Tag: 2022

Is the number of long-term post-COVID symptoms relevant in hospitalized COVID-19 survivors?

Dear editor,

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease-2019 (COVID-19) is associated with heterogeneous symptoms at its acute phase but also at post-acute phase. Current evidence suggests that 50% of survivors experience post-COVID symptoms the following months after the acute infection [,]. The presence of post-COVID symptoms is associated with worse quality of life . In fact, up to 50 diffferent post-COVID symptoms have been described, and patients usually exhibit more than one symptom . Similarly, the number of symptoms at onset is also heterogeneous, and patients can exhibit several number of symptoms. It has been found that a higher number of onset symptoms at the acute phase (high viral load) is associated with a greater number of post-COVID symptoms . Previous studies focussing on post-COVID symptoms did not use machine learning analysis. Here we present the use of a network analysis for investigating the associations between COVID-19 onset symptoms at hospital admission and the presence of post-COVID symptoms at a long-term follow-up in previously hospitalised COVID-19 survivors recruited from different hospitals.

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Source: Fernández-de-Las-Peñas C, Varol U, Fuensalida-Novo S, Plaza-Canteli S, Valera-Calero JA. Is the number of long-term post-COVID symptoms relevant in hospitalized COVID-19 survivors? Eur J Intern Med. 2022 Jun;100:133-136. doi: 10.1016/j.ejim.2022.02.013. Epub 2022 Feb 14. PMID: 35181183; PMCID: PMC8841158. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8841158/ (Full text)

Mechanistic factors contributing to pain and fatigue in fibromyalgia and ME/CFS: autonomic and inflammatory insights from an experimental medicine study

Abstract:

Background: Fibromyalgia and ME/CFS are multifaceted conditions with overlapping symptoms(1); the pathoaetiological mechanisms are complex and debated(2), however there is a strong association with features of hereditary disorders of connective tissue (hypermobility) and autonomic and inflammatory abnormalities (1,2).

Objectives: To determine potential autonomic and inflammatory mechanisms of pain and fatigue in fibromyalgia and ME/CFS

Methods: After excluding participants with WCC higher than 10 (suggesting acute infection) baseline markers of inflammation (CRP and ESR) were available for 60 patients with confirmed diagnoses of Fibromyalgia and/ or ME/CFS and 23 matched controls. Participants then underwent full research diagnostic evaluation including a hypermobility assessment(1) and autonomic challenge (60 degree head up tilt, ISRCTN78820481). Subjective pain and fatigue were assessed before and after challenge (VAS). Linear regression models were used to explore predictors, with adjustment for confounders as appropriate. Mediation analyses (looking for mechanistic effects) were conducted according to the method of Hayes (3) and mediation considered significant if bootstrapped confidence intervals of the estimated indirect effect did not cross zero. In these mediation analyses predictor variable was group membership (patient or control), outcome variable was change in 1)pain and 2)fatigue induced by challenge and mediatiors 1)no of connective tissue features in hypermobility diagnostic criteria endorsed by participant; 2)baseline inflammatory markers.

Results: ESR and CRP were significantly higher in patients rather than controls, even after correcting for BMI, age and sex (B=5.15, t=2.05, p=0.044; B=1.77, t=2.15, p=0.044 respectively). Adjusted ESR and CRP correlated with both subjective fatigue (B=0.44, t=2.09, p=0.04; B=1.63, t=2.60, p=0.011) and pain severity (B=0.13, t=2.51, p=0.014; B=0.45, t=3.01, p=0.004) at baseline. Autonomic challenge amplified pain (B=14.20, t=2.87, p=0.005) and fatigue (B=31.48, t=5.95, p=<0.001) in patients to a significantly greater degree than controls, controlling for baseline levels. Baseline ESR and CRP also predicted challenge-induced increase in fatigue (B=0.78, t=370, p=<0.001; B=1.91, t=3.36, p=<0.001) and ESR challenge-induced increases in pain (B=0.46, t=2.35, p=0.021).

Mediation analysis demonstrated that number of connective tissue features expressed in hypermobility criteria mediated the degree to which subjective pain was increased by the autonomic challenge (Bootstraped 95% CI of indirect effect do not cross zero, 0.1572 – 6.8171). ESR mediated the degree to which subjective fatigue was increased by the autonomic challenge (Bootstraped 95% CI of indirect effect do not cross zero,0.7541 – 7.3888).

