Tag: covid-19

Cerebrospinal fluid immune phenotyping reveals distinct immunotypes of myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex heterogeneous multiorgan disease that can have severe impact on individuals’ quality of life. Diagnosis of ME/CFS is based on symptom presentation, and a significant goal for the field is to establish meaningful subtypes. The heterogeneity in the literature suggests that individuals living with ME/CFS may suffer from overlapping but different underlying pathophysiological mechanisms.

We enrolled 40 participants with ME/CFS and 41 matched healthy control subjects at the Bragée Clinic in Sweden. We assessed plasma samples from both ME/CFS cases and control groups and cerebrospinal fluid (CSF) samples from individuals with ME/CFS.

We investigated dysregulated pathways and disease profiles through clinical questionnaires; multiplex analyses of cytokines, hormones, and matrix metalloproteinases; pathogen seroreactivity through peptide display bacteria libraries; and high-throughput microarray for autoantibodies. All samples used were from humans.

We show altered interaction patterns between circulating biological factors in plasma of ME/CFS participants. Our analysis of CSF from individuals with ME/CFS revealed different immunotypes of disease. We found 2 patient clusters based on matrix metalloproteinases profiles. The subgroups had similar clinical presentation but distinct pathogen exposure and CSF inflammatory profiles.

Our findings shed light on ME/CFS immune phenotypes and generate hypotheses for future research in disease pathogenesis and treatment development by exploring disease subgroups.

Source: Bastos VC, Greene KA, Tabachnikova A, Bhattacharjee B, Sjögren P, Bertilson B, Reifert J, Zhang M, Kamath K, Shon J, Gehlhausen JR, Guan L, VanElzakker M, Proal A, Bragée B, Iwasaki A. Cerebrospinal fluid immune phenotyping reveals distinct immunotypes of myalgic encephalomyelitis/chronic fatigue syndrome. J Immunol. 2025 May 15:vkaf087. doi: 10.1093/jimmun/vkaf087. Epub ahead of print. PMID: 40373264. https://academic.oup.com/jimmunol/advance-article/doi/10.1093/jimmun/vkaf087/8133211 (Full text)

Therapeutic Approaches to the Neurologic Manifestations of COVID-19

Abstract:

As of May 2022, there have been more than 527 million infections with severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) and over 6.2 million deaths from Coronavirus Disease 2019 (COVID-19) worldwide. COVID-19 is a multisystem illness with important neurologic consequences that impact long-term morbidity and mortality.

In the acutely ill, the neurologic manifestations of COVID-19 can include distressing but relatively benign symptoms such as headache, myalgias, and anosmia; however, entities such as encephalopathy, stroke, seizures, encephalitis, and Guillain-Barre Syndrome can cause neurologic injury and resulting disability that persists long after the acute pulmonary illness. Furthermore, as many as one-third of patients may experience persistent neurologic symptoms as part of a Post-Acute Sequelae of SARS-CoV-2 infection (Neuro-PASC) syndrome.

This Neuro-PASC syndrome can affect patients who required hospitalization for COVID-19 or patients who did not require hospitalization and who may have had minor or no pulmonary symptoms. Given the large number of individuals affected and the ability of neurologic complications to impair quality of life and productivity, the neurologic manifestations of COVID-19 are likely to have major and long-lasting personal, public health, and economic consequences.

While knowledge of disease mechanisms and therapies acquired prior to the pandemic can inform us on how to manage patients with the neurologic manifestations of COVID-19, there is a critical need for improved understanding of specific COVID-19 disease mechanisms and development of therapies that target the neurologic morbidities of COVID-19. This current perspective reviews evidence for proposed disease mechanisms as they inform the neurologic management of COVID-19 in adult patients while also identifying areas in need of further research.

