Tag: long Covid

Respiratory SARS-CoV-2 Infection Causes Skeletal Muscle Atrophy and Long-Lasting Energy Metabolism Suppression

Abstract:

Muscle fatigue represents the most prevalent symptom of long-term COVID, with elusive pathogenic mechanisms. We performed a longitudinal study to characterize histopathological and transcriptional changes in skeletal muscle in a hamster model of respiratory SARS-CoV-2 infection and compared them with influenza A virus (IAV) and mock infections.

Histopathological and bulk RNA sequencing analyses of leg muscles derived from infected animals at days 3, 30, and 60 post-infection showed no direct viral invasion but myofiber atrophy in the SARS-CoV-2 group, which was accompanied by persistent downregulation of the genes related to myofibers, ribosomal proteins, fatty acid β-oxidation, tricarboxylic acid cycle, and mitochondrial oxidative phosphorylation complexes.

While both SARS-CoV-2 and IAV infections induced acute and transient type I and II interferon responses in muscle, only the SARS-CoV-2 infection upregulated TNF-α/NF-κB but not IL-6 signaling in muscle. Treatment of C2C12 myotubes, a skeletal muscle cell line, with combined IFN-γ and TNF-α but not with IFN-γ or TNF-α alone markedly impaired mitochondrial function.

We conclude that a respiratory SARS-CoV-2 infection can cause myofiber atrophy and persistent energy metabolism suppression without direct viral invasion. The effects may be induced by the combined systemic interferon and TNF-α responses at the acute phase and may contribute to post-COVID-19 persistent muscle fatigue.

Source: Homma ST, Wang X, Frere JJ, Gower AC, Zhou J, Lim JK, tenOever BR, Zhou L. Respiratory SARS-CoV-2 Infection Causes Skeletal Muscle Atrophy and Long-Lasting Energy Metabolism Suppression. Biomedicines. 2024 Jun 28;12(7):1443. doi: 10.3390/biomedicines12071443. PMID: 39062017; PMCID: PMC11275164. https://pmc.ncbi.nlm.nih.gov/articles/PMC11275164/ (Full text)

Persistent Fatigue, Weakness, and Aberrant Muscle Mitochondria in Survivors of Critical COVID-19

Abstract:

Objectives: Persistent skeletal muscle dysfunction in survivors of critical illness due to acute respiratory failure is common, but biological data elucidating underlying mechanisms are limited. The objective of this study was to elucidate the prevalence of skeletal muscle weakness and fatigue in survivors of critical illness due to COVID-19 and determine if cellular changes associate with persistent skeletal muscle dysfunction.

Design: A prospective observational study in two phases: 1) survivors of critical COVID-19 participating in physical outcome measures while attending an ICU Recovery Clinic at short-term follow-up and 2) a nested cohort of patients performed comprehensive muscle and physical function assessments with a muscle biopsy; data were compared with non-COVID controls.

Setting: ICU Recovery Clinic and clinical laboratory.

Patients/subjects: Survivors of critical COVID-19 and non-COVID controls.

Interventions: None.

Measurements and main results: One hundred twenty patients with a median of 56 years old (interquartile range [IQR], 42-65 yr old), 43% female, and 33% individuals of underrepresented race attended follow-up 44 ± 17 days after discharge. Patients had a median Acute Physiology and Chronic Health Evaluation-II score of 24.0 (IQR, 16-29) and 98 patients (82%) required mechanical ventilation with a median duration of 14 days (IQR, 9-21 d). At short-term follow-up significant physical dysfunction was observed with 93% of patients reporting generalized fatigue and performing mean 218 ± 151 meters on 6-minute walk test (45% ± 30% of predicted). Eleven patients from this group agreed to participate in long-term assessment and muscle biopsy occurring a mean 267 ± 98 days after discharge. Muscle tissue from COVID exhibited a greater abundance of M2-like macrophages and satellite cells and lower activity of mitochondrial complex II and complex IV compared with controls.

