Cortex Volume 173, April 2024, Pages 161-174
Behavioural Neurology
Enhanced motor network engagement during reward gain anticipation in fibromyalgia
Su Hyoun Park, Andrew M. Michael, Anne . Baker, Carina Lei, Katherine T. Martucci
Abstract
Reward motivation is essential in shaping human behavior and cognition. Both reward motivation and reward brain circuits are altered in chronic pain conditions, including fibromyalgia. In this study of fibromyalgia patients, we used a data-driven independent component analysis (ICA) approach to investigate how brain networks contribute to altered reward processing. From females with fibromyalgia (N = 24) and female healthy controls (N = 24), we acquired fMRI data while participants performed a monetary incentive delay (MID) reward task. After analyzing the task-based fMRI data using ICA to identify networks, we analyzed 3 networks of interest: motor network (left), value-driven attention network, and basal ganglia network. Then, we evaluated correlation coefficients between each network timecourse versus a task-based timecourse which modeled gain anticipation. Compared to controls, the fibromyalgia cohort demonstrated significantly stronger correlation between the left motor network timecourse and the gain anticipation timecourse, indicating the left motor network was more engaged with gain anticipation in fibromyalgia. In an exploratory analysis, we compared motor network engagement during early versus late phases of gain anticipation. Across cohorts, greater motor network engagement (i.e., stronger correlation between network and gain anticipation) occurred during the late timepoint, which reflected enhanced motor preparation immediately prior to response. Consistent with the main results, patients exhibited greater engagement of the motor network during both early and late phases compared with healthy controls. Visual-attention and basal ganglia networks revealed similar engagement in the task across groups. As indicated by post-hoc analyses, motor network engagement was positively related to anxiety and negatively related to reward responsiveness. In summary, we identified enhanced reward-task related engagement of the motor network in fibromyalgia using a novel data-driven ICA approach. Enhanced motor network engagement in fibromyalgia may relate to impaired reward motivation, heightened anxiety, and possibly to altered motor processing, such as restricted movement or dysregulated motor planning.
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Clin Neurophysiol. 2023 Jan; 145: 81–88.
Published online 2022 Nov 11. doi: 10.1016/j.clinph.2022.10.017
PMCID: PMC9650483 PMID: 36455453
Co-ultramicronized palmitoylethanolamide/luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome
Viviana Versace,a,⁎,1 Paola Ortelli,a,1 Sabrina Dezi,a Davide Ferrazzoli,a Alessia Alibardi,a Ilenia Bonini,a Michael Engl,b Roberto Maestri,c Martina Assogna,d Valentina Ajello,e Elke Pucks-Faes,f Leopold Saltuari,a Luca Sebastianelli,a Markus Kofler,f,2 and Giacomo Kochd,g,2
Abstract
Objective
Transcranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABAB-ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI).
Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI.
MethodsThirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700 mg + 70 mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity.
Results
Patients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected.
Conclusions
Eight weeks of treatment with PEA-LUT restore GABAB activity and cortical plasticity in long Covid patients.
Significance
This study confirms altered physiology of the motor cortex in long COVID-19 syndrome and indicates PEA-LUT as a candidate for the treatment of this post-viral condition.
Keywords: Palmitoylethanolamide, Long Covid, Transcranial magnetic stimulation, Long-interval intracortical inhibition, LTP-like cortical plasticity
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COVID Virus Can Remain in the Body Over a Year
Ralph Ellis
March 11, 2024 - Medscape
Scientists at the University of California San Francisco have discovered that remnants of the COVID-19 virus can linger in blood and tissue for more than a year after a person is first infected.
In their research on long COVID, the scientists found COVID antigens in the blood for up to 14 months after infection and in tissue samples for more than 2 years after infection.
"These two studies provide some of the strongest evidence so far that COVID antigens can persist in some people, even though we think they have normal immune responses," Michael Peluso, MD, an infectious disease researcher in the UCSF School of Medicine, who led both studies, said in a statement.
Scientists don't know what causes long COVID, in which symptoms of the illness persist months or years after recovery. The most common symptoms are extreme fatigue, shortness of breath, loss of smell, and muscle aches.
The UCSF research team examined blood samples from 171 infected people and found the COVID "spike" protein was still present up to 14 months after infection in some people. The antigens were found more often in people who were hospitalized with COVID or who reported being very sick but were not hospitalized.
Researchers next looked at the UCSF Long COVID Tissue Bank, which contains samples donated by patients with and without long COVID.
They found portions of viral RNA in the tissue up to 2 years after people were infected, though there was no evidence of reinfection. Those viral fragments were found in connective tissue where immune cells are, suggesting that the fragments caused the immune system to attack, according to the researchers.
The UCSF team is running clinical trials to find out if monoclonal antibodies or antiviral drugs can remove the virus.
The findings were presented in Denver this week at the Conference on Retroviruses and Opportunistic Infections.
SOURCES:
EurekAlert: "COVID-19 virus can stay in the body more than a year after infection."
University of California San Francisco: "First Tissue Bank May Help Solve Mystery of Long COVID Misery."
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Expert Opin Ther Targets. 2017 Aug;21(8):817-826.
doi: 10.1080/14728222.2017.1353603. Epub 2017 Jul 12.
Sleep disturbances and severe stress as glial activators: key targets for treating central sensitization in chronic pain patients?Jo Nijs 1 2 3, Marco L Loggia 4, Andrea Polli 1 2, Maarten Moens 5 6, Eva Huysmans 1 2, Lisa Goudman 1 2 5, Mira Meeus 1 7 8, Luc Vanderweeën 1 2 9, Kelly Ickmans 1 3, Daniel Clauw 10
PMID: 28685641 DOI: 10.1080/14728222.2017.1353603
AbstractThe mechanism of sensitization of the central nervous system partly explains the chronic pain experience in many patients, but the etiological mechanisms of this central nervous system dysfunction are poorly understood. Recently, an increasing number of studies suggest that aberrant glial activation takes part in the establishment and/or maintenance of central sensitization. Areas covered: This review focused on preclinical work and mostly on the neurobiochemistry studied in animals, with limited human studies available. Glial overactivation results in a low-grade neuroinflammatory state, characterized by high levels of BDNF, IL-1β, TNF-α, which in turn increases the excitability of the central nervous system neurons through mechanisms like long-term potentiation and increased synaptic efficiency. Aberrant glial activity in chronic pain might have been triggered by severe stress exposure, and/or sleeping disturbances, each of which are established initiating factors for chronic pain development. Expert opinion: Potential treatment avenues include several pharmacological options for diminishing glial activity, as well as conservative interventions like sleep management, stress management and exercise therapy. Pharmacological options include propentofylline, minocycline, β -adrenergic receptor antagonists, and cannabidiol. Before translating these findings from basic science to clinical settings, more human studies exploring the outlined mechanisms in chronic pain patients are needed.
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Worsening symptoms is associated with larger cerebral blood flow abnormalities during tilt-testing in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Authors: van Campen CMC, Rowe PC & Visser FC (Stichting CardioZorg, The Netherlands). Publication: Medicina
Link: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00323-1/fulltext
Previous studies have found that ME/CFS patients experience abnormal reduction in cerebral blood flow (CBF) during tilt testing. Studies have not previously examined the relationship between ME/CFS symptom severity and CBF reduction. The authors sought to examine whether there was a correlation between the severity of symptoms and the degree of CBF reduction during tilt testing.
110 ME/CFS patients (International Consensus Criteria (ICC)) were selected from the authors’ existing database. Patients had completed tilt testing and assessments of ME/CFS symptomology on the same day, and again at a subsequent follow-up. In addition, the authors combined the data from of two previous studies, which included 219 participants whose symptom severity had been defined by the ICC.
The authors found that of the 110 patients from their database, 71 were retested due to worsening symptoms. Within this group, the ICC disease severity changed, with a significant number of patients experiencing a more severe ICC disease rating, from 51% mild, 45% moderate and 4% severe at the initial visit, to 1% mild, 72% moderate and 27% severe at follow-up. In this group, the CBF reduction also changed, from 19% at the first test, to 31% at the follow-up. Of the 39 patients with stable disease, the severity of disease distribution and CBF reduction did not differ significantly between the initial visit and follow-up. When looking at the combined data from the two previous studies, the authors found that patients with mild, moderate, and severe disease experienced CBF reductions of 25%, 29%, and 33% respectively.
The authors conclude that there is a strong association between ME/CFS disease severity and percentage CBF reduction during tilt testing, with a more severe disease rating being associated with a larger reduction in CBF. The authors propose that this objective measure of confirming worsening symptoms may help to guide treatment and measure the effectiveness of therapies.
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Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post‐acute COVID‐19 syndrome with and without postural orthostatic tachycardia syndrome: a multi‐omic profiling study
Authors: Mahdi A, Zhao A, Fredengren E, Fedorowski A, Braunschweig F, Nygren‐Bonnier M, … Ståhlberg M (Karolinska University Hospital, Sweden)
Publication: Scientific Reports Link:https://doi.org/10.1038/s41598-023-47539-1
An estimated 30% of severely affected post-acute COVID-19 syndrome (PACS) patients experience postural orthostatic tachycardia syndrome (POTS) and present with microvascular endothelial dysfunction. To unravel the unknown pathological mechanisms underlying PACS with POTS, the authors applied an unbiased multi-omic approach to participants’ plasma to analyse cardio-metabolic proteins, pro-inflammatory cytokines/chemokines, and sphingolipids.
A total of 42 non-hospitalised patients with PACS (diagnosed according to the WHO definition) were recruited from the post-acute COVID-19 clinic at Karolinska University Hospital in Sweden. On average, participants had been unwell for 18 months. Participants were divided into 2 groups depending on the presence (PACS+POTS, 20 individuals) or absence (PACS-POTS, 22 individuals) of POTS, defined as (1) a persistent rise in heart rate of more than 30 beats/min, or (2) a heart rate inferior to 120 beats/min within 10 min of the tilt-up test. PACS patients were matched with 21 healthy individuals (healthy controls). There were no significant differences in symptom scores between the two PACS groups. Women were more represented than men in all groups.
Differential expression analysis of 700 plasma proteins showed that PACS patients had a clearly dysregulated plasma proteome with around 200 dysregulated proteins when compared to healthy controls. There were no significant differences in dysregulated proteins between the two PACS groups.
Gene ontology enrichment analysis revealed many significantly altered pathways in both PACS groups compared with healthy controls, including haemostasis, inflammation, amino acid metabolism, and apoptosis. Differential expression analysis of 36 cytokines showed similar cytokine dysregulation in both PACS groups, with 11 up-regulated cytokines compared to healthy controls. Differential expression analysis of 88 plasma sphingolipids showed 16 and 19 dysregulated lipids in PACS+POTS and PACS-POTS respectively, compared to healthy controls. Nevertheless, the authors found no significant difference in proteins, cytokines, or sphingolipids between PACS+POTS and PACS-POTS groups. Principal component analysis also failed to differentiate between these groups.
Collectively, this study suggests that the pro-inflammatory, proliferative and pro-coagulative state in PACS represents an important phenotype in the pathophysiology. Therefore, the resolution of inflammation and micro clots, combined with haemostasis correction, might alleviate PACS burden. The absence of distinctions between participants with and without POTS suggests that POTS may not be associated with the dysregulation of plasma proteins, cytokines, and sphingolipids observed in PACS.
