Risk Factors Associated With Post−COVID-19 ConditionA Systematic Review and Meta-analysisVasiliki Tsampasian, MD, MSc1,2; Hussein Elghazaly, MBBS3; Rahul Chattopadhyay, MBBS, MSc1,4; et alMaciej Debski, MD, PhD1,2; Thin Kyi, Phyu Naing, MBBS1,2; Pankaj Garg, PhD1,2; Allan Clark, PhD2; Eleana Ntatsaki, MD(Res), MA5,6; Vassilios S. Vassiliou, MBBS, PhD1,2
JAMA Intern Med. Published online March 23, 2023. doi:10.1001/jamainternmed.2023.0750
Key Points
Question Which individuals are at risk of developing post−COVID-19 condition (PCC)?
Findings This systematic review and meta-analysis of 41 studies including 860 783 patients found that female sex, older age, higher body mass index, smoking, preexisting comorbidities, and previous hospitalization or ICU admission were risk factors significantly associated with developing PCC, and that SARS-CoV-2 vaccination with 2 doses was associated with lower risk of PCC.
Meanings The findings of this systematic review and meta-analysis provide a profile of the characteristics associated with increased risk of developing PCC and suggest that vaccination may be protective against PCC.
Abstract
Importance Post−COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support.
Objective To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC.
Data sources Medline and Embase databases were systematically searched from inception to December 5, 2022.
Study Selection The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients.
Data Extraction and Synthesis Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023.
Main Outcomes and Measures The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19.
Results The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76).
Conclusions and Relevance This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination.
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Regional microglial activation in the substantia nigra is linked with fatigue in MS
Tarun Singhal, View ORCID ProfileSteven Cicero, Hong Pan, Kelsey Carter, Shipra Dubey, Renxin Chu, Bonnie Glanz, Shelley Hurwitz, Shahamat Tauhid, View ORCID ProfileMi-Ae Park, Marie Kijewski, Emily Stern, View ORCID ProfileRohit Bakshi, David Silbersweig, Howard L. Weiner
First published August 7, 2020, DOI: https://doi.org/10.1212/NXI.0000000000000854
Abstract
Objective The goal of our study is to assess the role of microglial activation in MS-associated fatigue (MSAF) using [F-18]PBR06-PET.
Methods Fatigue severity was measured using the Modified Fatigue Impact Scale (MFIS) in 12 subjects with MS (7 relapsing-remitting and 5 secondary progressive) and 10 healthy control participants who underwent [F-18]PBR06-PET. The MFIS provides a total fatigue score as well as physical, cognitive, and psychosocial fatigue subscale scores. Standardized Uptake Value (SUV) 60–90 minute frame PET maps were coregistered to 3T MRI. Voxel-by-voxel analysis using Statistical Parametric Mapping and atlas-based regional analyses were performed. SUV ratios (SUVRs) were global brain normalized.
Results Peak voxel-based level of significance for correlation between total fatigue score and PET uptake was localized to the right substantia nigra (T-score 4.67, p = 0.001). Simi, SUVRs derived from atlas-based segmentation of the substantia nigra showed significant correlation with MFIS (r = 0.76, p = 0.004). On multiple regression, the right substantia nigra was an independent predictor of total MFIS (p = 0.02) and cognitive MFIS subscale values (p = 0.007), after adjustment for age, disability, and depression. Several additional areas of significant correlations with fatigue scores were identified, including the right parahippocampal gyrus, right precuneus, and juxtacortical white matter (all p < 0.05). There was no correlation between fatigue scores and brain atrophy and lesion load in patients with MS.
Conclusion Substantia nigra microglial activation is linked to fatigue in MS. Microglial activation across key brain regions may represent a unifying mechanism for MSAF, and further evaluation of neuroimmunologic basis of MSAF is warranted.
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Deficient butyrate-producing capacity in the gut microbiome is associated with bacterial network disturbances and fatigue symptoms in ME/CFSCheng Guo 1, Xiaoyu Che 2, Thomas Briese 3, Amit Ranjan 1, Orchid Allicock 1, Rachel A Yates 1, Aaron Cheng 1, Dana March 4, Mady Hornig 4, Anthony L Komaroff 5, Susan Levine 6, Lucinda Bateman 7, Suzanne D Vernon 7, Nancy G Klimas 8, Jose G Montoya 9, Daniel L Peterson 10, W Ian Lipkin 11, Brent L Williams 12
PMID: 36758522 DOI: 10.1016/j.chom.2023.01.004 Published: 13 January 2023
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained debilitating fatigue, cognitive dysfunction, gastrointestinal disturbances, and orthostatic intolerance. Here, we report a multi-omic analysis of a geographically diverse cohort of 106 cases and 91 healthy controls that revealed differences in gut microbiome diversity, abundances, functional pathways, and interactions. Faecalibacterium prausnitzii and Eubacterium rectale, which are both recognized as abundant, health-promoting butyrate producers in the human gut, were reduced in ME/CFS. Functional metagenomics, qPCR, and metabolomics of fecal short-chain fatty acids confirmed a deficient microbial capacity for butyrate synthesis. Microbiome-based machine learning classifier models were robust to geographic variation and generalizable in a validation cohort. The abundance of Faecalibacterium prausnitzii was inversely associated with fatigue severity. These findings demonstrate the functional nature of gut dysbiosis and the underlying microbial network disturbance in ME/CFS, providing possible targets for disease classification and therapeutic trials.
Keywords: Faecalibacterium; biomarkers; butyrate; co-abundance network; irritable bowel syndrome; metabolomics; microbiome; myalgic encephalomyelitis/chronic fatigue syndrome; short-chain fatty acids; shotgun metagenomics.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
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Patients With Mild COVID-19 at Risk of Some Post–COVID-19 Condition SymptomsHoward D. Larkin January 18, 2023 JAMA. 2023;329(5):364. 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.
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Cell Host Microbe . 2023 Feb 8;31(2):273-287.e5. doi: 10.1016/j.chom.2023.01.001.
Multi-'omics of gut microbiome-host interactions in short- and long-term myalgic encephalomyelitis/chronic fatigue syndrome patientsRuoyun Xiong 1, Courtney Gunter 2, Elizabeth Fleming 2, Suzanne D Vernon 3, Lucinda Bateman 3, Derya Unutmaz 2, Julia Oh 4 PMID: 36758521
HighlightsMulti-‘omics identified phenotypic, gut microbial, and metabolic biomarkers for ME/CFS
Reduced gut microbial diversity and increased plasma sphingomyelins in ME/CFS
Short-term patients had more severe gut microbial dysbiosis with decreased butyrate
Long-term patients had more significant metabolic and clinical aberrations
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, debilitating disorder manifesting as severe fatigue and post-exertional malaise. The etiology of ME/CFS remains elusive. Here, we present a deep metagenomic analysis of stool combined with plasma metabolomics and clinical phenotyping of two ME/CFS cohorts with short-term (<4 years, n = 75) or long-term disease (>10 years, n = 79) compared with healthy controls (n = 79). First, we describe microbial and metabolomic dysbiosis in ME/CFS patients. Short-term patients showed significant microbial dysbiosis, while long-term patients had largely resolved microbial dysbiosis but had metabolic and clinical aberrations. Second, we identified phenotypic, microbial, and metabolic biomarkers specific to patient cohorts. These revealed potential functional mechanisms underlying disease onset and duration, including reduced microbial butyrate biosynthesis and a reduction in plasma butyrate, bile acids, and benzoate. In addition to the insights derived, our data represent an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.
Keywords: ME/CFS; biomarker; gut microbiome; metabolomics; metagenomics; multi-‘omics.
Copyright © 2023 Elsevier Inc. All rights reserved.
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Association of Post–COVID-19 Condition Symptoms and Employment StatusRoy H. Perlis, MD, MSc1,2; Kristin Lunz Trujillo, PhD3,4; Alauna Safarpour, PhD3,4; et alMauricio Santillana, PhD3; Katherine Ognyanova, PhD5; James Druckman, PhD6; David Lazer, PhD3
JAMA Netw Open. 2023;6(2):e2256152. doi:10.1001/jamanetworkopen.2022.56152
COVID-19 Resource Center
Key Points
Question Is post–COVID-19 condition (PCC), also known as long COVID, associated with differences in employment status that might suggest functional impairment?
Findings Among 15 308 individuals with prior COVID-19 infection, those with PCC were less likely to be employed full-time and more likely to be unemployed. These differences persisted after adjustment for demographic differences between those with and without PCC.
Meaning These findings suggest that individuals with PCC are less likely to be working and to be working full time.
