Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Post COVID-19 Condition (PCC) are debilitating, chronic multi-systemic illnesses that require multidisciplinary care. However, people with ME/CFS (pwME/CFS) and people with PCC (pwPCC) are often precluded from accessing necessary disability and social support services. These unmet care needs exacerbate the existing illness burdens experienced by pwME/CFS and pwPCC. To deliver appropriate care and optimise health outcomes for pwME/CFS and pwPCC, the development of evidence-based healthcare policies that recognise the disabling impacts of these illnesses must be prioritised. This systematic review summarises the health-related quality of life (HRQoL) of pwME/CFS and pwPCC when compared with healthy controls (HCs) to elucidate the impacts of these illnesses and guide healthcare policy reform.

CINAHL, Embase, MEDLINE, PubMed, PsycINFO and the Web of Science Core Collection were systematically searched from 1st January 2003 to 23rd July 2024. Eligible publications included observational studies capturing quantitative HRQoL data among pwME/CFS or pwPCC when compared with HCs. The use of validated patient-reported outcome measures (PROMs) was mandatory. Eligible studies were also required to employ the most stringent diagnostic criteria currently available, including the Canadian Consensus Criteria or International Consensus Criteria for ME/CFS and the World Health Organization case definition for PCC (PROSPERO ID: CRD42024501309).

This review captured 16 studies, including eight studies among pwME/CFS, seven studies among pwPCC and one study among both illness cohorts. Most participants were female and middle-aged. All pwPCC had experienced prolonged COVID-19 symptoms for at least three months. When compared with HCs, all HRQoL domains were significantly impaired among pwME/CFS and pwPCC. Both illnesses had a salient impact on physical health, including pain and ability to perform daily and work activities. While direct comparisons between pwME/CFS and pwPCC were limited by inconsistencies in the PROMs employed, comparable impact trends across HRQoL domain scores were observed.

ME/CFS and PCC have similar, profound impacts on HRQoL that warrant access to multidisciplinary disability and social support services. Future research must harmonise HRQoL data collection and prioritise longitudinal investigations among pwME/CFS and pwPCC to characterise PCC subgroups (including those fulfilling ME/CFS criteria) and predictors of prognosis.

The global impact of SARS-CoV-2 and its associated coronavirus disease (COVID-19) has necessitated urgent characterization of prognostic biomarkers. This study aimed to delineate the epidemiological and clinical predictors of mortality among hospitalized COVID-19 patients.

A retrospective cohort study was conducted on 123 patients with laboratory-confirmed COVID-19 admitted to Huoshenshan Hospital (Wuhan, China) from 1 February 2020 to 30 April 2020. Kaplan-Meier curve and multivariate Cox regression were used to assess the independent factors with survival time. Statistical significance was set at a p-value of <0.05.

The cohort exhibited a mortality rate of 49.6% (61/123), with the critical clinical type (HR = 7.970, p = 0.009), leukocytosis (HR = 3.408, p = 0.006), and lymphopenia (HR = 0.817, p = 0.038) emerging as independent predictors of reduced survival. Critical-type patients demonstrated significantly elevated inflammatory markers (neutrophils: 10.41 ± 6.23 × 109/L; CRP: 104.47 ± 29.18 mg/L) and coagulopathy (D-dimer: 5.21 ± 2.34 μg/ml) compared to non-critical cases. Deceased patients exhibited pronounced metabolic derangements, including hyperglycemia (9.81 ± 2.07 mmol/L) and hepatic dysfunction (ALP: 174.03 ± 30.13 U/L).

We revealed the epidemiological and clinical features of different clinical types of SARS-CoV-2 as summarized in this paper. We found that critical type, leukocyte, and lymphocyte are risk factors that affect survival time, which could be an early and helpful marker to improve management of COVID-19 patients.

The long-term health consequences following COVID-19 have largely been reported in adult populations living in high-income countries. We therefore did a systematic review of post COVID-19 condition symptoms reported in children and adolescents (<18 years), aiming to identify and include publications from low- or middle-income countries (LMICs). From EMBASE, Medline, and Pubmed until the 30th of October 2023, we searched all studies reporting original and complete data of long-term outcomes of at least 20 children or adolescents under 18 years of age with a history of confirmed acute COVID-19 infection. We excluded non-English publications, pre-prints, unreviewed articles, grey literature, studies with inaccessible full text, and those limited to a specific population. Risk of Bias was assessed using STROBE guidelines for observational studies. We used descriptive narrative analysis to summarize the findings. Forty studies reporting 825,849 children and adolescents; the median age of those with persistent symptoms was consistently in the adolescent age range but not all studies included young children (<5 years). Only one study, with 58 participants aged 6-17 years, population was from a LMIC. Studies relied on symptom reporting rather than objective measures of organ dysfunction. The definition of post COVID-19 condition varied; most studies used persistent symptom duration of two or three months or more. However, since the symptom onset was not specified, it was difficult to identify which study is truly consistent with WHO's definition of post COVID-19 condition. Prevalence of post COVID-19 condition ranged from 1.8% to 70% but with marked heterogeneity between study populations and reporting criteria including the severity of acute COVID presentation. Most studies were undertaken when the Alpha variant was the predominant strain. The prevalence of post COVID-19 condition ranged from 6.7% to 70% in the Alpha variant-, 23% to 61.9% in the Delta-, 17% to 34.6% in the Omicron-, and 3.7% to 34% in the Other-variant predominated studies. The most reported symptoms were fatigue (70%), headache (37.5%) and respiratory symptoms (35%); fatigue was most reported in all variant subgroups. Only half of the studies included a control group. The variations in study population, reporting methods, reliance on symptom reporting alone and lack of control groups make it challenging to determine the impact of COVID-19 on post COVID health in children and adolescents. The lack of data from LMIC populations especially infants and young children is a major gap.

