Tag: 2025

Distinct pro-inflammatory/pro-angiogenetic signatures distinguish children with Long COVID from controls

Abstract:

Background: Recent proteomic studies have documented that Long COVID in adults is characterized by a pro-inflammatory signature with thromboinflammation. However, if similar events happen also in children with Long COVID has never been investigated.

Methods: We performed an extensive protein analysis of blood plasma from pediatric patients younger than 19 years of age Long COVID and a control group of children with acute COVID-19, MIS-C, and healthy controls resulted similar for sex distribution and age. Children were classified as Long COVID if symptoms persisted for at least 8 weeks since the initial infection, negatively impacted daily life and could not be explained otherwise.

Results: 112 children were included in the study, including 34 children fulfilling clinical criteria of Long COVID, 32 acute SARS-CoV-2 infection, 27 MIS-C and 19 healthy controls. Compared with controls, pediatric Long COVID was characterized by higher expression of the proinflammatory and pro-angiogenetic set of chemokines CXCL11, CXCL1, CXCL5, CXCL6, CXCL8, TNFSF11, OSM, STAMBP1a. A Machine Learning model based on proteomic profile was able to identify LC with an accuracy of 0.93, specificity of 0.86 and sensitivity of 0.97.

Conclusions: Pediatric Long COVID patients have a well distinct blood protein signature marked by increased ongoing general and endothelial inflammation, similarly as happens in adults.

Impact:

  • Pediatric Long COVID has a distinct blood protein signature marked by increased ongoing general and endothelial inflammation.
  • This is the first study studying and documenting proinflammatory profile in blood samples of children with long COVID.
  • Long COVID was characterized by higher expression of the proinflammatory and pro-angiogenetic set of chemokines CXCL11, CXCL1, CXCL5, CXCL6, CXCL8, TNFSF11, OSM, STAMBP1a.
  • A proteomic profile was able to identify Long COVID with an accuracy of 0.93, specificity of 0.86 and sensitivity of 0.97.
  • These findings may inform development of future diagnostic tests.

Source: Buonsenso, D., Cotugno, N., Amodio, D. et al. Distinct pro-inflammatory/pro-angiogenetic signatures distinguish children with Long COVID from controls. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-03837-0  https://www.nature.com/articles/s41390-025-03837-0

Post-SARS-CoV-2 Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symptoms in Two Cohort Studies of COVID-19 Recovery

Abstract:

Objective: To determine how many people with long COVID also meet diagnostic criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Methods: We identified which participants with long COVID also met the Institute of Medicine (IOM) or the 2003 Canadian Consensus Criteria (CCC) for ME/CFS at approximately 6-8 months post-SARS-CoV-2 infection in two cohorts: (1) the JHU COVID Recovery cohort, which enrolled participants within 4 weeks of infection and (2) the Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort, which enriched for participants with long COVID. Neither study administered ME/CFS-specific surveys, so available data elements were mapped onto each ME/CFS diagnostic criteria.

Results: Of 97 JHU participants with long COVID, 5 met IOM criteria and 2 met CCC criteria. Of 281 LIINC participants with long COVID, 51 met the IOM criteria and 29 met the CCC criteria. In LIINC, participants with long COVID meeting ME/CFS criteria were more likely to be female and report a greater number of post-COVID symptoms (p<0.001).

Conclusions: The co-occurrence of ME/CFS symptoms and long COVID suggests that SARS-CoV-2 is a cause of ME/CFS. ME/CFS-specific measures should be incorporated into studies of post-acute COVID-19 to advance studies of post-SARS-CoV-2 onset ME/CFS.