Source: Graham EL, Koralnik IJ, Liotta EM. Therapeutic Approaches to the Neurologic Manifestations of COVID-19. Neurotherapeutics. 2022 Sep;19(5):1435-1466. doi: 10.1007/s13311-022-01267-y. Epub 2022 Jul 21. PMID: 35861926; PMCID: PMC9302225. https://pmc.ncbi.nlm.nih.gov/articles/PMC9302225/ (Full text)

‘A gift and a curse’: the benefits and limitations of self-tracking Long COVID

Abstract:

People living with Long COVID are dealing with significant challenges related to limited understanding of this novel condition, social stigma, and lack of support from medical professionals and others in their lives. This article discusses findings from a qualitative study about how people with Long COVID have spontaneously engaged in self-tracking for the purposes of understanding and managing their illness. It draws on 30 semi-structured interviews with study participants in the USA, UK, Australia, Germany, Denmark and Canada.

The study’s findings reveal that the personal health data generated by people with Long COVID through practices of self-tracking create new forms of knowledge about a novel post-viral condition and to some extent challenge the power differentials and fraught sociopolitical climate of the pandemic. The benefits provided by self-tracking data reflect the often psychologised and understudied position of post-viral conditions such as Long COVID.

All participants described self-tracking as a valuable tool to gain insight into symptoms and evaluate interventions. It provided them with a sense of empowerment, control, encouragement, and very importantly, validation. However, for some participants, self-tracking their Long COVID symptoms was also sometimes experienced as overwhelming, anxiety-inducing, and frustrating. The study findings are interpreted with references to the broader contexts of novel chronic illness, medical power, lay expertise, COVID politics and digitised information and care work.

Source: Jayadeva, S., & Lupton, D. (2025). ‘A gift and a curse’: the benefits and limitations of self-tracking Long COVID. Information, Communication & Society, 1–17. https://doi.org/10.1080/1369118X.2025.2483834 https://www.tandfonline.com/doi/full/10.1080/1369118X.2025.2483834 (Full text)

Health outcomes one year after Omicron infection among 12,789 adults: a community-based cross-sectional study

Summary:

Background: Characterizing the paradigm and impact of long COVID is crucial for addressing this worldwide health challenge. This study aimed to investigate the prevalence of long COVID one year after primary Omicron infection and characterize differences in long-term health consequence between participants with persistent long COVID and those who fully recovered.

Methods: This a community-based cross-sectional study conducted from December 2023 to March 2024 at the China-Japan Friendship Hospital and 16 administrative districts in Beijing. 12,789 participants infected with Omicron between December 2022 and January 2023 were recruited through stratified multistage random sampling and included in the final analysis. Of them, 376 participants with persistent long COVID and 229 without long COVID were matched for further physical examinations. The primary outcome was the prevalence of long COVID one year after infection. Secondary outcomes included muscle strength, exercise capacity, health-related quality of life (HRQoL), mental health, work status, laboratory tests, and examinations.

Findings: Among 12,789 participants (media [IQR] age, 48.4 [37.3 to 61.4] years; 7817 females [61.1%]), 995 of them (7.8%) experienced long COVID within one year, with 651 (5.1%) having persistent symptoms. Fatigue (598/995 [60.1%]) and post-exertional malaise (367/995 [36.9%]) were the most common symptoms. Brain fog had the lowest resolution proportion as 4.2% within one year. The odds of long COVID increased with reinfections (odds ratios for one reinfection 2.592 [95% CI: 2.188 to 3.061]; two or more: 6.171 [3.227 to 11.557]; all p < 0.001). Participants with persistent long COVID had markedly lower muscle strength (upper-limb: 26.9 ± 12.4 vs. 29.1 ± 14.5 Kg; lower-limb: 40.0 [27.0 to 62.0] vs. 43.0 [28.0 to 59.0] s), worse exercise capacity and poorer HRQoL, and meaningful difference in laboratory tests results compared to those without long COVID. They also exhibited significantly higher proportions of abnormal lung function (FEV1 %pred<80%: 13.0% vs. 2.0%; DLco %pred<80%: 32.7% vs. 19.9%) and lung imaging abnormalities (23.5% vs. 13.6%).

Interpretation: The considerable health burden of long COVID and the progression of neurological symptoms following Omicron infection warrant close monitoring. Utilizing professional questionnaires and developing reliable diagnostic tools are necessary for improving diagnosis and treatment of long COVID.

Funding: This work was supported by Beijing Research Center for Respiratory Infectious Diseases (BJRID2024-012), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2022-I2M-CoV19-005/CIFMS 2021-I2M-1-048), the National Natural Science Foundation of China (82241056/82200114/82200009), the New Cornerstone Science Foundation.

