Category: Overlapping Illnesses

Digital health app data reveals an effect of ovarian hormones on long COVID and myalgic encephalomyelitis symptoms

Abstract:

Background. Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) disproportionately affect females, suggesting modulation by sex hormones. We sought to investigate whether symptom severity is influenced by changes in sex hormones over the menstrual cycle, or by hormonal contraception.

Methods: We carried out a retrospective analysis of menstrual and symptom data, prospectively collected via the Visible app from individuals with long COVID, ME/CFS, or both, who had regular menstrual cycles, between 7 September 2022 and 6 March 2024. Mixed-effects models were used to examine associations between symptom severity, menstrual cycle phase and contraception type.

Findings: 948 users were included; 100% of users were female and 92.6% identified as women. The most tracked symptoms were fatigue (99.5% of users), brain fog (88.3%), headaches (85.1%) and muscle aches (78.6%). All menstrual cycle phases showed a modest, but significant, improvement compare to the menstrual phase, most markedly in the early luteal (IRR 0.963%, 95% CI: 0.958 – 0.968), but also the follicular (IRR = 0.985, 95% CI: 0.981 – 0.990) and late luteal phase (IRR = 0.980, 95% CI: 0.974-0.985). Crashes (sudden and severe worsening of symptoms following exertion) were significantly more frequent during menstruation than in other phases. Users of combined hormonal contraception (n=70) had a statistically significant reduction in overall symptom score (OR = 0.827, 95% CI: 0.690 – 0.992) and crash incidence (OR = 0.548, 95% CI: 0.350 – 0.856) compared to those not using hormonal contraception (=786).

Interpretation: Menstruation is associated with worsened symptoms in long COVID and ME/CFS. Users of combined hormonal contraception report a lower symptom burden than non-users, suggesting a modulatory role of ovarian hormones. These findings could empower menstruating people living with long COVID and ME/CFS to anticipate cyclical changes in symptoms and plan their activities accordingly, and could also inform their use of contraception.

Source: Abigail Goodship, Rory Preston, Joseph T Hicks, Harry Leeming, Christian Morgenstern, Victoria Male. Digital health app data reveals an effect of ovarian hormones on long COVID and myalgic encephalomyelitis symptoms. medRxiv 2025.01.24.25321092; doi: https://doi.org/10.1101/2025.01.24.25321092 https://www.medrxiv.org/content/10.1101/2025.01.24.25321092v1 (Full text available as PDF file)

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/

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)

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)

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)

Incidence and Prevalence of Post-COVID-19 Myalgic Encephalomyelitis: A Report from the Observational RECOVER-Adult Study

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may occur after infection. How often people develop ME/CFS after SARS-CoV-2 infection is unknown.

Objective: To determine the incidence and prevalence of post-COVID-19 ME/CFS among adults enrolled in the Researching COVID to Enhance Recovery (RECOVER-Adult) study.

Design, setting, and participants: RECOVER-Adult is a longitudinal observational cohort study conducted across the U.S. We included participants who had a study visit at least 6 months after infection and had no pre-existing ME/CFS, grouped as (1) acute infected, enrolled within 30 days of infection or enrolled as uninfected who became infected (n=4515); (2) post-acute infected, enrolled greater than 30 days after infection (n=7270); and (3) uninfected (1439).

Measurements: Incidence rate and prevalence of post-COVID-19 ME/CFS based on the 2015 Institute of Medicine ME/CFS clinical diagnostic criteria.

Results: The incidence rate of ME/CFS in participants followed from time of SARS-CoV-2 infection was 2.66 (95% CI 2.63-2.70) per 100 person-years while the rate in matched uninfected participants was 0.93 (95% CI 0.91-10.95) per 100 person-years: a hazard ratio of 4.93 (95% CI 3.62-6.71). The proportion of all RECOVER-Adult participants that met criteria for ME/CFS following SARS-CoV-2 infection was 4.5% (531 of 11,785) compared to 0.6% (9 of 1439) in uninfected participants. Post-exertional malaise was the most common ME/CFS symptom in infected participants (24.0%, 2830 of 11,785). Most participants with post-COVID-19 ME/CFS also met RECOVER criteria for long COVID (88.7%, 471 of 531).

Limitations: The ME/CFS clinical diagnostic criteria uses self-reported symptoms. Symptoms can wax and wane.

Conclusion: ME/CFS is a diagnosable sequela that develops at an increased rate following SARS-CoV-2 infection. RECOVER provides an unprecedented opportunity to study post-COVID-19 ME/CFS.