Source: Jamal A, Dalhuisen T, Gallego Márquez N, Dziarski AD, Uy J, Walch SN, Thomas SA, Fehrman EA, Romero AE, Zelaya AS, Akasreku EA, Adeagbo TV, Pasetes EC, Akbas SY, Azola AM, Deeks SG, Kelly JD, Martin JN, Henrich TJ, Landay AL, Peluso MJ, Antar AAR. Post-SARS-CoV-2 Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symptoms in Two Cohort Studies of COVID-19 Recovery. medRxiv [Preprint]. 2024 Nov 8:2024.11.08.24316976. doi: 10.1101/2024.11.08.24316976. PMID: 39867374; PMCID: PMC11759845. https://pmc.ncbi.nlm.nih.gov/articles/PMC11759845/

Tetrahydrobiopterin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Friend or Foe?

Abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a chronic multisystem disease characterized by severe muscle fatigue, pain, dizziness, and brain fog. The two most common symptoms are post-exertional malaise (PEM) and orthostatic intolerance (OI). ME/CFS patients with OI (ME+OI) suffer from dizziness or faintness due to a sudden drop in blood pressure while maintaining an upright posture. Clinical research has demonstrated that patients with OI display severe cardiovascular abnormalities resulting in reduced effective blood flow in the cerebral blood vessels. However, despite intense investigation, it is not known why the effective cerebral blood flow is reduced in OI patients. Based on our recent findings, we observed that tetrahydrobiopterin (BH4) metabolism was highly dysregulated in ME+OI patients. In the current review article, we attempted to summarize our recent findings on BH4 metabolism to shed light on the molecular mechanisms of OI.

Source: Rahman AFMT, Benko A, Bulbule S, Gottschalk CG, Arnold LA, Roy A. Tetrahydrobiopterin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Friend or Foe? Biomolecules. 2025 Jan 10;15(1):102. doi: 10.3390/biom15010102. PMID: 39858496; PMCID: PMC11763651. https://pmc.ncbi.nlm.nih.gov/articles/PMC11763651/ (Full text)

Exploring the shared mechanism of fatigue between systemic lupus erythematosus and myalgic encephalomyelitis/chronic fatigue syndrome: monocytic dysregulation and drug repurposing

Abstract:

Background: SLE and ME/CFS both present significant fatigue and share immune dysregulation. The mechanisms underlying fatigue in these disorders remain unclear, and there are no standardized treatments. This study aims to explore shared mechanisms and predict potential therapeutic drugs for fatigue in SLE and ME/CFS.

Methods: Genes associated with SLE and ME/CFS were collected from disease target and clinical sample databases to identify overlapping genes. Bioinformatics analyses, including GO, KEGG, PPI network construction, and key target identification, were performed. ROC curve and correlation analysis of key targets, along with single-cell clustering, were conducted to validate their expression in different cell types. Additionally, an inflammation model was established using THP-1 cells to simulate monocyte activation in both diseases in vitro, and RT-qPCR was used to validate the expression of the key targets. A TF-mRNA-miRNA co-regulatory network was constructed, followed by drug prediction and molecular docking.

Results: Fifty-eight overlapping genes were identified, mainly involved in innate immunity and inflammation. Five key targets were identified (IL1β, CCL2, TLR2, STAT1, IFIH1). Single-cell sequencing revealed that monocytes are enriched with these targets. RT-qPCR confirmed significant upregulation of these targets in the model group. A co-regulatory network was constructed, and ten potential drugs, including suloctidil, N-Acetyl-L-cysteine, simvastatin, ACMC-20mvek, and camptothecin, were predicted. Simvastatin and camptothecin showed high affinity for the key targets.

Conclusion: SLE and ME/CFS share immune and inflammatory pathways. The identified key targets are predominantly enriched in monocytes at the single-cell level, suggesting that classical monocytes may be crucial in linking inflammation and fatigue. RT-qPCR confirmed upregulation in activated monocytes. The TF-mRNA-miRNA network provides a foundation for future research, and drug prediction suggests N-Acetyl-L-cysteine and camptothecin as potential therapies.