Background: Hyperbaric Oxygen Therapy (HBOT) is a medical treatment that involves administering 100% oxygen at increased atmospheric pressure to enhance oxygen delivery to tissues. Initially developed for decompression sickness, HBOT has since been utilized for a wide range of medical conditions, including severe infections, non-healing wounds, and, more recently, COVID-19. Objective: This review explores the historical development of HBOT, its principles, its emerging role in the management of and its outcome as treatment in COVID-19, particularly in mitigating inflammation, hypoxemia, and oxidative stress. Methods: A comprehensive review of the literature was conducted, analyzing case reports and case series that examined the effectiveness of HBOT in various clinical scenarios, with a focus on COVID-19. Results: HBOT has been shown to enhance tissue oxygenation, reduce inflammation, and modulate oxidative stress, thereby improving clinical outcomes in patients with severe COVID-19. The therapy's ability to increase dissolved oxygen levels in blood and tissues, independent of hemoglobin, makes it particularly beneficial in conditions like COVID-19, where hypoxemia and inflammation are prominent. Conclusion: HBOT offers a promising adjunctive treatment for severe COVID-19, with the potential to reduce mortality and improve recovery by targeting key pathophysiological processes such as hypoxemia, inflammation, and oxidative stress. Further research is warranted to optimize treatment protocols and confirm long-term benefits.

Although post-COVID major depressive disorder (MDD) is frequent, the physiological mechanisms associated with it remain unclear. This study aimed to assess the association between 10 residual blood markers of inflammation and the presence of MDD 4 months after the acute phase of COVID-19.

This is a cross-sectional study of the COMEBAC cohort that followed patients 4 months after hospitalization for COVID-19 at Bicêtre Hospital. Patients with lingering symptoms or who had been in critical care (n = 177) were invited to a day hospital for assessment of MDD and peripheral inflammation. Ten peripheral inflammatory markers were examined: plasmatic C-reactive protein; leukocyte, monocyte, neutrophil, and lymphocyte counts; the neutrophil to lymphocyte ratio; the systemic inflammatory index (i.e., the (platelet x neutrophil) to lymphocyte ratio); cortisol, ferritin, and hemoglobin levels. Current MDD was assessed through structured interviews with a psychiatrist, depressive symptoms through self-questionnaires. Peripheral inflammatory markers were compared between patients with post-COVID MDD and patients without a lifetime history of psychiatric disorders (controls).

Out of 177 patients, 24 (13.6%) had MDD. No significant differences in peripheral inflammatory markers were observed between patients with post-COVID MDD and controls. Furthermore, peripheral inflammatory markers were not correlated with symptoms of depression.

We found no association between post-COVID MDD and 10 peripheral inflammatory markers 4 months after COVID-19 infection. Other potential mechanisms warrant investigation.

More than 100 million people worldwide have been infected by SARS-CoV-2 virus, the virus responsible for the acute disease COVID-19. Multiple studies have shown how various symptoms in these patients can persist for several months after resolution of the acute process, a phenomenon known as post-COVID syndrome. Neurological symptoms are varied, but the great majority of patients present fatigue.

To analyse post-COVID fatigue.

We present a prospective, single-centre, case-control study comparing patients with fatigue in the context of post-COVID syndrome with patients with history of COVID-19 but without post-COVID fatigue. Data were recorded at baseline (April 2021) and at 6 months. Data were recorded on clinical variables, fatigue questionnaires, sleep disorders, depression, anxiety, cognitive impairment, and quality of life. Basic laboratory analysis was performed with blood samples collected at the 2 visits. In addition, a substudy of proinflammatory (IL-6, IL-1β, TNF-α) and anti-inflammatory (IL-10) cytokines was performed.

Fatigue as measured by the Chalder Fatigue Scale was mixed (physical and psychological) and of moderate intensity. At 6 months, physical fatigue improved, but psychological fatigue did not. Significant differences were found in sleepiness, cognitive impairment, anxiety, and quality of life. Significant alterations were observed in TNF-α levels, but not in the remaining cytokines.