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Catalytic antibodies may contribute to demyelination in myalgic encephalomyelitis/chronic fatigue syndromeAuthors: Jensen MA, Dafoe ML, Wilhelmy J, Cervantes L, Okumu AN, Kipp L, … Davis RW (Stanford University, USA)
Publication: Biochemistry Link: https://doi.org/10.1071/AH23106
Multiple sclerosis (MS) is an autoimmune inflammatory disease affecting the central nervous system (CNS), characterised by symptoms of pain and impaired nerve communication from the demyelination caused by catalytic antibodies (antibodies with enzyme-like behaviour (Abzs)). There are considerable overlaps between MS and ME/CFS. MRI and PET studies have found physical abnormalities in the brain of ME/CFS patients, and ME/CFS shares symptoms of pain and impaired nerve communication that may be caused by the digestion of myelin basic protein (MBP). The aim of this study was to examine the role of Abzs in ME/CFS.
Total plasma antibodies (Abs) were collected from 19 patients with ME/CFS (diagnosed using the Canadian Consensus Criteria), 19 healthy controls (HC), and 3 patients with MS to be used as an expected metric comparison. Samples were analysed to identify catalytic antibodies.
When added to bovine brain MBP substrate, 47% of ME/CFS Abs showed digestion, compared to 5% of HC. The authors suggest that those with ME/CFS whose Abs did not cleave MBP may have symptoms unrelated to myelin breakdown or that, similar to MS, there may be patterns of remission and relapse. The Abzs were shown to have serine protease-like activity. Three additional substrates (casein, a-lactalbumin, and lysozyme) were used to determine that breakdown was myelin-specific, not random proteolysis. Purification and size-exclusion assays proved that there was no protease involvement in the MBP breakdown. When the MS drug, glatiramer acetate (GA) was added to ME/CFS Abs + MBP assays, the breakdown of MBP was significantly reduced. GA was shown to be Abzs-specific and did not cause inhibition of general serine protease enzyme activity. Fractionated GA demonstrated the higher molecular weight fragments having greater potency.
The concentration of GA used in these assays far exceeds the general dosage used in MS (and thus what is proposed for usage in myelin-associated ME/CFS). However, demyelination has a long-term cumulative effect, and treatment with GA often takes 6 to 9 months before effects become apparent. As such, the authors believe that the higher dosage used in these assays accounts for these longer-term effects. The authors recommend that a prospective study be undertaken over a long period of time to discover whether there is a similar relapsing-remission pattern in ME/CFS as seen in MS.
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‘We have no services for you...so you have to make the best out of it’: A qualitative study of myalgic encephalomyelitis/chronic fatigue syndrome patients’Authors:Melby, L. & das Nair, R. (SINTEF, Norway) Publication:Health Expectations
Link: https://www.abc.net.au/news/2023-12-08/dave-clark-on-living-with-chronic-fatigue-syndrome/103071294
The authors of this study sought to gain a comprehensive understanding of Norwegian ME/CFS patients’ experiences of dissatisfaction with healthcare services and to explore the reasons for this dissatisfaction.
The authors used in-depth interviews conducted in participants’ homes, lasting between 40 and 150 minutes, to gain an understanding of participants’ encounters with healthcare services as well as to assess participants’ reasons for satisfaction or dissatisfaction with these healthcare services. In total, 48 participants from 24 households in Norway participated in the interviews. This number included 37 individuals diagnosed with ME/CFS (25 females, 12 males, age range 10-59), in addition to family and household members.
The authors identified four key reasons why ME/CFS patients and their families experienced dissatisfaction with healthcare services. The first was nonexistent services, which involved study participants feeling as though they received a lack of practical help and information, or they were told effective treatment was not a possibility after receiving their ME/CFS diagnosis. The second reason was non-personalised services, where participants received healthcare services that were not adapted to their needs, resulting in these services being viewed as inappropriate or damaging. The third was slow services, where ME/CFS patients and their families believed they received services too late in their ME/CFS trajectory for these services to be useful. The fourth was inappropriate services, where participants believed the healthcare services they received, did not address their ME/CFS, and they felt sicker than they had previously.
The authors concluded that dissatisfaction with healthcare services that Norwegian ME/CFS patients and their families experienced may stem from a variety of factors including systemic issues such as bureaucracy within the healthcare industry, inadequate knowledge of ME/CFS leading to a lack of precise recommendations and uncertainty amongst healthcare professionals, poor personalisation and flexibility from healthcare services, healthcare providers’ disbelief in ME/CFS as a medical condition, and a lack of patient involvement in the design of healthcare services.
The authors note the importance of highlighting ME/CFS patients’ negative healthcare experiences in order to improve future services. The authors suggest that future research should investigate how ME/CFS patients can be involved in healthcare service design to help improve healthcare services.
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Is Low Cortisol a Marker of Long COVID?Armin Alaedini, PhD Stafford Lightman, PhD Gary P. Wormser, MD
Published:March 21, 2024DOI:https://doi.org/10.1016/j.amjmed.2024.03.013
Cortisol is the primary glucocorticoid hormone produced by the adrenal glands, playing a critical role in multiple physiological processes, including metabolism, immune response regulation, cardiovascular regulation, and the body's stress response
. The secretion of cortisol is closely regulated by the hypothalamus-pituitary-adrenal (HPA) axis. The process is initiated by the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which stimulates the production of adrenocorticotropic hormone (ACTH) by the pituitary gland. In turn, ACTH prompts the adrenal glands to release cortisol
. Cortisol measurements have been used extensively in research to investigate the hormone's relationship with various physiological disruptions and health conditions, including mental health disorders, immune system dysfunction, and metabolic disorders
. However, it is essential to recognize the potential pitfalls in the assessment and interpretation of cortisol levels in translational research, as overlooking them can foster misinformation and confusion regarding potential clinical or diagnostic relevance of the findings.
In two recent studies (Klein et al. in 2023 and Fleischer et al. in 2024 ), researchers reported on the analysis of hormonal and other markers in blood samples from individuals with post-acute sequelae of SARS CoV-2 infection (PASC)—commonly known as long COVID (LC). Long COVID is associated with a range of persistent symptoms, including fatigue, pain, and brain fog that can be debilitating. Notably, the most compelling and statistically significant finding of the Klein et al. study revolved around the levels of cortisol, which were reported to be much lower in long COVID patients than in controls without long COVID . The authors of the study concluded that “[s]erum cortisol was the most significant predictor of LC status in the model, and cortisol alone achieved an AUC.of 0.96”
. The findings have been widely publicized in the media, engendering speculation regarding their therapeutic and biomarker potential in long COVID.. On the other hand, a more recent study by Fleischer et al. found no significant difference or trends in the cortisol levels in a comparison of post-COVID-19 patients, with and without persistent symptoms, apparently contradicting the results reported in the earlier study. While the cortisol assessments in both of these two studies may represent remarkable and consequential findings in the context of long COVID, unfortunately, they are impacted by significant limitations and concerns regarding how the cortisol levels were assessed and interpreted.
The levels of cortisol in the body are very dynamic, following a distinct circadian pattern throughout the day. Levels typically increase in the first half hour after awakening by up to 60%, in what has been called the cortisol awakening response, followed by a sharp drop over the next few hours, reaching their lowest point in the evening.. Underlying this circadian rhythm, cortisol also exhibits ultradian fluctuations in a pulsatile pattern with several peaks and troughs throughout the day that change in amplitude.. Because of these fluctuations and the wide and rapid changes in circulating levels, reliable and reproducible evaluation of cortisol secretion is not trivial. Such assessment cannot be based on only a single measurement, but rather requires the collection of multiple blood, saliva, or urine samples throughout the day. Any single measurement would also ideally need to account for the time elapsed since awakening and not necessarily just the time of day. In assessing the difference in cortisol output between groups, multiple measurements in blood or saliva samples are usually used to analyze the change from baseline, the size of the cortisol awakening response, or the elevation and slopepe of the diurnal curve Surprisingly, none of these approaches was taken in either of the two cited studies of cortisol levels in long COVID. Both studies conducted a single measurement in blood plasma or serum, taking note of the time of day, but not the time since awakening, for the sample collection. More importantly, no attempt was made to take serial samples to overcome the problem associated with the very rapid changes occurring due to ultradian rhythmicity. Considering the dramatic ultradian and diurnal cortisol oscillations, meaningful interpretation of the reported cortisol levels in these two studies is simply not possible. The issue is further compounded by the potential association of long COVID with sleep disturbances , including earlier than average awakening times, which could significantly shift the cortisol diurnal curve, giving the appearance of uniformly lower circulating levels during the daytime. The additional finding that the time of sample collection was not a significant predictor of cortisol levels in the study by Klein et al. adds weight to existing concerns about the validity of the reported results and the conclusions regarding the value of blood cortisol concentration as a potential biomarker of long COVID.
Given the presence of persistent fatigue as a hallmark symptom of long COVID, the evaluation of HPA axis function through the assessment of cortisol output is a logical approach. However, considering the available data and the major methodological shortcomings noted in the two published studies, it is clear that neither the utility of cortisol as a biomarker nor the therapeutic role of corticosteroids in treating long COVID can be justified at this juncture. The issues raised here underscore the need for further rigorous and comprehensive investigations into the relationship between cortisol response and long COVID, taking special note of the cortisol diurnal pattern, potential confounding factors impacting this pattern, and the utilization of well-documented and established methods of assessing cortisol levels
. The recent availability of new techniques to measure cortisol levels sequentially across the full 24 hours, including during sleep should provide the methodology needed for obtaining reliable and accurate data on HPA axis function in long COVID and other conditions.
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Redox Biol. 2023 Sep:65:102796. doi: 10.1016/j.redox.2023.102796. Epub 2023 Jul 3.
Autoantibodies to selenoprotein P in chronic fatigue syndrome suggest selenium transport impairment and acquired resistance to thyroid hormoneQian Sun 1, Elisa Oltra 2, D A Janneke Dijck-Brouwer 3, Thilo Samson Chillon 4, Petra Seemann 5, Sabrina Asaad 4, Kamil Demircan 4, José Andrés Espejo-Oltra 2, Teresa Sánchez-Fito 2, Eva Martín-Martínez 6, Waldemar B Minich 4, Frits A J Muskiet 3, Lutz Schomburg 7
PMID: 37423160 PMCID: PMC10338150 DOI: 10.1016/j.redox.2023.102796
AbstractChronic Fatigue Syndrome (CFS) presents with symptoms of hypothyroidism, including mental and physical fatigue, poor sleep, depression, and anxiety. However, thyroid hormone (TH) profiles of elevated thyrotropin and low thyroxine (T4) are not consistently observed. Recently, autoantibodies to the Se transporter SELENOP (SELENOP-aAb) have been identified in Hashimoto's thyroiditis and shown to impair selenoprotein expression. We hypothesized that SELENOP-aAb are prevalent in CFS, and associate with reduced selenoprotein expression and impaired TH deiodination. Se status and SELENOP-aAb prevalence was compared by combining European CFS patients (n = 167) and healthy controls (n = 545) from different sources. The biomarkers total Se, glutathione peroxidase (GPx3) and SELENOP showed linear correlations across the samples without reaching saturation, indicative of Se deficiency. SELENOP-aAb prevalence was 9.6-15.6% in CFS versus 0.9-2.0% in controls, depending on cut-off for positivity. The linear correlation between Se and GPx3 activity was absent in SELENOP-aAb positive patients, suggesting impaired Se supply of kidney. A subgroup of paired control (n = 119) and CSF (n = 111) patients had been characterized for TH and biochemical parameters before. Within this subgroup, SELENOP-aAb positive patients displayed particularly low deiodinase activity (SPINA-GD index), free T3 levels, total T3 to total T4 (TT3/TT4) and free T3 to free T4 (FT3/FT4) ratios. In 24 h urine, iodine concentrations were significantly lower in SELENOP-aAb positive than in SELENOP-aAb negative patients or controls (median (IQR); 43.2 (16.0) vs. 58.9 (45.2) vs. 89.0 (54.9) μg/L). The data indicate that SELENOP-aAb associate with low deiodination rate and reduced activation of TH to active T3. We conclude that a subset of CFS patients express SELENOP-aAb that disturb Se transport and reduce selenoprotein expression in target tissues. Hereby, TH activation decreases as an acquired condition not reflected by thyrotropin and T4 in blood. This hypothesis opens new diagnostic and therapeutic options for SELENOP-aAb positive CFS, but requires clinical evidence from intervention trials.
