Tag: 2025

Long COVID as an Infection-Associated Chronic Condition: Implications

In-Brief:

A link between infection and chronic illness has been recognized, along with the complexities of interactions between pathogen, environment, host genetics, route of exposure, and timing of outcomes. The COVID-19 pandemic has brought this issue to the forefront and Long COVID is recognized to be an infection associated chronic condition. However, given the wide range of Long COVID presentations, the singular expression gives a false sense of simplicity. Long COVID is best considered as a group of infection associated conditions requiring developing research studies and treatment trials that address the inherent heterogeneity.
Source: Unger ER. Long COVID as an Infection-Associated Chronic Condition: Implications. Am J Health Promot. 2025 Jul;39(6):960-965. doi: 10.1177/08901171241308066b. Epub 2025 Jun 8. PMID: 40485158. https://journals.sagepub.com/doi/10.1177/08901171241308066b (Full text)

Mechanistic Insights Into Long Covid: Viral Persistence, Immune Dysregulation, and Multi-Organ Dysfunction

Abstract:

Long Covid is a post-viral syndrome characterized by persistent symptoms targeting multiple organ systems after initial SARS-CoV-2 infection. Current literature suggests that the mechanisms causing Long Covid involve viral persistence, immune dysregulation, systemic inflammation, endothelial dysfunction, and metabolic disturbances.

By forming reservoirs in the tissues of various organs, SARS-CoV-2 may evade immunological clearances while triggering immune responses and contributing to chronic symptoms through cytokine imbalances, T-cell exhaustion, and systemic inflammation. These symptoms parallel other post-viral syndromes such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), suggesting similar mechanisms of pathology.

The coronavirus has also been linked to neuroinflammation and endothelial dysfunction causing cognitive symptoms and cardiovascular complications. Furthermore, its ability to lower energy production links it to post-exertion malaise (PEM) and muscle pain. These symptoms may result from iron dysregulation and persistent oxidative stress due to Covid-impaired mitochondrial function.

This review synthesizes current data on the mechanisms that drive Long Covid pathogenesis and explores potential therapeutic strategies to mitigate viral persistence, immune dysfunction, and metabolic disturbances. It is critical to understand these interactions to develop targeted interventions that address the long-term sequelae of SARS-CoV-2 infection and improve patient outcomes.

Source: Gupta G, Buonsenso D, Wood J, Mohandas S, Warburton D. Mechanistic Insights Into Long Covid: Viral Persistence, Immune Dysregulation, and Multi-Organ Dysfunction. Compr Physiol. 2025 Jun;15(3):e70019. doi: 10.1002/cph4.70019. PMID: 40474772. https://pubmed.ncbi.nlm.nih.gov/40474772/

How pandemics reshape our brain: Common links and targets between long-haul COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), oxidative stress, and neurodegeneration

Highlights:

  • Fatiguing syndromes affect millions of patients in the United States and globally, but are grossly underserved in the clinic and in the contemplative design of basic research.
  • Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem metabolic-immune-inflammatory disorder. Although research on this condition is in its infancy, it appears to involve the immune system and central nervous system malfunction, with cellular oxidative stress as a predominant feature.
  • Approximately half of the cases of long-haul coronavirus disease 2019 meet the diagnostic criteria for ME/CFS, burgeoning the number of affected individuals.
  • Recent strides in neurobiology have yet to transfer the understanding of the neurodegenerative aspects, and potential for neuroprotection, of ME/CFS.
  • ME/CFS may represent a useful paradigm and research model for the study of the impact of sustained oxidative stress on the central nervous system and the body at large.

Archeological findings from the bubonic plague era onward have demonstrated how pandemics can exert selective pressures, as will be highlighted. In particular, the short-term survival advantage during pandemics of individuals with greater immune “plasticity” comes at the cost of increased susceptibility to autoimmunity. Certain viral infections appear to trigger persistent immune system dysregulation, leading to broad autoimmunity and a sequelae of multisystem pathophysiologies with diverse symptoms long after the virus is cleared.

Human coronavirus 2019 (HCoV-19) is the most recent virus that appears to have elevated the incidence of autoimmune diseases in infected individuals. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an autoimmune, multisystem fatiguing syndrome affecting approximately 20 million people globally, representing 1.3% of adults in the United States.1, 2 It involves metabolic, immune, and inflammatory processes, with central nervous system (CNS) dysfunction and cellular oxidative stress being prominent features. Notably, about half of long-haul coronavirus disease 2019 (COVID-19) cases meet the diagnostic criteria for ME/CFS, potentially doubling or tripling its prevalence.