Source: Zheng D, Li X, Wang P, Zhu Q, Huang Z, Zhao T. Exploring the shared mechanism of fatigue between systemic lupus erythematosus and myalgic encephalomyelitis/chronic fatigue syndrome: monocytic dysregulation and drug repurposing. Front Immunol. 2025 Jan 7;15:1440922. doi: 10.3389/fimmu.2024.1440922. PMID: 39845969; PMCID: PMC11752880. https://pmc.ncbi.nlm.nih.gov/articles/PMC11752880/ (Full text)

Provocation of brachial plexus and systemic symptoms during the elevated arm stress test in individuals with myalgic encephalomyelitis/chronic fatigue syndrome or idiopathic chronic fatigue

Abstract:

Background: We have noted that some adolescents and young adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) report difficulty with arms-overhead activities, suggestive of brachial plexus dysfunction or thoracic outlet syndrome (TOS). In the TOS literature, diagnostic maneuvers focus on the provocation of upper limb symptoms (arm fatigue and heaviness, paresthesias, neck and upper back pain), but not on elicitation of systemic symptoms.

Objectives: To estimate the proportion of patients with fatiguing illness who experience local and systemic symptoms during a common maneuver used in evaluating TOS-the elevated arm stress test (EAST).

Methods: Patients were eligible for this retrospective study if they had been referred to the Johns Hopkins Chronic Fatigue Clinic between January 2020 and July 2023 and (a) reported difficulty maintaining arms-overhead postures, (b) were evaluated with an abbreviated one-minute EAST, and (c) had not undergone surgery in the upper limb, neck, or skull base. Modified EAST procedure: patients sat with their arms in a “hands up” or “candlestick” position while opening and closing their hands every 2-3 s repeatedly for 1 min, rather than the customary 3 min. The test was considered abnormal for local symptoms if the participant experienced pain, fatigue, heaviness, paresthesias, warmth or tremulousness in the upper limb, shoulder, neck, head, or upper back. The test was considered abnormal for systemic symptoms if the participant experienced overall fatigue, cognitive fogginess, lightheadedness, racing heart, diaphoresis, dyspnea, overall warmth, or nausea.

Results: Of 154 patients evaluated during the study period, 64 (42%) met the eligibility criteria (61/64 female, median age 18 years [range, 13 to 50]). Of the 64, 50 (78%) had ME/CFS, 13 (20%) had idiopathic chronic fatigue with associated orthostatic intolerance (OI), and one had idiopathic chronic fatigue without OI. Of the 64, 58% had evidence of joint hypermobility. Local symptoms were provoked by EAST in 62/64 (97%) within a median of 20 s. During EAST, 26/64 (41%) reported systemic symptoms (1 had only systemic but no upper limb symptoms), most commonly lightheadedness (19%) and generalized fatigue (11%).

Conclusions: Even with an abbreviated test duration, the EAST maneuver provoked local and systemic symptoms in a substantial proportion of patients with chronic fatigue, OI, and ME/CFS who had reported difficulty with arms-overhead postures. Further studies are needed to explore the prevalence of brachial plexus or TOS symptoms in unselected individuals with ME/CFS or OI, and the proportion with systemic symptoms during and after EAST.

Source: Edwards CC 3rd, Byrnes JM, Broussard CA, Azola AM, Swope ME, Marden CL, Swope RL, Lum YW, Violand RL, Rowe PC. Provocation of brachial plexus and systemic symptoms during the elevated arm stress test in individuals with myalgic encephalomyelitis/chronic fatigue syndrome or idiopathic chronic fatigue. J Transl Med. 2025 Jan 22;23(1):106. doi: 10.1186/s12967-025-06137-7. PMID: 39844172; PMCID: PMC11752803. https://pmc.ncbi.nlm.nih.gov/articles/PMC11752803/ (Full text)

ME patient experiences: Sampling bias limits the external validity of findings

Abstract:

In a recent paper in Journal of Health Psychology, Kielland et al. present a study with the first objective of documenting how helpful or unhelpful persons with ME perceive common services and interventions. The authors recruited participants by respondent driven sampling, a method that aims to produce estimates that correct for sampling bias. However, we argue that the main assumptions of the method are not met, and that the results of the study thus cannot be generalised to the intended target population.

