Immune Dysregulation and Persistent Symptoms: Insights into T Cell Dynamics in Post-COVID among Athletes from the CoSmo-S Study.

Long COVID is characterized by persistent symptoms following acute SARS-CoV-2 infection, yet its biological mechanisms remain incompletely understood. Emerging evidence suggests that immune dysregulation, mitochondrial dysfunction, and altered cell survival pathways may contribute to prolonged symptomatology.In this cross-sectional study, peripheral blood mononuclear cells were collected from individuals with Long COVID approximately 10months post-infection and from recovered individuals without Long COVID symptoms. Symptom burden was assessed using a composite domain-based score. mRNA expression of immune and antiviral genes (IL-6, IL-1β, IL-10, SOCS3, HIF-1α, OAS1, MAVS, IFN-α, IFN-γ), anti-apoptotic markers (MCL1, BCL-2, XIAP, LIVIN), cell cycle kinases (CDK4, CDK6), mitochondrial biogenesis and dynamics markers (NRF1, TFAM, PGC-1α, DRP1, MFN1/2, OPA1), and mitophagy regulators (PARKIN, PINK1) were quantified using quantitative real-time PCR. Data was analyzed by SPSS and GraphPad Prism. Individuals with Long COVID demonstrated significantly higher expressions of IL-6, IL-1β, IL-10, SOCS3, HIF-1α, OAS1, MAVS, NRF1, DRP1, PARKIN, MCL1, and LIVIN compared with recovered controls after using the Benjamini-Hochberg False Discovery Rate (FDR) method. Several transcriptional markers, particularly HIF-1α, IL-1β, IL-10, and NRF1, remained independently associated with symptom burden after adjustment for age and sex. Correlation analysis demonstrated coordinated transcriptional co-expression patterns across immune, antiviral, mitochondrial, and apoptosis-related genes. Long COVID at 10months post-infection is associated with coordinated transcriptional alterations across multiple biological pathways. The association of these changes with symptom burden suggests a potential link between persistent immunometabolic activation and clinical manifestations. These findings are exploratory and highlight the need for longitudinal and functional studies to further elucidate underlying mechanisms.

Introduction: The long-term effects of COVID-19 in children remain poorly defined, particularly in low- and middle-income countries where healthcare resources are limited. While children often experience milder acute symptoms than adults, a significant subset may develop persistent physical and psychological symptoms post-infection. This study aimed to evaluate the prevalence, nature, and risk factors of post-COVID-19 conditions in pediatric patients in Egypt. Methods: A descriptive, cross-sectional survey was conducted between December 2021 and December 2022 at Minia University Hospital, Egypt. A total of 160 children and adolescents aged one month to 18 years with confirmed SARS-CoV-2 infection (PCR or serology) were enrolled. Participants were assessed 12 weeks post-infection through structured interviews with caregivers and, where appropriate, the children themselves. Data were collected using a validated symptom checklist covering physical, gastrointestinal, respiratory, cardiovascular, neurological, and psychiatric domains. Statistical analysis was performed using SPSS (version 21.0), employing chi-square tests, Fisher’s exact test, and Mann-Whitney U tests to assess associations, with p-values <0.05 considered statistically significant. Results: The median age of participants was 96.0 months (8 years), and 44.83% were male. At the 12-week follow-up, 36.25% of children exhibited persistent post-COVID-19 symptoms. The most frequently reported symptoms were fatigue (82.8%), sleep disturbances (70.7%), respiratory symptoms (50.0%), and neuropsychiatric issues such as memory problems and mood disturbances (46.6%). Gastrointestinal symptoms like abdominal pain (17.2%) and diarrhea (20.7%) were also reported. Statistical analysis revealed significant associations between persistent symptoms and neuropsychiatric (p < 0.001), gastrointestinal (p = 0.001), and cardiovascular symptoms (p = 0.025), as well as fever during acute infection (p = 0.029). Children with pre-existing conditions (e.g., asthma, neurological issues) were more likely to experience prolonged symptoms. Discussion: This study highlights the substantial burden of long COVID in pediatric populations, even in cases with mild initial disease. The multisystem involvement observed in post-COVID cases suggests that long COVID in children is not limited to isolated symptoms but reflects a systemic condition potentially driven by immune dysregulation, persistent inflammation, or viral remnants. These findings align with global data but are among the first from a developing country context. The use of standardized psychiatric screening (Pediatric Symptom Checklist) strengthens the assessment of psychological effects. However, limitations include the single-center setting, absence of viral genotyping, and reliance on caregiver-reported symptoms, which may introduce recall or reporting bias. Conclusion: A significant proportion of pediatric patients continue to experience long-term health effects following COVID-19 infection, especially fatigue, sleep issues, and neuropsychiatric disturbances. Early identification and multidisciplinary care are essential for managing these patients, particularly in under-resourced settings. Further multicenter and longitudinal studies are needed to elucidate the underlying mechanisms and inform targeted interventions.