This article highlights ME/CFS, a nascent research area, as a model for neurological pathophysiological outcomes resulting from persistently high oxidative stress levels. Patients with ME/CFS, many who have had this condition for decades, form an underutilized patient population for this study.

A second objective of this Research Highlight is to correct recent reports that have attempted to “retrofit” principles and outcomes from other neurologic diseases to ME/CFS. This has led some neuroscientists to extrapolate erroneously that ME/CFS is not a neurodegenerative disorder. However, substantial evidence indicates that autoimmune ME/CFS is a neurodegenerative disease.

Source: Herman ME. How pandemics reshape our brain: common links and targets between long-haul COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), oxidative stress, and neurodegeneration. Neuroprotection. 2025; 1–8. doi:10.1002/nep3.70007 https://onlinelibrary.wiley.com/doi/10.1002/nep3.70007 (Full text)

 

Ignored, dismissed, and minimized: Understanding the harmful consequences of invalidation in health care-A systematic meta-synthesis of qualitative research

Abstract:

The upsurge in the prevalence of contested, ambiguous, and difficult-to-diagnose illnesses presents challenges for clinicians who too often respond by invalidating patients’ symptoms. Although numerous qualitative studies have reported the effects of invalidation on patients’ psychological and behavioral outcomes, this body of research has not been systematically reviewed. Informed by Linehan’s (1993) conceptualization of invalidation, this systematic review elucidated the negative consequences, of symptom invalidation, or the dismissal or minimization of a person’s experiences with illness.

We reviewed 151 qualitative reports representing 11,307 individuals with Ehlers-Danlos syndrome, endometriosis, fibromyalgia syndrome, Gulf War syndrome, irritable bowel syndrome, long COVID, multiple chemical sensitivity, myalgic encephalomyelitis/chronic fatigue syndrome, postural orthostatic tachycardia syndrome, systemic lupus erythematosus, and vulvodynia.

Consistent with Linehan’s theorizing, thematic analysis identified four broad classes of consequences: induced emotional states and beliefs (e.g., shame, suicidality), induced health care emotional states and beliefs (e.g., health care-related anxiety and trauma), induced health care behavior (e.g., health care system avoidance), and diagnostic delay.

Informed by these findings, we developed a novel conceptual model explaining how symptom invalidation leads to these consequences and thereby undermines health outcomes. Future work should explore the proposed conceptual model and identify theoretically informed interventions and policies aimed at preventing symptom invalidation to improve psychological, behavioral, and health outcomes. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Source: Bontempo AC, Bontempo JM, Duberstein PR. Ignored, dismissed, and minimized: Understanding the harmful consequences of invalidation in health care-A systematic meta-synthesis of qualitative research. Psychol Bull. 2025 Apr;151(4):399-427. doi: 10.1037/bul0000473. PMID: 40310228. https://psycnet.apa.org/fulltext/2026-10154-001.html (Full text)

Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness characterized by post-exertional malaise (PEM), a worsening of symptoms following exertion. The biological mechanisms underlying PEM remain unclear. Extracellular vesicles (EVs) play a key role in cell-cell communication and may provide insight into ME/CFS pathophysiology post-exertion. Emerging evidence suggests similarities between ME/CFS and Long COVID, including PEM and overlapping immune and metabolic dysfunctions, highlighting the need for deeper mechanistic understanding.

Methods: This study explores the EV proteome response to exercise in 10 males with ME/CFS and 12 well-matched sedentary male controls. Participants underwent a maximal cardiopulmonary exercise test, and plasma samples were collected at baseline, 15 min, and 24 h postexercise. EVs were isolated from plasma using size-exclusion chromatography and characterized with nanoparticle tracking analysis. EV protein abundance was quantified with untargeted proteomics (nanoLC-MS/MS). Comprehensive analyses included differential abundance, pathway enrichment, protein-protein interaction networks, and correlations between EV protein dynamics and clinical or exercise physiology data.