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Investigating the Human Intestinal DNA Virome and Predicting Disease-Associated Virus–Host Interactions in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Shen-Yuan Hsieh 1 , George M. Savva 2 , Andrea Telatin 1 , Sumeet K. Tiwari 1 , Mohammad A. Tariq 1,† , Fiona Newberry 1,‡, Katharine A. Seton 1 , Catherine Booth 2 , Amolak S. Bansal 3 , Thomas Wileman 1,4 , Evelien M. Adriaenssens 1 and Simon R. Carding 1,4, Food, Microbiome, and Health Research Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK; [email protected] (S.-Y.H.); [email protected] (A.T.); [email protected] (S.K.T.); [email protected] (M.A.T.); [email protected] (F.N.); [email protected] (K.A.S.); [email protected] (T.W.) 2
Core Science Resources, Quadram Institute Bioscience, Norwich NR4 7UQ, UK; [email protected] (G.M.S.); [email protected] (C.B.) 3 Spire St. Anthony’s Hospital, Surrey SM3 9DW, UK; [email protected] 4 Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK *
Correspondence: [email protected] † Present affiliation: Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, UK. ‡ Present affiliation: Department of Biosciences, School of Science & Technology, Nottingham Trent University, Nottingham NG11 8NS, UK.
Abstract: Understanding how the human virome, and which of its constituents, contributes to health or disease states is reliant on obtaining comprehensive virome profiles. By combining DNA viromes from isolated virus-like particles (VLPs) and whole metagenomes from the same faecal sample of a small cohort of healthy individuals and patients with severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we have obtained a more inclusive profile of the human intestinal DNA virome. Key features are the identification of a core virome comprising tailed phages of the class Caudoviricetes, and a greater diversity of DNA viruses including extracellular phages and integrated prophages. Using an in silico approach, we predicted interactions between members of the Anaerotruncus genus and unique viruses present in ME/CFS microbiomes. This study therefore provides a framework and rationale for studies of larger cohorts of patients to further investigate disease-associated interactions between the intestinal virome and the bacteriome.
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LANCET: ARTICLES| VOLUME 24, ISSUE 3, P256-265, MARCH 2024
A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled trial
Raphaela I Lau, MSc ,Qi Su, PhD ,Ivan S F Lau, MBBCh, Jessica Y L Ching, PhDProf Martin C S Wong, MD,Louis H S Lau, MBChB,et al.
Published:December 07, 2023DOI:https://doi.org/10.1016/S1473-3099(23)00685-0
SummaryBackgroundPost-acute COVID-19 syndrome (PACS) affects over 65 million individuals worldwide but treatment options are scarce. We aimed to assess a synbiotic preparation (SIM01) for the alleviation of PACS symptoms.
MethodsIn this randomised, double-blind, placebo-controlled trial at a tertiary referral centre in Hong Kong, patients with PACS according to the US Centers for Disease Control and Prevention criteria were randomly assigned (1:1) by random permuted blocks to receive SIM01 (10 billion colony-forming units in sachets twice daily) or placebo orally for 6 months. Inclusion criterion was the presence of at least one of 14 PACS symptoms for 4 weeks or more after confirmed SARS-CoV-2 infection, including fatigue, memory loss, difficulty in concentration, insomnia, mood disturbance, hair loss, shortness of breath, coughing, inability to exercise, chest pain, muscle pain, joint pain, gastrointestinal upset, or general unwellness. Individuals were excluded if they were immunocompromised, were pregnant or breastfeeding, were unable to receive oral fluids, or if they had received gastrointestinal surgery in the 30 days before randomisation. Participants, care providers, and investigators were masked to group assignment. The primary outcome was alleviation of PACS symptoms by 6 months, assessed by an interviewer-administered 14-item questionnaire in the intention-to-treat population. Forward stepwise multivariable logistical regression was performed to identify predictors of symptom alleviation. The trial is registered with ClinicalTrials.gov, NCT04950803.
FindingsBetween June 25, 2021, and Aug 12, 2022, 463 patients were randomly assigned to receive SIM01 (n=232) or placebo (n=231). At 6 months, significantly higher proportions of the SIM01 group had alleviation of fatigue (OR 2·273, 95% CI 1·520–3·397, p=0·0001), memory loss (1·967, 1·271–3·044, p=0·0024), difficulty in concentration (2·644, 1·687–4·143, p<0·0001), gastrointestinal upset (1·995, 1·304–3·051, p=0·0014), and general unwellness (2·360, 1·428–3·900, p=0·0008) compared with the placebo group. Adverse event rates were similar between groups during treatment (SIM01 22 [10%] of 232 vs placebo 25 [11%] of 231; p=0·63). Treatment with SIM01, infection with omicron variants, vaccination before COVID-19, and mild acute COVID-19, were predictors of symptom alleviation (p<0·0036).
InterpretationTreatment with SIM01 alleviates multiple symptoms of PACS. Our findings have implications on the management of PACS through gut microbiome modulation. Further studies are warranted to explore the beneficial effects of SIM01 in other chronic or post-infection conditions.
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Article https://doi.org/10.1038/s41467-023-44432-3
Muscle abnormalities worsen after postexertional malaise in long COVID
Brent Appelman 1,2,15, Braeden T. Charlton 3,4,15, Richie P. Goulding3,4, Tom J. Kerkhoff 3,4,5,6, Ellen A. Breedveld 3,4, Wendy Noort3,4, Carla Offringa3,4, Frank W. Bloemers4,7, Michel van Weeghel 8 , Bauke V. Schomakers8 , Pedro Coelho9,10,11, Jelle J. Posthuma7,12, Eleonora Aronica 11, W. Joost Wiersinga 1,2,13, Michèle van Vugt2,14,15 & Rob C. I. Wüst 3,4,15
A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear.
With this longitudinal casecontrol study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exerciseinduced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of postexertional malaise.
This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases. Chronic sequelae after acute infections contribute to debilitating conditions that affect millions worldwide1–5 . After an acute SARS-CoV-2 infection, a subgroup of patients suffers from post-acute sequelae of COVID-19 (PASC), also called long COVID1,6–10. The most reported symptoms of long COVID include limited exercise tolerance and postexertional malaise, representing the worsening of symptoms after mental or physical exertion1,8,10. Current, yet unproven hypotheses explaining exercise tolerance and post-exertional malaise in long COVID include mitochondrial dysfunction, amyloid-containing deposit accumulation in blood vessels causing local hypoxia, systemic and local inflammation, disturbed immunological responses, hormonal imbalance, and viral persistence11–18. The extent to which the underlying physiology of impaired exercise capacity can be separated from factors related to the onset of post-exertional malaise remains unclear, largely due to indirect assessment of the underlying biomedical and psychological parameters, the cross-sectional nature of most studies, and patient heterogeneity. In this study, we systematically induced post-exertional malaise in a cohort of 25 well-defined patients with long COVID and controls. We obtained blood and skeletal muscle biopsies before and after a maximal exercise test (Supplemental Fig. 1) with the aim to study the biological factors contributing to the limited exercise capacity and postexertional malaise in long COVID. Results were compared with those obtained from 21 age- and sex-matched controls who fully recovered from a mild SARS-CoV-2 infection (Table 1). We characterized Long COVID based on the criteria established by the World Health Organization, and an important inclusion criterion was the presence of postexertional malaise19. Both groups were healthy and socially active prior to the initial PCR-proven SARS-CoV-2 infection. No participants were hospitalized due to SARS-CoV-2 infection. Fatigue questionnaires and accelerometer data confirmed the impact of long COVID on daily life (Supplemental Fig. 2). We show that skeletal muscle structure is associated with a lower exercise capacity in patients and that local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of postexertional malaise.
Results Limited exercise capacity in long COVID
Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article
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Original Investigation Physical Medicine and Rehabilitation April 4, 2024
Functional Limitations and Exercise Intolerance in Patients With Post-COVID ConditionA Randomized Crossover Clinical TrialAndrea Tryfonos, PhD1,2; Kaveh Pourhamidi, MD, PhD3; Gustav Jörnåker, MSc1; et alMartin Engvall, MD1,4; Lisa Eriksson, MSc1; Sara Elhallos, BSc1; Nicole Asplund1; Mirko Mandić, PhD1; Patrik Sundblad, MD, PhD1,4; Atif Sepic, MSc3; Eric Rullman, MD, PhD1,4; Lars Hyllienmark, MD, PhD3; Helene Rundqvist, PhD1,4; Tommy R. Lundberg, PhD1,4; Thomas Gustafsson, MD, PhD1,4
JAMA Netw Open. 2024;7(4):e244386. doi:10.1001/jamanetworkopen.2024.4386
Key Points
Question Do nonhospitalized patients experiencing post-COVID condition (PCC) have exaggerated postexercise symptoms after high-intensity interval training (HIIT), moderate-intensity continuous training (MICT), and strength training (ST)?
Findings In this randomized crossover clinical trial of 31 patients with PCC and 31 matched control participants, the exercise response was largely comparable between groups, with no profound symptom exacerbation. Patients with PCC reported more muscle pain after HIIT and concentration problems after MICT and had lower aerobic capacity and less muscle strength; 62% showed myopathic signs.
Meaning The findings suggest that cautious exercise rehabilitation should be recommended to prevent further deconditioning among patients with PCC.
Abstract
Importance Many patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration.
Objective To assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC.
Design, Setting, and Participants In this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited.
Interventions After comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise.
Main Outcomes and Measures The primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC.
Results Thirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: −6.8 mL/kg/min; 95% CI, −10.7 to −2.9 mL/kg/min; P < .001) and less isometric knee extension muscle strength (mean difference: −37 Nm; 95% CI, −67 to −7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, −26.5 minutes/d; 95% CI, −42.0 to −11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing.
Conclusions and Relevance In this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC.
Trial Registration ClinicalTrials.gov Identifier: NCT05445830
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Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeMichael Anthony Jensen,Miranda Lee Dafoe,Julie Wilhelmy,Layla Cervantes,Anna N Okumu,Lucas Kipp,Mohsen Nemat-Gorgani, and Ronald Wayne Davis
Biochemistry 2024, 63, 1, 9–18 Publication Date:November 27, 2023 https://doi.org/10.1021/acs.biochem.3c00433
Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY-NC-ND 4.0.