Patients with fatigue presented a poorer quality of life, with an improvement being observed at 6 months, which suggests a course that may be self-limiting; however, this will have to be confirmed with longer studies.

With the outbreak of COVID-19 in China, a large number of COVID-19 patients are at risk of long COVID after recovery. The purpose of our research is to systematically review the existing clinical studies to understand the current prevalence and related risk factors of long COVID in COVID-19 patients in China.

The protocol of this systematic review was registered on PROSPERO (CRD42024519375). We searched six electronic databases from 1st January 2020-1st March 2024. Literature screening, data extraction, and risk bias assessment were independently carried out by two reviewers. Quality of the included studies was evaluated by AHRQ and NOS. The meta-analysis was performed by R software 4.2.3 to derive the prevalence of long COVID and risk factors.

Overall, 50 studies with 65880 participants were included. The results showed that the prevalence of long COVID (with at least one symptom) among the COVID-19 patients was approximately 50 % (95 %Confidence Interval (CI) 42-58 %) in China. Although we conducted meta-regression and subgroup analysis, the heterogeneity of the study was high. But the Omicron BA.2 variant had a statistically significant effect on the prevalence of long COVID (P = 0.0004). The three most common symptoms of long COVID were fatigue (0.33, 95 %CI 0.28-0.39), cognitive decline (0.30, 95 %CI 0.14-0.46) and shortness of breath (0.29, 95 %CI 0.15-0.43). Patients with severe acute phase of COVID-19 (Odds Ratio (OR) 1.57, 95 % CI 1.39-1.77), combined 2 comorbidities (OR 1.80, 95 % CI 1.40-2.32), combined 3 comorbidities (OR 2.13, 95 % CI 1.64-2.77), advanced age (OR 1.02, 95 % CI 1.01-1.04), female (OR 1.58, 95 % CI 1.44-1.73) were the risk factors for long COVID prevalence.

Current systematic review found that nearly half of COVID-19 patients may suffering from long COVID in China. Establishing a long COVID recovery-support platform and regular follow-up would help to long-term monitor and manage the patients, especially those high-risk population.

SARS-CoV-2 disrupts lung vascular endothelial integrity, contributing to severe COVID-19 complications. However, the molecular mechanisms driving endothelial dysfunction remain underexplored, and targeted therapeutic strategies are lacking.

This study investigates Naringenin-7-O-glucoside (N7G) as a multi-target therapeutic candidate for modulating vascular integrity and immune response by inhibiting MMP1, MMP7, and SERPINE1-key regulators of extracellular matrix (ECM) remodeling and inflammation.

RNA-seq analysis of COVID-19 lung tissues identified 17 upregulated N7G targets, including MMP1, MMP7, and SERPINE1, with the latter exhibiting the highest expression. PPI network analysis linked these targets to ECM degradation, IL-17, HIF-1, and AGE-RAGE signaling pathways, and endothelial dysfunction. Disease enrichment associated these genes with idiopathic pulmonary fibrosis and asthma. Molecular docking, 200 ns MD simulations (triplicate), and MMGBSA calculations confirmed N7G's stable binding affinity to MMP1, MMP7, and SERPINE1. Immune profiling revealed increased neutrophils and activated CD4+ T cells, alongside reduced mast cells, NK cells, and naïve B cells, indicating immune dysregulation. Correlation analysis linked MMP1, MMP7, and SERPINE1 to distinct immune cell populations, supporting N7G's immunomodulatory role.

These findings suggest that N7G exhibits multi-target therapeutic potential by modulating vascular integrity, ECM remodeling, and immune dysregulation, positioning it as a promising candidate for mitigating COVID-19-associated endothelial dysfunction.

Background: Postoperative complications in individuals with a prior history of COVID-19 infection have been insufficiently investigated. This study is conducted to explore the postoperative complications of prostate biopsy in patients following a COVID-19 infection. Materials and Methods: Data from individuals who underwent a prostate biopsy at a tertiary hospital in Taizhou city from 1 February to 15 November 2023 were collected, including a history of COVID-19 infection, a history of chronic disease, and postoperative complications of prostate biopsy. Results: A total of 526 participants were enrolled in the study, with 325 individuals having a prior history of COVID-19 infection. The interval between infection and prostate biopsy was 29.25 ± 12.75 weeks, with a fluctuation range from 0.71 to 87.57 weeks. In individuals with a history of COVID-19 infection, 72 were asymptomatic, 110 experienced respiratory symptoms, and 145 had fever. In total, 198 patients reported postoperative complications, which showed no statistically significant difference with a history of COVID-19 infection (p=0.217). The top three reported postoperative complications were hematuria, perineal pain, and urinary retention, which tended not to be related to a history of COVID-19 infection (p=0.448, p=0.991, and p=0.277, respectively). Conclusion: The incidence of postoperative complications of prostate biopsy in post-COVID-19 patients, who currently have no symptoms of COVID-19 infection, was comparable to patients with no history of COVID-19 infection. In clinical practice, for males with a history of controlled COVID-19 infection, the risk of postoperative complications from prostate biopsy should not be a major concern.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to widespread post-acute sequelae of COVID-19 (PASC), affecting multiple body systems. Despite its prevalence, PASC's pathogenesis remains unclear, with hypotheses suggesting viral persistence, immune activation, and autoimmune responses among the pathogenetic mechanism. This study aimed to evaluate T cell memory response in PASC patients, one year post-hospital discharge and correlate it with clinical parameters to identify a potential PASC-associated fingerprint.