Source: Selvakumar J, Wyller VBB. ME patient experiences: Sampling bias limits the external validity of findings. J Health Psychol. 2025 Jan 21:13591053241310320. doi: 10.1177/13591053241310320. Epub ahead of print. PMID: 39838600. https://pubmed.ncbi.nlm.nih.gov/39838600/

Abnormal T-Cell Activation And Cytotoxic T-Cell Frequency Discriminates Symptom Severity In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating but poorly-understood disease. ME/CFS symptoms can range from mild to severe, and include immune system effects alongside incapacitating fatigue and post-exertional disease exacerbation. In this study, we examined immunological profiles of people living with ME/CFS by flow cytometry, focusing on cytotoxic cells, to determine whether people with mild/moderate (n= 43) or severe ME/CFS (n=53) expressed different immunological markers.

We found that people with mild/moderate ME/CFS had increased expression of cytotoxic effector molecules alongside enhanced proportions of early-immunosenescence cells, determined by the CD28 – CD57 – phenotype, indicative of persistent viral infection. In contrast, people with severe ME/CFS had higher proportions of activated circulating lymphocytes, determined by CD69 + and CD38 + expression, and expressed more pro-inflammatory cytokines, including IFNγ, TNF and IL-17, following stimulation in vitro , indicative of prolonged non-specific inflammation.

These changes were consistent across different cell types including CD8 + T cells, mucosal associated invariant T cells and Natural Killer cells, indicating generalised altered cytotoxic responses across the innate and adaptive immune system. These immunological differences likely reflect different disease pathogenesis mechanisms occurring in the two clinical groups, opening up opportunities for the development of prognostic markers and stratified treatments.

Source: Lee JS, Lacerda E, Kingdon C, Susannini G, Dockrell HM, Nacul L, Cliff JM. Abnormal T-Cell Activation And Cytotoxic T-Cell Frequency Discriminates Symptom Severity In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. medRxiv [Preprint]. 2025 Jan 6:2025.01.02.24319359. doi: 10.1101/2025.01.02.24319359. PMID: 39830245; PMCID: PMC11741448. https://pubmed.ncbi.nlm.nih.gov/39830245/

Machine learning and multi-omics in precision medicine for ME/CFS

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and multifaceted disorder that defies simplistic characterisation. Traditional approaches to diagnosing and treating ME/CFS have often fallen short due to the condition’s heterogeneity and the lack of validated biomarkers. The growing field of precision medicine offers a promising approach which focuses on the genetic and molecular underpinnings of individual patients.

In this review, we explore how machine learning and multi-omics (genomics, transcriptomics, proteomics, and metabolomics) can transform precision medicine in ME/CFS research and healthcare. We provide an overview on machine learning concepts for analysing large-scale biological data, highlight key advancements in multi-omics biomarker discovery, data quality and integration strategies, while reflecting on ME/CFS case study examples. We also highlight several priorities, including the critical need for applying robust computational tools and collaborative data-sharing initiatives in the endeavour to unravel the biological intricacies of ME/CFS.

Source: Huang K, Lidbury BA, Thomas N, Gooley PR, Armstrong CW. Machine learning and multi-omics in precision medicine for ME/CFS. J Transl Med. 2025 Jan 14;23(1):68. doi: 10.1186/s12967-024-05915-z. PMID: 39810236. Huang K, Lidbury BA, Thomas N, Gooley PR, Armstrong CW. Machine learning and multi-omics in precision medicine for ME/CFS. J Transl Med. 2025 Jan 14;23(1):68. doi: 10.1186/s12967-024-05915-z. PMID: 39810236. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05915-z (Full text)

Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study

Abstract:

Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients share similar symptoms including post-exertional malaise, neurocognitive impairment, and memory loss. The neurocognitive impairment in both conditions might be linked to alterations in the hippocampal subfields. Therefore, this study compared alterations in hippocampal subfields of 17 long COVID, 29 ME/CFS patients, and 15 healthy controls (HC).