Results: ME/CFS patients exhibited many significantly altered EV proteomic responses compared with controls, including downregulation of TCA cycle-related proteins and upregulation of complement system proteins at 15 min postexercise. Changes in proteins involved in protein folding and the endoplasmic reticulum (ER) stress response during recovery were highly correlated with PEM severity, highlighting their potential as therapeutic targets. EV protein changes postexercise were also associated with disease severity and unrefreshing sleep. Correlations between EV protein levels and the exercise parameters VO₂ peak and ventilatory anaerobic threshold were observed in controls but were absent in ME/CFS patients, suggesting disrupted EV-mediated physiological processes.

Conclusions: ME/CFS patients exhibit a maladaptive EV proteomic response to exercise, characterized by metabolic impairments, immune overactivation, and ER stress response dysregulation. These findings provide insight into the molecular basis of PEM and suggest promising targets for improving recovery and energy metabolism in ME/CFS.

Source: Glass KA, Giloteaux L, Zhang S, Hanson MR. Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with myalgic encephalomyelitis/chronic fatigue syndrome. Clin Transl Med. 2025 May;15(5):e70346. doi: 10.1002/ctm2.70346. PMID: 40465195; PMCID: PMC12135887. https://pmc.ncbi.nlm.nih.gov/articles/PMC12135887/ (Full text)

Comprehensive transcriptome assessment in PBMCs of post-COVID patients at a median follow-up of 28 months after a mild COVID infection reveals upregulation of JAK/STAT signaling and a prolonged immune response

Abstract:

Background: Post-acute sequelae of SARS-CoV-2 infection (PASC), also known as post-COVID-19 condition (here abbreviated as post-COVID) is an escalating global health issue. The aim of our study was to investigate the mechanisms and clinical manifestations of post-COVID following a mild SARS-CoV-2 infection.

Methods: We analyzed the gene expression profile in PBMCs from 60 middle-aged post-COVID patients and 50 age-matched controls at a median time of 28 months following a mild SARS-CoV-2 infection. The clinical assessments included intensity of post-COVID symptoms, physical and mental fatigue, depression and anxiety. Sixty-seven participants performed a mild exertion ergometer test with assessment of lactate concentrations. Transcriptome analysis was performed on mRNA selected by poly-A enrichment and SARS-CoV-2 RNA fragments were analyzed using the ARTIC protocol.

Results: We identified 463 differentially expressed transcripts in PBMCs, of which 324 were upregulated and 129 downregulated in post-COVID patients. Upregulated genes in post-COVID individuals were enriched for processes involving JAK-STAT signaling, negative regulation of ubiquitination, IL9 signaling, and negative regulation of viral process, suggesting chronic inflammation. Downregulated genes were enriched for processes involving mitochondrial ATP synthesis, and oxidative phosphorylation, suggesting mitochondrial dysfunction. No SARS-CoV-2 gene fragments were detected in PBMCs of patients with post-COVID and no IFN genes were found differentially expressed in post-COVID patients. Post-COVID was associated with elevated lactate levels in blood, both at rest and after a short recovery phase following exertion, suggesting increased anaerobic activity in skeletal muscles. We did not find differences in the transcriptional profiles or clinical manifestations when comparing patients who contracted the infection from early SARS-CoV-2 variants with those who contracted the infection during the period when the Omicron variant was prevalent.

Conclusions: Our findings highlight molecular changes compatible with a persistent immune response in PBMCs of post-COVID subjects at a median follow-up of 28 months after a mild infection, supporting the hypothesis that post-COVID is a chronic inflammatory condition. The upregulation of JAK/STAT signaling suggests a potential therapeutic target in post-COVID.

Source: Serena Fineschi, Joakim Klar, Juan Ramon Lopez Egido, Jens Schuster, Jonas Bergquist, Ren Kaden, Niklas Dahl.Comprehensive transcriptome assessment in PBMCs of post-COVID patients at a median follow-up of 28 months after a mild COVID infection reveals upregulation of JAK/STAT signaling and a prolonged immune response.Front. Immunol., 29 May 2025. Viral Immunology: Volume 16 – 2025 | https://doi.org/10.3389/fimmu.2025.1589589 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1589589/full (Full text)

Low Dose Rapamycin Alleviates Clinical Symptoms of Fatigue and PEM in ME/CFS Patients via Improvement of Autophagy

Abstract:

Background: mTOR activation is associated with chronic inflammation in ME/CFS. Previous studies have shown that sustained mTOR activation can cause chronic muscle fatigue by inhibiting ATG13-mediated autophagy. This highlights the pivotal role of mTOR in the pathogenesis of ME/CFS.