Abstract
Importance Little is known about the functional correlates of post–COVID-19 condition (PCC), also known as long COVID, particularly the relevance of neurocognitive symptoms.
Objective To characterize prevalence of unemployment among individuals who did, or did not, develop PCC after acute infection.
Design, Setting, and Participants This survey study used data from 8 waves of a 50-state US nonprobability internet population-based survey of respondents aged 18 to 69 years conducted between February 2021 and July 2022.
Main Outcomes and Measures The primary outcomes were self-reported current employment status and the presence of PCC, defined as report of continued symptoms at least 2 months beyond initial month of symptoms confirmed by a positive COVID-19 test.
Results The cohort included 15 308 survey respondents with test-confirmed COVID-19 at least 2 months prior, of whom 2236 (14.6%) reported PCC symptoms, including 1027 of 2236 (45.9%) reporting either brain fog or impaired memory. The mean (SD) age was 38.8 (13.5) years; 9679 respondents (63.2%) identified as women and 10 720 (70.0%) were White. Overall, 1418 of 15 308 respondents (9.3%) reported being unemployed, including 276 of 2236 (12.3%) of those with PCC and 1142 of 13 071 (8.7%) of those without PCC; 8229 respondents (53.8%) worked full-time, including 1017 (45.5%) of those with PCC and 7212 (55.2%) without PCC. In survey-weighted regression models excluding retired respondents, the presence of PCC was associated with a lower likelihood of working full-time (odds ratio [OR], 0.71 [95% CI, 0.63-0.80]; adjusted OR, 0.84 [95% CI, 0.74-0.96]) and with a higher likelihood of being unemployed (OR, 1.45 [95% CI, 1.22-1.73]; adjusted OR, 1.23 [95% CI, 1.02-1.48]). The presence of any cognitive symptom was associated with lower likelihood of working full time (OR, 0.70 [95% CI, 0.56-0.88]; adjusted OR, 0.75 [95% CI, 0.59-0.84]).
Conclusions and Relevance PCC was associated with a greater likelihood of unemployment and lesser likelihood of working full time in adjusted models. The presence of cognitive symptoms was associated with diminished likelihood of working full time. These results underscore the importance of developing strategies to treat and manage PCC symptoms.
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Severe Fatigue and Persistent Symptoms at Three Months Following SARS-CoV-2 Infections During the Pre-Delta, Delta, and Omicron Time Periods: A Multicenter Prospective Cohort Study.Gottlieb M1,Wang R2,Yu H3,Spatz ES4,Montoy JC5,Rodriguez R6,Chang AM7,Elmore JG8,Hannikainen PA9,Hill M10,Huebinger RM11,Idris AH12,Lin Z13,Koo K14,McDonald S15,O'Laughlin KN16,Plumb ID17,Santangelo M18,Saydah S17,Willis M19
Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, 27 Jan 2023, :ciad045 DOI: 10.1093/cid/ciad045 PMID: 36705268
Abstract BackgroundMost research on SARS-CoV-2 variants focuses on initial symptomatology with limited data on longer-term sequelae. We sought to characterize the prevalence and differences in prolonged symptoms at three months post SARS-CoV-2-infection across the three major variant time-periods (pre-Delta, Delta, and Omicron).
Methods
This multicenter prospective cohort study of adults with acute illness tested for SARS-CoV-2 compared fatigue severity, fatigue symptoms, individual and organ system-based symptoms, and presence of ≥3 total symptoms across variants among COVID-positive and COVID-negative participants 3 months after their initial SARS-CoV-2 diagnosis. Variant periods were defined by dates with ≥50% dominant strain. We performed a sensitivity analysis using ≥90% dominance threshold and multivariable logistic regression modeling to estimate the independent effects of each variant adjusting for socio-demographic characteristics, baseline health, and vaccine status.
Results
The study included 3,223 participants (2,402 COVID-positive and 821 COVID-negative). Among the COVID-positive cohort, 463 (19.3%) were pre-Delta, 1,198 (49.9%) during Delta, and 741 (30.8%) during Omicron. Prolonged severe fatigue was highest in the pre-Delta COVID-positive cohort compared with Delta and Omicron cohorts (16.7% vs 11.5% vs 12.3%, respectively; p = 0.017), as was presence of ≥3 prolonged symptoms (28.4% vs 21.7% vs 16.0%; p < 0.001). No difference was seen in the COVID-negative cohort between variant time-periods. In multivariable models, there was no difference in severe fatigue between variants. There was decreased odds of having ≥3 symptoms in Omicron compared with other variants; this was not significant after adjusting for vaccination status.
Conclusions
Prolonged symptoms following SARS-CoV-2 infection were more common among participants infected during the pre-Delta period compared with Delta and Omicron periods; however, these differences were no longer significant after adjusting for vaccination status. This suggests a potential beneficial effect of vaccination on the risk of developing long-term symptoms.
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2023 Feb 10;2023.02.09.527892. doi: 10.1101/2023.02.09.527892. Preprint
Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV2Kailin Yin, Michael J Peluso, Reuben Thomas, Min-Gyoung Shin, Jason Neidleman, Xiaoyu Luo, Rebecca Hoh, Khamal Anglin, Beatrice Huang, Urania Argueta, Monica Lopez, Daisy Valdivieso, Kofi Asare, Rania Ibrahim, Ludger Ständker, Scott Lu, Sarah A Goldberg, Sulggi A Lee, Kara L Lynch, J Daniel Kelly, Jeffrey N Martin, Jan Münch, Steven G Deeks, Timothy J Henrich, Nadia R Roan PMID: 36798286 PMCID: PMC9934605AbstractLong COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple "omics" assays (CyTOF, RNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis. Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses. Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.
© Federation of European Neuroscience Societies and John Wiley & Sons Ltd
Edited By: John Foxe Online ISSN: 1460-9568 Volume 57, Issue 4 February 2023
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Exosome-associated mitochondrial DNA from patients with myalgic encephalomyelitis/chronic fatigue syndrome stimulates human microglia to release IL-1βIrene Tsilioni, Benjamin Natelson, Theoharis C. Theoharides
First published: 24 September 2022 https://doi.org/10.1111/ejn.15828
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease that presents with fatigue, sleep disturbances, malaise, and cognitive problems. The pathogenesis of ME/CFS is presently unknown, and serum levels of potential biomarkers have been inconsistent. Here, we show that mitochondrial DNA (mtDNA) associated with serum exosomes, is increased in ME/CFS patients only after exercise. Moreover, exosomes isolated from patients with ME/CFS stimulate significant release of IL-1β from cultured human microglia. These results provide evidence that activation of microglia by serum-derived exosomes may serve as a potential novel pathogenetic factor and target for treatment of ME/CFS.
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Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in AdultsA Systematic Review and Meta-analysisMatthew S. Durstenfeld, MD, MAS1,2; Kaiwen Sun, MD1; Peggy Tahir, MLIS, MA3; et alMichael J. Peluso, MD, MHS, MPhil, DTMH1,4; Steven G. Deeks, MD1,4; Mandar A. Aras, MD, PhD1,5; Donald J. Grandis, MD1,5; Carlin S. Long, MD1,5; Alexis Beatty, MD1,5,6; Priscilla Y. Hsue, MD1,2
JAMA Netw Open. 2022;5(10):e2236057. doi:10.1001/jamanetworkopen.2022.36057 Cardiology October 12, 2022
COVID-19 Resource Center
Key Points
Question Is exercise capacity reduced more than 3 months after SARS-CoV-2 infection among those with long COVID-19 (LC) symptoms compared with recovered individuals without symptoms, and what patterns of limitations on cardiopulmonary exercise testing (CPET) are common?
Findings In this systematic review and meta-analysis of 38 studies comprising 2160 participants, exercise capacity was reduced by 4.9 mL/kg/min among individuals with symptoms consistent with LC compared with individuals without symptoms more than 3 months after SARS-CoV-2 infection. Findings among individuals with exertional intolerance suggest that deconditioning, dysfunctional breathing, chronotropic incompetence, and abnormal peripheral oxygen extraction and/or use may contribute to reduced exercise capacity.
Meaning These findings suggest that CPET may provide insight into the mechanisms for reduced exercise capacity among individuals with LC.
Abstract
Importance Reduced exercise capacity is commonly reported among individuals with COVID-19 symptoms more than 3 months after SARS-CoV-2 infection (long COVID-19 [LC]). Cardiopulmonary exercise testing (CPET) is the criterion standard to measure exercise capacity and identify patterns of exertional intolerance.
Objectives To estimate the difference in exercise capacity among individuals with and without LC symptoms and characterize physiological patterns of limitations to elucidate possible mechanisms of LC.