Abstract
Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatiguesyndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP). We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness. In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP. Furthermore, we found that aprotinin, which is a specific serine protease inhibitor, specifically prevents breakdown of MBP while the other classes of protease inhibitors had no effect. This coincides with the published literature describing catalytic antibodies as having serine protease-like activity. Postpandemic research has also provided several reports of demyelination in COVID-19. Because COVID-19 has been described as a trigger for ME/CFS, demyelination could play a bigger role in patient symptoms for those recently diagnosed with ME/CFS. Therefore, by studying proteolytic antibodies in ME/CFS, their target substrates, and inhibitors, a new mechanism of action could lead to better treatment and a possible cure for the disease.This publication is licensed under
CC-BY-NC-ND 4.0.
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Persistent complement dysregulation with signs of thromboinflammation in active Long CovidCARLO CERVIA-HASLER HTTPS://ORCID.ORG/0000-0001-7120-8739, SARAH C. BRÜNINGK HTTPS://ORCID.ORG/0000-0003-3176-1032, TOBIAS HOCH HTTPS://ORCID.ORG/0000-0003-0319-6064, BOWEN FAN, GIULIA MUZIO HTTPS://ORCID.ORG/0000-0001-5999-2030, RYAN C. THOMPSON HTTPS://ORCID.ORG/0000-0002-0450-8181, LAURA CEGLAREK HTTPS://ORCID.ORG/0009-0005-7117-0335, ROMAN MELEDIN HTTPS://ORCID.ORG/0000-0001-6921-825X, PATRICK WESTERMANN HTTPS://ORCID.ORG/0000-0003-2894-6140, [...], AND ONUR BOYMAN HTTPS://ORCID.ORG/0000-0001-8279-5545 +18 authors
SCIENCE 19 Jan 2024 Vol 383, Issue 6680 DOI: 10.1126/science.adg7942
Editor’s summarySome individuals can endure persistent, debilitating symptoms for many months after an initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the factors underpinning these health issues, called Long Covid, are poorly understood. Comparing the blood of patients with confirmed SARS-CoV-2 infection with that of uninfected controls, Cervia-Hasler et al. found that patients experiencing Long COVID exhibited changes to blood serum proteins indicating activation of the immune system’s complement cascade, altered coagulation, and tissue injury (see the Perspective by Ruf). At the cellular level, Long Covid was linked to aggregates comprising monocytes and platelets. These findings provide a resource of potential biomarkers for diagnosis and may inform directions for treatments. —Sarah H. Ross
Structured Abstract INTRODUCTIONAcute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes various clinical phenotypes, ranging from asymptomatic to life-threatening COVID-19. About 5% of all infected individuals do not recover from acute disease but develop long-term complications, called Long Covid. Current hypotheses on factors contributing to Long Covid include tissue damage, viral reservoirs, autoimmunity, and persistent inflammation. There are currently no diagnostic tests or therapeutic solutions for affected patients.
RATIONALEWe followed 39 healthy controls and 113 COVID-19 patients for up to 1 year after initial confirmation of acute SARS-CoV-2 infection to identify biomarkers associated with Long Covid. At 6-month follow-up, 40 patients had Long Covid symptoms. Repeated clinical assessments were paired with blood draws, resulting in a total of 268 longitudinal blood samples. We measured >6500 proteins in serum by proteomics. Top candidate biomarkers were identified using computational tools and further evaluated experimentally.
RESULTSLong Covid patients exhibited increased complement activation during acute disease, which also persisted at 6-month follow-up. The complement system is part of the innate immune system and contributes to immunity and homeostasis by targeting pathogens and damaged cells, among other functions. Interestingly, blood complement levels normalized in Long Covid patients recovering before their 6-month follow-up. The complement system can be activated by various triggers, resulting in formation of the terminal complement complex (TCC), made of the complement components C5b-9. These complexes can integrate into cell membranes and induce cell activation or lysis. Long Covid patients showed imbalanced TCC formation, marked by increased soluble C5bC6 complexes and decreased levels of C7-containing TCC formations that can incorporate into cell membranes. This suggested increased membrane insertion of TCCs in Long Covid patients, contributing to tissue damage. Accordingly, Long Covid patients showed elevated tissue injury markers in blood and a thromboinflammatory signature, characterized by markers of endothelial activation, such as von Willebrand factor (vWF), and red blood cell lysis. Low antithrombin III levels in Long Covid patients were accompanied by signs of increased cleavage by thrombin, a driver of TCC formation. Furthermore, Long Covid patients had elevated platelet activation markers and monocyte–platelet aggregates at 6-month follow-up, particularly in cases where Long Covid persisted for 12 months or more. These patients also showed signs of antibody-mediated activation of the classical complement pathway, which was associated with increased anti-CMV (cytomegalovirus, also known as human herpesvirus 5) and anti-EBV (Epstein-Barr virus) immunoglobulin G (IgG) antibody levels.
CONCLUSIONOur data suggest that active Long Covid is accompanied by a blood protein signature marked by increased complement activation and thromboinflammation, including activated platelets and markers of red blood cell lysis. Tissue injury may also be complement-mediated and, in turn, activate the complement system. Moreover, complement activation may be driven by antigen–antibody complexes, involving autoantibodies and antibodies against herpesviruses, as well as cross-talk with a dysregulated coagulation system. In addition to offering a basis for new diagnostic solutions, our work provides support for clinical research on complement modulators for patients suffering from Long Covid.
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Original Investigation Physical Medicine and Rehabilitation April 4, 2024
Functional Limitations and Exercise Intolerance in Patients With Post-COVID Condition A Randomized Crossover Clinical TrialAndrea Tryfonos, PhD1,2; Kaveh Pourhamidi, MD, PhD3; Gustav Jörnåker, MSc1; et alMartin Engvall, MD1,4; Lisa Eriksson, MSc1; Sara Elhallos, BSc1; Nicole Asplund1; Mirko Mandić, PhD1; Patrik Sundblad, MD, PhD1,4; Atif Sepic, MSc3; Eric Rullman, MD, PhD1,4; Lars Hyllienmark, MD, PhD3; Helene Rundqvist, PhD1,4; Tommy R. Lundberg, PhD1,4; Thomas Gustafsson, MD, PhD1,4
JAMA Netw Open. 2024;7(4):e244386. doi:10.1001/jamanetworkopen.2024.4386
Key Points
Question Do nonhospitalized patients experiencing post-COVID condition (PCC) have exaggerated postexercise symptoms after high-intensity interval training (HIIT), moderate-intensity continuous training (MICT), and strength training (ST)?
Findings In this randomized crossover clinical trial of 31 patients with PCC and 31 matched control participants, the exercise response was largely comparable between groups, with no profound symptom exacerbation. Patients with PCC reported more muscle pain after HIIT and concentration problems after MICT and had lower aerobic capacity and less muscle strength; 62% showed myopathic signs.
Meaning The findings suggest that cautious exercise rehabilitation should be recommended to prevent further deconditioning among patients with PCC.
Abstract
Importance Many patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration.
Objective To assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC.
Design, Setting, and Participants In this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited.
Interventions After comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise.
Main Outcomes and Measures The primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC.
Results Thirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: −6.8 mL/kg/min; 95% CI, −10.7 to −2.9 mL/kg/min; P < .001) and less isometric knee extension muscle strength (mean difference: −37 Nm; 95% CI, −67 to −7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, −26.5 minutes/d; 95% CI, −42.0 to −11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing.
Conclusions and Relevance In this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC.
Trial Registration ClinicalTrials.gov Identifier: NCT05445830
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ARTICLE Vol 5 Issue 1, 101373, Jan 16,2024
Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation
Highlights COVID-19 disease severity is associated with demographic and clinical risk factorsPopulation-level variables can confound severity and outcome models
Shifting standards of care, testing practices, and sampling skew outcome metrics
SummarySevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with enhanced transmissibility and immune escape have emerged periodically throughout the coronavirus disease 2019 (COVID-19) pandemic, but the impact of these variants on disease severity has remained unclear. In this single-center, retrospective cohort study, we examined the association between SARS-CoV-2 clade and patient outcome over a two-year period in Chicago, Illinois. Between March 2020 and March 2022, 14,252 residual diagnostic specimens were collected from SARS-CoV-2-positive inpatients and outpatients alongside linked clinical and demographic metadata, of which 2,114 were processed for viral whole-genome sequencing. When controlling for patient demographics and vaccination status, several viral clades were associated with risk for hospitalization, but this association was negated by the inclusion of population-level confounders, including case count, sampling bias, and shifting standards of care. These data highlight the importance of integrating non-virological factors into disease severity and outcome models for the accurate assessment of patient risk.
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A phenomenological study on the lived experience of men with Chronic Fatigue SyndromeGracie Elizabeth Snell https://orcid.org/0000-0002-1472-8196 [email protected], Catherine Heidi Seage https://orcid.org/0000-0002-8590-867X, and Jenny Mercer
Journal of Health Psychology Volume 29, Issue 3 https://doi.org/10.1177/13591053231186385
AbstractWhilst chronic fatigue syndrome (CFS) has been widely researched amongst women, studies investigating how men experience a CFS diagnosis is limited. This study utilised an interpretative phenomenological approach to interview five men who have a medical diagnosis of CFS. Six themes emerged to demonstrate the participants’ experiences prior to, during and after obtaining their CFS diagnosis. Findings revealed that participants were initially reluctant to accept their condition, confounded by their perception that symptoms compromised their sense of masculinity. They also felt that healthcare professionals had limited recognition of CFS leading them to seek social support and legitimisation from other sources. The struggle to come to terms with a different lifestyle and sense of masculinity prevailed. Such knowledge could be effectively utilised by researchers, practitioners and employers to facilitate an increased understanding of male accounts of the condition and more bespoke interventions where required.
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Experts call for more research into long COVID, as study reveals high prevalence in WA
Authors: Smith EJB, Trigger R, Pin P
Publication: ABC News
Link: https://www.abc.net.au/news/2024-04-03/research-finds-long-covid-rates-high-in-wa/103647042
An Australian National University (ANU) study of 11,000 people in Western Australia who had tested positive for COVID-19 during a 2022 Omicron outbreak found that almost 20% had persistent symptoms three months after initially becoming sick. Researchers say that this suggests that the rate of long COVID is high in WA and urges more research into the condition.
Dr Michael Livingston, a rural GP in WA’s Wheatbelt, said that people should not be complacent about COVID-19 prevention. He suggested that the government should develop a “clean air” policy, and fit air filters into spaces like offices and schools to minimise transmission.
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Proc Natl Acad Sci U S A. 2023 Sep 12; 120(37): e2304722120.
Published online 2023 Sep 5. doi: 10.1073/pnas.2304722120
PMCID: PMC10500270 PMID: 37669378
Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection
Anoop T. Ambikan,# a , 1 Nazif Elaldi,# b , 1 Sara Svensson-Akusjärvi, a Binnur Bagci, c Ayse Nur Pektas, d Roger Hewson, e , f Gokhan Bagci, g Mehmet Arasli, h Sofia Appelberg, i Adil Mardinoglu, j , k Vikas Sood, a , l Ákos Végvári, m Rui Benfeitas, a Soham Gupta, a Ilhan Cetin, n Ali Mirazimi, i , o , p and Ujjwal Neogi a , 2
SIGNIFICANCE
Our study identified a dysregulation and hyperactivity of the critical metabolic process of the central carbon and energy metabolism, and metabolic flux related to the amino acid metabolism during the acute progressive phases of infection can promote the exhausted phenotype upon recovery leading to postviral fatigue syndrome in CCHFV (Crimean-Congo hemorrhagic fever virus) infection.
