with ME/CFS. Future clinical trials should further assess the potential benefits of NAD+ supplements for reducing some of the clinical features of ME/CFS.
__________________________________________________________________________________
 
Queensland researchers find overlap in pathology of long COVID and chronic fatigue syndromeABC Gold Coast  / By Heidi Sheehan   Posted Thu 11 Aug 2022 at 10:37amThursday 11 Aug 2022 at 10:37am, updated Thu 11 Aug 2022 at 2:52pm
Researchers say they have found a link in the pathology between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). 
Key points:
  • Griffith University researchers say their findings could help to treat those suffering from long COVID
  • A woman with chronic fatigue syndrome says she suffered a relapse in symptoms after contracting COVID earlier this year
  • AMA Queensland says the findings should be independently verified and that more funding for such research should be made available
The work is being carried out by Professor Sonya Marshall-Gradisnik and the team at Griffith University's National Centre for Neuroimmunology and Emerging Diseases (NCNED).
"It is the first of its kind in the world to actually biologically identify the overlap in the dysfunction with long COVID and ME/CFS patients," she said.
Dr Marshall-Gradisnik said damaged receptors, like a dysfunctional lock and key, do not allow enough calcium in.
"The receptors are located on every cell in the body," she said.
"These ion channels, or the lock and the key that tries to open the door — when we look at ME/CFS patients, that's been significantly impaired.
"When we looked at the same receptor [in long COVID patients], we're now reporting the same change."
The findings will be published in the Journal of Molecular Medicine.
 
__________________________________________________________________________________
 
Brain Behav Immun Health. 2022 Oct; 24: 100485.
Published online 2022 Jul 3. doi: 10.1016/j.bbih.2022.100485  PMCID: PMC9250701 PMID: 35814187
Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study
Brendan O'Kelly,a,b,∗ Louise Vidal,b Tina McHugh,b James Woo,a Gordana Avramovic,b and John S. Lamberta,b
Abstract
Background
Up to 37.7% of patients experience symptoms beyond 12 weeks after infection with SARS-CoV-2. To date care for people with long covid has centred around multidisciplinary rehabilitation, self care and self pacing. No pharmacotherapy has been shown to be beneficial.
MethodsIn this single centre interventional pre post study, the safety of Low Dose Naltrexone (LDN) was explored in patients with Post COVID-19 Syndrome (PCS), defined by NICE as patients with ongoing symptoms 12 or more weeks after initial infections with SARS-CoV-2 where alternative explanation for symptoms cannot be found. Patients were recruited through a Post COVID clinic, had a baseline quality of life questionnaire in symmetrical Likert format, were prescribed 2 months (1 mg month one, 2 mg month two) of LDN and repeated the same questionnaire at the end of the second month. Patients were monitored to adverse events.
FindingsIn total 52 patients participated of whom 40(76.9%) were female. The median age was 43.5 years(IQR 33.2–49). Healthcare workers represented the largest occupational cohort n = 16(34.8%). The median time from diagnosis of COVID-19 until enrolment was 333 days (IQR 171–396.5). Thirty-eight participants (73.1%) were known to commence LDN, two of whom (5.3%) stopped taking LDN post commencement due to new onset diarrhoea and also described fatigue. In total 36(69.2%) participants completed the questionnaire at the end of the two-month period. Improvement was seen in 6 of 7 parameters measured; recovery from COVID-19, limitation in activities of daily living, energy levels, pain levels, levels of concentration and sleep disturbance (p ≤ 0.001), improvement in mood approached but was not significant (p = 0.054).
ConclusionsLDN is safe in patients with PCS and may improve well-being and reduce symptomatology in this cohort. Randomised control trials are needed to further explore this.
__________________________________________________________________________________

Res Sq  . 2022 Jun 21;rs.3.rs-1716096.  doi: 10.21203/rs.3.rs-1716096/v1. Preprint
A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation (taVNS) to manage long COVID symptomsBashar W Badran, Sarah M Huffman, Morgan Dancy, Christopher W Austelle, Marom Bikson, Steven A Kautz, Mark S George PMID: 35765566  PMCID: PMC9238186   
AbstractBackground Although the coronavirus disease 19 (COVID-19) pandemic has now impacted the world for over two years, the persistent secondary neuropsychiatric effects are still not fully understood. These "long COVID" symptoms, also referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), can persist for months after infection without any effective treatments. Long COVID involves a complex heterogenous symptomology and can lead to disability and limit work. Long COVID symptoms may be due to sustained inflammatory responses and prolonged immune response after infection. Interestingly, vagus nerve stimulation (VNS) may have anti-inflammatory effects, however, until recently, VNS could not be self-administered, at-home, noninvasively. Methods We created a double-blind, noninvasive transcutaneous auricular VNS (taVNS) system that can be self-administered at home with simultaneous remote monitoring of physiological biomarkers and video supervision by study staff. Subsequently, we carried out a pilot (n = 13) randomized, sham-controlled, trial with this system for four weeks to treat nine predefined long covid symptoms (anxiety, depression, vertigo, anosmia, ageusia, headaches, fatigue, irritability, brain fog). No in-person patient contact was needed, with informed consent, trainings, ratings, and all procedures being conducted remotely during the pandemic (2020-2021) and equipment being shipped to individuals' homes. This trial was registered onClinicalTrials.gov under the identifier: NCT04638673. Results Four-weeks of at-home self-administered taVNS (two, one-hour sessions daily, delivered at suprathreshold intensities) was feasible and safe. Although our trial was not powered to determine efficacy as an intervention in a heterogenous population, the trends in the data suggest taVNS may have a mild to moderate effect in reducing mental fatigue symptoms in a subset of individuals. This innovative study demonstrates the safety and feasibility of supervised self-administered taVNS under a fully contactless protocol and suggests that future studies can safely investigate this novel form of brain stimulation at-home for a variety of neuropsychiatric and motor recovery applications.
 
__________________________________________________________________________________
 
J Translational Medicine 2022 Jun 28;20(1):295.  doi: 10.1186/s12967-022-03488-3.
Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trialAlan Cash 1, David Lyons Kaufman 2 PMID: 35764955  PMCID: PMC9238249
AbstractBackground: There is no approved pharmaceutical intervention for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). Fatigue in these patients can last for decades. Long COVID may continue to ME/CFS, and currently, it is estimated that up to 20 million Americans have significant symptoms after COVID, and the most common symptom is fatigue. Anhydrous Enol-Oxaloacetate, (AEO) a nutritional supplement, has been anecdotally reported to relieve physical and mental fatigue and is dimished in ME/CFS patients. Here, we examine the use of higher dosage AEO as a medical food to relieve pathological fatigue.
Methods: ME/CFS and Long-COVID patients were enrolled in an open label dose escalating "Proof of Concept" non-randomized controlled clinical trial with 500 mg AEO capsules. Control was provided by a historical ME/CFS fatigue trial and supporting meta-analysis study, which showed average improvement with oral placebo using the Chalder Scale of 5.9% improvement from baseline. At baseline, 73.7% of the ME/CFS patients were women, average age was 47 and length of ME/CFS from diagnosis was 8.9 years. The Long-COVID patients were a random group that responded to social media advertising (Face Book) with symptoms for at least 6 months. ME/CFS patients were given separate doses of 500 mg BID (N = 23), 1,000 mg BID (N = 29) and 1000 mg TID (N = 24) AEO for six weeks. Long COVID patients were given 500 mg AEO BID (N = 22) and 1000 mg AEO (N = 21), again over a six-week period. The main outcome measure was to compare baseline scoring with results at 6 weeks with the Chalder Fatigue Score (Likert Scoring) versus historical placebo. The hypothesis being tested was formulated prior to data collection.
Results: 76 ME/CFS patients (73.7% women, median age of 47) showed an average reduction in fatigue at 6 weeks as measured by the "Chalder Fatigue Questionnaire" of 22.5% to 27.9% from baseline (P < 0.005) (Likert scoring). Both physical and mental fatigue were significantly improved over baseline and historical placebo. Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Long COVID patients' fatigue was significantly reduced by up to 46.8% in 6-weeks.
Conclusions: Significant reductions in physical and metal fatigue for ME/CFS and Long-COVID patients were seen after 6 weeks of treatment. As there has been little progress in providing fatigue relief for the millions of ME/CFS and Long COVID patients, anhydrous enol oxaloacetate may bridge this important medical need. Further study of oxaloacetate supplementation for the treatment of ME/CFS and Long COVID is warranted. 

__________________________________________________________________________________

Biochem J   . 2022 Aug 31;479(16):1653-1708. doi: 10.1042/BCJ20220154.
The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implicationsDouglas B Kell 1 2 3, Etheresia Pretorius PMID: 36043493Abstract
Ischaemia-reperfusion (I-R) injury, initiated via bursts of reactive oxygen species produced during the reoxygenation phase following hypoxia, is well known in a variety of acute circumstances. We argue here that I-R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, our chief focus and most proximally, Long COVID. Ischaemia may be initiated via fibrin amyloid microclot blockage of capillaries, for instance as exercise is started; reperfusion is a necessary corollary when it finishes. We rehearse the mechanistic evidence for these occurrences here, in terms of their manifestation as oxidative stress, hyperinflammation, mast cell activation, the production of marker metabolites and related activities. Such microclot-based phenomena can explain both the breathlessness/fatigue and the post-exertional malaise that may be observed in these conditions, as well as many other observables. The recognition of these processes implies, mechanistically, that therapeutic benefit is potentially to be had from antioxidants, from anti-inflammatories, from iron chelators, and via suitable, safe fibrinolytics, and/or anti-clotting agents. We review the considerable existing evidence that is consistent with this, and with the biochemical mechanisms involved.

__________________________________________________________________________________
Associations of Depression, Anxiety, Worry, Perceived Stress, and Loneliness Prior to Infection With Risk of Post–COVID-19 ConditionsSiwen Wang, MD1; Luwei Quan, BA2; Jorge E. Chavarro, ScD1,3,4; et alNatalie Slopen, ScD5; Laura D. Kubzansky, PhD5; Karestan C. Koenen, PhD3,5,6; Jae Hee Kang, ScD4; Marc G. Weisskopf, PhD2; Westyn Branch-Elliman, MD7,8; Andrea L. Roberts, PhD2
JAMA Psychiatry. Published online September 7, 2022. doi:10.1001/jamapsychiatry.2022.2640
Key Points
Question  Is psychological distress before SARS-CoV-2 infection associated with risk of COVID-19–related symptoms lasting 4 weeks or longer, known as post–COVID-19 conditions?
Findings  This cohort study found that among participants who did not report SARS-CoV-2 infection at baseline (April 2020) and reported a positive SARS-CoV-2 test result over 1 year of follow-up (N = 3193), depression, anxiety, perceived stress, loneliness, and worry about COVID-19 were prospectively associated with a 1.3- to 1.5-fold increased risk of self-reported post–COVID-19 conditions, as well as increased risk of daily life impairment related to post–COVID-19 conditions.
Meaning  In this study, preinfection psychological distress was associated with risk of post–COVID-19 conditions and daily life impairment in those with post–COVID-19 conditions.
Abstract
Importance  Few risk factors for long-lasting (≥4 weeks) COVID-19 symptoms have been identified.
Objective  To determine whether high levels of psychological distress before SARS-CoV-2 infection, characterized by depression, anxiety, worry, perceived stress, and loneliness, are prospectively associated with increased risk of developing post–COVID-19 conditions (sometimes called long COVID).
Design, Setting, and Participants  This prospective cohort study used data from 3 large ongoing, predominantly female cohorts: Nurses’ Health Study II, Nurses’ Health Study 3, and the Growing Up Today Study. Between April 2020 and November 2021, participants were followed up with periodic surveys. Participants were included if they reported no current or prior SARS-CoV-2 infection at the April 2020 baseline survey when distress was assessed and returned 1 or more follow-up questionnaires.
Exposures  Depression, anxiety, worry about COVID-19, perceived stress, and loneliness were measured at study baseline early in the pandemic, before SARS-CoV-2 infection, using validated questionnaires.
Main Outcomes and Measures  SARS-CoV-2 infection was self-reported during each of 6 monthly and then quarterly follow-up questionnaires. COVID-19–related symptoms lasting 4 weeks or longer and daily life impairment due to these symptoms were self-reported on the final questionnaire, 1 year after baseline.
Results  Of 54 960 participants, 38.0% (n = 20 902) were active health care workers, and 96.6% (n = 53 107) were female; the mean (SD) age was 57.5 (13.8) years. Six percent (3193 participants) reported a positive SARS-CoV-2 test result during follow-up (1-47 weeks after baseline). Among these, probable depression (risk ratio [RR], 1.32; 95% CI = 1.12-1.55), probable anxiety (RR = 1.42; 95% CI, 1.23-1.65), worry about COVID-19 (RR, 1.37; 95% CI, 1.17-1.61), perceived stress (highest vs lowest quartile: RR, 1.46; 95% CI, 1.18-1.81), and loneliness (RR, 1.32; 95% CI, 1.08-1.61) were each associated with post–COVID-19 conditions (1403 cases) in generalized estimating equation models adjusted for sociodemographic factors, health behaviors, and comorbidities. Participants with 2 or more types of distress prior to infection were at nearly 50% increased risk for post–COVID-19 conditions (RR, 1.49; 95% CI, 1.23-1.80). All types of distress were associated with increased risk of daily life impairment (783 cases) among individuals with post–COVID-19 conditions (RR range, 1.15-1.51).
Conclusions and Relevance  The findings of this study suggest that preinfection psychological distress may be a risk factor for post–COVID-19 conditions in individuals with SARS-CoV-2 infection. Future work should examine the biobehavioral mechanism linking psychological distress with persistent postinfection symptoms.

__________________________________________________________________________________

Mol Cell Neurosci  . 2022 May;120:103731.  doi: 10.1016/j.mcn.2022.103731. Epub 2022 Apr 26.
Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE)Gunnar Gottschalk 1, Daniel Peterson 2, Konstance Knox 3, Marco Maynard 4, Ryan J Whelan 4, Avik Roy 5     PMID: 35487443
Abstract
Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a multisystem illness characterized by extreme muscle fatigue associated with pain, neurocognitive impairment, and chronic inflammation. Despite intense investigation, the molecular mechanism of this disease is still unknown. Here we demonstrate that autophagy-related protein ATG13 is strongly upregulated in the serum of ME/CFS patients, indicative of impairment in the metabolic events of autophagy. A Thioflavin T-based protein aggregation assay, array screening for autophagy-related factors, densitometric analyses, and confirmation with ELISA revealed that the level of ATG13 was strongly elevated in serum samples of ME/CFS patients compared to age-matched controls. Moreover, our microglia-based oxidative stress response experiments indicated that serum samples of ME/CFS patients evoke the production of reactive oxygen species (ROS) and nitric oxide in human HMC3 microglial cells, whereas neutralization of ATG13 strongly diminishes the production of ROS and NO, suggesting that ATG13 plays a role in the observed stress response in microglial cells. Finally, an in vitro ligand binding assay provided evidence that ATG13 employs the Receptor for Advanced Glycation End-products (RAGE) to stimulate ROS in microglial cells. Collectively, our results suggest that an impairment of autophagy following the release of ATG13 into serum could be a pathological signal in ME/CFS.
Keywords: ATG13; Autophagy; ME/CFS; Microglia: RAGE; NO; ROS.

__________________________________________________________________________________

2022 Jun 23;9:917019.  doi: 10.3389/fmed.2022.917019. eCollection 2022.
Orthostatic Challenge Causes Distinctive Symptomatic, Hemodynamic and Cognitive Responses in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue SyndromeSuzanne D Vernon 1, Sherlyn Funk 2, Lucinda Bateman 1, Gregory J Stoddard 2, Sarah Hammer 1, Karen Sullivan 1, Jennifer Bell 1, Saeed Abbaszadeh 1, W Ian Lipkin 3, Anthony L Komaroff 4
PMID: 35847821  PMCID: PMC9285104
AbstractBackground: Some patients with acute COVID-19 are left with persistent, debilitating fatigue, cognitive impairment ("brain fog"), orthostatic intolerance (OI) and other symptoms ("Long COVID"). Many of the symptoms are like those of other post-infectious fatigue syndromes and may meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Common diagnostic laboratory tests are often unrevealing.
Methods: We evaluated whether a simple, standardized, office-based test of OI, the 10-min NASA Lean Test (NLT), would aggravate symptoms and produce objective hemodynamic and cognitive abnormalities, the latter being evaluated by a simple smart phone-based app.
Participants: People with Long COVID (N = 42), ME/CFS (N = 26) and healthy control subjects (N = 20) were studied just before, during, immediately after, 2 and 7 days following completion of the NLT.
Results: The NLT provoked a worsening of symptoms in the two patient groups but not in healthy control subjects, and the severity of all symptoms was similar and significantly worse in the two patient groups than in the control subjects (p < 0.001). In the two patient groups, particularly those with Long COVID, the NLT provoked a marked and progressive narrowing in the pulse pressure. All three cognitive measures of reaction time worsened in the two patient groups immediately following the NLT, compared to the healthy control subjects, particularly in the Procedural Reaction Time (p < 0.01).
Conclusions: A test of orthostatic stress easily performed in an office setting reveals different symptomatic, hemodynamic and cognitive abnormalities in people with Long COVID and ME/CFS, compared to healthy control subjects. Thus, an orthostatic challenge easily performed in an office setting, and the use of a smart phone app to assess cognition, can provide objective confirmation of the orthostatic intolerance and brain fog reported by patients with Long COVID and ME/CFS.

__________________________________________________________________________________

Vasc Health Risk Manag  . 2022 Sep 6;18:711-719.  doi: 10.2147/VHRM.S371468. eCollection 2022.
Chronic Fatigue Associated with Post-COVID Syndrome versus Transient Fatigue Caused by High-Intensity Exercise: Are They Comparable in Terms of Vascular Effects?Michal Chudzik 1 2, Anna Cender 1, Robert Mordaka 1, Jacek Zielinski 3, Joanna Katarzynska 4, Andrzej Marcinek 4 5, Jerzy Gebicki 4 5
PMID: 36097586  PMCID: PMC9464031
Abstract
Purpose: The pathophysiology of chronic fatigue associated with post-COVID syndrome is not well recognized. It is assumed that this condition is partly due to vascular dysfunction developed during an acute phase of infection. There is great demand for a diagnostic tool that is able to clinically assess post-COVID syndrome and monitor the rehabilitation process.
Patients and methods: The Flow Mediated Skin Fluorescence (FMSF) technique appears uniquely suitable for the analysis of basal microcirculatory oscillations and reactive hyperemia induced by transient ischemia. The FMSF was used to measure vascular circulation in 45 patients with post-COVID syndrome. The results were compared with those for a group of 26 amateur runners before and after high-intensity exercise as well as for a control group of 32 healthy age-matched individuals.
Results: Based on the observed changes in the NOI (Normoxia Oscillatory Index) and RHR (Reactive Hyperemia Response) parameters measured with the FMSF technique, it was found that chronic fatigue associated with post-COVID syndrome is comparable with transient fatigue caused by high-intensity exercise in terms of vascular effects, which are associated with vascular stress in the macrocirculation and microcirculation. Acute and chronic fatigue symptomatology shared similarly altered changes in the NOI and RHR parameters and both can be linked to calcium homeostasis modification.
Conclusion: The NOI and RHR parameters measured with the FMSF technique can be used for non-invasive clinical assessment of post-COVID syndrome as well as for monitoring the rehabilitation process.

__________________________________________________________________________________
 
Biochem J. 2022 Aug 31;479(16):1653-1708.   doi: 10.1042/BCJ20220154.
The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implicationsDouglas B Kell 1 2 3, Etheresia Pretorius 1 3PMID: 36043493  PMCID: PMC9484810
Abstract
Ischaemia-reperfusion (I-R) injury, initiated via bursts of reactive oxygen species produced during the reoxygenation phase following hypoxia, is well known in a variety of acute circumstances. We argue here that I-R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, our chief focus and most proximally, Long COVID. Ischaemia may be initiated via fibrin amyloid microclot blockage of capillaries, for instance as exercise is started; reperfusion is a necessary corollary when it finishes. We rehearse the mechanistic evidence for these occurrences here, in terms of their manifestation as oxidative stress, hyperinflammation, mast cell activation, the production of marker metabolites and related activities. Such microclot-based phenomena can explain both the breathlessness/fatigue and the post-exertional malaise that may be observed in these conditions, as well as many other observables. The recognition of these processes implies, mechanistically, that therapeutic benefit is potentially to be had from antioxidants, from anti-inflammatories, from iron chelators, and via suitable, safe fibrinolytics, and/or anti-clotting agents. We review the considerable existing evidence that is consistent with this, and with the biochemical mechanisms involved.

__________________________________________________________________________________
Comparison of the Degree of Deconditioning in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients with and without Orthostatic Intolerance – (Linda) M.C. van Campen, MD; Frans C. Visser, MD24 september 2022
ABSTRACT    Background
Orthostatic intolerance (OI) is a core finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS).
Deconditioning is often proposed as an important determinant for OI. Deconditioning can be objectively classified using the predicted peak oxygen consumption (%VO2 peak) values as derived from cardiopulmonary exercise testing (CPET) and OI can be objectively quantified using cerebral blood flow (CBF) changes during tilt testing.
Therefore, if deconditioning contributes to OI, a correlation between peak VO2 and the %CBF reduction is expected.
 
Methods and results
18 healthy controls (HC) and 122 ME/CFS patients without hypotension or tachycardia on tilt- testing were studied. Deconditioning was classified as follows: %VO2 peak ≥85%= no deconditioning, %VO2 peak 65-85%= mild deconditioning, %VO2 peak<65%= severe deconditioning.
HC had higher %VO2 peak compared to ME/CFS patients (p<0.0001). ME/CFS patients had significantly larger CBF reduction than HC (p<0.0001).
No relation between the degree of deconditioning by the %VO2 peak and the %CBF reduction in ME/CFS patients was found. Moreover, we separately analyzed ME/CFS patients without an abnormal CBF reduction. Despite equal CBF reductions compared to HC and large differences between these patients and the patients with an abnormal CBF reduction, cardiac index (CI) changes (measured by suprasternal Doppler) were significantly less compared to ME/CFS patients with an abnormal CBF reduction (p<0.0001) but larger than in HC (p=0.004).
Despite these different hemodynamic findings, %VO2 values were not different between the two patient groups, argumenting again against the causative role of hemodynamic abnormalities in deconditioning. 
Conclusion
In ME/CFS patients without hypotension or tachycardia there is no relation between the %VO2 peak during CPET and the %CBF and %CI reduction during tilt testing, whether or not patients have an abnormal CBF reduction during tilt testing. It suggests again that deconditioning does not play an important role in OI.
Source: ESMED, June 20, 2022

__________________________________________________________________________________
Pre-illness data reveals differences in multiple metabolites and metabolic pathways in those who do and do not recover from infectious mononucleosis 
Abstract:      Metabolic pathways related to energy production, amino acids, nucleotides, nitrogen, lipids, and neurotransmitters in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may contribute to the pathophysiology of ME/CFS.
Methods: 4501 Northwestern University college students were enrolled in a prospective, longitudinal study. We collected data before illness, during infectious mononucleosis (IM), and at a 6 month follow-up for those who recovered (N = 18) versus those who went on to develop ME/CFS 6 months later (N = 18).
Outcomes:  Examining pre-illness blood samples, we found significant detectable metabolite differences between participants fated to develop severe ME/CFS following IM versus recovered controls. We identified glutathione metabolism, nucleotide metabolism, and the TCA cycle (among others) as potentially dysregulated pathways.
The pathways that differed between cases and controls are essential for proliferating cells, particularly during a pro-inflammatory immune response.
Performing a series of binary logistic regressions using a leave-one-out cross-validation (LOOCV), our models correctly classified the severe ME/CFS group and recovered controls with an accuracy of 97.2%, sensitivity of 94.4%, and specificity of 100.0%.
Conclusion:  These changes are consistent with the elevations in pro-inflammatory cytokines that we have reported for patients fated to develop severe ME/CFS 6 months after IM.
Jason, Conroy, Furst, Vasan & Katz  - Source: Molecular Omics

__________________________________________________________________________________
Pathophysiology of exercise intolerance in ME/CFS & long COVID – 
David Systrom, MD, Harvard Medical: Dr David Systrom’s keynote talk at the IACFS/ME Conference covered several different topics which were all related to acute exercise intolerance: preload failure, small nerve fibre neuropathy, skeletal muscle mitochondrial dysfunction, Long Covid and potential treatment.  Data presented was a mixture of published and unpublished studies. 
The basis of Dr Systrom’s research and work is based on using invasive cardiopulmonary exercise testing which was first used in heart and lung disease, however, not all patients were seen to fit this diagnosis, and led him to investigate ME/CFS. These patients were seen to have “preload failure”– where a consistently reduced max oxygen consumption (VO2) alongside reduced right atrial pressure (RAP), this means that there is poor oxygen extraction. It is this preload failure that contributes to post-exertional malaise (PEM). 
Dr Systrom’s research has also looked into small Nerve Fibre Neuropathy, which has been found in a subset (around 50% of patients), and he expects this might be related to exercise intolerance in ME/CFS. Similar findings have also been seen in POTS and fibromyalgia. As part of this branch of research, the immune response “TRAIL” which is a cytokine that is produced and secreted by most normal tissue cells, responsible for apoptosis (the death of cells). 
Another part of Dr Systrom’s talk also covered impaired oxygen extraction, which may be causing the depression in VO2 max. For this part of the research muscle biopsies were examined which suggests this might be linked to muscle mitochondrial dysfunction. 
Dr Systrom has also investigated exercise intolerance in Long Covid, which appears to be the same as ME/CFS with preload failure presence. Ventilatory inefficiency (VE/VCO2) is also present in Long Covid, which is due to hyperventilation (seen in a subset of patients). These findings are thought to be related to dyspnea. Furthermore, using upright tilt table testing for POTS and Long Covid patients verus controls has shown hyperventilation similar to that when performing exercise with depression of cerebral blood flow. 
Dr Systrom presented some unpublished data for ME/CFS, POTS and small Nerve Fibre Neuropathy showing that preload failure is present in all. 
Finally, the talk was concluded by a small introduction to treatment, using a small dose of pyridostigmine to treat preload failure. Results currently suggest in a subset of patients this treatment may be useful. 
Source: ME Association

__________________________________________________________________________________
Phenotypic characteristics of peripheral immune cells of Myalgic encephalomyelitis/chronic fatigue syndrome via transmission electron microscopy: A pilot study:    AbstractPrevious studies have shown ME/CFS-associated alterations in the immune system and mitochondria. We used transmission electron microscopy (TEM) to investigate the morphology and ultrastructure of unstimulated and stimulated ME/CFS immune cells and their intracellular organelles, including mitochondria.
Method:   PBMCs from four participants were studied: a pair of identical twins discordant for moderate ME/CFS, as well as two age- and gender- matched unrelated subjects-one with an extremely severe form of ME/CFS and the other healthy.
Outcomes: TEM analysis of CD3/CD28-stimulated T cells suggested a significant increase in the levels of apoptotic and necrotic cell death in T cells from ME/CFS patients (over 2-fold).
Stimulated T-cells of ME/CFS patients also had higher numbers of swollen mitochondria.
We also found a large increase in intracellular giant lipid droplet-like organelles in the stimulated PBMCs from the extremely severe ME/CFS patient potentially indicative of a lipid storage disorder.
Lastly, we observed a slight increase in platelet aggregation in stimulated cells, suggestive of a possible role of platelet activity in ME/CFS pathophysiology and disease severity.
Conclusion:  These results indicate extensive morphological alterations in the cellular and mitochondrial phenotypes of ME/CFS patients’ immune cells and suggest new insights into ME/CFS biology.
Fereshteh Jahanbani, Rajan D Maynard, Justin Cyril Sing, Shaghayegh Jahanbani, John J Perrino, Damek V Spacek, Ronald W Davis, Michael P Snyder
Source: PubMed, Aug. 9, 2022

__________________________________________________________________________________
Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVIDAbstract:  Background and Objectives
COVID-19 can be serious not only in the acute phase but also after the acute phase and some patients develop ME/CFS.
There have been few studies on patients with long COVID in whom ME/CFS was diagnosed by physicians based on standardized criteria after examinations and exclusion diagnosis and not based on only subjective symptoms. The purpose of this study was to elucidate the detailed characteristics of ME/CFS in patients with long COVID.
Materials and Methods: A retrospective descriptive study was performed for patients who visited a COVID-19 aftercare clinic established in Okayama University Hospital during the period from February 2021 to April 2022.
Results:  Clinical data were obtained from medical records for 281 patients, and 279 patients who met the definition of long COVID were included. The overall prevalence rate of ME/CFS diagnosed by three sets of ME/CFS criteria (Fukuda, Canadian and IOM criteria) was 16.8% (48.9% in male and 51.1% in females).
The most frequent symptoms in ME/CFS patients were general fatigue and post-exertional malaise (89.4% of the patients), headache (34.0%), insomnia (23.4%), dysosmia (21.3%) and dysgeusia (19.1%). Dizziness, chest pain, insomnia and headache were characteristic symptoms related to ME/CFS.
The male to female ratio in ME/CFS patients was equal in the present study, although ME/CFS was generally more common in women in previous studies.
Given that patients with ME/CFS had more severe conditions in the acute phase of COVID-19, the severity of the acute infectious state might be involved in the pathophysiology of ME/CFS.
Conclusions: The prevalence rate of ME/CFS and the characteristic sequelae in the long COVID condition were revealed in this study.
Tokumasu, Honda, Sunda, Sakurada, Matsuda, Yamamoto, Nakano, Hasegawi, Yamamoto, Otsuka, Hagiya, Kataoka, Ueda & Otsuka

__________________________________________________________________________________
Inflammations in the brain in ME – Prof. Jarred YoungerWe have heard little from Prof Jarred Younger for a long time. Perhaps there was even a fear that he was no longer engaged in ME research. Fortunately, nothing could be further from the truth, as evidenced by a recent webinar facilitated by Solve ME.
In it, he explains not only what he has been doing over the past few years, but also the promising progress he has made. Central to this remains the demonstration of (low-grade) inflammations in the brain in ME.
Demonstrating inflammations in the brain - To do so, he uses three angles:
1. Temperature measurements
2. Tracking of leucocytes
3. Tracking of microglia
Its ultimate goal is to find treatments for ME.
In the video Prof. Younger gives a comprehensive account of those three techniques and the possible results. The focus is on microglia, the nerve cells in the brain. Virtually all symptoms in ME may result from low-grade, chronic inflammation of these.
Tracking leucocytes (T- & B-cells)
You can’t open the skull and then take out some cells to see if it contains Leukocytes that don’t belong there (and can do a lot of damage). He now adds Zircon89 and manages to make them visible with scans, because it takes three days for leukocytes to reach the brain (if they do). In 4 healthy, he found no leukocytes in the brain.
He is now going to apply that to 1 ME patient first. Exciting…   Should he find leukocytes in their brains, there will be a fast track to treatments. He hopes to announce the results in about three months’ time.
Tracking microglia
Done with a PET scan and an injected radioactive substance (DPA 714), which attaches itself to microglia that are inflamed. That technique is already being used. It has not yet been used in ME research mainly due to cost.
Conclusions
There is a lot going on, and he expects to announce much of it in the second half of 2022. He advises every patient to participate in research, if possible. Because patient participation (and also ongoing NGO funding of pilot studies) are the basis for achieving discoveries on a larger scale.
Source text and photo: https://youtu.be/DU0UgWGyi0A
Extract ME Global Chronicle

__________________________________________________________________________________
Survey of Anti-Pathogen Antibody Levels in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Abstract
Infectious pathogens are implicated in the etiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) because of the occurrence of outbreaks of the disease.
While a number of different infectious agents have been associated with the onset of ME/CFS, the identity of a specific organism has been difficult to determine in individual cases.
Aim
The aim of our study is to survey ME/CFS subjects for evidence of an infectious trigger and/or evidence of immune dysregulation via serological testing of plasma samples for antibodies to 122 different pathogen antigens.
Method
Immune profiles were compared to age-, sex-, and BMI-matched controls to provide a basis for comparison.
Results
Antibody levels to individual antigens surveyed in this study do not implicate any one of the pathogens in ME/CFS, nor do they rule out common pathogens that frequently infect the US population.
However, our results revealed sex-based differences in steady-state humoral immunity, both within the ME/CFS cohort and when compared to trends seen in the healthy control cohort.
O’Neal, Glass, Emig, Vitug, Henry, Shungu, Mao, Levine & Hanson
Source: MDPI Proteomes

__________________________________________________________________________________

Activity monitoring and patient-reported outcome measures in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients
Abstract:   Introduction:  Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with no validated specific and sensitive biomarker, and no standard approved treatment. In this observational study with no intervention, participants used a Fitbit activity tracker. The aims were to explore natural symptom variation, feasibility of continuous activity monitoring, and to compare activity data with patient reported outcome measures (PROMs).
Materials and methods:   In this pilot study, 27 patients with mild to severe ME/CFS, of mean age 42.3 years, used the Fitbit Charge 3 continuously for six months. Patients wore a SenseWear activity bracelet for 7 days at baseline, at 3 and 6 months. At baseline and follow-up they completed the Short Form 36 Health Survey (SF-36) and the DePaul Symptom Questionnaire-Short Form (DSQ-SF).
Results:  The mean number of steps per day decreased with increasing ME/CFS severity; mild 5566, moderate 4991 and severe 1998.
The day-by-day variation was mean 47% (range 25%-79%). Mean steps per day increased from the first to the second three-month period, 4341 vs 4781 steps. The maximum differences in outcome measures between 4-week periods (highest vs lowest), were more evident in a group of eight patients with milder disease (baseline SF-36 PF > 50 or DSQ-SF < 55) as compared to 19 patients with higher symptom burden (SF-36 PF < 50 and DSQ-SF > 55), for SF-36 PF raw scores: 16.9 vs 3.4 points, and for steps per day: 958 versus 479 steps.
The correlations between steps per day and self-reported SF-36 Physical function, SF-36 Social function, and DSQ-SF were significant. Fitbit recorded significantly higher number of steps than SenseWear. Resting heart rates were stable during six months.
Conclusion:  Continuous activity registration with Fitbit Charge 3 trackers is feasible and useful in studies with ME/CFS patients to monitor steps and resting heart rate, in addition to self-reported outcome measures.       Rekeland, Sørland, Bruland, Risa, Alme, Dahl, Tronstad, Mella & Fluge
Source: PLOS ONE 

__________________________________________________________________________________

Brain, Behavior, and Immunity       Volume 102, May 2022, Pages 362-369
 
Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk lociRiadHajdarevicabAsgeirLandeaJesperMehlsencAnneRydlandabDaisy D.SosadeElin B.StrandfgOlavMellahFlemmingPociotiØysteinFlugehBenedicte A.LieabjMarte K.Vikenaj
Received 26 September 2021, Revised 3 March 2022, Accepted 16 March 2022, Available online 19 March 2022, Version of Record 23 March 2022.

Highlights
Largest ME/CFS genetic study to date.
Three different cohorts totaling >2500 patients.
First Immunochip study in ME/CFS.
Possible implication of TPPP genetic region.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis, which manifests in a variety of symptoms like post-exertional malaise, brain fog, fatigue and pain. Hereditability is suggested by an increased disease risk in relatives, however, genome-wide association studies in ME/CFS have been limited by small sample sizes and broad diagnostic criteria, therefore no established risk loci exist to date. In this study, we have analyzed three ME/CFS cohorts: a Norwegian discovery cohort (N = 427), a Danish replication cohort (N = 460) and a replication dataset from the UK biobank (N = 2105). To the best of our knowledge, this is the first ME/CFS genome-wide association study of this magnitude incorporating 2532 patients for the genome-wide analyses and 460 patients for a targeted analysis. Even so, we did not find any ME/CFS risk loci displaying genome-wide significance. In the Norwegian discovery cohort, the TPPP gene region showed the most significant association (rs115523291, P = 8.5 × 10−7), but we could not replicate the top SNP. However, several other SNPs in the TPPP gene identified in the Norwegian discovery cohort showed modest association signals in the self-reported UK biobank CFS cohort, which was also present in the combined analysis of the Norwegian and UK biobank cohorts, TPPP (rs139264145; P = 0.00004). Interestingly, TPPP is expressed in brain tissues, hence it will be interesting to see whether this association, with time, will be verified in even larger cohorts. Taken together our study, despite being the largest to date, could not establish any ME/CFS risk loci, but comprises data for future studies to accumulate the power needed to reach genome-wide significance.

__________________________________________________________________________________

Orji et al. BMC Public Health (2022) 22:1516 https://doi.org/10.1186/s12889-022-13929-9 
RESEARCH Prevalence of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) in Australian primary care patients: only part of the story?
Nneka Orji1 , Julie A. Campbell1 , Karen Wills1 , Martin Hensher1 , Andrew J. Palmer1 , Melissa Rogerson2 , Ryan Kelly2 and Barbara de Graaf1* 
Abstract/ Background: ME/CFS is a disorder characterized by recurrent fatigue and intolerance to exertion which manifests as profound post-exertional malaise. Prevalence studies internationally have reported highly variable results due to the 20+diagnostic criteria. For Australia, the prevalence of ME/CFS based on current case defnitions is unknown. 
Objectives: To report prevalence of ME/CFS in patients aged≥13 years attending Australian primary care settings for years 2015–2019, and provide context for patterns of primary care attendance by people living with ME/CFS. 
Methodology: Conducted in partnership with the Patient Advisory Group, this study adopted a mixed methods approach. De-identifed primary care data from the national MedicineInsight program were analyzed. The cohort were regularly attending patients, i.e. 3 visits in the preceding 2 years. Crude prevalence rates were calculated for years 2015–2019, by sex, 10-year age groups, remoteness and socioeconomic status. Rates are presented per 100,000population (95% confdence intervals (CI)). Qualitative data was collected through focus groups and in-depth 1:1 interview. 
Results: Qualitative evidence identifed barriers to reaching diagnosis, and limited interactions with primary care due to a lack of available treatments/interventions, stigma and disbelief in ME/CFS as a condition. In each year of interest, crude prevalence in the primary care setting ranged between 94.9/100,000 (95% CI: 91.5–98.5) and 103.9/100,000 population (95%CI: 100.3–107.7), equating to between 20,140 and 22,050 people living with ME/ CFS in Australia in 2020. Higher rates were observed for age groups 50-59 years and 40-49 years. Rates were substantially higher in females (130.0–141.4/100,000) compared to males (50.9–57.5/100,000). In the context of the qualitative evidence, our prevalence rates likely represent an underestimate of the true prevalence of ME/CFS in the Australian primary care setting. 
Conclusion: ME/CFS afects a substantial number of Australians. Whilst this study provides prevalence estimates for the Australian primary care setting, the qualitative evidence highlights the limitations of these. Future research should focus on using robust case ascertainment criteria in a community setting. Quantifcation of the burden of disease can be used to inform health policy and planning, for this understudied condition. Keywords: Chronic fatigue syndrome, Myalgic encephalomyelitis, ME/CFS, Prevalence, Primary care, Mixed method

__________________________________________________________________________________
 
Understanding myalgic encephalomyelitis
Myalgic encephalomyelitis and Long Covid have overlapping presentation
SONYA MARSHALL-GRADISNIK AND NATALIE EATON-FITCH
SCIENCE 8 Sep 2022  Vol 377, Issue 6611  pp. 1150-1151  DOI: 10.1126/science.abo1261
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe condition characterized by post-exertional neuroimmune exhaustion (PENE) accompanied by neurological, immunological, gastrointestinal (GI), and mitochondrial disturbances (1). The global prevalence of ME/CFS is ∼1%, affecting 17 million to 24 million people (2). ME/CFS is heterogeneous not only in symptom presentation but also illness trajectories, which can be worsening, plateauing, improving, or relapsing-remitting. Approximately 25% of patients with ME/CFS are considered severe and are bound to their homes. Although the etiology of ME/CFS is elusive, a large proportion of patients (∼60%) report post-infectious onset, such as after Epstein-Barr virus infection (3). The recent emergence of a chronic post-infectious condition, called Long Covid, overlaps considerably with ME/CFS in immunological, mitochondrial, and neurological dysfunctions (4). These similarities have resulted in increased interest and acceptance of ME/CFS as a disease and may stimulate research, the development of a diagnostic test, and pharmacotherapeutic interventions in ME/CFS that may be applied to Long Covid.
 
Neurological disturbances such as cognitive impairment, autonomic dysfunction, altered pain and sensory perception, and sleep disturbances are essential for diagnosis of ME/CFS and are commonly reported in Long Covid (see the figure). The World Health Organization (WHO) categorizes ME/CFS as a disease of the nervous system. Neuroimaging of ME/CFS patients has revealed anatomical, neurochemical, and functional brain changes. For example, brain magnetic resonance imaging (MRI) found global gray and white matter volume changes and also differences in the cortical and subcortical regional volumes in ME/CFS patients (5). Impaired brainstem connectivity identified with functional MRI (fMRI) and regression of white matter was associated with autonomic nervous system (ANS) measures in ME/CFS, including sleep disturbances and respiratory rate, which may lead to other symptoms, including pain, fatigue, impaired concentration and memory, and sensory and motor dysfunction (6). Such neurological symptoms are also commonly reported by Long Covid patients, and brain MRI has shown higher gray matter volumes in hippocampi that correlated with memory loss, a result also reported in ME/CFS (4). Overall, the underlying mechanism resulting in these MRI findings is unclear. Nonetheless, MRI and fMRI are important techniques to help elucidate the pathology of ME/CFS, as well as Long Covid.

__________________________________________________________________________________
 
Autoimmun Rev  . 2016 Jun;15(6):552-7.  doi: 10.1016/j.autrev.2016.02.011. Epub 2016 Feb 12.
Autoantibody pain
Andreas Goebel 1
PMID: 26883460
Abstract
As autoantibodies bind to target tissues, Fc-region dependent inflammation can induce pain via mediators exciting nociceptors. But recently another possibility has emerged, where autoantibody binding to nociceptors can directly cause pain, without inflammation. This is thought to occur as a result of Fab-region mediated modification of nerve transduction, transmission, or neuropeptide release. In three conditions, complex regional pain syndrome, anti-voltage gated potassium channel complex autoimmunity, and chronic fatigue syndrome, all associated with no or only little inflammation, initial laboratory-, and clinical trial-results have suggested a potential role for autoantibody-mediated mechanisms. More research assessing the pathogenic roles of autoantibodies in these and other chronic pain conditions is required. The concept of autoantibody-mediated pain offers hope for the development of novel therapies for currently intractable pains.
Keywords: Autoantibody; CRPS; Chronic fatigue syndrome; Complex regional pain syndrome; Neuropathic pain; Pain; Voltage gated potassium channels.

__________________________________________________________________________________
Autoimmunity Reviews Volume 21, Issue 3, March 2022, 103015The autoimmune aetiology of unexplained chronic painAuthor links open overlay panelAndreasGoebela1DavidAnderssonb1ZsuzsannaHelyesc1J. DavidClarkd1DebraDulakee1CamillaSvenssonf1
https://doi.org/10.1016/j.autrev.2021.103015Get rights and content
Abstract
Chronic pain is the leading cause of life years lived with disability worldwide. The aetiology of most chronic pain conditions has remained poorly understood and there is a dearth of effective therapies. The WHO ICD-11 has categorised unexplained chronic pain states as ‘chronic primary pains’ (CPP), which are further defined by their association with significant distress and/or dysfunction. The new mechanistic term, ‘nociplasticic pain’ has been developed to illustrate their presumed generation by a structurally intact, but abnormally functioning nociceptive system. Recently, researchers have unravelled the surprising, ubiquitous presence of pain-sensitising autoantibodies in four investigated CPP indicating autoimmune causation. In persistent complex regional pain syndrome, fibromyalgia syndrome, chronic post-traumatic limb pain, and non-inflammatory joint pain associated with rheumatoid arthritis, passive transfer experiments have shown that either IgG or IgM antibodies from patient-donors cause symptoms upon injection to rodents that closely resemble those of the clinical disorders. Targets of antibody-binding and downstream effects vary between conditions, and more research is needed to elucidate the molecular and cellular details. The central nervous system appears largely unaffected by antibody binding, suggesting that the clinically evident CNS symptoms associated with CPP might arise downstream of peripheral processes. In this narrative review pertinent findings are described, and it is suggested that additional symptom-based disorders might be examined for the contribution of antibody-mediated autoimmune mechanisms.