BackgroundLong-COVID immunopathogenesis involves diverse factors. We longitudinally characterize hospitalized COVID-19 patients, examining the role of SARS-CoV-2 RNAemia and inflammation in immune dysregulation.MethodsHospitalized patients are evaluated during acute infection (T0), 3 months post-symptom onset (T1), and 3 years if symptoms persisted (T2). Immune profile includes characterization of SARS-CoV-2-specific/non-specific T/B cells (flow cytometry) and antibodies (ELISA, neutralization, ADCC). RNAemia and cytokines are quantified (RT-PCR, cytometric beads array) and correlated. Statistics: non-parametric cross-sectional, longitudinal and correlation analyses.ResultsHere we show 48 hospitalized individuals during acute COVID-19, 38 exhibit early persistent symptoms (EPS+) 3 months post-symptoms onset, 10 do not (EPS−). Groups are comparable for age, sex, co-morbidities. The EPS+ shows fatigue, dyspnoea, anosmia/dysgeusia, diarrhea, chronic pain, mnestic disorders. Over time, they show a reduction of neutralization ability and total SARS-CoV-2-specific CD4 T cells, with increased total CD4 TEMRA, and failure to increase RBD-specific B cells and IgA+ MBCs. EPS+ patients show higher levels of T0-IFN-γ + CD4 TEMRA, T1-IL-2 + CD4 TEM and T1-TNF-α + CD4 cTfh. In EPS+, baseline SARS-CoV-2 RNAemia positively correlates with CD4 TEMRA, follow-up SARS-CoV-2 RNAemia with ADCC. Among 38 EPS+ individuals at T1, 33 are evaluated 3 years after infection, 5 are lost at follow-up. 10/33 EPS+ show long-term symptoms (late persistent symptoms, EPS + LPS+), whereas 23/33 fully recover (EPS + LPS−). Antibodies, RNAemia, and cytokines show no differences between/within groups at any time point.ConclusionsEarly persistent symptoms are associated with multi-layered SARS-CoV-2-specific/non-SARS-CoV-2-specific immune dysregulation. The shift towards non-Ag-specific TEMRA and ADCC trigger in EPS+ may relate to SARS-CoV-2 RNAemia. Early immune dysregulation does not associate with long-term persistent symptoms. Further research on SARS-CoV-2 RNAemia and early immune dysregulation is needed.