Keywords: Crimean-Congo hemorrhagic fever virus, genome-scale metabolic models, post viral fatigue
Behavioural Neurology
Enhanced motor network engagement during reward gain anticipation in fibromyalgia
Su Hyoun Park, Andrew M. Michael, Anne . Baker, Carina Lei, Katherine T. Martucci
Abstract
Reward motivation is essential in shaping human behavior and cognition. Both reward motivation and reward brain circuits are altered in chronic pain conditions, including fibromyalgia. In this study of fibromyalgia patients, we used a data-driven independent component analysis (ICA) approach to investigate how brain networks contribute to altered reward processing. From females with fibromyalgia (N = 24) and female healthy controls (N = 24), we acquired fMRI data while participants performed a monetary incentive delay (MID) reward task. After analyzing the task-based fMRI data using ICA to identify networks, we analyzed 3 networks of interest: motor network (left), value-driven attention network, and basal ganglia network. Then, we evaluated correlation coefficients between each network timecourse versus a task-based timecourse which modeled gain anticipation. Compared to controls, the fibromyalgia cohort demonstrated significantly stronger correlation between the left motor network timecourse and the gain anticipation timecourse, indicating the left motor network was more engaged with gain anticipation in fibromyalgia. In an exploratory analysis, we compared motor network engagement during early versus late phases of gain anticipation. Across cohorts, greater motor network engagement (i.e., stronger correlation between network and gain anticipation) occurred during the late timepoint, which reflected enhanced motor preparation immediately prior to response. Consistent with the main results, patients exhibited greater engagement of the motor network during both early and late phases compared with healthy controls. Visual-attention and basal ganglia networks revealed similar engagement in the task across groups. As indicated by post-hoc analyses, motor network engagement was positively related to anxiety and negatively related to reward responsiveness. In summary, we identified enhanced reward-task related engagement of the motor network in fibromyalgia using a novel data-driven ICA approach. Enhanced motor network engagement in fibromyalgia may relate to impaired reward motivation, heightened anxiety, and possibly to altered motor processing, such as restricted movement or dysregulated motor planning.
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Clin Neurophysiol. 2023 Jan; 145: 81–88.
Published online 2022 Nov 11. doi: 10.1016/j.clinph.2022.10.017
PMCID: PMC9650483 PMID: 36455453
Co-ultramicronized palmitoylethanolamide/luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome
Viviana Versace,a,⁎,1 Paola Ortelli,a,1 Sabrina Dezi,a Davide Ferrazzoli,a Alessia Alibardi,a Ilenia Bonini,a Michael Engl,b Roberto Maestri,c Martina Assogna,d Valentina Ajello,e Elke Pucks-Faes,f Leopold Saltuari,a Luca Sebastianelli,a Markus Kofler,f,2 and Giacomo Kochd,g,2
Abstract
Objective
Transcranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABAB-ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI).
Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI.
MethodsThirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700 mg + 70 mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity.
Results
Patients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected.
Conclusions
Eight weeks of treatment with PEA-LUT restore GABAB activity and cortical plasticity in long Covid patients.
Significance
This study confirms altered physiology of the motor cortex in long COVID-19 syndrome and indicates PEA-LUT as a candidate for the treatment of this post-viral condition.
Keywords: Palmitoylethanolamide, Long Covid, Transcranial magnetic stimulation, Long-interval intracortical inhibition, LTP-like cortical plasticity
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COVID Virus Can Remain in the Body Over a Year
Ralph Ellis
March 11, 2024 - Medscape
Scientists at the University of California San Francisco have discovered that remnants of the COVID-19 virus can linger in blood and tissue for more than a year after a person is first infected.
In their research on long COVID, the scientists found COVID antigens in the blood for up to 14 months after infection and in tissue samples for more than 2 years after infection.
"These two studies provide some of the strongest evidence so far that COVID antigens can persist in some people, even though we think they have normal immune responses," Michael Peluso, MD, an infectious disease researcher in the UCSF School of Medicine, who led both studies, said in a statement.
Scientists don't know what causes long COVID, in which symptoms of the illness persist months or years after recovery. The most common symptoms are extreme fatigue, shortness of breath, loss of smell, and muscle aches.
The UCSF research team examined blood samples from 171 infected people and found the COVID "spike" protein was still present up to 14 months after infection in some people. The antigens were found more often in people who were hospitalized with COVID or who reported being very sick but were not hospitalized.
Researchers next looked at the UCSF Long COVID Tissue Bank, which contains samples donated by patients with and without long COVID.
They found portions of viral RNA in the tissue up to 2 years after people were infected, though there was no evidence of reinfection. Those viral fragments were found in connective tissue where immune cells are, suggesting that the fragments caused the immune system to attack, according to the researchers.
The UCSF team is running clinical trials to find out if monoclonal antibodies or antiviral drugs can remove the virus.
The findings were presented in Denver this week at the Conference on Retroviruses and Opportunistic Infections.
SOURCES:
EurekAlert: "COVID-19 virus can stay in the body more than a year after infection."
University of California San Francisco: "First Tissue Bank May Help Solve Mystery of Long COVID Misery."
40
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Expert Opin Ther Targets. 2017 Aug;21(8):817-826.
doi: 10.1080/14728222.2017.1353603. Epub 2017 Jul 12.
Sleep disturbances and severe stress as glial activators: key targets for treating central sensitization in chronic pain patients?Jo Nijs 1 2 3, Marco L Loggia 4, Andrea Polli 1 2, Maarten Moens 5 6, Eva Huysmans 1 2, Lisa Goudman 1 2 5, Mira Meeus 1 7 8, Luc Vanderweeën 1 2 9, Kelly Ickmans 1 3, Daniel Clauw 10
PMID: 28685641 DOI: 10.1080/14728222.2017.1353603
AbstractThe mechanism of sensitization of the central nervous system partly explains the chronic pain experience in many patients, but the etiological mechanisms of this central nervous system dysfunction are poorly understood. Recently, an increasing number of studies suggest that aberrant glial activation takes part in the establishment and/or maintenance of central sensitization. Areas covered: This review focused on preclinical work and mostly on the neurobiochemistry studied in animals, with limited human studies available. Glial overactivation results in a low-grade neuroinflammatory state, characterized by high levels of BDNF, IL-1β, TNF-α, which in turn increases the excitability of the central nervous system neurons through mechanisms like long-term potentiation and increased synaptic efficiency. Aberrant glial activity in chronic pain might have been triggered by severe stress exposure, and/or sleeping disturbances, each of which are established initiating factors for chronic pain development. Expert opinion: Potential treatment avenues include several pharmacological options for diminishing glial activity, as well as conservative interventions like sleep management, stress management and exercise therapy. Pharmacological options include propentofylline, minocycline, β -adrenergic receptor antagonists, and cannabidiol. Before translating these findings from basic science to clinical settings, more human studies exploring the outlined mechanisms in chronic pain patients are needed.
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Worsening symptoms is associated with larger cerebral blood flow abnormalities during tilt-testing in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Authors: van Campen CMC, Rowe PC & Visser FC (Stichting CardioZorg, The Netherlands). Publication: Medicina
Link: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00323-1/fulltext
Previous studies have found that ME/CFS patients experience abnormal reduction in cerebral blood flow (CBF) during tilt testing. Studies have not previously examined the relationship between ME/CFS symptom severity and CBF reduction. The authors sought to examine whether there was a correlation between the severity of symptoms and the degree of CBF reduction during tilt testing.
110 ME/CFS patients (International Consensus Criteria (ICC)) were selected from the authors’ existing database. Patients had completed tilt testing and assessments of ME/CFS symptomology on the same day, and again at a subsequent follow-up. In addition, the authors combined the data from of two previous studies, which included 219 participants whose symptom severity had been defined by the ICC.
The authors found that of the 110 patients from their database, 71 were retested due to worsening symptoms. Within this group, the ICC disease severity changed, with a significant number of patients experiencing a more severe ICC disease rating, from 51% mild, 45% moderate and 4% severe at the initial visit, to 1% mild, 72% moderate and 27% severe at follow-up. In this group, the CBF reduction also changed, from 19% at the first test, to 31% at the follow-up. Of the 39 patients with stable disease, the severity of disease distribution and CBF reduction did not differ significantly between the initial visit and follow-up. When looking at the combined data from the two previous studies, the authors found that patients with mild, moderate, and severe disease experienced CBF reductions of 25%, 29%, and 33% respectively.
The authors conclude that there is a strong association between ME/CFS disease severity and percentage CBF reduction during tilt testing, with a more severe disease rating being associated with a larger reduction in CBF. The authors propose that this objective measure of confirming worsening symptoms may help to guide treatment and measure the effectiveness of therapies.
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Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post‐acute COVID‐19 syndrome with and without postural orthostatic tachycardia syndrome: a multi‐omic profiling study
Authors: Mahdi A, Zhao A, Fredengren E, Fedorowski A, Braunschweig F, Nygren‐Bonnier M, … Ståhlberg M (Karolinska University Hospital, Sweden)
Publication: Scientific Reports Link:https://doi.org/10.1038/s41598-023-47539-1
An estimated 30% of severely affected post-acute COVID-19 syndrome (PACS) patients experience postural orthostatic tachycardia syndrome (POTS) and present with microvascular endothelial dysfunction. To unravel the unknown pathological mechanisms underlying PACS with POTS, the authors applied an unbiased multi-omic approach to participants’ plasma to analyse cardio-metabolic proteins, pro-inflammatory cytokines/chemokines, and sphingolipids.
A total of 42 non-hospitalised patients with PACS (diagnosed according to the WHO definition) were recruited from the post-acute COVID-19 clinic at Karolinska University Hospital in Sweden. On average, participants had been unwell for 18 months. Participants were divided into 2 groups depending on the presence (PACS+POTS, 20 individuals) or absence (PACS-POTS, 22 individuals) of POTS, defined as (1) a persistent rise in heart rate of more than 30 beats/min, or (2) a heart rate inferior to 120 beats/min within 10 min of the tilt-up test. PACS patients were matched with 21 healthy individuals (healthy controls). There were no significant differences in symptom scores between the two PACS groups. Women were more represented than men in all groups.
Differential expression analysis of 700 plasma proteins showed that PACS patients had a clearly dysregulated plasma proteome with around 200 dysregulated proteins when compared to healthy controls. There were no significant differences in dysregulated proteins between the two PACS groups.
Gene ontology enrichment analysis revealed many significantly altered pathways in both PACS groups compared with healthy controls, including haemostasis, inflammation, amino acid metabolism, and apoptosis. Differential expression analysis of 36 cytokines showed similar cytokine dysregulation in both PACS groups, with 11 up-regulated cytokines compared to healthy controls. Differential expression analysis of 88 plasma sphingolipids showed 16 and 19 dysregulated lipids in PACS+POTS and PACS-POTS respectively, compared to healthy controls. Nevertheless, the authors found no significant difference in proteins, cytokines, or sphingolipids between PACS+POTS and PACS-POTS groups. Principal component analysis also failed to differentiate between these groups.
Collectively, this study suggests that the pro-inflammatory, proliferative and pro-coagulative state in PACS represents an important phenotype in the pathophysiology. Therefore, the resolution of inflammation and micro clots, combined with haemostasis correction, might alleviate PACS burden. The absence of distinctions between participants with and without POTS suggests that POTS may not be associated with the dysregulation of plasma proteins, cytokines, and sphingolipids observed in PACS.