Methods: We conducted a decentralized, uncontrolled trial of rapamycin in 86 patients with ME/CFS to evaluate its safety and efficacy. Low-dose rapamycin (6 mg/week) was administered, and core ME/CFS symptoms were assessed on days 30 (T1), 60 (T2), and 90 (T3). Plasma levels of autophagy metabolites, such as pSer258-ATG13 and BECLIN-1, were measured and correlated with clinical outcomes, specifically MFI.

Results: Rapamycin (6 mg/week) was tolerated without any SAEs. Of the 40 patients, 29 (72.5%) showed strong recovery in PEM, fatigue, and OI, along with improvements in MFI fatigue domains and SF-36 aspects. High levels of BECLIN-1 were detected in T3. Plasma pSer258-ATG13 levels were strongly downregulated at T1. Spearman’s correlation analysis indicated an association between autophagy impairment and reduced activity.

Conclusions: Low-dose rapamycin effectively reduced PEM and other key symptoms in patients with ME/CFS, as measured by BAS, SSS, MFI, and SF-36.  Future studies should encompass dose optimization and develop a diagnostic tool to identify responders with mTOR-mediated autophagy disruption.

Source: Brian T. Ruan, Sarojini Bulbule, Amy Reyes et al. Low Dose Rapamycin Alleviates Clinical Symptoms of Fatigue and PEM in ME/CFS Patients via Improvement of Autophagy, 03 June 2025, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-6596158/v1] https://www.researchsquare.com/article/rs-6596158/v1 (Full text)

The Effect on Quality of Life of Therapeutic Plasmapheresis and Intravenous Immunoglobulins on a Population of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients with Elevated β-Adrenergic and M3-Muscarinic Receptor Antibodies—A Pilot Study

Abstract:

Background/Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition with not fully understood causes, though evidence points to immune system involvement and possible autoimmunity. ME/CFS could be triggered by various infectious pathogens, like SARS-CoV-2; furthermore, a subset of the post-COVID-19 condition (PCC) patients fulfill the diagnostic criteria of ME/CFS. According to the Canadian Consensus Criteria (CCC), the presence of specific symptoms such as fatigue, post-exertional malaise, sleep dysfunction, pain, neurological/cognitive manifestations, and symptoms from at least two of the following categories lead to the diagnosis of ME/CFS: autonomic, neuroendocrine, and immune manifestation. In this study, the patient selection was based on the identification of ME/CFS patients with elevated autoantibodies, regardless of the triggering factor of their condition.
Methods: The aim of this study was to identify ME/CFS patients among long COVID patients with elevated autoantibodies. In seven cases, plasmapheresis (PE) and intravenous immunoglobulins (IVIGs) with repetitive autoantibody measurements were applied: four PE sessions on days 1, 5, 30, and 60, and a low-dose IVIG therapy after each treatment. Antibodies were measured before the first PE and two weeks after the last PE session. To monitor clinical outcomes, the following somatic and psychometric follow-up assessments were conducted before the first PE, 2 weeks after the second, and 2 weeks after the last PE: the Schellong test, ISI (insomnia), FSS (fatigue), HADS (depression and anxiety), and EQ-5D-5L (quality of life) questionnaires.
Results: There was a negative association between both the β2-adrenergic and M3-muscarinic receptor autoantibody concentration and the quality of life measurements assessed with the EQ-5D-5L questionnaire. Per 1 U/mL increase in the concentration levels of β2-adrenergic receptor antibodies or M3-muscarinic acetylcholine receptor antibodies, the EQ-5D-5L index score [−0.59 to 1] decreased by 0.01 (0.63%) or 0.02 (1.26%), respectively. There were no significant associations between the ISI, HADS, and FSS questionnaires and the β1-adrenergic and M4-muscarinic receptor antibodies titers.
Conclusions: After a thorough selection of patients with present autoantibodies, this pilot study found negative associations concerning autoantibody concentration and somatic, as well as psychological wellbeing. To validate these promising feasibility study results—indicating the potential therapeutic potential of antibody-lowering methods—further investigation with larger sample sizes is needed.
Source: Oesch-Régeni B, Germann N, Hafer G, Schmid D, Arn N. The Effect on Quality of Life of Therapeutic Plasmapheresis and Intravenous Immunoglobulins on a Population of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients with Elevated β-Adrenergic and M3-Muscarinic Receptor Antibodies—A Pilot Study. Journal of Clinical Medicine. 2025; 14(11):3802. https://doi.org/10.3390/jcm14113802 https://www.mdpi.com/2077-0383/14/11/3802 (Full text)

Precision phenotyping for curating research cohorts of patients with unexplained post-acute sequelae of COVID-19

Abstract:

Background: Scalable identification of patients with post-acute sequelae of COVID-19 (PASC) is challenging due to a lack of reproducible precision phenotyping algorithms, which has led to suboptimal accuracy, demographic biases, and underestimation of the PASC.