Conclusions: Our findings suggest that aberrant repair and altered mitochondrial activity in skeletal muscle associates with long-term impairments in patients surviving an ICU admission for COVID-19.

Source: Mayer KP, Ismaeel A, Kalema AG, Montgomery-Yates AA, Soper MK, Kern PA, Starck JD, Slone SA, Morris PE, Dupont-Versteegden EE, Kosmac K. Persistent Fatigue, Weakness, and Aberrant Muscle Mitochondria in Survivors of Critical COVID-19. Crit Care Explor. 2024 Oct 16;6(10):e1164. doi: 10.1097/CCE.0000000000001164. PMID: 39412208; PMCID: PMC11487221. https://pmc.ncbi.nlm.nih.gov/articles/PMC11487221/ (Full text)

Epigenetic changes in patients with post-acute COVID-19 symptoms (PACS) and long-COVID: A systematic review

Abstract:

Background: Up to 30% of people infected with SARS-CoV-2 report disabling symptoms 2 years after the infection. Over 100 persistent symptoms have been associated with Post-Acute COVID-19 Symptoms (PACS) and/or long-COVID, showing a significant clinical heterogeneity. To develop effective, patient-targeted treatment, a better understanding of underlying mechanisms is needed. Epigenetics has helped elucidating the pathophysiology of several health conditions and it might help unravelling inter-individual differences in patients with PACS and long-COVID. As accumulating research is exploring epigenetic mechanisms in PACS and long-COVID, we systematically summarized the available literature on the topic.

Methods: We interrogated five databases (Medline, Embase, Web of Science, Scopus and medXriv/bioXriv) and followed PRISMA and SWiM guidelines to report our results.

Results: Eight studies were included in our review. Six studies explored DNA methylation in PACS and/or long-COVID, while two studies explored miRNA expression in long-COVID associated with lung complications. Sample sizes were mostly small and study quality was low or fair. The main limitation of the included studies was a poor characterization of the patient population that made a homogeneous synthesis of the literature challenging. However, studies on DNA methylation showed that mechanisms related to the immune and the autonomic nervous system, and cell metabolism might be implicated in the pathophysiology of PACS and long-COVID.

Conclusion: Epigenetic changes might help elucidating PACS and long-COVID underlying mechanisms, aid subgrouping, and point towards tailored treatments. Preliminary evidence is promising but scarce. Biological and epigenetic research on long-COVID will benefit millions of people suffering from long-COVID and has the potential to be transferable and benefit other conditions as well, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We urge future research to employ longitudinal designs and provide a better characterization of included patients.

Source: Shekhar Patil M, Richter E, Fanning L, Hendrix J, Wyns A, Barrero Santiago L, Nijs J, Godderis L, Polli A. Epigenetic changes in patients with post-acute COVID-19 symptoms (PACS) and long-COVID: A systematic review. Expert Rev Mol Med. 2024 Oct 22;26:e29. doi: 10.1017/erm.2024.32. PMID: 39435694. https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/epigenetic-changes-in-patients-with-postacute-covid19-symptoms-pacs-and-longcovid-a-systematic-review/BCF992CF0E491FC0AD0FEDC3A8AFFD4B (Full text)

A review of intravenous immunoglobulin in the treatment of neuroimmune conditions, acute COVID-19 infection, and post-acute sequelae of COVID-19 Syndrome

Abstract:

Intravenous immunoglobulin (IVIG) is an immunomodulatory therapy that has been studied in several neuroimmune conditions, such as Guillain-Barré Syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and multiple sclerosis. It has also been proposed as a potential treatment option for acute COVID-19 infection and post-acute sequelae of SARS-CoV-2 infection (PASC). IVIG is thought to function by providing the recipient with a pool of antibodies, which can, in turn, modulate immune responses through multiple mechanisms including neutralization of cytokines and autoantibodies, saturation of neonatal fragment crystallizable receptors, inhibition of complement activation, and regulation of T and B cell mediated inflammation.