Peripheral blood mononuclear cells (PBMCs) from PASC patients and healthy controls (HC) were stimulated with a pool of spike peptides. CD4+ and CD8+ T cell responses were evaluated by flow cytometry using the activation-induced markers assay (AIM).

Findings showed significant activation of the CD4+ T cell compartment, with a higher proportion of responders among PASC patients. Central memory (CM) T cells expressing pro-inflammatory cytokines were more prevalent in responders. Clinical correlations revealed higher SARS-CoV-2-specific T cell responses in patients with reduced diffuse lung capacity for carbon monoxide (DLCO) and residual symptoms.

These immune changes, especially in CM T cells, could play a pivotal role in PASC's development and persistence, impacting patients' daily lives.

It has been estimated that ∼4% of individuals infected with SARS-CoV-2 will be diagnosed with post-COVID condition. Previous studies have evidenced the presence of cognitive dysfunction and structural brain changes in infected individuals; however, the relationship between structural changes and cognitive alterations in post-COVID condition is still not clear. Consequently, the aim of this work is to study structural brain alterations in post-COVID condition patients after almost 2 years of infection and their likely relationship with patients' cognitive impairment. Additionally, the association with blood biomarkers and clinical variables was also explored. One hundred and twenty-eight individuals with post-COVID condition and 37 non-infected healthy controls from the Nautilus Project (ClinicalTrials.gov IDs: NCT05307549 and NCT05307575) underwent structural brain magnetic resonance imaging and a comprehensive neuropsychological assessment. A subsample of 66 post-COVID participants also underwent blood extraction to obtain levels of blood biomarkers. Cortical thickness and subcortical volumes were obtained and analysed using FreeSurfer (v7.1). FMRIB Software Library software (v6.0.4) was used to perform grey matter voxel-based analysis and to study microstructural white matter integrity. Patients with post-COVID performed significantly worse in working and verbal memory, processing speed, verbal fluency and executive functions, compared to healthy controls. Moreover, patients with post-COVID showed increased cortical thickness in the right superior frontal and the right rostral middle frontal gyri that negatively correlated with working memory performance. Diffusion tensor imaging data showed lower fractional anisotropy in patients in the right superior longitudinal fasciculus, the splenium and genu of the corpus callosum, the right uncinate fasciculus and the forceps major, that negatively correlated with subjective memory failures. No differences in blood biomarkers were found. Once patients were classified according to their cognitive status, post-COVID clinically cognitively altered presented increased cortical thickness compared to those classified as non-cognitively altered. In conclusion, our study showed that grey and white matter brain changes are relevant in this condition after almost 2 years of infection and partly explain long-term cognitive sequelae. These findings underscore the critical importance of monitoring this at-risk population over time.

Background and Objectives: Long COVID as a condition typically manifests itself three months after the initial onset of SARS-CoV-2 infection, with symptoms persisting for a minimum of two months. The aim of the present research was to identify potential predictors of post-COVID-19 syndrome (long COVID-19) and to evaluate factors associated with the presence of post-COVID-19 interstitial lung disease and functional decline. Materials and Methods: 210 patients hospitalized for confirmed SARS-CoV-2 infections mild, moderate, severe, and critical form have been evaluated at 3, 6 and twelve months. Results: Among them only one has been with a suspicion of interstitial lung disease after one year, the rest had no change in the lung. No risk factor from the baseline/3-month or 6-month evaluations significantly influenced patients' status at 12 months. The longer the duration of hospitalization, the lower the FVC and DLCO were at 3 months, but the longer the duration of hospitalization, the higher the number of symptoms at 3 months and 6 months. In a multivariate linear regression analysis, the number of hospitalization days remained statistically significant only for the number of symptoms at 3 months and 6 months. Conclusions: Long COVID seems to be related to the severity of the initial disease, and among the most persistent. Post-COVID-19 interstitial lung disease does not seem to be a frequent entity, as in our study only 0.5% out of 210 patients had it.