Source: Vernon SD, Zheng T, Do H, Marconi VC, Jason LA, Singer NG, Natelson BH, Sherif ZA, Bonilla HF, Taylor E, Mullington JM, Ashktorab H, Laiyemo AO, Brim H, Patterson TF, Akintonwa TT, Sekar A, Peluso MJ, Maniar N, Bateman L, Horwitz LI, Hess R; NIH Researching COVID to Enhance Recovery (RECOVER) Consortium. Incidence and Prevalence of Post-COVID-19 Myalgic Encephalomyelitis: A Report from the Observational RECOVER-Adult Study. J Gen Intern Med. 2025 Jan 13. doi: 10.1007/s11606-024-09290-9. Epub ahead of print. PMID: 39804551. https://link.springer.com/article/10.1007/s11606-024-09290-9 (Full text)

Cluster analysis to identify long COVID phenotypes using 129Xe magnetic resonance imaging: a multicentre evaluation

Abstract:

Background: Long COVID impacts ∼10% of people diagnosed with coronavirus disease 2019 (COVID-19), yet the pathophysiology driving ongoing symptoms is poorly understood. We hypothesised that 129Xe magnetic resonance imaging (MRI) could identify unique pulmonary phenotypic subgroups of long COVID. Therefore, we evaluated ventilation and gas exchange measurements with cluster analysis to generate imaging-based phenotypes.

Methods: COVID-negative controls and participants who previously tested positive for COVID-19 underwent 129Xe MRI ∼14 months post-acute infection across three centres. Long COVID was defined as persistent dyspnoea, chest tightness, cough, fatigue, nausea and/or loss of taste/smell at MRI; participants reporting no symptoms were considered fully recovered. 129Xe MRI ventilation defect percent (VDP) and membrane-to-gas (Mem/Gas), red blood cell-to-membrane (RBC/Mem) and red blood cell-to-gas (RBC/Gas) ratios were used in k-means clustering for long COVID, and measurements were compared using ANOVA with post-hoc Bonferroni correction.

Results: We evaluated 135 participants across three centres: 28 COVID-negative (mean±sd age 40±16 years), 34 fully recovered (42±14 years) and 73 long COVID (49±13 years). RBC/Mem (p=0.03) and forced expiratory volume in 1 s (FEV1) (p=0.04) were different between long COVID and COVID-negative; FEV1 and all other pulmonary function tests (PFTs) were within normal ranges. Four unique long COVID clusters were identified compared with recovered and COVID-negative. Cluster 1 was the youngest with normal MRI and mild gas trapping; Cluster 2 was the oldest, characterised by reduced RBC/Mem but normal PFTs; Cluster 3 had mildly increased Mem/Gas with normal PFTs; and Cluster 4 had markedly increased Mem/Gas with concomitant reduction in RBC/Mem and restrictive PFT pattern.

Conclusions: We identified four 129Xe MRI long COVID phenotypes with distinct characteristics. 129Xe MRI can dissect pathophysiological heterogeneity of long COVID to enable personalised patient care.

Source: Eddy RL, Mummy D, Zhang S, Dai H, Bechtel A, Schmidt A, Frizzell B, Gerayeli FV, Leipsic JA, Leung JM, Driehuys B, Que LG, Castro M, Sin DD, Niedbalski PJ. Cluster analysis to identify long COVID phenotypes using 129Xe magnetic resonance imaging: a multicentre evaluation. Eur Respir J. 2024 Mar 28;63(3):2302301. doi: 10.1183/13993003.02301-2023. PMID: 38331459; PMCID: PMC10973687. https://pmc.ncbi.nlm.nih.gov/articles/PMC10973687/ (Full text)

Relationship between major depressive disorder and myalgic encephalomyelitis/chronic fatigue syndrome: a two-sample mendelian randomization study analysis

Abstract:

Major depressive disorder (MDD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) frequently occur together; yet their causal relationship remains unclear. To investigate the potential genetic causal link between these conditions, we conducted a two-sample Mendelian randomization (MR) analysis.

Summary data from Genome-Wide Association Studies (GWAS) for MDD were sourced from the UK Biobank and the Psychiatric Genomics Consortium, while GWAS data for ME/CFS were retrieved from the UK Biobank. Inverse-variance weighting (IVW), the MR-Egger method, and weighted median, simple and weighted modes were used to perform the MR analysis. In addition, Cochrane’s Q-test was used to detect heterogeneity among the MR results. Horizontal pleiotropy was detected using the MR-Egger intercept and the MR pleiotropy residual sum and outlier (MR-PRESSO) tests. Leave-one-out analysis was performed to investigate the sensitivity of the association between MDD and ME/CFS.

The results of the MR analysis revealed no causal relationship between MDD and ME/CFS. The pleiotropy test revealed that causality bias was improbable, and no evidence of heterogeneity was found among the genetic variants. Finally, the leave-one-out test confirmed the stability and robustness of our findings.

Source: Song, W., Hou, X., Wu, M. et al. Relationship between major depressive disorder and myalgic encephalomyelitis/chronic fatigue syndrome: a two-sample mendelian randomization study analysis. Sci Rep 15, 1155 (2025). https://doi.org/10.1038/s41598-025-85217-6 https://www.nature.com/articles/s41598-025-85217-6 (Full text)