Data Sources A search of PubMed, EMBASE, Web of Science, preprint servers, conference abstracts, and cited references was performed on December 20, 2021, and again on May 24, 2022. A preprint search of medrxiv.org, biorxiv.org, and researchsquare.com was performed on June 9, 2022.
Study Selection Studies of adults with SARS-CoV-2 infection more than 3 months earlier that included CPET-measured peak oxygen consumption (V̇o2) were screened independently by 2 blinded reviewers; 72 (2%) were selected for full-text review, and 35 (1%) met the inclusion criteria. An additional 3 studies were identified from preprint servers.
Data Extraction and Synthesis Data extraction was performed by 2 independent reviewers according to the PRISMA reporting guideline. Data were pooled using random-effects models.
Main Outcomes and Measures Difference in peak V̇o2 (in mL/kg/min) among individuals with and without persistent COVID-19 symptoms more than 3 months after SARS-CoV-2 infection.
Results A total of 38 studies were identified that performed CPET on 2160 individuals 3 to 18 months after SARS-CoV-2 infection, including 1228 with symptoms consistent with LC. Most studies were case series of individuals with LC or cross-sectional assessments within posthospitalization cohorts. Based on a meta-analysis of 9 studies including 464 individuals with LC symptoms and 359 without symptoms, the mean peak V̇o2 was −4.9 (95% CI, −6.4 to −3.4) mL/kg/min among those with symptoms with a low degree of certainty. Deconditioning and peripheral limitations (abnormal oxygen extraction) were common, but dysfunctional breathing and chronotropic incompetence were also described. The existing literature was limited by small sample sizes, selection bias, confounding, and varying symptom definitions and CPET interpretations, resulting in high risk of bias and heterogeneity.
Conclusions and Relevance The findings of this systematic review and meta-analysis study suggest that exercise capacity was reduced more than 3 months after SARS-CoV-2 infection among individuals with symptoms consistent with LC compared with individuals without LC symptoms, with low confidence. Potential mechanisms for exertional intolerance other than deconditioning include altered autonomic function (eg, chronotropic incompetence, dysfunctional breathing), endothelial dysfunction, and muscular or mitochondrial pathology.
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Front. Mol. Biosci., 14 December 2022
Sec. Molecular Diagnostics and Therapeutics
Volume 9 - 2022 | https://doi.org/10.3389/fmolb.2022.1044964
Tissue specific signature of HHV-6 infection in ME/CFSFrancesca Kasimir1†, Danny Toomey2†, Zheng Liu1, Agnes C. Kaiping1, Maria Eugenia Ariza3 and Bhupesh K. Prusty1*
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Severe and Very Severe Myalgic Encephalopathy/Chronic Fatigue Syndrome ME/CFS in Norway: Symptom Burden and Access to CareKristian Sommerfelt Trude Schei 2 and Arild Angelsen
Children and Youth Clinic, Institute of Clinical Medicine 2, University of Bergen, P.O. Box 7804, 5020 Bergen, Norway
Norwegian ME Association, Nedre Slottsgate 4 M, 0157 Oslo, Norway
School of Economics and Business, Norwegian University of Life Sciences (NMBU), P.O. Box 5003, 1432 Ås, Norway
*
J. Clin. Med. 2023, 12(4), 1487; https://doi.org/10.3390/jcm12041487
Received: 22 January 2023 / Revised: 6 February 2023 / Accepted: 9 February 2023 / Published: 13 February 2023
(This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Epidemiology, Treatment and Prognosis)
AbstractThere is a striking lack of systematic knowledge regarding the symptom burden, capacity for activities of daily living, and supportive measures for the most severely ill ME/CFS patients. The present study seeks to address this through a national, Internet-based survey targeting patients with severe and very severe ME/CFS and their carers. Responses from 491 patients were included, with 444 having severe and 47 very severe ME/CFS with the classification based on the best estimate from patient responses. In addition, 95 respondents were reclassified from patients’ own classification to moderate and included for comparison. The onset was before 15 years of age for 45% in the very severe and 32% in the severe group. Disease duration was more than 15 years for 19% in the very severe and 27% in the severe group. Patient symptom burden was extensive. The most severely affected were totally bedridden, unable to talk, and experienced dramatic worsening of symptoms after minimal activity or sensory stimuli. Care and assistance from healthcare and social services were often described as insufficient or inadequate, often worsening the symptom load and burden of care. A substantial lack of disease knowledge among healthcare providers in general was reported. Yet approximately 60% in the severe and very severe groups found services provided by occupational therapists and family doctors (general practitioners) helpful, while a smaller proportion experienced appropriate help from other health personnel groups. This indicates that help and support are highly needed and possible to provide. On the other hand, this must be approached carefully, as a substantial number of patients experienced deterioration from contact with healthcare personnel. Family carers described an extensive burden of care with often inadequate help from healthcare providers or municipal authorities. Patient care by family members of very severe ME/CFS patients constituted more than 40 h a week for 71% of this patient group. The carers described a large negative impact on their work and financial situation, and on their mental wellbeing. We conclude that childhood onset was common, burden of disease was extensive, and support from responsible societal health and social support providers was commonly grossly inadequate.
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Unexplained post-acute infection syndromesJan Choutka, Viraj Jansari, Mady Hornig & Akiko Iwasaki
Nature Medicine volume 28, pages911–923 (2022) Review Article Published: 18 May
Abstract
SARS-CoV-2 is not unique in its ability to cause post-acute sequelae; certain acute infections have long been associated with an unexplained chronic disability in a minority of patients. These post-acute infection syndromes (PAISs) represent a substantial healthcare burden, but there is a lack of understanding of the underlying mechanisms, representing a significant blind spot in the field of medicine. The relatively similar symptom profiles of individual PAISs, irrespective of the infectious agent, as well as the overlap of clinical features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggest the potential involvement of a common etiopathogenesis. In this Review, we summarize what is known about unexplained PAISs, provide context for post-acute sequelae of SARS-CoV-2 infection (PASC), and delineate the need for basic biomedical research into the underlying mechanisms behind this group of enigmatic chronic illnesses.
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Risk Factors Associated With Post−COVID-19 ConditionA Systematic Review and Meta-analysisVasiliki Tsampasian, MD, MSc1,2; Hussein Elghazaly, MBBS3; Rahul Chattopadhyay, MBBS, MSc1,4; et alMaciej Debski, MD, PhD1,2; Thin Kyi Phyu Naing, MBBS1,2; Pankaj Garg, PhD1,2; Allan Clark, PhD2; Eleana Ntatsaki, MD(Res), MA5,6; Vassilios S. Vassiliou, MBBS, PhD1,2
JAMA Intern Med. Published online March 23, 2023. doi:10.1001/jamainternmed.2023.0750
Key Points
Question Which individuals are at risk of developing post−COVID-19 condition?
Findings This systematic review and meta-analysis of 41 studies including 860 783 patients found that female sex, older age, higher body mass index, smoking, preexisting comorbidities, and previous hospitalization or ICU admission were risk factors significantly associated with developing PCC, and that SARS-CoV-2 vaccination with 2 doses was associated with lower risk of PCC.
Meanings The findings of this systematic review and meta-analysis provide a profile of the characteristics associated with increased risk of developing PCC and suggest that vaccination may be protective against PCC.
Abstract
Importance Post−COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support.
Objective To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC.
Data sources Medline and Embase databases were systematically searched from inception to December 5, 2022.
Study Selection The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients.
Data Extraction and Synthesis Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023.
Main Outcomes and Measures The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19.
Results The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76).
Conclusions and Relevance This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination.
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The Behavior of Muscle Oxygen Saturation, Oxy and Deoxy Hemoglobin during a Fatigue Test in FibromyalgiaSantos Villafaina 1, Pablo Tomas-Carus 2 3, Vanda Silva 4, Ana Rodrigues Costa 5, Orlando Fernandes 2 3, Jose A Parraca 2 3 PMID: 36672640 PMCID: PMC9856161 DOI: 10.3390/biomedicines11010132 2023 Jan 4;11(1):132. doi: 10.3390/biomedicines11010132.