In the years following the global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or COVID-19, researchers have become acutely aware of long-term symptomology associated with this disease, often termed long COVID. Long COVID is associated with pervasive symptoms affecting multiple organ systems. Neurocognitive symptoms are reported by up to 40% of long COVID patients, with resultant effects of loss of daily functioning, employment issues, and enormous economic impact and high healthcare utilization. The literature on effective, safe, and non-invasive interventions for the remediation of the cognitive consequences of long COVID is scarce and poorly described. Of specific interest to this narrative review is the identification of potential interventions for long COVID-associated neurocognitive deficits. Articles were sourced from PubMed, EBSCO, Scopus, and Embase following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles published between the dates of January 2020 and 30 June 2024 were included in the search. Twelve studies were included in the narrative review, including a feasibility study, a pilot study, a case series, a case study, and an observational study, in addition to three randomized clinical trials and four interventional studies. Overall, treatment interventions such as cognitive training, non-invasive brain stimulation therapy, exercise rehabilitation, targeted pharmacological intervention, and other related treatment paradigms show promise in reducing long COVID cognitive issues. This narrative review highlights the need for more rigorous experimental designs and future studies are needed to fully evaluate treatment interventions for persistent cognitive deficits associated with long COVID.

The profile of gastrointestinal (GI) tract outcomes associated with the postacute and chronic phases of COVID-19 in children and adolescents remains unclear.

To investigate the risks of GI tract symptoms and disorders during the postacute (28-179 days after documented SARS-CoV-2 infection) and the chronic (180-729 days after documented SARS-CoV-2 infection) phases of COVID-19 in the pediatric population.

This retrospective cohort study was performed from March 1, 2020, to September 1, 2023, at 29 US health care institutions. Participants included pediatric patients 18 years or younger with at least 6 months of follow-up. Data analysis was conducted from November 1, 2023, to February 29, 2024.

Presence or absence of documented SARS-CoV-2 infection. Documented SARS-CoV-2 infection included positive results of polymerase chain reaction analysis, serological tests, or antigen tests for SARS-CoV-2 or diagnosis codes for COVID-19 and postacute sequelae of SARS-CoV-2.

GI tract symptoms and disorders were identified by diagnostic codes in the postacute and chronic phases following documented SARS-CoV-2 infection. The adjusted risk ratios (ARRs) and 95% CI were determined using a stratified Poisson regression model, with strata computed based on the propensity score.

The cohort consisted of 1 576 933 pediatric patients (mean [SD] age, 7.3 [5.7] years; 820 315 [52.0%] male). Of these, 413 455 patients had documented SARS-CoV-2 infection and 1 163 478 did not; 157 800 (13.6%) of those without documented SARS-CoV-2 infection had a complex chronic condition per the Pediatric Medical Complexity Algorithm. Patients with a documented SARS-CoV-2 infection had an increased risk of developing at least 1 GI tract symptom or disorder in both the postacute (8.64% vs 6.85%; ARR, 1.25; 95% CI, 1.24-1.27) and chronic (12.60% vs 9.47%; ARR, 1.28; 95% CI, 1.26-1.30) phases compared with patients without a documented infection. Specifically, the risk of abdominal pain was higher in COVID-19-positive patients during the postacute (2.54% vs 2.06%; ARR, 1.14; 95% CI, 1.11-1.17) and chronic (4.57% vs 3.40%; ARR, 1.24; 95% CI, 1.22-1.27) phases.

In this cohort study, the increased risk of GI tract symptoms and disorders was associated with the documented SARS-CoV-2 infection in children or adolescents during the postacute or chronic phase. Clinicians should note that lingering GI tract symptoms may be more common in children after documented SARS-CoV-2 infection than in those without documented infection.

The post-acute sequelae of COVID-19 (PASC) poses a significant health challenge in the post-pandemic world. However, the underlying biological mechanisms of PASC remain intricate and elusive. Network-based methods can leverage electronic health record data and biological knowledge to investigate the impact of COVID-19 on PASC and uncover the underlying biological mechanisms. This study analyzed territory-wide longitudinal electronic health records (from January 1, 2020 to August 31, 2022) of 50 296 COVID-19 patients and a healthy non-exposed group of 100 592 individuals to determine the impact of COVID-19 on disease progression, provide molecular insights, and identify associated biomarkers. We constructed a comorbidity network and performed disease-protein mapping and protein-protein interaction network analysis to reveal the impact of COVID-19 on disease trajectories. Results showed disparities in prevalent disease comorbidity patterns, with certain patterns exhibiting a more pronounced influence by COVID-19. Overlapping proteins elucidate the biological mechanisms of COVID-19's impact on each comorbidity pattern, and essential proteins can be identified based on their weights. Our findings can help clarify the biological mechanisms of COVID-19, discover intervention methods, and decode the molecular basis of comorbidity associations, while also yielding potential biomarkers and corresponding treatments for specific disease progression patterns.

COVID-19 symptoms may persist beyond acute SARS-CoV-2 infection, as ongoing symptomatic COVID-19 [OSC] (symptom duration 4-12 weeks) and post-COVID syndrome [PCS] (symptom duration ≥12 weeks). Vaccination against SARS-CoV-2 decreases OSC/PCS in individuals subsequently infected with SARS-CoV-2 post-vaccination. Whether vaccination against SARS-CoV-2, or any other vaccinations (such as against influenza) affects symptoms in individuals already experiencing OSC/PCS, more than natural symptom evolution, is unknown.