Post-acute COVID-19 syndrome (PACS) presents with persistent symptoms such as fatigue, dyspnea, and cognitive impairment, even after apparent clinical recovery. Although widely reported, the biological basis of these symptoms remains unclear. This study aimed to investigate the underlying cellular, immunological, oxidative, and biochemical disturbances during the recovery phase of COVID-19 and evaluate their association with clinical symptomatology. A cross-sectional observational study was conducted involving 120 participants who were previously SARS-CoV-2 positive, recruited ≥30 days post-recovery. Peripheral blood samples were analyzed for ER stress markers (HSP70, CHOP, GRP78), Pro- and anti-inflammatory cytokines (IL-6, TNF-α, IFN-γ, IL-10), oxidative biomarkers (MDA, SOD, GSH), and biochemical parameters (ALT, AST, CRP, ferritin). T cell subsets were evaluated via flow cytometry. Statistical comparisons and correlation analyses were performed using SPSS v22.0. Significant elevations were observed in all stress and inflammatory markers (p < 0.05). IL-6, CRP, and MDA showed strong positive correlations with fatigue and dyspnea scores. Treg percentages were reduced, and males exhibited higher biomarker levels than females. Persistent immune and oxidative activation was evident in the recovery phase. Post-acute COVID-19 is associated with quantifiable cellular and molecular disturbances. This integrated analysis of ER stress, immune dysregulation, and oxidative imbalance provides a novel and comprehensive view of long COVID pathophysiology.

Background After almost 2 years of fighting against SARS-CoV-2 pandemic, the number of patients enduring persistent symptoms long after acute infection is a matter of concern. This set of symptoms was referred to as “long COVID”, and it was defined more recently as “Post COVID-19 condition” by the World health Organization (WHO). Although studies have revealed that long COVID can manifest whatever the severity of inaugural illness, the underlying pathophysiology is still enigmatic. Aim To conduct a comprehensive review to address the putative pathophysiology underlying the persisting symptoms of long COVID. Method We searched 11 bibliographic databases (Cochrane Library, JBI EBP Database, Medline, Embase, PsycInfo, CINHAL, Ovid Nursing Database, Journals@Ovid, SciLit, EuropePMC, and CoronaCentral). We selected studies that put forward hypotheses on the pathophysiology, as well as those that encompassed long COVID patients in their research investigation. Results A total of 98 articles were included in the systematic review, 54 of which exclusively addressed hypotheses on pathophysiology, while 44 involved COVID patients. Studies that included patients displayed heterogeneity with respect to the severity of initial illness, timing of analysis, or presence of a control group. Although long COVID likely results from long-term organ damage due to acute-phase infection, specific mechanisms following the initial illness could contribute to the later symptoms possibly affecting many organs. As such, autonomic nervous system damage could account for many symptoms without clear evidence of organ damage. Immune dysregulation, auto-immunity, endothelial dysfunction, occult viral persistence, as well as coagulation activation are the main underlying pathophysiological mechanisms so far. Conclusion Evidence on why persistent symptoms occur is still limited, and available studies are heterogeneous. Apart from long-term organ damage, many hints suggest that specific mechanisms following acute illness could be involved in long COVID symptoms. KEY MESSAGES Long-COVID is a multisystem disease that develops regardless of the initial disease severity. Its clinical spectrum comprises a wide range of symptoms. The mechanisms underlying its pathophysiology are still unclear. Although organ damage from the acute infection phase likely accounts for symptoms, specific long-lasting inflammatory mechanisms have been proposed, as well. Existing studies involving Long-COVID patients are highly heterogeneous, as they include patients with various COVID-19 severity levels and different time frame analysis, as well.

Lyme disease, the most common tick-borne disease in the United States, is caused by infection with the spirochete Borrelia burgdorferi. While most patients with acute Lyme disease recover completely if treated with antibiotics shortly after the onset of infection, approximately 10-30% experience post-treatment symptoms and 5-10% have residual symptoms with functional impairment (post-treatment Lyme disease syndrome or PTLDS). These patients typically experience pain, cognitive problems, and/or fatigue. This narrative review provides a broad overview of Lyme disease, focusing on neuropsychiatric manifestations and persistent symptoms. While the etiology of persistent symptoms remains incompletely understood, potential explanations include persistent infection, altered neural activation, and immune dysregulation. Widely recognized is that new treatment options are needed for people who have symptoms that persist despite prior antibiotic therapy. After a brief discussion of treatment approaches, the article focuses on vagus nerve stimulation (VNS), a neuromodulation approach that is FDA-approved for depression, epilepsy, and headache syndromes and has been reported to be helpful for other diseases characterized by inflammation and neural dysregulation. Transcutaneous VNS stimulates the external branch of the vagus nerve, is minimally invasive, and is well-tolerated in other conditions with few side effects. If well-controlled double-blinded studies demonstrate that transcutaneous auricular VNS helps patients with chronic syndromes such as persistent symptoms after Lyme disease, taVNS will be a welcome addition to the treatment options for these patients.