AbstractPrevious studies have reported that people with fibromyalgia (FM) could suffer from mitochondrial dysfunction. However, the consumption of muscle oxygen during physical exercise has been poorly studied. Therefore, this study aimed to explore the response of muscle oxygen during a fatigue protocol in people with FM and healthy controls (HC). In addition, the peak torque and the total work were assessed. A total of 31 participants (eighteen were people with fibromyalgia and thirteen were healthy controls) were enrolled in this cross-sectional study. All the participants underwent a fatigue protocol consisting of 20 repetitions at 180°·s−1 of quadriceps flexions and extensions using a Biodex System 3. The muscle oxygen saturation (SmO2), total hemoglobin (THb), deoxygenated hemoglobin (HHb) and oxygenated hemoglobin (O2Hb) values were measured using a portable near-infrared spectroscopy (NIRS) device. Significant differences between people with FM and healthy controls were found at baseline: SmO2 (FM: 56.03 ± 21.36; HC: 77.41 ± 10.82; p = 0.036), O2Hb (FM: 6.69 ± 2.59; HC: 9.37 ± 1.31; p = 0.030) and HHb (FM: 5.20 ± 2.51; HC: 2.73 ± 1.32; p = 0.039); during the fatigue protocol: SmO2 (FM: 48.54 ± 19.96; HC: 58.87 ± 19.72; p = 0.038), O2Hb (FM: 5.70 ± 2.34; HC: 7.06 ± 2.09; p = 0.027) and HHb (FM: 5.69 ± 2.65; HC: 4.81 ± 2.39; p = 0.048); and in the recovery at three min and six min for SmO2, O2Hb and HHb (p < 0.005). Furthermore, healthy control values of SmO2, O2Hb and HHb have been significantly altered by the fatigue protocol (p < 0.005). In contrast, people with FM did not show any significant alteration in these values. Moreover, significant differences were found in the peak torque at extension (FM: 62.48 ± 24.45; HC: 88.31 ± 23.51; p = 0.033) and flexion (FM: 24.16 ± 11.58; HC: 42.05 ± 9.85; p = 0.010), and the total work performed at leg extension (FM: 1039.78 ± 434.51; HC: 1535.61 ± 474.22; p = 0.007) and flexion (FM: 423.79 ± 239.89; HC: 797.16 ± 194.37; p = 0.005).
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Factors Influencing the Prognosis of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Diagnostics
Academic Editor: François-Jérôme Authier Received: 19 September 2022 Accepted: 17 October 2022 Published: 19 October 202
Alaa Ghali 1,* , Carole Lacout 1 , Jacques-Olivier Fortrat 2 , Karine Depres 1 , Maria Ghali 3 and Christian Lavigne 1 1 Department of Internal Medicine and Clinical Immunology, Angers University Hospital, F-49000 Angers, France 2 Department of Vascular Medicine,
Abstract: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term debilitating multisystem condition with poor prognosis. Studies that examined predictors of ME/CFS outcomes yielded contradictory results. We aimed to explore epidemiological and clinical prognostic factors of ME/CFS using operationalized criteria for recovery/improvement. Adult ME/CFS patients who attended the Internal Medicine Department of Angers University Hospital, Angers, France between October 2011 and December 2019, and were followed up until December 2020, were included retrospectively.
Their medical records were reviewed for data collection. Patients were classified into two groups according to the presence or absence of recovery/improvement (R/I) and compared for epidemiological characteristics, fatigue features, post-exertional malaise severity, clinical manifestations, and comorbidities. The subgroups of recovered and significantly improved patients were then compared. 168 patients were included. Recovery and improvement rates were 8.3% and 4.8%, respectively. Older age at disease onset was associated with R/I (OR 1.06 [95% CI 1.007–1.110] (p = 0.028)), while diagnostic delay was inversely associated with R/I (OR 0.98 [95% CI 0.964–0.996] (p = 0.036)). The study findings confirmed the poor prognosis of ME/CFS and the deleterious effect of diagnostic delay on disease progression. Interestingly, being older at disease onset was associated with better outcomes, which offers hope to patients for recovery/improvement even at an advanced age.
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Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue SyndromeElisabeth Petter, Carmen Scheibenbogen, Peter Linz, Christian Stehning, Klaus Wirth, Titus Kuehne & Marcus Kelm
Journal of Translational Medicine volume 20, Pub: 09 December 2022
Article number: 580 (2022)
AbstractBackgroundMuscle fatigue and pain are key symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Although the pathophysiology is not yet fully understood, there is ample evidence for hypoperfusion which may result in electrolyte imbalance and sodium overload in muscles. Therefore, the aim of this study was to assess levels of sodium content in muscles of patients with ME/CFS and to compare these to healthy controls.
MethodsSix female patients with ME/CFS and six age, BMI and sex matched controls underwent 23Na-MRI of the left lower leg using a clinical 3T MR scanner before and after 3 min of plantar flexion exercise. Sodium reference phantoms with solutions of 10, 20, 30 and 40 mmol/L NaCl were used for quantification. Muscle sodium content over 40 min was measured using a dedicated plugin in the open-source DICOM viewer Horos. Handgrip strength was measured and correlated with sodium content.
ResultsBaseline tissue sodium content was higher in all 5 lower leg muscle compartments in ME/CFS compared to controls. Within the anterior extensor muscle compartment, the highest difference in baseline muscle sodium content between ME/CFS and controls was found (mean ± SD; 12.20 ± 1.66 mM in ME/CFS versus 9.38 ± 0.71 mM in controls, p = 0.0034). Directly after exercise, tissue sodium content increased in gastrocnemius and triceps surae muscles with + 30% in ME/CFS (p = 0.0005) and + 24% in controls (p = 0.0007) in the medial gastrocnemius muscle but not in the extensor muscles which were not exercised. Compared to baseline, the increase of sodium content in medial gastrocnemius muscle was stronger in ME/CFS than in controls with + 30% versus + 17% to baseline at 12 min (p = 0.0326) and + 29% versus + 16% to baseline at 15 min (p = 0.0265). Patients had reduced average handgrip strength which was associated with increased average muscle tissue sodium content (p = 0.0319, R2 = 0.3832).
ConclusionMuscle sodium content before and after exercise was higher in ME/CFS than in healthy controls. Furthermore, our findings indicate an inverse correlation between muscle sodium content and handgrip strength. These findings provide evidence that sodium overload may play a role in the pathophysiology of ME/CFS and may allow for potential therapeutic targeting.
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Long COVID: major findings, mechanisms and recommendationsHannah E. Davis, Lisa McCorkell, Julia Moore Vogel & Eric J. Topol
Nature Reviews Microbiology volume 21, pages133–146 (2023)Cite this article
Abstract
Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.
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Griffith University researchers identify similar brain structure changes in both chronic fatigue syndrome and long COVIDBy Janelle Miles
Posted Tue 14 Mar 2023 at 8:36amTuesday 14 Mar 2023 at 8:36am, updated Wed 15 Mar 2023 at 11:45amWednesday 15 Mar 2023 at 11:45am
abc.net.au/news/long-covid-queensland-research-chronic-fatigue-syndrome/102089452
In a world-first study, Queensland researchers have identified similar changes in brain structure among people who have long COVID and chronic fatigue syndrome.
Key points:
Eight had long COVID, 10 people had been diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and 10 were healthy volunteers.
The researchers, from Griffith's National Centre for Neuroimmunology and Emerging Diseases, found the brainstem was significantly larger in long COVID patients and those with ME/CFS compared to people who had never been diagnosed with either ailment.
"Structural changes in the brain stem of ME/CFS and long COVID patients could result in severe and varied deficits in brain function," they wrote in a study published in the journal, Frontiers in Neuroscience.
"The symptom overlap between ME/CFS and long COVID patients is consistent with our current findings of similar abnormalities in the brainstem."
Lead researcher Kiran Thapaliya said brain stem similarities in people with long COVID and ME/CFS patients may explain why they exhibited common core symptoms, such as brain fog, fatigue, pain and breathing difficulties.
Dr Thapaliya, a Griffith University research fellow, said the researchers were recruiting more people to continue to investigate the findings of their pilot study in a larger number of patients with long COVID and ME/CFS.
They used a high-resolution MRI machine at the University of Queensland's Centre for Advanced Imaging for the pilot study.
"This specialised MRI provides crisp images and also greater detailed information … and uncovered abnormalities that might not be detected in other MRIs," Dr Thapaliya said.
Professor Sonya Marshall-Gradnisnik, director of Griffith's National Centre for Neuroimmunology and Emerging Diseases, said the purpose of the study was to demonstrate potential consistencies between ME/CFS and long COVID patients.
Brain scans of a Long COVID patient (left) and a chronic fatigue patient (right).(Supplied: Griffith University)
The research comes seven months after Griffith University researchers reported a shared link in the pathology of long COVID and ME/CFS.
In the first study of its kind in the world to identify a biological overlap between the two conditions, they reported similar damage to receptors on cells – described as like a dysfunctional lock and key – which fail to allow enough calcium in.
"Patients can experience different symptoms depending on which cells in the body are affected – from brain fog and muscle fatigue to possible organ failure," Professor Marshall-Gradnisnik has said previously.