Using data from the ZOE COVID Symptom Study app, two comparative analyses were carried out, both in prospectively-reporting individuals with OSC/PCS: A) symptoms in individuals receiving first vaccination against SARS-CoV-2, compared with unvaccinated individuals, matched for age, sex, BMI and week of test (n=1679 in each group); B) symptoms in individuals receiving vaccination against influenza, compared with unvaccinated individuals, matched for age, sex, BMI, week of test and number of SARS-CoV-2 vaccinations (n=692 in each group). In both analyses, vaccination date (or equivalent time from start of symptoms in the unvaccinated group) was considered as the index time, and symptom evolution was measured by comparing symptoms during the second week before and second week after vaccination. Symptoms were considered by prevalence and burden over the considered periods; all results were adjusted for multiple comparisons.

After first vaccination against SARS-CoV-2, many symptoms in individuals with OSC/PCS improved more rapidly than natural history resolution, including the commonly reported symptoms of fatigue (p<0.0001, β=--0.9 [95% CI: -1.86; -0.67]) and myalgia (p<0.001, β=-0.3 [95% CI: -0.50; -0.12]). No symptom worsened after vaccination. In contrast, there was no improvement in OSC/PCS symptoms beyond natural history resolution after vaccination against influenza.

In individuals with OSC/PCS, symptom resolution improved after vaccination against SARS-CoV-2 ; this was not observed, however, after other vaccinations.

The global impact of coronavirus disease 2019 (COVID-19) marked by numerous pandemic peaks is attributed to its high variability and infectious nature, transforming it into a persistent global public health concern. With hundreds of millions of cases reported globally, the illness is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite its initial classification as an acute respiratory illness, recent evidence indicates that lingering effects on various bodily systems, such as cardiovascular, pulmonary, nervous, gastrointestinal (GI), and musculoskeletal, may endure well beyond the acute phase. These persistent manifestations following COVID-19, commonly known as long COVID, have the potential to affect individuals across the entire range of illness severity, with a tendency to be more prevalent in mild to moderate cases. At present, there are no established criteria for diagnosing long COVID. Nonetheless, it is conceptualized as a multi-organ disorder encompassing a diverse array of clinical manifestations. The most common, persistent, and debilitating symptoms of long COVID may be neurological, known as neurological complications of post-acute sequelae of COVID-19 (NC-PASC). More than one-third of individuals with a prior SARS-CoV-2 infection show involvement of both the central nervous system (CNS) and peripheral nervous system (PNS), as evidenced by an approximately threefold higher incidence of neurological symptoms in observational studies. The persistent neurological symptoms of long COVID encompass fatigue, headache, cognitive decline, "brain fog", dysautonomia, neuropsychiatric issues, loss of smell (anosmia), loss of taste (ageusia), and peripheral nerve problems (peripheral neuropathy). Reported pathogenic mechanisms encompass viral persistence and neuro-invasion by SARS-CoV-2, neuroinflammation, autoimmunity, coagulopathy, and endotheliopathy. Raising awareness of potential complications is crucial for preventing and alleviating the long-term effects of long COVID and enhancing the prognosis for affected patients. This review explores the hypothetical pathophysiological mechanisms and pathways of NC-PASC with a sole aim to increase awareness about this crippling disease.

Long COVID is a common complication of infection with severe acute respiratory syndrome coronavirus 2, but the prevalence and predictors of the condition remain poorly characterized.

We prospectively studied adults (≥18 years) with acute coronavirus disease 2019 (COVID-19) presenting to an urban safety net hospital and associated clinics between July 2020 and December 2022. Logistic regression models were used to evaluate the association between baseline demographic, clinical, and laboratory characteristics with long COVID status, defined as symptoms persisting at least 9 months after acute disease. Among unrecovered participants, we describe the prevalence of individual symptoms.

We enrolled 222 participants, 162 (73%) of whom had known recovery status by 9 months. Median age was 54 years, half (55%) were female, and the majority of participants (78%) had at least 1 comorbidity at the time of COVID-19 diagnosis. Based on acute illness characteristics, the adjusted odds ratio for long COVID was 3.0 (95% confidence interval [CI], 1.1-8.0) among those with detectable nucleocapsid antigen and 3.6 (95% CI, 1.2-11) for those who required supplemental oxygen. Of the 41% of participants with symptoms persisting at least 9 months, central nervous system and psychological symptoms were most commonly reported, with 57% reporting functional limitations due to their persistent symptoms.

The strong association with initial disease suggests a decreasing prevalence of long COVID as acute illnesses become milder. However, many contemporary patients still experience high viral burden with extended viral replication, even after vaccination. Our findings highlight the importance of properly characterizing long COVID as viral evolution shifts acute disease presentation.