Long COVID-19—it's not over until?

Multidisciplinary consensus on a stepwise treatment algorithm for management of chronic rhinosinusitis with nasal polyps.

SARS-CoV-2 has claimed more than 7 million lives worldwide and has been associated with prolonged inflammation, immune dysregulation and persistence of symptoms following severe infection. Understanding the T cell mediated immune response and factors impacting development and continuity of SARS-CoV-2 specific memory T cells is pivotal for developing better therapeutic and monitoring strategies for those most at risk from COVID-19. Here we present a comprehensive analysis of memory T cells in a convalescent cohort (n=20), three months post Omicron infection. Utilising flow cytometry to investigate CD4+CD45RO+ and CD8+CD45RO+ memory T cell IL-2 expression following Omicron (B.1.1.529/BA.1) peptide pool stimulation, alongside T cell receptor repertoire profiling and RNA-Seq analysis, we have identified several immunological features associated with hospitalised status. We observed that while there was no significant difference in median CD4+CD45RO+ IL-2+ and CD8+ CD45RO+ IL-2+ memory T cell count between subgroups, the hospitalised subgroup expressed significantly more IL-2 per cell following Omicron peptide pool exposure in the CD8+CD45RO+ population (p <0.03) and trended towards significance in CD4+CD45RO+ cells (p <0.06). T cell receptor repertoire analysis found that the non-hospitalised subgroup had a much higher number of circulating clonotypes, targeting a wider range of predominantly MHC-I epitopes across the SARS-CoV-2 genome. Several immunodominant epitopes, conserved between both subgroups, were observed, however hospitalised individuals were less likely to express putative HLA alleles responsible for pMHC presentation which may impact TCR affinity. We observed a bias towards shorter CDR3 segments in TCRβ repertoire analysis within the hospitalised subgroup, alongside lower rates of repertoire overlap in CDR3 sequences compared to the non-hospitalised subgroup. We found a significant proportion of TCRs targeted epitopes along the SARS-CoV-2 genome including non-structural proteins, responsible for viral replication and immune evasion. These findings highlight how the continuity of T cell based protective immunity is impacted by both the viral replication cycle of SARS-CoV-2 upon intracellular and innate immune responses, and HLA-type upon TCR affinity and clonotype formation. Our novel Epitope Target Analysis Pipeline (Epi-TAP) could prove beneficial in development of new therapeutic strategies through rapid identification of shared immunodominant epitopes across non-hospitalised and hospitalised subgroups.

Persistent physical symptoms (synonymous with persistent somatic symptoms) is an umbrella term for distressing somatic complaints that last several months or more, regardless of their cause. These symptoms are associated with substantial disability and represent a major burden for patients, health-care professionals, and society. Persistent physical symptoms can follow infections, injuries, medical diseases, stressful life events, or arise de novo. As symptoms persist, their link to clearly identifiable pathophysiology often weakens, making diagnosis and treatment challenging. Multiple biological and psychosocial risk factors and mechanisms contribute to the persistence of somatic symptoms, including persistent inflammation; epigenetic profiles; immune, metabolic and microbiome dysregulation; early adverse life experiences; depression; illness-related anxiety; dysfunctional symptom expectations; symptom focusing; symptom learning; and avoidance behaviours, with many factors being common across symptoms and diagnoses. Basic care consists of addressing underlying pathophysiology and using person-centred communication techniques with validation, appropriate reassurance, and biopsychosocial explanation. If basic care is insufficient, targeted psychological and pharmacological interventions can be beneficial. A better understanding of the multifactorial persistence of somatic symptoms should lead to more specific, personalised, and mechanism-based treatment, and a reduction in the stigma patients commonly face.