JAMA Intern Med. Published online March 23, 2023. doi:10.1001/jamainternmed.2023.0750
Key Points
Question Which individuals are at risk of developing post−COVID-19 condition (PCC)?
Findings This systematic review and meta-analysis of 41 studies including 860 783 patients found that female sex, older age, higher body mass index, smoking, preexisting comorbidities, and previous hospitalization or ICU admission were risk factors significantly associated with developing PCC, and that SARS-CoV-2 vaccination with 2 doses was associated with lower risk of PCC.
Meanings The findings of this systematic review and meta-analysis provide a profile of the characteristics associated with increased risk of developing PCC and suggest that vaccination may be protective against PCC.
Abstract
Importance Post−COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support.
Objective To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC.
Data sources Medline and Embase databases were systematically searched from inception to December 5, 2022.
Study Selection The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients.
Data Extraction and Synthesis Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023.
Main Outcomes and Measures The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19.
Results The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76).
Conclusions and Relevance This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination.
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Regional microglial activation in the substantia nigra is linked with fatigue in MS
Tarun Singhal, View ORCID ProfileSteven Cicero, Hong Pan, Kelsey Carter, Shipra Dubey, Renxin Chu, Bonnie Glanz, Shelley Hurwitz, Shahamat Tauhid, View ORCID ProfileMi-Ae Park, Marie Kijewski, Emily Stern, View ORCID ProfileRohit Bakshi, David Silbersweig, Howard L. Weiner
First published August 7, 2020, DOI: https://doi.org/10.1212/NXI.0000000000000854
Abstract
Objective The goal of our study is to assess the role of microglial activation in MS-associated fatigue (MSAF) using [F-18]PBR06-PET.
Methods Fatigue severity was measured using the Modified Fatigue Impact Scale (MFIS) in 12 subjects with MS (7 relapsing-remitting and 5 secondary progressive) and 10 healthy control participants who underwent [F-18]PBR06-PET. The MFIS provides a total fatigue score as well as physical, cognitive, and psychosocial fatigue subscale scores. Standardized Uptake Value (SUV) 60–90 minute frame PET maps were coregistered to 3T MRI. Voxel-by-voxel analysis using Statistical Parametric Mapping and atlas-based regional analyses were performed. SUV ratios (SUVRs) were global brain normalized.
Results Peak voxel-based level of significance for correlation between total fatigue score and PET uptake was localized to the right substantia nigra (T-score 4.67, p = 0.001). Simi, SUVRs derived from atlas-based segmentation of the substantia nigra showed significant correlation with MFIS (r = 0.76, p = 0.004). On multiple regression, the right substantia nigra was an independent predictor of total MFIS (p = 0.02) and cognitive MFIS subscale values (p = 0.007), after adjustment for age, disability, and depression. Several additional areas of significant correlations with fatigue scores were identified, including the right parahippocampal gyrus, right precuneus, and juxtacortical white matter (all p < 0.05). There was no correlation between fatigue scores and brain atrophy and lesion load in patients with MS.
Conclusion Substantia nigra microglial activation is linked to fatigue in MS. Microglial activation across key brain regions may represent a unifying mechanism for MSAF, and further evaluation of neuroimmunologic basis of MSAF is warranted.
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Deficient butyrate-producing capacity in the gut microbiome is associated with bacterial network disturbances and fatigue symptoms in ME/CFSCheng Guo 1, Xiaoyu Che 2, Thomas Briese 3, Amit Ranjan 1, Orchid Allicock 1, Rachel A Yates 1, Aaron Cheng 1, Dana March 4, Mady Hornig 4, Anthony L Komaroff 5, Susan Levine 6, Lucinda Bateman 7, Suzanne D Vernon 7, Nancy G Klimas 8, Jose G Montoya 9, Daniel L Peterson 10, W Ian Lipkin 11, Brent L Williams 12
PMID: 36758522 DOI: 10.1016/j.chom.2023.01.004 Published: 13 January 2023
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained debilitating fatigue, cognitive dysfunction, gastrointestinal disturbances, and orthostatic intolerance. Here, we report a multi-omic analysis of a geographically diverse cohort of 106 cases and 91 healthy controls that revealed differences in gut microbiome diversity, abundances, functional pathways, and interactions. Faecalibacterium prausnitzii and Eubacterium rectale, which are both recognized as abundant, health-promoting butyrate producers in the human gut, were reduced in ME/CFS. Functional metagenomics, qPCR, and metabolomics of fecal short-chain fatty acids confirmed a deficient microbial capacity for butyrate synthesis. Microbiome-based machine learning classifier models were robust to geographic variation and generalizable in a validation cohort. The abundance of Faecalibacterium prausnitzii was inversely associated with fatigue severity. These findings demonstrate the functional nature of gut dysbiosis and the underlying microbial network disturbance in ME/CFS, providing possible targets for disease classification and therapeutic trials.
Keywords: Faecalibacterium; biomarkers; butyrate; co-abundance network; irritable bowel syndrome; metabolomics; microbiome; myalgic encephalomyelitis/chronic fatigue syndrome; short-chain fatty acids; shotgun metagenomics.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
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Patients With Mild COVID-19 at Risk of Some Post–COVID-19 Condition SymptomsHoward D. Larkin January 18, 2023 JAMA. 2023;329(5):364. 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.
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Cell Host Microbe . 2023 Feb 8;31(2):273-287.e5. doi: 10.1016/j.chom.2023.01.001.
Multi-'omics of gut microbiome-host interactions in short- and long-term myalgic encephalomyelitis/chronic fatigue syndrome patientsRuoyun Xiong 1, Courtney Gunter 2, Elizabeth Fleming 2, Suzanne D Vernon 3, Lucinda Bateman 3, Derya Unutmaz 2, Julia Oh 4 PMID: 36758521
HighlightsMulti-‘omics identified phenotypic, gut microbial, and metabolic biomarkers for ME/CFS
Reduced gut microbial diversity and increased plasma sphingomyelins in ME/CFS
Short-term patients had more severe gut microbial dysbiosis with decreased butyrate
Long-term patients had more significant metabolic and clinical aberrations
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, debilitating disorder manifesting as severe fatigue and post-exertional malaise. The etiology of ME/CFS remains elusive. Here, we present a deep metagenomic analysis of stool combined with plasma metabolomics and clinical phenotyping of two ME/CFS cohorts with short-term (<4 years, n = 75) or long-term disease (>10 years, n = 79) compared with healthy controls (n = 79). First, we describe microbial and metabolomic dysbiosis in ME/CFS patients. Short-term patients showed significant microbial dysbiosis, while long-term patients had largely resolved microbial dysbiosis but had metabolic and clinical aberrations. Second, we identified phenotypic, microbial, and metabolic biomarkers specific to patient cohorts. These revealed potential functional mechanisms underlying disease onset and duration, including reduced microbial butyrate biosynthesis and a reduction in plasma butyrate, bile acids, and benzoate. In addition to the insights derived, our data represent an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.
Keywords: ME/CFS; biomarker; gut microbiome; metabolomics; metagenomics; multi-‘omics.
Copyright © 2023 Elsevier Inc. All rights reserved.
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Association of Post–COVID-19 Condition Symptoms and Employment StatusRoy H. Perlis, MD, MSc1,2; Kristin Lunz Trujillo, PhD3,4; Alauna Safarpour, PhD3,4; et alMauricio Santillana, PhD3; Katherine Ognyanova, PhD5; James Druckman, PhD6; David Lazer, PhD3
JAMA Netw Open. 2023;6(2):e2256152. doi:10.1001/jamanetworkopen.2022.56152
COVID-19 Resource Center
Key Points
Question Is post–COVID-19 condition (PCC), also known as long COVID, associated with differences in employment status that might suggest functional impairment?
Findings Among 15 308 individuals with prior COVID-19 infection, those with PCC were less likely to be employed full-time and more likely to be unemployed. These differences persisted after adjustment for demographic differences between those with and without PCC.
Meaning These findings suggest that individuals with PCC are less likely to be working and to be working full time.
Abstract
Importance Little is known about the functional correlates of post–COVID-19 condition (PCC), also known as long COVID, particularly the relevance of neurocognitive symptoms.
Objective To characterize prevalence of unemployment among individuals who did, or did not, develop PCC after acute infection.
Design, Setting, and Participants This survey study used data from 8 waves of a 50-state US nonprobability internet population-based survey of respondents aged 18 to 69 years conducted between February 2021 and July 2022.
Main Outcomes and Measures The primary outcomes were self-reported current employment status and the presence of PCC, defined as report of continued symptoms at least 2 months beyond initial month of symptoms confirmed by a positive COVID-19 test.