There are estimated tens of millions of individuals throughout the world suffering from a variety of postinfectious sequela following infection with severe acute respiratory syndrome coronavirus 2 also commonly referred to as long coronavirus disease (COVID). Long COVID is providing an opportunity for the field of rheumatology to explore the relationship between similar syndromes including fibromyalgia seen in patients with underlying inflammatory and noninflammatory rheumatic diseases, as well as other postacute infectious sequela and bring our field's traditional skill sets to bear on improving our understanding of these disorders and the care of such patients.

The COVID-19 pandemic has resulted in a post-infectious syndrome designated as long-COVID or post-COVID condition (PCC) that presents with numerous symptoms including fatigue and myalgias. This study evaluated myopathic electromyography (EMG) findings in non-hospitalized PCC patients in relation to symptom severity, quality of life (QoL), and physical function.

Twenty-nine PCC patients with persistent symptoms ≥ 3 months after laboratory-confirmed SARS-CoV-2 infection, without hospitalization or comorbidities, were included. EMG, nerve conduction studies (NCS), and quantitative sensory testing (QST) were performed. Symptom severity was measured with visual analog scales, QoL with validated questionnaires, and physical function with the 6-min walk test, cardiopulmonary exercise testing, handgrip strength, and isokinetic dynamometry.

Myopathic findings on EMG were present in 62% of PCC patients (n = 18). Symptom severity (muscle pain and fatigue) and QoL (physical function and fatigue) were similar between patients with and without myopathic EMG findings. The 6-min walk test (457 ± 81 vs. 459 ± 86 m) and peak VO2 (29 ± 9 vs. 28 ± 6 mL/kg/min) were similar between patients with and without myopathic EMG findings. Handgrip strength (32 [29-43] vs. 33 [29-50] kg) and quadriceps muscle strength (136 [111-191] vs. 136 [114-184] Nm) were comparable between the groups. NCS and QST results were normal in all patients.

Myopathic findings on EMG are common in PCC patients, but no significant differences in symptom severity, QoL, or physical function were found between those with and without myopathic EMG findings. Myopathic EMG changes in PCC patients should be interpreted with caution, considering the overall clinical context.

Sleep disturbances in "long COVID" are common, but the associations between the severity of sleep problems and the severity of COVID infection are unclear. We evaluated the prevalence, persistence, comorbidities, and clinical effects of insomnia following recovery from acute COVID-19 infection in a COVID-specific clinic.

Inpatients discharged after COVID infection and outpatients referred for persistent post-COVID symptoms were surveyed on insomnia severity (Insomnia Severity Index), other neuropsychological symptoms, cardiopulmonary symptoms and physiological functions (6-minute walk distance and others), and functional outcome and quality of life. Multivariable regression models evaluated the severity of Insomnia Severity Index against independent variables.

A total of 280 patients met criteria at the initial visit. The prevalence of significant insomnia at the initial visit was 50% and 42% at the subsequent visit (obtained in 78 of the 280 patients). Lower age, female sex, non-White race, and non-Hispanic ethnicity were significantly associated with worse initial Insomnia Severity Index scores. More severe symptoms of anxiety and depression were strong correlates with worse Insomnia Severity Index scores. Interval improvements in insomnia severity correlated with improvements in anxiety and posttraumatic stress disorder scores. Physiological sequelae of infection did not correlate with insomnia at any stage.

Initial and persistent insomnia is common in long COVID. Treatment for insomnia with the use of evidence-based approaches (such as cognitive behavioral therapy for insomnia) may best suit this particular post-COVID symptom.

Kadl A, Davis EM, Oliver SF, et al. Prevalence and associations of insomnia after COVID-19 infection. J Clin Sleep Med. 2025;21(2):383-391.

Growing evidence suggests the neurobiological mechanism upholding post-COVID-19 depression mainly relates to immune response and subsequent unresolved low-grade inflammation. Herein we exploit a broad panel of cytokines serum levels measured in COVID-19 survivors at one- and three-month since infection to predict post-COVID-19 depression. 87 COVID survivors were screened for depressive symptomatology at one- and three-month after discharge through the Beck Depression Inventory (BDI-13) and the Zung Self-Rating Depression Scale (ZSDS) at San Raffaele Hospital. Blood samples were collected at both timepoints and analyzed through Luminex. We entered one-month 42 inflammatory compounds into two separate penalized logistic regression models to evaluate their reliability in identifying COVID-19 survivors suffering from clinical depression at the two timepoints, applied within a machine learning routine. Delta values of analytes lowering between timepoints were entered in a third model predicting presence long-term depression. 5000 bootstraps were computed to determine significance of predictors. The cross-sectional model reached a balance accuracy (BA) of 76 % and a sensitivity of 70 %. Post-COVID-19 depression was predicted by high levels of CCL17, CCL22. On the other hand, CXCL10, CCL2, CCL3, CCL8, CXCL5, CCL15, CCL23, CXCL13, and GM-CSF showed protective effects. The longitudinal model obtained good performance as well (BA = 74 % and sensitivity = 68 %), revealing CXCL16 and CCL25 as additional drivers of clinical depression. Moreover, dynamic changes of analytes over time accurately predicted long-term depression (BA = 76 % and sensitivity = 75 %). Our findings unveil a putative immune profile upholding post-COVID-19 depression, thus reinforcing the need to deepen molecular mechanisms to appropriately target depression.