Long COVID is a multifactorial and long-lasting condition that affects a significant proportion of individuals following SARS-CoV-2 infection, characterized by persistent symptoms such as fatigue, cognitive dysfunction, and cardiovascular alterations. It is estimated that 30% to 60% of infected individuals experience symptoms lasting longer than 12 weeks. Despite advances in the understanding of acute infection, the pathophysiological mechanisms underlying Long COVID remain poorly understood, with hypotheses involving viral persistence, immune dysregulation, and metabolic disturbances. To investigate these alterations, this thesis employed omics technologies, with a focus on metabolomic and lipidomic approaches using mass spectrometry. We developed a paper-based immunoassay for the sensitive detection of the SARS- CoV-2 nucleocapsid (N) protein, integrating an innovative amplification strategy using dendrimers and a cleavable ionic probe coupled to mass spectrometry. This method achieved a limit of detection (LOD) of 2.4 pM and demonstrated stability after 30 days of storage at room temperature, showing promise for both point-of- care (POC) and direct-to-consumer (DTC) applications. Additionally, we conducted targeted lipidomic analysis using Multiple Reaction Monitoring (MRM) on plasma samples from Long COVID patients, revealing significant alterations in the levels of lysophosphatidylcholine (LPC), phosphatidylcholine (PC), cholesteryl esters (CE), and fatty acids (FA), with emphasis on mitochondrial dysfunction and dysregulation of glycerophospholipid and sphingolipid metabolism. Several lipid species demonstrated strong discriminatory power (AUC&#62;0.89), indicating their potential as biomarkers for the condition. Finally, we explored the novel application of pinhole paper spray mass spectrometry using embossed, hydrophobic paper substrates, enabling rapid and direct analysis of human plasma without prior sample preparation. Untargeted metabolomic analysis revealed distinct metabolic profiles between groups, highlighting alterations in lipid metabolism, mitochondrial function, and inflammatory pathways. These findings underscore the potential of paper-based approaches integrated with mass spectrometry as promising tools for clinical screening, biomarker discovery, and elucidation of the molecular mechanisms underlying Long COVID, with significant implications for the development of personalized diagnostic and therapeutic strategies.

During the global rollout of COVID-19 vaccines, a subset of individuals reported persistent symptoms following vaccination, with clinical presentations overlapping those of Long COVID and requiring individualised treatment strategies. Distinguishing between vaccine-related adverse events and post-infectious sequelae is challenging, particularly given the potential for unrecognised asymptomatic or mild SARS-CoV-2 infection before or after vaccination. To address this complexity, we defined our disease cohort as individuals experiencing persistent symptoms ( 12 weeks) following SARS-CoV-2 vaccination, without a confirmed history of prolonged symptoms after acute infection; for clarity, we refer to this group as presenting with Post-Vaccination/Post-Infection Syndrome (PV/PIS). In this study, we conducted a plasma proteomic analysis of digested microclot deposits isolated from platelet-poor plasma samples of 14 individuals with PV/PIS compared to 16 healthy controls, using liquid-chromatography-mass spectrometry. We identified significant alterations in coagulation factors, acute phase proteins, and immune response modulators in the PV/PIS group compared to controls. Notably, elevated levels of serum amyloid A1 and A2, attractin, and coagulation factors X and XI were observed, alongside downregulation of immune-regulatory proteins. These findings suggest that PV/PIS is characterised by persistent immune dysregulation and coagulopathy. This proteomic signature was found to only partially overlap with that previously reported in a proteomics analysis on Long COVID samples, collected prior to vaccination availability. Our results highlight the complex interplay between immune activation, endothelial dysfunction, and coagulation pathologies in PV/PIS, with distinct differences detected between these systems in Long COVID and PV/PIS, paving the way for more targeted protein research in these conditions.