Source: Zhang, Hui et al.Health outcomes one year after Omicron infection among 12,789 adults: a community-based cross-sectional study. The Lancet Regional Health – Western Pacific, Volume 0, Issue 0, 101507  https://www.thelancet.com/journals/lanwpc/article/PIIS2666-6065(25)00044-6/fulltext (Full text)

Serum Spike Protein Persistence Post COVID Is Not Associated with ME/CFS

Abstract:

Background/Objectives: According to the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC), an estimated 3-6% of people suffer from post-COVID condition or syndrome (PCS). A subset meets the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies have reported that SARS-CoV-2 proteins or RNA can persist after acute infection in serum or tissues, but their role in PCS is unclear.

Methods: Here, SARS-CoV-2 spike protein was analyzed in the serum of 121 PCS patients with predominant fatigue and exertional intolerance, of whom 72 met diagnostic criteria for ME/CFS, 37 post-COVID recovered healthy controls, and 32 pre-pandemic healthy controls.

Results: Spike protein was detected in the serum of 11% of recovered controls, 2% of PCS patients, and 14% of ME/CFS patients between 4 and 31 months after SARS-CoV-2 infection, but not in pre-pandemic samples. The occurrence and concentration of spike protein did not correlate with infection or vaccination timepoints. In ME/CFS patients, spike protein presence was not associated with the severity of symptoms or functional disability. In 5 out of 22 patients who under-went immunoglobulin depletion, spike protein levels were reduced or undetectable after treatment, indicating binding to immunoglobulins.

Conclusions: In summary, this study identified serum spike protein in a subset of patients but found no association with ME/CFS.

Source: Fehrer A, Sotzny F, Kim L, Kedor C, Freitag H, Heindrich C, Grabowski P, Babel N, Scheibenbogen C, Wittke K. Serum Spike Protein Persistence Post COVID Is Not Associated with ME/CFS. J Clin Med. 2025 Feb 8;14(4):1086. doi: 10.3390/jcm14041086. PMID: 40004616. https://www.mdpi.com/2077-0383/14/4/1086 (Full text)

Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination

Summary:

COVID-19 vaccines have prevented millions of COVID-19 deaths. Yet, a small fraction of the population reports a chronic debilitating condition after COVID-19 vaccination, often referred to as post-vaccination syndrome (PVS). To explore potential pathobiological features associated with PVS, we conducted a decentralized, cross-sectional study involving 42 PVS participants and 22 healthy controls enrolled in the Yale LISTEN study.

Compared with controls, PVS participants exhibited differences in immune profiles, including reduced circulating memory and effector CD4 T cells (type 1 and type 2) and an increase in TNFα+ CD8 T cells. PVS participants also had lower anti-spike antibody titers, primarily due to fewer vaccine doses. Serological evidence of recent Epstein-Barr virus (EBV) reactivation was observed more frequently in PVS participants. Further, individuals with PVS exhibited elevated levels of circulating spike protein compared to healthy controls.

These findings reveal potential immune differences in individuals with PVS that merit further investigation to better understand this condition and inform future research into diagnostic and therapeutic approaches.

Source: Bornali Bhattacharjee, Peiwen Lu, Valter Silva Monteiro, Alexandra Tabachnikova, Kexin Wang, William B. Hooper, Victoria Bastos, Kerrie Greene, Mitsuaki Sawano, Christian Guirgis, Tiffany J. Tzeng, Frederick Warner, Pavlina Baevova, Kathy Kamath, Jack Reifert, Danice Hertz, Brianne Dressen, Laura Tabacof, Jamie Wood, Lily Cooke, Mackenzie Doerstling, Shadan Nolasco, Amer Ahmed, Amy Proal, David Putrino, Leying Guan, Harlan M. Krumholz, Akiko Iwasaki. Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination medRxiv 2025.02.18.25322379; doi: https://doi.org/10.1101/2025.02.18.25322379 https://www.medrxiv.org/content/10.1101/2025.02.18.25322379v1.full-text (Full text)

Exploring DNA methylation, telomere length, mitochondrial DNA, and immune function in patients with Long-COVID

Abstract:

Background: Long-COVID is defined as the persistency or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation. Common persistent symptoms are fatigue, sleep disturbances, post-exertional malaise (PEM), pain, and cognitive problems. Long-COVID is estimated to be present in about 65 million people. We aimed to explore clinical and biological factors that might contribute to Long-COVID.