__________________________________________________________________________________
 
Infectious Diseases  September 27, 2022
Association of SARS-CoV-2 Seropositivity With Myalgic Encephalomyelitis and/or Chronic Fatigue Syndrome Among Children and Adolescents in GermanyAnna-Lisa Sorg, MSc1,2; Selina Becht, MSc1; Marietta Jank, MD3; et alJakob Armann, MD4; Ulrich von Both, MD5; Markus Hufnagel, MD6; Fabian Lander, MD7; Johannes G. Liese, MD8; Tim Niehues, MD9; Eva Verjans, MD10; Martin Wetzke, MD11; Silvia Stojanov, MD12; Uta Behrends, MD12; Christian Drosten, MD13; Horst Schroten, MD3; Rüdiger von Kries, MD1
JAMA Netw Open. 2022;5(9):e2233454. doi:10.1001/jamanetworkopen.2022.33454
Key Points
Question  Is SARS-CoV-2 seropositivity associated with symptoms of myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) in children and adolescents?
Findings  This cross-sectional study of hospital-based SARS-CoV-2 seroprevalence surveys in Germany compared seropositive and seronegative children and adolescents and identified an excess of possible ME/CFS symptoms with serological evidence of preceding SARS-CoV-2 infection. This association almost disappeared with adjustment for confounders and restriction to children and adolescents unaware of preceding infection.
Meaning  These findings suggest that the risk of ME/CFS after SARS-CoV-2 infection in children and adolescents may be small and that recall bias may contribute to risk estimates.
Abstract
Importance  During the COVID-19 pandemic, a reduction in quality of life and physical and mental health among children and adolescents has been reported that may be associated with SARS-CoV-2 infection and/or containment measures.
Objective  To assess the association of SARS-CoV-2 seropositivity with symptoms that may be related to myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) among children and adolescents.
Design, Setting, and Participants  This substudy of the cross-sectional SARS-CoV-2 seroprevalence surveys in Germany (SARS-CoV-2 KIDS) was performed in 9 pediatric hospitals from May 1 to October 31, 2021. Pediatric patients were recruited during an inpatient or outpatient visit regardless of the purpose of the visit. Parental questionnaires and serum samples were collected during clinically indicated blood draws. The parental questionnaire on demographic and clinical information was extended by items according to the DePaul Symptom Questionnaire, a pediatric screening tool for ME/CFS in epidemiological studies in patients aged 5 to 17 years.
Exposures  Seropositivity was determined by SARS-CoV-2 IgG antibodies in serum samples using enzyme-linked immunosorbent assays.
Main Outcomes and Measures  Key symptoms of ME/CFS were evaluated separately or as clustered ME/CFS symptoms according to the DePaul Symptom Questionnaire, including fatigue.
Results  Among 634 participants (294 male [46.4%] and 340 female [53.6%]; median age, 11.5 [IQR, 8-14] years), 198 (31.2%) reported clustered ME/CFS symptoms, including 40 of 100 SARS-CoV-2–seropositive (40.0%) and 158 of 534 SARS-CoV-2–seronegative (29.6%) children and adolescents. After adjustment for sex, age group, and preexisting disease, the risk ratio for reporting clustered ME/CFS symptoms decreased from 1.35 (95% CI, 1.03-1.78) to 1.18 (95% CI, 0.90-1.53) and for substantial fatigue from 2.45 (95% CI, 1.24-4.84) to 2.08 (95% CI, 1.05-4.13). Confinement to children and adolescents with unknown previous SARS-CoV-2 infection status (n = 610) yielded lower adjusted risks for all symptoms except joint pain ME/CFS–related symptoms. The adjusted risk ratio was 1.08 (95% CI, 0.80-1.46) for reporting clustered ME/CFS symptoms and 1.43 (95% CI, 0.63-3.23) for fatigue.
Conclusions and Relevance  These findings suggest that the risk of ME/CFS in children and adolescents owing to SARS-CoV-2 infection may be very small. Recall bias may contribute to risk estimates of long COVID-19 symptoms in children. Extensive lockdowns must be considered as an alternative explanation for complex unspecific symptoms during the COVID-19 pandemic.
0 Comments

Abstracts from June 1st

1/6/2022

0 Comments

 
 Medscape Medical News > Conference News > SLEEP 2022
'Alarming' New Data on Disordered Sleep After COVID
Megan Brooks  June 07, 2022
 
Moderate to severe sleep disturbances and severe fatigue affect up to 40% of patients with long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC). Such disturbances are especially common among Black people, new research shows.
The "high" prevalence of moderate to severe sleep disturbances is "alarming," study investigator Cinthya Pena Orbea, MD, sleep specialist at the Cleveland Clinic, told Medscape Medical News.
The findings were presented at SLEEP 2022: 36th Annual Meeting of the Associated Professional Sleep Societies.
Pena and colleagues analyzed data on 962 patients with PASC seen at the Cleveland Clinic ReCOVer Clinic between February 2021 and April 2022.
More than two thirds of patients (67.2%) reported at least moderate fatigue, while 21.8% reported severe fatigue, Pena reported.
In addition, 41.3% reported at least moderate sleep disturbances, while 8% of patients reported severe sleep disturbances, including insomnia, "which may impair quality of life," Pena said.
Obesity, mood disorders, and Black race emerged as contributors to problems with sleep and fatigue after COVID.
Notably, after adjusting for demographics, Black race conferred threefold higher odds of moderate to severe sleep disturbances.
"We don't know why this is, and one of our next steps is to better understand race-specific determinants of sleep disturbances after COVID and create targeted interventions," Pena said.
How long after COVID the fatigue and sleep problems last "remains uncertain," Pena acknowledged. However, she added, in her clinical experience with therapy, patients' sleep and fatigue may improve after 6 or 8 months.
Ruth Benca, MD, PhD, co-chair of the Alliance for Sleep, is not surprised by the Cleveland Clinic findings.
"Sleep disturbances and fatigue are part of the sequelae of COVID," Benca, who was not involved in the study, told Medscape Medical News.
"We know that people who have had COVID have more trouble sleeping afterwards. There is the COVID insomnia created in all of us just out of our worries, fears, isolation, and stress. And then there's an actual impact of having the infection itself on worsening sleep," said Benca, with Wake Forest University School of Medicine and Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina.
The study had no specific funding. The authors have disclosed no relevant financial relationships. Benca is a consultant for Idorsia Pharmaceuticals.
SLEEP 2022: 36th Annual Meeting of the Associated Professional Sleep Societies: Abstract 0735. Presented June 6, 2022.
____________________________________________________________________________________
 
Front Neurol  . 2022 May 6;13:862976. doi: 10.3389/fneur.2022.862976. eCollection 2022.
Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain​
Gabriela Ioachim 1, Howard J M Warren 1, Jocelyn M Powers 1, Roland Staud 2, Caroline F Pukall 1 3, Patrick W Stroman 1 4 5
PMID: 35599729  PMCID: PMC9120571 DOI: 10.3389/fneur.2022.862976
AbstractChronic pain associated with fibromyalgia (FM) affects a large portion of the population but the underlying mechanisms leading to this altered pain are still poorly understood. Evidence suggests that FM involves altered neural processes in the central nervous system and neuroimaging methods such as functional magnetic resonance imaging (fMRI) are used to reveal these underlying alterations. While many fMRI studies of FM have been conducted in the brain, recent evidence shows that the changes in pain processing in FM may be linked to autonomic and homeostatic dysregulation, thus requiring further investigation in the brainstem and spinal cord. Functional magnetic resonance imaging data from 15 women with FM and 15 healthy controls were obtained in the cervical spinal cord and brainstem at 3 tesla using previously established methods. In order to investigate differences in pain processing in these groups, participants underwent trials in which they anticipated and received a predictable painful stimulus, randomly interleaved with trials with no stimulus. Differences in functional connectivity between the groups were investigated by means of structural equation modeling. The results demonstrate significant differences in brainstem/spinal cord network connectivity between the FM and control groups which also correlated with individual differences in pain responses. The regions involved in these differences in connectivity included the LC, hypothalamus, PAG, and PBN, which are known to be associated with autonomic homeostatic regulation, including fight or flight responses. This study extends our understanding of altered neural processes associated with FM and the important link between sensory and autonomic regulation systems in this disorder.
Keywords: brainstem; chronic; fMRI; fibromyalgia; human; pain; spinal cord.
Copyright © 2022 Ioachim, Warren, Powers, Staud, Pukall and Stroman.
____________________________________________________________________________________

Plos one  2022 Mar 15;17(3):e0265315.   doi: 10.1371/journal.pone.0265315. eCollection 2022.
Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Multi-site Clinical Assessment of ME/CFS (MCAM) sub-studyDane B Cook 1 2, Stephanie VanRiper 1 2, Ryan J Dougherty 3, Jacob B Lindheimer 1 2 4, Michael J Falvo 5 6, Yang Chen 7, Jin-Mann S Lin 7, Elizabeth R Unger 7, MCAM Study Group
PMID: 35290404  PMCID: PMC8923458   
AbstractBackground: Cardiopulmonary exercise testing has demonstrated clinical utility in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, to what extent exercise responses are independent of, or confounded by, aerobic fitness remains unclear.
Purpose: To characterize and compare exercise responses in ME/CFS and controls with and without matching for aerobic fitness.
Methods: As part of the Multi-site Clinical Assessment of ME/CFS (MCAM) study, 403 participants (n = 214 ME/CFS; n = 189 controls), across six ME/CFS clinics, completed ramped cycle ergometry to volitional exhaustion. Metabolic, heart rate (HR), and ratings of perceived exertion (RPE) were measured. Ventilatory equivalent ([Formula: see text], [Formula: see text]), metrics of ventilatory efficiency, and chronotropic incompetence (CI) were calculated. Exercise variables were compared using Hedges' g effect size with 95% confidence intervals. Differences in cardiopulmonary and perceptual features during exercise were analyzed using linear mixed effects models with repeated measures for relative exercise intensity (20-100% peak [Formula: see text]). Subgroup analyses were conducted for 198 participants (99 ME/CFS; 99 controls) matched for age (±5 years) and peak [Formula: see text] (~1 ml/kg/min-1).
Results: Ninety percent of tests (n = 194 ME/CFS, n = 169 controls) met standard criteria for peak effort. ME/CFS responses during exercise (20-100% peak [Formula: see text]) were significantly lower for ventilation, breathing frequency, HR, measures of efficiency, and CI and significantly higher for [Formula: see text], [Formula: see text] and RPE (p<0.05adjusted). For the fitness-matched subgroup, differences remained for breathing frequency, [Formula: see text], [Formula: see text], and RPE (p<0.05adjusted), and higher tidal volumes were identified for ME/CFS (p<0.05adjusted). Exercise responses at the gas exchange threshold, peak, and for measures of ventilatory efficiency (e.g., [Formula: see text]) were generally reflective of those seen throughout exercise (i.e., 20-100%).
Conclusion: Compared to fitness-matched controls, cardiopulmonary responses to exercise in ME/CFS are characterized by inefficient exercise ventilation and augmented perception of effort. These data highlight the importance of distinguishing confounding fitness effects to identify responses that may be more specifically associated with ME/CFS.
____________________________________________________________________________________
 
Front. Cell. Neurosci., 09 May 2022 | https://doi.org/10.3389/fncel.2022.888232
The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

Herbert Renz-Polster1*, Marie-Eve Tremblay2,3,4,5,6,7, Dorothee Bienzle8 and  Joachim E. Fischer1
Although 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.
____________________________________________________________________________________
 
BMJ  . 2022 Feb 9;376:e068414.  doi: 10.1136/bmj-2021-068414.
Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study
Ken Cohen 1, Sheng Ren 2, Kevin Heath 3, Micah C Dasmariñas 2, Karol Giuseppe Jubilo 2, Yinglong Guo 2, Marc Lipsitch 4, Sarah E Daugherty 2
PMID: 35140117 PMCID: PMC8828141 DOI: 10.1136/bmj-2021-068414
AbstractObjective: To characterize the risk of persistent and new clinical sequelae in adults aged ≥65 years after the acute phase of SARS-CoV-2 infection.
Design: Retrospective cohort study.
Setting: UnitedHealth Group Clinical Research Database: deidentified administrative claims and outpatient laboratory test results.
Participants: Individuals aged ≥65 years who were continuously enrolled in a Medicare Advantage plan with coverage of prescription drugs from January 2019 to the date of diagnosis of SARS-CoV-2 infection, matched by propensity score to three comparison groups that did not have covid-19: 2020 comparison group (n=87 337), historical 2019 comparison group (n=88 070), and historical comparison group with viral lower respiratory tract illness (n=73 490).
Main outcome measures: The presence of persistent and new sequelae at 21 or more days after a diagnosis of covid-19 was determined with ICD-10 (international classification of diseases, 10th revision) codes. Excess risk for sequelae caused by infection with SARS-CoV-2 was estimated for the 120 days after the acute phase of the illness with risk difference and hazard ratios, calculated with 95% Bonferroni corrected confidence intervals. The incidence of sequelae after the acute infection was analyzed by age, race, sex, and whether patients were admitted to hospital for covid-19.
Results: Among individuals who were diagnosed with SARS-CoV-2, 32% (27 698 of 87 337) sought medical attention in the post-acute period for one or more new or persistent clinical sequelae, which was 11% higher than the 2020 comparison group. Respiratory failure (risk difference 7.55, 95% confidence interval 7.18 to 8.01), fatigue (5.66, 5.03 to 6.27), hypertension (4.43, 2.27 to 6.37), memory difficulties (2.63, 2.23 to 3.13), kidney injury (2.59, 2.03 to 3.12), mental health diagnoses (2.50, 2.04 to 3.04), hypercoagulability 1.47 (1.2 to 1.73), and cardiac rhythm disorders (2.19, 1.76 to 2.57) had the greatest risk differences compared with the 2020 comparison group, with similar findings to the 2019 comparison group. Compared with the group with viral lower respiratory tract illness, however, only respiratory failure, dementia, and post-viral fatigue had increased risk differences of 2.39 (95% confidence interval 1.79 to 2.94), 0.71 (0.3 to 1.08), and 0.18 (0.11 to 0.26) per 100 patients, respectively. Individuals with severe covid-19 disease requiring admission to hospital had a markedly increased risk for most but not all clinical sequelae.
Conclusions: The results confirm an excess risk for persistent and new sequelae in adults aged ≥65 years after acute infection with SARS-CoV-2. Other than respiratory failure, dementia, and post-viral fatigue, the sequelae resembled those of viral lower respiratory tract illness in older adults. These findings further highlight the wide range of important sequelae after acute infection with the SARS-CoV-2 virus.
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
____________________________________________________________________________________

JACC: Heart Failure Volume 9, Issue 12, December 2021, Pages 927-937
Use of Cardiopulmonary Stress Testing for Patients With Unexplained Dyspnea Post–Coronavirus Disease
Author links open overlay panelDonna M.ManciniMDabDanielle L.BrunjesPHDaAnuradhaLalaMDabMaria GiovannaTrivieriMD, PHDaJohanna P.ContrerasMD, MScaBenjamin H.NatelsonMDc
https://doi.org/10.1016/j.jchf.2021.10.002Get rights and content
Robert Naeije, Sergio Caravita
JACC: Heart Failure, Volume 10, Issue 3, March 2022, Pages 214-215
Abstract

ObjectivesThe authors used cardiopulmonary exercise testing (CPET) to define unexplained dyspnea in patients with post-acute sequelae of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection (PASC). We assessed participants for criteria to diagnose myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

BackgroundApproximately 20% of patients who recover from coronavirus disease (COVID) remain symptomatic. This syndrome is named PASC. Its etiology is unclear. Dyspnea is a frequent symptom.

MethodsThe authors performed CPET and symptom assessment for ME/CFS in 41 patients with PASC 8.9 ± 3.3 months after COVID. All patients had normal pulmonary function tests, chest X-ray, and chest computed tomography scans. Peak oxygen consumption (peak VO2), slope of minute ventilation to CO2 production (VE/VCO2 slope), and end tidal pressure of CO2 (PetCO2) were measured. Ventilatory patterns were reviewed with dysfunctional breathing defined as rapid erratic breathing.

ResultsEighteen men and 23 women (average age: 45 ± 13 years) were studied. Left ventricular ejection fraction was 59% ± 9%. Peak VO2 averaged 20.3 ± 7 mL/kg/min (77% ± 21% predicted VO2). VE/VCO2 slope was 30 ± 7. PetCO2 at rest was 33.5 ± 4.5 mm Hg. Twenty-four patients (58.5%) had a peak VO2 <80% predicted. All patients with peak VO2 <80% had a circulatory limitation to exercise. Fifteen of 17 patients with normal peak VO2 had ventilatory abnormalities including peak respiratory rate >55 (n = 3) or dysfunctional breathing (n = 12). For the whole cohort, 88% of patients (n = 36) had ventilatory abnormalities with dysfunctional breathing (n = 26), increased VE/VCO2 (n = 17), and/or hypocapnia PetCO2 <35 (n = 25). Nineteen patients (46%) met criteria for ME/CFS.

ConclusionsCirculatory impairment, abnormal ventilatory pattern, and ME/CFS are common in patients with PASC. The dysfunctional breathing, resting hypocapnia, and ME/CFS may contribute to symptoms. CPET is a valuable tool to assess these patients.
____________________________________________________________________________________
 
Nearly 1 in 5 Adults Who Had COVID Have Lingering Symptoms: US StudyBy Reuters Staff  June 24, 2022
 
(Reuters) - Nearly 1 in 5 American adults in a survey who reported having COVID-19 in the past are still having symptoms of long COVID, according to data collected in the first two weeks of June, U.S. health officials said on Wednesday.
Overall, an estimated 1 in 13 adults in the United States have long COVID symptoms lasting for three months or more after first contracting the disease, and which they did not have before the infection, the data suggests.
The data was collected using an online questionnaire from June 1-13 by the U.S. Census Bureau's Household Pulse Survey, and analyzed by the U.S. Centers for Disease Control and Prevention (CDC).
Long COVID symptoms range from fatigue, rapid heartbeat, shortness of breath, cognitive difficulties, chronic pain, sensory abnormalities and muscle weakness. They can be debilitating and last for weeks or months after recovery from the initial infection.
The CDC analysis also found that younger adults were more likely to report persistent symptoms than older adults.
Women were also more likely to report long COVID than men, according to the study, with 9.4% of U.S. adult women reporting long COVID symptoms compared to 5.5% of men.
The survey found nearly 9% of Hispanic adults reported long COVID, higher than non-Hispanic white and Black adults, and more than twice the percentage of non-Hispanic Asian adults.
There were also differences based on U.S states, with the highest percentage of adults reporting long COVID symptoms in Kentucky and Alabama, while Hawaii, Maryland and Virginia had the lowest.
Among the experimental survey's limitations, the CDC cautions in technical notes, is that the percentage of adults who self-report ever having had COVID-19 is lower than estimates based on national seroprevalence studies. The survey also relies on online responses, and had a low (6.2%) response rate.
SOURCE: https://bit.ly/3NdZjyQ Household Pulse Survey Dashboard, online June 22, 2022.
____________________________________________________________________________________
 
Cardiovasc Diabetol  . 2021 Aug 23;20(1):172. doi: 10.1186/s12933-021-01359-7.
Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin
Etheresia Pretorius 1, Mare Vlok 2, Chantelle Venter 3, Johannes A Bezuidenhout 3, Gert Jacobus Laubscher 4, Janami Steenkamp 3 5, Douglas B Kell 6 7 8
PMID: 34425843 PMCID: PMC8381139  DOI: 10.1186/s12933-021-01359-7
AbstractBackground: Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by acute clinical pathologies, including various coagulopathies that may be accompanied by hypercoagulation and platelet hyperactivation. Recently, a new COVID-19 phenotype has been noted in patients after they have ostensibly recovered from acute COVID-19 symptoms. This new syndrome is commonly termed Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Here we refer to it as Long COVID/PASC. Lingering symptoms persist for as much as 6 months (or longer) after acute infection, where COVID-19 survivors complain of recurring fatigue or muscle weakness, being out of breath, sleep difficulties, and anxiety or depression. Given that blood clots can block microcapillaries and thereby inhibit oxygen exchange, we here investigate if the lingering symptoms that individuals with Long COVID/PASC manifest might be due to the presence of persistent circulating plasma microclots that are resistant to fibrinolysis.
Methods: We use techniques including proteomics and fluorescence microscopy to study plasma samples from healthy individuals, individuals with Type 2 Diabetes Mellitus (T2DM), with acute COVID-19, and those with Long COVID/PASC symptoms.
Results: We show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits (microclots). We also show that these microclots in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis (compared to plasma from controls and T2DM), even after trypsinisation. After a second trypsinization, the persistent pellet deposits (microclots) were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC, versus the equivalent volume of fully digested fluid of the control samples and T2DM. Of particular interest was a substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits.
Conclusions: Clotting pathologies in both acute COVID-19 infection and in Long COVID/PASC might benefit from following a regime of continued anticlotting therapy to support the fibrinolytic system function.
____________________________________________________________________________________

J Clin Sleep Med  . 2020 Dec 15;16(12):2009-2019.   doi: 10.5664/jcsm.8740.
Effects of trazodone versus cognitive behavioral therapy in the insomnia with short sleep duration phenotype: a preliminary study
Alexandros N Vgontzas 1, Kristina Puzino 1, Julio Fernandez-Mendoza 1, Venkatesh Basappa Krishnamurthy 1, Maria Basta 2, Edward O Bixler 1
PMID: 32780015   PMCID: PMC7848933
AbstractStudy objectives: The insomnia with objective short sleep duration phenotype is associated with increased risk for adverse health outcomes, physiological hyperarousal, and a blunted response to cognitive behavioral therapy for insomnia (CBT-I). Whether insomnia with objective short sleep duration responds better to pharmacological treatment compared to CBT-I has not been examined.
Methods: Participants included 15 patients with chronic insomnia (86.7% female), aged 45.3 ± 8.1 years. Eight patients were randomized to CBT-I and 7 to trazodone. Patients were examined with 2 weeks of actigraphy, salivary cortisol, and the insomnia severity index at 3 time points (pretreatment, 3-month posttreatment, and 6-month follow-up). Mixed between-within-subjects analysis of variance and univariate analysis of covariance were conducted to assess the impact of trazodone and CBT-I on patients' total sleep time, salivary cortisol, and insomnia severity index scores across the 3 time points.
Results: Trazodone, but not CBT-I, significantly lengthened total sleep time (when measured with actigraphy) both at posttreatment (51.01 minutes vs -11.73 minutes; P = .051; Cohen's d = 1.383) and at follow-up (50.35 minutes vs -7.56 minutes; P = .012; Cohen's d = 1.725), respectively. In addition, trazodone, but not CBT-I, showed a clinically meaningful decrease in salivary cortisol from pretreatment to posttreatment (-36.07% vs -11.70%; Cohen's d = 0.793) and from pretreatment to follow-up (-21.37% vs -5.79%; Cohen's d = 0.284), respectively. Finally, there were no differences on insomnia severity index scores between the trazodone and the CBT-I groups.
Conclusions: The current preliminary, open-label, randomized trial suggests that trazodone, but not CBT-I, significantly improves objective sleep duration and reduces hypothalamic-pituitary-adrenal axis activation, suggesting a differential treatment response in the insomnia with objective short sleep duration phenotype.
Clinical trial registration: Registry: ClinicalTrials.gov; Name: Study of Trazodone & Cognitive Behavioral Therapy to Treat Insomnia; URL: https://clinicaltrials.gov/ct2/show/NCT01348542; Identifier: NCT01348542.
____________________________________________________________________________________

Neuropsychopharmacology  
2020 Jan;45(1):205-216. doi: 10.1038/s41386-019-0439-z. Epub 2019 Jun 17.
Sleep deficiency and chronic pain: potential underlying mechanisms and clinical implications
Monika Haack 1 2, Norah Simpson 3, Navil Sethna 4 5, Satvinder Kaur 6 4, Janet Mullington 6 4
PMID: 31207606 PMCID: PMC6879497
Abstract
Pain can be both a cause and a consequence of sleep deficiency. This bidirectional relationship between sleep and pain has important implications for clinical management of patients, but also for chronic pain prevention and public health more broadly. The review that follows will provide an overview of the neurobiological evidence of mechanisms thought to be involved in the modulation of pain by sleep deficiency, including the opioid, monoaminergic, orexinergic, immune, melatonin, and endocannabinoid systems; the hypothalamus-pituitary-adrenal axis; and adenosine and nitric oxide signaling. In addition, it will provide a broad overview of pharmacological and non-pharmacological approaches for the management of chronic pain comorbid with sleep disturbances and for the management of postoperative pain, as well as discuss the effects of sleep-disturbing medications on pain amplification.
____________________________________________________________________________________

Bridging Knowledge Gaps in the Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19
Jennifer A. Frontera, MD1; Naomi M. Simon, MD, MSc2
JAMA Psychiatry. Published online June 29, 2022. doi:10.1001/jamapsychiatry.2022.1616
COVID-19 Resource Center
Abstract
Importance  Neuropsychiatric symptoms have been reported as a prominent feature of postacute sequelae of COVID-19 (PASC), with common symptoms that include cognitive impairment, sleep difficulties, depression, posttraumatic stress, and substance use disorders. A primary challenge of parsing PASC epidemiology and pathophysiology is the lack of a standard definition of the syndrome, and little is known regarding mechanisms of neuropsychiatric PASC.
Observations  Rates of symptom prevalence vary, but at least 1 PASC neuropsychiatric symptom has been reported in as many as 90% of patients 6 months after COVID-19 hospitalization and in approximately 25% of nonhospitalized adults with COVID-19. Mechanisms of neuropsychiatric sequelae of COVID-19 are still being elucidated. They may include static brain injury accrued during acute COVID-19, neurodegeneration triggered by secondary effects of acute COVID-19, autoimmune mechanisms with chronic inflammation, viral persistence in tissue reservoirs, or reactivation of other latent viruses. Despite rapidly emerging data, many gaps in knowledge persist related to the variable definitions of PASC, lack of standardized phenotyping or biomarkers, variability in virus genotypes, ascertainment biases, and limited accounting for social determinants of health and pandemic-related stressors.
Conclusions and Relevance  Growing data support a high prevalence of PASC neuropsychiatric symptoms, but the current literature is heterogeneous with variable assessments of critical epidemiological factors. By enrolling large patient samples and conducting state-of-the-art assessments, the Researching COVID to Enhance Recovery (RECOVER), a multicenter research initiative funded by the National Institutes of Health, will help clarify PASC epidemiology, pathophysiology, and mechanisms of injury, as well as identify targets for therapeutic intervention.
____________________________________________________________________________________

Long covid patients travel abroad for expensive and experimental “blood washing”
BMJ 2022; 378 doi: https://doi.org/10.1136/bmj.o1671 (Published 12 July 2022)Cite this as: BMJ 2022;378:o1671
Patients with long covid are travelling to private clinics in Cyprus, Germany, and Switzerland for blood filtering apheresis and anticoagulation drugs. Experts question whether these invasive treatments should be offered without sufficient evidence. Madlen Davies reports
Gitte Boumeester, a trainee psychiatrist in Almelo, the Netherlands, was infected with SARS-CoV-2 in November 2020. She was tired for weeks afterwards but chalked it up to the virus. Soon, she was experiencing such extreme fatigue that it took her two hours to walk to the kitchen to make breakfast. She had brain fog and heart palpitations, was short of breath, often felt sick, and woke up in the night with chest pain. A battery of tests found nothing wrong with her heart or lungs, and she was sent back to her GP. She left her job in November 2021, after two failed attempts to go back to work.
She joined a Facebook group for patients with long covid, many of whom discussed travel to Germany for apheresis, what some of them call a “blood washing” treatment. Apheresis, in which large needles are inserted into the veins and the blood is filtered, removing lipids and inflammatory proteins, is recommended by the German Society of Nephrology as a standard last resort in the country for lipid disorders. A new clinic offering apheresis for long covid patients, called the Long Covid Center, was opening in Cyprus, and she could be treated there in March. “I thought, what’s the worst thing I’ve got to lose?” she said. “Money was the only thing. I thought, OK, well, why not give it a try?”
Two months later she was back home in the Netherlands, having spent nearly all her savings—more than €15 000 (£12 700; $15 000)—with no improvement in her symptoms.
Thousands of patients like Boumeester, frustrated at the lack of treatment available for long covid, are travelling to Cyprus, Germany, and Switzerland for apheresis, an investigation by The BMJ and ITV News can reveal. Many are also prescribed anticlotting drugs, including clopidogrel, apixaban, and heparin, on a hypothesis that the symptoms of long covid are caused by small clots in the blood that are blocking the flow of oxygen through capillaries. Although some doctors and researchers believe that apheresis and anticoagulation drugs may be promising treatments for long covid, others worry that desperate patients are spending life changing sums on invasive, unproved treatments.
____________________________________________________________________________________

THE LANCET: ARTICLES| VOLUME 400, ISSUE 10347, P170-184, JULY 16, 2022
Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis
Franco De Crescenzo, MD  Gian Loreto D'Alò, MD †  Edoardo G Ostinelli, MD † Marco Ciabattini, MD et al  Published:July 16, 2022DOI:https://doi.org/10.1016/S0140-6736(22)00878-9

BackgroundBehavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder.
MethodsIn this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ.
FindingsWe included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36–0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27–0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52–0·99; moderate], 0·70 [0·51–0·95; moderate] and 0·71 [0·52–0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28–3·13; very low]; zolpidem: 1·79 [1·25–2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01–3·33; low]), daridorexant (3·45 [1·41–8·33; low), and suvorexant (3·13 [1·47–6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27–2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36–0·90; very low]; lemborexant: 0·41 [0·04–0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16–1·10; very low]) and zolpidem (0·60 [0·00–1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20–0·93; very low]; zolpidem: 0·43 [0·19–0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11–3·70; very low]).
InterpretationOverall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice.
____________________________________________________________________________________

Cell  . 2022 Jul 7;185(14):2452-2468.e16. doi: 10.1016/j.cell.2022.06.008. Epub 2022 Jun 13.
Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
Anthony Fernández-Castañeda 1, et al    PMID: 35768006  PMCID: PMC9189143  
Abstract
COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
____________________________________________________________________________________

Front Neurol  . 2022 Apr 11;13:841310.  doi: 10.3389/fneur.2022.841310. eCollection 2022.
Molecular Hydrogen as a Medical Gas for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Possible Efficacy Based on a Literature Review
Shin-Ichi Hirano 1, Yusuke Ichikawa 1 2, Bunpei Sato 1 2, Yoshiyasu Takefuji 3 4, Fumitake Satoh 1 2   PMID: 35493814 PMCID: PMC9042428
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder that is characterized by fatigue that persists for more than 6 months, weakness, sleep disturbances, and cognitive dysfunction. There are multiple possible etiologies for ME/CFS, among which mitochondrial dysfunction plays a major role in abnormal energy metabolism. The potential of many substances for the treatment of ME/CFS has been examined; however, satisfactory outcomes have not yet been achieved. The development of new substances for curative, not symptomatic, treatments is desired. Molecular hydrogen (H2) ameliorates mitochondrial dysfunction by scavenging hydroxyl radicals, the most potent oxidant among reactive oxygen species. Animal experiments and clinical trials reported that H2 exerted ameliorative effects on acute and chronic fatigue. Therefore, we conducted a literature review on the mechanism by which H2 improves acute and chronic fatigue in animals and healthy people and showed that the attenuation of mitochondrial dysfunction by H2 may be involved in the ameliorative effects. Although further clinical trials are needed to determine the efficacy and mechanism of H2 gas in ME/CFS, our literature review suggested that H2 gas may be an effective medical gas for the treatment of ME/CFS.
Keywords: chronic fatigue syndrome (CFS); hydroxyl radicals; long COVID; mitochondrial dysfunction; molecular hydrogen; myalgic encephalomyelitis (ME); oxidative stress; post COVID.
Copyright © 2022 Hirano, Ichikawa, Sato, Takefuji and Satoh.
____________________________________________________________________________________

Original Investigation Pediatrics  July 22, 2022
Post–COVID-19 Conditions Among Children 90 Days After SARS-CoV-2 Infection
Anna L. Funk, PhD, MSc1; et al for the Pediatric Emergency Research Network–COVID-19 Study Team
JAMA Netw Open. 2022;5(7):e2223253. doi:10.1001/jamanetworkopen.2022.23253
COVID-19 Resource Center
Key Points
Question  What proportion of children infected with SARS-CoV-2 who were tested in emergency departments (EDs) reported post–COVID-19 conditions (PCCs) 90 days after their ED visits?
Findings  In this cohort study of 1884 SARS-CoV-2–positive children with 90-day follow-up, 5.8% of patients, including 9.8% of hospitalized children and 4.6% of discharged children, reported PCCs. Characteristics associated with PCCs included being hospitalized 48 hours or more, having 4 or more symptoms reported at the index ED visit, and being 14 years of age or older.
Meaning  This study suggests that, given the prevalence of PCCs, appropriate guidance and follow-up are required for children testing positive for SARS-CoV-2.
Abstract
Importance  Little is known about the risk factors for, and the risk of, developing post–COVID-19 conditions (PCCs) among children.
Objectives  To estimate the proportion of SARS-CoV-2–positive children with PCCs 90 days after a positive test result, to compare this proportion with SARS-CoV-2–negative children, and to assess factors associated with PCCs.
Design, Setting, and Participants  This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2–positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2–negative controls.
Exposure  SARS-CoV-2 detected via nucleic acid testing.
Main Outcomes and Measures  Post–COVID-19 conditions, defined as any persistent, new, or recurrent health problems reported in the 90-day follow-up survey.
Results  Of 8642 enrolled children, 2368 (27.4%) were SARS-CoV-2 positive, among whom 2365 (99.9%) had index ED visit disposition data available; among the 1884 children (79.7%) who completed follow-up, the median age was 3 years (IQR, 0-10 years) and 994 (52.8%) were boys. A total of 110 SARS-CoV-2–positive children (5.8%; 95% CI, 4.8%-7.0%) reported PCCs, including 44 of 447 children (9.8%; 95% CI, 7.4%-13.0%) hospitalized during the acute illness and 66 of 1437 children (4.6%; 95% CI, 3.6%-5.8%) not hospitalized during the acute illness (difference, 5.3%; 95% CI, 2.5%-8.5%). Among SARS-CoV-2–positive children, the most common symptom was fatigue or weakness (21 [1.1%]). Characteristics associated with reporting at least 1 PCC at 90 days included being hospitalized 48 hours or more compared with no hospitalization (adjusted odds ratio [aOR], 2.67 [95% CI, 1.63-4.38]); having 4 or more symptoms reported at the index ED visit compared with 1 to 3 symptoms (4-6 symptoms: aOR, 2.35 [95% CI, 1.28-4.31]; ≥7 symptoms: aOR, 4.59 [95% CI, 2.50-8.44]); and being 14 years of age or older compared with younger than 1 year (aOR, 2.67 [95% CI, 1.43-4.99]). SARS-CoV-2–positive children were more likely to report PCCs at 90 days compared with those who tested negative, both among those who were not hospitalized (55 of 1295 [4.2%; 95% CI, 3.2%-5.5%] vs 35 of 1321 [2.7%; 95% CI, 1.9%-3.7%]; difference, 1.6% [95% CI, 0.2%-3.0%]) and those who were hospitalized (40 of 391 [10.2%; 95% CI, 7.4%-13.7%] vs 19 of 380 [5.0%; 95% CI, 3.0%-7.7%]; difference, 5.2% [95% CI, 1.5%-9.1%]). In addition, SARS-CoV-2 positivity was associated with reporting PCCs 90 days after the index ED visit (aOR, 1.63 [95% CI, 1.14-2.35]), specifically systemic health problems (eg, fatigue, weakness, fever; aOR, 2.44 [95% CI, 1.19-5.00]).
Conclusions and Relevance  In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older.
____________________________________________________________________________________

Eur Respir J. 2022 Mar 2 : 2103101. doi: 10.1183/13993003.03101-2021
 [Epub ahead of print]  PMCID: PMC8900538 PMID: 35236727
Inspiratory Muscle Training Enhances Recovery Post COVID-19: A Randomised Controlled Trial
Melitta A McNarry, 1 Ronan M G Berg,2 James Shelley,1 Joanne Hudson,1 Zoe L Saynor,3 Jamie Duckers,4 Keir Lewis,5,6 Gwyneth A Davies,6 and Kelly A Mackintosh1
Abstract:   Background
Many people recovering from COVID-19 experience prolonged symptoms, particularly breathlessness. We urgently need to identify safe and effective COVID-19 rehabilitative strategies. The aim of the current study was to investigate the potential rehabilitative role of inspiratory muscle training (IMT).
Methods:   281 adults (46.6±12.2 years; 88% female) recovering from self-reported COVID-19 (9.0±4.2 months post-acute infection) were randomised 4:1 to an 8-week IMT or a “usual care” wait list control arm. Health-related quality of life and breathlessness questionnaires (King's Brief Interstitial Lung Disease (KBILD) and Transition Dyspnoea Index (TDI)), respiratory muscle strength and fitness (Chester Step Test) were assessed pre- and post-intervention. The primary endpoint was KBILD total score, with the KBILD subdomains and TDI being key secondary outcomes.Results:  According to intention to treat (ITT), there was no difference between groups in KBILD total score post-intervention (Control: 59.5±12.4; IMT: 58.2±12.3; p<0.05) but IMT elicited clinically meaningful improvements in the KBILD subdomains of breathlessness (Control: 59.8±12.6; IMT: 62.2±16.2; p<0.05) and chest symptoms (Control: 59.2±18.7; IMT: 64.5±18.2; p<0.05), along with clinically meaningful improvements in breathlessness according to TDI (Control: 0.9±1.7 versus 2.0±2.0; p<0.05). IMT also improved respiratory muscle strength and estimated aerobic fitness.Conclusions:   IMT may represent an important home-based rehabilitation strategy for wider implementation as part of COVID-19 rehabilitative strategies. Given the diverse nature of long-COVID, further research is warranted on the individual responses to rehabilitation - the withdrawal rate herein highlights that no one strategy is likely to be appropriate for all.
____________________________________________________________________________________

Respiration  . 2022;101(6):593-601.doi: 10.1159/000522118. Epub 2022 Feb 24.
Outpatient Pulmonary Rehabilitation in Patients with Long COVID Improves Exercise Capacity, Functional Status, Dyspnea, Fatigue, and Quality of Life
Stephan Nopp 1, Florian Moik 1, Frederikus A Klok 2, Dietlinde Gattinger 3, Milos Petrovic 3, Karin Vonbank 4, Andreas R Koczulla 5 6, Cihan Ay 1, Ralf Harun Zwick 3 7
nPMID: 35203084  PMCID: PMC9059007
 
Abstract
Background: COVID-19 survivors face the risk of long-term sequelae including fatigue, breathlessness, and functional limitations. Pulmonary rehabilitation has been recommended, although formal studies quantifying the effect of rehabilitation in COVID-19 patients are lacking.
Methods: We conducted a prospective observational cohort study including consecutive patients admitted to an outpatient pulmonary rehabilitation center due to persistent symptoms after COVID-19. The primary endpoint was change in 6-min walk distance (6MWD) after undergoing a 6-week interdisciplinary individualized pulmonary rehabilitation program. Secondary endpoints included change in the post-COVID-19 functional status (PCFS) scale, Borg dyspnea scale, Fatigue Assessment Scale, and quality of life. Further, changes in pulmonary function tests were explored.
Results: Of 64 patients undergoing rehabilitation, 58 patients (mean age 47 years, 43% women, 38% severe/critical COVID-19) were included in the per-protocol-analysis. At baseline (i.e., in mean 4.4 months after infection onset), mean 6MWD was 584.1 m (±95.0), and functional impairment was graded in median at 2 (IQR, 2-3) on the PCFS. On average, patients improved their 6MWD by 62.9 m (±48.2, p < 0.001) and reported an improvement of 1 grade on the PCFS scale. Accordingly, we observed significant improvements across secondary endpoints including presence of dyspnea (p < 0.001), fatigue (p < 0.001), and quality of life (p < 0.001). Also, pulmonary function parameters (forced expiratory volume in 1 s, lung diffusion capacity, inspiratory muscle pressure) significantly increased during rehabilitation.
Conclusion: In patients with long COVID, exercise capacity, functional status, dyspnea, fatigue, and quality of life improved after 6 weeks of personalized interdisciplinary pulmonary rehabilitation. Future studies are needed to establish the optimal protocol, duration, and long-term benefits as well as cost-effectiveness of rehabilitation.
____________________________________________________________________________________

MEDICAL NEWS – UNIVADIS (MEDSCAPE)Long COVID substantially less common in children than adultsDawn O'Shea   |   27 July 2022
Almost 6 per cent of children who presented to the emergency department (ED) with COVID-19 develop long COVID, according to a large international study published by JAMA Network Open.
 
The prospective cohort study was conducted in 36 EDs in eight countries between March 7, 2020, and January 20, 2021, and included 1884 children with COVID-19 who completed 90 days of follow-up. Of these, 1686 were matched by hospitalisation status, country, and recruitment date with 1701 SARS-CoV-2-negative controls.
Long COVID was defined as any persistent, new, or recurrent health problems over a 90-day period.
 
Among the participants, 5.8 per cent reported symptoms of long COVID. The rate increased to 9.8 per cent of hospitalised children and 4.6 per cent among discharged children. Characteristics associated with long COVID included being hospitalised for 48 hours or more, having four or more symptoms at the index ED visit, and being 14 years of age or older.
,
“Reported rates of long COVID in adults are substantially higher than what we found in children,” said co-principal investigator Nathan Kuppermann, from the University of California. “Our findings can inform public health policy decisions regarding COVID-19 mitigation strategies for children and screening approaches for long COVID among those with severe infections.”
0 Comments

Abstracts from 1 April 2022

1/4/2022

0 Comments

 
Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain 
Annemarie Dedek, Jian Xu, Louis-Étienne Lorenzo, Antoine G Godin, Chaya M Kandegedara, Geneviève Glavina, Jeffrey A Landrigan, Paul J Lombroso, Yves De Koninck, Eve C Tsai ... Show more
Brain, awab408, https://doi.org/10.1093/brain/awab408
Published:  23 March 2022
 Abstract
The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn, direct investigations using rodent and human preclinical pain models have been lacking.
Here, we discovered that in the Freund’s adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal horn neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in superficial dorsal horn neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDAR potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females.
This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.

_____________________________________________________________________________________
Fatigue: Biomedicine, Health & Behavior    Volume 9, 2021 - Issue 2COVID-19 symptoms over time: comparing long-haulers to ME/CFSLeonard A. Jason, Mohammed F. Islam, Karl Conroy, Joseph Cotler, Chelsea Torres, Mady Johnson.     https://doi.org/10.1080/21641846.2021.1922140
ABSTRACT
IntroductionOur objective was to determine which symptoms among long-hauler COVID-19 patients change over time, and how their symptoms compare to another chronic illness group.
Methods278 long-haulers completed two symptom questionnaires at one time point, with one recounting experiences during the first two weeks of their illness, an average of 21.7 weeks prior. We used a comparison group of 502 patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Participants completed a standardized symptom questionnaire and a list of additional CDC COVID-19 symptoms.
ResultsOver time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.
ConclusionsThese types of differential patterns of symptoms over time might contribute to helping better understand the pathophysiology of those reporting prolonged illness following COVID-19.
 
_____________________________________________________________________________________
 
An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue SyndromeKlaus J Wirth 1, Carmen Scheibenbogen 2, Friedemann Paul 3
 J Transl Med. 2021 Nov 22;19(1):471.
 PMID: 34809664  PMCID: PMC8607226   DOI: 10.1186/s12967-021-03143-3
Erratum in·       Correction to: An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Wirth KJ, Scheibenbogen C, Paul F.J Transl Med. 2022 Jan 11;20(1):25. doi: 10.1186/s12967-021-03216-3.PMID: 35016692 
AbstractThere is accumulating evidence of endothelial dysfunction, muscle and cerebral hypoperfusion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In this paper we deduce the pathomechanisms resulting in central nervous pathology and the myriad of neurocognitive symptoms. We outline tentative mechanisms of impaired cerebral blood flow, increase in intracranial pressure and central adrenergic hyperactivity and how they can well explain the key symptoms of cognitive impairment, brain fog, headache, hypersensitivity, sleep disturbances and dysautonomia.
Keywords: Brain fog; Chronic Fatigue Syndrome; Cognitive impairment; Dysautonomia; Headache; Hypersensitivity; Myalgic Encephalomyelitis; Neurological symptoms; Post-Covid-19 syndrome; Sleep disturbance.
© 2021. The Author(s).