Results The cohort included 15 308 survey respondents with test-confirmed COVID-19 at least 2 months prior, of whom 2236 (14.6%) reported PCC symptoms, including 1027 of 2236 (45.9%) reporting either brain fog or impaired memory. The mean (SD) age was 38.8 (13.5) years; 9679 respondents (63.2%) identified as women and 10 720 (70.0%) were White. Overall, 1418 of 15 308 respondents (9.3%) reported being unemployed, including 276 of 2236 (12.3%) of those with PCC and 1142 of 13 071 (8.7%) of those without PCC; 8229 respondents (53.8%) worked full-time, including 1017 (45.5%) of those with PCC and 7212 (55.2%) without PCC. In survey-weighted regression models excluding retired respondents, the presence of PCC was associated with a lower likelihood of working full-time (odds ratio [OR], 0.71 [95% CI, 0.63-0.80]; adjusted OR, 0.84 [95% CI, 0.74-0.96]) and with a higher likelihood of being unemployed (OR, 1.45 [95% CI, 1.22-1.73]; adjusted OR, 1.23 [95% CI, 1.02-1.48]). The presence of any cognitive symptom was associated with lower likelihood of working full time (OR, 0.70 [95% CI, 0.56-0.88]; adjusted OR, 0.75 [95% CI, 0.59-0.84]).
Conclusions and Relevance PCC was associated with a greater likelihood of unemployment and lesser likelihood of working full time in adjusted models. The presence of cognitive symptoms was associated with diminished likelihood of working full time. These results underscore the importance of developing strategies to treat and manage PCC symptoms.
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Severe Fatigue and Persistent Symptoms at Three Months Following SARS-CoV-2 Infections During the Pre-Delta, Delta, and Omicron Time Periods: A Multicenter Prospective Cohort Study.Gottlieb M1,Wang R2,Yu H3,Spatz ES4,Montoy JC5,Rodriguez R6,Chang AM7,Elmore JG8,Hannikainen PA9,Hill M10,Huebinger RM11,Idris AH12,Lin Z13,Koo K14,McDonald S15,O'Laughlin KN16,Plumb ID17,Santangelo M18,Saydah S17,Willis M19
Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, 27 Jan 2023, :ciad045 DOI: 10.1093/cid/ciad045 PMID: 36705268
Abstract BackgroundMost research on SARS-CoV-2 variants focuses on initial symptomatology with limited data on longer-term sequelae. We sought to characterize the prevalence and differences in prolonged symptoms at three months post SARS-CoV-2-infection across the three major variant time-periods (pre-Delta, Delta, and Omicron).
Methods
This multicenter prospective cohort study of adults with acute illness tested for SARS-CoV-2 compared fatigue severity, fatigue symptoms, individual and organ system-based symptoms, and presence of ≥3 total symptoms across variants among COVID-positive and COVID-negative participants 3 months after their initial SARS-CoV-2 diagnosis. Variant periods were defined by dates with ≥50% dominant strain. We performed a sensitivity analysis using ≥90% dominance threshold and multivariable logistic regression modeling to estimate the independent effects of each variant adjusting for socio-demographic characteristics, baseline health, and vaccine status.
Results
The study included 3,223 participants (2,402 COVID-positive and 821 COVID-negative). Among the COVID-positive cohort, 463 (19.3%) were pre-Delta, 1,198 (49.9%) during Delta, and 741 (30.8%) during Omicron. Prolonged severe fatigue was highest in the pre-Delta COVID-positive cohort compared with Delta and Omicron cohorts (16.7% vs 11.5% vs 12.3%, respectively; p = 0.017), as was presence of ≥3 prolonged symptoms (28.4% vs 21.7% vs 16.0%; p < 0.001). No difference was seen in the COVID-negative cohort between variant time-periods. In multivariable models, there was no difference in severe fatigue between variants. There was decreased odds of having ≥3 symptoms in Omicron compared with other variants; this was not significant after adjusting for vaccination status.
Conclusions
Prolonged symptoms following SARS-CoV-2 infection were more common among participants infected during the pre-Delta period compared with Delta and Omicron periods; however, these differences were no longer significant after adjusting for vaccination status. This suggests a potential beneficial effect of vaccination on the risk of developing long-term symptoms.
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2023 Feb 10;2023.02.09.527892. doi: 10.1101/2023.02.09.527892. Preprint
Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV2Kailin Yin, Michael J Peluso, Reuben Thomas, Min-Gyoung Shin, Jason Neidleman, Xiaoyu Luo, Rebecca Hoh, Khamal Anglin, Beatrice Huang, Urania Argueta, Monica Lopez, Daisy Valdivieso, Kofi Asare, Rania Ibrahim, Ludger Ständker, Scott Lu, Sarah A Goldberg, Sulggi A Lee, Kara L Lynch, J Daniel Kelly, Jeffrey N Martin, Jan Münch, Steven G Deeks, Timothy J Henrich, Nadia R Roan PMID: 36798286 PMCID: PMC9934605AbstractLong COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple "omics" assays (CyTOF, RNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis. Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses. Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.
© Federation of European Neuroscience Societies and John Wiley & Sons Ltd
Edited By: John Foxe Online ISSN: 1460-9568 Volume 57, Issue 4 February 2023
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Exosome-associated mitochondrial DNA from patients with myalgic encephalomyelitis/chronic fatigue syndrome stimulates human microglia to release IL-1βIrene Tsilioni, Benjamin Natelson, Theoharis C. Theoharides
First published: 24 September 2022 https://doi.org/10.1111/ejn.15828
AbstractMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease that presents with fatigue, sleep disturbances, malaise, and cognitive problems. The pathogenesis of ME/CFS is presently unknown, and serum levels of potential biomarkers have been inconsistent. Here, we show that mitochondrial DNA (mtDNA) associated with serum exosomes, is increased in ME/CFS patients only after exercise. Moreover, exosomes isolated from patients with ME/CFS stimulate significant release of IL-1β from cultured human microglia. These results provide evidence that activation of microglia by serum-derived exosomes may serve as a potential novel pathogenetic factor and target for treatment of ME/CFS.
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Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in AdultsA Systematic Review and Meta-analysisMatthew S. Durstenfeld, MD, MAS1,2; Kaiwen Sun, MD1; Peggy Tahir, MLIS, MA3; et alMichael J. Peluso, MD, MHS, MPhil, DTMH1,4; Steven G. Deeks, MD1,4; Mandar A. Aras, MD, PhD1,5; Donald J. Grandis, MD1,5; Carlin S. Long, MD1,5; Alexis Beatty, MD1,5,6; Priscilla Y. Hsue, MD1,2
JAMA Netw Open. 2022;5(10):e2236057. doi:10.1001/jamanetworkopen.2022.36057 Cardiology October 12, 2022
COVID-19 Resource Center
Key Points
Question Is exercise capacity reduced more than 3 months after SARS-CoV-2 infection among those with long COVID-19 (LC) symptoms compared with recovered individuals without symptoms, and what patterns of limitations on cardiopulmonary exercise testing (CPET) are common?
Findings In this systematic review and meta-analysis of 38 studies comprising 2160 participants, exercise capacity was reduced by 4.9 mL/kg/min among individuals with symptoms consistent with LC compared with individuals without symptoms more than 3 months after SARS-CoV-2 infection. Findings among individuals with exertional intolerance suggest that deconditioning, dysfunctional breathing, chronotropic incompetence, and abnormal peripheral oxygen extraction and/or use may contribute to reduced exercise capacity.
Meaning These findings suggest that CPET may provide insight into the mechanisms for reduced exercise capacity among individuals with LC.
Abstract
Importance Reduced exercise capacity is commonly reported among individuals with COVID-19 symptoms more than 3 months after SARS-CoV-2 infection (long COVID-19 [LC]). Cardiopulmonary exercise testing (CPET) is the criterion standard to measure exercise capacity and identify patterns of exertional intolerance.
Objectives To estimate the difference in exercise capacity among individuals with and without LC symptoms and characterize physiological patterns of limitations to elucidate possible mechanisms of LC.
Data Sources A search of PubMed, EMBASE, Web of Science, preprint servers, conference abstracts, and cited references was performed on December 20, 2021, and again on May 24, 2022. A preprint search of medrxiv.org, biorxiv.org, and researchsquare.com was performed on June 9, 2022.
Study Selection Studies of adults with SARS-CoV-2 infection more than 3 months earlier that included CPET-measured peak oxygen consumption (V̇o2) were screened independently by 2 blinded reviewers; 72 (2%) were selected for full-text review, and 35 (1%) met the inclusion criteria. An additional 3 studies were identified from preprint servers.
