Tag: long Covid

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)

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)

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)

Gastrointestinal Barrier Disruption in Post-COVID Syndrome Fatigue Patients

Abstract:

Background: Post-COVID Syndrome (PCS) is the term for a condition with persistent symptoms in a proportion of COVID-19 patients after asymptomatic, mild, or severe disease courses. Numbers vary, but the current estimate is that after COVID-19 approximately 10% develop PCS. The aim of our study was to evaluate the impact of SARS-CoV-2 infection on the gastrointestinal (GI) tract and associations with the development of PCS with fatigue, post-exertional malaise (PEM), orthostatic dysregulation, autonomous dysregulation, and/or neurocognitive dysregulation.

Methods: By combining medical record data from a prospective observational study with symptom analysis before, during, and after SARS-CoV-2 infection, we aimed to identify potential risk factors and predictive markers for PCS. Additionally, we analyzed blood, saliva, and stool samples from this well-characterized PCS patient cohort to biologically validate our findings.

Results: We identified significant associations between pre-existing GI complaints and the development of PCS Fatigue. PCS patients showed higher LBP/sCD14 ratios, lower IL-33 levels, and higher IL-6 levels compared to control groups. Our results highlight the critical role of the GI tract in PCS development of post-viral Fatigue.

Conclusion: We propose that the viral infection disrupts pathways related to the innate immune response and GI barrier function, evidenced by intestinal low-grade inflammation and GI barrier leakage. Monitoring GI symptoms and markers before, during, and after SARS-CoV-2 infection is crucial for identifying predictive clinical phenotypes in PCS. Understanding the interaction between viral infections, immune responses, and gut integrity could lead to more effective diagnostic and treatment strategies, ultimately reducing the burden on PCS patients.

Source: Rohrhofer J, Wolflehner V, Schweighardt J, Koidl L, Stingl M, Zehetmayer S, Séneca J, Pjevac P, Untersmayr E. Gastrointestinal Barrier Disruption in Post-COVID Syndrome Fatigue Patients. Allergy. 2025 May 15. doi: 10.1111/all.16593. Epub ahead of print. PMID: 40372110. https://onlinelibrary.wiley.com/doi/10.1111/all.16593 (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)

Untargeted analysis in post-COVID-19 patients reveals dysregulated lipid pathways two years after recovery

Abstract:

Introduction: Similar to what it has been reported with preceding viral epidemics (such as MERS, SARS, or influenza), SARS-CoV-2 infection is also affecting the human immunometabolism with long-term consequences. Even with underreporting, an accumulated of almost 650 million people have been infected and 620 million recovered since the start of the pandemic; therefore, the impact of these long-term consequences in the world population could be significant. Recently, the World Health Organization recognized the post-COVID syndrome as a new entity, and guidelines are being established to manage and treat this new condition. However, there is still uncertainty about the molecular mechanisms behind the large number of symptoms reported worldwide.

Aims and Methods: In this study we aimed to evaluate the clinical and lipidomic profiles (using non-targeted lipidomics) of recovered patients who had a mild and severe COVID-19 infection (acute phase, first epidemic wave); the assessment was made two years after the initial infection.

Results: Fatigue (59%) and musculoskeletal (50%) symptoms as the most relevant and persistent. Functional analyses revealed that sterols, bile acids, isoprenoids, and fatty esters were the predicted metabolic pathways affected in both COVID-19 and post-COVID-19 patients. Principal Component Analysis showed differences between study groups. Several species of phosphatidylcholines and sphingomyelins were identified and expressed in higher levels in post-COVID-19 patients compared to controls. The paired analysis (comparing patients with an active infection and 2 years after recovery) show 170 dysregulated features. The relationship of such metabolic dysregulations with the clinical symptoms, point to the importance of developing diagnostic and therapeuthic markers based on cell signaling pathways.