_____________________________________________________________________________________

Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis
 Felicia Ceban a,b , Susan Ling a,d , Leanna M.W. Lui a , Yena Lee a,c , Hartej Gill a , Kayla M. Teopiz a , Nelson B. Rodrigues a , Mehala Subramaniapillai a , Joshua D. Di Vincenzo a,d , Bing Cao e , Kangguang Lin f,g , Rodrigo B. Mansur a,h , Roger C. Ho i,j , Joshua D. Rosenblat a,d,h , Kamilla W. Miskowiak k,l , Maj Vinberg m,n , Vladimir Maletic o , Roger S. 
Brain Behavior and Immunity journal homepage: www.elsevier.com/locate/ybrbi
 
ABSTRACT Importance: COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome. Objective: To quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis, and to characterize the inflammatory correlates and functional consequences of post-COVID-19 syndrome. 
Data sources: Systematic searches were conducted without language restrictions from database inception to June 8, 2021 on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, and select reference lists. Study selection: Primary research articles which evaluated individuals at least 12 weeks after confirmed COVID-19 diagnosis and specifically reported on fatigue, cognitive impairment, inflammatory parameters, and/or functional outcomes were selected. Data extraction & synthesis: Two reviewers independently extracted published summary data and assessed methodological quality and risk of bias. A meta-analysis of proportions was conducted to pool Freeman-Tukey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model. 
Main outcomes & measures: The co-primary outcomes were the proportions of individuals reporting fatigue and cognitive impairment, respectively, 12 or more weeks following COVID-19 infection. The secondary outcomes were inflammatory correlates and functional consequences associated with post-COVID-19 syndrome. 
Abbreviation: PCS, Post-COVID-19 syndrome. * Corresponding author at: University Health Network, 399 Bathurst S
_____________________________________________________________________________________
 
Does pre-infection stress increase the risk of long COVID? Longitudinal associations between adversity worries and experiences in the month prior to COVID-19 infection and the development of long COVID and specific long COVID symptoms
 View ORCID ProfileElise Paul,  View ORCID ProfileDaisy Fancourt
doi: https://doi.org/10.1101/2022.04.06.22273444 
 
Abstract
Summary
Background Long COVID is increasingly recognised as public health burden. Demographic and infection-related characteristics have been identified as risk factors, but less research has focused on psychosocial predictors such as stress immediately preceding the index infection. Research on whether stressors predict the development of specific long COVID symptoms is also lacking.
Methods Data from 1,966 UK adults who had previously been infected with COVID-19 and who took part in the UCL COVID-19 Social Study were analysed. The number of adversity experiences (e.g., job loss) and the number of worries about adversity experiences within the month prior to COVID-19 infection were used to predict the development of self-reported long COVID and the presence of three specific long COVID symptoms (difficulty with mobility, cognition, and self-care). The interaction between a three-level index of socio-economic position (SEP; with higher values indicating lower SEP) and the exposure variables in relation to long COVID status was also examined. Analyses controlled for a range of COVID-19 infection characteristics, socio-demographics, and health-related factors.
Findings Odds of self-reported long COVID increased by 1.25 (95% confidence interval [CI]: 1.04 to 1.51) for each additional worry about adversity in the month prior to COVID-19 infection. Although there was no evidence for an interaction between SEP and either exposure variable, individuals in the lowest SEP group were nearly twice as likely to have developed long COVID as those in the highest SEP group (OR: 1.95; 95% CI: 1.19 to 3.19) and worries about adversity experiences remained a predictor of long COVID (OR: 1.43; 95% CI: 1.04 to 1.98). The number of worries about adversity experiences also corresponded with increased odds of certain long COVID symptoms such as difficulty with cognition (e.g., difficulty remembering or concentrating) by 1.46 (95% CI: 1.02 to 2.09) but not with mobility (e.g., walking or climbing steps) or self-care (e.g., washing all over or dressing).
Interpretation Results suggest a key role of stress in the time preceding the acute COVID-19 infection for the development of long COVID and for difficulty with cognition specifically. These findings point to the importance of mitigating worries and experiences of adversities during pandemics both to reduce their psychological impact but also help reduce the societal burden of longer-term illness.
Funding The Nuffield Foundation [WEL/FR-000022583], the MARCH Mental Health Network funded by the Cross-Disciplinary Mental Health Network Plus initiative supported by UK Research and Innovation [ES/S002588/1], and the Wellcome Trust [221400/Z/20/Z and 205407/Z/16/Z].
 
_____________________________________________________________________________________
 
Front. Neurol., 11 April 2022 | https://doi.org/10.3389/fneur.2022.841310
Molecular Hydrogen as a Medical Gas for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Possible Efficacy Based on a Literature ReviewShin-ichi Hirano1*, Yusuke Ichikawa1,2, Bunpei Sato1,2, Yoshiyasu Takefuji3,4 and Fumitake Satoh1,2
  • 1Department of Research and Development, MiZ Company Limited, Kamakura, Japan
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder that is characterized by fatigue that persists for more than 6 months, weakness, sleep disturbances, and cognitive dysfunction. There are multiple possible etiologies for ME/CFS, among which mitochondrial dysfunction plays a major role in abnormal energy metabolism. The potential of many substances for the treatment of ME/CFS has been examined; however, satisfactory outcomes have not yet been achieved. The development of new substances for curative, not symptomatic, treatments is desired. Molecular hydrogen (H2) ameliorates mitochondrial dysfunction by scavenging hydroxyl radicals, the most potent oxidant among reactive oxygen species. Animal experiments and clinical trials reported that H2 exerted ameliorative effects on acute and chronic fatigue. Therefore, we conducted a literature review on the mechanism by which H2 improves acute and chronic fatigue in animals and healthy people and showed that the attenuation of mitochondrial dysfunction by H2 may be involved in the ameliorative effects. Although further clinical trials are needed to determine the efficacy and mechanism of H2 gas in ME/CFS, our literature review suggested that H2 gas may be an effective medical gas for the treatment of ME/CFS.

 _____________________________________________________________________________________
Non-improvement in chronic fatigue syndrome: relation to activity patterns, uplifts and hassles, and autonomic dysfunctionFriedberg, Fred PhD1; Adamowicz, Jenna L. MA2; Bruckenthal, Patricia PhD, APRN-BC, FAAN3; Milazzo, Maria PhD, RN3; Ramjan, Sameera MA4; Quintana, Daniel PhD5
Author Information
Psychosomatic Medicine: April 15, 2022 - Volume - Issue - 10.1097/PSY.0000000000001082
doi: 10.1097/PSY.0000000000001082
AbstractObjective To test a model of non-improvement in chronic fatigue syndrome (CFS) utilizing self-report activity patterns (e.g., “push-crash”), uplifts and hassles, and a biological measure of cardiac autonomic function. Activity pattern impacts on symptoms and objective measures of autonomic and physical activity were also examined.
Methods This prospective study in CFS collected all data remotely, including six months of weekly web diaries that recorded symptom ratings, activity patterns, and hassles and uplifts. In addition, six months of weekly heart monitoring and three months of daily waking actigraphy data were collected. Improvement or non-improvement status was assessed using semi-structured interviews at 6 months follow-up.
Results 148 individuals (87.2% female) were enrolled and 12.2% were lost to follow-up. Participants reporting non-improvement (n = 92), as compared to improvement (n = 38) showed greater autonomic dysfunction (lower heart rate variability [HRV], group difference = 5.93 (SE = 2.73) ms; p = .032) and lower mean intensity of behavioral uplifts (group difference = 0.14 (SE = 0.16); p = .043), but no significant differences in any activity pattern, including push-crash, limiting activity, and healthy pacing.
Conclusions This study provided evidence for linking patient-reported non-improvement to a biological variable indexing autonomic dysfunction and a behavioral measure indicating a deficit in psychological uplifts. These findings suggest a possible marker of illness trajectory that could potentially advance the biomedical underpinnings of CFS.
Trial Registration: ClinicalTrials.gov ID: NCT02948556
Copyright © 2022 by the American Psychosomatic Society

 _____________________________________________________________________________________
Late-Onset Hypogonadism in a Male Patient with Long COVID Diagnosed by Exclusion of ME/CFSby 
Yoshiaki Soejima Yuki Otsuka, Kazuki Tokumasu, Yasuhiro Nakano, Ko Harada. Kenta Nakamoto, Naruhiko Sunada, Yasue Sakurada, Kou Hasegawa, Hideharu Hagiya,Keigo Ueda, and Fumio Otsuka
 *Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
Medicina 2022, 58(4), 536; https://doi.org/10.3390/medicina58040536
Received: 18 March 2022 / Revised: 7 April 2022 / Accepted: 11 April 2022 / Published: 13 April 2022
(This article belongs to the Special Issue Advances in ME/CFS Research and Clinical Care)
Abstract
After the acute phase of COVID-19, some patients have been reported to have persistent symptoms including general fatigue. We have established a COVID-19 aftercare clinic (CAC) to provide care for an increasing number of these patients. Here, we report the case of a 36-year-old man who developed post-COVID fatigue after acute infection with SARS-CoV-2. In the acute phase of COVID-19, the patient’s fever resolved within four days; however, general fatigue persisted for three months, and he visited our CAC 99 days after the initial infection. Examination revealed a high Aging Male’s Symptoms (AMS) score of 44 and low free testosterone (FT) level of 5.5 pg/mL, which meet the Japanese criteria of late-onset hypogonadism (LOH) syndrome. Imaging studies revealed an atrophic pituitary in addition to fatty liver and low bone mineral density. Anterior pituitary function tests showed a low follicle-stimulating hormonelevel and delayed reaction of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation, indicating the possibility of hypothalamic hypogonadism in addition to primary hypogonadism seen in patients with post-COVID-19 conditions. After the initiation of Japanese traditional medicine (Kampo medicine: hochuekkito followed by juzentaihoto), the patient’s symptoms as well as his AMS score and serum FT level were noticeably improved. Furthermore, follow-up tests of GnRH stimulation revealed improvements in LH responsiveness. Although many patients have been reported to meet the criteria of ME/CFS such as our case, we emphasize the possibility of other underlying pathologies including LOH syndrome. In conclusion, LOH syndrome should be considered a cause of general fatigue in patients with post-COVID-19 conditions and herbal treatment might be effective for long COVID symptoms due to LOH (264 words).
Keywords: general fatigue; free testosterone; late-onset hypogonadism; long COVID; post-COVID condition

 _____________________________________________________________________________________
Frontiers in Neuroendocrinology Available online 11 April 2022, 100995The underlying sex differences in neuroendocrine adaptations relevant to Myalgic Encephalomyelitis Chronic Fatigue SyndromeAuthor links open overlay panel       NatalieThomasaCarolineGurvichbKatherineHuangaPaul RGooleyaChristopher WArmstronga
https://doi.org/10.1016/j.yfrne.2022.100995Get rights and content
Abstract
IntroductionMyalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a complex multisystem disease characterised by severe and disabling new-onset symptoms of post-exertional malaise (PEM), fatigue, brain fog, and sleep dysfunction that lasts for at least six months. Accumulating evidence suggests that sex and endocrine events have a significant influence on symptom onset and moderation of ME/CFS, with female sex being one of the most consistent and credible predictive risk factors associated with diagnosis. Such sex differences suggest sex chromosomes and sex steroids may play a part in the development of the condition or moderation of symptoms, although this has yet to be explored in detail.
Methods/AimsThis narrative review outlines sex differences in ME/CFS in terms of vulnerability factors and clinical phenotype and explores the known sex differences in neuroendocrine systems affected in ME/CFS and how this may relate to disease risk, onset, pathophysiology, and potential treatment avenues.
ConclusionsThere is clear evidence of a sex dimorphism with regards to prevalence (3:1 female preponderance), clinical phenotypes, and aetiological triggers prior to symptom onset of ME/CFS. Endocrinological events, particularly those throughout the female lifespan, are associated with ME/CFS and include reproductive menstrual cycle fluctuations, pregnancy, post-partum and perimenopause. Further, there is evidence for gonadal sex, adrenal stress and renal neuroendocrine systems as implicated in ME/CFS, including changes in estrogen, progesterone compounds, aldosterone, and cortisol levels, of which there are established sex differences. The broad effects of steroid hormones on the physiological systems may also speak to the diversity of ME/CFS symptomatology observed in patients. Further attention must be paid to sex, age, and steroid biology in ME/CFS.

 _____________________________________________________________________________________
Health-related quality of life in Young People with Chronic fatigue syndrome/ Myalgic encephalomyelitis
Similä, Wenche Ann  Doctoral thesis  URI  https://hdl.handle.net/11250/2991015 Date 2022
Institutt for klinisk og molekylær medisin [2565]
Abstract
Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) is a disease that affects people of all ages. CFS/ME significantly limits the activity level of those affected, including in relation to physical activity, schooling, occupational life and social life. High levels of school absence among young people with CFS/ME result in loss of important learning and social development among peers. As such, there is increasing uncertainty about their future, and personal and socio-economic consequences could put them at risk of becoming disabled at a young age. Measurements of health-related quality of life (HRQoL), including being able to function in school, have shown that young people with CFS/ME score lower than their counterparts without CFS/ME.
Aims
The overall aim of this project was to explore HRQoL among young people with CFS/ME, including the factors associated with HRQoL in relation to school and everyday life. More specifically, the aim was to firstly (Study1) examine HRQoL, including factors that are positively or negatively associated with HRQoL, in a cohort of young people with CFS/ME. Study 1, along with the previous literature, provided the basis for an in-depth study (Study 2) to investigate the positive and negative factors that young people with CFS/ME experience in school and everyday life. Based on the findings from Study 1 and Study 2, a third study (Study 3) was planned to explore teachers’, counsellors’ and school nurses’ experiences with educational and social adaptation at school for young people with CFS/ME.
Method
To explore HRQoL and the factors associated with HRQoL among young people with CFS/ME (Studies 1 & 2), a cross-sectional survey- and interview-based study was conducted. The participants of the cross-sectional study were recruited to participate in the interview study. To explore the experiences of teachers, counsellors and school nurses with education and social adaptions at school for young people with CFS/ME (Study 3), an interview study was conducted with participants recruited among school personnel and school nurses in secondary school (educating students aged 13-16), high school (educating students aged 16-19) and educational psychological services (EPS).
Results
A total of 63 participants were included in the cross-sectional study, 18 of whom participated in the interview study. A total of 12 participants were included in the interview study with the teachers, counsellors and school nurses. In the cross-sectional study (Study 1), young people with CFS/ME scored lower on HRQoL than their counterparts who were healthy or had other chronic diseases. Contact with school and teachers was associated with a higher HRQoL among young people with CFS/ME. This association could be due to that more contact resulted from adaptations of education and social life at school, or that fewer health problems due to CFS/ME had abled the young people to maintain the contact with school and teachers. In Study 2, it was found that an adapted plan for education and social life at school for young people with CFS/ME could increase the possibility of continuing schooling with peers. The lack of an adapted plan for education and social life at school could lead to increased school absence as well as loss of education, social contact and development among peers. Subsequently, this could lead to depressive thoughts and worry about the future. The school personnel and school nurses in Study 3 experienced that young people with CFS/ME lost confidence in school. The challenges experienced by school personnel included (1) understanding students’ needs before they received a diagnosis and before school personnel received information from healthcare providers and (2) maintaining the teacher–student relationship and (3) the continuity of teaching. In terms of measures for better management, early problematization of school absence, interdisciplinary collaboration on early measures, ensuring the maintenance of the teacher–student relationship and increasing CFS/ME-related competence in schools were proposed. These measures could contribute to prevent loss of function and school absence among young people with CFS/ME.
Conclusion
HRQoL among young people with CFS/ME was associated with contact with school and teachers, but a causal relationship could not be proven. Interviews with young people with CFS/ME and school personnel suggested that interdisciplinary strategies for early adaptations to education and social life at school for young people with CFS/ME may benefit education and social development among peers for young people with CFS/ME. Lack of educational and social adaptations at school might lead to loss of education, social life and development among peers.
 
_____________________________________________________________________________________
 
Cognitive sequelae of long COVID may not be permanent: A prospective studyOscar H. Del Brutto,Denisse A. Rumbea,Bettsy Y. Recalde,Robertino M. Mera
First published: 16 December 2021  https://doi.org/10.1111/ene.15215
AbstractBackground and purposeCognitive decline is a recognized manifestation of long COVID, even among patients who experience mild disease. However, there is no evidence regarding the length of cognitive decline in these patients. This study aimed to assess whether COVID-19-related cognitive decline is a permanent deficit or if it improves over time.
MethodsCognitive performance was evaluated by means of the Montreal Cognitive Assessment (MoCA) in COVID-19 survivors and noninfected individuals. All study participants had four cognitive evaluations, two of them before the pandemic and the other two, 6 and 18 months after the initial SARS-CoV-2 outbreak infection in the village. Linear mixed effects models for longitudinal data were fitted to assess differences in cognitive performance across COVID-19 survivors and noninfected individuals.
ResultsThe study included 78 participants, 50 with history of mild COVID-19 and 28 without. There was a significant—likely age-related—decline in MoCA scores between the two prepandemic tests (β = −1.53, 95% confidence interval [CI] = −2.14 to −0.92, p < 0.001), which did not differ across individuals who later developed COVID-19 when compared to noninfected individuals. Six months after infection, only COVID-19 survivors had a significant decline in MoCA scores (β = −1.37, 95% CI = −2.14 to −0.61, p < 0.001), which reversed after 1 additional year of follow-up (β = 0.66, 95% CI = −0.11 to 1.42, p = 0.092). No differences were noticed among noninfected individuals when both postpandemic MoCA scores were compared.
ConclusionsStudy results suggest that long COVID-related cognitive decline may spontaneously improve over time.

Peripheral muscle fatigue limits post-COVID exercise
20 April 2022     FROM ESC PREVENTIVE CARDIOLOGY 2022
Peripheral muscle fatigue was the most common cause of exercise limitation in patients recovered from COVID-19 regardless of disease severity, in a study of nearly 300 individuals.
The source and magnitude of exercise intolerance in post–COVID-19 patients has not been well studied, said Mauricio Milani, MD, of Fitcordis Exercise Medicine Clinic, Brasilia, Brazil, in a presentation at the annual congress of the European Association of Preventive Cardiology.
To assess exercise intolerance, the researchers performed cardiopulmonary exercise testing (CPET) on 144 adults who had recovered from COVID-19 and 144 matched controls who had not had COVID-19. The average age of the participants was 43 years, and 57% were male. COVID-19 was defined as mild, moderate, or severe in 60%, 21%, and 19% of the cases, respectively.
Residual symptoms were present in 41% of cases. CPET was performed at roughly 14 weeks after disease onset.
Among the COVID-19 patients, most of the CPET limitations (92%) were caused by muscle fatigue; cardiovascular limitations were noted in 2%, and pulmonary limitations were noted in 6%.
Data from the post-COVID CPET showed differences in peak oxygen consumption, as well as the first and second ventilatory thresholds (VT1 and VT2) between COVID-19 patients and controls, and with lower values related to higher illness severities, Dr. Milani said. Heart rate also varied according to illness severity, with lower values significantly related to higher illness severities and significant differences between COVID patients and controls.
A total of 42 individuals with COVID-19 had previous CPET data for comparison (27 with mild disease and 15 with moderate or severe disease), Dr. Milani said. In the subgroup with mild disease, the only significant difference in CPET results before and after COVID-19 was peak speed. In the moderate/severe group, the researchers observed higher reductions in peak speed and also reductions in oxygen consumption at peak and thresholds.
However, peak oxygen flows were not different before and after COVID-19 in either the mild or moderate/severe subgroups, Dr. Milani said.
The study findings were limited in part by the relatively small study population; however, the results indicate that peripheral muscle fatigue is the primary etiology in exercise limitation in post–COVID-19 patients.
“Our data suggest that treatment should emphasize comprehensive rehabilitation programs, including aerobic and muscle strengthening components,” Dr. Milani concluded.

 _____________________________________________________________________________________

Unbiased immune profiling reveals a natural killer cell-peripheral nerve  axis in fibromyalgiaVivek Verma 1, Gillian L Drury, Marc Parisien, Ayşe N Özdağ Acarli, Tho-Alfakar Al-Aubodah, Anastasia Nijnik, Xia Wen, Nicol Tugarinov, Maria Verner, Richie Klares 3rd, Alexander Linton, Emerson Krock, Carlos E Morado Urbina, Bendik Winsvold, Lars G Fritsche, Egil A Fors, Ciriaco Piccirillo, Arkady Khoutorsky, Camilla I Svensson, Mary A Fitzcharles, Pablo M Ingelmo, Nicole F Bernard, Franck P Dupuy, Nurcan Üçeyler, Claudia Sommer, Irah L King, Carolina B Meloto, Luda Diatchenko, HUNT-All In Pain
  • PMID: 34913882 PMCID: PMC8942876 (available on 2023-03-24) DOI: 10.1097/j.pain.0000000000002498
AbstractThe pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16-binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.
Copyright © 2021 International Association for the Study of Pain.
_____________________________________________________________________________________
 
Natelson et al. Journal of Translational Medicine (2022) 20:95 https://doi.org/10.1186/s12967-022-03289-8 RESEARCH 
Physiological assessment of orthostatic intolerance in chronic fatigue syndrome Benjamin H. Natelson1*, Jin‑Mann S. Lin2 , Michelle Blate1 , Sarah Khan1 , Yang Chen2 and Elizabeth R. Unger2 
Abstract
Background: Orthostatic intolerance-OI is common in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-ME/ CFS. We used a 10-min passive vertical lean test as orthostatic challenge-OC and measured changes in vitals and end tidal CO2 (eTCO2). An abnormal physiologic response to OC was identifed in 60% of the 63 patients evaluated from one to three times over several years. Hypocapnia, either resting or induced by OC, was the most frequent abnormal‑ ity, followed by postural orthostatic tachycardia. 
Objective: Evaluate the physiologic response of patients with ME/CFS to a standardized OC. 
Design: Respiratory and heart rate, blood pressure and eTCO2 were recorded twice at the end of 10-min supine rest and then every minute during the 10-min lean. Hypocapnia was eTCO2≤32 mmHg. Orthostatic tachycardia was heart rate increase≥30 beats per minute compared with resting or≥120 BPM. Orthostatic hypotension was decreased sys‑ tolic pressure≥20 mmHg from baseline. Tachypnea was respiratory rate of ≥20 breaths per minute—either supine or leaning. Questionnaire data on symptom severity, quality of life and mood were collected at visit #2. Patients: 63 consecutive patients fulflling the 1994 case defnition for CFS underwent lean testing at frst visit and then annually at visit 2 (n=48) and 3 (n=29). 
Measures: Supine hypocapnia; orthostatic tachycardia, hypocapnia or hypotension. 
Results: The majority of ME/CFS patients (60.3%, 38/63) had an abnormality detected during a lean test at any visit (51%, 50% and 45% at visits 1, 2 and 3, respectively). Hypocapnia at rest or induced by OC was more common and more likely to persist than postural orthostatic tachycardia. Anxiety scores did not difer between those with and without hypocapnia.
 Conclusions: The 10-min lean test is useful in evaluation of OI in patients with ME/CFS. The most frequent abnormal‑ ity, hypocapnia, would be missed without capnography.

_____________________________________________________________________________________
 
Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients
  • Natalie Eaton-Fitch, Stanley Du Preez, Hélène Cabanas, Katsuhiko Muraki, Donald Staines & Sonya Marshall-Gradisnik 
Journal of Translational Medicine volume 20, Article number: 94 (2022) Cite this article
AbstractBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious disorder of unknown aetiology. While the pathomechanism of ME/CFS remains elusive, reduced natural killer (NK) cell cytotoxic function is a consistent immunological feature. NK cell effector functions rely on long-term sustained calcium (Ca2+) influx. In recent years evidence of transient receptor potential melastatin 3 (TRPM3) dysfunction supports the hypothesis that ME/CFS is potentially an ion channel disorder. Specifically, reports of single nucleotide polymorphisms, low surface expression and impaired function of TRPM3 have been reported in NK cells of ME/CFS patients. It has been reported that mu (µ)-opioid receptor (µOR) agonists, known collectively as opioids, inhibit TRPM3. Naltrexone hydrochloride (NTX), a µOR antagonist, negates the inhibitory action of µOR on TRPM3 function. Importantly, it has recently been reported that NTX restores impaired TRPM3 function in NK cells of ME/CFS patients.
MethodsLive cell immunofluorescent imaging was used to measure TRPM3-dependent Ca2+ influx in NK cells isolated from n = 10 ME/CFS patients and n = 10 age- and sex-matched healthy controls (HC) following modulation with TRPM3-agonist, pregnenolone sulfate (PregS) and TRPM3-antaognist, ononetin. The effect of overnight (24 h) NTX in vitro treatment on TRPM3-dependent Ca2+ influx was determined.
ResultsThe amplitude (p < 0.0001) and half-time of Ca2+ response (p < 0.0001) was significantly reduced at baseline in NK cells of ME/CFS patients compared with HC. Overnight treatment of NK cells with NTX significantly improved TRPM3-dependent Ca2+ influx in ME/CFS patients. Specifically, there was no significance between HC and ME/CFS patients for half-time response, and the amplitude of Ca2+ influx was significantly increased in ME/CFS patients (p < 0.0001).
ConclusionTRPM3-dependent Ca2+ influx was restored in ME/CFS patients following overnight treatment of isolated NK cells with NTX in vitro. Collectively, these findings validate that TRPM3 loss of function results in altered Ca2+ influx supporting the growing evidence that ME/CFS is a TRP ion channel disorder and that NTX provides a potential therapeutic intervention for ME/CFS.

 _____________________________________________________________________________________

Eye movements may be key to chronic fatigue syndrome diagnosis25 March 2022  Monash University
A Monash Central Clinical School scientist has been awarded $180,000 over three years to develop a way to help diagnose myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Associate Professor Joanne Fielding, from the Department of Neuroscience, Associate Professor Fielding is working with Dr Scott Kolbe and Dr Meaghan Clough , both from the Department, and co-investigator Dr Chris Armstrong from the University of Melbourne on the project.
An enigmatic disorder, ME/CFS is characterised by extreme tiredness, pain and a range of other symptoms. Remarkably, there is currently no reliable way to diagnose it and to objectively monitor the effect of treatment in people with the disorder.
“You can’t directly measure ME/CFS at the moment. A clinician’s role is to essentially eliminate other potential causes for the constellation of symptoms,” Associate Professor Fielding said. “While there are some suggested diagnostic criteria there are no formal criteria.
“What we’re trying to do is generate a unique ME/CFS signature based on characteristic changes to eye movements, a behaviourial signature that is specific to the disorder that can be used to help diagnose it and monitor the effects of any treatments.”
Associate Professor Fielding and her team will develop the clinically useful test using ocular-motor, machine learning and neuroimaging techniques.
“We’re using video-oculography, which is basically high-powered cameras that record the eye movements in response to a set of simple stimuli on the screen.
“People with ME/CFS are typically extremely fatigued – we need something very quick that gives a snapshot of how they’re performing.”
Participants in the study can be tested in the lab or in their own homes with a portable eye-tracker – helpful to someone with such a disabling disorder.
Associate Professor Fielding said the research might also give the scientists clues about what might be happening neuropathologically in ME/CFS.
“Tentatively, what we’ve found already looks like a set of aberrant eye movements that suggest that something might be going on at the level of the brain stem – but it’s early days and that’s at best, speculative,” she said.

 _____________________________________________________________________________________

Reduced Parasympathetic Reactivation during Recovery from Exercise in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeJessica Van Oosterwijck, Uros Marusic, [...], and Jo Nijs
AbstractAlthough autonomic nervous system (ANS) dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has been proposed, conflicting evidence makes it difficult to draw firm conclusions regarding ANS activity at rest in ME/CFS patients. Although severe exercise intolerance is one of the core features of ME/CFS, little attempts have been made to study ANS responses to physical exercise. Therefore, impairments in ANS activation at rest and following exercise were examined using a case-control study in 20 ME/CFS patients and 20 healthy people. Different autonomous variables, including cardiac, respiratory, and electrodermal responses were assessed at rest and following an acute exercise bout. At rest, parameters in the time-domain represented normal autonomic function in ME/CFS, while frequency-domain parameters indicated the possible presence of diminished (para)sympathetic activation. Reduced parasympathetic reactivation during recovery from exercise was observed in ME/CFS. This is the first study showing reduced parasympathetic reactivation during recovery from physical exercise in ME/CFS. Delayed HR recovery and/or a reduced HRV as seen in ME/CFS have been associated with poor disease prognosis, high risk for adverse cardiac events, and morbidity in other pathologies, implying that future studies should examine whether this is also the case in ME/CFS and how to safely improve HR recovery in this population.

 _____________________________________________________________________________________

The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)Rahel S. König, Werner C. Albrich, [...], and Sofia K. Forslund
 Front Immunol. 2022 March 30; 13: 878196.
AbstractMyalgic encephalomyelitis (ME) or Chronic Fatigue Syndrome (CFS) is a neglected, debilitating multi-systemic disease without diagnostic marker or therapy. Despite evidence for neurological, immunological, infectious, muscular and endocrine pathophysiological abnormalities, the etiology and a clear pathophysiology remains unclear. The gut microbiome gained much attention in the last decade with manifold implications in health and disease. Here we review the current state of knowledge on the interplay between ME/CFS and the microbiome, to identify potential diagnostic or interventional approaches, and propose areas where further research is needed. We iteratively selected and elaborated on key theories about a correlation between microbiome state and ME/CFS pathology, developing further hypotheses. Based on the literature we hypothesize that antibiotic use throughout life favours an intestinal microbiota composition which might be a risk factor for ME/CFS. Main proposed pathomechanisms include gut dysbiosis, altered gut-brain axis activity, increased gut permeability with concomitant bacterial translocation and reduced levels of short-chain-fatty acids, D-lactic acidosis, an abnormal tryptophan metabolism and low activity of the kynurenine pathway. We review options for microbiome manipulation in ME/CFS patients including probiotic and dietary interventions as well as fecal microbiota transplantations. Beyond increasing gut permeability and bacterial translocation, specific dysbiosis may modify fermentation products, affecting peripheral mitochondria. Considering the gut-brain axis we strongly suspect that the microbiome may contribute to neurocognitive impairments of ME/CFS patients. Further larger studies are needed, above all to clarify whether D-lactic acidosis and early-life antibiotic use may be part of ME/CFS etiology and what role changes in the tryptophan metabolism might play. An association between the gut microbiome and the disease ME/CFS is plausible. As causality remains unclear, we recommend longitudinal studies. Activity levels, bedridden hours and disease progression should be compared to antibiotic exposure, drug intakes and alterations in the composition of the microbiota. The therapeutic potential of fecal microbiota transfer and of targeted dietary interventions should be systematically evaluated.
 
_____________________________________________________________________________________
 
medRxiv. Preprint. 2022 Jan 11.   doi: 10.1101/2021.06.14.21258895
Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeXiaoyu Che,1,2,† Christopher R. Brydges,3,† Yuanzhi Yu,2 Adam Price,1 Shreyas Joshi,1 Ayan Roy,1 Bohyun Lee,1 Dinesh K. Barupal,4 Aaron Cheng,1 Dana March Palmer,5 Susan Levine,6 Daniel L. Peterson,7 Suzanne D. Vernon,8 Lucinda Bateman,8 Mady Hornig,5 Jose G. Montoya,9 Anthony L. Komaroff,10 Oliver Fiehn,3,* and W. Ian Lipkin1,*
AbstractBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.
MethodsUsing regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.
ResultsIn ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).
ConclusionOur findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.

 _____________________________________________________________________________________
Long-Term Effects of COVID-19  Shreeya Joshee, BS    Nikhil Vatti, MD   Christopher Chang, MD, PhD, MBA Published:January 11, 2022DOI:https://doi.org/10.1016/j.mayocp.2021.12.017
AbstractCoronavirus disease 2019 (COVID-19) is the third deadly coronavirus infection of the 21st century that has proven to be significantly more lethal than its predecessors, with the number of infected patients and deaths still increasing daily. From December 2019 to July 2021, this virus has infected nearly 200 million people and led to more than 4 million deaths. Our understanding of COVID-19 is constantly progressing, giving better insight into the heterogeneous nature of its acute and long-term effects. Recent literature on the long-term health consequences of COVID-19 discusses the need for a comprehensive understanding of the multisystemic pathophysiology, clinical predictors, and epidemiology to develop and inform an evidence-based, multidisciplinary management approach. A PubMed search was completed using variations on the term post-acute COVID-19. Only peer-reviewed studies in English published by July 17, 2021 were considered for inclusion. All studies discussed in this text are from adult populations unless specified (as with multisystem inflammatory syndrome in children). The preliminary evidence on the pulmonary, cardiovascular, neurological, hematological, multisystem inflammatory, renal, endocrine, gastrointestinal, and integumentary sequelae show that COVID-19 continues after acute infection. Interdisciplinary monitoring with holistic management that considers nutrition, physical therapy, psychological management, meditation, and mindfulness in addition to medication will allow for the early detection of post-acute COVID-19 sequelae symptoms and prevent long-term systemic damage. This review serves as a guideline for effective management based on current evidence, but clinicians should modify recommendations to reflect each patient's unique needs and the most up-to-date evidence. The presence of long-term effects presents another reason for vaccination against COVID-19.

 _____________________________________________________________________________________
Lancet Discovery Science:   Volume 47, May 2022, 101417
Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohortAdamHampshireaDoris A.ChatfieldbAnne ManktelowMPhilbAmyJollyaWilliamTrenderaPeter J.HellyeraMartina DelGiovaneaVirginia F.J.NewcombebJoanne G.OuttrimbBenWarnebJunaidBhattidLindaPointondAnneElmereNyarieSitholebfJohnBradleybghNathalieKingstonlStephen J.SawceriEdward T.Bullmorecdj…David K.Menonbck1
https://doi.org/10.1016/j.eclinm.2022.101417Get rights and content
Summary:BackgroundPreliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery.
Methods46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia.
FindingsCOVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=​​0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance.
InterpretationCognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed.

_____________________________________________________________________________________

Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome
Am J Respir Crit Care Med. 2022 Jan 1; 205(1): 126–129.
Published online 2021 Oct 19. doi: 10.1164/rccm.202108-1903LE
Esther de Boer, 1 , 2 Irina Petrache,  1 , 2 ,* Nir M. Goldstein, 1 J. Tod Olin, 1 Rebecca C. Keith, 1 , 2 Brian Modena, 1 Michael P. Mohning, 1 , 2 Zulma X. Yunt, 1 , 2 Inigo San-Millán, 2 , 3 , ‡ and Jeffrey J. Swigris 1 , 2 , ‡
After acute infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many individuals experience a range of symptoms including dyspnea, exercise intolerance, and chest pain commonly referred to as “post–COVID-19 syndrome” or as post-acute sequelae of SARS-CoV-2 infection (PASC) (1). Exertional dyspnea and physical activity intolerance in PASC can be debilitating despite mild acute coronavirus disease (COVID-19) and normal resting pulmonary physiology and cardiac function (2). There is an urgent need to understand the pathogenesis of PASC and find effective treatments. The cardiopulmonary exercise test (CPET) is commonly used to investigate unexplained exertional dyspnea; as such, it could provide insight into mechanisms of PASC. CPET data can be used to calculate rates of β-oxidation of fatty acids (FATox) and of lactate clearance, providing insight into mitochondrial function (3). Fit individuals have better mitochondrial function and a higher rate of FATox during exercise than less fit individuals (4). Our results suggest that patients with PASC have significant impairment in fat β-oxidation and increased blood lactate accumulation during exercise, regardless of previous comorbidities.
In this study, we investigated whether patients with PASC had compromised mitochondrial function during graded exercise. Data were obtained via retrospective review of the electronic medical record from a cohort of 50 subjects with PASC (n = 50, age = 50 ± 15 yr, 35 female) that were consecutively referred to and willing to complete CPET in the Pulmonary Physiology Laboratory at National Jewish Health between June 2020 and April 2021 (Table 1). No subject was excluded. Patients were assessed on a cycle ergometer (Vmax 29; SensorMedics Corp) using a continuous ramp protocol to exhaustion. Cardiovascular, ventilatory, metabolic, and gas exchange data were collected using a metabolic cart (Ultima Cardio2 System; Med graphics) per standard protocol (5). For calculations of total FATox and carbohydrate oxidation (CHOox), we used the stoichiometric equations by Frayn and colleagues: FATox [g/min]  = 1.67 × V˙o2 [L/min] – 1.67 × V˙co2 [L/min] and CHOox [g/min] = 4.55 × V˙o2 [L/min] – 3.21 × V˙co2 [L/min] (6). Patient data were compared with results from two published cohorts that included subjects tested with CPET in Denver, Colorado (i.e., the same altitude as our cohort). The characteristics of these cohorts have been previously described (3). Statistical analyses were performed in SPSS Statistics V.27 (IBM) and graphed with Prism V.9.1.0(221) (GraphPad Software). Our study was approved by The Biomedical Research Alliance of New York (BRANY) Institutional Review Board (IRB) study # 20-12-582-528.
 
Pulmonary function testing (PFT) showed mostly normal resting airflow and gas transfer capacity. All six patients (12%) with PFT abnormalities had preexisting illnesses, including asthma (n = 3) or interstitial lung disease (n = 1). Resting transthoracic echocardiogram was obtained in 39 patients (78%) within 2 ± 3 months of CPET. Left ventricular systolic function was normal (left ventricular ejection fraction 50–70%) in all patients. Among the 50 patients who underwent CPET, the mean time from COVID-19 diagnosis to the CPET was 6 ± 4 months. V˙o2max was normal (>84% predicted) in 34 (68%; mean peak V˙o2 107 ± 22% predicted) and reduced in 16 patients (32%; mean peak V˙o2 67 ± 13% predicted). Among these 16, none had ventilatory limitation, but 9 (56%) had cardiovascular limitation (heart rate reserve <15 beats per minute at peak exercise), and 10 (63%) had a low O2 pulse value at peak exercise.
Regardless of the presence of comorbidities, among the 39 patients with PASC who had arterial catheters in place, mean lactate was significantly higher (Figures 1A and 1B); and in all 50 patients with PASC, calculated levels of FATox were significantly lower (Figures 1C and 1D) during exercise when compared with historical cohorts of subjects who are moderately active or with metabolic syndrome (3). Calculated levels of CHOox in patients with PASC were not significantly different from these published cohorts (data not shown). Average power output, oxygen consumption, and blood lactate did not differ between patients with PASC with or without comorbidities (data not shown). Correlations between post–COVID-19 symptoms, Borg score for dyspnea and leg fatigue, and time lapse from COVID-19 diagnosis to CPET with the anaerobic threshold and mitochondrial dysfunction (i.e., FATox) did not yield statistically significant relationships.
Our data suggest abnormally low FATox and altered lactate production by skeletal muscle as a putative cause of—or contributor to—the functional limitation of patients with PASC. Normally, as glycolysis increases with exercise intensity, lactate is oxidized for fuel in mitochondria, mainly in adjacent slow-twitch muscle fibers. Like FATox, lactate clearance capacity is a useful surrogate for mitochondrial function. In patients with PASC, even in those with normal pre–COVID-19 physical fitness and free of comorbidities, the metabolic disturbances of the skeletal muscle during exercise may be worse than those reported in moderately active individuals or in individuals with metabolic syndrome (3). Whereas rising blood lactate levels are expected during high exercise intensity (as glycolytic flux exceeds the rate of mitochondrial pyruvate oxidation), a high blood lactate at lower exercise levels indicates mitochondrial dysfunction (7). The inappropriately high arterial lactate levels at relatively low exercise intensity (e.g., >9 mM at 150 W) in patients with PASC indicate that the transition from FATox to CHOox occurs prematurely, suggesting metabolic reprogramming and dysfunctional mitochondria.
Dysregulated lipid oxidation and decreased mitochondrial biogenesis have been reported in acute critically ill patients admitted to the ICU (8). However, the long-term weakness in ICU survivors is associated with heterogeneous muscle pathophysiology with variable combinations of muscle atrophy and impaired contractile capacity and not solely by diminished mitochondrial content (9).
Our study has several limitations, including a small cohort size, retrospective methodology, and lack of a contemporaneous control, relying on comparisons with historical cohorts that have distinct demographics. Therefore, our findings may not be generalizable and should be considered hypothesis-generating. They should provide impetus for further investigations into the molecular mechanisms linking COVID-19 to metabolic reprogramming and mitochondrial dysfunction. Our report is consistent with that by Pleguezuelos and colleagues, who also showed that patients with PACS that followed acute COVID-19 requiring admission to the ICU suffered from reduced exercise efficiency (10) and with that of Rinaldo and colleagues showing that disease severity does not impact exercise capacity in COVID-19 survivors; however, the study focused on peak values and cardiorespiratory peak values and not on metabolic/cellular adaptations as we did in our study (11).
To our knowledge, our study provides the first evidence of mitochondrial dysfunction that advances our understanding of the pathogenesis of PACS in patients with preserved pulmonary and cardiac function. Future studies into the mechanisms of mitochondrial dysfunction in individuals with PACS will help accelerate the development of therapies to improve their functional status.
 
_____________________________________________________________________________________

Comparison of Amitriptyline and US Food and Drug Administration–Approved Treatments for FibromyalgiaA Systematic Review and Network Meta-analysis
Hussein M. Farag, PharmD, MSc, PhD1; Ismaeel Yunusa, PharmD, PhD1,2; Hardik Goswami, BPharm, MSc, PhD1,3; et alIhtisham Sultan, PharmD1,4; Joanne A. Doucette, MSc, MSLIS1; Tewodros Eguale, MD, PhD1,5
JAMA Netw Open. 2022;5(5):e2212939. doi:10.1001/jamanetworkopen.2022.12939  Neurology May 19, 2022
Key Points
Question  What pharmacological treatments for adults with fibromyalgia are associated with the highest efficacy and acceptability?
Findings  In this systematic review and network meta-analysis of 36 randomized clinical trials (11 930 patients with fibromyalgia), duloxetine (120 mg) was associated with higher efficacy in treating pain and depression, while amitriptyline was associated with higher efficacy and acceptability in improving sleep, fatigue, and health-related quality of life outcomes.
Meaning  These findings suggest that with the heterogeneity of fibromyalgia symptoms, pharmacological treatments should be tailored to individual symptoms, including pain, sleep problems, depressed mood, fatigue, and health-related quality of life.
 
Abstract
Importance  Amitriptyline is an established medication used off-label for the treatment of fibromyalgia, but pregabalin, duloxetine, and milnacipran are the only pharmacological agents approved by the US Food and Drug Administration (FDA) to treat fibromyalgia.
Objective  To investigate the comparative effectiveness and acceptability associated with pharmacological treatment options for fibromyalgia.
Data Sources  Searches of PubMed/MEDLINE, Cochrane Library, Embase, and Clinicaltrials.gov were conducted on November 20, 2018, and updated on July 29, 2020.
Study Selection  Randomized clinical trials (RCTs) comparing amitriptyline or any FDA-approved doses of investigated drugs.
Data Extraction and Synthesis  This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Four independent reviewers extracted data using a standardized data extraction sheet and assessed quality of RCTs. A random-effects bayesian network meta-analysis (NMA) was conducted. Data were analyzed from August 2020 to January 2021.
Main Outcomes and Measures  Comparative effectiveness and acceptability (defined as discontinuation of treatment owing to adverse drug reactions) associated with amitriptyline (off-label), pregabalin, duloxetine, and milnacipran (on-label) in reducing fibromyalgia symptoms. The following doses were compared: 60-mg and 120-mg duloxetine; 150-mg, 300-mg, 450-mg, and 600-mg pregabalin; 100-mg and 200-mg milnacipran; and amitriptyline. Effect sizes are reported as standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes with 95% credible intervals (95% CrIs). Findings were considered statistically significant when the 95% CrI did not include the null value (0 for SMD and 1 for OR). Relative treatment ranking using the surface under the cumulative ranking curve (SUCRA) was also evaluated.
Results  A total of 36 studies (11 930 patients) were included. The mean (SD) age of patients was 48.4 (10.4) years, and 11 261 patients (94.4%) were women. Compared with placebo, amitriptyline was associated with reduced sleep disturbances (SMD, −0.97; 95% CrI, −1.10 to −0.83), fatigue (SMD, −0.64; 95% CrI, −0.75 to −0.53), and improved quality of life (SMD, −0.80; 95% CrI, −0.94 to −0.65). Duloxetine 120 mg was associated with the highest improvement in pain (SMD, −0.33; 95% CrI, −0.36 to −0.30) and depression (SMD, −0.25; 95% CrI, −0.32 to −0.17) vs placebo. All treatments were associated with inferior acceptability (higher dropout rate) than placebo, except amitriptyline (OR, 0.78; 95% CrI, 0.31 to 1.66). According to the SUCRA-based relative ranking of treatments, duloxetine 120 mg was associated with higher efficacy for treating pain and depression, while amitriptyline was associated with higher efficacy for improving sleep, fatigue, and overall quality of life.
Conclusions and Relevance  These findings suggest that clinicians should consider how treatments could be tailored to individual symptoms, weighing the benefits and acceptability, when prescribing medications to patients with fibromyalgia.