In acute COVID-19, studies have shown that early administration of IVIG and plasmapheresis in severe cases can reduce the need for mechanical ventilation, shorten ICU and hospital stays, and lower mortality. Similarly, in PASC, while research is still in early stages, IVIG has been shown to alleviate persistent symptoms in small patient cohorts.

Furthermore, IVIG has shown benefits in another condition which has symptomatic overlap with PASC, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), though studies have yielded mixed results. It is important to note that IVIG can be associated with several potential adverse effects, such as anaphylaxis, headaches, thrombosis, liver enzyme elevations and renal complications. In addition, the high cost of IVIG can be a deterrent for payers and patients.

This review provides a comprehensive update on the use of IVIG in multiple neuroimmune conditions, ME/CFS, acute COVID-19, and PASC, as well as covers its history, production, pricing, and mechanisms of action. We also identify key areas of future research, including the need to optimize the use of Ig product dosing, timing, and patient selection across conditions, particularly in the context of COVID-19 and PASC.

Source: Morse BA, Motovilov K, Michael Brode W, Michael Tee F, Melamed E. A review of intravenous immunoglobulin in the treatment of neuroimmune conditions, acute COVID-19 infection, and post-acute sequelae of COVID-19 Syndrome. Brain Behav Immun. 2024 Oct 8:S0889-1591(24)00648-2. doi: 10.1016/j.bbi.2024.10.006. Epub ahead of print. PMID: 39389388. https://www.sciencedirect.com/science/article/abs/pii/S0889159124006482

Inspiratory muscle training improves autonomic function in myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of SARS-CoV-2: a pilot study

Abstract:

Post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are debilitating post-viral conditions with many symptomatic overlaps, including exercise intolerance and autonomic dysfunction. Both conditions are growing in prevalence, and effective safe treatment strategies must be investigated. We hypothesized that inspiratory muscle training (IMT) could be used in PASC and mild to moderate ME/CFS to mitigate symptoms, improve exercise capacity, and improve autonomic function.

We recruited healthy controls (n=12; 10 women), people with PASC (n=9; 8 women), and people with mild to moderate ME/CFS (n=12; 10 women) to complete 8 weeks of IMT. This project was registered as a clinical trial (NCT05196529) with clinicaltrials.gov.

After completion of IMT, all groups experienced improvements in inspiratory muscle pressure (p<0.001), 6-minute walk distance (p=0.002), resting heart rate (p=0.037), heart rate variability (p<0.05), and symptoms related to sleep (p=0.009). In the ME/CFS group only, after completion of IMT, there were additional improvements with regard to vascular function (p=0.001), secretomotor function (p=0.023), the total weighted score (p=0.005) of the COMPASS 31 autonomic questionnaire, and symptoms related to pain (p=0.016).

We found that after 8 weeks of IMT, people with PASC and/or ME/CFS could see some overall improvements in their autonomic function and symptomology.

Source: Edgell H, Pereira TJ, Kerr K, Bray R, Tabassum F, Sergio L, Badhwar S. Inspiratory muscle training improves autonomic function in myalgic encephalomyelitis/chronic fatigue syndrome and post-acute sequelae of SARS-CoV-2: a pilot study. Respir Physiol Neurobiol. 2024 Oct 5:104360. doi: 10.1016/j.resp.2024.104360. Epub ahead of print. PMID: 39374820. https://www.sciencedirect.com/science/article/pii/S1569904824001538 (Full text)

A pilot cross-sectional investigation of symptom clusters and associations with patient-reported outcomes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post COVID-19 Condition