Source: López-Hernández Y, Oropeza-Valdez JJ, García Lopez DA, Borrego JC, Murgu M, Valdez J, López JA, Monárrez-Espino J. Untargeted analysis in post-COVID-19 patients reveals dysregulated lipid pathways two years after recovery. Front Mol Biosci. 2023 Mar 3;10:1100486. doi: 10.3389/fmolb.2023.1100486. PMID: 36936993; PMCID: PMC10022496. https://pmc.ncbi.nlm.nih.gov/articles/PMC10022496/ (Full text)

Long-COVID in children and their parents: A prospective cohort study

Abstract:

Background: Long-COVID is a significant global health concern, regardless of age. However, few reports have longitudinally evaluated the characteristics, prevalence, and risk factors of long-COVID in children.

Methods: Participants were Japanese children younger than 18 years hospitalized for COVID-19 between November 2021 and October 2022, along with their COVID-19 affected parents. During hospitalization and at 1-, 3-, and 6-month follow-ups, participants completed age-appropriate questionnaires on long-COVID symptoms. The quality of life (QOL) score was assessed in children older than 2 years. The prevalence of long-COVID symptoms by age group was compared. Multivariable logistic regression analysis was conducted to investigate risk factors affecting long-COVID. Analysis of covariance adjusted for potential confounders was conducted to determine which symptoms affect QOL score.

Results: Of 108 children enrolled, the prevalence of long-COVID was 44.9%, 37.8%, and 22.8% at 1, 3, and 6 months, respectively, after SARS-CoV-2 infection. There were no specific risk factors for long-COVID. Cough, fatigue, and sleep disturbance were the most common long-COVID symptoms, with sleep disturbance associated with a change in lower QOL score from admission at all three follow-ups (mean difference 9.25, 20.15, and 19.81; 95% CI, 1.58-16.91, 3.38-36.92, and 5.51-34.11). The prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms among 0-6 years was significantly lower than among 7-17 years and parents; there was no significant difference between 7 and 17 years and parents.

Conclusion: Even 6 months after SARS-CoV-2 infection, 22.8% of pediatric patients still had long-COVID symptoms. Some of these symptoms were similar to those of ME/CFS, potentially affecting children’s QOL.

Source: Iijima H, Funaki T, Kubota M. Long-COVID in children and their parents: A prospective cohort study. Pediatr Int. 2025 Jan-Dec;67(1):e70042. doi: 10.1111/ped.70042. PMID: 40351239. https://onlinelibrary.wiley.com/doi/full/10.1111/ped.70042 (Full text)

Post-exertional malaise in Long COVID: subjective reporting versus objective assessment

Abstract:

Background: Post-exertional malaise (PEM) is a central feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and has emerged as a prominent feature of Long COVID. The optimal clinical approach to PEM is inconclusive, and studies of the impact of exercise have yielded contradictory results.

Objective: The objective of this study was to examine PEM in Long COVID by assessing the prevalence of self-reported PEM across study cohorts and symptom responses of Long COVID patients to a standardized exercise stressor. Secondarily, Long COVID symptom responses to exercise were compared to those of ME/CFS and healthy volunteers.

Methods: Data from three registered clinical trials comprised four cohorts in this study: Long COVID Questionnaire Cohort (QC; n = 244), Long COVID Exercise Cohort (EC; n = 34), ME/CFS cohort (n = 9), and healthy volunteers (HV; n = 9). All cohorts completed questionnaires related to physical function, fatigue, and/or PEM symptoms. EC also performed a standardized exercise test (cardiopulmonary exercise test, CPET), and the PEM response to CPET was assessed using visual analog scales and qualitative interviews (QIs) administered serially over 72 h. EC PEM measures were compared to ME/CFS and HV cohorts. A secondary analysis of QI explored positive responses to CPET among EC, ME/CFS and HV.

Results: Self-reported PEM was 67% in QC and estimated at 27% in EC. Only 2 of 34 EC patients (5.9%) were observed to develop PEM after a CPET. In addition, PEM responses after CPET in Long COVID were not as severe and prolonged as those assessed in ME/CFS. Twenty-two of 34 EC patients (64.7%) expressed at least one of 7 positive themes after the CPET.

Conclusion: Self-report of PEM is common in Long COVID. However, observable PEM following an exercise stressor was not frequent in this small cohort. When present, PEM descriptions during QI were less severe in Long COVID than in ME/CFS. Positive responses after an exercise stressor were common in Long COVID. Exercise testing to determine the presence of PEM may have utility for guiding clinical management of Long COVID.