_____________________________________________________________________________________
 
Environ Health Perspect . 2022 May;130(5):57001. doi: 10.1289/EHP9009. Epub 2022 May 11.
Evaluation of a Gene-Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case-Control Study Drawn from the U.S. Military Health Survey's National Population SampleRobert W Haley 1, Gerald Kramer 1, Junhui Xiao 1, Jill A Dever 2, John F Teiber 1
PMID: 35543525 PMCID: PMC9093163  DOI: 10.1289/EHP9009
Abstract
Background: Consensus on the etiology of 1991 Gulf War illness (GWI) has been limited by lack of objective individual-level environmental exposure information and assumed recall bias.
Objectives: We investigated a prestated hypothesis of the association of GWI with a gene-environment (GxE) interaction of the paraoxonase-1 (PON1) Q192R polymorphism and low-level nerve agent exposure.
Methods: A prevalence sample of 508 GWI cases and 508 nonpaired controls was drawn from the 8,020 participants in the U.S. Military Health Survey, a representative sample survey of military veterans who served during the Gulf War. The PON1 Q192R genotype was measured by real-time polymerase chain reaction (RT-PCR), and the serum Q and R isoenzyme activity levels were measured with PON1-specific substrates. Low-level nerve agent exposure was estimated by survey questions on having heard nerve agent alarms during deployment.
Results: The GxE interaction of the Q192R genotype and hearing alarms was strongly associated with GWI on both the multiplicative [prevalence odds ratio (POR) of the interaction=3.41interaction=3.41; 95% confidence interval (CI): 1.20, 9.72] and additive (synergy index=4.71index=4.71; 95% CI: 1.82, 12.19) scales, adjusted for measured confounders. The Q192R genotype and the alarms variable were independent (adjusted POR in the controls=1.18controls=1.18; 95% CI: 0.81, 1.73; p=0.35p=0.35), and the associations of GWI with the number of R alleles and quartiles of Q isoenzyme were monotonic. The adjusted relative excess risk due to interaction (aRERI) was 7.69 (95% CI: 2.71, 19.13). Substituting Q isoenzyme activity for the genotype in the analyses corroborated the findings. Sensitivity analyses suggested that recall bias had forced the estimate of the GxE interaction toward the null and that unmeasured confounding is unlikely to account for the findings. We found a GxE interaction involving the Q-correlated PON1 diazoxonase activity and a weak possible GxE involving the Khamisiyah plume model, but none involving the PON1 R isoenzyme activity, arylesterase activity, paraoxonase activity, butyrylcholinesterase genotypes or enzyme activity, or pyridostigmine.
Discussion: Given gene-environment independence and monotonicity, the unconfounded aRERI>0aRERI>0 supports a mechanistic interaction. Together with the direct evidence of exposure to fallout from bombing of chemical weapon storage facilities and the extensive toxicologic evidence of biochemical protection from organophosphates by the Q isoenzyme, the findings provide strong evidence for an etiologic role of low-level nerve agent in GWI. https://doi.org/10.1289/EHP9009

_____________________________________________________________________________________

Decreased NO production in endothelial cells exposed to plasma from ME/CFS patientsRominaBertinataRobertoVillalobos-LabrabLidijaHofmanncJenniferBlauensteinercNunoSepúlvedadeFranciscoWestermeiercf
https://doi.org/10.1016/j.vph.2022.106953Get rights and content
Highlights•
ME/CFS-plasma reduced the ability of ECs to produce NO.
•
Decreased NO production was linked to higher inhibitory phosphorylation of eNOS at Thr495 at the basal state.
•
We provide new methodological approaches to study in vitro ED in ME/CFS.
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by severe and persistent fatigue. Along with clinical studies showing endothelial dysfunction (ED) in a subset of ME/CFS patients, we have recently reported altered ED-related microRNAs in plasma from affected individuals. Inadequate nitric oxide (NO), mainly produced by the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells (ECs), is a major cause of ED. In this study, we hypothesized that plasma from that cohort of ME/CFS patients induces eNOS-related ED in vitro. To test this, we cultured human umbilical vein endothelial cells (HUVECs) in the presence of plasma from either ME/CFS patients (ME/CFS-plasma, n = 11) or healthy controls (HC-plasma, n = 12). Then, we measured the NO production in the absence and presence of tyrosine kinase and G protein-coupled receptors agonists (TKRs and GPCRs, respectively), well-known to activate eNOS in ECs. Our data showed that HUVECs incubated with ME/CFS-plasma produced less NO either in the absence or presence of eNOS activators compared to ones in presence of HC-plasma. Also, the NO production elicited by bradykinin, histamine, and acetylcholine (GPCRs agonists) was more affected than the one triggered by insulin (TKR agonist). Finally, inhibitory eNOS phosphorylation at Thr495 was higher in HUVECs treated with ME/CFS-plasma compared to the same treatment with HC-plasma. In conclusion, this study in vitro shows a decreased NO production in HUVECs exposed to plasma from ME/CFS patients, suggesting an unreported role of eNOS in the pathophysiology of this disease.

_____________________________________________________________________________________

Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndromeArnaud Germain,1 Ludovic Giloteaux,1 Geoffrey E. Moore,2 Susan M. Levine,1 John K. Chia,3 Betsy A. Keller,2 Jared Stevens,4 Carl J. Franconi,1 Xiangling Mao,5 Dikoma C. Shungu,5 Andrew Grimson,1 and Maureen R. Hanson1
Published March 31, 2022 - Open Access | 10.1172/jci.insight.157621
Abstract
Post-exertional malaise (PEM) is a hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We monitored the evolution of 1157 plasma metabolites in 60 ME/CFS (45 female, 15 male) and 45 matched healthy control participants (30 female, 15 male) before and after 2 maximal cardiopulmonary exercise test (CPET) challenges separated by 24 hours, with the intent of provoking PEM in patients. Four time points allowed exploration of the metabolic response to maximal energy-producing capacity and the recovery pattern of participants with ME/CFS compared with the healthy control group. Baseline comparison identified several significantly different metabolites, along with an enriched percentage of yet-to-be identified compounds. Additionally, temporal measures demonstrated an increased metabolic disparity between cohorts, including unknown metabolites. The effects of exertion in the ME/CFS cohort predominantly highlighted lipid-related as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions. The 24-hour recovery period was distinct in the ME/CFS cohort, with over a quarter of the identified pathways statistically different from the controls. The pathways that are uniquely different 24 hours after an exercise challenge provide clues to metabolic disruptions that lead to PEM. Numerous altered pathways were observed to depend on glutamate metabolism, a crucial component of the homeostasis of many organs in the body, including the brain.

 _____________________________________________________________________________________

Long Covid at the crossroads: Comparisons and lessons from the treatment of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)Joanne Hunt , Charlotte Blease , Keith J Geraghty    
First Published March 27, 22 Research Article   https://doi.org/10.1177/13591053221084494
AbstractWhilst parallels have been drawn between Long Covid and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), there is a well-documented history of negative stereotyping and marginalisation of patients with ME/CFS. A socio-politically oriented comparison of scientific, clinical and societal responses to Long Covid and ME/CFS is thus important to prevent similar harms arising among Long Covid patients. We identify four reasons for injustices in the treatment of ME/CFS patients, and discuss the risk of Long Covid following a similar trajectory. We conclude with policy and practice recommendations to help prevent such injustices arising again, including consideration of critical reflexivity in medical education.

 _____________________________________________________________________________________

Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of PyridostigminePhillip Joseph, MD ∗Rosa Pari, MD ∗Sarah Miller, BS  Wenzhong Xiao, PhD Aaron B. Waxman, MD, PhDDavid M. Systrom, MD dcolour
Published:May 05, 2022DOI:https://doi.org/10.1016/j.chest.2022.04.146
ABSTRACTBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, post-exertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS.
Research QuestionDoes neurovascular dysregulation contribute to exercise intolerance in ME/CFS and can its treatment improve exercise capacity?
MethodsForty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60 mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 minutes later. The primary end point was the difference in peak exercise oxygen uptake (VO2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange.
ResultsTwenty-three subjects were assigned to pyridostigmine and 22 to placebo. The peak VO2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs. -40.2 ± 21.3 mL/min, P<0.05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, -105.2 to -2.0). Peak versus rest VO2 (25.9 ± 15.3 mL/min vs. -60.8 ± 25.6 mL/min, P<0.01), cardiac output (-0.2 ± 0.6 L/min vs. -1.9 ± 0.6 L/min, P<0.05), and RAP (1.0 ± 0.5 mm Hg vs. -0.6 ± 0.5 mm Hg, P<0.05) were greater in the pyridostigmine group compared to placebo.
InterpretationPyridostigmine improves peak VO2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise VO2, Qc, and RAP after placebo may signal the onset of post-exertional malaise. We suggest treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS.

_____________________________________________________________________________________

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure
Front Cell Neurosci. 2022; 16: 888232.  Published online 2022 May 9. doi: 10.3389/fncel.
Herbert Renz-Polster, Marie-Eve Tremblay, Dorothee Bienzl , Joachim E Fischer
Abstract
Although 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.
 
 _____________________________________________________________________________________

HYPOTHESIS AND THEORY  published: 25 May 2022 doi: 10.3389/fneur.2022.877772
Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to SustainDisease and Promote Relapses
Warren Tate 1,2*, Max Walker 1, Eiren Sweetman 1,3, Amber Helliwell 1, Katie Peppercorn 1,2, Christina Edgar 1, Anna Blair 4 and Aniruddha Chatterjee 5
 
1 Department of Biochemistry, University of Otago, Dunedin, New Zealand, 2 Brain Health Research Centre, University of Otago, Dunedin, New Zealand, 3 School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand,
4 Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia, 5 Department of Pathology, University of Otago, Dunedin, New Zealand
 
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease now well-documented ashaving arisen commonly from a viral infection, but also from other external stressors, like exposure to agricultural chemicals, other types of infection, surgery, or other severe stress events. Research has shown these events produce a systemic molecular inflammatory response and chronic immune activation and dysregulation. What has been more difficult to establish is the hierarchy of the physiological responses that give rise to the myriad of symptoms that ME/CFS patients experience, and why they do not resolve and are generally life-long. The severity of the symptoms frequently fluctuates through relapse recovery periods, withbrain-centered symptoms of neuroinflammation, loss of homeostatic control, “brain fog” affecting cognitive ability, lack of refreshing sleep, and poor response to even small stresses. How these brain effects develop with ME/CFS from the initiating external effector, whether virus or other cause, is poorly understood and that is what our paper aims to address. We propose the hypothesis that following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctionalblood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles. Signaling through recognized pathways from the brain back to body physiology is likely part of the process by which the illness cycle in the peripheral system is sustained and why healing does not occur. By contrast, Long COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness arising from the single pandemic virus, SARS-CoV-2. We believe the ME/CFS-like ongoing effectsof Long COVID are arising by very similar mechanisms involving neuroinflammation, but likely with someunique signaling, resulting from the pathology of the initial SARS-CoV-2 infection. The fact that there are verysimilar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both. 
 
0 Comments

Abstracts from 1 January 2022

1/1/2022

0 Comments

 
 Research Letter Neurology
October 22, 2021
Assessment of Cognitive Function in Patients After COVID-19 Infection
Jacqueline H. Becker, PhD1; Jenny J. Lin, MD, MPH1; Molly Doernberg, MPH1; et alKimberly Stone, MPH1; Allison Navis, MD2; Joanne R. Festa, PhD2; Juan P. Wisnivesky, MD, DrPH1,3
JAMA Netw Open. 2021;4(10):e2130645. doi:10.1001/jamanetworkopen.2021.30645
Introduction
People who have survived COVID-19 frequently complain of cognitive dysfunction, which has been described as brain fog. The prevalence of post–COVID-19 cognitive impairment and the association with disease severity are not well characterized. Previous studies on the topic have been limited by small sample sizes and suboptimal measurement of cognitive functioning.1 We investigated rates of cognitive impairment in survivors of COVID-19 who were treated in outpatient, emergency department (ED), or in hospital settings.
Methods
We analyzed data in this cross-sectional study from April 2020 through May 2021 from a cohort of patients with COVID-19 followed up through a Mount Sinai Health System registry. Study participants were 18 years or older, spoke English or Spanish, tested positive for SARS-CoV-2 or had serum antibody positivity, and had no history of dementia. Participant demographic characteristics (eg, age, race, and ethnicity) were collected via self-report. Cognitive functioning was assessed using well-validated neuropsychological measures: Number Span forward (attention) and backward (working memory), Trail Making Test Part A and Part B (processing speed and executive functioning, respectively), phonemic and category fluency (language), and the Hopkins Verbal Learning Test–Revised (memory encoding, recall, and recognition). The Mount Sinai Health System Institutional Review Board approved this study, and informed consent was obtained from study participants. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline.
We calculated the frequency of impairment on each measure, defined as a z score of less than or equal to 1.5 SDs below measure-specific age-, educational level–, and sex-adjusted norms.2,3 Logistic regression assessed the association between cognitive impairment and COVID-19 care site (outpatient, ED, or hospital), adjusting for race and ethnicity, smoking, body mass index, comorbidities, and depression. The threshold for statistical significance was α = .05, and the tests were 2-tailed. Analyses were performed using SAS, version 9.4 (SAS Institute).
Results
The mean (IQR) age of 740 participants was 49 (38-59) years, 63% (n = 464) were women, and the mean (SD) time from COVID-19 diagnosis was 7.6 (2.7) months (Table 1). Participants self-identified as Black (15%), Hispanic (20%), or White (54%) or selected multiracial or other race and ethnicity (11%; other race included Asian [4.5%, n = 33)] and those who selected “other” as race). The most prominent deficits were in processing speed (18%, n = 133), executive functioning (16%, n = 118), phonemic fluency (15%, n = 111) and category fluency (20%, n = 148), memory encoding (24%, n = 178), and memory recall (23%, n = 170; Table 2).
In adjusted analyses, hospitalized patients were more likely to have impairments in attention (odds ratio [OR]: 2.8; 95% CI: 1.3-5.9), executive functioning (OR: 1.8; 95% CI: 1.0-3.4), category fluency (OR: 3.0; 95% CI: 1.7-5.2), memory encoding (OR: 2.3; 95% CI: 1.3-4.1), and memory recall (OR: 2.2; 95% CI: 1.3-3.8) than those in the outpatient group. Patients treated in the ED were more likely to have impaired category fluency (OR: 1.8; 95% CI: 1.1-3.1) and memory encoding (OR: 1.7; 95% CI: 1.0-3.0) than those treated in the outpatient setting. No significant differences in impairments in other domains were observed between groups.
Discussion
In this study, we found a relatively high frequency of cognitive impairment several months after patients contracted COVID-19. Impairments in executive functioning, processing speed, category fluency, memory encoding, and recall were predominant among hospitalized patients. The relative sparing of memory recognition in the context of impaired encoding and recall suggests an executive pattern. This pattern is consistent with early reports describing a dysexecutive syndrome after COVID-194 and has considerable implications for occupational, psychological, and functional outcomes. It is well known that certain populations (eg, older adults) may be particularly susceptible to cognitive impairment after critical illness5; however, in the relatively young cohort in the present study, a substantial proportion exhibited cognitive dysfunction several months after recovering from COVID-19. The findings of this study are generally consistent with those of research on other viruses (eg, influenza).6
Limitations of this study include a potential sampling bias, as some participants may have presented to Mount Sinai Health System because of health concerns. Future studies should investigate long-term post–COVID-19 cognitive trajectories and the association with neuroimaging findings to assess potential mechanisms.
Conclusions
The association of COVID-19 with executive functioning raises key questions regarding patients’ long-term treatment. Future studies are needed to identify the risk factors and mechanisms underlying cognitive dysfunction as well as options for rehabilitation.

____________________________________________________________________________________
Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study
BMJ 2022; 376 doi: https://doi.org/10.1136/bmj-2021-068414 (Published 09 February 2022)Cite this as: BMJ 2022;376:e068414
  1. Ken Cohen,Sheng Ren, Kevin Heath, Micah C Dasmariñas, Karol Giuseppe Yinglong Guo, Marc Lipsitch, Sarah E Daugherty, 
  2. Correspondence to: K Cohen [email protected]
  • Accepted 24 December 2021
Abstract
Objective To characterize the risk of persistent and new clinical sequelae in adults aged ≥65 years after the acute phase of SARS-CoV-2 infection.
Design Retrospective cohort study.
Setting UnitedHealth Group Clinical Research Database: deidentified administrative claims and outpatient laboratory test results.
Participants Individuals aged ≥65 years who were continuously enrolled in a Medicare Advantage plan with coverage of prescription drugs from January 2019 to the date of diagnosis of SARS-CoV-2 infection, matched by propensity score to three comparison groups that did not have covid-19: 2020 comparison group (n=87 337), historical 2019 comparison group (n=88 070), and historical comparison group with viral lower respiratory tract illness (n=73 490).
Main outcome measures The presence of persistent and new sequelae at 21 or more days after a diagnosis of covid-19 was determined with ICD-10 (international classification of diseases, 10th revision) codes. Excess risk for sequelae caused by infection with SARS-CoV-2 was estimated for the 120 days after the acute phase of the illness with risk difference and hazard ratios, calculated with 95% Bonferroni corrected confidence intervals. The incidence of sequelae after the acute infection was analyzed by age, race, sex, and whether patients were admitted to hospital for covid-19.
Results Among individuals who were diagnosed with SARS-CoV-2, 32% (27 698 of 87 337) sought medical attention in the post-acute period for one or more new or persistent clinical sequelae, which was 11% higher than the 2020 comparison group. Respiratory failure (risk difference 7.55, 95% confidence interval 7.18 to 8.01), fatigue (5.66, 5.03 to 6.27), hypertension (4.43, 2.27 to 6.37), memory difficulties (2.63, 2.23 to 3.13), kidney injury (2.59, 2.03 to 3.12), mental health diagnoses (2.50, 2.04 to 3.04), hypercoagulability 1.47 (1.2 to 1.73), and cardiac rhythm disorders (2.19, 1.76 to 2.57) had the greatest risk differences compared with the 2020 comparison group, with similar findings to the 2019 comparison group. Compared with the group with viral lower respiratory tract illness, however, only respiratory failure, dementia, and post-viral fatigue had increased risk differences of 2.39 (95% confidence interval 1.79 to 2.94), 0.71 (0.3 to 1.08), and 0.18 (0.11 to 0.26) per 100 patients, respectively. Individuals with severe covid-19 disease requiring admission to hospital had a markedly increased risk for most but not all clinical sequelae.
Conclusions The results confirm an excess risk for persistent and new sequelae in adults aged ≥65 years after acute infection with SARS-CoV-2. Other than respiratory failure, dementia, and post-viral fatigue, the sequelae resembled those of viral lower respiratory tract illness in older adults. These findings further highlight the wide range of important sequelae after acute infection with the SARS-CoV-2 virus.
____________________________________________________________________________________

Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients
Author links open overlay panelR.BertinataR.Villalobos-LabrabL.HofmanncJ.BlauensteinercN.SepúlvedadeF.Westermeiercf
Available online 21 January 2022, 106953asculzr Vascular Pharmacology
https://doi.org/10.1016/j.vph.2022.106953Get rights and content
Highlights
•ME/CFS-plasma reduced the ability of ECs to produce NO.
Decreased NO production was linked to higher inhibitory phosphorylation of eNOS at Thr495 at the basal state.
We provide new methodological approaches to study in vitro ED in ME/CFS.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by severe and persistent fatigue. Along with clinical studies showing endothelial dysfunction (ED) in a subset of ME/CFS patients, we have recently reported altered ED-related microRNAs in plasma from affected individuals. Inadequate nitric oxide (NO), mainly produced by the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells (ECs), is a major cause of ED. In this study, we hypothesized that plasma from that cohort of ME/CFS patients induces eNOS-related ED in vitro. To test this, we cultured human umbilical vein endothelial cells (HUVECs) in the presence of either plasma from ME/CFS patients (ME/CFS-plasma, n = 11) or healthy controls (HC-plasma, n = 12). Then, we measured the NO production in the absence or presence of tyrosine kinase and G protein-coupled receptors agonists (TKRs and GPCRs, respectively), well-known to activate eNOS in ECs. Our data show that HUVECs incubated with ME/CFS-plasma produced less NO either in the absence or presence of eNOS activators compared to ones in presence of HC-plasma. Also, the NO production elicited by bradykinin, histamine, and acetylcholine (GPCRs agonists) was more affected than the one triggered by insulin (TKR agonist). Finally, inhibitory eNOS phosphorylation at Thr495 was higher in HUVECs treated with ME/CFS-plasma compared to the same treatment with HC-plasma. In conclusion, this study in vitro shows a decreased NO production in HUVECs exposed to plasma from ME/CFS patients, suggesting an unreported role of eNOS in the pathophysiology of this disease.
____________________________________________________________________________________

Multiple Early Factors Anticipate Post-Acute COVID-19 SequelaeYapeng Su 28
Dan Yuan 28Daniel G. Chen 28Mark M. Davis Jason D. Goldman James R. Heath 29
Published:January 24, 2022DOI:https://doi.org/10.1016/j.cell.2022.01.014
Highlights
  • Longitudinal multiomics associate PASC with autoantibodies, viremia and comorbidities
  • Reactivation of latent viruses during initial infection may contribute to PASC
  • Subclinical autoantibodies negatively correlate with anti-SARS-CoV-2 antibodies
  • Gastrointestinal PASC uniquely present with post-acute expansion of cytotoxic T cells
  • SUMMARY
Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
DOI: https://doi.org/10.1016/j.cell.2022.01.014

____________________________________________________________________________________

Reduced Parasympathetic Reactivation during Recovery from Exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Jessica Van Oosterwijck 1 2, Uros Marusic 3 4, Inge De Wandele 2, Mira Meeus 2 5, Lorna Paul 6, Luc Lambrecht 7, Greta Moorkens 8, Lieven Danneels 2, Jo Nijs 1 9
J Clin Med  . 2021 Sep 30
PMID: 34640544  PMCID: PMC8509376   DOI: 10.3390/jcm10194527
Abstract
Although autonomic nervous system (ANS) dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has been proposed, conflicting evidence makes it difficult to draw firm conclusions regarding ANS activity at rest in ME/CFS patients. Although severe exercise intolerance is one of the core features of ME/CFS, little attempts have been made to study ANS responses to physical exercise. Therefore, impairments in ANS activation at rest and following exercise were examined using a case-control study in 20 ME/CFS patients and 20 healthy people. Different autonomous variables, including cardiac, respiratory, and electrodermal responses were assessed at rest and following an acute exercise bout. At rest, parameters in the time-domain represented normal autonomic function in ME/CFS, while frequency-domain parameters indicated the possible presence of diminished (para)sympathetic activation. Reduced parasympathetic reactivation during recovery from exercise was observed in ME/CFS. This is the first study showing reduced parasympathetic reactivation during recovery from physical exercise in ME/CFS. Delayed HR recovery and/or a reduced HRV as seen in ME/CFS have been associated with poor disease prognosis, high risk for adverse cardiac events, and morbidity in other pathologies, implying that future studies should examine whether this is also the case in ME/CFS and how to safely improve HR recovery in this population.
Keywords: autonomic function; autonomic nervous system; electrocardiogram; electrodermal activity; heart rate.
____________________________________________________________________________________

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Overview
Undine-Sophie Deumer, Angelica Varesi, [...], and Giovanni Ricevuti
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic systemic disease that manifests via various symptoms such as chronic fatigue, post-exertional malaise, and cognitive impairment described as “brain fog”. These symptoms often prevent patients from keeping up their pre-disease onset lifestyle, as extended periods of physical or mental activity become almost impossible. However, the disease presents heterogeneously with varying severity across patients. Therefore, consensus criteria have been designed to provide a diagnosis based on symptoms. To date, no biomarker-based tests or diagnoses are available, since the molecular changes observed also largely differ from patient to patient. In this review, we discuss the infectious, genetic, and hormonal components that may be involved in CFS pathogenesis, we scrutinize the role of gut microbiota in disease progression, we highlight the potential of non-coding RNA (ncRNA) for the development of diagnostic tools and briefly mention the possibility of SARS-CoV-2 infection causing CFS.
Keywords: ME/CFS, immunity, dysbiosis, COVID-19, hormone, depression, genetics, miRNA, therapy, diagnosis
____________________________________________________________________________________

Cerebral blood flow remains reduced after tilt testing in myalgic encephalomyelitis/chronic fatigue syndrome patients
C. (Linda) M.C. van Campen, Peter C. Rowe, and Frans C. Visser
Clinical Neurophysiology practice  2021:6
Abstract   Objective
Orthostatic symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may be caused by an abnormal reduction in cerebral blood flow. An abnormal cerebral blood flow reduction was shown in previous studies, without information on the recovery pace of cerebral blood flow. This study examined the prevalence and risk factors for delayed recovery of cerebral blood flow in ME/CFS patients.
Methods
60 ME/CFS adults were studied: 30 patients had a normal heart rate and blood pressure response during the tilt test, 4 developed delayed orthostatic hypotension, and 26 developed postural orthostatic tachycardia syndrome (POTS) during the tilt. Cerebral blood flow measurements, using extracranial Doppler, were made in the supine position pre-tilt, at end-tilt, and in the supine position at 5 min post-tilt. Also, cardiac index measurements were performed,
using suprasternal Doppler imaging, as well as end-tidal PCO2 measurements. The change in cerebral blood flow from supine to end-tilt was expressed as a percent reduction with mean and (SD). Disease severity was scored as mild (approximately 50% reduction in activity), moderate (mostly housebound), or severe (mostly bedbound).
Results
End-tilt cerebral blood flow reduction was −29 (6)%, improving to −16 (7)% at post-tilt. No differences in either end-tilt or post-tilt measurements were found when patients with a normal heart rate and blood pressure were compared to those with POTS, or between patients with normocapnia (end-tidal PCO2 ≥ 30 mmHg) versus hypocapnia (end-tidal PCO2 < 30 mmHg) at end-tilt. A significant difference was found in the degree of abnormal cerebral blood flow reduction in the supine post-test in mild, moderate, and severe ME/CFS: mild: cerebral blood flow: −7 (2)%, moderate: −16 (3)%, and severe :-25 (4)% (p all < 0.0001). Cardiac index declined significantly during the tilt test in all 3 severity groups, with no significant differences between the groups. In the supine post-test cardiac index returned to normal in all patients.
Conclusions
During tilt testing, extracranial Doppler measurements show that cerebral blood flow is reduced in ME/CFS patients and recovery to normal supine values is incomplete, despite cardiac index returning to pre-tilt values. The delayed recovery of cerebral blood flow was independent of the hemodynamic findings of the tilt test (normal heart rate and blood pressure response, POTS, or delayed orthostatic hypotension), or the presence/absence of hypocapnia, and was only related to clinical ME/CFS severity grading. We observed a significantly slower recovery in cerebral blood flow in the most severely ill ME/CFS patients.
Significance
The finding that orthostatic stress elicits a post-stress cerebral blood flow reduction and that disease severity greatly influences the cerebral blood flow reduction may have implications on the advice of energy management after a stressor and on the advice of lying down after a stressor in these ME/CFS patients.
____________________________________________________________________________________

Risk factors and abnormal cerebrospinal fluid associate with cognitive symptoms after mild COVID-19
Alexandra C. Apple,Alexis Oddi,Michael J. Peluso,Breton M. Asken,Timothy J. Henrich,J. Daniel Kelly,Samuel J. Pleasure,Steven G. Deeks,Isabel Elaine Allen,Jeffrey N. Martin … See all authors 
Annals of transational and clinical neurology
First published: 19 January 2022   https://doi.org/10.1002/acn3.51498
Abstract
Cognitive post-acute sequelae of SARS-CoV-2 (PASC) can occur after mild COVID-19. Detailed clinical characterizations may inform pathogenesis. We evaluated 22 adults reporting cognitive PASC and 10 not reporting cognitive symptoms after mild SARS-CoV-2 infection through structured interviews, neuropsychological testing, and optional cerebrospinal fluid (CSF) evaluations (53%). Delayed onset of cognitive PASC occurred in 43% and associated with younger age. Cognitive PASC participants had a higher number of pre-existing cognitive risk factors (2.5 vs. 0; p = 0.03) and higher proportion with abnormal CSF findings (77% vs. 0%; p = 0.01) versus controls. Cognitive risk factors and immunologic mechanisms may contribute to cognitive PASC pathogenesis.
____________________________________________________________________________________

Restless legs syndrome severity in the National RLS Opioid Registry during the COVID-19 pandemic
BenjaminWipperChristopherRomero-GutierrezJohn W.Winkelman
https://doi.org/10.1016/j.sleep.2022.01.011
Abstract
Objective/background
No research has yet assessed the impact of the coronavirus disease 2019 (COVID-19) pandemic on restless legs syndrome (RLS). We hypothesized that RLS symptom severity would be increased during the COVID-19 pandemic in a sample of patients with diagnosed RLS.
Patients/methods
The National RLS Opioid Registry is a longitudinal observational study of patients using opioid medications for treatment of RLS. Questionnaires assessing RLS symptom severity, medication dosages, sleep disturbance, depression, and anxiety are administered at baseline and at recurring 6-month surveys. Survey responses from the outset of the pandemic in April/May 2020 were compared to responses completed by other participants in January/February 2020 (between-subjects analysis), as well as responses by the same participants at baseline, approximately six months later in September 2020 through February 2021, and approximately one year later in March through June 2021 (within-subjects analyses).
Results
These analyses provide evidence for higher RLS symptom severity scores at the outset of the COVID-19 pandemic in the US. Symptom severity scores were still elevated on subsequent questionnaires completed over six months into the pandemic but had returned towards baseline by the spring of 2021. Participants with increases in RLS severity were significantly more likely than others to see increases in sleep disturbance, depression, and anxiety.
Conclusions
This is the first study demonstrating increased RLS symptom severity during the earliest stage of the COVID-19 pandemic. These findings warrant similar investigations in other patient populations and suggest that clinicians should attend to RLS symptoms during times of socioeconomic and/or political uncertainty.
____________________________________________________________________________________

COVID-19: 1 in 3 older adults will develop post-COVID-19 syndrome
Cohen K & al.. BMJ, 09 February 2022
Takeaway
  • Roughly 1 in 3 older adults will develop persistent or new clinical sequelae post-acute COVID-19 infection.
Why this matters
  • Consider post-acute COVID-19 risk in older adults previously hospitalized for primary infection, especially those presenting with viral lower respiratory tract illness (vLRTI).
Key results
  • 132,847 matched pairs diagnosed pre-1 April 2020; median age, 74 years.
  • 87,337, post-acute care: 16% (13,992) 1 sequelae, 16% (13,706) ≥2.
  • Comparative group difference vs 2020: −11 (95% CI, −11.4 to −10.6); 2019: −7.9 (95% CI, −8.3 to −7.5); vLRTI: 1.4 (95% CI, 0.9-1.9).
  • Most common (all P<.001 vs 2020 comparator) risk difference (RD):
    • Respiratory failure: 7.55 (95% CI, 7.18-8.01).
    • Fatigue: 5.66 (95% CI, 5.03-6.27).
    • Hypertension: 4.43 (95% CI, 2.27-6.37).
    • Mental health diagnoses: 2.5 (95% CI, 2.04-3.04).
    • Acute kidney injury: 2.74 (95% CI, 2.39-3.07).
    • Memory issues: 2.63 (95% CI, 2.23-3.13).
    • Myalgia: 2.25 (95% CI, 1.57-2.95).
    • Cardiac rhythm disorders: 2.19 (95% CI, 1.76-2.57).
    • Hypercoagulability: 1.47 (95% CI, 1.2-1.73).
  • Vs vLRTI, RD:
    • Respiratory failure: 2.39 (95% CI, 1.79-2.94).
    • Dementia: 0.71 (95% CI, 0.3-1.08).
    • Postviral fatigue: 0.18 (95% CI, 0.11-0.26).
Study design
  • Retrospective cohort study estimating excess risk, new clinical sequelae post-acute SARS-CoV-2 infection phase in Medicare US adults aged ≥65 years.
  • Funding: Optum Laboratories.
____________________________________________________________________________________

Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome
Nat Commun. 2022; 13: 446.
Published online 2022 Jan 25. doi: 10.1038/s41467-021-27797-1 PMCID: PMC8789854
PMID: 35078982
Carlo Cervia,1 et al
1Department of Immunology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
Abstract
Following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a significant proportion of individuals develop prolonged symptoms, a serious condition termed post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) or long COVID. Predictors of PACS are needed. In a prospective multicentric cohort study of 215 individuals, we study COVID-19 patients during primary infection and up to one year later, compared to healthy subjects. We discover an immunoglobulin (Ig) signature, based on total IgM and IgG3 levels, which – combined with age, history of asthma bronchiale, and five symptoms during primary infection – is able to predict the risk of PACS independently of timepoint of blood sampling. We validate the score in an independent cohort of 395 individuals with COVID-19. Our results highlight the benefit of measuring Igs for the early identification of patients at high risk for PACS, which facilitates the study of targeted treatment and pathomechanisms of PACS.
____________________________________________________________________________________

Cortical autonomic network connectivity predicts symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Mark A.Zinn Leonard A.Jason
International Journal of Psychophysiology Volume 170, December 2021, Pages 89-101
https://doi.org/10.1016/j.ijpsycho.2021.10.004Get rights and content
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) represents a significant public health challenge given the presence of many unexplained patient symptoms. Research has shown that many features in ME/CFS may result from a dysfunctional autonomic nervous system (ANS). We explored the role of the cortical autonomic network (CAN) involved in higher-order control of ANS functioning in 34 patients with ME/CFS and 34 healthy controls under task-free conditions. All participants underwent resting-state quantitative electroencephalographic (qEEG) scalp recordings during an eyes-closed condition. Source analysis was performed using exact low-resolution electromagnetic tomography (eLORETA), and lagged coherence was used to estimate intrinsic functional connectivity between each node across 7 frequency bands: delta (1–3 Hz), theta (4–7 Hz), alpha-1 (8–10 Hz), alpha-2 (10–12 Hz), beta-1 (13–18 Hz), beta-2 (19–21 Hz), and beta-3 (22–30 Hz). Symptom ratings were measured using the DePaul Symptom Questionnaire and the Short Form (SF-36) health survey. Graph theoretical analysis of weighted, undirected connections revealed significant group differences in baseline CAN organization. Regression results showed that cognitive, affective, and somatomotor symptom cluster ratings were associated with alteration to CAN topology in patients, depending on the frequency band. These findings provide evidence for reduced higher-order homeostatic regulation and adaptability in ME/CFS. If confirmed, these findings address the CAN as a potential therapeutic target for managing patient symptoms.
____________________________________________________________________________________

Complement Component C1q as a Potential Diagnostic Tool for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subtyping
by Jesús Castro-Marrero Mario Zacares,Eloy Almenar-Pérez, José Alegre-Martín, Elisa Oltra*
J. Clin. Med. 2021, 10(18), 4171; https://doi.org/10.3390/jcm10184171
Received: 27 August 2021 / Revised: 10 September 2021 / Accepted: 13 September 2021 / Published: 15 September 2021
Abstract
Background: Routine blood analytics are systematically used in the clinic to diagnose disease or confirm individuals’ healthy status. For myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disease relying exclusively on clinical symptoms for its diagnosis, blood analytics only serve to rule out underlying conditions leading to exerting fatigue. However, studies evaluating complete and large blood datasets by combinatorial approaches to evidence ME/CFS condition or detect/identify case subgroups are still scarce. Methods: This study used unbiased hierarchical cluster analysis of a large cohort of 250 carefully phenotyped female ME/CFS cases toward exploring this possibility. Results: The results show three symptom-based clusters, classified as severe, moderate, and mild, presenting significant differences (p < 0.05) in five blood parameters. Unexpectedly the study also revealed high levels of circulating complement factor C1q in 107/250 (43%) of the participants, placing C1q as a key molecule to identify an ME/CFS subtype/subgroup with more apparent pain symptoms. Conclusions: The results obtained have important implications for the research of ME/CFS etiology and, most likely, for the implementation of future diagnosis methods and treatments of ME/CFS in the clinic.
____________________________________________________________________________________

Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
C. (Linda) M. C. van Campen,Peter C. Rowe, Frans C. Visser
Stichting CardioZorg, Planetenweg 5, 2132 HN Hoofddorp, The Netherlands
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Author to whom correspondence should be addressed.
Academic Editor: Olli J. Polo
Medicina 2022, 58(1), 28; https://doi.org/10.3390/medicina58010028
Received: 18 November 2021 / Revised: 18 December 2021 / Accepted: 21 December 2021 / Published: 24 December 2021
Abstract
Background and Objectives: Symptoms and hemodynamic findings during orthostatic stress have been reported in both long-haul COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but little work has directly compared patients from these two groups. To investigate the overlap in these clinical phenotypes, we compared orthostatic symptoms in daily life and during head-up tilt, heart rate and blood pressure responses to tilt, and reductions in cerebral blood flow in response to orthostatic stress in long-haul COVID-19 patients, ME/CFS controls, and healthy controls. Materials and Methods: We compared 10 consecutive long-haul COVID-19 cases with 20 age- and gender-matched ME/CFS controls with postural tachycardia syndrome (POTS) during head-up tilt, 20 age- and gender-matched ME/CFS controls with a normal heart rate and blood pressure response to head-up tilt, and 10 age- and gender-matched healthy controls. Identical symptom questionnaires and tilt test procedures were used for all groups, including measurement of cerebral blood flow and cardiac index during the orthostatic stress. Results: There were no significant differences in ME/CFS symptom prevalence between the long-haul COVID-19 patients and the ME/CFS patients. All long-haul COVID-19 patients developed POTS during tilt. Cerebral blood flow and cardiac index were more significantly reduced in the three patient groups compared with the healthy controls. Cardiac index reduction was not different between the three patient groups. The cerebral blood flow reduction was larger in the long-haul COVID-19 patients compared with the ME/CFS patients with a normal heart rate and blood pressure response. Conclusions: The symptoms of long-haul COVID-19 are similar to those of ME/CFS patients, as is the response to tilt testing. Cerebral blood flow and cardiac index reductions during tilt were more severely impaired than in many patients with ME/CFS. The finding of early-onset orthostatic intolerance symptoms, and the high pre-illness physical activity level of the long-haul COVID-19 patients, makes it unlikely that POTS in this group is due to deconditioning. These data suggest that similar to SARS-CoV-1, SARS-CoV-2 infection acts as a trigger for the development of ME/CFS.  
____________________________________________________________________________________

AJGP Volume 50, Issue 12, December 2021
Outcomes of COVID-19 in the community: A prospective cohort study
Stuart Tan   Lyndel Hewitt   Jose Cuenca   Dante Risi  
doi: 10.31128/AJGP-07-21-6078   
The literature indicates that patients who had previously had COVID-19 are reporting ongoing symptoms. The objective of this study was to examine ongoing symptoms, functional limitations and quality of life over time in a cohort of individuals who were deemed to have recovered.
Methods
This was a prospective observational study on biopsychosocial outcomes at enrolment and again one month later.
Results
In a cohort of 59 participants, ongoing symptoms were reported by 73% at 4.5 months (standard deviation = 1.4) post diagnosis, with 45% reporting difficulty with pre-illness activities of daily living. Of the 52 participants who completed the follow-up survey (mean 5.6 months post diagnosis), 42% reported ongoing symptoms, lower physical quality of life (12-Item Short Form Health Survey) and higher levels of anxiety, depression and stress (Depression, Anxiety and Stress Scale).
Discussion
Ongoing symptoms such as fatigue, pain and limb weakness as well as functional impairment post initial diagnosis were common. Improved understanding of this cohort can assist general practitioners in providing care.


COVID-19 is a viral infection that emerged from Wuhan, China, in December 2019. This disease has spread throughout the world (221 countries) and was declared a pandemic by the World Health Organization on 11 March 2020.1,2 Globally, by 21 June 2021, there were 178,433,377 confirmed cases, including 3,864,702 deaths (https://covid19.who.int). Of these reported cases, 163,827,935 were deemed to have recovered by various public health authorities (www.worldometers.info/coronavirus). In Australia, there had been 30,331 cases with 910 deaths at 21 June 2021, with 27,021 of these cases classified as recovered. Despite this, there have been many reports of individuals with COVID-19 experiencing debilitating symptoms long after being cleared of the acute infection.3 The term ‘long COVID’ has been used in the literature to describe the condition,4 and further studies are emerging to investigate the effects of this condition on the human body.


Various studies from other countries report ongoing morbidities of patients with COVID-19. These morbidities relate to severe pulmonary limitation,6 hepatic impairment,7 hemostatic changes8 and neurological complications.9 Carfi et al reported that in a cohort of 143 hospitalised patients who had recovered from COVID-19, 87.4% reported persistence of one symptom at a mean of 60.3 days (standard deviation [SD] = 13.6) after the onset of their first COVID-19 symptom.10 Similarly, Huang et al reported that 76% of patients hospitalised with COVID-19 (n = 1655) were symptomatic at follow-up.11 In a systematic literature review, Nasserie et al found that 72.5% of patients reported at least one symptom at 60 days or more after diagnosis, symptom onset or hospitalisation or at 30 days or more after recovery from acute illness or hospital discharge.12
The speed and ferocity of transmission of COVID-19 throughout the world has resulted in a scarcity of data on biopsychosocial and functional outcomes of survivors of COVID-19 in the community. An analysis of the clinical progress, ongoing morbidities, functional outcomes and demand on current services after a positive COVID-19 diagnosis would facilitate appropriate future resource allocation required to address these concerns and prevent their escalation before they put additional strain on the healthcare system.13 Based on Communicable Diseases Network Australia (CDNA) guidelines (version 5.1),14 an individual in the community who tested positive for COVID-19 is deemed to have recovered sufficiently to be discharged from virtual care under the following criteria: 1) 14 days after a positive polymerase chain reaction (PCR) test if asymptomatic, 2) if the patient has been afebrile for the preceding 72 hours with substantial improvement of respiratory symptoms or 3) 20 days after a positive PCR test even if still symptomatic. In April 2020, the criterion (version 2.7) was the patient being afebrile for three consecutive days in the preceding 10 days. 
It is hypothesised that individuals with a positive COVID-19 diagnosis will have ongoing health issues and needs after being classified as ‘recovered’ under current guidelines. The aim of this study was to investigate the biopsychosocial status of a cohort of individuals who had been diagnosed with COVID-19 and deemed to have recovered by health authorities, and to describe any ongoing symptoms and functional and/or mental health outcomes on enrolment to the study and one month later.
____________________________________________________________________________________

medRxiv 2022 Jan 11;2021.06.14.21258895.  doi: 10.1101/2021.06.14.21258895. Preprint
Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Xiaoyu Che, Christopher R Brydges, Yuanzhi Yu, Adam Price, Shreyas Joshi, Ayan Roy, Bohyun Lee, Dinesh K Barupal, Aaron Cheng, Dana March Palmer, Susan Levine, Daniel L Peterson, Suzanne D Vernon, Lucinda Bateman, Mady Hornig, Jose G Montoya, Anthony L Komaroff, Oliver Fiehn, W Ian Lipkin
PMID: 35043127 PMCID: PMC8764736 DOI: 10.1101/2021.06.14.21258895
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.
Methods: Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.
Results: In ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).
Conclusion: Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.
One sentence summary: Plasma levels of plasmalogens are decreased in patients with myalgic encephalomyelitis/chronic fatigue syndrome suggesting peroxisome dysfunction.
____________________________________________________________________________________

Peripheral Neuropathy Evaluations of Patients With Prolonged Long COVID
 View ORCID ProfileAnne Louise Oaklander, Alexander J. Mills, Mary Kelley, Lisa S. Toran, Bryan Smith, Marinos C. Dalakas, Avindra Nath     
First published March 1, 2022, DOI:
        https://doi.org/10.1212/NXI.0000000000001146
Abstract
Background and Objectives Recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears exponential, leaving a tail of patients reporting various long COVID symptoms including unexplained fatigue/exertional intolerance and dysautonomic and sensory concerns. Indirect evidence links long COVID to incident polyneuropathy affecting the small-fiber (sensory/autonomic) axons.
Methods We analyzed cross-sectional and longitudinal data from patients with World Health Organization (WHO)-defined long COVID without prior neuropathy history or risks who were referred for peripheral neuropathy evaluations. We captured standardized symptoms, examinations, objective neurodiagnostic test results, and outcomes, tracking participants for 1.4 years on average.
Results Among 17 patients (mean age 43.3 years, 69% female, 94% Caucasian, and 19% Latino), 59% had ≥1 test interpretation confirming neuropathy. These included 63% (10/16) of skin biopsies, 17% (2/12) of electrodiagnostic tests and 50% (4/8) of autonomic function tests. One patient was diagnosed with critical illness axonal neuropathy and another with multifocal demyelinating neuropathy 3 weeks after mild COVID, and ≥10 received small-fiber neuropathy diagnoses. Longitudinal improvement averaged 52%, although none reported complete resolution. For treatment, 65% (11/17) received immunotherapies (corticosteroids and/or IV immunoglobulins).
Discussion Among evaluated patients with long COVID, prolonged, often disabling, small-fiber neuropathy after mild SARS-CoV-2 was most common, beginning within 1 month of COVID-19 onset. Various evidence suggested infection-triggered immune dysregulation as a common mechanism.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause long-term disability (long COVID) with new neurologic manifestations after even mild infections.1 Reports of peripheral neuropathy include Guillain-Barré syndrome, mononeuritis multiplex, brachial plexitis, cranial neuropathies, and orthostatic intolerance, although some studies included patients with potentially contributory conditions. Various long COVID symptoms overlap with those of small-fiber polyneuropathy (SFN).2,3 Hence, we prospectively analyzed a cross-section of patients with long COVID evaluated for incident neuropathy.

____________________________________________________________________________________

Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms
MedRxiv
Cheng Guo, Xiaoyu Che, Thomas Briese,  View ORCID ProfileOrchid Allicock, Rachel A. Yates, Aaron Cheng, Amit Ranjan, Dana March,  View ORCID ProfileMady Hornig,  View ORCID ProfileAnthony L. Komaroff, Susan Levine,  View ORCID ProfileLucinda Bateman,  View ORCID ProfileSuzanne D. Vernon,  View ORCID ProfileNancy G. Klimas, Jose G. Montoya, Daniel L. Peterson,  View ORCID ProfileW. Ian Lipkin,  View ORCID ProfileBrent L. Williams
doi: https://doi.org/10.1101/2021.10.27.21265575
Abstract
Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating disease of unknown cause for which there is no specific therapy. Patients suffering from ME/CFS commonly experience persistent fatigue, post-exertional malaise, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever and irritable bowel syndrome (IBS). Recent evidence implicates gut microbiome dysbiosis in ME/CFS. However, most prior studies are limited by small sample size, differences in clinical criteria used to define cases, limited geographic sampling, reliance on bacterial culture or 16S rRNA gene sequencing, or insufficient consideration of confounding factors that may influence microbiome composition. In the present study, we evaluated the fecal microbiome in the largest prospective, case-control study to date (n=106 cases, n=91 healthy controls), involving subjects from geographically diverse communities across the United States.
Results Using shotgun metagenomics and qPCR and rigorous statistical analyses that controlled for important covariates, we identified decreased relative abundance and quantity of Faecalibacterium, Roseburia, and Eubacterium species and increased bacterial load in feces of subjects with ME/CFS. These bacterial taxa play an important role in the production of butyrate, a multifunctional bacterial metabolite that promotes human health by regulating energy metabolism, inflammation, and intestinal barrier function. Functional metagenomic and qPCR analyses were consistent with a deficient microbial capacity to produce butyrate along the acetyl-CoA pathway in ME/CFS. Metabolomic analyses of short-chain fatty acids (SCFAs) confirmed that fecal butyrate concentration was significantly reduced in ME/CFS. Further, we found that the degree of deficiency in butyrate-producing bacteria correlated with fatigue symptom severity among ME/CFS subjects. Finally, we provide evidence that IBS comorbidity is an important covariate to consider in studies investigating the microbiome of ME/CFS subjects, as differences in microbiota alpha diversity, some bacterial taxa, and propionate were uniquely associated with self-reported IBS diagnosis.
Conclusions Our findings indicate that there is a core deficit in the butyrate-producing capacity of the gut microbiome in ME/CFS subjects compared to healthy controls. The relationships we observed among symptom severity and these gut microbiome disturbances may be suggestive of a pathomechanistic linkage, however, additional research is warranted to establish any causal relationship. These findings provide support for clinical trials that explore the utility of dietary, probiotic and prebiotic interventions to boost colonic butyrate production in ME/CFS.