Conclusion: To our knowledge this is the first study to directly explore autonomic and inflammatory mechanisms of pain and fatigue in a combined population of Fibromyalgia and ME/CFS. This study this adds to the evidence-base of baseline inflammatory abnormalities in fibromyalgia and ME/CFS. It highlights their potential role in predicting symptom severity and their potential mechanistic role in autonomic induced pain and fatigue, suggesting future treatment strategies.

Source: Eccles J, Thompson C, Thompson B, et al. AB1209 MECHANISTIC FACTORS CONTRIBUTING TO PAIN AND FATIGUE IN FIBROMYALGIA AND ME/CFS: AUTONOMIC AND INFLAMMATORY INSIGHTS FROM AN EXPERIMENTAL MEDICINE STUDY. Annals of the Rheumatic Diseases 2022;81:1719 https://ard.bmj.com/content/annrheumdis/81/Suppl_1/1719.2.full.pdf (Full text available as PDF file)

The occurrence of hyperactivated platelets and fibrinaloid microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

We have previously demonstrated that platelet poor plasma (PPP) obtained from patients with LongCovid/Post-Acute Sequelae of COVID-19 (PASC) is characterized by a hypercoagulable state reflected in hyperactivated platelets and the presence of considerable numbers of fibrin(ogen) amyloid microclots or fibrinaloid microclots. Due to substantial overlap in symptoms and aetiology between PASC and ME/CFS, we investigated whether coagulopathies, platelet hyperactivation and/or fibrin amyloid formation differed between individuals exhibiting ME/CFS and gender- and age-matched healthy controls.

ME/CFS patients were statistically far more hypercoagulable as judged by thromboelastography of both whole blood and platelet-poor plasma. The area of plasma images containing fibrinaloid microclots was commonly more than 10-fold greater in untreated platelet-poor plasma from individuals with ME/CFS than in that of healthy controls. A similar difference was found when the plasma samples were treated with thrombin. Using fluorescently labelled PAC-1, which recognizes glycoprotein IIb/IIIa, and CD62P, which binds P-selectin, we observed massive hyperactivation and spreading of platelets in samples from individuals with ME/CFS. Using a quantitative scoring system, this was found to have a score of 2.72 ± 1.24 vs 1.00 (activation with pseudopodia formation) for healthy controls.

We conclude that ME/CFS is accompanied by substantial and measurable changes in coagulability, platelet hyperactivation, and fibrinaloid microclot formation. However, fibrinaloid microclot load was not as prevalent as was previously noted in PASC. Fibrinaloid microclots, in particular can provide a ready explanation, via (temporary) blockage of microcapillaries and hence ischaemia, for many of the symptoms, such as fatigue, seen in patients with ME/CFS. The discovery of these biomarkers pointing to significant and systemic endothelial inflammation, represents an important development in ME/CFS research. It also points at novel treatment strategies using known drugs and/or nutraceuticals that target systemic vascular pathology and endothelial inflammation.

Source: Massimo Nunes, Arneaux Kruger, Amy Proal et al. The occurrence of hyperactivated platelets and fibrinaloid microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), 08 June 2022, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-1727226/v1 (Full text)

Persistence of residual SARS-CoV-2 viral antigen and RNA in tissues of patients with long COVID-19

Abstract:

The World Health Organization has defined long COVID-19 (LC) as a condition where patients exhibit persistent symptoms over time after its acute phase, which cannot be explained by alternative diagnosis. Since we have previously reported residual viral antigens in tissues of convalescent patients, we now aim to assess the presence of such antigens in post-convalescent tissues. Here, we established the presence of residual virus within the appendix and breast tissue of 2 patients who exhibited LC symptoms, 175 to 462 days upon positive diagnosis, using immunohistological techniques. We observed positive staining for viral nucleocapsid protein (NP) in the appendix, and tumour-adjacent region of the breast, but not within the tumour via multiplex immunohistochemistry. Notably, with RNAscope, both positive-sense and negative-sense (replicative intermediate) viral RNA were detected. As a single-stranded virus, SARS-CoV-2, have to produce a replicative intermediate as a template to synthesize new genomic RNAs. Thus, the detection of negative-sense viral RNA suggests ongoing viral replication.
While viral RNA and antigen from gastrointestinal and stool samples of convalescent patients has been extensively reported, we believe this is the first study to detect viable virus. Furthermore, our positive finding in the breast tissue also corroborated with recent reports that immunocompromised patients had also experienced LC symptoms and persistent viral replication. Overall, our findings, along with emerging LC studies, raises the possibility of the gastrointestinal tract functioning as a reservoir.
Source: Denise Goh, Jeffrey Chun Tatt Lim, Sonia Bilbao Fernández et al. Persistence of residual SARS-CoV-2 viral antigen and RNA in tissues of patients with long COVID-19, 07 June 2022, PREPRINT (Version 2) available at Research Square https://doi.org/10.21203/rs.3.rs-1379777/v2  (Full text available as PDF file)

Comparing Operationalized Approaches for Substantial Reduction of Functioning in Chronic Fatigue Syndrome and Myalgic Encephalomyelitis

Abstract:

A core criterion for Chronic Fatigue Syndrome (CFS) and Myalgic Encephalomyelitis (ME) is a substantial reduction in functioning from pre-illness levels. Despite its ubiquity in diagnostic criteria, there is considerable debate regarding how to measure this domain. The current study assesses five distinct methods for measuring substantial reductions. The analysis used an international, aggregated dataset of patients (N = 2,368) and controls (N=359) to compare the effectiveness of each method.

Four methods involved sophisticated analytic approaches using the Medical Outcomes Survey Short Form-36; the fifth method included a single self-report item on the DePaul Symptom Questionnaire (DSQ). Our main finding was that all methods produced comparable results, though the DSQ item was the most valid in differentiating patients from controls. Having a simple, reliable method to capture a substantial reduction in functioning has considerable advantages for patients and health care workers.

Source: Wiedbusch E, Jason LA. Comparing Operationalized Approaches for Substantial Reduction of Functioning in Chronic Fatigue Syndrome and Myalgic Encephalomyelitis. Arch Community Med. 2022;4(1):59-63. doi: 10.36959/547/653. Epub 2022 Apr 21. PMID: 35673386; PMCID: PMC9168545. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9168545/ (Full text)

Community Advisory Committee Develops Priorities for ME/CFS Research

Press Release:

Posted by CII Coordinator, May 10, 2022

The Community Advisory Committee (CAC) for the NIH ME/CFS Research Network was established to bridge the gap between researchers and the ME/CFS community with the goal of accelerating the pace of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) research. The CAC is a group of 15 individuals from various professional backgrounds, all of whom have lived experience of the disease.

The CAC Research Priorities working group has authored a report on the challenges and priorities to be addressed to achieve needed outcomes for people with ME/CFS. This has become especially urgent given the large number of people who already have, and are expected to develop, ME/CFS following COVID-19.

ME/CFS is a debilitating, chronic, complex disease that most often follows an infection and is associated with neurological, autonomic, immunological, and metabolic abnormalities. Patients experience a substantial impairment in functioning, and symptoms such as sleep dysfunction, cognitive impairment, orthostatic intolerance, pain, fatigue, and the hallmark post-exertional malaise (PEM), an exacerbation of symptoms following even small amounts of previously tolerated activity. An estimated 836,000 to 2.5 million Americans suffer from ME/CFS with a greater prevalence in females, adults and possibly people who are Black and Latinx. There are no validated biomarkers or FDA-approved treatments and patients can struggle to access adequate clinical care. An estimated 25% are homebound or bedbound and 75% are unable to work. Recovery is rare and patients can remain ill for decades.

Progress in understanding the etiology of ME/CFS and developing biomarkers and treatments has been constrained by a number of interrelated challenges, such as the inherent complexity and heterogeneity of the disease, inadequate study methods, challenges in collaborating across all stakeholders, misunderstanding about the nature of the disease, and lack of research funding and researchers in the field. But even with these challenges, substantial progress has been made in understanding some of the underlying pathology.