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Catalytic antibodies may contribute to demyelination in myalgic encephalomyelitis/chronic fatigue syndromeAuthors: Jensen MA, Dafoe ML, Wilhelmy J, Cervantes L, Okumu AN, Kipp L, … Davis RW (Stanford University, USA)
Publication: Biochemistry Link: https://doi.org/10.1071/AH23106
Multiple sclerosis (MS) is an autoimmune inflammatory disease affecting the central nervous system (CNS), characterised by symptoms of pain and impaired nerve communication from the demyelination caused by catalytic antibodies (antibodies with enzyme-like behaviour (Abzs)). There are considerable overlaps between MS and ME/CFS. MRI and PET studies have found physical abnormalities in the brain of ME/CFS patients, and ME/CFS shares symptoms of pain and impaired nerve communication that may be caused by the digestion of myelin basic protein (MBP). The aim of this study was to examine the role of Abzs in ME/CFS.
Total plasma antibodies (Abs) were collected from 19 patients with ME/CFS (diagnosed using the Canadian Consensus Criteria), 19 healthy controls (HC), and 3 patients with MS to be used as an expected metric comparison. Samples were analysed to identify catalytic antibodies.
When added to bovine brain MBP substrate, 47% of ME/CFS Abs showed digestion, compared to 5% of HC. The authors suggest that those with ME/CFS whose Abs did not cleave MBP may have symptoms unrelated to myelin breakdown or that, similar to MS, there may be patterns of remission and relapse. The Abzs were shown to have serine protease-like activity. Three additional substrates (casein, a-lactalbumin, and lysozyme) were used to determine that breakdown was myelin-specific, not random proteolysis. Purification and size-exclusion assays proved that there was no protease involvement in the MBP breakdown. When the MS drug, glatiramer acetate (GA) was added to ME/CFS Abs + MBP assays, the breakdown of MBP was significantly reduced. GA was shown to be Abzs-specific and did not cause inhibition of general serine protease enzyme activity. Fractionated GA demonstrated the higher molecular weight fragments having greater potency.
The concentration of GA used in these assays far exceeds the general dosage used in MS (and thus what is proposed for usage in myelin-associated ME/CFS). However, demyelination has a long-term cumulative effect, and treatment with GA often takes 6 to 9 months before effects become apparent. As such, the authors believe that the higher dosage used in these assays accounts for these longer-term effects. The authors recommend that a prospective study be undertaken over a long period of time to discover whether there is a similar relapsing-remission pattern in ME/CFS as seen in MS.
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‘We have no services for you...so you have to make the best out of it’: A qualitative study of myalgic encephalomyelitis/chronic fatigue syndrome patients’Authors:Melby, L. & das Nair, R. (SINTEF, Norway) Publication:Health Expectations
Link: https://www.abc.net.au/news/2023-12-08/dave-clark-on-living-with-chronic-fatigue-syndrome/103071294
The authors of this study sought to gain a comprehensive understanding of Norwegian ME/CFS patients’ experiences of dissatisfaction with healthcare services and to explore the reasons for this dissatisfaction.
The authors used in-depth interviews conducted in participants’ homes, lasting between 40 and 150 minutes, to gain an understanding of participants’ encounters with healthcare services as well as to assess participants’ reasons for satisfaction or dissatisfaction with these healthcare services. In total, 48 participants from 24 households in Norway participated in the interviews. This number included 37 individuals diagnosed with ME/CFS (25 females, 12 males, age range 10-59), in addition to family and household members.
The authors identified four key reasons why ME/CFS patients and their families experienced dissatisfaction with healthcare services. The first was nonexistent services, which involved study participants feeling as though they received a lack of practical help and information, or they were told effective treatment was not a possibility after receiving their ME/CFS diagnosis. The second reason was non-personalised services, where participants received healthcare services that were not adapted to their needs, resulting in these services being viewed as inappropriate or damaging. The third was slow services, where ME/CFS patients and their families believed they received services too late in their ME/CFS trajectory for these services to be useful. The fourth was inappropriate services, where participants believed the healthcare services they received, did not address their ME/CFS, and they felt sicker than they had previously.
The authors concluded that dissatisfaction with healthcare services that Norwegian ME/CFS patients and their families experienced may stem from a variety of factors including systemic issues such as bureaucracy within the healthcare industry, inadequate knowledge of ME/CFS leading to a lack of precise recommendations and uncertainty amongst healthcare professionals, poor personalisation and flexibility from healthcare services, healthcare providers’ disbelief in ME/CFS as a medical condition, and a lack of patient involvement in the design of healthcare services.
The authors note the importance of highlighting ME/CFS patients’ negative healthcare experiences in order to improve future services. The authors suggest that future research should investigate how ME/CFS patients can be involved in healthcare service design to help improve healthcare services.
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Is Low Cortisol a Marker of Long COVID?Armin Alaedini, PhD Stafford Lightman, PhD Gary P. Wormser, MD
Published:March 21, 2024DOI:https://doi.org/10.1016/j.amjmed.2024.03.013
Cortisol is the primary glucocorticoid hormone produced by the adrenal glands, playing a critical role in multiple physiological processes, including metabolism, immune response regulation, cardiovascular regulation, and the body's stress response
. The secretion of cortisol is closely regulated by the hypothalamus-pituitary-adrenal (HPA) axis. The process is initiated by the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which stimulates the production of adrenocorticotropic hormone (ACTH) by the pituitary gland. In turn, ACTH prompts the adrenal glands to release cortisol
. Cortisol measurements have been used extensively in research to investigate the hormone's relationship with various physiological disruptions and health conditions, including mental health disorders, immune system dysfunction, and metabolic disorders
. However, it is essential to recognize the potential pitfalls in the assessment and interpretation of cortisol levels in translational research, as overlooking them can foster misinformation and confusion regarding potential clinical or diagnostic relevance of the findings.
In two recent studies (Klein et al. in 2023 and Fleischer et al. in 2024 ), researchers reported on the analysis of hormonal and other markers in blood samples from individuals with post-acute sequelae of SARS CoV-2 infection (PASC)—commonly known as long COVID (LC). Long COVID is associated with a range of persistent symptoms, including fatigue, pain, and brain fog that can be debilitating. Notably, the most compelling and statistically significant finding of the Klein et al. study revolved around the levels of cortisol, which were reported to be much lower in long COVID patients than in controls without long COVID . The authors of the study concluded that “[s]erum cortisol was the most significant predictor of LC status in the model, and cortisol alone achieved an AUC.of 0.96”
. The findings have been widely publicized in the media, engendering speculation regarding their therapeutic and biomarker potential in long COVID.. On the other hand, a more recent study by Fleischer et al. found no significant difference or trends in the cortisol levels in a comparison of post-COVID-19 patients, with and without persistent symptoms, apparently contradicting the results reported in the earlier study. While the cortisol assessments in both of these two studies may represent remarkable and consequential findings in the context of long COVID, unfortunately, they are impacted by significant limitations and concerns regarding how the cortisol levels were assessed and interpreted.
The levels of cortisol in the body are very dynamic, following a distinct circadian pattern throughout the day. Levels typically increase in the first half hour after awakening by up to 60%, in what has been called the cortisol awakening response, followed by a sharp drop over the next few hours, reaching their lowest point in the evening.. Underlying this circadian rhythm, cortisol also exhibits ultradian fluctuations in a pulsatile pattern with several peaks and troughs throughout the day that change in amplitude.. Because of these fluctuations and the wide and rapid changes in circulating levels, reliable and reproducible evaluation of cortisol secretion is not trivial. Such assessment cannot be based on only a single measurement, but rather requires the collection of multiple blood, saliva, or urine samples throughout the day. Any single measurement would also ideally need to account for the time elapsed since awakening and not necessarily just the time of day. In assessing the difference in cortisol output between groups, multiple measurements in blood or saliva samples are usually used to analyze the change from baseline, the size of the cortisol awakening response, or the elevation and slopepe of the diurnal curve Surprisingly, none of these approaches was taken in either of the two cited studies of cortisol levels in long COVID. Both studies conducted a single measurement in blood plasma or serum, taking note of the time of day, but not the time since awakening, for the sample collection. More importantly, no attempt was made to take serial samples to overcome the problem associated with the very rapid changes occurring due to ultradian rhythmicity. Considering the dramatic ultradian and diurnal cortisol oscillations, meaningful interpretation of the reported cortisol levels in these two studies is simply not possible. The issue is further compounded by the potential association of long COVID with sleep disturbances , including earlier than average awakening times, which could significantly shift the cortisol diurnal curve, giving the appearance of uniformly lower circulating levels during the daytime. The additional finding that the time of sample collection was not a significant predictor of cortisol levels in the study by Klein et al. adds weight to existing concerns about the validity of the reported results and the conclusions regarding the value of blood cortisol concentration as a potential biomarker of long COVID.
Given the presence of persistent fatigue as a hallmark symptom of long COVID, the evaluation of HPA axis function through the assessment of cortisol output is a logical approach. However, considering the available data and the major methodological shortcomings noted in the two published studies, it is clear that neither the utility of cortisol as a biomarker nor the therapeutic role of corticosteroids in treating long COVID can be justified at this juncture. The issues raised here underscore the need for further rigorous and comprehensive investigations into the relationship between cortisol response and long COVID, taking special note of the cortisol diurnal pattern, potential confounding factors impacting this pattern, and the utilization of well-documented and established methods of assessing cortisol levels
. The recent availability of new techniques to measure cortisol levels sequentially across the full 24 hours, including during sleep should provide the methodology needed for obtaining reliable and accurate data on HPA axis function in long COVID and other conditions.
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Redox Biol. 2023 Sep:65:102796. doi: 10.1016/j.redox.2023.102796. Epub 2023 Jul 3.
Autoantibodies to selenoprotein P in chronic fatigue syndrome suggest selenium transport impairment and acquired resistance to thyroid hormoneQian Sun 1, Elisa Oltra 2, D A Janneke Dijck-Brouwer 3, Thilo Samson Chillon 4, Petra Seemann 5, Sabrina Asaad 4, Kamil Demircan 4, José Andrés Espejo-Oltra 2, Teresa Sánchez-Fito 2, Eva Martín-Martínez 6, Waldemar B Minich 4, Frits A J Muskiet 3, Lutz Schomburg 7
PMID: 37423160 PMCID: PMC10338150 DOI: 10.1016/j.redox.2023.102796
AbstractChronic Fatigue Syndrome (CFS) presents with symptoms of hypothyroidism, including mental and physical fatigue, poor sleep, depression, and anxiety. However, thyroid hormone (TH) profiles of elevated thyrotropin and low thyroxine (T4) are not consistently observed. Recently, autoantibodies to the Se transporter SELENOP (SELENOP-aAb) have been identified in Hashimoto's thyroiditis and shown to impair selenoprotein expression. We hypothesized that SELENOP-aAb are prevalent in CFS, and associate with reduced selenoprotein expression and impaired TH deiodination. Se status and SELENOP-aAb prevalence was compared by combining European CFS patients (n = 167) and healthy controls (n = 545) from different sources. The biomarkers total Se, glutathione peroxidase (GPx3) and SELENOP showed linear correlations across the samples without reaching saturation, indicative of Se deficiency. SELENOP-aAb prevalence was 9.6-15.6% in CFS versus 0.9-2.0% in controls, depending on cut-off for positivity. The linear correlation between Se and GPx3 activity was absent in SELENOP-aAb positive patients, suggesting impaired Se supply of kidney. A subgroup of paired control (n = 119) and CSF (n = 111) patients had been characterized for TH and biochemical parameters before. Within this subgroup, SELENOP-aAb positive patients displayed particularly low deiodinase activity (SPINA-GD index), free T3 levels, total T3 to total T4 (TT3/TT4) and free T3 to free T4 (FT3/FT4) ratios. In 24 h urine, iodine concentrations were significantly lower in SELENOP-aAb positive than in SELENOP-aAb negative patients or controls (median (IQR); 43.2 (16.0) vs. 58.9 (45.2) vs. 89.0 (54.9) μg/L). The data indicate that SELENOP-aAb associate with low deiodination rate and reduced activation of TH to active T3. We conclude that a subset of CFS patients express SELENOP-aAb that disturb Se transport and reduce selenoprotein expression in target tissues. Hereby, TH activation decreases as an acquired condition not reflected by thyrotropin and T4 in blood. This hypothesis opens new diagnostic and therapeutic options for SELENOP-aAb positive CFS, but requires clinical evidence from intervention trials.