____________________________________________________________________________________

Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by  Manuela Simonato et al
PCare Laboratory, Fondazione Istituto di Ricerca Pediatrica, Citta’ della Speranza, 35127 Padova, Italy
These authors contributed equally to this work.
Academic Editors: Masaru Tanaka and Nóra Török
Biomedicines 2021, 9(11), 1724; https://doi.org/10.3390/biomedicines9111724
Received: 16 October 2021 / Revised: 14 November 2021 / Accepted: 15 November 2021 / Published: 19 November 2021
Abstract
Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease. Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls. Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine. ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A (p = 0.018), FABP-2 (p = 0.002), and 3-hydroxykynurenine (p = 0.037) and lower levels of kynurenine (p = 0.012) and serotonin (p = 0.045) than controls. Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively. No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease. Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism. Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.
____________________________________________________________________________________

Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome following Infectious Mononucleosis
Leonard A Jason1*, et al Emails: Leonard Jason: [email protected]; 
Abstract
Background: About 10% of individuals who contract infectious mononucleosis (IM) have symptoms 6 months later that meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).  Our study for the first time examined whether it is possible to predict who will develop ME/CFS following IM.
Methods: We have reported on a prospectively recruited cohort of 4,501 college students, of which 238 (5.3%) developed IM.  Those who developed IM were followed-up at six months to determine whether they recovered or met criteria for ME/CFS. The present study focuses on 48 students who after six months had a diagnosis of ME/CFS, and a matched control group of 58 students who had no further symptoms after their IM. All of these 106 students  had data at baseline (at least 6 weeks prior to the development of IM), when experiencing IM, and 6 months following IM. Of those who did not recover from IM, there were two groups: 30 were classified as ME/CFS and 18 were classified as severe ME/CFS. We measured the results of 7 questionnaires, physical examination findings, the severity of mononucleosis and cytokine analyses at baseline (pre-illness) and at the time of IM.  We examined predictors (e.g., pre-illness variables as well as variables at onset of IM) of  those who developed ME/CFS and severe ME/CFS following IM.
Results: From analyses using receiver operating characteristic statistics, the students who had had severe gastrointestinal symptoms of stomach pain, bloating, and an irritable bowel at baseline  and who also had abnormally low levels of the immune markers IL-13 and/or IL-5 at baseline, as well as severe gastrointestinal symptoms when then contracted IM,  were found to have a nearly 80% chance of having severe ME/CFS persisting six months following IM.
Conclusions: Our findings are consistent with emerging literature that gastrointestinal distress and autonomic symptoms, along with several immune markers, may be implicated in the development of severe ME/CFS.

____________________________________________________________________________________

Deep phenotyping of myalgic encephalomyelitis/chronic fatigue syndrome in Japanese population
Toshimori Kitami, Sanae Fukuda, [...], and Yasuyoshi Watanabe
Scientific reports – Nature research
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating disease with no molecular diagnostics and no treatment options. To identify potential markers of this illness, we profiled 48 patients and 52 controls for standard laboratory tests, plasma metabolomics, blood immuno-phenotyping and transcriptomics, and fecal microbiome analysis. Here, we identified a set of 26 potential molecular markers that distinguished ME/CFS patients from healthy controls. Monocyte number, microbiome abundance, and lipoprotein profiles appeared to be the most informative markers. When we correlated these molecular changes to sleep and cognitive measurements of fatigue, we found that lipoprotein and microbiome profiles most closely correlated with sleep disruption while a different set of markers correlated with a cognitive parameter. Sleep, lipoprotein, and microbiome changes occur early during the course of illness suggesting that these markers can be examined in a larger cohort for potential biomarker application. Our study points to a cluster of sleep-related molecular changes as a prominent feature of ME/CFS in our Japanese cohort.
____________________________________________________________________________________

Physiological assessment of orthostatic intolerance in chronic fatigue syndrome
Benjamin H. Natelson, Jin-Mann S. Lin, [...], and Elizabeth R. Unger
J Transl Med. 2022; 20: 95. Published online 2022 Feb 16. doi: 10.1186/s12967-022-03289-8
PMCID: PMC8849016 PMI D: 35172863
Abstract
Background
Orthostatic intolerance-OI is common in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-ME/CFS. We used a 10-min passive vertical lean test as orthostatic challenge-OC and measured changes in vitals and end tidal CO2 (eTCO2). An abnormal physiologic response to OC was identified in 60% of the 63 patients evaluated from one to three times over several years. Hypocapnia, either resting or induced by OC, was the most frequent abnormality, followed by postural orthostatic tachycardia.

Objective
Evaluate the physiologic response of patients with ME/CFS to a standardized OC. 
Design
Respiratory and heart rate, blood pressure and eTCO2 were recorded twice at the end of 10-min supine rest and then every minute during the 10-min lean. Hypocapnia was eTCO2 ≤ 32 mmHg. Orthostatic tachycardia was heart rate increase ≥ 30 beats per minute compared with resting or ≥ 120 BPM. Orthostatic hypotension was decreased systolic pressure ≥ 20 mmHg from baseline. Tachypnea was respiratory rate of  ≥ 20 breaths per minute—either supine or leaning. Questionnaire data on symptom severity, quality of life and mood were collected at visit #2.
Patients
63 consecutive patients fulfilling the 1994 case definition for CFS underwent lean testing at first visit and then annually at visit 2 (n = 48) and 3 (n = 29).
Measures
Supine hypocapnia; orthostatic tachycardia, hypocapnia or hypotension.

Results
The majority of ME/CFS patients (60.3%, 38/63) had an abnormality detected during a lean test at any visit (51%, 50% and 45% at visits 1, 2 and 3, respectively). Hypocapnia at rest or induced by OC was more common and more likely to persist than postural orthostatic tachycardia. Anxiety scores did not differ between those with and without hypocapnia.

Conclusions
The 10-min lean test is useful in evaluation of OI in patients with ME/CFS. The most frequent abnormality, hypocapnia, would be missed without capnography.
____________________________________________________________________________________

Limbic Perfusion Is Reduced in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
by Xia Li, Per Julin, Tie-Qiang Li
Institute of Information Engineering, China Jiliang University, 258 Xueyuan Street, Xiasha Higher 
Tomography 2021, 7(4), 675-687; https://doi.org/10.3390/tomography7040056
Received: 31 August 2021 / Revised: 13 October 2021 / Accepted: 18 October 2021 / Published: 1 November 2021
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by a diverse range of debilitating symptoms including autonomic, immunologic, and cognitive dysfunction. Although neurological and cognitive aberrations have been consistently reported, relatively little is known regarding the regional cerebral blood flow (rCBF) in ME/CFS. In this study, we studied a cohort of 31 ME/CSF patients (average age: 42.8 ± 13.5 years) and 48 healthy controls (average age: 42.9 ± 12.0 years) using the pseudo-continuous arterial spin labeling (PCASL) technique on a whole-body clinical 3T MRI scanner. Besides routine clinical MRI, the protocol included a session of over 8 min-long rCBF measurement. The differences in the rCBF between the ME/CSF patients and healthy controls were statistically assessed with voxel-wise and AAL ROI-based two-sample t-tests. Linear regression analysis was also performed on the rCBF data by using the symptom severity score as the main regressor. In comparison with the healthy controls, the patient group showed significant hypoperfusion (uncorrected voxel wise p ≤ 0.001, FWE p ≤ 0.01) in several brain regions of the limbic system, including the anterior cingulate cortex, putamen, pallidum, and anterior ventral insular area. For the ME/CFS patients, the overall symptom severity score at rest was significantly associated with a reduced rCBF in the anterior cingulate cortex. The results of this study show that brain blood flow abnormalities in the limbic system may contribute to ME/CFS pathogenesis.
Keywords: chronic fatigue syndrome; regional cerebral blood flow; pseudo-continuous arterial spin labeling; sustained attention; magnetic resonance imaging; limbic system
Front. Neurol., 13 December 2021 | https://doi.org/10.3389/fneur.2021.789784

____________________________________________________________________________________

Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Dominic Stanculescu1, Nuno Sepúlveda2,3, Chin Leong Lim4 and Jonas Bergquist5,6*
  • 1Independent Researcher, Sint Martens Latem, Belgium
  • 6The ME/CFS Collaborative Research Center at Uppsala University, Uppsala, Sweden
We here provide an overview of the pathophysiological mechanisms during heat stroke and describe similar mechanisms found in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Both conditions are characterized by disturbed homeostasis in which inflammatory pathways play a central role. Splanchnic vasoconstriction, increased gut permeability, gut-related endotoxemia, systemic inflammatory response, central nervous system dysfunction, blood coagulation disorder, endothelial-cell injury, and mitochondrial dysfunction underlie heat stroke. These mechanisms have also been documented in ME/CFS. Moreover, initial transcriptomic studies suggest that similar gene expressions are altered in both heat stroke and ME/CFS. Finally, some predisposing factors for heat stroke, such as pre-existing inflammation or infection, overlap with those for ME/CFS. Notwithstanding important differences - and despite heat stroke being an acute condition - the overlaps between heat stroke and ME/CFS suggest common pathways in the physiological responses to very different forms of stressors, which are manifested in different clinical outcomes. The human studies and animal models of heat stroke provide an explanation for the self-perpetuation of homeostatic imbalance centered around intestinal wall injury, which could also inform the understanding of ME/CFS. Moreover, the studies of novel therapeutics for heat stroke might provide new avenues for the treatment of ME/CFS. Future research should be conducted to investigate the similarities between heat stroke and ME/CFS to help identify the potential treatments for ME/CFS.
Journal of Advanced Research
____________________________________________________________________________________

Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome
Author links open overlay panelOlga A.Sukochevaab1RebekahMaksoudbc1Narasimha M.BeerakadSabbaRao V.MadhunapantuladeMikhailSinelnikovfVladimir N.NikolenkofMargarita E.NeganovagSergey G.KlochkovgMohammadAmjad KamalhiDonald RStainesbcSonyaMarshall-Gradisnikbc
https://doi.org/10.1016/j.jare.2021.11.013Get rights and content
Abstract
Background
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease (COVID-19) triggers the development of numerous pathologies and infection-linked complications and exacerbates existing pathologies in nearly all body systems. Aside from the primarily targeted respiratory organs, adverse SARS-CoV-2 effects were observed in nervous, cardiovascular, gastrointestinal/metabolic, immune, and other systems in COVID-19 survivors. Long-term effects of this viral infection have been recently observed and represent distressing sequelae recognised by the World Health Organisation (WHO) as a distinct clinical entity defined as post-COVID-19 condition. Considering the pandemic is still ongoing, more time is required to confirm post COVID-19 condition diagnosis in the COVID-19 infected cohorts, although many reported post COVID-19 symptoms overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Aims of Review
In this study, COVID-19 clinical presentation and associated post-infection sequelae (post-COVID-19 condition) were reviewed and compared with ME/CFS symptomatology.
Key Scientific Concepts of Review
The onset, progression, and symptom profile of post COVID-19 condition patients have considerable overlap with ME/CFS. Considering the large scope and range of pro-inflammatory effects of this virus, it is reasonable to expect development of post COVID-19 clinical complications in a proportion of the affected population. There are reports of a later debilitating syndrome onset three months post COVID-19 infection (often described as long-COVID-19), marked by the presence of fatigue, headache, cognitive dysfunction, post-exertional malaise, orthostatic intolerance, and dyspnoea. Acute inflammation, oxidative stress, and increased levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), have been reported in SARS-CoV-2 infected patients. Longitudinal monitoring of post COVID-19 patients is warranted to understand the long-term effects of SARS-CoV-2 infection and the pathomechanism of post COVID-19 condition.

____________________________________________________________________________________

Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts
Daniel Missailidis 1, Oana Sanislav 1, Claire Y Allan 1, Paige K Smith 2, Sarah J Annesley 1, Paul R Fisher 1
PMID: 33669532 PMCID: PMC7921983  DOI: 10.3390/ijms22042046
Int J Mol Sci. 2021 Feb 19;22(4):2046.
Abstract
Although understanding of the biomedical basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is growing, the underlying pathological mechanisms remain uncertain. We recently reported a reduction in the proportion of basal oxygen consumption due to ATP synthesis by Complex V in ME/CFS patient-derived lymphoblast cell lines, suggesting mitochondrial respiratory inefficiency. This was accompanied by elevated respiratory capacity, elevated mammalian target of rapamycin complex 1 (mTORC1) signaling activity and elevated expression of enzymes involved in the TCA cycle, fatty acid β-oxidation and mitochondrial transport. These and other observations led us to hypothesise the dysregulation of pathways providing the mitochondria with oxidisable substrates. In our current study, we aimed to revisit this hypothesis by applying a combination of whole-cell transcriptomics, proteomics and energy stress signaling activity measures using subsets of up to 34 ME/CFS and 31 healthy control lymphoblast cell lines from our growing library. While levels of glycolytic enzymes were unchanged in accordance with our previous observations of unaltered glycolytic rates, the whole-cell proteomes of ME/CFS lymphoblasts contained elevated levels of enzymes involved in the TCA cycle (p = 1.03 × 10-4), the pentose phosphate pathway (p = 0.034, G6PD p = 5.5 × 10-4), mitochondrial fatty acid β-oxidation (p = 9.2 × 10-3), and degradation of amino acids including glutamine/glutamate (GLS p = 0.034, GLUD1 p = 0.048, GOT2 p = 0.026), branched-chain amino acids (BCKDHA p = 0.028, BCKDHB p = 0.031) and essential amino acids (FAH p = 0.036, GCDH p = 0.006). The activity of the major cellular energy stress sensor, AMPK, was elevated but the increase did not reach statistical significance. The results suggest that ME/CFS metabolism is dysregulated such that alternatives to glycolysis are more heavily utilised than in controls to provide the mitochondria with oxidisable substrates.
Keywords: ME/CFS; Myalgic Encephalomyelitis; TCA cycle; amino acid catabolism; beta-oxidation; glycolysis; metabolism; mitochondria; proteomics; transcriptomics.



0 Comments

Abstracts from 1 Dec 2021

1/12/2021

0 Comments

 
Stellate ganglion block reduces symptoms of Long COVID: A case series 
Short communication – Journal of neuroimmunology
Luke D. Liu, Deborah L. Duricka * Neuroversion Inc., Anchorage, AK, USA ARTICLE INFO
 Keywords: Long COVID/PASC Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) Postural orthopedic tachycardia syndrome (POTS) Dysautonomia Stellate ganglion block Cerebral blood flow

 ABSTRACT After recovering from COVID-19, a significant proportion of symptomatic and asymptomatic individuals develop Long COVID. Fatigue, orthostatic intolerance, brain fog, anosmia, and ageusia/dysgeusia in Long COVID resemble “sickness behavior,” the autonomic nervous system response to pro-inflammatory cytokines (Dantzer et al., 2008). Aberrant network adaptation to sympathetic/parasympathetic imbalance is expected to produce long-standing dysautonomia. Cervical sympathetic chain activity can be blocked with local anesthetic, allowing the regional autonomic nervous system to “reboot.” In this case series, we successfully treated two Long COVID patients using stellate ganglion block, implicating dysautonomia in the pathophysiology of Long COVID and suggesting a novel treatment.

__________________________________________________________________________________

Post COVID-19 syndrome associated with orthostatic cerebral hypoperfusion syndrome, small fiber neuropathy and benefit of immunotherapy: a case report
Peter Novak 1
eNeurologicalSci  . 2020 Dec;21:100276.
 doi: 10.1016/j.ensci.2020.100276. Epub 2020 Sep 20.
PMID: 32984564PMCID: PMC7502253
Abstract
Coronavirus disease (COVID-19) is a novel highly contagious infectious disease caused by the coronavirus SARS-CoV2. The virus affects the human respiratory and other systems, and presents mostly as acute respiratory syndrome with fever, fatigue, dry cough, myalgia and dyspnea. The clinical manifestations vary from no symptoms to multiple organ failure. Majority of patients fully recover. Several postinfectious presumably autoimmune complications of COVID-19 affecting the brain or peripheral large nerve fibers have been reported. This report describes a post COVID-19 patient who developed chronic fatigue, orthostatic dizziness and brain fog consistent with orthostatic hypoperfusion syndrome (OCHOS), a form of orthostatic intolerance, and painful small fiber neuropathy (SFN). Initially, the patient was diagnosed with. OCHOS (detected by the tilt test with transcranial Doppler monitoring) and SFN (confirmed by skin biopsy), and both OCHOS/SFN were attributed to Post Treatment Lyme Disease Syndrome of presumed autoimmune etiology. Patient recovered on symptomatic therapy. COVID-19 triggered exacerbation of OCHOS/SFN responded to immunotherapy with intravenous immunoglobulins. This case suggests that post COVID-19 syndrome may present as an autoimmune OCHOS/SFN and that early immunotherapy may be effective. Further studies are necessary to confirm the link between OCHOS/SFN and COVID-19 disease as well as to confirm the benefit of immunotherapy.
© 2020 Published by Elsevier B.V.


​__________________________________________________________________________________

PLoS One
 2019 Feb 12;14(2):e0212222. doi: 10.1371/journal.pone.0212222. eCollection 2019.
Association of small fiber neuropathy and post treatment Lyme disease syndrome
Peter Novak 1, Donna Felsenstein 2, Charlotte Mao 3, Nadlyne R Octavien 4, Nevena Zubcevik 5
PMID: 30753241  PMCID: PMC6372188


Abstract
Objectives: To examine whether post-treatment Lyme disease syndrome (PTLDS) defined by fatigue, cognitive complaints and widespread pain following the treatment of Lyme disease is associated with small fiber neuropathy (SFN) manifesting as autonomic and sensory dysfunction.
Methods: This single center, retrospective study evaluated subjects with PTLDS. Skin biopsies for assessment of epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD) and functional autonomic testing (deep breathing, Valsalva maneuver and tilt test) were performed to assess SFN, severity of dysautonomia and cerebral blood flow abnormalities. Heart rate, end tidal CO2, blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery using transcranial Doppler were monitored.
Results: 10 participants, 5/5 women/men, age 51.3 ± 14.7 years, BMI 27.6 ± 7.3 were analyzed. All participants were positive for Lyme infection by CDC criteria. At least one skin biopsy was abnormal in all ten participants. Abnormal ENFD was found in 9 participants, abnormal SGNFD in 5 participants, and both abnormal ENFD and SGNFD were detected in 4 participants. Parasympathetic failure was found in 7 participants and mild or moderate sympathetic adrenergic failure in all participants. Abnormal total CBFv score was found in all ten participants. Low orthostatic CBFv was found in 7 participants, three additional participants had abnormally reduced supine CBFv.
Conclusions: SFN appears to be associated with PTLDS and may be responsible for certain sensory symptoms. In addition, dysautonomia related to SFN and abnormal CBFv also seem to be linked to PTLDS. Reduced orthostatic CBFv can be associated with cerebral hypoperfusion and may lead to cognitive dysfunction. Autonomic failure detected in PTLDS is mild to moderate. SFN evaluation may be useful in PTLDS.

​__________________________________________________________________________________

Diverse functional autoantibodies in patients with COVID-19
Eric Y Wang # 1, Tianyang Mao # 1, Jon Klein # 1, Yile Dai # 1, John D Huck 1, Jillian R Jaycox 1, Feimei Liu 1, Ting Zhou 1, Benjamin Israelow 1, Patrick Wong 1, Andreas Coppi 2, Carolina Lucas 1, Julio Silva 1, Ji Eun Oh 1, Eric Song 1, Emily S Perotti 1, Neil S Zheng 1, Suzanne Fischer 1, Melissa Campbell 3, John B Fournier 3, Anne L Wyllie 4, Chantal B F Vogels 4, Isabel M Ott 4, Chaney C Kalinich 4, Mary E Petrone 4, Anne E Watkins 4, Yale IMPACT Team; Charles Dela Cruz 5, Shelli F Farhadian 3, Wade L Schulz 2 6, Shuangge Ma 7, Nathan D Grubaugh 4, Albert I Ko 3 4, Akiko Iwasaki 8 9 10, Aaron M Ring 11 12
PMID: 34010947   DOI: 10.1038/s41586-021-03631-y
Nature   2021 Jul;595(7866):283-288.  doi: 10.1038/s41586-021-03631-y. Epub 2021 May 19
Abstract
COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1-6. Although pathological innate immune activation is well-documented in severe disease1, the effect of autoantibodies on disease progression is less well-defined. Here we use a high-throughput autoantibody discovery technique known as rapid extracellular antigen profiling7 to screen a cohort of 194 individuals infected with SARS-CoV-2, comprising 172 patients with COVID-19 and 22 healthcare workers with mild disease or asymptomatic infection, for autoantibodies against 2,770 extracellular and secreted proteins (members of the exoproteome). We found that patients with COVID-19 exhibit marked increases in autoantibody reactivities as compared to uninfected individuals, and show a high prevalence of autoantibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins). We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signalling and by altering peripheral immune cell composition, and found that mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infection. Our analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics. Our findings suggest a pathological role for exoproteome-directed autoantibodies in COVID-19, with diverse effects on immune functionality and associations with clinical outcomes.

​__________________________________________________________________________________

ORIGINAL RESEARCH article
Front. Syst. Neurosci., 01 September 2021 | https://doi.org/10.3389/fnsys.2021.698240
Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Gerard Pereira1*, Hunter Gillies1, Sanjay Chanda1, Michael Corbett1, Suzanne D. Vernon2, Tina Milani2 and Lucinda Bateman2
Cortene Inc., Burlingame, CA, United States 2Bateman Horne Center, Salt Lake City, UT, 
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.
Materials and Methods: This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.
Results: ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.
Conclusion: The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.
International Journal of Environmental Research and Public Health

​__________________________________________________________________________________

Impact of Life Stressors on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symptoms: An Australian Longitudinal Study 
Cassandra Balinas 1,2,3,†, Natalie Eaton-Fitch 1,2,3,†, Rebekah Maksoud 1,2,* ,† , Donald Staines 1,2 and Sonya Marshall-Gradisnik 1,2   Citation: Balinas, C.; Eaton-Fitch, N.; Maksoud, R.; Staines, D.; Marshall-Gradisnik, S. Impact of Life Stressors on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symptoms: An Australian Longitudinal Study. Int. J. Environ. Res. Public Health 2021, 18, 10614. https://doi.org/10.3390/ ijerph182010614 Academic Editor: Paul B. Tchounwou Received: 1 September 2021 Accepted: 6 October 2021 Published: 11 October 2021 
The National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast 4215, Australia; 
Abstract: (1) Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multifaceted illness. The pathomechanism, severity and progression of this illness is still being investigated. Stressors have been implicated in symptom exacerbation for ME/CFS, however, there is limited information for an Australian ME/CFS cohort. The aim of this study was to assess the potential effect of life stressors including changes in work, income, or family scenario on symptom severity in an Australian ME/CFS cohort over five months; (2) Methods: Australian residents with ME/CFS responded to questions relating to work, income, living arrangement, access to healthcare and support services as well as symptoms experienced; (3) Results: thirty-six ME/CFS patients (age: 41.25 ± 12.14) completed all questionnaires (response rate 83.7%). Muscle pain and weakness, orthostatic intolerance and intolerance to extreme temperatures were experienced and fluctuated over time. Sleep disturbances were likely to present as severe. Work and household income were associated with worsened cognitive, gastrointestinal, body pain and sleep symptoms. Increased access to healthcare services was associated with improved symptom presentation; (4) Conclusions: life stressors such as work and financial disruptions may significantly contribute to exacerbation of ME/CFS symptoms. Access to support services correlates with lower symptom scores. 

​__________________________________________________________________________________

The impact of COVID-19 critical illness on new disability, functional outcomes and return to work at 6 months: a prospective cohort study
Carol L. Hodgson, Alisa M. Higgins, 
The COVID-Recovery Study Investigators and the ANZICS Clinical Trials Group
Critical Care volume 25, Article number: 382 (2021)  Published: 08 November 2021

Abstract
Background
There are few reports of new functional impairment following critical illness from COVID-19. We aimed to describe the incidence of death or new disability, functional impairment and changes in health-related quality of life of patients after COVID-19 critical illness at 6 months.
Methods
In a nationally representative, multicenter, prospective cohort study of COVID-19 critical illness, we determined the prevalence of death or new disability at 6 months, the primary outcome. We measured mortality, new disability and return to work with changes in the World Health Organization Disability Assessment Schedule 2.0 12L (WHODAS) and health status with the EQ5D-5LTM.
Results
Of 274 eligible patients, 212 were enrolled from 30 hospitals. The median age was 61 (51–70) years, and 124 (58.5%) patients were male. At 6 months, 43/160 (26.9%) patients died and 42/108 (38.9%) responding survivors reported new disability. Compared to pre-illness, the WHODAS percentage score worsened (mean difference (MD), 10.40% [95% CI 7.06–13.77]; p < 0.001). Thirteen (11.4%) survivors had not returned to work due to poor health. There was a decrease in the EQ-5D-5LTM utility score (MD, − 0.19 [− 0.28 to − 0.10]; p < 0.001). At 6 months, 82 of 115 (71.3%) patients reported persistent symptoms. The independent predictors of death or new disability were higher severity of illness and increased frailty.
Conclusions
At six months after COVID-19 critical illness, death and new disability was substantial. Over a third of survivors had new disability, which was widespread across all areas of functioning.
Clinical trial registration NCT04401254 May 26, 2020.

​__________________________________________________________________________________

Submaximal Exercise Provokes Increased Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of Postexertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Rakib U. Rayhan and James N. Baraniuk
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue and postexertiona*l malaise. We developed a provocation paradigm with two submaximal bicycle exercise stress tests on consecutive days bracketed by magnetic resonance imaging, orthostatic intolerance, and symptom assessments before and after exercise in order to induce objective changes of exercise induced symptom exacerbation and cognitive dysfunction.
Method: Blood oxygenation level dependent (BOLD) scans were performed while at rest on the preexercise and postexercise days in 34 ME/CFS and 24 control subjects. Seed regions from the FSL data library with significant BOLD signals were nodes that clustered into networks using independent component analysis. Differences in signal amplitudes between groups on pre- and post-exercise days were determined by general linear model and ANOVA.
Results: The most striking exercise-induced effect in ME/CFS was the increased spontaneous activity in the medial prefrontal cortex that is the anterior node of the Default Mode Network (DMN). In contrast, this region had decreased activation for controls. Overall, controls had higher BOLD signals suggesting reduced global cerebral blood flow in ME/CFS.
Conclusion: The dynamic increase in activation of the anterior DMN node after exercise may be a biomarker of postexertional malaise and symptom exacerbation in CFS. The specificity of this postexertional finding in ME/CFS can now be assessed by comparison to post-COVID fatigue, Gulf War Illness, fibromyalgia, chronic idiopathic fatigue, and fatigue in systemic medical and psychiatric diseases.
Keywords: postexertional malaise, default mode network, DMN, blood oxygenation level dependent, BOLD, fibromyalgia, chronic idiopathic fatigue, submaximal exercise

​__________________________________________________________________________________

Insights into Metabolite Diagnostic Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Emi Yamano, Yasuyoshi Watanabe, and Yosky Kataoka
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, and with a minimum duration of 6 consecutive months. Its pathogenesis is not fully understood. There are no firmly established diagnostic biomarkers or treatment, due to incomplete understanding of the etiology of ME/CFS and diagnostic uncertainty. Establishing a biomarker for the objective diagnosis is urgently needed to treat a lot of patients. Recently, research on ME/CFS using metabolome analysis methods has been increasing. Here, we overview recent findings concerning the metabolic features in patients with ME/CFS and the animal models which contribute to the development of diagnostic biomarkers for ME/CFS and its treatment. In addition, we discuss future perspectives of studies on ME/CFS.
Keywords: ME/CFS, etiology, biomarker, metabolome, objective diagnosis

​__________________________________________________________________________________

TRYPTOPHAN METABOLITES, CYTOKINES, AND FATTY ACID BINDING PROTEIN 2 IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME –
 PROF. ALDO BARITUSSIO ET AL
Abstract
Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease.
Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls.
Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine.
ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A (p = 0.018), FABP-2 (p = 0.002), and 3-hydroxykynurenine (p = 0.037) and lower levels of kynurenine (p = 0.012) and serotonin (p = 0.045) than controls.
Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively.
No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease.
Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism.
Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.

​__________________________________________________________________________________

BACK TO THE FUTURE? IMMUNOGLOBULIN THERAPY FOR MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME
Helen Brownlie and Nigel Speight
ABSTRACT
The findings of controlled trials on use of intravenous immunoglobulin G (IV IgG) to treat myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are generally viewed as representing mixed results. On detailed review, a clearer picture emerges, which suggests that the potential therapeutic value of this intervention has been underestimated.
Our analysis is consistent with the propositions that:
(1) IgG is highly effective for a proportion of patients with severe and well-characterised ME/CFS;
(2) responders can be predicted with a high degree of accuracy based on markers of immune dysfunction.
Rigorous steps were taken in the research trials to record adverse events, with transient symptom exacerbation commonly experienced in both intervention and placebo control groups, suggesting that this reflected the impact of participation on people with an illness characterised by post-exertional symptom exacerbation.
Worsening of certain specific symptoms, notably headache, did occur more commonly with IgG and may have been concomitant to effective treatment, being associated with clinical improvement.
The findings emerging from this review are supported by clinical observations relating to treatment of patients with severe and very severe ME/CFS, for whom intramuscular and subcutaneous administration provide alternative options.
We conclude that:  (1) there is a strong case for this area of research to be revived;
(2) pending further research, clinicians would be justified in offering a course of IgG to selected ME/CFS patients at the more severe end of the spectrum.   As the majority of trial participants had experienced an acute viral or viral-like onset, we further suggest that IgG treatment may be pertinent to the care of some patients who remain ill following infection with SARS-CoV-2 virus
Free full text: Healthcare

​__________________________________________________________________________________

A Possible Role for Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination       published on November 24, 2021, at NEJM.org.
 William J. Murphy, Ph.D., and Dan L. Longo, M.D.


The pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is incompletely understood, with its effects on multiple organ systems1 and the syndrome of “long Covid” occurring long after the resolution of infection.2 The development of multiple efficacious vaccines has been critical in the control of the pandemic, but their efficacy has been limited by the appearance of viral variants, and the vaccines can be associated with rare off-target or toxic effects, including allergic reactions, myocarditis, and immune-mediated thrombosis and thrombocytopenia in some healthy adults. Many of these phenomena are likely to be immune-mediated.3 How can we understand this diversity in immune responses in different persons?
One way of thinking about the complexity of the immune response is through the lens of anti-idiotype immune responses. The Network Hypothesis, formulated in 1974 by Niels Jerne, described a mechanism by which the antibody responses to an antigen themselves induced downstream antibody responses against the antigen-specific antibody.4 Every antibody that is induced and specific for an antigen (termed “Ab1” antibody) has immunogenic regions, particularly in their variable-region antigen-binding domains, that are unique as a result of genetic recombination of immunoglobulin variable, diversity, and joining (VDJ) genes; VDJ recombination results in new and therefore immunogenic amino acid sequences called idiotopes, which are then capable of inducing specific antibodies against Ab1 antibodies as a form of down-regulation. A similar paradigm has been proposed for T cells. However, these regulatory immune responses are also capable of doing much more. The paratopes, or antigen-binding domains, of some of the resulting anti-idiotype (or “Ab2”) antibodies that are specific for Ab1 can structurally resemble that of the original antigens themselves. Thus, the Ab2 antigen-binding region can potentially represent an exact mirror image of the initial targeted antigen in the Ab1 response, and Ab2 antibodies have even been examined for potential use as a surrogate for the antigen in vaccine studies. However, as a result of this mimicry, Ab2 antibodies also have the potential to bind the same receptor that the original antigen was targeting (Figure 1). Ab2 antibodies binding to the original receptor on normal cells therefore have the potential to mediate profound effects on the cell that could result in pathologic changes, particularly in the long term — long after the original antigen itself has disappeared.
This aspect of regulation of immune-cell responses was postulated by Plotz in 1983 as a possible cause of autoimmunity arising after viral infection5 and has since been supported experimentally by direct transfer of anti-idiotype antibodies. Ab2 antibodies generated against the enterovirus coxsackievirus B3 in mice can bind myocyte antigens, resulting in autoimmune myocarditis,6 and anti-idiotype responses can act as acetylcholine receptor agonists, leading to myasthenia gravis symptoms in rabbits.7 In addition, by displaying the mirror image of the viral antigen, Ab2 alone can even mimic the deleterious effects of the virus particle itself, as has been shown with bovine viral diarrhea virus antigen.8
For SARS-CoV-2 infection, attention centers on the spike (S) protein and its critical use of the angiotensin-converting–enzyme 2 (ACE2) receptor to gain entry into the cell. Given its critical role in regulating angiotensin responses, many physiological effects can be influenced by ACE2 engagement.9 The S protein itself has a direct effect on suppressing ACE2 signaling by a variety of mechanisms and can also directly trigger toll-like receptors and induce inflammatory cytokines.10 Anti-idiotype responses may affect ACE2 function, resulting in similar effects. However, preclinical and clinical assessments of antibody responses to SARS-CoV-2 vaccines have focused solely on Ab1 responses and virus-neutralizing efficacy. The delineation of potential anti-idiotype responses has inherent difficulties because of the polyclonal nature of responses, dynamic kinetics, and the concurrent presence of both Ab1 and Ab2 antibodies. Furthermore, ACE2 expression within cells and tissues can be variable. The different vaccine constructs (RNA, DNA, adenoviral, and protein) are also likely to have differential effects on Ab2 induction or in the mediation of vaccine effects that differ from responses to infection. Some off-target effects may not be directly linked to Ab2 responses. The association of thrombotic events with some SARS-CoV-2 vaccines in young women and the etiologic role of anti–platelet factor 4–polyanion antibodies may be the result of the adenoviral vector. However, the reported occurrence of myocarditis after vaccine administration bears striking similarities to the myocarditis associated with Ab2 antibodies induced after some viral infections.6 Ab2 antibodies could also mediate neurologic effects of SARS-CoV-2 infection or vaccines, given the expression of ACE2 on neuronal tissues, the specific neuropathologic effects of SARS-CoV-2 infection,11 and the similarity of these effects to Ab2-mediated neurologic effects observed in other viral models.
It would therefore be prudent to fully characterize all antibody and T-cell responses to the virus and the vaccines, including Ab2 responses over time. Using huACE2 transgenic mice and crossing them with strains that are predisposed to autoimmunity or other human pathologic conditions can also provide important insights. An understanding of potential Ab2 responses may also provide insights into Ab1 maintenance and efficacy and into the application of antibody-based therapeutic agents. However, much more basic science research is needed to determine the potential role idiotype-based immunoregulation of both humoral and cell-mediated responses may play both in antiviral efficacy and in unwanted side effects of both SARS-CoV-2 infection and the vaccines that protect us from it.

​__________________________________________________________________________________

Graded exercise therapy for ME/CFS: finding consensus between the royal colleges, patients, and researchers
BMJ 2021; 375 doi: https://doi.org/10.1136/bmj.n3026 (Published 08 December 2021)Cite this as: BMJ 2021;375:n3026
The BMJ reports the royal colleges’ discontent with the new National Institute for Health and Care Excellence guideline on myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS), particularly regarding graded exercise therapy (GET).12 The quality of the evidence and the rigour of its assessment are contested by the colleges, patient representatives, and researchers.34 In summary, the colleges emphasise the potential benefits of exercise for patients with ME/CFS, the patient community emphasises the potential harm that exercise can cause, and both communities quote research supporting their hypotheses, the quality of which is contested. Is there any agreement on the guideline?
Consider a patient with ME/CFS who, after attempting a therapy based on exercise, reports a worsening of their symptoms, sequelae which they regard as harmful. Should the treating physician interpret this as “the bodies [sic] normal response” and press on? Or should they defer to the NICE assertion that “treatment programmes that result in symptom exacerbation are not recommended” and abandon exercise based approaches?5
The guideline is quite clear: “Health and social care professionals should take time to build supportive, trusting, and empathetic relationships.” Trust cannot be achieved if a patient believes the prescribed treatment is causing them harm. Surely royal colleges, researchers, and patients can all agree on this?

​__________________________________________________________________________________

SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19
Lize M. Grobbelaar, Sample analysis, Visualization, Writing—original draft, Chantelle Venter, Data curation, Project administration, [...], and Etheresia Pretorius, 
Bioscience reports Volume 41, Issue 8 – August 2021
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients. Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation.
Using platelet-poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to β and γ fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1. Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.
Keywords: COVID-19, electron microscopy, Fibrin(ogen), fluorescence microscopy, Microclot, Spike protein Sa

​__________________________________________________________________________________

MEDICAL NEWS: New metabolic phenotype of long COVID identified
Heather Mason   |   18 January 2022
A potential new cluster phenotype for patients with post-acute COVID syndrome (PACS) is described in an article published in Open Forum Infectious Diseases, which reports on the prevalence of this metabolic-associated fatty liver disease (MAFLD) phenotype.
The analysis included 235 patients who were followed at a single university outpatient clinic. The primary outcome was the prevalence of MAFLD, detected by transient elastography, during the first post-discharge follow-up visit, compared with the MAFLD prevalence at the time of hospital admission. Figures were calculated retrospectively using the hepatic steatosis index.
The results showed that the prevalence of MAFLD was 55.3 per cent at follow-up and 37.3 per cent on admission. Among the independent predictors of MAFLD were insulin resistance (odds ratio [OR] 1.5), body mass index (OR 1.14), and metabolic syndrome (OR 2.54).
Regarding a possible link with other clusters, the researchers found that MAFLD had weak or very weak associations, indicating that it may represent an independent PACS cluster, with potential metabolic and cardiovascular health consequences in the long-COVID-19.
The authors highlight the importance of careful follow-up of patients with MAFLD in the context of PACS since it is necessary to understand the clinical implications of this syndrome.

​__________________________________________________________________________________

Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis
KJETIL BJORNEVIK HTTPS://ORCID.ORG/0000-0002-2892-6986MARIANNA CORTESE HTTPS://ORCID.ORG/0000-0002-3665-2006BRIAN C. HEALY HTTPS://ORCID.ORG/0000-0001-5272-2425JENS KUHLEMICHAEL J. MINA HTTPS://ORCID.ORG/0000-0002-0674-5762YUMEI LENG HTTPS://ORCID.ORG/0000-0003-2512-9284STEPHEN J. ELLEDGE HTTPS://ORCID.ORG/0000-0001-7923-6283DAVID W. NIEBUHRANN I. SCHER[...]ALBERTO ASCHERIO  
SCIENCE • 13 Jan 2022 • Vol 375, Issue 6578 • pp. 296-301 • DOI: 10.1126/science.abj8222
Stronger evidence for viral connection
Multiple sclerosis is a chronic demyelinating disease of the central nervous system. The underlying cause of this disease is not known, but Epstein-Barr virus is thought to be a possible culprit. However, most people infected with this common virus do not develop multiple sclerosis, and it is not feasible to directly demonstrate causation of this disease in humans. Using data from millions of US military recruits monitored over a 20-year period, Bjornevik et al. determined that Epstein-Barr virus infection greatly increased the risk of subsequent multiple sclerosis and that it preceded the development of disease, supporting its potential role in the pathogenesis of multiple sclerosis (see the Perspective by Robinson and Steinman). —YN
Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

​__________________________________________________________________________________

FDA OKs New Adult Insomnia Med  - Medscape medical news
Erik Greb
January 10, 2022
The US Food and Drug Administration (FDA) has approved the dual orexin receptor antagonist daridorexant (Quviviq) for the treatment of insomnia in adults, the drug's manufacturer, Idorsia, has announced.
The FDA's decision was based partly on a phase 3 trial of adults with moderate-to-severe insomnia who were randomly assigned to receive 25 or 50 mg of daridorexant or matching placebo. Daridorexant was associated with dose-dependent improvements in wake after sleep onset, total sleep time, and latency to persistent sleep.
Whereas the overall results are very positive, the improvements in daytime functioning are especially "exciting," Thomas Roth, PhD, director of the Sleep Disorders and Research Center at Henry Ford Hospital in Detroit, Michigan, told Medscape Medical News.
"That's sort of a big deal. For me, that's the biggest deal there is," said Roth, who was a consultant on the design of the phase 3 trial and on the interpretation of the data.
The drug will be available in doses of 25 mg and 50 mg, and the FDA has recommended that it be classified as a controlled substance. After it is scheduled by the US Drug Enforcement Administration, daridorexant is expected to be made available in May.


Favorable Safety Profile
Insomnia is a common disorder characterized by difficulty falling asleep or staying asleep and by early morning awakenings. Patients with insomnia often report fatigue, irritability, and difficulty with concentration. The condition can also result in significant problems with work and social activities, thus contributing to anxiety or depression.
As with other dual orexin receptor antagonists, daridorexant competitively binds with both orexin receptors in the lateral hypothalamus to block the activity of orexin in a reversible way. This approach decreases the downstream action of the wake-promoting neurotransmitters that are overactive in patients with insomnia.
The phase 3 trial measured daytime functioning using the new Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), a patient-reported outcome instrument. Daridorexant was associated with significant improvements in daytime function, particularly in sleepiness and mood.
Previous trials of other dual orexin receptor antagonists did not use the IDSIQ as an outcome, so it is not possible to compare daridorexant with those drugs in this respect, Roth noted. Researchers also have not conducted head-to-head trials of the drug with other dual orexin receptor antagonists.
Daridorexant also had a favorable safety profile and was not associated with rebound insomnia or withdrawal effects. The most common adverse events were headache and somnolence or fatigue.
"They had no effect on sleep stage distribution [and] they had no significant effects on sleep and breathing in people with mild to moderate sleep apnea," said Roth, who presented the phase 3 findings at SLEEP 2020. 