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is associated with long-term disability and poor quality of life (QoL). Cardinal ME/CFS symptoms (including post-exertional malaise, cognitive dysfunction and sleep disturbances) have been observed in Post COVID-19 Condition (PCC). To gain further insight into the potential role of ME/CFS as a post-COVID-19 sequela, this study investigates associations between symptoms and patient-reported outcomes, as well as symptom clusters.
Methods: Participants included Australian residents aged between 18 and 65 years formally diagnosed with ME/CFS fulfilling the Canadian or International Consensus Criteria or PCC meeting the World Health Organization case definition. Validated, self-administered questionnaires collected participants’ sociodemographic and illness characteristics, symptoms, QoL and functional capacity. Associations between symptoms and patient-reported outcomes were investigated with multivariate linear regression models. Hierarchical cluster analysis was performed to identify symptom clusters.
Results: Most people with ME/CFS (pwME/CFS) and people with PCC (pwPCC) were female (n = 48/60, 80.0% and n = 19/30, 63.3%, respectively; p = 0.12). PwME/CFS were significantly younger (x̄=41.75, s = 12.91 years) than pwPCC (x̄=48.13, s =10.05 years; p =0.017). Autonomic symptoms (notably dyspnoea) were associated with poorer scores in most patient-reported outcome domains for both cohorts. None of the four symptom clusters identified were unique to ME/CFS or PCC. Clusters were largely delineated by the presence of gastrointestinal and neurosensory symptoms, illness duration, ME/CFS criteria met and total symptoms.
Conclusions: Illness duration may explain differences in symptom burden between pwME/CFS and pwPCC. PCC diagnostic criteria must be refined to distinguish pwPCC at risk of long-term ME/CFS-like illness and subsequently deliver necessary care and support.
Source: Weigel B, Eaton-Fitch N, Thapaliya K, Marshall-Gradisnik S. A pilot cross-sectional investigation of symptom clusters and associations with patient-reported outcomes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post COVID-19 Condition. Qual Life Res. 2024 Oct 3. doi: 10.1007/s11136-024-03794-x. Epub ahead of print. PMID: 39361124. https://link.springer.com/article/10.1007/s11136-024-03794-x (Full text)

 

Exploring the role of galectin-9 and artemin as biomarkers in long COVID with chronic fatigue syndrome: links to inflammation and cognitive function

Abstract:

This study aimed to assess plasma galectin-9 (Gal-9) and artemin (ARTN) concentrations as potential biomarkers to differentiate individuals with Long COVID (LC) patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) from SARS-CoV-2 recovered (R) and healthy controls (HCs).

Receiver operating characteristic (ROC) curve analysis determined a cut-off value of plasma Gal-9 and ARTN to differentiate LC patients from the R group and HCs in two independent cohorts.

Positive correlations were observed between elevated plasma Gal-9 levels and inflammatory markers (e.g. SAA and IP-10), as well as sCD14 and I-FABP in LC patients. Gal-9 also exhibited a positive correlation with cognitive failure scores, suggesting its potential role in cognitive impairment in LC patients with ME/CFS.

This study highlights plasma Gal-9 and/or ARTN as sensitive screening biomarkers for discriminating LC patients from controls. Notably, the elevation of LPS-binding protein in LC patients, as has been observed in HIV infected individuals, suggests microbial translocation. However, despite elevated Gal-9, we found a significant decline in ARTN levels in the plasma of people living with HIV (PLWH). Our study provides a novel and important role for Gal-9/ARTN in LC pathogenesis.

Source: Elahi Shokrollah , Rezaeifar Maryam , Osman Mohammed , Shahbaz Shima. Exploring the role of galectin-9 and artemin as biomarkers in long COVID with chronic fatigue syndrome: links to inflammation and cognitive function. Frontiers in Immunology, Vol 15, 2024. DOI=10.3389/fimmu.2024.1443363. ISSN=1664-3224. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1443363 (Full text)

 

The persistence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) after SARS-CoV-2 infection: A systematic review and meta-analysis

Highlights:

  • SARS-CoV-2 can trigger Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
  • 51% of Long COVID-19 patients have Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
  • Long COVID-19 is a new name for an old disease.