Structural MRI data was acquired with sub-millimeter isotropic resolution on a 7 Telsa MRI scanner and hippocampal subfield volumes were then estimated for each participant using FreeSurfer software. Our study found significantly larger volumes in the left hippocampal subfields of both long COVID and ME/CFS patients compared to HC.

These included the left subiculum head (long COVID; p = 0.01, ME/CFS; p = 0.002,), presubiculum head (long COVID; p = 0.004, ME/CFS; p = 0.005), molecular layer hippocampus head (long COVID; p = 0.014, ME/CFS; p = 0.011), and whole hippocampal head (long COVID; p = 0.01, ME/CFS; p = 0.01). Notably, hippocampal subfield volumes were similar between long COVID and ME/CFS patients.

Additionally, we found significant associations between hippocampal subfield volumes and severity measures of ‘Pain’, ‘Duration of illness’, ‘Severity of fatigue’, ‘Impaired concentration’, ‘Unrefreshing sleep’, and ‘Physical function’ in both conditions. These findings suggest that hippocampal alterations may contribute to the neurocognitive impairment experienced by long COVID and ME/CFS patients. Furthermore, our study highlights similarities between these two conditions.

Source: Thapaliya K, Marshall-Gradisnik S, Eaton-Fitch N, Barth M, Inderyas M, Barnden L. Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study. PLoS One. 2025 Jan 13;20(1):e0316625. doi: 10.1371/journal.pone.0316625. PMID: 39804864; PMCID: PMC11729965. https://pmc.ncbi.nlm.nih.gov/articles/PMC11729965/ (Full text)

Autoantibody-Driven Monocyte Dysfunction in Post-COVID Syndrome with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Post-COVID syndrome (PCS) has emerged as a significant health concern with persisting symptoms. A subset of PCS patients develops severe myalgic encephalomyelitis/chronic fatigue syndrome (pcME/CFS). Dysregulated autoantibodies (AABs) have been implicated in PCS, contributing to immune dysregulation, impairment of autonomous nerve and vascular function. As recently shown in autoimmune diseases, IgG fractions translate disease-specific pathways into various cells. Therefore, we asked whether IgG fractions from PCS patients could be applied in vitro to identify specific cytokine rersponses for PCS patients without (nPCS) and with pcME/CSF.

To assess this, we have stimulated monocyte cell lines with IgG fractions from PCS patients. Our findings reveal distinct patterns of immune regulation by AABs in vascular and immune dysfunction. In contrast to nPCS, pcME/CSF AABs induced enhanced neurotrophic responses, characterized by significant cytokine correlations involving brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF) and LIGHT. AAB-induced cytokine levels correlate with clinical symptoms. Further, this study emphasizes a contribution of AAB in PCS, in mitigating long-term immune dysregulation, and a need for therapies modulating IgG-induced pathways.

Source: Alexander Hackel, Franziska Sotzny, Elise Mennenga, Harald Heidecke, Kai Schulze-Foster,  Kontantinos Fourlakis,  Susanne Lueders, Hanna Grasshoff, Kerstin Rubarth, Frank Konietschke, Tanja Lange, Carmen Scheibenbogen, Reza Akbarzade, Gabriela Riemekasten. Autoantibody-Driven Monocyte Dysfunction in Post-COVID Syndrome with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. medRxiv 2025.01.09.25320264; doi: https://doi.org/10.1101/2025.01.09.25320264 https://www.medrxiv.org/content/10.1101/2025.01.09.25320264v1.full.pdf+html (Full text available as PDF file)