​__________________________________________________________________________________

The Lancet: ARTICLES| VOLUME 21, ISSUE 2, P125-139, FEBRUARY 01, 2022
Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials
  • Prof Emmanuel Mignot, MD  David Mayleben, PhD Prof Ingo Fietze, MD Damien Leger, MD Gary Zammit, PhD Claudio L A Bassetti, MD et al.
Published:February, 2022DOI:https://doi.org/10.1016/S1474-4422(21)00436-1
Summary
Background
Daytime functioning is impaired in people with insomnia disorder. Currently available dual orexin receptor antagonists have shown efficacy in insomnia disorder, but do not address all aspects of this disease. We aimed to assess safety and efficacy of daridorexant, a novel orexin receptor antagonist, on night-time and daytime symptoms of insomnia.
Methods
We did two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials at 156 sites in 17 countries. Adults (aged ≥18 years) with insomnia disorder were randomly assigned using interactive response technology (1:1:1) to receive daridorexant 50 mg, 25 mg, or placebo (study 1) or daridorexant 25 mg, 10 mg, or placebo (study 2) every evening for 3 months. Participants, investigators, and site personnel were masked to treatment allocation. The primary endpoints were change from baseline in wake time after sleep onset (WASO) and latency to persistent sleep (LPS), measured by polysomnography, at months 1 and 3. The secondary endpoints were change from baseline in self-reported total sleep time and the sleepiness domain score of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) at months 1 and 3. Study-wise type I error rate (5%) was controlled for all pairwise comparisons. Efficacy was analysed in all randomly assigned participants, and safety in all participants who received at least one dose of treatment. The studies are registered at ClinicalTrials.gov, NCT03545191 (study 1) and NCT03575104 (study 2).
Findings
Between June 4, 2018 and Feb 25, 2020, 930 participants were randomly assigned to receive daridorexant 50 mg (n=310), daridorexant 25 mg (n=310), or placebo (n=310) in study 1. Between May 29, 2018, and May 14, 2020, 924 participants were randomly assigned to receive daridorexant 25 mg (n=309), daridorexant 10 mg (n=307), or placebo (n=308) in study 2. In study 1, WASO and LPS were significantly reduced among participants in the daridorexant 50 mg group compared with participants in the placebo group at month 1 (least squares mean [LSM] difference −22·8 min [95% CI −28·0 to −17·6], p<0·0001 for WASO; –11·4 min [−16·0 to −6·7], p<0·0001 for LPS) and month 3 (−18·3 min [−23·9 to −12·7], p<0·0001 for WASO; −11·7 min [−16·3 to −7·0], p<0·0001 for LPS). WASO and LPS were significantly reduced among participants in the daridorexant 25 mg group compared with the placebo group at month 1 (LSM difference −12·2 min [−17·4 to −7·0], p<0·0001 for WASO; –8·3 min [−13·0 to −3·6], p=0·0005 for LPS) and month 3 (−11·9 min [−17·5 to −6·2], p<0·0001 for WASO; −7·6 min [−12·3 to −2·9], p=0·0015 for LPS). Compared with placebo, participants in the daridorexant 50 mg group had significantly improved self-reported total sleep time at month 1 (LSM difference 22·1 min [14·4 to 29·7], p<0·0001) and month 3 (19·8 min [10·6 to 28·9], p<0·0001), and IDSIQ sleepiness domain scores at month 1 (–1·8 [–2·5 to –1·0], p<0·0001) and month 3 (–1·9 [–2·9 to –0·9], p=0·0002). Compared with the placebo group, participants in the daridorexant 25 mg group had significantly improved self-reported total sleep time at month 1 (LSM difference 12·6 min [5·0 to 20·3], p=0·0013) and month 3 (9·9 min [0·8 to 19·1], p=0·033), but not IDSIQ sleepiness domain scores (–0·8 [–1·5 to 0·01], p=0·055 at month 1; –1·0 [–2·0 to 0·01], p=0·053 at month 3). In study 2, WASO was significantly reduced among participants in the daridorexant 25 mg group compared with participants in the placebo group at month 1 (LSM difference −11·6 min [−17·6 to −5·6], p=0·0001) and month 3 (−10·3 min [−17·0 to −3·5], p=0·0028), whereas no significant differences in LPS were observed at month 1 (–6·5 min [–12·3 to –0·6], p=0·030) or month 3 (–9·0 [–15·3 to –2·7], p=0·0053). Compared with the placebo group, participants in the daridorexant 25 mg group had significant improvement in self-reported total sleep time at month 1 (LSM difference 16·1 min [8·2 to 24·0], p<0·0001) and month 3 (19·1 [10·1 to 28·0], p<0·0001), but not in IDSIQ sleepiness domain scores (–0·8 [–1·6 to 0·1], p=0·073 at month 1; –1·3 [–2·2 to –0·3], p=0·012 at month 3). Compared with the placebo group, no significant differences were observed among participants in the daridorexant 10 mg group for WASO (LSM difference –2·7 min [–8·7 to 3·2], p=0·37 at month 1; –2·0 [–8·7 to 4·8], p=0·57 at month 3), LPS (–2·6 min [–8·4 to 3·2], p=0·38 at month 1; –3·2 min [–9·5 to 3·1], p=0·32 at month 3), self-reported total sleep time (13·4 min [5·5 to 21·2], p=0·0009 at month 1; 13·6 min [4·7 to 22·5], p=0·0028 at month 3), nor IDSIQ sleepiness domain scores (–0·4 [–1·3 to 0·4], p=0·30 at month 1; –0·7 [–1·7 to 0·2], p=0·14 at month 3). Overall incidence of adverse events was comparable between treatment groups (116 [38%] of 308 participants in the daridorexant 50 mg group, 117 [38%] of 310 in the daridorexant 25 mg group, and 105 [34%] of 309 in the placebo group in study 1; 121 [39%] of 308 participants in the daridorexant 25 mg group, 117 [38%] of 306 in the daridorexant 10 mg group, and 100 [33%] of 306 in the placebo group). Nasopharyngitis and headache were the most common adverse events in all groups. One death (cardiac arrest) occurred in the daridorexant 25 mg group in study 1, which was not deemed to be treatment-related.
Interpretation
Daridorexant 25 mg and 50 mg improved sleep outcomes, and daridorexant 50 mg also improved daytime functioning, in people with insomnia disorder, with a favourable safety profile.

​__________________________________________________________________________________
Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae
Yapeng Su et al
Published in Cell: Accepted: January 19, 2022 Received in revised form: December 14, 2021Received: September 29, 2021
Highlights
  • Longitudinal multiomics associate PASC with autoantibodies, viremia and comorbidities
  • Reactivation of latent viruses during initial infection may contribute to PASC
  • Subclinical autoantibodies negatively correlate with anti-SARS-CoV-2 antibodies
  • Gastrointestinal PASC uniquely present with post-acute expansion of cytotoxic T cells
SUMMARY
Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
0 Comments

Abstracts from 1 October 2021

1/10/2021

0 Comments

 
Current status of fecal microbiota transplantation for irritable bowel syndrome
Magdy El-Salhy,Trygve Hausken,Jan Gunnar Hatlebakk,
First published: 08 July 2021 https://doi.org/10.1111/nmo.14157
Neurogastroenterology and motility
Abstract
Background
Irritable bowel syndrome (IBS) is a common gastrointestinal functional disorder. Although IBS is a benign condition, it reduces the quality of life considerably. While there is currently no effective treatment for this disorder, fecal microbiota (FMT) seems to be promising.
Purpose
The aim of this review was to analysis possible factors affecting the success or failure of the randomized controlled trials (RCTs) of FMT for IBS and highlighting the gaps in our knowledge that need to be filled and of sketching a possible model for successful FMT in IBS patients.
MethodsA systematic search was conducted of literature published in English from January 2015 to December 2020 using the keywords: fecal microbiota transplantation, randomized trials, and IBS.
Key Results
Seven randomized controlled trials (RCTs) on the efficacy of FMT for IBS were found in the literature. Four of the seven RCTs found various positive effects, while the other three did not find any effect.
Conclusions and Inferences
The efficacy of FMT for IBS appears to be donor-dependent. The effective (super) donor would need to have a favorable microbiota signature, and 11 clinical criteria that are known to be associated with a favorable microbiota have been suggested for selecting FMT donors for IBS. Comparing the microbiota of the effective donors with those of healthy subjects would reveal the favorable microbiota signature required for a super-donor. However, the studies reviewed were not designed to compare efficacy of different donor types. The dose of the fecal transplant is also an important factor influencing the outcome of FMT for IBS. However, further studies designed to test the effect of fecal transplant dose are needed to answer this question. Administering the fecal transplant to either the small or large intestine seems to be effective, but the optimal route of administration remains to be determined. Moreover, whether single or repeated FMT is more effective is also still unclear. A 1-year follow-up of IBS patients who received FMT showed that adverse events of abdominal pain, diarrhea, and constipation were both mild and self-limiting.
-----------------------------------------------------------------------------------
Research Letter Neurology    October 22, 2021
Assessment of Cognitive Function in Patients After COVID-19 Infection
Jacqueline H. Becker, PhD1; Jenny J. Lin, MD, MPH1; Molly Doernberg, MPH1; et alKimberly Stone, MPH1; Allison Navis, MD2; Joanne R. Festa, PhD2; Juan P. Wisnivesky, MD, DrPH1,3
JAMA Netw Open. 2021;4(10):e2130645. doi:10.1001/jamanetworkopen.2021.30645
COVID-19 Resource Center
Introduction
People who have survived COVID-19 frequently complain of cognitive dysfunction, which has been described as brain fog. The prevalence of post–COVID-19 cognitive impairment and the association with disease severity are not well characterized. Previous studies on the topic have been limited by small sample sizes and suboptimal measurement of cognitive functioning.1 We investigated rates of cognitive impairment in survivors of COVID-19 who were treated in outpatient, emergency department (ED), or inpatient hospital settings.
Methods
We analyzed data in this cross-sectional study from April 2020 through May 2021 from a cohort of patients with COVID-19 followed up through a Mount Sinai Health System registry. Study participants were 18 years or older, spoke English or Spanish, tested positive for SARS-CoV-2 or had serum antibody positivity, and had no history of dementia. Participant demographic characteristics (eg, age, race, and ethnicity) were collected via self-report. Cognitive functioning was assessed using well-validated neuropsychological measures: Number Span forward (attention) and backward (working memory), Trail Making Test Part A and Part B (processing speed and executive functioning, respectively), phonemic and category fluency (language), and the Hopkins Verbal Learning Test–Revised (memory encoding, recall, and recognition). The Mount Sinai Health System Institutional Review Board approved this study, and informed consent was obtained from study participants. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
We calculated the frequency of impairment on each measure, defined as a z score of less than or equal to 1.5 SDs below measure-specific age-, educational level–, and sex-adjusted norms.2,3 Logistic regression assessed the association between cognitive impairment and COVID-19 care site (outpatient, ED, or hospital), adjusting for race and ethnicity, smoking, body mass index, comorbidities, and depression. The threshold for statistical significance was α = .05, and the tests were 2-tailed. Analyses were performed using SAS, version 9.4 (SAS Institute).
Results
The mean (IQR) age of 740 participants was 49 (38-59) years, 63% (n = 464) were women, and the mean (SD) time from COVID-19 diagnosis was 7.6 (2.7) months (Table 1). Participants self-identified as Black (15%), Hispanic (20%), or White (54%) or selected multiracial or other race and ethnicity (11%; other race included Asian [4.5%, n = 33)] and those who selected “other” as race). The most prominent deficits were in processing speed (18%, n = 133), executive functioning (16%, n = 118), phonemic fluency (15%, n = 111) and category fluency (20%, n = 148), memory encoding (24%, n = 178), and memory recall (23%, n = 170; Table 2).
In adjusted analyses, hospitalized patients were more likely to have impairments in attention (odds ratio [OR]: 2.8; 95% CI: 1.3-5.9), executive functioning (OR: 1.8; 95% CI: 1.0-3.4), category fluency (OR: 3.0; 95% CI: 1.7-5.2), memory encoding (OR: 2.3; 95% CI: 1.3-4.1), and memory recall (OR: 2.2; 95% CI: 1.3-3.8) than those in the outpatient group. Patients treated in the ED were more likely to have impaired category fluency (OR: 1.8; 95% CI: 1.1-3.1) and memory encoding (OR: 1.7; 95% CI: 1.0-3.0) than those treated in the outpatient setting. No significant differences in impairments in other domains were observed between groups.
Discussion
In this study, we found a relatively high frequency of cognitive impairment several months after patients contracted COVID-19. Impairments in executive functioning, processing speed, category fluency, memory encoding, and recall were predominant among hospitalized patients. The relative sparing of memory recognition in the context of impaired encoding and recall suggests an executive pattern. This pattern is consistent with early reports describing a dysexecutive syndrome after COVID-194 and has considerable implications for occupational, psychological, and functional outcomes. It is well known that certain populations (eg, older adults) may be particularly susceptible to cognitive impairment after critical illness5; however, in the relatively young cohort in the present study, a substantial proportion exhibited cognitive dysfunction several months after recovering from COVID-19. The findings of this study are generally consistent with those of research on other viruses (eg, influenza).6
Limitations of this study include a potential sampling bias, as some participants may have presented to Mount Sinai Health System because of health concerns. Future studies should investigate long-term post–COVID-19 cognitive trajectories and the association with neuroimaging findings to assess potential mechanisms.
Conclusions
The association of COVID-19 with executive functioning raises key questions regarding patients’ long-term treatment. Future studies are needed to identify the risk factors and mechanisms underlying cognitive dysfunction as well as options for rehabilitation.


-----------------------------------------------------------------------------------
Heliyon:     The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in myalgic encephalomyelitis/chronic fatigue syndrome: A meta-analysis of public DNA methylation and gene expression data
João Malato, Franziska Sotzny, [...], and Nuno Sepúlveda
Abstract
People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report a high frequency of viral infections and flu-like symptoms during their disease course. Given that this reporting agrees with different immunological abnormalities and altered gene expression profiles observed in the disease, we aimed at answering whether the expression of the human angiotensin-converting enzyme 2 (ACE2), the major cell entry receptor for SARS-CoV-2, is also altered in these patients. In particular, a low expression of ACE2 could be indicative of a high risk of developing COVID-19. We then performed a meta-analysis of public data on CpG DNA methylation and gene expression of this enzyme and its homologous ACE protein in peripheral blood mononuclear cells and related subsets. We found that patients with ME/CFS have decreased methylation levels of four CpG probes in the ACE locus (cg09920557, cg19802564, cg21094739, and cg10468385) and of another probe in the promoter region of the ACE2 gene (cg08559914). We also found a decreased expression of ACE2 but not of ACE in patients when compared to healthy controls. Accordingly, in newly collected data, there was evidence for a significant higher proportion of samples with an ACE2 expression below the limit of detection in patients than healthy controls. Altogether, patients with ME/CFS can be at a higher COVID-19 risk and, if so, they should be considered a priority group for vaccination by public health authorities. To further support this conclusion, similar research is recommended for other human cell entry receptors and cell types, namely, those cells targeted by the virus.
Keywords: Myalgic encephalomyelitis/chronic fatigue syndrome, SARS-CoV-2, ACE2, Gene expression, DNA methylation


-----------------------------------------------------------------------------------
An Audit of UK Hospital Doctors’ Knowledge and Experience of Myalgic Encephalomyelitis
Keng Ngee Hng,  Keith Geraghty,  Derek F. H. Pheby
 Medicina 2021, 57(9), 885; https://doi.org/10.3390/medicina57090885
Received: 21 July 2021 / Revised: 13 August 2021 / Accepted: 24 August 2021 / Published: 27 August 2021
Abstract
Background and Objectives: There is some evidence that knowledge and understanding of ME among doctors is limited. Consequently, an audit study was carried out on a group of hospital doctors attending a training event to establish how much they knew about ME and their attitudes towards it. Materials and Methods: Participants at the training event were asked to complete a questionnaire, enquiring about prior knowledge and experience of ME and their approaches to diagnosis and treatment. A total of 44 completed questionnaires were returned. Responses were tabulated, proportions selecting available options determined, 95% confidence limits calculated, and the significance of associations determined by Fisher’s exact test. Results: Few respondents had any formal teaching on ME, though most had some experience of it. Few knew how to diagnose it and most lacked confidence in managing it. None of the respondents who had had teaching or prior experience of ME considered it a purely physical illness. Overall, 91% of participants believed ME was at least in part psychological. Most participants responded correctly to a series of propositions about the general epidemiology and chronicity of ME. There was little knowledge of definitions of ME, diagnosis, or of clinical manifestations. Understanding about appropriate management was very deficient. Similarly, there was little appreciation of the impact of the disease on daily living or quality of life. Where some doctors expressed confidence diagnosing or managing ME, this was misplaced as they were incorrect on the nature of ME, its diagnostic criteria and its treatment. Conclusion: This audit demonstrates that most doctors lack training and clinical expertise in ME. Nevertheless, participants recognised a need for further training and indicated a wish to participate in this. It is strongly recommended that factually correct and up-to-date medical education on ME be made a priority at undergraduate and postgraduate levels. It is also recommended that this audit be repeated following a period of medical education.
Keywords: myalgic encephalomyelitis; chronic fatigue syndrome; ME/CFS; ME; medical education; postgraduate education



-----------------------------------------------------------------------------------

The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients
J of translational medicine

Natalie Eaton-Fitch, Hélène Cabanas, [...], and Sonya Marshall-Gradisnik
Abstract:       Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious multifactorial disorder. The origin remains ambiguous, however reduced natural killer (NK) cell cytotoxicity is a consistent immunological feature of ME/CFS. Impaired transient receptor potential melastatin 3 (TRPM3), a phosphatidylinositol dependent channel, and impaired calcium mobilisation have been implicated in ME/CFS pathology. This investigation aimed to examine the localisation of TRPM3 at the NK cell plasma membrane and co-localisation with phosphatidylinositol 4,5-bisphosphate (PIP2). The effect of IL-2 priming and treatment using pregnenolone sulfate (PregS) and ononetin on TRPM3 co-localisation and NK cell cytotoxicity in ME/CFS patients and healthy controls (HC) was also investigated.
Methods
NK cells were isolated from 15 ME/CFS patients and 15 age- and sex-matched HC. Immunofluorescent technique was used to determine co-localisation of TRPM3 with the NK cell membrane and with PIP2 of ME/CFS patients and HC. Flow cytometry was used to determine NK cell cytotoxicity. Following IL-2 stimulation and treatment with PregS and ononetin changes in co-localisation and NK cell cytotoxicity were measured.
Results
Overnight treatment of NK cells with PregS and ononetin resulted in reduced co-localisation of TRPM3 with PIP2 and actin in HC. Co-localisation of TRPM3 with PIP2 in NK cells was significantly reduced in ME/CFS patients compared with HC following priming with IL-2. A significant increase in co-localisation of TRPM3 with PIP2 was reported following overnight treatment with ononetin within ME/CFS patients and between groups. Baseline NK cell cytotoxicity was significantly reduced in ME/CFS patients; however, no changes were observed following overnight incubation with IL-2, PregS and ononetin between HC and ME/CFS patients. IL-2 stimulation significantly enhanced NK cell cytotoxicity in HC and ME/CFS patients.
Conclusion
Significant changes in co-localisation suggest PIP2-dependent TRPM3 function may be impaired in ME/CFS patients. Stimulation of NK cells with IL-2 significantly enhanced cytotoxic function in ME/CFS patients demonstrating normal function compared with HC. A crosstalk exists between IL-2 and TRPM3 intracellular signalling pathways which are dependent on Ca2+ influx and PIP2. While IL-2R responds to IL-2 binding in vitro, Ca2+ dysregulation and impaired intracellular signalling pathways impede NK cell function in ME/CFS patients.
-----------------------------------------------------------------------------------
ME/CFS: Exercise goals should be set by patients and not driven by treatment plan, says NICE
BMJ 2021; 375 doi: https://doi.org/10.1136/bmj.n2643 (Published 29 October 2021)Cite this as: BMJ 2021;375:n2643
Graded exercise therapy (GET) should no longer be used to treat patients with myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS), says the National Institute for Health and Care Excellence in long awaited updated guidance.1
Patients may still be offered exercise programmes provided they are not based on fixed incremental increases in physical activity or exercise. Instead, programmes should be based around person centred energy management, which is a self-management strategy led by the patient with support from a healthcare professional in an ME/CFS specialist team, the guideline advises.
Energy management should consider all types of activity (cognitive, physical, emotional, and social) that help patients learn to use the amount of energy they have, while reducing their risk of post-exertional malaise or worsening their symptoms by exceeding their limits.
Cognitive behavioural therapy has sometimes been assumed to be a cure for ME/CFS, the guideline acknowledges. Now it should be offered only to help people manage their symptoms, improve their functioning, and reduce the distress associated with having a chronic illness.


-----------------------------------------------------------------------------------
Association of Self-reported COVID-19 Infection and SARS-CoV-2 Serology Test Results With Persistent Physical Symptoms Among French Adults During the COVID-19 Pandemic
Joane Matta, PhD1; Emmanuel Wiernik, PhD1; Olivier Robineau, MD, PhD2,3; et alFabrice Carrat, MD, PhD3; Mathilde Touvier, PhD4; Gianluca Severi, PhD5,6; Xavier de Lamballerie, MD, PhD7; Hélène Blanché, PhD8; Jean-François Deleuze, PhD8; Clément Gouraud, MD, MSc9; Nicolas Hoertel, MD, PhD10; Brigitte Ranque, MD, PhD11; Marcel Goldberg, MD, PhD1; Marie Zins, MD, PhD1; Cédric Lemogne, MD, PhD12; for the Santé, Pratiques, Relations et Inégalités Sociales en Population Générale Pendant la Crise COVID-19–Sérologie (SAPRIS-SERO) Study Group
JAMA Intern Med. Published online November 8, 2021. doi:10.1001/jamainternmed.2021.6454
Key Points
Question  Are the belief in having had COVID-19 infection and actually having had the infection as verified by SARS-CoV-2 serology testing associated with persistent physical symptoms during the COVID-19 pandemic?
Findings  In this cross-sectional analysis of 26 823 adults from the population-based French CONSTANCES cohort during the COVID-19 pandemic, self-reported COVID-19 infection was associated with most persistent physical symptoms, whereas laboratory-confirmed COVID-19 infection was associated only with anosmia. Those associations were independent from self-rated health or depressive symptoms.
Meaning  Findings suggest that persistent physical symptoms after COVID-19 infection should not be automatically ascribed to SARS-CoV-2; a complete medical evaluation may be needed to prevent erroneously attributing symptoms to the virus.
Abstract
Importance  After an infection by SARS-CoV-2, many patients present with persistent physical symptoms that may impair their quality of life. Beliefs regarding the causes of these symptoms may influence their perception and promote maladaptive health behaviors.
Objective  To examine the associations of self-reported COVID-19 infection and SARS-CoV-2 serology test results with persistent physical symptoms (eg, fatigue, breathlessness, or impaired attention) in the general population during the COVID-19 pandemic.
Design, Setting, and Participants  Participants in this cross-sectional analysis were 26 823 individuals from the French population-based CONSTANCES cohort, included between 2012 and 2019, who took part in the nested SAPRIS and SAPRIS-SERO surveys. Between May and November 2020, an enzyme-linked immunosorbent assay was used to detect anti–SARS-CoV-2 antibodies. Between December 2020 and January 2021, the participants reported whether they believed they had experienced COVID-19 infection and had physical symptoms during the previous 4 weeks that had persisted for at least 8 weeks. Participants who reported having an initial COVID-19 infection only after completing the serology test were excluded.
Main Outcomes and Measures  Logistic regressions for each persistent symptom as the outcome were computed in models including both self-reported COVID-19 infection and serology test results and adjusting for age, sex, income, and educational level.
Results  Of 35 852 volunteers invited to participate in the study, 26 823 (74.8%) with complete data were included in the present study (mean [SD] age, 49.4 [12.9] years; 13 731 women [51.2%]). Self-reported infection was positively associated with persistent physical symptoms, with odds ratios ranging from 1.39 (95% CI, 1.03-1.86) to 16.37 (95% CI, 10.21-26.24) except for hearing impairment (odds ratio, 1.45; 95% CI, 0.82-2.55) and sleep problems (odds ratio, 1.14; 95% CI, 0.89-1.46). A serology test result positive for SARS-COV-2 was positively associated only with persistent anosmia (odds ratio, 2.72; 95% CI, 1.66-4.46), even when restricting the analyses to participants who attributed their symptoms to COVID-19 infection. Further adjusting for self-rated health or depressive symptoms yielded similar results. There was no significant interaction between belief and serology test results.
Conclusions and Relevance  The findings of this cross-sectional analysis of a large, population-based French cohort suggest that persistent physical symptoms after COVID-19 infection may be associated more with the belief in having been infected with SARS-CoV-2 than with having laboratory-confirmed COVID-19 infection. Further research in this area should consider underlying mechanisms that may not be specific to the SARS-CoV-2 virus. A medical evaluation of these patients may be needed to prevent symptoms due to another disease being erroneously attributed to “long COVID.”
-----------------------------------------------------------------------------------
Local immune response to food antigens drives meal-induced abdominal pain
Javier Aguilera-Lizarraga, Morgane V. Florens, Guy E. Boeckxstaens 
Nature volume 590, pages151–156 (2021) 
Abstract
Up to 20% of people worldwide develop gastrointestinal symptoms following a meal1, leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H1-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders.


-----------------------------------------------------------------------------------
Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms
Cheng Guo, Xiaoyu Che, Thomas Briese,  View ORCID ProfileOrchid Allicock, Rachel A. Yates, Aaron Cheng, Amit Ranjan, Dana March,  View ORCID ProfileMady Hornig,  View ORCID ProfileAnthony L. Komaroff, Susan Levine,  View ORCID ProfileLucinda Bateman,  View ORCID ProfileSuzanne D. Vernon,  View ORCID ProfileNancy G. Klimas, Jose G. Montoya, Daniel L. Peterson,  View ORCID ProfileW. Ian Lipkin,  View ORCID ProfileBrent L. Williams
doi:  https://doi.org/10.1101/2021.10.27.21265575  BMJ Yale
Abstract
Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating disease of unknown cause for which there is no specific therapy. Patients suffering from ME/CFS commonly experience persistent fatigue, post-exertional malaise, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever and irritable bowel syndrome (IBS). Recent evidence implicates gut microbiome dysbiosis in ME/CFS. However, most prior studies are limited by small sample size, differences in clinical criteria used to define cases, limited geographic sampling, reliance on bacterial culture or 16S rRNA gene sequencing, or insufficient consideration of confounding factors that may influence microbiome composition. In the present study, we evaluated the fecal microbiome in the largest prospective, case-control study to date (n=106 cases, n=91 healthy controls), involving subjects from geographically diverse communities across the United States.
Results Using shotgun metagenomics and qPCR and rigorous statistical analyses that controlled for important covariates, we identified decreased relative abundance and quantity of Faecalibacterium, Roseburia, and Eubacterium species and increased bacterial load in feces of subjects with ME/CFS. These bacterial taxa play an important role in the production of butyrate, a multifunctional bacterial metabolite that promotes human health by regulating energy metabolism, inflammation, and intestinal barrier function. Functional metagenomic and qPCR analyses were consistent with a deficient microbial capacity to produce butyrate along the acetyl-CoA pathway in ME/CFS. Metabolomic analyses of short-chain fatty acids (SCFAs) confirmed that fecal butyrate concentration was significantly reduced in ME/CFS. Further, we found that the degree of deficiency in butyrate-producing bacteria correlated with fatigue symptom severity among ME/CFS subjects. Finally, we provide evidence that IBS comorbidity is an important covariate to consider in studies investigating the microbiome of ME/CFS subjects, as differences in microbiota alpha diversity, some bacterial taxa, and propionate were uniquely associated with self-reported IBS diagnosis.
Conclusions Our findings indicate that there is a core deficit in the butyrate-producing capacity of the gut microbiome in ME/CFS subjects compared to healthy controls. The relationships we observed among symptom severity and these gut microbiome disturbances may be suggestive of a pathomechanistic linkage, however, additional research is warranted to establish any causal relationship. These findings provide support for clinical trials that explore the utility of dietary, probiotic and prebiotic interventions to boost colonic butyrate production in ME/CFS.
-----------------------------------------------------------------------------------
Front. Med., 05 July 2021 | https://doi.org/10.3389/fmed.2021.686736
Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank
Tiago Dias Domingues1,2, Anna D. Grabowska3, Ji-Sook Lee4, Jose Ameijeiras-Alonso5, Francisco Westermeier6,7, Carmen Scheibenbogen8, Jacqueline M. Cliff4, Luis Nacul9,10, Eliana M. Lacerda9, Helena Mouriño1,11 and Nuno Sepúlveda2,4,8*
The evidence of an association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and chronic herpesviruses infections remains inconclusive. Two reasons for the lack of consistent evidence are the large heterogeneity of the patients' population with different disease triggers and the use of arbitrary cutoffs for defining seropositivity. In this work we re-analyzed previously published serological data related to 7 herpesvirus antigens. Patients with ME/CFS were subdivided into four subgroups related to the disease triggers: S0-42 patients who did not know their disease trigger; S1-43 patients who reported a non-infection trigger; S2-93 patients who reported an infection trigger, but that infection was not confirmed by a lab test; and S3-48 patients who reported an infection trigger and that infection was confirmed by a lab test. In accordance with a sensitivity analysis, the data were compared to those from 99 healthy controls allowing the seropositivity cutoffs to vary within a wide range of possible values. We found a negative association between S1 and seropositivity to Epstein-Barr virus (VCA and EBNA1 antigens) and Varicella-Zoster virus using specific seropositivity cutoff. However, this association was not significant when controlling for multiple testing. We also found that S3 had a lower seroprevalence to the human cytomegalovirus when compared to healthy controls for all cutoffs used for seropositivity and after adjusting for multiple testing using the Benjamini-Hochberg procedure. However, this association did not reach statistical significance when using Benjamini-Yekutieli procedure. In summary, herpesviruses serology could distinguish subgroups of ME/CFS patients according to their disease trigger, but this finding could be eventually affected by the problem of multiple testing.


-----------------------------------------------------------------------------------
A Comprehensive Examination of Severely Ill ME/CFS Patients
Chia-Jung Chang,Li-Yuan Hung, Andreas M. Kogelnik, David KaufmanRaeka, S. Aiyar,Angela M. Chu,Julie Wilhelmy,Peng Li,,l Tannenbaum, Wenzhong Xiao, and Ronald W. Davis
 ME/CFS Collaborative Research Center at Stanford, Stanford University School of Medicine, Palo Alto, CA 94305, USA
These authors have contributed equally to this work and share first authorship.
Academic Editors: Kenneth J. Friedman, Lucinda Bateman and Kenny Leo De Meirleir
Healthcare 2021, 9(10), 1290; https://doi.org/10.3390/healthcare9101290
Received: 1 September 2021 / Revised: 20 September 2021 / Accepted: 22 September 2021 / Published: 29 September 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
One in four myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients are estimated to be severely affected by the disease, and these house-bound or bedbound patients are currently understudied. Here, we report a comprehensive examination of the symptoms and clinical laboratory tests of a cohort of severely ill patients and healthy controls. The greatly reduced quality of life of the patients was negatively correlated with clinical depression. The most troublesome symptoms included fatigue (85%), pain (65%), cognitive impairment (50%), orthostatic intolerance (45%), sleep disturbance (35%), post-exertional malaise (30%), and neurosensory disturbance (30%). Sleep profiles and cognitive tests revealed distinctive impairments. Lower morning cortisol level and alterations in its diurnal rhythm were observed in the patients, and antibody and antigen measurements showed no evidence for acute infections by common viral or bacterial pathogens. These results highlight the urgent need of developing molecular diagnostic tests for ME/CFS. In addition, there was a striking similarity in symptoms between long COVID and ME/CFS, suggesting that studies on the mechanism and treatment of ME/CFS may help prevent and treat long COVID and vice versa.
Keywords: severe ME/CFS; quality of life; clinical symptoms; sleep; cognitive tests; laboratory tests; viral infection; antibody and antigen; long COVID; post-acute sequelae SARS-CoV-2 infection (PASC)


-----------------------------------------------------------------------------------
PERSPECTIVE 
Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome 
Bindu D. Paula,b,c,1, Marian D. Lemled , Anthony L. Komaroffe , and Solomon H. Snydera,b,c,1 
Edited by Maureen R. Hanson, Cornell University, Ithaca, NY, and accepted by Editorial Board Member Philippa Marrack June 25, 2021
 (received for review February 28, 2021) 
Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called “long COVID-19,” reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases. We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics. COVID-19 | chronic fatigue syndrome | myalgic encephalomyelitis 


-----------------------------------------------------------------------------------
 Health, Wellbeing, and Prognosis of Australian Adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Case-Controlled Follow-Up Study
Elisha K. Josev,Adam Scheinberg,Katherine Rowe,Lionel Lubitz and,,Sarah J. Knight
Neurodisability and Rehabilitation, Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne 3052, Australia
J. Clin. Med. 2021, 10(16), 3603; https://doi.org/10.3390/jcm10163603
Received: 30 June 2021 / Revised: 1 August 2021 / Accepted: 9 August 2021 / Published: 16 August 2021
Abstract
Background: The purpose of this study was to follow-up an Australian cohort of adolescents newly-diagnosed with ME/CFS at a tertiary paediatric ME/CFS clinic and healthy controls over a mean period of two years (range 1–5 years) from diagnosis. Objectives were to (a) examine changes over time in health and psychological wellbeing, (b) track ME/CFS symptomatology and fulfillment of paediatric ME/CFS diagnostic criteria over time, and (c) determine baseline predictors of ME/CFS criteria fulfilment at follow-up. Methods: 34 participants aged 13–18 years (25 ME/CFS, 23 controls) completed standardised questionnaires at diagnosis (baseline) and follow-up assessing fatigue, sleep quality and hygiene, pain, anxiety, depression, and health-related quality of life. ME/CFS symptomatology and diagnostic criteria fulfilment was also recorded. Results: ME/CFS patients showed significant improvement in most health and psychological wellbeing domains over time, compared with controls who remained relatively stable. However, fatigue, pain, and health-related quality of life remained significantly poorer amongst ME/CFS patients compared with controls at follow-up. Sixty-five percent of ME/CFS patients at baseline continued to fulfil ME/CFS diagnostic criteria at follow-up, with pain the most frequently experienced symptom. Eighty-two percent of patients at follow-up self-reported that they still had ME/CFS, with 79% of these patients fulfilling criteria. No significant baseline predictors of ME/CFS criteria fulfilment at follow-up were observed, although pain experienced at baseline was significantly associated with criteria fulfilment at follow-up (R = 0.6, p = 0.02). Conclusions: The majority of Australian adolescents with ME/CFS continue to fulfil diagnostic criteria at follow-up, with fatigue, pain, and health-related quality of life representing domains particularly relevant to perpetuation of ME/CFS symptoms in the early years following diagnosis. This has direct clinical impact for treating clinicians in providing a more realistic prognosis and highlighting the need for intervention with young people with ME/CFS at the initial diagnosis and start of treatment.
Keywords: chronic fatigue syndrome; myalgic encephalomyelitis; follow-up; adolescence; health; wellbeing; diagnostic criteria
0 Comments

Abstracts from August

1/8/2021

0 Comments

 
Chronic fatigue syndrome and long covid: individualisation, not compartmentalisation
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1863 (Published 28 July 2021)Cite this as: BMJ 2021;374:n1863
  1. Russell S Malcolm, specialty doctor

Newman’s investigation of chronic fatigue syndrome and long covid supports the development of specialised multidisciplinary support for patients with long covid.1 But compartmentalisation of a problem like chronic fatigue syndrome can sometimes miss the point.
Dysregulated systems, by their nature, cannot be manipulated into functionality, so the clinical modelling of a system disturbance is often best undertaken by a clinician with dedicated expertise in multisystem assessment who can pull the “hard” and “soft” data together.
Specialised teams, such as the fatigue clinic at the Royal London Hospital for Integrated Medicine, routinely individualise chronic fatigue syndrome cases to a high level of detail. In the absence of objective data, the use of advanced and holistic history taking can explore the factors that perpetuate the clinical state.
The “forensic” part of the inquiry searches for the symptomatic features of pathophysiological change, hypothalamic dysregulation, or ongoing immunological disturbance. The physical and functional inquiry is then contextualised by an empathic and holistic psychosocial survey.
Each patient has a unique combination of perpetuating factors in chronic fatigue syndrome and long covid, so treatment approaches should also be individualised to a high degree. This level of individualisation is not always possible using a compartmentalised method of assessment.

_____________________________________________________________________________________
Long covid: reshaping conversations about medically unexplained symptoms

BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1859 (Published 28 July 2021)Cite this as: BMJ 2021;374:n1859
  1. Sean L Davidson, psychiatry registrar1,  
  2. David B Menkes, academic psychiatrist2
  3. [email protected]
Newman’s article, a linked patient commentary, and the tranche of rapid responses show how “long covid” has reignited debate about the causes and management of chronic fatigue syndrome.1 Rather than moving beyond the controversy, most of the ensuing arguments have fallen back into familiar grooves deepened by confirmation bias and dualistic thinking.123 On a more positive note, the intense media attention on and public interest in long covid present a golden opportunity to reshape and extend discussions about medically unexplained symptoms.
Patients presenting with symptoms in the presence of normal diagnostic tests account for 26-35% of consultations in primary care.4 The banner of medically unexplained symptoms encompasses heterogeneous issues—simple transient problems, recognised symptom complexes such as chronic fatigue syndrome, and emerging phenomena like long covid. All present challenges to the doctor-patient relationship, confer risks of overdiagnosis and overtreatment, and can provoke frustration and anxiety in junior and experienced clinicians alike.25
These common clinical scenarios emphasise the pressing need for a framework to aid communication with patients who are frustrated by the mismatch of disabling symptoms and normal investigations. The contrasting societal and medical narratives that Newman outlines regarding chronic fatigue exemplify the challenges that doctors and patients face together in coming to a shared understanding of diagnosis and management options.12 These consultations often carry the weight of decades of power imbalance, psychological stigma, and bitter dualistic debate, leaving both doctor and patient dissatisfied.13
In contrast to most medical specialties, neurologists have made remarkable progress in establishing a patient led terminology and common framework to positively identify and manage functional disorders.6 Other disciplines should strive to match this example but recognise that complex and undifferentiated presentations will doubtless persist and require skill and judgment to investigate appropriately and to constructively manage uncertainty. Crucially, this approach must leave room for an evolving evidence base because “unexplained” does not mean “unexplainable.” Long covid provides an opportunity for the medical profession to move beyond stale controversies and to reconsider how we discuss symptoms lacking clear cause with patients, students, and colleagues.
_____________________________________________________________________________________
Exclusive: Four members of NICE’s guideline committee on ME/CFS stand down
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1937 (Published 03 August 2021)Cite this as: BMJ 2021;374:n1937
  1. Ingrid Torjesen
Four members of the NICE guideline development committee for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) left the group just weeks before the final guideline was due to be published, The BMJ has learnt.
The departures suggest divisions within the committee over the guideline’s final content, which is an update on 2007 guidance on diagnosing and managing ME/CFS. Three have resigned, and one has been removed by NICE.
The draft guidance, published in November 2020,1 included significant changes to the 2007 recommendations2 and raised questions about how the evidence could have shifted so substantially.
In 2007 NICE recommended interventions such as cognitive behavioural therapy and graded exercise therapy for people with mild or moderate ME/CFS, whereas the draft update cites a “lack of evidence for the effectiveness of these interventions.” …
_____________________________________________________________________________________
Nutrients. 2021 May; 13(5): 1397.
Published online 2021 Apr 21. doi: 10.3390/nu13051397 PMCID: PMC8143286 PMID: 33919346
Véronique Morel,1 Marie-Eva Pickering,2 Jonathan Goubayon,1 Marguérite Djobo,1 Nicolas Macian,1 and Gisèle Pickering1,*
Maria Perticone, Academic Editor


Clinical Investigation Center, Inserm CIC 1405, Bat 3C, University Hospital Clermont-Ferrand, F-63000 Clermont-Ferrand, France; rf.dnarreftnomrelc-uhc@lerom_v (V.M.); rf.dnarreftnomrelc-uhc@noyabuogj (J.G.); rf.dnarreftnomrelc-uhc@obojdm (M.D.); rf.dnarreftnomrelc-uhc@naicamn (N.M.)
Abstract
Background: Magnesium (Mg) is commonly used in clinical practice for acute and chronic pain and has been reported to reduce pain intensity and analgesics consumption in a number of studies. Results are, however, contested. 
Objectives: This review aims to investigate randomised clinical trials (RCTs) on the effectiveness of Mg treatment on pain and analgesics consumption in situations including post-operative pain, migraine, renal pain, chronic pain, neuropathic pain and fibromyalgia. 
Results: The literature search identified 81 RCTs (n = 5447 patients) on Mg treatment in pain (50 RCTs in post-operative pain, 18 RCTs in migraine, 5 RCTs in renal pain, 6 RCTs in chronic/neuropathic pain, 2 RCTs in fibromyalgia). 
Conclusion: The level of evidence for the efficacy of Mg in reducing pain and analgesics consumption is globally modest and studies are not very numerous in chronic pain. A number of gaps have been identified in the literature that need to be addressed especially in methodology, rheumatic disease, and cancer. Additional clinical trials are needed to achieve a sufficient level of evidence and to better optimize the use of Mg for pain and pain comorbidities in order to improve the quality of life of patients who are in pain.

_____________________________________________________________________________________

Cerebral Blood Flow Is Reduced in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients During Mild Orthostatic Stress Testing: An Exploratory Study at 20 Degrees of Head-Up Tilt Testing
by C (Linda) M.C. van Campen,Peter C. Rowe, Frans C. Visser
 Stichting CardioZorg, 2132 HN Hoofddorp, The Netherlands
Department of Paediatrics, John Hopkins University School of Medicine, Baltimore, MD 21205, USA
Healthcare 2020, 8(2), 169; https://doi.org/10.3390/healthcare8020169
Received: 5 May 2020 / Revised: 1 June 2020 / Accepted: 10 June 2020 / Published: 13 June 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Introduction: In a study of 429 adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we demonstrated that 86% had symptoms of orthostatic intolerance in daily life. Using extracranial Doppler measurements of the internal carotid and vertebral arteries during a 30-min head-up tilt to 70 degrees, 90% had an abnormal reduction in cerebral blood flow (CBF). A standard head-up tilt test of this duration might not be tolerated by the most severely affected bed-ridden ME/CFS patients. This study examined whether a shorter 15-min test at a lower 20 degree tilt angle would be sufficient to provoke reductions in cerebral blood flow in severe ME/CFS patients. Methods and results: Nineteen severe ME/CFS patients with orthostatic intolerance complaints in daily life were studied: 18 females. The mean (SD) age was 35(14) years, body surface area (BSA) was 1.8(0.2) m2 and BMI was 24.0(5.4) kg/m2. The median disease duration was 14 (IQR 5–18) years. Heart rate increased, and stroke volume index and end-tidal CO2 decreased significantly during the test (p ranging from <0.001 to <0.0001). The cardiac index decreased by 26(7)%: p < 0.0001. CBF decreased from 617(72) to 452(63) mL/min, a 27(5)% decline. All 19 severely affected ME/CFS patients met the criteria for an abnormal CBF reduction. Conclusions: Using a less demanding 20 degree tilt test for 15 min in severe ME/CFS patients resulted in a mean CBF decline of 27%. This is comparable to the mean 26% decline previously noted in less severely affected patients studied during a 30-min 70 degree head-up tilt. These observations have implications for the evaluation and treatment of severely affected individuals with ME/CFS. 
_____________________________________________________________________________________
Homebound versus Bedridden Status among Those with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Karl Conroy, Shaun Bhatia, Mohammed Islam, Leonard A. Jason
Center for Community Research, DePaul University, Chicago, IL 60614, USA
*Healthcare 2021, 9(2), 106; https://doi.org/10.3390/healthcare9020106
Received: 29 December 2020 / Revised: 16 January 2021 / Accepted: 19 January 2021 / Published: 20 January 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Persons living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) vary widely in terms of the severity of their illness. It is estimated that of those living with ME/CFS in the United States, about 385,000 are homebound. There is a need to know more about different degrees of being homebound within this severely affected group. The current study examined an international sample of 2138 study participants with ME/CFS, of whom 549 were severely affected (operationalized as ‘Homebound’). A subsample of 89 very severely affected participants (operationalized as ‘Homebound-bedridden’) was also examined. The findings showed a significant association between severely and very severely affected participants within the post-exertional malaise (PEM) symptom domain. The implications of these findings are discussed.  

_____________________________________________________________________________________
The Lonely, Isolating, and Alienating Implications of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Samir Boulazreg, Ami Rokach
Faculty of Education, University of Western Ontario, London, ON N6A 3K7, Canada
Department of Psychology, York University, Toronto, ON M3J 1P3, Canada
*Healthcare 2020, 8(4), 413; https://doi.org/10.3390/healthcare8040413
Received: 17 July 2020 / Revised: 27 September 2020 / Accepted: 11 October 2020 / Published: 20 October 2020
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
This article provides a narrative review on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) through a psychosocial lens and examines how this impairment affects its sufferers during adolescence and adulthood, as well as how it impacts family caregivers and healthcare professionals’ mental health. Since there has been a lack of investigation in the literature, the primary psychosocial stressor that this review focuses on is loneliness. As such, and in an attempt to help establish a theoretical framework regarding how loneliness may impact ME/CFS, loneliness is comprehensively reviewed, and its relation to chronic illness is described. We conclude by discussing a variety of coping strategies that may be employed by ME/CFS individuals to address their loneliness. Future directions and ways with which the literature may investigate loneliness and ME/CFS are discussed.
_____________________________________________________________________________________
Heliyon. 2021 Aug;7(8):e07665.
 doi: 10.1016/j.heliyon.2021.e07665. Epub 2021 Jul 29.
The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in myalgic encephalomyelitis/chronic fatigue syndrome: A meta-analysis of public DNA methylation and gene expression data
João Malato 1 2, Franziska Sotzny 3, Sandra Bauer 3, Helma Freitag 3, André Fonseca 4, Anna D Grabowska 5, Luís Graça 1, Clara Cordeiro 2 4, Luís Nacul 6 7, Eliana M Lacerda 6, Jesus Castro-Marrero 8, Carmen Scheibenbogen 3, Francisco Westermeier 9 10, Nuno Sepúlveda 2 3 11
PMID: 34341773   PMCID: PMC8320404   DOI: 10.1016/j.heliyon.2021.e07665
Abstract
People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report a high frequency of viral infections and flu-like symptoms during their disease course. Given that this reporting agrees with different immunological abnormalities and altered gene expression profiles observed in the disease, we aimed at answering whether the expression of the human angiotensin-converting enzyme 2 (ACE2), the major cell entry receptor for SARS-CoV-2, is also altered in these patients. In particular, a low expression of ACE2 could be indicative of a high risk of developing COVID-19. We then performed a meta-analysis of public data on CpG DNA methylation and gene expression of this enzyme and its homologous ACE protein in peripheral blood mononuclear cells and related subsets. We found that patients with ME/CFS have decreased methylation levels of four CpG probes in the ACE locus (cg09920557, cg19802564, cg21094739, and cg10468385) and of another probe in the promoter region of the ACE2 gene (cg08559914). We also found a decreased expression of ACE2 but not of ACE in patients when compared to healthy controls. Accordingly, in newly collected data, there was evidence for a significant higher proportion of samples with an ACE2 expression below the limit of detection in patients than healthy controls. Altogether, patients with ME/CFS can be at a higher COVID-19 risk and, if so, they should be considered a priority group for vaccination by public health authorities. To further support this conclusion, similar research is recommended for other human cell entry receptors and cell types, namely, those cells targeted by the virus.
_____________________________________________________________________________________
Orthostatic stress testing in myalgic encephalomyelitis/chronic fatigue syndrome patients with or without concomitant fibromyalgia: effects on pressure pain thresholds and temporal summation
 C.(L.)M.C. van Campen1 , P.C. Rowe2 , F.W.A. Verheugt3 , F.C. Visser
ABSTRACT 
Objective. Muscle pain and fibromyalgia (FM) are common among individuals with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). We recently demonstrated that during orthostatic stress testing, adults with ME/CFS reported increased pain. In the current study, we hypothesised that pain pressure thresholds (PPT) would decrease and temporal summation (windup) would increase after head-up tilt testing (HUT), and that the presence of co-morbid FM would be associated with greater change in both measures. 
Methods. We studied adult ME/CFS patients undergoing HUT. PPT and temporal summation (or windup) measurements were obtained pre- and post-HUT at the finger and shoulder. 
Conclusion. Pressure pain threshold decreased in ME/CFS patients with or without fibromyalgia after head-up tilt test (HUT), but did not change postHUT in healthy controls. Windup preand post-HUT was significantly higher compared to healthy controls, but did not change from pre- to post-HUT. These results demonstrate that, like exercise, orthostatic stress can negatively influence the physiology of pain perception in ME/CFS. Furthermore, the physiology of pain perception is even more negatively influenced by concomitant fibromyalgia. 
_____________________________________________________________________________________
Hypothalamic-Pituitary Autoimmunity and Related Impairment of Hormone Secretions in Chronic Fatigue Syndrome
Annamaria De Bellis, Giuseppe Bellastella, Vlenia Pernice, Paolo Cirillo, Miriam Longo, Antonietta Maio, Lorenzo Scappaticcio, Maria Ida Maiorino, Antonio Bellastella, Katherine Esposito ... Show more
The Journal of Clinical Endocrinology & Metabolism, dgab429, https://doi.org/10.1210/clinem/dgab429     Published:13 July 2021
 Context
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe chronic illness that reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized.
Objective
This work aims to investigate the occurrence of antipituitary (APA) and antihypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients.