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Investigating the Human Intestinal DNA Virome and Predicting Disease-Associated Virus–Host Interactions in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Shen-Yuan Hsieh 1 , George M. Savva 2 , Andrea Telatin 1 , Sumeet K. Tiwari 1 , Mohammad A. Tariq 1,† , Fiona Newberry 1,‡, Katharine A. Seton 1 , Catherine Booth 2 , Amolak S. Bansal 3 , Thomas Wileman 1,4 , Evelien M. Adriaenssens 1 and Simon R. Carding 1,4, Food, Microbiome, and Health Research Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK; [email protected] (S.-Y.H.); [email protected] (A.T.); [email protected] (S.K.T.); [email protected] (M.A.T.); [email protected] (F.N.); [email protected] (K.A.S.); [email protected] (T.W.) 2
Core Science Resources, Quadram Institute Bioscience, Norwich NR4 7UQ, UK; [email protected] (G.M.S.); [email protected] (C.B.) 3 Spire St. Anthony’s Hospital, Surrey SM3 9DW, UK; [email protected] 4 Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK *
Correspondence: [email protected] † Present affiliation: Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, UK. ‡ Present affiliation: Department of Biosciences, School of Science & Technology, Nottingham Trent University, Nottingham NG11 8NS, UK.
Abstract: Understanding how the human virome, and which of its constituents, contributes to health or disease states is reliant on obtaining comprehensive virome profiles. By combining DNA viromes from isolated virus-like particles (VLPs) and whole metagenomes from the same faecal sample of a small cohort of healthy individuals and patients with severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we have obtained a more inclusive profile of the human intestinal DNA virome. Key features are the identification of a core virome comprising tailed phages of the class Caudoviricetes, and a greater diversity of DNA viruses including extracellular phages and integrated prophages. Using an in silico approach, we predicted interactions between members of the Anaerotruncus genus and unique viruses present in ME/CFS microbiomes. This study therefore provides a framework and rationale for studies of larger cohorts of patients to further investigate disease-associated interactions between the intestinal virome and the bacteriome.
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LANCET: ARTICLES| VOLUME 24, ISSUE 3, P256-265, MARCH 2024
A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled trial
Raphaela I Lau, MSc ,Qi Su, PhD ,Ivan S F Lau, MBBCh, Jessica Y L Ching, PhDProf Martin C S Wong, MD,Louis H S Lau, MBChB,et al.
Published:December 07, 2023DOI:https://doi.org/10.1016/S1473-3099(23)00685-0
SummaryBackgroundPost-acute COVID-19 syndrome (PACS) affects over 65 million individuals worldwide but treatment options are scarce. We aimed to assess a synbiotic preparation (SIM01) for the alleviation of PACS symptoms.
MethodsIn this randomised, double-blind, placebo-controlled trial at a tertiary referral centre in Hong Kong, patients with PACS according to the US Centers for Disease Control and Prevention criteria were randomly assigned (1:1) by random permuted blocks to receive SIM01 (10 billion colony-forming units in sachets twice daily) or placebo orally for 6 months. Inclusion criterion was the presence of at least one of 14 PACS symptoms for 4 weeks or more after confirmed SARS-CoV-2 infection, including fatigue, memory loss, difficulty in concentration, insomnia, mood disturbance, hair loss, shortness of breath, coughing, inability to exercise, chest pain, muscle pain, joint pain, gastrointestinal upset, or general unwellness. Individuals were excluded if they were immunocompromised, were pregnant or breastfeeding, were unable to receive oral fluids, or if they had received gastrointestinal surgery in the 30 days before randomisation. Participants, care providers, and investigators were masked to group assignment. The primary outcome was alleviation of PACS symptoms by 6 months, assessed by an interviewer-administered 14-item questionnaire in the intention-to-treat population. Forward stepwise multivariable logistical regression was performed to identify predictors of symptom alleviation. The trial is registered with ClinicalTrials.gov, NCT04950803.
FindingsBetween June 25, 2021, and Aug 12, 2022, 463 patients were randomly assigned to receive SIM01 (n=232) or placebo (n=231). At 6 months, significantly higher proportions of the SIM01 group had alleviation of fatigue (OR 2·273, 95% CI 1·520–3·397, p=0·0001), memory loss (1·967, 1·271–3·044, p=0·0024), difficulty in concentration (2·644, 1·687–4·143, p<0·0001), gastrointestinal upset (1·995, 1·304–3·051, p=0·0014), and general unwellness (2·360, 1·428–3·900, p=0·0008) compared with the placebo group. Adverse event rates were similar between groups during treatment (SIM01 22 [10%] of 232 vs placebo 25 [11%] of 231; p=0·63). Treatment with SIM01, infection with omicron variants, vaccination before COVID-19, and mild acute COVID-19, were predictors of symptom alleviation (p<0·0036).
InterpretationTreatment with SIM01 alleviates multiple symptoms of PACS. Our findings have implications on the management of PACS through gut microbiome modulation. Further studies are warranted to explore the beneficial effects of SIM01 in other chronic or post-infection conditions.
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Article https://doi.org/10.1038/s41467-023-44432-3
Muscle abnormalities worsen after postexertional malaise in long COVID
Brent Appelman 1,2,15, Braeden T. Charlton 3,4,15, Richie P. Goulding3,4, Tom J. Kerkhoff 3,4,5,6, Ellen A. Breedveld 3,4, Wendy Noort3,4, Carla Offringa3,4, Frank W. Bloemers4,7, Michel van Weeghel 8 , Bauke V. Schomakers8 , Pedro Coelho9,10,11, Jelle J. Posthuma7,12, Eleonora Aronica 11, W. Joost Wiersinga 1,2,13, Michèle van Vugt2,14,15 & Rob C. I. Wüst 3,4,15
A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear.
With this longitudinal casecontrol study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exerciseinduced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of postexertional malaise.
This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases. Chronic sequelae after acute infections contribute to debilitating conditions that affect millions worldwide1–5 . After an acute SARS-CoV-2 infection, a subgroup of patients suffers from post-acute sequelae of COVID-19 (PASC), also called long COVID1,6–10. The most reported symptoms of long COVID include limited exercise tolerance and postexertional malaise, representing the worsening of symptoms after mental or physical exertion1,8,10. Current, yet unproven hypotheses explaining exercise tolerance and post-exertional malaise in long COVID include mitochondrial dysfunction, amyloid-containing deposit accumulation in blood vessels causing local hypoxia, systemic and local inflammation, disturbed immunological responses, hormonal imbalance, and viral persistence11–18. The extent to which the underlying physiology of impaired exercise capacity can be separated from factors related to the onset of post-exertional malaise remains unclear, largely due to indirect assessment of the underlying biomedical and psychological parameters, the cross-sectional nature of most studies, and patient heterogeneity. In this study, we systematically induced post-exertional malaise in a cohort of 25 well-defined patients with long COVID and controls. We obtained blood and skeletal muscle biopsies before and after a maximal exercise test (Supplemental Fig. 1) with the aim to study the biological factors contributing to the limited exercise capacity and postexertional malaise in long COVID. Results were compared with those obtained from 21 age- and sex-matched controls who fully recovered from a mild SARS-CoV-2 infection (Table 1). We characterized Long COVID based on the criteria established by the World Health Organization, and an important inclusion criterion was the presence of postexertional malaise19. Both groups were healthy and socially active prior to the initial PCR-proven SARS-CoV-2 infection. No participants were hospitalized due to SARS-CoV-2 infection. Fatigue questionnaires and accelerometer data confirmed the impact of long COVID on daily life (Supplemental Fig. 2). We show that skeletal muscle structure is associated with a lower exercise capacity in patients and that local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of postexertional malaise.
Results Limited exercise capacity in long COVID
Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article
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Original Investigation Physical Medicine and Rehabilitation April 4, 2024
Functional Limitations and Exercise Intolerance in Patients With Post-COVID ConditionA Randomized Crossover Clinical TrialAndrea Tryfonos, PhD1,2; Kaveh Pourhamidi, MD, PhD3; Gustav Jörnåker, MSc1; et alMartin Engvall, MD1,4; Lisa Eriksson, MSc1; Sara Elhallos, BSc1; Nicole Asplund1; Mirko Mandić, PhD1; Patrik Sundblad, MD, PhD1,4; Atif Sepic, MSc3; Eric Rullman, MD, PhD1,4; Lars Hyllienmark, MD, PhD3; Helene Rundqvist, PhD1,4; Tommy R. Lundberg, PhD1,4; Thomas Gustafsson, MD, PhD1,4
JAMA Netw Open. 2024;7(4):e244386. doi:10.1001/jamanetworkopen.2024.4386
Key Points
Question Do nonhospitalized patients experiencing post-COVID condition (PCC) have exaggerated postexercise symptoms after high-intensity interval training (HIIT), moderate-intensity continuous training (MICT), and strength training (ST)?
Findings In this randomized crossover clinical trial of 31 patients with PCC and 31 matched control participants, the exercise response was largely comparable between groups, with no profound symptom exacerbation. Patients with PCC reported more muscle pain after HIIT and concentration problems after MICT and had lower aerobic capacity and less muscle strength; 62% showed myopathic signs.
Meaning The findings suggest that cautious exercise rehabilitation should be recommended to prevent further deconditioning among patients with PCC.
Abstract
Importance Many patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration.
Objective To assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC.
Design, Setting, and Participants In this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited.
Interventions After comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise.
Main Outcomes and Measures The primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC.
Results Thirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: −6.8 mL/kg/min; 95% CI, −10.7 to −2.9 mL/kg/min; P < .001) and less isometric knee extension muscle strength (mean difference: −37 Nm; 95% CI, −67 to −7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, −26.5 minutes/d; 95% CI, −42.0 to −11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing.
Conclusions and Relevance In this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC.
Trial Registration ClinicalTrials.gov Identifier: NCT05445830
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Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeMichael Anthony Jensen,Miranda Lee Dafoe,Julie Wilhelmy,Layla Cervantes,Anna N Okumu,Lucas Kipp,Mohsen Nemat-Gorgani, and Ronald Wayne Davis
Biochemistry 2024, 63, 1, 9–18 Publication Date:November 27, 2023 https://doi.org/10.1021/acs.biochem.3c00433
Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY-NC-ND 4.0.