Data Extraction and Synthesis Data extraction was performed by 2 independent reviewers according to the PRISMA reporting guideline. Data were pooled using random-effects models.
Main Outcomes and Measures Difference in peak V̇o2 (in mL/kg/min) among individuals with and without persistent COVID-19 symptoms more than 3 months after SARS-CoV-2 infection.
Results A total of 38 studies were identified that performed CPET on 2160 individuals 3 to 18 months after SARS-CoV-2 infection, including 1228 with symptoms consistent with LC. Most studies were case series of individuals with LC or cross-sectional assessments within posthospitalization cohorts. Based on a meta-analysis of 9 studies including 464 individuals with LC symptoms and 359 without symptoms, the mean peak V̇o2 was −4.9 (95% CI, −6.4 to −3.4) mL/kg/min among those with symptoms with a low degree of certainty. Deconditioning and peripheral limitations (abnormal oxygen extraction) were common, but dysfunctional breathing and chronotropic incompetence were also described. The existing literature was limited by small sample sizes, selection bias, confounding, and varying symptom definitions and CPET interpretations, resulting in high risk of bias and heterogeneity.
Conclusions and Relevance The findings of this systematic review and meta-analysis study suggest that exercise capacity was reduced more than 3 months after SARS-CoV-2 infection among individuals with symptoms consistent with LC compared with individuals without LC symptoms, with low confidence. Potential mechanisms for exertional intolerance other than deconditioning include altered autonomic function (eg, chronotropic incompetence, dysfunctional breathing), endothelial dysfunction, and muscular or mitochondrial pathology.
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Front. Mol. Biosci., 14 December 2022
Sec. Molecular Diagnostics and Therapeutics
Volume 9 - 2022 | https://doi.org/10.3389/fmolb.2022.1044964
Tissue specific signature of HHV-6 infection in ME/CFSFrancesca Kasimir1†, Danny Toomey2†, Zheng Liu1, Agnes C. Kaiping1, Maria Eugenia Ariza3 and Bhupesh K. Prusty1*
- 1Institute for Virology and Immunobiology, Julius-Maximilians-University of Würzburg, Würzburg, Germany
- 2HHV-6 Foundation, Santa Barbara, CA, United States
- 3Department of Cancer Biology and Genetics (CBG), Institute for Behavioral Medicine Research (IBMR), The Ohio State University, Columbus, OH, United States
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Severe and Very Severe Myalgic Encephalopathy/Chronic Fatigue Syndrome ME/CFS in Norway: Symptom Burden and Access to CareKristian Sommerfelt Trude Schei 2 and Arild Angelsen
Children and Youth Clinic, Institute of Clinical Medicine 2, University of Bergen, P.O. Box 7804, 5020 Bergen, Norway
Norwegian ME Association, Nedre Slottsgate 4 M, 0157 Oslo, Norway
School of Economics and Business, Norwegian University of Life Sciences (NMBU), P.O. Box 5003, 1432 Ås, Norway
*
J. Clin. Med. 2023, 12(4), 1487; https://doi.org/10.3390/jcm12041487
Received: 22 January 2023 / Revised: 6 February 2023 / Accepted: 9 February 2023 / Published: 13 February 2023
(This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Epidemiology, Treatment and Prognosis)
AbstractThere is a striking lack of systematic knowledge regarding the symptom burden, capacity for activities of daily living, and supportive measures for the most severely ill ME/CFS patients. The present study seeks to address this through a national, Internet-based survey targeting patients with severe and very severe ME/CFS and their carers. Responses from 491 patients were included, with 444 having severe and 47 very severe ME/CFS with the classification based on the best estimate from patient responses. In addition, 95 respondents were reclassified from patients’ own classification to moderate and included for comparison. The onset was before 15 years of age for 45% in the very severe and 32% in the severe group. Disease duration was more than 15 years for 19% in the very severe and 27% in the severe group. Patient symptom burden was extensive. The most severely affected were totally bedridden, unable to talk, and experienced dramatic worsening of symptoms after minimal activity or sensory stimuli. Care and assistance from healthcare and social services were often described as insufficient or inadequate, often worsening the symptom load and burden of care. A substantial lack of disease knowledge among healthcare providers in general was reported. Yet approximately 60% in the severe and very severe groups found services provided by occupational therapists and family doctors (general practitioners) helpful, while a smaller proportion experienced appropriate help from other health personnel groups. This indicates that help and support are highly needed and possible to provide. On the other hand, this must be approached carefully, as a substantial number of patients experienced deterioration from contact with healthcare personnel. Family carers described an extensive burden of care with often inadequate help from healthcare providers or municipal authorities. Patient care by family members of very severe ME/CFS patients constituted more than 40 h a week for 71% of this patient group. The carers described a large negative impact on their work and financial situation, and on their mental wellbeing. We conclude that childhood onset was common, burden of disease was extensive, and support from responsible societal health and social support providers was commonly grossly inadequate.
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Unexplained post-acute infection syndromesJan Choutka, Viraj Jansari, Mady Hornig & Akiko Iwasaki
Nature Medicine volume 28, pages911–923 (2022) Review Article Published: 18 May
Abstract
SARS-CoV-2 is not unique in its ability to cause post-acute sequelae; certain acute infections have long been associated with an unexplained chronic disability in a minority of patients. These post-acute infection syndromes (PAISs) represent a substantial healthcare burden, but there is a lack of understanding of the underlying mechanisms, representing a significant blind spot in the field of medicine. The relatively similar symptom profiles of individual PAISs, irrespective of the infectious agent, as well as the overlap of clinical features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggest the potential involvement of a common etiopathogenesis. In this Review, we summarize what is known about unexplained PAISs, provide context for post-acute sequelae of SARS-CoV-2 infection (PASC), and delineate the need for basic biomedical research into the underlying mechanisms behind this group of enigmatic chronic illnesses.
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Risk Factors Associated With Post−COVID-19 ConditionA Systematic Review and Meta-analysisVasiliki Tsampasian, MD, MSc1,2; Hussein Elghazaly, MBBS3; Rahul Chattopadhyay, MBBS, MSc1,4; et alMaciej Debski, MD, PhD1,2; Thin Kyi Phyu Naing, MBBS1,2; Pankaj Garg, PhD1,2; Allan Clark, PhD2; Eleana Ntatsaki, MD(Res), MA5,6; Vassilios S. Vassiliou, MBBS, PhD1,2
JAMA Intern Med. Published online March 23, 2023. doi:10.1001/jamainternmed.2023.0750
Key Points
Question Which individuals are at risk of developing post−COVID-19 condition?
Findings This systematic review and meta-analysis of 41 studies including 860 783 patients found that female sex, older age, higher body mass index, smoking, preexisting comorbidities, and previous hospitalization or ICU admission were risk factors significantly associated with developing PCC, and that SARS-CoV-2 vaccination with 2 doses was associated with lower risk of PCC.
Meanings The findings of this systematic review and meta-analysis provide a profile of the characteristics associated with increased risk of developing PCC and suggest that vaccination may be protective against PCC.
Abstract
Importance Post−COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support.
Objective To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC.
Data sources Medline and Embase databases were systematically searched from inception to December 5, 2022.
Study Selection The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients.
Data Extraction and Synthesis Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023.
Main Outcomes and Measures The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19.
Results The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76).
Conclusions and Relevance This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination.
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The Behavior of Muscle Oxygen Saturation, Oxy and Deoxy Hemoglobin during a Fatigue Test in FibromyalgiaSantos Villafaina 1, Pablo Tomas-Carus 2 3, Vanda Silva 4, Ana Rodrigues Costa 5, Orlando Fernandes 2 3, Jose A Parraca 2 3 PMID: 36672640 PMCID: PMC9856161 DOI: 10.3390/biomedicines11010132 2023 Jan 4;11(1):132. doi: 10.3390/biomedicines11010132.
