Tag: long Covid

The pivotal role of central sensitization in long COVID, fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Introduction: Long COVID is a condition characterized by persistent unexplained symptoms following COVID-19 infection. These symptoms are not related to another disease or organ damage and are similar to those in fibromyalgia and myslgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Areas covered: The similar clinical and pathophysiological features and management of long COVID, fibromyalgia and ME/CFS are explored from the unifying framework of central sensitivity syndromes. The article is based on a literature search utilizing PubMed for content published between 2021 and 1 May 2025, using search terms: long COVID, long COVID syndrome, post-COVID-19, post-acute SARS-CoV-2, fibromyalgia, ME/CFS, post-exertional malaise and central sensitization.

Expert opinion: Once long COVID is redefined to exclude patients with well-defined organ disease, it fits best as a model of central sensitization. Long COVID is a single syndrome, rather than many distinct diseases. Optimal management of long COVID and similar central sensitivity

Source: Goldenberg DL. The pivotal role of central sensitization in long COVID, fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome. Expert Rev Neurother. 2025 Jun 13:1-17. doi: 10.1080/14737175.2025.2516097. Epub ahead of print. PMID: 40512228. https://www.tandfonline.com/doi/full/10.1080/14737175.2025.2516097

Concentrations of uremic bacterial metabolites in patients with post-COVID-19 syndrome

Abstract:

Post-COVID-19 syndrome (PCS) is characterized by persistent symptoms and reduced mental and physical performance following the acute phase of COVID-19. The underlying mechanisms remain unclear but may involve gut microbiota dysbiosis and immune-related changes in amino acid metabolism. This pilot study aimed to investigate whether specific bacterial uremic metabolites (BUM) are altered in patients with post-infectious syndromes and whether these alterations are associated with PCS symptoms.

We examined BUM in 25 PCS patients, 8 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients, and 8 healthy controls (Ctrls). Concentrations of BUM were determined in second morning urine samples using mass spectrometry (Biovis Diagnostik, Limburg, Germany). Standardized questionnaires assesed physical, cognitive, psychological, and somatic symptoms and mental health status.

PCS and ME/CFS patients exhibited significantly higher scores for post-exertional malaise (PEM) and somatic symptom severity compared to healthy controls (p<0.001). Elevated BUM concentrations were found in 64% of PCS patients, compared to 37.5% of both healthy controls and ME/CFS patients. While overall BUM levels did not significantly differ between groups, heatmap clustering revealed distinct metabolic patterns.

Elevated tryptamine and 4-hydroxyphenylpropionic acid (HPHPA) and higher hippuric acid and trimethylamine concentrations, were exclusively analysed in patients with post-infectious syndromes. Our pilot study suggests that urine metabolomic analysis may be a useful approach for investigating the role of gut dysbiosis and BUM in patients with PCS.

Source: Brigo N, Mayr W, Taenzer M, Löffler-Ragg J, Schroll A, Engl S, Schütz B, Rappl P, Heine T, Weiss G, Kurz K. Concentrations of uremic bacterial metabolites in patients with post-COVID-19 syndrome. Front Cell Infect Microbiol. 2025 May 29;15:1582972. doi: 10.3389/fcimb.2025.1582972. PMID: 40510799; PMCID: PMC12159039. https://pmc.ncbi.nlm.nih.gov/articles/PMC12159039/ (Full text)

Long COVID-19 autoantibodies and their potential effect on fertility

Abstract:

Impaired spermatogenesis has been reported in coronavirus disease 2019 (COVID-19) patients. However, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on male fertility remains unclear. The purpose of this multicenter study was to investigate the possible impact of SARS-CoV-2 infection on male fertility and determine the potential reasons leading to impaired male reproductive functions.

In silico approach identified ~60 amino acid sequences containing at least five continuous residues shared by SARS-CoV-2 Spike glycoprotein and spermatogenesis-linked proteins. Four synthetic peptides were tested with sera from independent cohorts of patients with acute and long COVID-19 syndrome (LCS), and naïve vaccinated subjects. Immunogenicity and pathogenicity studies were performed by immunizing mice with two selected peptides and testing the antigenicity of induced antibodies.

While none of four peptides were recognized by antibodies from vaccinated people, infected patients exhibited high reactivity to peptide 4, and LCS patients, especially women, showed elevated antibody levels against peptide 2. Women with LCS and chronic fatigue syndrome had higher levels of peptide 2-reacting antibodies than those with idiopathic chronic fatigue syndrome. Noteworthy, peptide 2 antibodies showed, in in vitro experiment, a specific interaction with mouse testicular tissue antigens.

These findings raise the possibility that cross-reactive epitopes between SARS-CoV-2 Spike protein and spermatogenesis-related antigens may affect infected patients’ fertility, suggesting a potential for autoimmune responses with human consequences.

Source: Talamini L, Fonseca DLM, Kanduc D, Chaloin O, Verdot C, Galmiche C, Dotan A, Filgueiras IS, Borghi MO, Meroni PL, Gavrilova NY, Ryabkova VA, Churilov LP, Halpert G, Lensch C, Thurner L, Fong SW, Ng LFP, Rénia L, Young BE, Lye DC, Lozano JM, Cabral-Marques O, Shoenfeld Y, Muller S. Long COVID-19 autoantibodies and their potential effect on fertility. Front Immunol. 2025 May 27;16:1540341. doi: 10.3389/fimmu.2025.1540341. PMID: 40496870; PMCID: PMC12149208.  https://pmc.ncbi.nlm.nih.gov/articles/PMC12149208/ (Full text)

Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest

Abstract:

Patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suffer from a reduced exercise capacity, skeletal muscle abnormalities and post-exertional malaise (PEM), where symptoms worsen with cognitive or physical exertion. PEM often results in avoidance of physical activity, resulting in a lower aerobic fitness, which may contribute to skeletal muscle abnormalities. Here, we compared whole-body exercise responses and skeletal muscle adaptations after strict 60-day bed rest in healthy people with those in patients with long COVID and ME/CFS, and healthy age- and sex-matched controls.

Bed rest altered the respiratory and cardiovascular responses to (sub)maximal exercise, while patients exhibited respiratory alterations only at submaximal exercise. Bed rest caused muscle atrophy, and the reduced oxidative phosphorylation related to reductions in maximal oxygen uptake.

Patients with long COVID and ME/CFS did not have muscle atrophy, but had less capillaries and a more glycolytic fibers, none of which were associated with maximal oxygen uptake. While the whole-body aerobic capacity is similar following bed rest compared to patients, the skeletal muscle characteristics differed, suggesting that physical inactivity alone does not explain the lower exercise capacity in long COVID and ME/CFS.

Source: Braeden T. Charlton, Anouk Slaghekke, Brent Appelman, Moritz Eggelbusch, Jelle Y. Huijts, Wendy Noort, Paul W. Hendrickse, Frank W. Bloemers, Jelle J. Posthuma, Paul van Amstel, Richie P. Goulding, Hans Degens, Richard T. Jaspers, Michèle van Vugt, Rob C.I. Wüst. Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest. medRxiv 2025.05.02.25326885; doi: https://doi.org/10.1101/2025.05.02.25326885 https://www.medrxiv.org/content/10.1101/2025.05.02.25326885v1.full?_x_tr_sl=nl&_x_tr_tl=en&_x_tr_hl=en (Full text)

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)

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)