Source: Stussman B, Camarillo N, McCrossin G, Stockman M, Norato G, Vetter CS, Ferrufino A, Adedamola A, Grayson N, Nath A, Chan L, Walitt B, Chin LMK. Post-exertional malaise in Long COVID: subjective reporting versus objective assessment. Front Neurol. 2025 Apr 23;16:1534352. doi: 10.3389/fneur.2025.1534352. PMID: 40337174; PMCID: PMC12055772. https://pmc.ncbi.nlm.nih.gov/articles/PMC12055772/ (Full text)

Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID: Commonalities Detected by Invasive Cardiopulmonary Exercise Testing

Abstract:

Rationale: There is substantial overlap of exertional symptoms in Long COVID (LC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) including intractable fatigue, post-exertional malaise (PEM), and orthostatic intolerance, but very little objective data liking the two. This study compares exercise pathophysiology in the two disorders and normal controls using invasive cardiopulmonary exercise testing (iCPET).

Methods: Between January 2019 and December 2024, 1,518 patients underwent a clinical iCPET at Brigham and Women’s Hospital. Exclusion criteria included morbid obesity (BMI>40 kg/m2), severe anemia ([Hb]<9.0 g/dL), elite athletes (peak VO2 (pVO2)>120% predicted), sub-maximum effort (RER<1.05), a primary pulmonary mechanical limit (VE @ AT/MVV>0.7), and comorbidities such as active/treated cancer, interstitial lung disease, or other respiratory related diseases. iCPET results from 438 ME/CFS patients, 73 LC patients, and 43 symptomatic but otherwise normal controls were analyzed. pV02, peak cardiac output (pQc), peak right atrial pressure (pRAP), peak systemic oxygen extraction (pSOE; Ca-vO2/[Hb]), and ventilatory inefficiency (VE/VCO2 slope) were compared among groups. Statistical significance was determined using Kruskal-Wallis tests for global comparisons, with post-hoc Dunn tests for pairwise group comparisons. Holm-Bonferroni adjustments were applied to control for multiple comparisons.

Results: LC and ME/CFS displayed reduced pVO2 % predicted compared to controls (LC: 78.4 ± 18%, ME/CFS: 78.1 ± 17%, Controls: 97.5 ± 10%, P≤0.0001). Reduced pQc % predicted was also observed compared to controls (LC: 91.1 ± 18%, ME/CFS: 96.3%, Controls: 101 ± 11%, P≤0.001). pRAP were significantly less compared to controls (LC: 1.1 ± 3.1 mmHg, ME/CFS: 1.3 ± 2.8 mmHg, Controls: 3.6 ± 3.4 mmHg, P≤0.001). Significant reductions in pSOE were seen for LC and ME/CFS (LC: 0.81 ± 0.1, ME/CFS: 0.81 ± 0.1, Controls, 0.91 ± 0.1, P≤0.0001). The only measure with no significant difference between disease and control was VE/VCO2 slope (LC: 31.4 ± 8.4, ME/CFS: 31.6 ± 6.9, Controls: 32.0 ± 6.7, P≥0.261). Most interestingly, no significant differences were seen between the two diseases for any of the analyzed measures (P≥0.245).

Conclusions: We report the largest cohort of ME/CFS and LC investigated with iCPET to date. ME/CFS and LC share symptomatic, reduced aerobic capacity at peak exercise, which is driven by preload insufficiency and impaired systemic O2 extraction, the latter compatible with peripheral left-to-right shunting and/or limb skeletal muscle dysfunction. These findings should drive future diagnostics and personalized medicine in both diseases. We hope these data inform the pending prospective NIH RECOVER iCPET study of LC.

Source: J. Squires, S. Palwayi, P. Li, W. Xiao, K. LeWine, S.W. Johnson, D. Felsenstein, A.B. Waxman, and D.M. Systrom. Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID: Commonalities Detected by Invasive Cardiopulmonary Exercise Testing [abstract]. Am J Respir Crit Care Med 2025;211:A7881. https://www.atsjournals.org/doi/​10.1164/ajrccm.2025.211.Abstracts.A7881