AbstractPrevious studies have reported that people with fibromyalgia (FM) could suffer from mitochondrial dysfunction. However, the consumption of muscle oxygen during physical exercise has been poorly studied. Therefore, this study aimed to explore the response of muscle oxygen during a fatigue protocol in people with FM and healthy controls (HC). In addition, the peak torque and the total work were assessed. A total of 31 participants (eighteen were people with fibromyalgia and thirteen were healthy controls) were enrolled in this cross-sectional study. All the participants underwent a fatigue protocol consisting of 20 repetitions at 180°·s−1 of quadriceps flexions and extensions using a Biodex System 3. The muscle oxygen saturation (SmO2), total hemoglobin (THb), deoxygenated hemoglobin (HHb) and oxygenated hemoglobin (O2Hb) values were measured using a portable near-infrared spectroscopy (NIRS) device. Significant differences between people with FM and healthy controls were found at baseline: SmO2 (FM: 56.03 ± 21.36; HC: 77.41 ± 10.82; p = 0.036), O2Hb (FM: 6.69 ± 2.59; HC: 9.37 ± 1.31; p = 0.030) and HHb (FM: 5.20 ± 2.51; HC: 2.73 ± 1.32; p = 0.039); during the fatigue protocol: SmO2 (FM: 48.54 ± 19.96; HC: 58.87 ± 19.72; p = 0.038), O2Hb (FM: 5.70 ± 2.34; HC: 7.06 ± 2.09; p = 0.027) and HHb (FM: 5.69 ± 2.65; HC: 4.81 ± 2.39; p = 0.048); and in the recovery at three min and six min for SmO2, O2Hb and HHb (p < 0.005). Furthermore, healthy control values of SmO2, O2Hb and HHb have been significantly altered by the fatigue protocol (p < 0.005). In contrast, people with FM did not show any significant alteration in these values. Moreover, significant differences were found in the peak torque at extension (FM: 62.48 ± 24.45; HC: 88.31 ± 23.51; p = 0.033) and flexion (FM: 24.16 ± 11.58; HC: 42.05 ± 9.85; p = 0.010), and the total work performed at leg extension (FM: 1039.78 ± 434.51; HC: 1535.61 ± 474.22; p = 0.007) and flexion (FM: 423.79 ± 239.89; HC: 797.16 ± 194.37; p = 0.005).
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Factors Influencing the Prognosis of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Diagnostics
Academic Editor: François-Jérôme Authier Received: 19 September 2022 Accepted: 17 October 2022 Published: 19 October 202
Alaa Ghali 1,* , Carole Lacout 1 , Jacques-Olivier Fortrat 2 , Karine Depres 1 , Maria Ghali 3 and Christian Lavigne 1 1 Department of Internal Medicine and Clinical Immunology, Angers University Hospital, F-49000 Angers, France 2 Department of Vascular Medicine,
Abstract: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term debilitating multisystem condition with poor prognosis. Studies that examined predictors of ME/CFS outcomes yielded contradictory results. We aimed to explore epidemiological and clinical prognostic factors of ME/CFS using operationalized criteria for recovery/improvement. Adult ME/CFS patients who attended the Internal Medicine Department of Angers University Hospital, Angers, France between October 2011 and December 2019, and were followed up until December 2020, were included retrospectively.
Their medical records were reviewed for data collection. Patients were classified into two groups according to the presence or absence of recovery/improvement (R/I) and compared for epidemiological characteristics, fatigue features, post-exertional malaise severity, clinical manifestations, and comorbidities. The subgroups of recovered and significantly improved patients were then compared. 168 patients were included. Recovery and improvement rates were 8.3% and 4.8%, respectively. Older age at disease onset was associated with R/I (OR 1.06 [95% CI 1.007–1.110] (p = 0.028)), while diagnostic delay was inversely associated with R/I (OR 0.98 [95% CI 0.964–0.996] (p = 0.036)). The study findings confirmed the poor prognosis of ME/CFS and the deleterious effect of diagnostic delay on disease progression. Interestingly, being older at disease onset was associated with better outcomes, which offers hope to patients for recovery/improvement even at an advanced age.
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Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue SyndromeElisabeth Petter, Carmen Scheibenbogen, Peter Linz, Christian Stehning, Klaus Wirth, Titus Kuehne & Marcus Kelm
Journal of Translational Medicine volume 20, Pub: 09 December 2022
Article number: 580 (2022)
AbstractBackgroundMuscle fatigue and pain are key symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Although the pathophysiology is not yet fully understood, there is ample evidence for hypoperfusion which may result in electrolyte imbalance and sodium overload in muscles. Therefore, the aim of this study was to assess levels of sodium content in muscles of patients with ME/CFS and to compare these to healthy controls.
MethodsSix female patients with ME/CFS and six age, BMI and sex matched controls underwent 23Na-MRI of the left lower leg using a clinical 3T MR scanner before and after 3 min of plantar flexion exercise. Sodium reference phantoms with solutions of 10, 20, 30 and 40 mmol/L NaCl were used for quantification. Muscle sodium content over 40 min was measured using a dedicated plugin in the open-source DICOM viewer Horos. Handgrip strength was measured and correlated with sodium content.
ResultsBaseline tissue sodium content was higher in all 5 lower leg muscle compartments in ME/CFS compared to controls. Within the anterior extensor muscle compartment, the highest difference in baseline muscle sodium content between ME/CFS and controls was found (mean ± SD; 12.20 ± 1.66 mM in ME/CFS versus 9.38 ± 0.71 mM in controls, p = 0.0034). Directly after exercise, tissue sodium content increased in gastrocnemius and triceps surae muscles with + 30% in ME/CFS (p = 0.0005) and + 24% in controls (p = 0.0007) in the medial gastrocnemius muscle but not in the extensor muscles which were not exercised. Compared to baseline, the increase of sodium content in medial gastrocnemius muscle was stronger in ME/CFS than in controls with + 30% versus + 17% to baseline at 12 min (p = 0.0326) and + 29% versus + 16% to baseline at 15 min (p = 0.0265). Patients had reduced average handgrip strength which was associated with increased average muscle tissue sodium content (p = 0.0319, R2 = 0.3832).
ConclusionMuscle sodium content before and after exercise was higher in ME/CFS than in healthy controls. Furthermore, our findings indicate an inverse correlation between muscle sodium content and handgrip strength. These findings provide evidence that sodium overload may play a role in the pathophysiology of ME/CFS and may allow for potential therapeutic targeting.
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Long COVID: major findings, mechanisms and recommendationsHannah E. Davis, Lisa McCorkell, Julia Moore Vogel & Eric J. Topol
Nature Reviews Microbiology volume 21, pages133–146 (2023)Cite this article
Abstract
Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.
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Griffith University researchers identify similar brain structure changes in both chronic fatigue syndrome and long COVIDBy Janelle Miles
Posted Tue 14 Mar 2023 at 8:36amTuesday 14 Mar 2023 at 8:36am, updated Wed 15 Mar 2023 at 11:45amWednesday 15 Mar 2023 at 11:45am
abc.net.au/news/long-covid-queensland-research-chronic-fatigue-syndrome/102089452
In a world-first study, Queensland researchers have identified similar changes in brain structure among people who have long COVID and chronic fatigue syndrome.
Key points:
- Researchers compared patients with chronic fatigue syndrome, long COVID and people with neither condition
- They discovered similarities in brain stem size for those with long COVID or chronic fatigue
- There is no public clinic for dedicated long COVID treatment in Queensland
Eight had long COVID, 10 people had been diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and 10 were healthy volunteers.
The researchers, from Griffith's National Centre for Neuroimmunology and Emerging Diseases, found the brainstem was significantly larger in long COVID patients and those with ME/CFS compared to people who had never been diagnosed with either ailment.
"Structural changes in the brain stem of ME/CFS and long COVID patients could result in severe and varied deficits in brain function," they wrote in a study published in the journal, Frontiers in Neuroscience.
"The symptom overlap between ME/CFS and long COVID patients is consistent with our current findings of similar abnormalities in the brainstem."
Lead researcher Kiran Thapaliya said brain stem similarities in people with long COVID and ME/CFS patients may explain why they exhibited common core symptoms, such as brain fog, fatigue, pain and breathing difficulties.
Dr Thapaliya, a Griffith University research fellow, said the researchers were recruiting more people to continue to investigate the findings of their pilot study in a larger number of patients with long COVID and ME/CFS.
They used a high-resolution MRI machine at the University of Queensland's Centre for Advanced Imaging for the pilot study.
"This specialised MRI provides crisp images and also greater detailed information … and uncovered abnormalities that might not be detected in other MRIs," Dr Thapaliya said.
Professor Sonya Marshall-Gradnisnik, director of Griffith's National Centre for Neuroimmunology and Emerging Diseases, said the purpose of the study was to demonstrate potential consistencies between ME/CFS and long COVID patients.
Brain scans of a Long COVID patient (left) and a chronic fatigue patient (right).(Supplied: Griffith University)
The research comes seven months after Griffith University researchers reported a shared link in the pathology of long COVID and ME/CFS.
In the first study of its kind in the world to identify a biological overlap between the two conditions, they reported similar damage to receptors on cells – described as like a dysfunctional lock and key – which fail to allow enough calcium in.
"Patients can experience different symptoms depending on which cells in the body are affected – from brain fog and muscle fatigue to possible organ failure," Professor Marshall-Gradnisnik has said previously.
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