Methods: Prospective longitudinal cohort study including patients infected with SARS-CoV-2 between March 2020 and March 2022. Patients were assessed between 4 and 12 months after infection at the COVID follow-up clinic at UZ Leuven. We performed a comprehensive clinical assessment (including questionnaires and the 6-min walking test) and biological measures (global DNA methylation, telomere length, mitochondrial DNA copy number, inflammatory cytokines, and serological markers such as C-reactive protein, D-dimer, troponin T).

Results: Of the 358 participants, 328 were hospitalised, of which 130 had severe symptoms requiring intensive care admission; 30 patients were ambulatory referrals. Based on their clinical presentation, we could identify 6 main clusters. One-hundred and twenty-seven patients (35.4%) belonged to at least one cluster. The bigger cluster included PEM, fatigue, sleep disturbances, and pain (n = 57). Troponin T and telomere shortening were the two main markers predicting Long-COVID and PEM-fatigue symptoms.

Conclusions: Long-COVID is not just one entity. Different clinical presentations can be identified. Cardiac involvement (as measured by troponin T levels) and telomere shortening might be a relevant risk factor for developing PEM-fatigue symptoms and deserve further exploring.

Source: Polli A, Godderis L, Martens DS, Patil MS, Hendrix J, Wyns A, Van Campenhout J, Richter E, Fanning L, Vandekerckhove O, Claeys E, Janssens W, Lorent N. Exploring DNA methylation, telomere length, mitochondrial DNA, and immune function in patients with Long-COVID. BMC Med. 2025 Feb 4;23(1):60. doi: 10.1186/s12916-025-03881-x. PMID: 39901177; PMCID: PMC11792217. https://pmc.ncbi.nlm.nih.gov/articles/PMC11792217/ (Full text)

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

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)

Effect of Immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS

Abstract:

Autoreactive antibodies (AAB) are currently being investigated as causative or aggravating factors during post-COVID. In this study we analyze the effect of immunoadsorption therapy on symptom improvement and the relationship with immunological parameters in post-COVID patients exhibiting symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) induced or aggravated by an SARS-CoV-2 infection. This observational study includes 12 post-COVID patients exhibiting a predominance of ME/CFS symptoms alongside increased concentrations of autonomic nervous system receptors (ANSR) autoantibodies and neurological impairments.

We found that following immunoadsorption therapy, the ANSR autoantibodies were nearly eliminated from the patients’ blood. The removal of IgG antibodies was accompanied by a decrease of pro-inflammatory cytokines including IL4, IL2, IL1β, TNF and IL17A serum levels, and a significant reduction of soluble spike protein. Notably, a strong positive correlation between pro-inflammatory cytokines and ASNR-AABs β1, β2, M3, and M4 was observed in spike protein-positive patients, whereas no such correlation was evident in spike protein-negative patients.

30 days post-immunoadsorption therapy, patients exhibited notable improvement in neuropsychological function and a modest but statistically significant amelioration of hand grip strength was observed. However, neither self-reported symptoms nor scores on ME/CFS questionnaires showed a significant improvement and a rebound of the removed proteins occurring within a month.

Source: Anft M, Wiemers L, Rosiewicz KS, Doevelaar A, Skrzypczyk S, Kurek J, Kaliszczyk S, Seidel M, Stervbo U, Seibert FS, Westhoff TH, Babel N. Effect of Immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS. Mol Ther. 2025 Jan 9:S1525-0016(25)00011-5. doi: 10.1016/j.ymthe.2025.01.007. Epub ahead of print. PMID: 39797400. https://www.cell.com/molecular-therapy-family/molecular-therapy/pdf/S1525-0016(25)00011-5.pdf (Full text) https://pubmed.ncbi.nlm.nih.gov/39797400/ (Abstract)