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
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
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
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.
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.
- This is the most comprehensive meta-analysis to date covering long COVID.
- Findings underscore the importance of prioritising care for long COVID.
- 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.
- 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.
- 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.
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
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
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.
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