Abstract
Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatiguesyndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP). We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness. In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP. Furthermore, we found that aprotinin, which is a specific serine protease inhibitor, specifically prevents breakdown of MBP while the other classes of protease inhibitors had no effect. This coincides with the published literature describing catalytic antibodies as having serine protease-like activity. Postpandemic research has also provided several reports of demyelination in COVID-19. Because COVID-19 has been described as a trigger for ME/CFS, demyelination could play a bigger role in patient symptoms for those recently diagnosed with ME/CFS. Therefore, by studying proteolytic antibodies in ME/CFS, their target substrates, and inhibitors, a new mechanism of action could lead to better treatment and a possible cure for the disease.This publication is licensed under
CC-BY-NC-ND 4.0.
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Persistent complement dysregulation with signs of thromboinflammation in active Long CovidCARLO CERVIA-HASLER HTTPS://ORCID.ORG/0000-0001-7120-8739, SARAH C. BRÜNINGK HTTPS://ORCID.ORG/0000-0003-3176-1032, TOBIAS HOCH HTTPS://ORCID.ORG/0000-0003-0319-6064, BOWEN FAN, GIULIA MUZIO HTTPS://ORCID.ORG/0000-0001-5999-2030, RYAN C. THOMPSON HTTPS://ORCID.ORG/0000-0002-0450-8181, LAURA CEGLAREK HTTPS://ORCID.ORG/0009-0005-7117-0335, ROMAN MELEDIN HTTPS://ORCID.ORG/0000-0001-6921-825X, PATRICK WESTERMANN HTTPS://ORCID.ORG/0000-0003-2894-6140, [...], AND ONUR BOYMAN HTTPS://ORCID.ORG/0000-0001-8279-5545 +18 authors
SCIENCE 19 Jan 2024 Vol 383, Issue 6680 DOI: 10.1126/science.adg7942
Editor’s summarySome individuals can endure persistent, debilitating symptoms for many months after an initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the factors underpinning these health issues, called Long Covid, are poorly understood. Comparing the blood of patients with confirmed SARS-CoV-2 infection with that of uninfected controls, Cervia-Hasler et al. found that patients experiencing Long COVID exhibited changes to blood serum proteins indicating activation of the immune system’s complement cascade, altered coagulation, and tissue injury (see the Perspective by Ruf). At the cellular level, Long Covid was linked to aggregates comprising monocytes and platelets. These findings provide a resource of potential biomarkers for diagnosis and may inform directions for treatments. —Sarah H. Ross
Structured Abstract INTRODUCTIONAcute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes various clinical phenotypes, ranging from asymptomatic to life-threatening COVID-19. About 5% of all infected individuals do not recover from acute disease but develop long-term complications, called Long Covid. Current hypotheses on factors contributing to Long Covid include tissue damage, viral reservoirs, autoimmunity, and persistent inflammation. There are currently no diagnostic tests or therapeutic solutions for affected patients.
RATIONALEWe followed 39 healthy controls and 113 COVID-19 patients for up to 1 year after initial confirmation of acute SARS-CoV-2 infection to identify biomarkers associated with Long Covid. At 6-month follow-up, 40 patients had Long Covid symptoms. Repeated clinical assessments were paired with blood draws, resulting in a total of 268 longitudinal blood samples. We measured >6500 proteins in serum by proteomics. Top candidate biomarkers were identified using computational tools and further evaluated experimentally.
RESULTSLong Covid patients exhibited increased complement activation during acute disease, which also persisted at 6-month follow-up. The complement system is part of the innate immune system and contributes to immunity and homeostasis by targeting pathogens and damaged cells, among other functions. Interestingly, blood complement levels normalized in Long Covid patients recovering before their 6-month follow-up. The complement system can be activated by various triggers, resulting in formation of the terminal complement complex (TCC), made of the complement components C5b-9. These complexes can integrate into cell membranes and induce cell activation or lysis. Long Covid patients showed imbalanced TCC formation, marked by increased soluble C5bC6 complexes and decreased levels of C7-containing TCC formations that can incorporate into cell membranes. This suggested increased membrane insertion of TCCs in Long Covid patients, contributing to tissue damage. Accordingly, Long Covid patients showed elevated tissue injury markers in blood and a thromboinflammatory signature, characterized by markers of endothelial activation, such as von Willebrand factor (vWF), and red blood cell lysis. Low antithrombin III levels in Long Covid patients were accompanied by signs of increased cleavage by thrombin, a driver of TCC formation. Furthermore, Long Covid patients had elevated platelet activation markers and monocyte–platelet aggregates at 6-month follow-up, particularly in cases where Long Covid persisted for 12 months or more. These patients also showed signs of antibody-mediated activation of the classical complement pathway, which was associated with increased anti-CMV (cytomegalovirus, also known as human herpesvirus 5) and anti-EBV (Epstein-Barr virus) immunoglobulin G (IgG) antibody levels.
CONCLUSIONOur data suggest that active Long Covid is accompanied by a blood protein signature marked by increased complement activation and thromboinflammation, including activated platelets and markers of red blood cell lysis. Tissue injury may also be complement-mediated and, in turn, activate the complement system. Moreover, complement activation may be driven by antigen–antibody complexes, involving autoantibodies and antibodies against herpesviruses, as well as cross-talk with a dysregulated coagulation system. In addition to offering a basis for new diagnostic solutions, our work provides support for clinical research on complement modulators for patients suffering from Long Covid.
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Original Investigation Physical Medicine and Rehabilitation April 4, 2024
Functional Limitations and Exercise Intolerance in Patients With Post-COVID Condition A Randomized Crossover Clinical TrialAndrea Tryfonos, PhD1,2; Kaveh Pourhamidi, MD, PhD3; Gustav Jörnåker, MSc1; et alMartin Engvall, MD1,4; Lisa Eriksson, MSc1; Sara Elhallos, BSc1; Nicole Asplund1; Mirko Mandić, PhD1; Patrik Sundblad, MD, PhD1,4; Atif Sepic, MSc3; Eric Rullman, MD, PhD1,4; Lars Hyllienmark, MD, PhD3; Helene Rundqvist, PhD1,4; Tommy R. Lundberg, PhD1,4; Thomas Gustafsson, MD, PhD1,4
JAMA Netw Open. 2024;7(4):e244386. doi:10.1001/jamanetworkopen.2024.4386
Key Points
Question Do nonhospitalized patients experiencing post-COVID condition (PCC) have exaggerated postexercise symptoms after high-intensity interval training (HIIT), moderate-intensity continuous training (MICT), and strength training (ST)?
Findings In this randomized crossover clinical trial of 31 patients with PCC and 31 matched control participants, the exercise response was largely comparable between groups, with no profound symptom exacerbation. Patients with PCC reported more muscle pain after HIIT and concentration problems after MICT and had lower aerobic capacity and less muscle strength; 62% showed myopathic signs.
Meaning The findings suggest that cautious exercise rehabilitation should be recommended to prevent further deconditioning among patients with PCC.
Abstract
Importance Many patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration.
Objective To assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC.
Design, Setting, and Participants In this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited.
Interventions After comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise.
Main Outcomes and Measures The primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC.
Results Thirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: −6.8 mL/kg/min; 95% CI, −10.7 to −2.9 mL/kg/min; P < .001) and less isometric knee extension muscle strength (mean difference: −37 Nm; 95% CI, −67 to −7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, −26.5 minutes/d; 95% CI, −42.0 to −11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing.
Conclusions and Relevance In this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC.
Trial Registration ClinicalTrials.gov Identifier: NCT05445830
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ARTICLE Vol 5 Issue 1, 101373, Jan 16,2024
Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation
Highlights COVID-19 disease severity is associated with demographic and clinical risk factorsPopulation-level variables can confound severity and outcome models
Shifting standards of care, testing practices, and sampling skew outcome metrics
SummarySevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with enhanced transmissibility and immune escape have emerged periodically throughout the coronavirus disease 2019 (COVID-19) pandemic, but the impact of these variants on disease severity has remained unclear. In this single-center, retrospective cohort study, we examined the association between SARS-CoV-2 clade and patient outcome over a two-year period in Chicago, Illinois. Between March 2020 and March 2022, 14,252 residual diagnostic specimens were collected from SARS-CoV-2-positive inpatients and outpatients alongside linked clinical and demographic metadata, of which 2,114 were processed for viral whole-genome sequencing. When controlling for patient demographics and vaccination status, several viral clades were associated with risk for hospitalization, but this association was negated by the inclusion of population-level confounders, including case count, sampling bias, and shifting standards of care. These data highlight the importance of integrating non-virological factors into disease severity and outcome models for the accurate assessment of patient risk.
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A phenomenological study on the lived experience of men with Chronic Fatigue SyndromeGracie Elizabeth Snell https://orcid.org/0000-0002-1472-8196 [email protected], Catherine Heidi Seage https://orcid.org/0000-0002-8590-867X, and Jenny Mercer
Journal of Health Psychology Volume 29, Issue 3 https://doi.org/10.1177/13591053231186385
AbstractWhilst chronic fatigue syndrome (CFS) has been widely researched amongst women, studies investigating how men experience a CFS diagnosis is limited. This study utilised an interpretative phenomenological approach to interview five men who have a medical diagnosis of CFS. Six themes emerged to demonstrate the participants’ experiences prior to, during and after obtaining their CFS diagnosis. Findings revealed that participants were initially reluctant to accept their condition, confounded by their perception that symptoms compromised their sense of masculinity. They also felt that healthcare professionals had limited recognition of CFS leading them to seek social support and legitimisation from other sources. The struggle to come to terms with a different lifestyle and sense of masculinity prevailed. Such knowledge could be effectively utilised by researchers, practitioners and employers to facilitate an increased understanding of male accounts of the condition and more bespoke interventions where required.
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Experts call for more research into long COVID, as study reveals high prevalence in WA
Authors: Smith EJB, Trigger R, Pin P
Publication: ABC News
Link: https://www.abc.net.au/news/2024-04-03/research-finds-long-covid-rates-high-in-wa/103647042
An Australian National University (ANU) study of 11,000 people in Western Australia who had tested positive for COVID-19 during a 2022 Omicron outbreak found that almost 20% had persistent symptoms three months after initially becoming sick. Researchers say that this suggests that the rate of long COVID is high in WA and urges more research into the condition.
Dr Michael Livingston, a rural GP in WA’s Wheatbelt, said that people should not be complacent about COVID-19 prevention. He suggested that the government should develop a “clean air” policy, and fit air filters into spaces like offices and schools to minimise transmission.
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Proc Natl Acad Sci U S A. 2023 Sep 12; 120(37): e2304722120.
Published online 2023 Sep 5. doi: 10.1073/pnas.2304722120
PMCID: PMC10500270 PMID: 37669378
Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection
Anoop T. Ambikan,# a , 1 Nazif Elaldi,# b , 1 Sara Svensson-Akusjärvi, a Binnur Bagci, c Ayse Nur Pektas, d Roger Hewson, e , f Gokhan Bagci, g Mehmet Arasli, h Sofia Appelberg, i Adil Mardinoglu, j , k Vikas Sood, a , l Ákos Végvári, m Rui Benfeitas, a Soham Gupta, a Ilhan Cetin, n Ali Mirazimi, i , o , p and Ujjwal Neogi a , 2
SIGNIFICANCE
Our study identified a dysregulation and hyperactivity of the critical metabolic process of the central carbon and energy metabolism, and metabolic flux related to the amino acid metabolism during the acute progressive phases of infection can promote the exhausted phenotype upon recovery leading to postviral fatigue syndrome in CCHFV (Crimean-Congo hemorrhagic fever virus) infection.
Keywords: Crimean-Congo hemorrhagic fever virus, genome-scale metabolic models, post viral fatigue
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