The pandemic has created the tragic opportunity to finally understand how an infection can result in chronic illness. At the same time, the knowledge and expertise gained from years of ME/CFS research has provided valuable insights for Long COVID research.

Leveraging this opportunity for ME/CFS requires ME/CFS-specific funding and a ME/CFS strategic research plan to expedite progress in ME/CFS diagnostics and treatments. It also requires the integration of learnings from ME/CFS research into the PASC strategy, not only to help accelerate research in Long COVID but to better understand ME/CFS onset, natural history, and pathology. A natural experiment is underway which cannot be replicated, and this calls for swift, decisive action before the window of opportunity to study early-onset ME/CFS closes as the pandemic resolves.

People with ME/CFS, including those who have developed ME/CFS following COVID-19, are waiting.

The CAC Research Priorities working group developed this comprehensive but concise report outlining the long-standing barriers that have constrained progress in ME/CFS and strategies for their resolution, as well as key short and longer term research priorities that need to be progressed to accelerate meaningful research and achieve outcomes for people with ME/CFS, including those whose ME/CFS developed following COVID-19. These recommendations can be used by researchers to generate new study designs and refine existing goals, facilitate collaborations between research domains and stakeholders, and by federal and private funders to guide award distribution and agenda setting.

Click here to download the CAC Research Priorities Report

The Research Priorities working group is available and eager to discuss the contents of this document with researchers. Please contact us at any time at: CAC.MECFS@gmail.com

The authors of this guide are: Mary Dimmock, Rochelle Joslyn (chair), Sabrina Poirier, Jaime Seltzer and CAC Director, Allison Kanas.

This work was supported by US Public Health Service grant 5U54AI138370 and 5U24NS105535. This content does not represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health.

Gastric herpes simplex virus type 1 infection is associated with functional gastrointestinal disorders in the presence and absence of comorbid fibromyalgia: a pilot case-control study

Abstract:

Purpose: Animal studies have linked gastric herpesvirus infections to symptoms associated with functional gastrointestinal disorders (FGIDs). Herpesviruses have also been hypothesized to contribute to fibromyalgia (FM), a chronic pain syndrome frequently comorbid with FGIDs. The purpose of this study was to compare the prevalence of gastric herpesvirus infection in patients with FGIDs, with and without comorbid FM, to that of controls.

Methods: For this pilot case-control study, we enrolled 30 patients who met both the Rome IV diagnostic criteria for one or more FGIDs and the American College of Rheumatology 2010 criteria for FM, 15 patients with one or more FGIDs without comorbid FM, and 15 control patients. Following endoscopic examination, gastric biopsies were analyzed for herpesvirus DNA and protein, Helicobacter pylori infection, and histological evidence of gastritis. Importantly, the viral nonstructural protein ICP8 was used as a marker to differentiate cell-associated actively replicating virus from latent infection and/or free virus passing through the GI tract.

Results: Gastric herpes simplex virus type 1 (HSV-1) infection, as indicated by ICP8 presence, was significantly associated with FGIDs in the presence (OR 70.00, 95% CI 7.42-660.50; P < .001) and absence (OR 38.50, 95% CI 3.75-395.40; P < .001) of comorbid FM. Neither histological gastritis nor H. pylori infection were found to be associated with FGIDs or FM.

Conclusions: HSV-1 infection was identified in gastric mucosal biopsies from patients with diverse FGIDs, with and without comorbid FM. Larger, multi-center studies investigating the prevalence of this association are warranted.

Source: Duffy C, Pridgen WL, Whitley RJ. Gastric herpes simplex virus type 1 infection is associated with functional gastrointestinal disorders in the presence and absence of comorbid fibromyalgia: a pilot case-control study. Infection. 2022 Apr 21. doi: 10.1007/s15010-022-01823-w. Epub ahead of print. PMID: 35445970.  https://link.springer.com/article/10.1007/s15010-022-01823-w (Full text)

Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome

To the Editor:

After acute infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many individuals experience a range of symptoms including dyspnea, exercise intolerance, and chest pain commonly referred to as “post–COVID-19 syndrome” or as post-acute sequelae of SARS-CoV-2 infection (PASC) (). Exertional dyspnea and physical activity intolerance in PASC can be debilitating despite mild acute coronavirus disease (COVID-19) and normal resting pulmonary physiology and cardiac function (). There is an urgent need to understand the pathogenesis of PASC and find effective treatments. The cardiopulmonary exercise test (CPET) is commonly used to investigate unexplained exertional dyspnea; as such, it could provide insight into mechanisms of PASC. CPET data can be used to calculate rates of β-oxidation of fatty acids (FATox) and of lactate clearance, providing insight into mitochondrial function (). Fit individuals have better mitochondrial function and a higher rate of FATox during exercise than less fit individuals (). Our results suggest that patients with PASC have significant impairment in fat β-oxidation and increased blood lactate accumulation during exercise, regardless of previous comorbidities.

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Source: de Boer, E., Petrache, I., Goldstein, N. M., Olin, J. T., Keith, R. C., Modena, B., Mohning, M. P., Yunt, Z. X., San-Millán, I., & Swigris, J. J. (2022). Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome. American journal of respiratory and critical care medicine, 205(1), 126–129. https://doi.org/10.1164/rccm.202108-1903LE  I https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865580/ (Full text)

Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain

Abstract:

Chronic pain associated with fibromyalgia (FM) affects a large portion of the population but the underlying mechanisms leading to this altered pain are still poorly understood. Evidence suggests that FM involves altered neural processes in the central nervous system and neuroimaging methods such as functional magnetic resonance imaging (fMRI) are used to reveal these underlying alterations. While many fMRI studies of FM have been conducted in the brain, recent evidence shows that the changes in pain processing in FM may be linked to autonomic and homeostatic dysregulation, thus requiring further investigation in the brainstem and spinal cord.

Functional magnetic resonance imaging data from 15 women with FM and 15 healthy controls were obtained in the cervical spinal cord and brainstem at 3 tesla using previously established methods. In order to investigate differences in pain processing in these groups, participants underwent trials in which they anticipated and received a predictable painful stimulus, randomly interleaved with trials with no stimulus. Differences in functional connectivity between the groups were investigated by means of structural equation modeling.

The results demonstrate significant differences in brainstem/spinal cord network connectivity between the FM and control groups which also correlated with individual differences in pain responses. The regions involved in these differences in connectivity included the LC, hypothalamus, PAG, and PBN, which are known to be associated with autonomic homeostatic regulation, including fight or flight responses. This study extends our understanding of altered neural processes associated with FM and the important link between sensory and autonomic regulation systems in this disorder.

Source: Ioachim G, Warren HJM, Powers JM, Staud R, Pukall CF, Stroman PW. Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain. Front Neurol. 2022 May 6;13:862976. doi: 10.3389/fneur.2022.862976. PMID: 35599729; PMCID: PMC9120571. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120571/ (Full text)

Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET

Abstract:

A significant number of COVID-19 patients develop ‘long COVID’, a condition defined by long-lasting debilitating, often neurological, symptoms. The pathophysiology of long COVID is unknown. Here we present in-vivo evidence of widespread neuroinflammation in long COVID, using a quantitative assessment, [18F]DPA-714 PET, in two long COVID patients. We reanalyzed historical data from three matched healthy control subjects, for comparison purposes. Both patients with long COVID had widespread increases in [18F]DPA-714 binding throughout the brain. Quantitative measures of binding (BPND values) were increased on average by 121% and 76%, respectively. This implicates profound neuroinflammation in the pathophysiology of long COVID.

Source: Denise Visser, Sandeep S.V. Golla, Sander C.J. Verfaillie, Emma M. Coomans, Roos M. Rikken, Elsmarieke M. van de Giessen, Marijke E. den Hollander, Anouk Verveen, Maqsood Yaqub, Frederik Barkhof, Janneke Horn, Bart Koopman, Patrick Schober, Dook W. Koch, Robert C. Schuit, Albert D. Windhorst, Michael Kassiou, Ronald Boellaard, Michele van Vugt, Hans Knoop, Nelleke Tolboom, Bart N.M. van Berckel. Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET. medRxiv 2022.06.02.22275916; doi: https://doi.org/10.1101/2022.06.02.22275916 https://www.medrxiv.org/content/10.1101/2022.06.02.22275916v1.full-text (Full text)