Methods
This is a case-control study conducted in a university hospital setting (Stanford, California, USA; and Naples, Italy). Thirty women with ME/CSF (group 1) diagnosed according to Fukuda, Canadian, and Institute of Medicine criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls. APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands. APA and AHA titers both were assessed and the prevalence of pituitary hormone deficiencies was also investigated.

Results
Patients in group 1 showed a high prevalence of AHA (33%) and APA (56%) and significantly lower levels of adrenocorticotropin (ACTH)/cortisol, and growth hormone (GH) peak/insulin-like growth factor-1 (IGF-1) vs controls (all AHA/APA negative). Patients in group 1A (13 patients positive at high titers, ≥ 1:32) showed ACTH/cortisol and GH peak/IGF-1 levels significantly lower and more severe forms of ME/CFS with respect to patients in group 1B (7 positive at middle/low titers, 1:16-1:8) and 1C (10 antibody-negative patients).
Conclusion
Both AHA and/or APA at high titers were associated with hypothalamic/pituitary dysfunction, suggesting that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms.

_____________________________________________________________________________________

Front. Med., 18 June 2021 | https://doi.org/10.3389/fmed.2021.688486
The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review
Adam J. O'Neal and Maureen R. Hanson*
  • Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, United States
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in secondary infection sites, including the central nervous system, muscle, and heart. To date, the body of research that has investigated enterovirus infections in relation to ME/CFS supports an increased prevalence of chronic or persistent enteroviral infections in ME/CFS patient cohorts than in healthy individuals. Nevertheless, inconsistent results have fueled a decline in related studies over the past two decades. This review covers the aspects of ME/CFS pathophysiology that are consistent with a chronic enterovirus infection and critically reviews methodologies and approaches used in past EV-related ME/CFS studies. We describe the prior sample types that were interrogated, the methods used and the limitations to the approaches that were chosen. We conclude that there is considerable evidence that prior outbreaks of ME/CFS were caused by one or more enterovirus groups. Furthermore, we find that the methods used in prior studies were inadequate to rule out the presence of chronic enteroviral infections in individuals with ME/CFS. Given the possibility that such infections could be contributing to morbidity and preventing recovery, further studies of appropriate biological samples with the latest molecular methods are urgently needed.
_____________________________________________________________________________________
GPs need awareness about post-covid ME/CFS
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1995 (Published 12 August 2021)Cite this as: BMJ 2021;374:n1995
  1. Caroline Kamau-Mitchell, senior lecturer
  2. [email protected]

Wise reports that general practitioners might be under-reporting long covid in patient records.1 Approximately 25% of people infected with SARS-CoV-1 developed debilitating fatigue and other symptoms that met diagnostic criteria for myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) that continued for more than four years.2 So patients with long covid who have had chronic fatigue for six or more months, together with other mandatory symptoms, are likely to be diagnosed as having ME/CFS.
A recent inquiry report for the House of Lords discussed the need for GPs to follow-up patients with suspected long covid and to determine whether those still experiencing severe fatigue after six months meet the other diagnostic criteria for ME/CFS.3 Although there is no known cure, viruses are known to be one of the possible causes of ME/CFS,4 so recognising the chronic fatigue reported by many patients with long covid can help GPs direct them to appropriate support.3 Without enough awareness, patients presenting with long covid symptoms might not be believed by some GPs or might receive misdiagnoses for mental conditions. Not all patients with long covid have ME/CFS but, for those who do, GPs must identify the need for appropriate support, including referrals to occupational rehabilitation support services.3
Data are needed to clarify rates of ME/CFS after covid-19, and GPs can help by conducting six month follow-up of patients who report long covid.
_____________________________________________________________________________________
Long covid—mechanisms, risk factors, and management
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1648 (Published 26 July 2021)Cite this as: BMJ 2021;374:n1648
Harry Crook, research assistant1,  Sanara Raza, research assistant1,  Joseph Nowell, research assistant1,  Megan Young, clinical research officer1,  Paul Edison, clinical senior lecturer, honorary professor12
  1. Correspondence to P Edison [email protected]
Abstract
Since its emergence in Wuhan, China, covid-19 has spread and had a profound effect on the lives and health of people around the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 million deaths. Recent evidence has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-2 infection, and this condition is now coined long covid by recognized research institutes. Studies have shown that long covid can affect the whole spectrum of people with covid-19, from those with very mild acute disease to the most severe forms. Like acute covid-19, long covid can involve multiple organs and can affect many systems including, but not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive impairment, sleep disturbances, symptoms of post-traumatic stress disorder, muscle pain, concentration problems, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.
_____________________________________________________________________________________
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management
Lucinda Bateman, MD,Alison C. Bested, MD,Hector F. Bonilla, MD,Ilene S. Ruhoy, MD, PhD, Maria A. Vera-Nunez, MD, MSBI, Brayden P. Yellman, MD
Open Access Published:August 25, 2021DOI:https://doi.org/10.1016/j.mayocp.2021.07.004
Abstract
Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment. These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS. Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.
CBT (cognitive behavioral therapy), GET (graded exercise therapy), ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome), NAM (National Academy of Medicine), PEM (post-exertional malaise)
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, multi-system disease affecting millions of people worldwide. Despite its high prevalence and disabling nature, medical education programs rarely cover ME/CFS and guidance for practicing clinicians is often outdated and inappropriate. 
 Standard tests typically return normal results, and some clinicians are wholly unaware of or question the legitimacy of ME/CFS.
 Consequently, up to 91% of affected people are undiagnosed or misdiagnosed with other conditions, such as depression.
 To obtain a diagnosis, patients frequently have had to see multiple clinicians over a number of years. Even after diagnosis, patients struggle to obtain appropriate care and have often been prescribed treatments, such as cognitive-behavioral therapy (CBT) and graded exercise therapy (GET), that could worsen their condition.
In 2015, the US National Academy of Medicine (NAM, previously the Institute of Medicine) created new ME/CFS clinical diagnostic criteria that required the hallmark symptom of post-exertional malaise (PEM).
 The US Centers for Disease Control and Prevention have adopted these new criteria, have removed recommendations for CBT and GET, and have begun to incorporate the best clinical practices of ME/CFS experts. These steps will help improve the speed and accuracy of diagnosis and the quality of clinical care.
Lingering symptoms including fatigue follow various types of infectious illnesses.
 These “postinfectious” fatigue syndromes resemble ME/CFS.
 Moreover, ME/CFS itself often follows an infectious-like illness.
 On occasion, the infectious illness preceding ME/CFS, such as infectious mononucleosis,
 Coxiella burnetii infection,
 giardiasis,
 or severe acute respiratory syndrome (caused by a coronavirus similar to the etiologic agent of COVID-19), has been well documented, but often, no attempt has been made to diagnose the infectious agent.
Following acute COVID-19, whether hospitalized or not, many patients continue to experience debility and symptoms for many months.
 Some of these “long haulers” may have symptoms reflecting organ damage, such as to the lungs or heart, from the acute disease.
 Other long haulers are symptomatic despite having no clear evidence of such organ damage.
 A study of patients ill 6 months after mild or moderate acute COVID-19 found that about half met criteria for ME/CFS.
 One review suggested that the number of cases of ME/CFS could double as a result of the pandemic.
 Like ME/CFS patients, those with post-COVID conditions have recounted being dismissed by health care professionals.
This article provides essential information about how to diagnose and care for adults with ME/CFS and echoes other recent ME/CFS guidance
 Accurately and expeditiously diagnosing ME/CFS is important. There are many steps a clinician can take to improve the health, function, and quality of life of these patients. Even if they do not go on to develop ME/CFS, some patients with post-COVID conditions may also benefit from approaches such as pacing.
_____________________________________________________________________________________

Front. Syst. Neurosci., 01 September 2021 | https://doi.org/10.3389/fnsys.2021.698240

Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
 Suzanne D. Vernon2, Tina Milani2 and Lucinda Bateman2Gerard Pereira1*, Hunter Gillies1, Sanjay Chanda1, Michael Corbett
1Cortene Inc., Burlingame, CA, United States
Bateman Horne Center, Salt Lake City, UT, United States

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.
Materials and Methods: This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.
Results: ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.
Conclusion: The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.

_____________________________________________________________________________________
Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study
Michela Antonelli et al-based,

Published:September 01, 2021 DOI:https://doi.org/10.1016/S1473-3099(21)00460-6 nested, Summary
Background
COVID-19 vaccines show excellent efficacy in clinical trials and effectiveness in real-world data, but some people still become infected with SARS-CoV-2 after vaccination. This study aimed to identify risk factors for post-vaccination SARS-CoV-2 infection and describe the characteristics of post-vaccination illness.
Methods
This prospective, community-based, nested, case-control study used self-reported data (eg, on demographics, geographical location, health risk factors, and COVID-19 test results, symptoms, and vaccinations) from UK-based, adult (≥18 years) users of the COVID Symptom Study mobile phone app. For the risk factor analysis, cases had received a first or second dose of a COVID-19 vaccine between Dec 8, 2020, and July 4, 2021; had either a positive COVID-19 test at least 14 days after their first vaccination (but before their second; cases 1) or a positive test at least 7 days after their second vaccination (cases 2); and had no positive test before vaccination. Two control groups were selected (who also had not tested positive for SARS-CoV-2 before vaccination): users reporting a negative test at least 14 days after their first vaccination but before their second (controls 1) and users reporting a negative test at least 7 days after their second vaccination (controls 2). Controls 1 and controls 2 were matched (1:1) with cases 1 and cases 2, respectively, by the date of the post-vaccination test, health-care worker status, and sex. In the disease profile analysis, we sub-selected participants from cases 1 and cases 2 who had used the app for at least 14 consecutive days after testing positive for SARS-CoV-2 (cases 3 and cases 4, respectively). Controls 3 and controls 4 were unvaccinated participants reporting a positive SARS-CoV-2 test who had used the app for at least 14 consecutive days after the test, and were matched (1:1) with cases 3 and 4, respectively, by the date of the positive test, health-care worker status, sex, body-mass index (BMI), and age. We used univariate logistic regression models (adjusted for age, BMI, and sex) to analyse the associations between risk factors and post-vaccination infection, and the associations of individual symptoms, overall disease duration, and disease severity with vaccination status.
Findings
Between Dec 8, 2020, and July 4, 2021, 1 240 009 COVID Symptom Study app users reported a first vaccine dose, of whom 6030 (0·5%) subsequently tested positive for SARS-CoV-2 (cases 1), and 971 504 reported a second dose, of whom 2370 (0·2%) subsequently tested positive for SARS-CoV-2 (cases 2). In the risk factor analysis, frailty was associated with post-vaccination infection in older adults (≥60 years) after their first vaccine dose (odds ratio [OR] 1·93, 95% CI 1·50–2·48; p<0·0001), and individuals living in highly deprived areas had increased odds of post-vaccination infection following their first vaccine dose (OR 1·11, 95% CI 1·01–1·23; p=0·039). Individuals without obesity (BMI <30 kg/m2) had lower odds of infection following their first vaccine dose (OR 0·84, 95% CI 0·75–0·94; p=0·0030). For the disease profile analysis, 3825 users from cases 1 were included in cases 3 and 906 users from cases 2 were included in cases 4. Vaccination (compared with no vaccination) was associated with reduced odds of hospitalisation or having more than five symptoms in the first week of illness following the first or second dose, and long-duration (≥28 days) symptoms following the second dose. Almost all symptoms were reported less frequently in infected vaccinated individuals than in infected unvaccinated individuals, and vaccinated participants were more likely to be completely asymptomatic, especially if they were 60 years or older.
Interpretation
To minimise SARS-CoV-2 infection, at-risk populations must be targeted in efforts to boost vaccine effectiveness and infection control measures. Our findings might support caution around relaxing physical distancing and other personal protective measures in the post-vaccination era, particularly around frail older adults and individuals living in more deprived areas, even if these individuals are vaccinated, and might have implications for strategies such as booster vaccinations.

_____________________________________________________________________________________
2021 Jul 13;12:687806.Frontiers in Immunology  doi: 10.3389/fimmu.2021.687806. eCollection 2021.
Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment
Helene Cabanas 1 2, Katsuhiko Muraki 2 3, Natalie Eaton-Fitch 1 2, Donald Ross Staines 1 2, Sonya Marshall-Gradisnik 1 2 PMID: 34326841 PMCID: PMC8313851  
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-systemic chronic condition of unknown aetiology classified as an immune dysfunction syndrome and neurological disorder. The discovery of the widely expressed Transient Receptor Potential Melastatin 3 (TRPM3) as a nociceptor channel substantially targeted by certain opioid receptors, and its implication in calcium (Ca2+)-dependent Natural Killer (NK) cell immune functions has raised the possibility that TRPM3 may be pharmacologically targeted to treat characteristic symptoms of ME/CFS. Naltrexone hydrochloride (NTX) acts as an antagonist to the mu (μ)-opioid receptor thus negating its inhibitory function on TRPM3. Based on the benefits reported by patients on their symptoms, low dose NTX (LDN, 3.0-5.0 mg/day) treatment seems to offer some potential benefit suggesting that its effect may be targeted towards the pathomechanism of ME/CFS. As there is no literature confirming the efficacy of LDN for ME/CFS patients in vitro, this study investigates the potential therapeutic effect of LDN in ME/CFS patients. TRPM3 ion channel activity was measured after modulation with Pregnenolone sulfate (PregS) and ononetin in NK cells on 9 ME/CFS patients taking LDN and 9 age- and sex-matched healthy controls using whole-cell patch-clamp technique. We report that ME/CFS patients taking LDN have restored TRPM3-like ionic currents in NK cells. Small ionic currents with a typical TRPM3-like outward rectification were measured after application of PregS, a TRPM3-agonist, in NK cells from patients taking LDN. Additionally, PregS-evoked ionic currents through TRPM3 were significantly modulated by ononetin, a TRPM3-antagonist, in NK cells from ME/CFS patients taking LDN. These data support the hypothesis that LDN may have potential as a treatment for ME/CFS by characterising the underlying regulatory mechanisms of LDN treatment involving TRPM3 and opioid receptors in NK cells. Finally, this study may serve for the repurpose of marketed drugs, as well as support the approval of prospective randomized clinical studies on the role and dose of NTX in treating ME/CFS patients.
_____________________________________________________________________________________
Published by De Gruyter April 22, 2020
Diagnosis of mast cell activation syndrome: a global “consensus-2”
Lawrence B. Afrin , Mary B. Ackerley, Linda S. Bluestein, Joseph H. Brewer, Jill B. Brook, Ariana D. Buchanan, Jill R. Cuni, William P. Davey, Tania T. Dempsey , Shanda R. Dorff, Martin S. Dubravec, Alena G. Guggenheim, Kimberly J. Hindman, Bruce Hoffman, David L. Kaufman, Stephanie J. Kratzer, Theodore M. Lee, Mindy S. Marantz, Andrew J. Maxwell, Kelly K. McCann, Dwight L. McKee, Laurie Menk Otto, Laura A. Pace, Dahra D. Perkins, Laurie Radovsky, Mary S. Raleigh, Sonia A. Rapaport, Emma J. Reinhold, Mark L. Renneker, William A. Robinson, Aaron M. Roland, E. Scott Rosenbloom, Peter C. Rowe, Ilene S. Ruhoy, David S. Saperstein, David A. Schlosser, Jill R. Schofield, Janet E. Settle, Leonard B. Weinstock, Martina Wengenroth, Mark Westaway, Shijun Cindy Xi and Gerhard J. Molderings
From the journal Diagnosis   https://doi.org/10.1515/dx-2020-0005
Abstract
The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of “mast cell activation syndrome” (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a “consensus” (re-termed here as “consensus-1”). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as “consensus-2”), resembling “consensus-1” in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by “consensus-2” criteria has potential to be problematic, but underdiagnosis by “consensus-1” criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.
Keywords: chronic illness; mast cell activation disease; mast cell activation syndrome; medical controversies; medically unexplained symptoms; misdiagnosis

_____________________________________________________________________________________

Long COVID: low prevalence in SARS-CoV-2 infected children
Radtke T & al.. JAMA, 15 July 2021 Miriam Davis, PhD   |   16 September 2021
Takeaway
  • Long-term symptoms after SARS-CoV-2 infection (so-called long COVID) affect 4% of children and adolescents vs 2% of uninfected control participants, according to a longitudinal cohort study.
Why this matters
  • This is the first report of long COVID prevalence in a population-based cohort of children and adolescents with the use of an uninfected control group.
Study design
  • Population-based longitudinal cohort study of children from randomly selected classes in 55 randomly selected schools in the canton of Zurich, Switzerland.
  • SARS-CoV-2 infection was determined by serology testing at 2 points and long COVID was assessed by online symptom questionnaires.
  • 109 seropositive children were compared with 1246 seronegative children (between October 2020 and March/April 2021).
  • Funding: Swiss Federal Office of Public Health; University of Zurich Foundation; private funders.
Key results
  • Median age, 11 years; interquartile range, 9-13 years; 54% girls.
  • Age and sex patterns were similar between seropositive and seronegative children.
  • Long COVID prevalence: 4% of 109 seropositive children vs 2% of seronegative control participants reported ≥1 symptom lasting >12 weeks.
  • Most frequently reported symptoms in seropositive vs seronegative children were:
    • Tiredness (3% vs 1%).
    • Difficulty in concentrating (2% vs 1%).
    • Increased need for sleep (2% vs 0%).
Limitations
  • Small number of seropositive children.
  • Lack of information regarding exact time of SARS-CoV-2 infection.
  • Potential misclassification because of false seropositive results.
_____________________________________________________________________________________

Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset
Sophie Steiner, Sonya C. Becker, [...], and Carmen Scheibenbogen
Abstract
Single nucleotide polymorphisms (SNP) in various genes have been described to be associated with susceptibility to autoimmune disease. In this study, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients and controls were genotyped for five immune gene SNPs in tyrosine phosphatase non-receptor type 22 (PTPN22, rs2476601), cytotoxic T-lymphocyte-associated protein 4 (CTLA4, rs3087243), tumor necrosis factor (TNF, rs1800629 and rs1799724), and interferon regulatory factor 5 (IRF5, rs3807306), which are among the most important risk variants for autoimmune diseases. Analysis of 305 ME/CFS patients and 201 healthy controls showed significant associations of the PTPN22 rs2476601 and CTLA4 rs3087243 autoimmunity-risk alleles with ME/CFS. The associations were only found in ME/CFS patients, who reported an acute onset of disease with an infection (PTPN22 rs2476601: OR 1.63, CI 1.04–2.55, p = 0.016; CTLA4 rs3087243: OR 1.53, CI 1.17–2.03, p = 0.001), but not in ME/CFS patients without infection-triggered onset (PTPN22 rs2476601: OR 1.09, CI 0.56–2.14, p = 0.398; CTLA4 rs3087243: OR 0.89, CI 0.61–1.30, p= 0.268). This finding provides evidence that autoimmunity might play a role in ME/CFS with an infection-triggered onset. Both genes play a key role in regulating B and T cell activation.
Keywords: single nucleotide polymorphism (SNP), tyrosine phosphatase non-receptor type 22 (PTPN22), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), interferon regulatory factor 5 (IRF5), tumor necrosis factor (TNF), myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), autoimmunity
_____________________________________________________________________________________

MEDICAL NEWS   Rates of persistent COVID-19 symptoms a year after hospital discharge    Dawn O'Shea   |   30 August 2021
Half of hospitalised COVID-19 survivors experience at least one persistent symptom a year after discharge, suggests a study published in The Lancet.
The study assessed 1276 COVID-19 survivors at six and 12 months following discharge from Jin Yin-tan Hospital in Wuhan, China, between January 7 and May 29, 2020.
At six months, 68 per cent had at least one sequelae symptom, decreasing to 49 per cent at 12 months (P<.0001). The proportion of patients with dyspnoea, characterised by a modified British Medical Research Council (mMRC) score of ≥1, was 26 per cent at six months and 30 per cent at 12 months (P=.014). Additionally, more patients had anxiety or depression at 12 months (26%) than at six months (23%). There was no significant change in distance walked in 6 min (6MWD).
Eighty-eight per cent of patients who were employed before COVID-19 had returned to their original work at 12 months.
Compared with men, women had an odds ratio (OR) for fatigue or muscle weakness (1.43; 95% CI 1.04-1.96), anxiety or depression (OR 2.00; 95% CI 1.48-2.69), and impaired diffusion (OR 2.97; 95% CI 1.50-5.88).
At 12 months, COVID-19 survivors had more problems with mobility, pain or discomfort, and anxiety or depression, and had more prevalent symptoms than controls.

_____________________________________________________________________________________
Front. Med., 07 May 2021 | https://doi.org/10.3389/fmed.2021.672370
Theory: Treatments for Prolonged ICU Patients May Provide New Therapeutic Avenues for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Dominic Stanculescu1, Lars Larsson2 and Jonas Bergquist3,4*
  • 1Independent Researcher, Sint Martens Latem, Belgium
  • 2Basic and Clinical Muscle Biology, Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden
  • 3Analytical Chemistry and Neurochemistry, Department of Chemistry–Biomedical Center, Uppsala University, Uppsala, Sweden
  • 4The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden
We here provide an overview of treatment trials for prolonged intensive care unit (ICU) patients and theorize about their relevance for potential treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these treatment trials generally target: (a) the correction of suppressed endocrine axes, notably through a “reactivation” of the pituitary gland's pulsatile secretion of tropic hormones, or (b) the interruption of the “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. There are significant parallels in the treatment trials for prolonged critical illness and ME/CFS; this is consistent with the hypothesis of an overlap in the mechanisms that prevent recovery in both conditions. Early successes in the simultaneous reactivation of pulsatile pituitary secretions in ICU patients—and the resulting positive metabolic effects—could indicate an avenue for treating ME/CFS. The therapeutic effects of thyroid hormones—including in mitigating O&NS and inflammation and in stimulating the adreno-cortical axis—also merit further studies. Collaborative research projects should further investigate the lessons from treatment trials for prolonged critical illness for solving ME/CFS.

_____________________________________________________________________________________
Adolescent and Young Adult ME/CFS After Confirmed or Probable COVID-19 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116546/#
Lindsay S. Petracek, Stacy J. Suskauer, [...], and Peter C. Rowe
Abstract
Introduction: Fatigue is a common acute symptom following SARS-CoV-2 infection (COVID-19). The presence of persistent fatigue and impaired daily physical and cognitive function has led to speculation that like SARS-CoV-1 infection, COVID-19 will be followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Methods and Results: We describe three adolescent and young adult patients who had confirmed or probable COVID-19 infections early on during the pandemic and were referred for evaluation to the Chronic Fatigue Clinic at the Johns Hopkins Children's Center. All patients reported orthostatic intolerance symptoms within the first 2 weeks of illness, and 10-min passive standing tests were consistent with postural tachycardia syndrome. After 6 months of illness, all three patients met criteria for ME/CFS. Clinical features of interest included strong histories of allergies in all three patients, two of whom had elevations in 
plasma histamine. Each demonstrated limitations in symptom-free range of motion of the limbs and spine and two presented with pathological Hoffman reflexes. These comorbid features have been reported in adolescents and young adults with ME/CFS.
Conclusion: ME/CFS can be triggered by COVID-19 in adolescents and young adults. Further work is needed to determine the pathogenesis of ME/CFS after COVID-19 and optimal methods of treating these patients. Our preliminary study calls attention to several comorbid features that deserve further attention as potential targets for intervention. These include neuromuscular limitations that could be treated with manual forms of therapy, orthostatic intolerance and POTS for which there are multiple medications and non-pharmacologic therapies, treatable allergic and mast cell phenomena, and neurologic abnormalities that may require specific treatment. Larger studies will need to ascertain the prevalence of these abnormalities.

_____________________________________________________________________________________
Post-acute sequelae of COVID-19 in a non-hospitalized cohort: Results from the Arizona CoVHORT
Melanie L. Bell , Collin J. Catalfamo,Leslie V. Farland,Kacey C. Ernst,Elizabeth T. Jacobs,Yann C. Klimentidis, 
Megan Jehn, Kristen Pogreba-Brown

Published: August 4, 2021    https://doi.org/10.1371/journal.pone.0254347

Clinical presentation, outcomes, and duration of COVID-19 has ranged dramatically. While some individuals recover quickly, others suffer from persistent symptoms, collectively known as long COVID, or post-acute sequelae of SARS-CoV-2 (PASC). Most PASC research has focused on hospitalized COVID-19 patients with moderate to severe disease. We used data from a diverse population-based cohort of Arizonans to estimate prevalence of PASC, defined as experiencing at least one symptom 30 days or longer, and prevalence of individual symptoms. There were 303 non-hospitalized individuals with a positive lab-confirmed COVID-19 test who were followed for a median of 61 days (range 30–250). COVID-19 positive participants were mostly female (70%), non-Hispanic white (68%), and on average 44 years old. Prevalence of PASC at 30 days post-infection was 68.7% (95% confidence interval: 63.4, 73.9). The most common symptoms were fatigue (37.5%), shortness-of-breath (37.5%), brain fog (30.8%), and stress/anxiety (30.8%). The median number of symptoms was 3 (range 1–20). Amongst 157 participants with longer follow-up (≥60 days), PASC prevalence was 77.1%.

_____________________________________________________________________________________

Guillain-Barré syndrome after SARS-CoV-2 infection in an international prospective cohort study 
Linda W G Luijten, Sonja E Leonhard, Annemiek A van der Eijk, Alex Y Doets, Luise Appeltshauser, Samuel Arends, Shahram Attarian, Luana Benedetti, Chiara Briani, Carlos Casasnovas  
Brain, awab279, https://doi.org/10.1093/brain/awab279  Published: 23 September 2021

Abstract
In the wake of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, an increasing number of patients with neurological disorders, including Guillain-Barré syndrome (GBS), have been reported following this infection. It remains unclear, however, if these cases are coincidental or not, as most publications were case reports or small regional retrospective cohort studies. The International GBS Outcome Study is an ongoing prospective observational cohort study enrolling patients with GBS within 2 weeks from onset of weakness. Data from patients included in this study, between 30 January 2020 and 30 May 2020, were used to investigate clinical and laboratory signs of a preceding or concurrent SARS-CoV-2 infection and to describe the associated clinical phenotype and disease course. Patients were classified according to the SARS-CoV-2 case definitions of the European Centre for Disease Prevention and Control and laboratory recommendations of the World Health Organization. Forty-nine patients with GBS were included, of whom eight (16%) had a confirmed and three (6%) a probable SARS-CoV-2 infection. Nine of these 11 patients had no serological evidence of other recent preceding infections associated with GBS, whereas two had serological evidence of a recent Campylobacter jejuni infection. Patients with a confirmed or probable SARS-CoV-2 infection frequently had a sensorimotor variant 8/11 (73%) and facial palsy 7/11 (64%). The eight patients who underwent electrophysiological examination all had a demyelinating subtype, which was more prevalent than the other patients included in the same time window [14/30 (47%), P = 0.012] as well as historical region and age-matched control subjects included in the International GBS Outcome Study before the pandemic [23/44 (52%), P = 0.016]. The median time from the onset of infection to neurological symptoms was 16 days (interquartile range 12–22). Patients with SARS-CoV-2 infection shared uniform neurological features, similar to those previously described in other post-viral GBS patients. The frequency (22%) of a preceding SARS-CoV-2 infection in our study population was higher than estimates of the contemporaneous background prevalence of SARS-CoV-2, which may be a result of recruitment bias during the pandemic, but could also indicate that GBS may rarely follow a recent SARS-CoV-2 infection. Consistent with previous studies, we found no increase in patient recruitment during the pandemic for our ongoing International GBS Outcome Study compared to previous years, making a strong relationship of GBS with SARS-CoV-2 unlikely. A case-control study is required to determine if there is a causative link or not.
*
_____________________________________________________________________________________
Exploring Symptom Fluctuations and Triggers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Novel Patient-Centred N-of-1 Observational Designs: A Protocol for a Feasibility and Acceptability Study
Suzanne McDonald, Smuel X. Tan, Shamima Banu, Mieke van Driel, James M. McGree, Geoffrey Mitchell & Jane Nikles 
The Patient - Patient-Centered Outcomes Research (2021)Published: 09 August 2021


Abstract Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic condition of unknown aetiology associated with a range of disabling symptoms, including post-exertional malaise, chronic fatigue, musculoskeletal pain, orthostatic intolerance, unrefreshing sleep, and cognitive dysfunction. ME/CFS is a heterogeneous disorder, with significant variation in symptom type and severity between individuals, as well as within individuals over time. The diversity of ME/CFS symptom presentation makes management challenging; treatments supported by data from randomised controlled trials may not work for all individuals due to the variability in experienced symptoms. Studies using quantitative N-of-1 observational designs involve repeated outcome measurements in an individual over time and can generate rigorous individual-specific conclusions about symptom patterns and triggers in individuals with ME/CFS. This study aims to explore the feasibility and acceptability of using novel patient-centred N-of-1 observational designs to explore symptom fluctuations and triggers in ME/CFS at the individual level.
Methods and Analysis
Individuals with a medical diagnosis of ME/CFS will be recruited through ME/CFS patient organisations to participate in a series of patient-centred N-of-1 observational studies. Using a wrist-worn electronic diary, participants will complete ecological momentary assessments of fatigue, stress, mood, and cognitive demand, three times per day for a period of 6–12 weeks. Personally relevant symptoms and triggers will also be incorporated into the questionnaire design. Physical activity will be objectively measured via an integrated accelerometer. Feasibility and acceptability outcomes will be assessed including the percentage of diary entries completed, as well as recruitment and retention rate, feasibility of analysing and interpreting the data collected, and participant views about participation elicited via a post-study semi-structured interview.
Discussion
This study will assess the feasibility and acceptability of patient-centred N-of-1 observational studies to assess diseases with complex presentations such as ME/CFS, as well as provide individual-level evidence about fluctuations and triggers of ME/CFS symptoms that may aid self-management.

_____________________________________________________________________________________

Causal attributions and perceived stigma for myalgic encephalomyelitis/chronic fatigue syndrome
Laura Froehlich, Daniel BR Hattesohl, Joseph Cotler, .First Published July 9, 2021 Research Article   https://doi.org/10.1177/13591053211027631  J of Health Psychology

Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic disease with the hallmark symptom of post-exertional malaise. Evidence for physiological causes is converging, however, currently no diagnostic test or biomarker is available. People with ME/CFS experience stigmatization, including the perception that the disease is psychosomatic. In a sample of 499 participants with self-diagnosed ME/CFS, we investigated perceived stigma as a pathway through which perceived others’ causal attributions relate to lower satisfaction with social roles and activities and functional status. Higher perceived attributions by others to controllable and unstable causes predicted lower health-related and social outcomes via higher perceived stigma.

_____________________________________________________________________________________

Mayo Clinic Proceedings
Available online 25 August 2021
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management
Author links open overlay panelLucindaBatemanMDaAlison C.BestedMDbHector F.BonillaMDdBela V.ChhedaMDeLilyChuMD, MSHSfJennifer M.CurtinMDeTania T.DempseyMDgMary E.DimmockBAhTheresa G.DowellDNP, MPTiDonnaFelsensteinMDjDavid L.KaufmanMDeNancy G.KlimasMDcAnthony L.KomaroffMDkCharles W.LappMBME, MDlSusan M.LevineMDmJose G.MontoyaMDnBenjamin H.NatelsonMDoDaniel L.PetersonMDp…Brayden P.YellmanMDa
https://doi.org/10.1016/j.mayocp.2021.07.004Get rights and content
Under a Creative Commons license
Abstract
Despite myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affecting millions of people worldwide, many clinicians lack the knowledge to appropriately diagnose or manage ME/CFS. Unfortunately, clinical guidance has been scarce, obsolete, or potentially harmful. Consequently, up to 91% of patients in the United States remain undiagnosed, and those diagnosed often receive inappropriate treatment. These problems are of increasing importance because after acute COVID-19, a significant percentage of people remain ill for many months with an illness similar to ME/CFS. In 2015, the US National Academy of Medicine published new evidence-based clinical diagnostic criteria that have been adopted by the US Centers for Disease Control and Prevention. Furthermore, the United States and other governments as well as major health care organizations have recently withdrawn graded exercise and cognitive-behavioral therapy as the treatment of choice for patients with ME/CFS. Recently, 21 clinicians specializing in ME/CFS convened to discuss best clinical practices for adults affected by ME/CFS. This article summarizes their top recommendations for generalist and specialist health care providers based on recent scientific progress and decades of clinical experience. There are many steps that clinicians can take to improve the health, function, and quality of life of those with ME/CFS, including those in whom ME/CFS develops after COVID-19. Patients with a lingering illness that follows acute COVID-19 who do not fully meet criteria for ME/CFS may also benefit from these approaches.
​
0 Comments

Abstracts from 1 April 2021

14/6/2021

0 Comments

 
Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
International Journal of environmental research and public health.
Joshua Bond, Tessa Nielsen, and Lynette Hodges
Abstract
Background: Evidence is emerging that individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may suffer from chronic vascular dysfunction as a result of illness-related oxidative stress and vascular inflammation. The study aimed to examine the impact of maximal-intensity aerobic exercise on vascular function 48 and 72 h into recovery. Methods:ME/CFS (n = 11) with gender and age-matched controls (n = 11) were randomly assigned to either a 48 h or 72 h protocol. Each participant had measures of brachial blood pressure, augmentation index (AIx75, standardized to 75 bpm) and carotid-radial pulse wave velocity (crPWV) taken. This was followed by a maximal incremental cycle exercise test. Resting measures were repeated 48 or 72 h later (depending on group allocation). Results: No significant differences were found when ME/CFS were directly compared to controls at baseline. During recovery, the 48 h control group experienced a significant 7.2% reduction in AIx75 from baseline measures (p < 0.05), while the matched ME/CFS experienced no change in AIx75. The 72 h ME/CFS group experienced a non-significant increase of 1.4% from baseline measures. The 48 h and 72 h ME/CFS groups both experienced non-significant improvements in crPWV (0.56 ms−1 and 1.55 ms−1, respectively). Conclusions: The findings suggest that those with ME/CFS may not experience exercise-induced vasodilation due to chronic vascular damage, which may be a contributor to the onset of post-exertional malaise (PEM).
Keywords: myalgic encephalomyelitis, chronic fatigue syndrome, arterial stiffness, post-exertional malaise
________________________________________________________________________________
Mortality of people with chronic fatigue syndrome: a retrospective cohort study in England and Wales from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) Register 
Emmert Roberts, Simon Wessely, Trudie Chalder, Chin-Kuo Chang*, Matthew Hotopf*
Lancet 2016; 387: 1638–43
Summary 
Background 
Mortality associated with chronic fatigue syndrome is uncertain. We investigated mortality in individuals diagnosed with chronic fatigue syndrome in secondary and tertiary care using data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) register. 
Methods We calculated standardised mortality ratios (SMRs) for all-cause, suicide-specific, and cancer-specific mortality for a 7-year observation period using the number of deaths observed in SLaM records compared with age specific and sex-specific mortality statistics for England and Wales. Study participants were included if they had had contact with the chronic fatigue service (referral, discharge, or case note entry) and received a diagnosis of chronic fatigue syndrome.
 Findings 
We identified 2147 cases of chronic fatigue syndrome from CRIS and 17 deaths from Jan 1, 2007, to Dec 31, 2013. 1533 patients were women of whom 11 died, and 614 were men of whom six died. There was no significant difference in age-standardised and sex-standardised mortality ratios (SMRs) for all-cause mortality (SMR 1·14, 95% CI 0·65–1·85; p=0·67) or cancer-specific mortality (1·39, 0·60–2·73; p=0·45) in patients with chronic fatigue syndrome when compared with the general population in England and Wales. This remained the case when deaths from suicide were removed from the analysis. There was a significant increase in suicide-specific mortality (SMR 6·85, 95% CI 2·22–15·98; p=0·002).
 Interpretation
 We did not note increased all-cause mortality in people with chronic fatigue syndrome, but our findings show a substantial increase in mortality from suicide. This highlights the need for clinicians to be aware of the increased risk of completed suicide and to assess suicidality adequately in patients with chronic fatigue syndrome. 
________________________________________________________________________________

 2021 Mar 22;8:642710.Front. Med. Lausanne.
 doi: 10.3389/fmed.2021.642710. eCollection 2021.
Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Results From Open-Label Cyclophosphamide Intervention Study
Kari Sørland 1 2, Miriam Kristine Sandvik 3, Ingrid Gurvin Rekeland 1 4, Lis Ribu 2, Milada Cvancarova Småstuen 2, Olav Mella 1 4, Øystein Fluge 1 4
PMID: 33829023 PMCID: PMC8019750 DOI: 10.3389/fmed.2021.642710
Abstract
Introduction: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with a range of symptoms including post-exertional malaise (PEM), orthostatic intolerance, and autonomic dysfunction. Dysfunction of the blood vessel endothelium could be an underlying biological mechanism, resulting in inability to fine-tune regulation of blood flow according to the metabolic demands of tissues. The objectives of the present study were to investigate endothelial function in ME/CFS patients compared to healthy individuals, and assess possible changes in endothelial function after intervention with IV cyclophosphamide. Methods: This substudy to the open-label phase II trial "Cyclophosphamide in ME/CFS" included 40 patients with mild-moderate to severe ME/CFS according to Canadian consensus criteria, aged 18-65 years. Endothelial function was measured by Flow-mediated dilation (FMD) and Post-occlusive reactive hyperemia (PORH) at baseline and repeated after 12 months. Endothelial function at baseline was compared with two cohorts of healthy controls (N = 66 and N = 30) from previous studies. Changes in endothelial function after 12 months were assessed and correlated with clinical response to cyclophosphamide. Biological markers for endothelial function were measured in serum at baseline and compared with healthy controls (N = 30). Results: Baseline FMD was significantly reduced in patients (median FMD 5.9%, range 0.5-13.1, n = 35) compared to healthy individuals (median FMD 7.7%, range 0.7-21, n = 66) (p = 0.005), as was PORH with patient score median 1,331 p.u. (range 343-4,334) vs. healthy individuals 1,886 p.u. (range 808-8,158) (p = 0.003). No significant associations were found between clinical response to cyclophosphamide intervention (reported in 55% of patients) and changes in FMD/PORH from baseline to 12 months. Serum levels of metabolites associated with endothelial dysfunction showed no significant differences between ME/CFS patients and healthy controls. 


Conclusions: Patients with ME/CFS had reduced endothelial function affecting both large and small vessels compared to healthy controls. Changes in endothelial function did not follow clinical responses during follow-up after cyclophosphamide IV intervention.
________________________________________________________________________________

Intramuscular Pressure Is Almost Three Times Higher in Fibromyalgia Patients: A Possible Mechanism for Understanding the Muscle Pain and Tenderness
Robert S. Katz, Frank Leavitt, Alexandra Katz Small and Ben J. Small
The Journal of Rheumatology April 2021, 48 (4) 598-602; DOI: https://doi.org/10.3899/jrheum.191068
Abstract
Objective Widespread pain in fibromyalgia syndrome (FMS) is conventionally viewed as arising from disordered central processing. This study examines intramuscular pressure in the trapezius as an alternative mechanism for understanding FMS pain.
Methods One hundred eight patients who satisfied the American College of Rheumatology criteria for FMS and 30 patients who met the ACR criteria for another rheumatic disease comprised the study groups. Muscle pressure was measured in mmHg using a pressure gauge attached to a no. 22 needle inserted into the mid-portion of the trapezius muscle. In addition, patients with FMS and rheumatic disease controls had dolorimetry testing, digital palpation, and reported pain scores.
Results Muscle pressure was substantially higher in patients with FMS with a mean value of 33.48 ± 5.90 mmHg. Only 2 of 108 patients had muscle pressure of < 23 mmHg. The mean pressure in rheumatic disease controls was 12.23 ± 3.75 mmHg, with a range from 3–22 mmHg. Patients with FMS were more tender than controls based on both dolorimetry (P < 0.001) and digital palpation (P < 0.001). The mean pain score in patients with FMS and controls was 6.68 ± 1.91 and 1.43 ± 1.79, respectively (P < 0.001).
Conclusion Pressure in the trapezius muscle of patients with FMS is remarkably elevated and may be an intrinsic feature of FMS that could be monitored as part of the diagnostic evaluation. The burden of the pressure abnormality may help explain the diffuse muscle pain of FMS. Therefore, FMS as a disorder of exclusively central pain processing should be revisited. Therapeutically, the reduction of muscle pressure may change the clinical picture significantly.
________________________________________________________________________________

021 Apr 12;archdischild-2020-320196.
Recovery from chronic fatigue syndrome: a systematic review-heterogeneity of definition limits study comparison
Yasmin Moore 1, Teona Serafimova 1, Nina Anderson 1 2, Hayley King 1, Alison Richards 1 3, Amberly Brigden 1, Parisa Sinai 1, Julian Higgins 1, Caitlin Ascough 1, Philippa Clery 1, Esther M Crawley 4 5
PMID: 33846138   DOI: 10.1136/archdischild-2020-320196
Abstract
Background: Paediatric chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a common illness with a major impact on quality of life. Recovery is poorly understood. Our aim was to describe definitions of recovery in paediatric CFS/ME, the rate of recovery and the time to recovery.
Methods: This systematic review included a detailed search of MEDLINE, EMBASE, PsycInfo and Cochrane Library between 1994 and July 2018. Inclusion criteria were (1) clinical trials and observational studies, (2) participants aged <19 years with CFS/ME, (3) conducted in Western Healthcare systems and (4) studies including a measure of recovery and time taken to recover.
Results: Twelve papers (10 studies) were identified, involving 826 patients (range 23-135). Recovery rates were highly varied, ranging between 4.5% and 83%.Eleven distinct definitions of recovery were used; six were composite outcomes while five used unidimensional outcomes. Outcome measures used to define recovery were highly heterogeneous. School attendance (n=8), fatigue (n=6) and physical functioning (n=4) were the most common outcomes included in definition of recovery. Only five definitions included a personal measure of recovery.
Implications: Definitions of recovery are highly variable, likely secondary to differences in study design, outcomes used, follow-up and study populations. Heterogeneous definitions of recovery limit meaningful comparison between studies, highlighting the need for a consensus definition going forward. Recovery is probably best defined from the child's own perspective with a single self-reported measure. If composite measures are used for research, there should be agreement on the core outcome set used.