Abstract:

Objectives: Long COVID-19 (LC) patients experience a number of chronic idiopathic symptoms that are highly similar to those of post-viral Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We have therefore performed a systematic review and meta-analysis to determine the proportion of LC patients that satisfy ME/CFS diagnostic criteria.

Methods: Clinical studies published between January 2020 to May 2023 were identified using the PubMed, Web of Science, Embase and CINAHL databases. Publication inclusion/exclusion criteria were formulated using the global CoCoPop framework. Data were pooled using a random-effects model with a restricted maximum-likelihood estimator. Study quality was assessed using the Joanna Briggs Institute critical assessment tool.

Results: We identified 13 eligible studies that reported a total of 1,973 LC patients. Our meta-analysis indicated that 51% (95% CI, 42%-60%) of LC patients satisfied ME/CFS diagnostic criteria with fatigue, sleep disruption, and muscle/joint pain being the most common symptoms. Importantly, LC patients also experienced the ME/CFS hallmark symptom, post-exertional malaise.

Conclusions: Our study not only demonstrates that LC patients exhibit similar symptom clusters to ME/CFS, but that approximately half of LC patients satisfy a diagnosis of ME/CFS. Our findings suggest that current ME/CFS criteria could be adapted to the identification of a subset of LC patients that may facilitate the standardized diagnosis, management and the recruitment for clinical studies in the future.

Source: Ankush Dehlia, Mark A. Guthridge. The persistence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) after SARS-CoV-2 infection: A systematic review and meta-analysis. Journal of Infection, 2024, 106297, ISSN 0163-4453, https://doi.org/10.1016/j.jinf.2024.106297.
https://www.sciencedirect.com/science/article/pii/S0163445324002317 (Full text)

A Network Medicine Approach to Investigating ME/CFS Pathogenesis in Severely Ill Patients: A Pilot Study

Abstract:

This pilot study harnessed the power of network medicine to unravel the complex pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). By utilizing a network analysis on whole genome sequencing (WGS) data from the Severely Ill Patient Study (SIPS), we identified ME/CFS-associated proteins and delineated the corresponding network-level module, termed the SIPS disease module, together with its relevant pathways. This module demonstrated significant overlap with genes implicated in fatigue, cognitive disorders, and neurodegenerative diseases.

Our pathway analysis revealed potential associations between ME/CFS and conditions such as COVID-19, Epstein-Barr virus (EBV) infection, neurodegenerative diseases, and pathways involved in cortisol synthesis and secretion, supporting the hypothesis that ME/CFS is a neuroimmune disorder. Additionally, our findings underscore a potential link between ME/CFS and estrogen signaling pathways, which may elucidate the higher prevalence of ME/CFS in females.

These findings provide insights into the pathogenesis of ME/CFS from a network medicine perspective and highlight potential therapeutic targets. Further research is needed to validate these findings and explore their implications for improving diagnosis and treatment.

Source: Li-Yuan Hung, Chan-Shuo Wu, Chia-Jung Chang, Peng Li, Kimberly Hicks, Becky Taurog, Joshua J Dibble, Braxton Morrison, Chimere L Smith, Ronald W Davis, Wenzhong Xiao. A Network Medicine Approach to Investigating ME/CFS Pathogenesis in Severely Ill Patients: A Pilot Study.
medRxiv 2024.09.26.24314417; doi: https://doi.org/10.1101/2024.09.26.24314417 https://www.medrxiv.org/content/10.1101/2024.09.26.24314417v1 (Full text available as PDF file)

Inhibition of HIF-2α Pathway as a Potential Therapeutic Strategy for Endothelial Dysfunction in Post-COVID Syndrome

Abstract:

Background SARS-CoV-2 infection may lead to Post-COVID Syndrome (PCS), characterized by debilitating symptoms like persistent fatigue, cardiovascular symptoms, and cognitive dysfunction. Persistent endothelial dysfunction (ED) is a potential driver of ongoing symptoms. Yet, the underlying biological mechanisms remain unclear.