Methods: In a retrospective case-control study, we developed a precision phenotyping algorithm for identifying cohorts of patients with PASC. We used longitudinal electronic health records data from over 295,000 patients from 14 hospitals and 20 community health centers in Massachusetts. The algorithm employs an attention mechanism to simultaneously exclude sequelae that prior conditions can explain and include infection-associated chronic conditions. We performed independent chart reviews to tune and validate the algorithm.

Findings: The PASC phenotyping algorithm improves precision and prevalence estimation and reduces bias in identifying PASC cohorts compared to the ICD-10-CM code U09.9. The algorithm identified a cohort of over 24,000 patients with 79.9% precision. Our estimated prevalence of PASC was 22.8%, which is close to the national estimates for the region. We also provide in-depth analyses, encompassing identified lingering effects by organ, comorbidity profiles, and temporal differences in the risk of PASC.

Conclusions: PASC precision phenotyping boasts superior precision and prevalence estimation while exhibiting less bias in identifying patients with PASC. The cohort derived from this algorithm will serve as a springboard for delving into the genetic, metabolomic, and clinical intricacies of PASC, surmounting the constraints of prior PASC cohort studies.

Source: Azhir A, Hügel J, Tian J, Cheng J, Bassett IV, Bell DS, Bernstam EV, Farhat MR, Henderson DW, Lau ES, Morris M, Semenov YR, Triant VA, Visweswaran S, Strasser ZH, Klann JG, Murphy SN, Estiri H. Precision phenotyping for curating research cohorts of patients with unexplained post-acute sequelae of COVID-19. Med. 2025 Mar 14;6(3):100532. doi: 10.1016/j.medj.2024.10.009. Epub 2024 Nov 8. PMID: 39520983; PMCID: PMC11911085. https://pmc.ncbi.nlm.nih.gov/articles/PMC11911085/ (Full text)

Causal relationship between immune cells and post-viral fatigue syndrome: a Mendelian randomization study

Abstract:

Background: Accumulating evidence has hinted at a correlation between immune cells and post-viral fatigue syndrome (PVFS). However, it is still ambiguous whether these associations indicate a causal connection.

Objective: To elucidate the potential causal link between immune cells and PVFS, we performed a two-sample Mendelian randomization (MR) study.

Methods: We obtained summary data on PVFS cases (Ncase = 195) and controls (Ncontrol = 382,198) from the FinnGen consortium. Additionally, we retrieved comprehensive statistical information on 731 immune cell features. Our analysis encompassed both forward and reverse MR approaches. To ensure the reliability and validity of our findings, we conducted rigorous sensitivity analyses, addressing issues of robustness and heterogeneity.

Result: Our study presents compelling evidence of a probable causal link between immune cells and PVFS. Notably, we have pinpointed 28 distinct types of immune cell traits that potentially exhibit a causal association with PVFS. Among a pool of 7 31 immune cell traits, we identified 28 immune cell types that exhibited a potential causal association with PVFS. These included 9 B cells, 1 conventional dendritic cell (cDC), 1 maturation stage of T cell, 3 myeloid cells, 9 T, B, NK, and monocyte cells (TBNK), and 5 regulatory T cells (Treg).

Conclusion: Through genetic analyses, our study has unveiled profound causal connections between specific types of immune cells and PVFS, offering valuable guidance for forthcoming clinical investigations.

Source: Wang Z, Bai Z, Sun Y. Causal relationship between immune cells and post-viral fatigue syndrome: a Mendelian randomization study. Virol J. 2025 May 30;22(1):171. doi: 10.1186/s12985-025-02809-4. PMID: 40448142; PMCID: PMC12124062. https://pmc.ncbi.nlm.nih.gov/articles/PMC12124062/ (Full text)