________________________________________________________________________________

Journal of the Neurological Sciences Volume 422, 15 March 2021, 117326
Modulatory effects of cognitive exertion on regional functional connectivity of the salience network in women with ME/CFS: A pilot study
RiccardoMancaa1KatijaKhanb1MicaelaMitolocMatteo De MarcoaLynseyGrievesondRosemaryVarleyeIain D.WilkinsonfAnnalenaVenneria
https://doi.org/10.1016/j.jns.2021.117326 
Highlights
Cognitive effort can induce PEM and worsening of ME/CFS symptoms.
PEM is associated with changes in functional connectivity of the salience network.
Increased right insular FC with frontal areas is associated with symptom worsening.
Abstract
Background
A common symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is post-exertional malaise (PEM). Various brain abnormalities have been observed in patients with ME/CFS, especially in insular and limbic areas, but their link with ME/CFS symptoms is still unclear. This pilot study aimed at investigating the association between PEM in ME/CFS and changes in functional connectivity (FC) of two main networks: the salience network (SN) and the default-mode network (DMN).
Methods
A total of 16 women, 6 with and 10 without ME/CFS, underwent clinical and MRI assessment before and after cognitive exertion. Resting-state FC maps of 7 seeds (3 for the SN and 4 for the DMN) and clinical measures of fatigue, pain and cognition were analysed with repeated-measure models. FC-symptom change associations were also investigated.
Results
Exertion induced increases in fatigue and pain in patients with ME/CFS compared to the control group, while no changes were found in cognitive performance. At baseline, patients showed altered FC between some DMN seeds and frontal areas and stronger FC between all SN seeds and left temporal areas and the medulla. Significantly higher FC increases in patients than in controls were found only between the right insular seed and frontal and subcortical areas; these increases correlated with worsening of symptoms.
Conclusions
Cognitive exertion can induce worsening of ME/CFS-related symptoms. These changes were here associated with strengthening of FC of the right insula with areas involved in reward processing and cognitive control.
________________________________________________________________________________

Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts 
Daniel Missailidis,Oana Sanislav,Claire Y. Allan,Paige K. Smith,Sarah J. Annesley,Paul R. Fisher
Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, VIC 3086, Australia
Monash Health, Melbourne, VIC 3186, Australia
Int. J. Mol. Sci. 2021, 22(4), 2046; https://doi.org/10.3390/ijms22042046
Received: 16 January 2021 / Revised: 8 February 2021 / Accepted: 15 February 2021 / Published: 19 February 2021
Abstract
Although understanding of the biomedical basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is growing, the underlying pathological mechanisms remain uncertain. We recently reported a reduction in the proportion of basal oxygen consumption due to ATP synthesis by Complex V in ME/CFS patient-derived lymphoblast cell lines, suggesting mitochondrial respiratory inefficiency. This was accompanied by elevated respiratory capacity, elevated mammalian target of rapamycin complex 1 (mTORC1) signaling activity and elevated expression of enzymes involved in the TCA cycle, fatty acid β-oxidation and mitochondrial transport. These and other observations led us to hypothesise the dysregulation of pathways providing the mitochondria with oxidisable substrates. In our current study, we aimed to revisit this hypothesis by applying a combination of whole-cell transcriptomics, proteomics and energy stress signaling activity measures using subsets of up to 34 ME/CFS and 31 healthy control lymphoblast cell lines from our growing library. While levels of glycolytic enzymes were unchanged in accordance with our previous observations of unaltered glycolytic rates, the whole-cell proteomes of ME/CFS lymphoblasts contained elevated levels of enzymes involved in the TCA cycle (p = 1.03 × 10−4), the pentose phosphate pathway (p = 0.034, G6PD p = 5.5 × 10−4), mitochondrial fatty acid β-oxidation (p = 9.2 × 10−3), and degradation of amino acids including glutamine/glutamate (GLS p = 0.034, GLUD1 p = 0.048, GOT2 p = 0.026), branched-chain amino acids (BCKDHA p = 0.028, BCKDHB p = 0.031) and essential amino acids (FAH p = 0.036, GCDH p = 0.006). The activity of the major cellular energy stress sensor, AMPK, was elevated but the increase did not reach statistical significance. The results suggest that ME/CFS metabolism is dysregulated such that alternatives to glycolysis are more heavily utilised than in controls to provide the mitochondria with oxidisable substrates. View Full-Text
________________________________________________________________________________

Front Med (Lausanne) . 2021 Mar 22;8:642710. doi: 10.3389/fmed.2021.642710. eCollection 2021.
Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Results From Open-Label Cyclophosphamide Intervention Study
Kari Sørland 1 2, Miriam Kristine Sandvik 3, Ingrid Gurvin Rekeland 1 4, Lis Ribu 2, Milada Cvancarova Småstuen 2, Olav Mella 1 4, Øystein Fluge 1 4
PMID: 33829023 PMCID: PMC8019750  DOI: 10.3389/fmed.2021.642710
Abstract
Introduction: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with a range of symptoms including post-exertional malaise (PEM), orthostatic intolerance, and autonomic dysfunction. Dysfunction of the blood vessel endothelium could be an underlying biological mechanism, resulting in inability to fine-tune regulation of blood flow according to the metabolic demands of tissues. The objectives of the present study were to investigate endothelial function in ME/CFS patients compared to healthy individuals, and assess possible changes in endothelial function after intervention with IV cyclophosphamide. Methods: This substudy to the open-label phase II trial "Cyclophosphamide in ME/CFS" included 40 patients with mild-moderate to severe ME/CFS according to Canadian consensus criteria, aged 18-65 years. Endothelial function was measured by Flow-mediated dilation (FMD) and Post-occlusive reactive hyperemia (PORH) at baseline and repeated after 12 months. Endothelial function at baseline was compared with two cohorts of healthy controls (N = 66 and N = 30) from previous studies. Changes in endothelial function after 12 months were assessed and correlated with clinical response to cyclophosphamide. Biological markers for endothelial function were measured in serum at baseline and compared with healthy controls (N = 30). Results: Baseline FMD was significantly reduced in patients (median FMD 5.9%, range 0.5-13.1, n = 35) compared to healthy individuals (median FMD 7.7%, range 0.7-21, n = 66) (p = 0.005), as was PORH with patient score median 1,331 p.u. (range 343-4,334) vs. healthy individuals 1,886 p.u. (range 808-8,158) (p = 0.003). No significant associations were found between clinical response to cyclophosphamide intervention (reported in 55% of patients) and changes in FMD/PORH from baseline to 12 months. Serum levels of metabolites associated with endothelial dysfunction showed no significant differences between ME/CFS patients and healthy controls. Conclusions: Patients with ME/CFS had reduced endothelial function affecting both large and small vessels compared to healthy controls. Changes in endothelial function did not follow clinical responses during follow-up after cyclophosphamide IV intervention.
________________________________________________________________________________

 Aliment Pharmacol Ther  2021 Jan;53(1):79-86.  doi: 10.1111/apt.16166. Epub 2020 Nov 18.
Randomised clinical trial: high-dose oral thiamine versus placebo for chronic fatigue in patients with quiescent inflammatory bowel disease
Palle Bager 1, Christian Lodberg Hvas 1, Charlotte Lock Rud 1, Jens Frederik Dahlerup 1
PMID: 33210299
Abstract
Background: Fatigue is a burdensome symptom for patients with inflammatory bowel disease (IBD). Few pharmacological interventions have documented effect on fatigue in patients with IBD. A pilot study indicated a 20-day effect with high-dose thiamine.
Aims: To investigate the effect and safety of high-dose oral thiamine (600-1800 mg/d) based on gender and weight on chronic fatigue in patients with quiescent IBD.
Methods: This was a randomised, double-blinded, placebo-controlled crossover trial. Patients had quiescent IBD, severe chronic fatigue and no other explanation for fatigue. Patients were allocated 1:1 to either 1) high-dose oral thiamine for 4 weeks, 4 weeks of washout, 4 weeks of oral placebo or 2) oral placebo for 4 weeks, 4 weeks of washout, 4 weeks of high-dose oral thiamine. Fatigue was measured using the Inflammatory Bowel Disease-Fatigue Questionnaire. The primary outcome was improvement (≥3 points) of fatigue after 4 weeks on thiamine.
Results: Forty patients were enrolled between November 2018 and October 2019. Crossover analysis showed a mean reduction of 4.5 points (95% CI 2.6-6.2) in fatigue after thiamine compared with a mean increase of 0.75 point (95% CI -1.3-2.8; P = 0.0003) after placebo. Furthermore, 55% of group 1 and 75% of group 2 showed an improvement ≥ 3 points while on thiamine compared with 25% of group 1 and 35% of group 2 while on placebo. Only mild side effects were detected.
Conclusion: We showed a significant beneficial effect of high-dose oral thiamine on chronic fatigue in IBD. The treatment was well tolerated.
________________________________________________________________________________

Mysterious Ailment, Mysterious Relief: Vaccines Help Some COVID Long Haulers 
Will Stone – Kaiser Health News
April 16, 2021
.
An estimated 10% to 30% of people who get covid-19 suffer from lingering symptoms of the disease, or what's known as "long covid."
Judy Dodd, who lives in New York City, is one of them. She spent nearly a year plagued by headaches, shortness of breath, extreme fatigue and problems with her sense of smell, among other symptoms.
She said she worried that this "slog through life" was going to be her new normal.
Everything changed after she got her covid vaccine.
"I was like a new person. It was the craziest thing ever," said Dodd, referring to how many of her health problems subsided significantly after her second shot.
As the U.S. pushes to get people vaccinated, a curious benefit is emerging for those with this post-illness syndrome: Their symptoms are easing and, in some cases, fully resolving after vaccination.
It's the latest clue in the immunological puzzle of long covid, a still poorly understood condition that leaves some who get infected with wide-ranging symptoms months after the initial illness.
The notion that a vaccine aimed at preventing the disease may also treat it has sparked optimism among patients, and scientists who study the post-illness syndrome are taking a close look at these stories.
"I didn't expect the vaccine to make people feel better," said Akiko Iwasaki, an immunologist at the Yale School of Medicine who's researching long covid.
"More and more, I started hearing from people with long covid having their symptoms reduced or completely recovering, and that's when I started to get excited because this might be a potential cure for some people."
While promising, it's still too early to know just how many people with long covid feel better as a result of being vaccinated and whether that amounts to a statistically meaningful difference.
In the meantime, Iwasaki and other researchers are beginning to incorporate this question into ongoing studies of long haulers by monitoring their symptoms pre- and post-vaccination and collecting blood samples to study their immune response.
There are several leading theories for why vaccines could alleviate the symptoms of long covid: It's possible the vaccines clear up leftover virus or fragments, interrupt a damaging autoimmune response or in some other way "reset" the immune system.
"It's all biologically plausible and, importantly, should be easy to test," said Dr. Steven Deeks of the University of California-San Francisco, who is also studying the long-term impacts of the coronavirus on patients.
"
Among the patients of Dr. Daniel Griffin at Columbia University Medical Center in New York, "brain fog" and gastrointestinal problems are two of the most common symptoms that seem to resolve post-vaccination.
Griffin, who is running a long-term study of post-covid illness, initially estimated that about 30% to 40% of his patients felt better. Now, he believes the number may be higher, as more patients receive their second dose and see further improvements.
"We've been sort of chipping away at this [long covid] by treating each symptom," he said. "If it's really true that at least 40% of people have significant recovery with a therapeutic vaccination, then, to date, this is the most effective intervention we have for long covid."
A small U.K. study, not yet peer-reviewed, found about 23% of long-covid patients had an "increase in symptom resolution" post-vaccination, compared with about 15% of those who were unvaccinated.
But not all clinicians are seeing the same level of improvement.
Clinicians at post-covid clinics at the University of Washington in Seattle, Oregon Health & Science University in Portland, National Jewish Health in Denver and the University of Pittsburgh Medical Center told NPR and KHN that, so far, a small number of patients — or none at all — have reported feeling better after vaccination, but it wasn't a widespread phenomenon.
"I've heard anecdotes of people feeling worse, and you can scientifically come up with an explanation for it going in either direction," said UCSF's Deeks.

Why Are Patients Feeling Better?
There are several theories for why vaccines could help some patients — each relying on different physiological understandings of long covid, which manifests in a variety of ways.
"The clear story is that long covid isn't just one issue," said Dr. Eric Topol, director of the Scripps Research Translational Institute, which is also studying long covid and the possible therapeutic effects of vaccination.
Some people have fast resting heart rates and can't tolerate exercise. Others suffer primarily from cognitive problems, or some combination of symptoms like exhaustion, trouble sleeping and issues with smell and taste, he said.
As a result, it's likely that different therapies will work better for some versions of long covid than others, said Deeks.
One theory is that people who are infected never fully clear the coronavirus, and a viral "reservoir," or fragments of the virus, persist in parts of the body and cause inflammation and long-term symptoms, said Iwasaki, the Yale immunologist.
According to that explanation, the vaccine might induce an immune response that gives the body extra firepower to beat back the residual infection.
"That would actually be the most straightforward way of getting rid of the disease, because you're getting rid of the source of inflammation," Iwasaki said.
Griffin at Columbia Medical Center said this "viral persistence" idea is supported by what he's seeing in his patients and hearing from other researchers and clinicians. He said patients seem to be improving after receiving any of the covid vaccines, generally about "two weeks later, when it looks like they're having what would be an effective, protective response."
Another possible reason that some patients improve comes from the understanding of long covid as an autoimmune condition, in which the body's immune cells end up damaging its own tissues.
A vaccine could hypothetically kick into gear the "innate immune system" and "dampen the symptoms," but only temporarily, said Iwasaki, who has studied the role of harmful proteins, called autoantibodies, in covid.
This self-destructive immune response happens in a subset of covid patients while they are ill, and the autoantibodies produced can circulate for months later. But it's not yet clear how that may contribute to long covid, said John Wherry, director of the Institute for Immunology at the University of Pennsylvania.
Another theory is that the infection has "miswired" the immune system in some other way and caused chronic inflammation, perhaps like chronic fatigue syndrome, Wherry said. In that scenario, the vaccination might somehow "reset" the immune system.
________________________________________________________________________________

BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n693 (Published 31 March 2021)Cite this as: BMJ 2021;372:n693
Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study
Daniel Ayoubkhani, principal statistician1,  Kamlesh Khunti, professor of primary care diabetes and vascular medicine2,  Vahé Nafilyan, principal statistician1, Thomas Maddox, statistician1,  Ben Humberstone, deputy director of health analysis and life events division1,  Ian Diamond, UK national statistician1,  Amitava Banerjee, associate professor of clinical data science and honorary consultant cardiologist
Accepted 15 March 2021
Abstract
Objective To quantify rates of organ specific dysfunction in individuals with covid-19 after discharge from hospital compared with a matched control group from the general population.
Design Retrospective cohort study.
Setting NHS hospitals in England.
Participants 47 780 individuals (mean age 65, 55% men) in hospital with covid-19 and discharged alive by 31 August 2020, exactly matched to controls from a pool of about 50 million people in England for personal and clinical characteristics from 10 years of electronic health records.
Main outcome measures Rates of hospital readmission (or any admission for controls), all cause mortality, and diagnoses of respiratory, cardiovascular, metabolic, kidney, and liver diseases until 30 September 2020. Variations in rate ratios by age, sex, and ethnicity.
Results Over a mean follow-up of 140 days, nearly a third of individuals who were discharged from hospital after acute covid-19 were readmitted (14 060 of 47 780) and more than 1 in 10 (5875) died after discharge, with these events occurring at rates four and eight times greater, respectively, than in the matched control group. Rates of respiratory disease (P<0.001), diabetes (P<0.001), and cardiovascular disease (P<0.001) were also significantly raised in patients with covid-19, with 770 (95% confidence interval 758 to 783), 127 (122 to 132), and 126 (121 to 131) diagnoses per 1000 person years, respectively. Rate ratios were greater for individuals aged less than 70 than for those aged 70 or older, and in ethnic minority groups compared with the white population, with the largest differences seen for respiratory disease (10.5 (95% confidence interval 9.7 to 11.4) for age less than 70 years v 4.6 (4.3 to 4.8) for age ≥70, and 11.4 (9.8 to 13.3) for non-white v 5.2 (5.0 to 5.5) for white individuals).
Conclusions Individuals discharged from hospital after covid-19 had increased rates of multiorgan dysfunction compared with the expected risk in the general population. The increase in risk was not confined to the elderly and was not uniform across ethnicities. The diagnosis, treatment, and prevention of post-covid syndrome requires integrated rather than organ or disease specific approaches, and urgent research is needed to establish the risk factors.
________________________________________________________________________________

Neural therapy for fibromyalgia: Myth or improving quality of life?
Elif Balevi Batur   Tuğba Atan      First published: 21 September 2020  https://doi.org/10.1111/ijcp.13719    International Journal of Clinical practice
Abstract
Background
Fibromyalgia is a common rheumatic disease, which is thought to be a neuroendocrine dysregulation disorder. Patients’ quality of life (QOL) is severely affected by this disease. Though neural therapy, as a treatment option, attempts to correct the underlying neuroendocrine dysfunction, yet there is no proven evidence of its effect on this disease. The present study aimed to evaluate the effectiveness of neural therapy on pain and functionality in patients with fibromyalgia.
Methods
The study was a 1‐year retrospective cohort study and held in physical medicine and rehabilitation clinics. A total of 60 female patients diagnosed with fibromyalgia were included. Sixty female patients with fibromyalgia were included in this study. Patients were divided into two groups; the first group (n = 30) received neural therapy, the second group (n = 30) received conventional physical therapy and each of the two groups received the same home exercise (stretching, strengthening and aerobic exercises) programme for four weeks. The primer outcomes were visual analogue scale (VAS), Short Form‐36 (SF‐36) and Fibromyalgia Impact Questionnaire (FIQ) scores after the treatment.
Results
The social functioning score exhibited a significant improvement only in the intra‐group comparison of the neural therapy group (P < .001). However, after treatment, the VAS, FIQ and all the SF‐36 parameters, except role limitations because of physical health, were detected to be significantly improved in the neural therapy group compared with the exercise group (P < .001).
Conclusions
Neural therapy may be an effective alternative treatment for improving the QOL in patients with fibromyalgia.
________________________________________________________________________________

Pharmacological Research
Volume 165, March 2021, 105465
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Where will the drugs come from?
Peter L.ToogoodabDaniel J.ClauwcSameerPhadkebDavidHoffmand
https://doi.org/10.1016/j.phrs.2021.105465Get rights and content
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating disease characterized by severe and disabling fatigue that fails to improve with rest; it is commonly accompanied by multifocal pain, as well as sleep disruption, and cognitive dysfunction. Even mild exertion can exacerbate symptoms. The prevalence of ME/CFS in the U.S. is estimated to be 0.5–1.5 % and is higher among females. Viral infection is an established trigger for the onset of ME/CFS symptoms, raising the possibility of an increase in ME/CFS prevalence resulting from the ongoing COVID-19 pandemic. Current treatments are largely palliative and limited to alleviating symptoms and addressing the psychological sequelae associated with long-term disability. While ME/CFS is characterized by broad heterogeneity, common features include immune dysregulation and mitochondrial dysfunction. However, the underlying mechanistic basis of the disease remains poorly understood. Herein, we review the current understanding, diagnosis and treatment of ME/CFS and summarize past clinical studies aimed at identifying effective therapies. We describe the current status of mechanistic studies, including the identification of multiple targets for potential pharmacological intervention, and ongoing efforts towards the discovery of new medicines for ME/CFS treatment.


Graphical abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Where will the drugs come from? P. Toogood, D. Clauw, S. Phadke, D. Hoffman.

Picture

________________________________________________________________________________

Antibody-dependent cell-mediated cytotoxicity (ADCC) in familial myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Alexander P. Sung,Jennifer J.-J. Tang,Michael J. Guglielmo,Julie Smith-Gagen,Lucinda Bateman ,Lydia Navarrete-Galvan, show all
Pages 226-244 | Received 17 Nov 2020, Accepted 12 Jan 2021, Published online: 02 Feb 2021
 ABSTRACT
Background
Chronic fatigue syndrome (CFS) is an illness of unknown origin that may have familial risks. Low natural killer (NK) lymphocyte activity was proposed as a risk for familial CFS in 1998. Since then, there have been many studies of NK lymphocytes in CFS in general populations but few in familial CFS. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK lymphocytes helps control viral infections. ADCC is affected by variant CD16A receptors for antibody that are genetically encoded by FCGR3A.
Methods
This report characterizes ADCC effector NK cell numbers, ADCC activities, and FCGR3A variants of five families each with 2–5 CFS patients, their family members without CFS and unrelated controls. The patients met the Fukuda diagnostic criteria. We determined: CD16Apositive blood NK cell counts; EC50s for NK cell recognition of antibody; ADCC lytic capacity; FCGR3A alleles encoding CD16A variants, ROC tests for biomarkers, and synergistic risks.
Results
CFS patients and their family members had fewer CD16Apositive NK cells, required more antibody, and had ADCC that was lower than the unrelated controls. CFS family members were predominantly genetically CD16A F/F s for the variant with low affinity for antibodies. ROC tests indicated unsuitability of ADCC as a biomarker for CFS because of the low ADCC of family members without CFS. Familial synergistic risk vs. controls was evident for the combination of CD16Apositive NK cell counts with ADCC capacity.
Conclusions
Low ADCC may be a risk factor for familial CFS. Furthermore, characterization of familial CFS represents an opportunity to identify pathogenic mechanisms of CFS.
________________________________________________________________________________

Potential role of microbiome in Chronic Fatigue Syndrome/Myalgic Encephalomyelits (CFS/ME)
Giuseppe Francesco Damiano Lupo,Gabriele Rocchetti, Luigi Lucini,  Lorenzo Lorusso, Elena Manara, Matteo Bertelli, Edoardo Puglisi & Enrica Capelli 
Scientific Reports volume 11, Article number: 7043 (2021)  
Abstract
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a severe multisystemic disease characterized by immunological abnormalities and dysfunction of energy metabolism. Recent evidences suggest strong correlations between dysbiosis and pathological condition. The present research explored the composition of the intestinal and oral microbiota in CFS/ME patients as compared to healthy controls. The fecal metabolomic profile of a subgroup of CFS/ME patients was also compared with the one of healthy controls. The fecal and salivary bacterial composition in CFS/ME patients was investigated by Illumina sequencing of 16S rRNA gene amplicons. The metabolomic analysis was performed by an UHPLC-MS. The fecal microbiota of CFS/ME patients showed a reduction of Lachnospiraceae, particularly Anaerostipes, and an increased abundance of genera Bacteroides and Phascolarctobacterium compared to the non-CFS/ME groups. The oral microbiota of CFS/ME patients showed an increase of Rothia dentocariosa. The fecal metabolomic profile of CFS/ME patients revealed high levels of glutamic acid and argininosuccinic acid, together with a decrease of alpha-tocopherol. Our results reveal microbial signatures of dysbiosis in the intestinal microbiota of CFS/ME patients. Further studies are needed to better understand if the microbial composition changes are cause or consequence of the onset of CFS/ME and if they are related to any of the several secondary symptoms.
________________________________________________________________________________

Perceptions of European ME/CFS Experts Concerning Knowledge and Understanding of ME/CFS among Primary Care Physicians in Europe: A Report from the European ME/CFS Research Network (EUROMENE)
John Cullinan 1, Derek F H Pheby 2, Diana Araja 3, Uldis Berkis 3, Elenka Brenna 4, Jean-Dominique de Korwin 5 6, Lara Gitto 7, Dyfrig A Hughes 8, Rachael M Hunter 9, Dominic Trepel 10 11, Xia Wang-Steverding 12    PMID: 33652747   PMCID: PMC7996783  DOI: 10.3390/medicina57030208
Abstract
Background and Objectives: We have conducted a survey of academic and clinical experts who are participants in the European ME/CFS Research Network (EUROMENE) to elicit perceptions of general practitioner (GP) knowledge and understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and suggestions as to how this could be improved. Materials and Methods: A questionnaire was sent to all national representatives and members of the EUROMENE Core Group and Management Committee. Survey responses were collated and then summarized based on the numbers and percentages of respondents selecting each response option, while weighted average responses were calculated for questions with numerical value response options. Free text responses were analysed using thematic analysis. Results: Overall there were 23 responses to the survey from participants across 19 different European countries, with a 95% country-level response rate. Serious concerns were expressed about GPs' knowledge and understanding of ME/CFS, and, it was felt, about 60% of patients with ME/CFS went undiagnosed as a result. The vast majority of GPs were perceived to lack confidence in either diagnosing or managing the condition. Disbelief, and misleading illness attributions, were perceived to be widespread, and the unavailability of specialist centres to which GPs could refer patients and seek advice and support was frequently commented upon. There was widespread support for more training on ME/CFS at both undergraduate and postgraduate levels. Conclusion: The results of this survey are consistent with the existing scientific literature. ME/CFS experts report that lack of knowledge and understanding of ME/CFS among GPs is a major cause of missed and delayed diagnoses, which renders problematic attempts to determine the incidence and prevalence of the disease, and to measure its economic impact. It also contributes to the burden of disease through mismanagement in its early stages.
Keywords: GP knowledge and understanding; ME/CFS; chronic fatigue syndrome; myalgic encephalomyelitis; primary care.
________________________________________________________________________________

 Clin Med. 2020 Oct 31;9(11):3527.    doi: 10.3390/jcm9113527.
Evidence of Mitochondrial Dysfunction in Fibromyalgia: Deviating Muscle Energy Metabolism Detected Using Microdialysis and Magnetic Resonance
Björn Gerdle 1 2, Bijar Ghafouri 1, Eva Lund 3, Ann Bengtsson 1, Peter Lundberg 2 4, Helene van Ettinger-Veenstra 1 2, Olof Dahlqvist Leinhard 2 4 5, Mikael Fredrik Forsgren 2 4 5
Affiliations expand PMID: 33142767  PMCID: PMC7693920  DOI: 10.3390/jcm9113527
Abstract
In fibromyalgia (FM) muscle metabolism, studies are sparse and conflicting associations have been found between muscle metabolism and pain aspects. This study compared alterations in metabolic substances and blood flow in erector spinae and trapezius of FM patients and healthy controls. FM patients (n = 33) and healthy controls (n = 31) underwent a clinical examination that included pressure pain thresholds and physical tests, completion of a health questionnaire, participation in microdialysis investigations of the etrapezius and erector spinae muscles, and also underwent phosphorus-31 magnetic resonance spectroscopy of the erector spinae muscle. At the baseline, FM had significantly higher levels of pyruvate in both muscles. Significantly lower concentrations of phosphocreatine (PCr) and nucleotide triphosphate (mainly adenosine triphosphate) in erector spinae were found in FM. Blood flow in erector spinae was significantly lower in FM. Significant associations between metabolic variables and pain aspects (pain intensity and pressure pain threshold PPT) were found in FM. Our results suggest that FM has mitochondrial dysfunction, although it is unclear whether inactivity, obesity, aging, and pain are causes of, the results of, or coincidental to the mitochondrial dysfunction. The significant regressions of pain intensity and PPT in FM agree with other studies reporting associations between peripheral biological factors and pain aspects.
________________________________________________________________________________

Front. Med., 28 January 2021 | https://doi.org/10.3389/fmed.2021.628029
Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Dominic Stanculescu1, Lars Larsson2 and Jonas Bergquist3,4*
  • 1Independent Researcher, Sint Martens Latem, Belgium
  • 2Basic and Clinical Muscle Biology, Department of Physiology and Pharmacology, Karolinska Institute, Solna, Sweden
  • 3Analytical Chemistry and Neurochemistry, Department of Chemistry – Biomedical Center, Uppsala University, Uppsala, Sweden
  • 4The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden
Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some intensive care unit (ICU) patients may also underlie Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these mechanisms are: (a) suppression of the pituitary gland's pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. This hypothesis should be investigated through collaborative research projects.
________________________________________________________________________________

Chest: 2021 Feb 10;S0012-3692(21)00256-7.  doi: 10.1016/j.chest.2021.01.082. 
Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Phillip Joseph 1, Carlo Arevalo 2, Rudolf K F Oliveira 3, Mariana Faria-Urbina 4, Donna Felsenstein 5, Anne Louise Oaklander 6, David M Systrom 4    PMID: 33577778
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in approximately 50% of POTS and fibromyalgia patients.
Research question: Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5-immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN?
Study design and methods: We analyzed 1,516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mm Hg, results from 160 patients meeting ME/CFS criteria who had skin biopsy test results were compared with 36 control subjects. Rest-to-peak changes in cardiac output (Qc) were compared with oxygen uptake (Qc/VO2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO2 tertiles.
Results: During exercise, the 160 ME/CFS patients averaged lower RAP (1.9 ± 2 vs 8.3 ± 1.5; P < .0001) and peak VO2 (80% ± 21% vs 101.4% ± 17%; P < .0001) than control subjects. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4% ± 19% vs 99.5% ± 23.8% vs 99.9% ± 19.5% predicted; P < .01). In contrast, systemic oxygen extraction was impaired in high-flow vs low- and normal-flow participants (0.74% ± 0.1% vs 0.88 ± 0.11 vs 0.86 ± 0.1; P < .0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% were consistent with SFN (epidermal innervation ≤5.0% of predicted; P < .0001). Denervation severity did not correlate with exertional measures.
Interpretation: These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance-depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return.
________________________________________________________________________________

Healthcare (Basel)  . 2020 Jun 30;8(3):192.    doi: 10.3390/healthcare8030192.
Two-Day Cardiopulmonary Exercise Testing in Females with a Severe Grade of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison with Patients with Mild and Moderate Disease
C Linda Mc van Campen 1, Peter C Rowe 2, Frans C Visser 1    PMID: 32629923    PMCID: PMC7551790
Abstract
Introduction: Effort intolerance along with a prolonged recovery from exercise and post-exertional exacerbation of symptoms are characteristic features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The gold standard to measure the degree of physical activity intolerance is cardiopulmonary exercise testing (CPET). Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, and that a 2-day CPET protocol further discriminates between ME/CFS patients and sedentary controls. Limited information is present on ME/CFS patients with a severe form of the disease. Therefore, the aim of this study was to compare the effects of a 2-day CPET protocol in female ME/CFS patients with a severe grade of the disease to mildly and moderately affected ME/CFS patients.
Methods and results: We studied 82 female patients who had undergone a 2-day CPET protocol. Measures of oxygen consumption (VO2), heart rate (HR) and workload both at peak exercise and at the ventilatory threshold (VT) were collected. ME/CFS disease severity was graded according to the International Consensus Criteria. Thirty-one patients were clinically graded as having mild disease, 31 with moderate and 20 with severe disease. Baseline characteristics did not differ between the 3 groups. Within each severity group, all analyzed CPET parameters (peak VO2, VO2 at VT, peak workload and the workload at VT) decreased significantly from day-1 to day-2 (p-Value between 0.003 and <0.0001). The magnitude of the change in CPET parameters from day-1 to day-2 was similar between mild, moderate, and severe groups, except for the difference in peak workload between mild and severe patients (p = 0.019). The peak workload decreases from day-1 to day-2 was largest in the severe ME/CFS group (-19 (11) %).
Conclusion: This relatively large 2-day CPET protocol study confirms previous findings of the reduction of various exercise variables in ME/CFS patients on day-2 testing. This is the first study to demonstrate that disease severity negatively influences exercise capacity in female ME/CFS patients. Finally, this study shows that the deterioration in peak workload from day-1 to day-2 is largest in the severe ME/CFS patient group.

________________________________________________________________________________

The impact of tryptophan supplementation on sleep quality: a systematic review, meta-analysis, and meta-regression
Clarinda N Sutanto, Wen Wei Loh, Jung Eun Kim
Nutrition Reviews, nuab027, https://doi.org/10.1093/nutrit/nuab027 Published: 03 May 2021
Abstract
Context
L-tryptophan (Trp) has been documented to aid sleep, but a systematic compilation of its effect on sleep quality is still limited.
Objective
We assessed the effect of Trp supplementation on sleep quality via meta-analysis and meta-regression. The effects of daily Trp dose (<1 g and ≥1 g) were also assessed.
Data sources
A database search was done in PubMed, Medline (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane and a total of 18 articles were collected.
Data extraction
Extracted data from 4 articles were also analyzed using random-effect meta-analysis and meta-regression. Standardized mean difference (SMD) was used in meta-analysis.
Data analysis
Results from the study suggested that Trp supplementation can shorten wake after sleep onset (−81.03 min/g, P = 0.017; SMD, −1.08 min [95%CI, −1.89 to −0.28]). In addition, the group receiving ≥1 g Trp supplementation had a shorter wake after sleep onset than the group with Trp < 1g supplementation (Trp <1 g vs Trp ≥1 g: 56.55 vs 28.91 min; P = 0.001). However, Trp supplementation did not affect other sleep components.
Conclusion
Trp supplementation, especially at ≥1 g can help improve sleep quality.

________________________________________________________________________________

COVID-19 symptoms over time: comparing long-haulers to ME/CFS
Leonard A. Jason,Mohammed F. Islam,Karl Conroy,Joseph Cotler,Chelsea Torres,Mady Johnson & show all
Received 21 Apr 2021, Accepted 22 Apr 2021, Published online: 05 May 2021  
Fatigue,Biomedicine, Health and Behaviouir

ABSTRACT
Introduction
Our objective was to determine which symptoms among long-hauler COVID-19 patients change over time, and how their symptoms compare to another chronic illness group.
Methods
278 long-haulers completed two symptom questionnaires at one time point, with one recounting experiences during the first two weeks of their illness, an average of 21.7 weeks prior. We used a comparison group of 502 patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Participants completed a standardized symptom questionnaire and a list of additional CDC COVID-19 symptoms.
Results
Over time, the long-haulers reported an overall reduction of most symptoms including unrefreshing sleep and post-exertional malaise, but an intensification of neurocognitive symptoms. When compared to ME/CFS, the COVID-19 sample was initially more symptomatic for the immune and orthostatic domains but over time, the long-haulers evidenced significantly less severe symptoms than those with ME/CFS, except in the orthostatic domain. Among the COVID-19 long haulers, several neurocognitive symptoms got worse over time, whereas improvements occurred in most other areas.
Conclusions
These types of differential patterns of symptoms over time might contribute to helping better understand the pathophysiology of those reporting prolonged illness following COVID-19.
________________________________________________________________________________

Sci Rep . 2021 Feb 25;11(1):4541.  doi: 10.1038/s41598-021-83660-9.
Recursive ensemble feature selection provides a robust mRNA expression signature for myalgic encephalomyelitis/chronic fatigue syndrome
Paula I Metselaar 1, Lucero Mendoza-Maldonado 2, Andrew Yung Fong Li Yim 3, Ilias Abarkan 4, Peter Henneman 3, Anje A Te Velde 1, Alexander Schönhuth 5, Jos A Bosch 6 7, Aletta D Kraneveld 4, Alejandro Lopez-Rincon 8 9
Affiliations expand PMID: 33633136  PMCID: PMC7907358
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disorder characterized by disabling fatigue. Several studies have sought to identify diagnostic biomarkers, with varying results. Here, we innovate this process by combining both mRNA expression and DNA methylation data. We performed recursive ensemble feature selection (REFS) on publicly available mRNA expression data in peripheral blood mononuclear cells (PBMCs) of 93 ME/CFS patients and 25 healthy controls, and found a signature of 23 genes capable of distinguishing cases and controls. REFS highly outperformed other methods, with an AUC of 0.92. We validated the results on a different platform (AUC of 0.95) and in DNA methylation data obtained from four public studies on ME/CFS (99 patients and 50 controls), identifying 48 gene-associated CpGs that predicted disease status as well (AUC of 0.97). Finally, ten of the 23 genes could be interpreted in the context of the derailed immune system of ME/CFS.
________________________________________________________________________________

Cytokine networks analysis uncovers further differences between those who develop myalgic encephalomyelitis/chronic fatigue syndrome following infectious mononucleosis
Leonard A. Jason,Joseph Cotler,Mohammed F. Islam,Jacob Furst,Matthew Sorenson &Ben Z. Katz
Pages 45-57 | Received 24 Feb 2021, Accepted 07 Apr 2021, Published online: 18 Apr 2021 
https://doi.org/10.1080/21641846.2021.1915131
ABSTRACT
Background
We followed college students before, during, and after infectious mononucleosis (IM) for the development of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Aim
We used network analysis to study relationships between pre-illness cytokine data amongst three groups of participants: those 30 who went on to develop ME/CFS following IM (and met one case definition), those 18 who went on to develop severe ME/CFS (S-ME-CFS) following IM (and met greater than one case definition), and those 58 who recovered following IM (controls).
Methods
We recruited 4501 college students; approximately 5% developed IM during their enrollment at university. Those who developed IM were evaluated at a 6-month follow-up to determine whether they recovered or met criteria for ME/CFS; those who met >1 set of criteria for ME/CFS were termed S-ME/CFS. Patterns of pre-illness cytokine networks were then classified according to the following characteristics: membership, modularity, Eigen centrality, Total centrality, and mean degree. Network statistics were compared across groups using a one-way analysis of variance (ANOVA).
Results
Those with S-ME/CFS had a more interconnected network of cytokines, whereas recovered controls had more differentiated networks and more subgroupings of cytokine connections. Those with ME/CFS had a network that was denser than the controls, but less dense than those with severe ME/CFS.
Conclusions
The distinct network differences between these three groups implies that there may be biological differences between our three groups of study participants at baseline.
________________________________________________________________________________

Front. Med., 22 March 2021 | https://doi.org/10.3389/fmed.2021.642710
Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome–Results From Open-Label Cyclophosphamide Intervention Study
Kari Sørland1,2*, Miriam Kristine Sandvik3, Ingrid Gurvin Rekeland1,4, Lis Ribu2, Milada Cvancarova Småstuen2, Olav Mella1,4 and Øystein Fluge1,4
  • 1Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
  • 2Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway
  • 3Porsgrunn District Psychiatric Centre, Telemark Hospital Trust, Porsgrunn, Norway
  • 4Department of Clinical Science, Institute of Medicine, University of Bergen, Bergen, Norway
Introduction: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with a range of symptoms including post-exertional malaise (PEM), orthostatic intolerance, and autonomic dysfunction. Dysfunction of the blood vessel endothelium could be an underlying biological mechanism, resulting in inability to fine-tune regulation of blood flow according to the metabolic demands of tissues. The objectives of the present study were to investigate endothelial function in ME/CFS patients compared to healthy individuals, and assess possible changes in endothelial function after intervention with IV cyclophosphamide.
Methods: This substudy to the open-label phase II trial “Cyclophosphamide in ME/CFS” included 40 patients with mild-moderate to severe ME/CFS according to Canadian consensus criteria, aged 18–65 years. Endothelial function was measured by Flow-mediated dilation (FMD) and Post-occlusive reactive hyperemia (PORH) at baseline and repeated after 12 months. Endothelial function at baseline was compared with two cohorts of healthy controls (N = 66 and N = 30) from previous studies. Changes in endothelial function after 12 months were assessed and correlated with clinical response to cyclophosphamide. Biological markers for endothelial function were measured in serum at baseline and compared with healthy controls (N = 30).
Results: Baseline FMD was significantly reduced in patients (median FMD 5.9%, range 0.5–13.1, n = 35) compared to healthy individuals (median FMD 7.7%, range 0.7–21, n = 66) (p = 0.005), as was PORH with patient score median 1,331 p.u. (range 343–4,334) vs. healthy individuals 1,886 p.u. (range 808–8,158) (p = 0.003). No significant associations were found between clinical response to cyclophosphamide intervention (reported in 55% of patients) and changes in FMD/PORH from baseline to 12 months. Serum levels of metabolites associated with endothelial dysfunction showed no significant differences between ME/CFS patients and healthy controls.
Conclusions: Patients with ME/CFS had reduced endothelial function affecting both large and small vessels compared to healthy controls. Changes in endothelial function did not follow clinical responses during follow-up after cyclophosphamide IV intervention.
________________________________________________________________________________

Homebound versus Bedridden Status among Those with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Karl Conroy   Shaun Bhatia  Mohammed Islam and Leonard A. Jason
Center for Community Research, DePaul University, Chicago, IL 60614, USA
Healthcare 2021, 9(2), 106; https://doi.org/10.3390/healthcare9020106
Received: 29 December 2020 / Revised: 16 January 2021 / Accepted: 19 January 2021 / Published: 20 January 2021
(This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)
Abstract
Persons living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) vary widely in terms of the severity of their illness. It is estimated that of those living with ME/CFS in the United States, about 385,000 are homebound. There is a need to know more about different degrees of being homebound within this severely affected group. The current study examined an international sample of 2138 study participants with ME/CFS, of whom 549 were severely affected (operationalized as ‘Homebound’). A subsample of 89 very severely affected participants (operationalized as ‘Homebound-bedridden’) was also examined. The findings showed a significant association between severely and very severely affected participants within the post-exertional malaise (PEM) symptom domain. The implications of these findings are discussed.
________________________________________________________________________________

In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling
Arnaud Germain Susan M. Levine and Maureen R. Hanson *
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Proteomes 2021, 9(1), 6; https://doi.org/10.3390/proteomes9010006
Received: 1 January 2021 / Revised: 24 January 2021 / Accepted: 25 January 2021 / Published: 29 January 2021
(This article belongs to the Special Issue Functional Proteomics 2020)
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease with worldwide prevalence and limited therapies exclusively aimed at treating symptoms. To gain insights into the molecular disruptions in ME/CFS, we utilized an aptamer-based technology that quantified 4790 unique human proteins, allowing us to obtain the largest proteomics dataset yet available for this disease, detecting highly abundant proteins as well as rare proteins over a nine-log dynamic range. We report a pilot study of 20 ME/CFS patients and 20 controls, all females. Significant differences in the levels of 19 proteins between cohorts implicate pathways related to the extracellular matrix, the immune system and cell–cell communication. Outputs of pathway and cluster analyses robustly highlight the ephrin pathway, which is involved in cell–cell signaling and regulation of an expansive variety of biological processes, including axon guidance, angiogenesis, epithelial cell migration, and immune response. Receiver Operating Characteristic (ROC) curve analyses distinguish the plasma proteomes of ME/CFS patients from controls with a high degree of accuracy (Area Under the Curve (AUC) > 0.85), and even higher when using protein ratios (AUC up to 0.95), that include some protein pairs with established biological relevance. Our results illustrate the promise of plasma proteomics for diagnosing and deciphering the molecular basis of ME/CFS.
Brain and Behavior
________________________________________________________________________________

ORIGINAL RESEARCH
Open-label study with the monoamine stabilizer (-)-OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome
Sara Haghighi, Sara Forsmark, Olof Zachrisson, Arvid Carlsson, Marie K. L. Nilsson, Maria L. Carlsson, Robert C. Schuit, Carl-Gerhard Gottfries
First published: 02 February 2021    https://doi.org/10.1002/brb3.2040
Abstract
Objectives
The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (-)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (-)-OSU6162 in ME/CFS was evaluated by means of observer-rated scales and self-assessment rating scales.
Materials and Methods
In the current study using an open-label single-arm design ME/CFS patient received treatment with (-)-OSU6162 during 12 weeks. The patients received the following doses of (-)-OSU6162: 15 mg b.i.d. during the first 4-week period, up to 30 mg b.i.d. during the second 4-week period and up to 45 mg b.i.d. during the third 4-week period, with follow-up visits after 16 and 20 weeks.
Results
Out of 33 included patients, 28 completed the 12 weeks treatment period. (-)-OSU6162 was well tolerated; only one patient discontinued due to an adverse event. Vital signs and physical examinations showed no abnormal changes. Blood analyses showed an increase in serum prolactin. Therapeutically, improvements were seen on the Clinical Global Impression of Change scale, the FibroFatigue scale, the Mental Fatigue Scale, the Fatigue Severity Scale, Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire.
Conclusions
(-)-OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health-related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo-controlled double-blind trials.
________________________________________________________________________________

UK Moves to Revise Guidelines for Treatment of Chronic Fatigue Syndrome
AJN, American Journal of Nursing: March 2021 - Volume 121 - Issue 3 - p 16
doi: 10.1097/01.NAJ.0000737248.67484.2e
Abstract
Advocates hail rejection of debunked exercise and cognitive behavior therapies.
Proposed guidelines for management of myalgic encephalomyelitis, or chronic fatigue syndrome (ME/CFS), from the United Kingdom's National Institute for Health and Care Excellence (NICE) are being hailed for their rejection of graded exercise therapy and cognitive behavior therapy (CBT) as routine treatment. Major medical organizations, advocacy groups, and patients have strongly advocated for NICE to align guidelines with scientific evidence.
The U.S. Centers for Disease Control and Prevention (CDC) in 2017 eliminated these largely useless and, in some cases, harmful therapies from its recommendations. That NICE is now following suit is good news, though many say it is long overdue. Moreover, patients are unlikely to see immediate results as new science can take years to reach clinical practice.
The illness is characterized by debilitating fatigue and difficulty with concentration and memory. An estimated 2.5 million Americans are diagnosed with ME/CFS, most of them women. Because symptoms can range widely and standard laboratory tests yield little insight as to cause, ME/CFS has been viewed as a stress-induced disorder in some women.
Graded exercise therapy and CBT became the go-to therapies for ME/CFS based on findings of a 2011 study, known as PACE, published in the Lancet. According to the study investigators, these treatments produced a sustained improvement in patients' levels of fatigue and physical function, even leading to recovery for some. Top researchers who reviewed the study, however, found major flaws. Patients also reacted negatively, saying the study's results did not reflect their experiences and reinforced inaccurate and stigmatizing beliefs about the illness as a psychological and behavioral disorder. Eventually, over 100 academics, patient groups, and others called for an independent reanalysis of the data. Despite this forceful opposition, the study remained influential with clinicians and continued to underpin treatment recommendations of major medical organizations, including the CDC and NICE.
Perceptions began to change with the 2015 release of the Institute of Medicine's landmark report, Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness, in which the authors described ME/CFS as a “serious, chronic, complex, systemic disease” and cited newly identified biomarkers indicating immunological and neurological dysfunction. The report and continuing pressure from scientists, clinicians, and patients led the CDC to remove recommendations for graded exercise therapy and CBT as its British counterpart, NICE, now proposes to do.--Karen Roush, PhD, RN, FNP-BC, news director
0 Comments
<<Previous
Forward>>

    Abstracts supplied by Dr. Vallings

    Abstracts are updated frequently

    Archives

    December 2024
    July 2024
    May 2024
    March 2024
    January 2024
    October 2023
    August 2023
    June 2023
    April 2023
    February 2023
    December 2022
    October 2022
    August 2022
    June 2022
    April 2022
    January 2022
    December 2021
    October 2021
    August 2021
    June 2021
    April 2021
    February 2021
    December 2020
    October 2020
    July 2020
    May 2020
    February 2020
    December 2019
    October 2019
    July 2019
    April 2019
    November 2018
    April 2018
    January 2018
    June 2017
    October 2016
    July 2016
    March 2016
    November 2015

    Categories

    All

    RSS Feed

Website designed by Chelsea Vallings Graphic Design
Copyright © 2015