Methods In this prospective observational study, we characterized 41 PCS patients and 24 healthy controls (HC, matched out of n = 204, recruited before the pandemic) and investigated the effect of SARS-CoV-2 Spike protein 1 (S1) and plasma from PCS patients on human retinal endothelial cells (HREC).

Results Plasma samples from PCS patients exhibited significantly elevated erythropoietin, VEGF and MCP-1 alongside decreased IL-6 levels compared to HC. Low Haemoglobin and Haematocrit were negatively associated with PCS severity. VEGF levels were positively correlated with Anti-S1 IgG levels in patients and upregulated on mRNA level in HREC exposed to S1. Additionally, S1 exposure promoted ROS production and transiently activated HIF-1α in HREC. Persistent activation of HIF-2α by S1 led to disrupted endothelial integrity. HREC exposed to plasma from severely affected PCS patients showed increased ROS and compromised barrier function. Treatment with Belzutifan, a HIF-2α inhibitor, restored barrier integrity in HREC exposed to S1 or PCS-plasma.

Conclusion These findings suggest that HIF-2α-mediated ED in PCS might be a potential therapeutical target for Belzutifan.

Trial registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT05635552

What Is Known?

  • Endothelial dysfunction (ED) is a consequence of acute SARS-CoV-2 infection and may lead to Post-COVID syndrome (PCS) symptoms.

  • Patients with PCS show elevated inflammation and endothelial dysfunction markers.

  • Spike proteins can persist for up to 12 months post-infection, driving ongoing inflammation and immune activation.

What New Information Does This Article Contribute?

  • Low haemoglobin (Hb) and high VEGF correlate with higher Anti-S1 IgG and low Hb is associated with higher C19-YRS severity score.

  • PCS patients exhibit higher Erythropoietin (EPO) levels when compared to HC.

  • Spike protein 1 (S1) alone and PCS patient’s plasma induce endothelial dysfunction primarily through HIF-2α activation.

  • Both S1 and PCS plasma cause oxidative stress and disrupting endothelial integrity.

  • Inhibition of HIF-2α effectively restores endothelial barrier integrity disrupted by S1 and PCS plasma.

What New Information Does This Article Contribute? Persistent circulation of spike proteins can sustain chronic inflammation and immune activation in patients with PCS. Here we show that plasma from PCS patients exhibits significantly elevated levels of VEGF which positively correlates with Anti-S1 IgG. Low haemoglobin was associated with higher Anti-S1 IgG titres and correlated with a higher C19-YRS severity score. Levels of EPO were higher in PCS patients, with a more pronounced effect observed in patients with cardiovascular symptoms. In human retinal endothelial cells, both S1 and plasma from PCS patients primarily induce ED through HIF-2α activation, rather than NF-κB. Both factors lead to significant oxidative stress, evidenced by increased ROS production which in turn disrupts endothelial barrier integrity and function. Notably, Belzutifan, a HIF-2α inhibitor, can restore this compromised endothelial function, offering a potential therapeutic target for PCS.

Source: Andrea Ribeiro, Timon Kuchler, Maciej Lech, Javier Carbajo-Lozoya, Kristina Adorjan, Hans Christian Stubbe, Martina Seifert, Anna Wöhnle, Veronika Kesseler, Johanna Negele, Uwe Heemann, Christoph Schmaderer. Inhibition of HIF-2α Pathway as a Potential Therapeutic Strategy for Endothelial Dysfunction in Post-COVID Syndrome medRxiv 2024.09.10.24313403; doi: https://doi.org/10.1101/2024.09.10.24313403 https://www.medrxiv.org/content/10.1101/2024.09.10.24313403v1.full-text (Full text)