BackgroundPost-COVID-19 condition refers to persistent or new onset symptoms occurring three months after acute COVID-19, which are unrelated to alternative diagnoses. Symptoms include fatigue, breathlessness, palpitations, pain, concentration difficulties ("brain fog"), sleep disorders, and anxiety/depression. The prevalence of post-COVID-19 condition ranges widely across studies, affecting 10–20% of patients and reaching 50–60% in certain cohorts, while the associated risk factors remain poorly understood.MethodsThis multicentre cohort study, both retrospective and prospective, aims to assess the incidence and risk factors of post-COVID-19 condition in a cohort of recovered patients. Secondary objectives include evaluating the association between circulating SARS-CoV-2 variants and the risk of post-COVID-19 condition, as well as assessing long-term residual organ damage (lung, heart, central nervous system, peripheral nervous system) in relation to patient characteristics and virology (variant and viral load during the acute phase). Participants will include hospitalised and outpatient COVID-19 patients diagnosed between 01/03/2020 and 01/02/2025 from 8 participating centres. A control group will consist of hospitalised patients with respiratory infections other than COVID-19 during the same period.Patients will be followed up at the post-COVID-19 clinic of each centre at 2–3, 6–9, and 12–15 months after clinical recovery. Routine blood exams will be conducted, and patients will complete questionnaires to assess persisting symptoms, fatigue, dyspnoea, quality of life, disability, anxiety and depression, and post-traumatic stress disorders.DiscussionThis study aims to understand post-COVID-19 syndrome's incidence and predictors by comparing pandemic waves, utilising retrospective and prospective data. Gender association, especially the potential higher prevalence in females, will be investigated. Symptom tracking via questionnaires and scales will monitor duration and evolution. Questionnaires will also collect data on vaccination, reinfections, and new health issues. Biological samples will enable future studies on post-COVID-19 sequelae mechanisms, including inflammation, immune dysregulation, and viral reservoirs.Trial registrationThis study has been registered with ClinicalTrials.gov under the identifier NCT05531773.

Spondylodiscitis caused by Aspergillus fumigatus is rare, particularly in immunocompetent individuals. This case highlights a unique instance of post-COVID Aspergillus spondylodiscitis, emphasizing the potential role of COVID-19-related immune dysregulation in predisposing patients to opportunistic fungal infections. A 75-year-old man with a history of hypertension, hypothyroidism, and severe COVID-19 (requiring ICU admission and steroid therapy) presented with chronic low back pain and acute bilateral lower limb weakness. Imaging revealed L1-L2 disc space narrowing, vertebral destruction, and epidural compression. Histopathological and microbiological analyses confirmed Aspergillus fumigatus infection. The patient underwent surgical decompression, debridement, and posterior stabilization, followed by intravenous voriconazole therapy, resulting in significant clinical improvement. This case underscores the importance of considering fungal etiologies in spondylodiscitis, especially in post-COVID patients with persistent symptoms. A multidisciplinary approach involving radiological, microbiological, and histopathological evaluation is critical for timely diagnosis and management. Combined surgical and antifungal therapy yielded favorable outcomes, aligning with existing literature recommendations. Further research is needed to explore the link between COVID-19 and opportunistic fungal infections.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced the medical community to the phenomenon of long COVID, a condition characterized by persistent symptoms following the resolution of the acute phase of infection. Among the myriad of symptoms reported by long COVID sufferers, chronic fatigue, cognitive disturbances, and exercise intolerance are predominant, suggesting systemic alterations beyond the initial viral pathology. Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms. This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction. Through a comprehensive analysis of the literature, we highlight the significance of mitochondrial health in the pathophysiology of long COVID, drawing parallels with similar clinical syndromes linked to post-infectious states in other diseases where mitochondrial impairment has been implicated. We discuss potential therapeutic strategies targeting mitochondrial function, including pharmacological interventions, lifestyle modifications, exercise, and dietary approaches, and emphasize the need for further research and collaborative efforts to advance our understanding and management of long COVID. This review underscores the critical role of mitochondrial dysfunction in long COVID and calls for a multidisciplinary approach to address the gaps in our knowledge and treatment options for those affected by this condition.