Long COVID (also known as post-acute sequelae of SARS-CoV-2 infection [PASC] or post-COVID syndrome) is characterized by persistent symptoms that extend beyond the acute phase of SARS-CoV-2 infection, affecting approximately 10% to over 30% of those infected. It presents a significant clinical challenge, notably due to pronounced neurocognitive symptoms such as brain fog. The mechanisms underlying these effects are multifactorial, with mounting evidence pointing to a central role of cerebromicrovascular dysfunction. This review investigates key pathophysiological mechanisms contributing to cerebrovascular dysfunction in long COVID and their impacts on brain health. We discuss how endothelial tropism of SARS-CoV-2 and direct vascular infection trigger endothelial dysfunction, impaired neurovascular coupling, and blood-brain barrier disruption, resulting in compromised cerebral perfusion. Furthermore, the infection appears to induce mitochondrial dysfunction, enhancing oxidative stress and inflammation within cerebral endothelial cells. Autoantibody formation following infection also potentially exacerbates neurovascular injury, contributing to chronic vascular inflammation and ongoing blood-brain barrier compromise. These factors collectively contribute to the emergence of white matter hyperintensities, promote amyloid pathology, and may accelerate neurodegenerative processes, including Alzheimer's disease. This review also emphasizes the critical role of advanced imaging techniques in assessing cerebromicrovascular health and the need for targeted interventions to address these cerebrovascular complications. A deeper understanding of the cerebrovascular mechanisms of long COVID is essential to advance targeted treatments and mitigate its long-term neurocognitive consequences.

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), is increasingly recognized as a condition affecting not only adults but also children and adolescents. While children often experience milder acute COVID-19 symptoms compared to adults, some develop persistent physical, psychological, and neurological symptoms lasting for weeks or months after initial infection. The most commonly reported symptoms include debilitating fatigue, respiratory issues, headaches, muscle pain, gastrointestinal disturbances, and cognitive difficulties, which significantly impact daily activities, schooling, and social interactions. Additionally, many children with long COVID experience psychological symptoms, such as anxiety, depression, mood swings, and irritability, likely exacerbated by prolonged illness and lifestyle disruptions. Risk factors for long COVID in children include pre-existing health conditions such as asthma, obesity, and neurological disorders, with adolescents and females seemingly more affected. Hypothesized mechanisms underlying long COVID include chronic immune dysregulation, persistent viral particles stimulating inflammation, autonomic nervous system dysfunction, and mitochondrial impairment, which may collectively contribute to the variety of observed symptoms. Long-term outcomes remain uncertain; however, long COVID can lead to school absenteeism, social withdrawal, and psychological distress, potentially affecting cognitive development. Severe cases may develop chronic conditions such as postural orthostatic tachycardia syndrome (POTS) and reduced exercise tolerance. This review synthesizes the existing literature on long COVID in children, examining its prevalence, symptomatology, risk factors, and potential mechanisms, with an emphasis on the need for further clinical studies. While existing research largely relies on surveys and self-reported data, clinical assessments are essential to accurately characterize long COVID in pediatric populations and to guide effective management strategies.

Intravenous immunoglobulin (IVIG) is an immunomodulatory therapy that has been studied in several neuroimmune conditions, such as Guillain-Barré Syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and multiple sclerosis. It has also been proposed as a potential treatment option for acute COVID-19 infection and post-acute sequelae of SARS-CoV-2 infection (PASC). IVIG is thought to function by providing the recipient with a pool of antibodies, which can, in turn, modulate immune responses through multiple mechanisms including neutralization of cytokines and autoantibodies, saturation of neonatal fragment crystallizable receptors, inhibition of complement activation, and regulation of T and B cell mediated inflammation. In acute COVID-19, studies have shown that early administration of IVIG and plasmapheresis in severe cases can reduce the need for mechanical ventilation, shorten ICU and hospital stays, and lower mortality. Similarly, in PASC, while research is still in early stages, IVIG has been shown to alleviate persistent symptoms in small patient cohorts. Furthermore, IVIG has shown benefits in another condition which has symptomatic overlap with PASC, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), though studies have yielded mixed results. It is important to note that IVIG can be associated with several potential adverse effects, such as anaphylaxis, headaches, thrombosis, liver enzyme elevations and renal complications. In addition, the high cost of IVIG can be a deterrent for payers and patients. This review provides a comprehensive update on the use of IVIG in multiple neuroimmune conditions, ME/CFS, acute COVID-19, and PASC, as well as covers its history, production, pricing, and mechanisms of action. We also identify key areas of future research, including the need to optimize the use of Ig product dosing, timing, and patient selection across conditions, particularly in the context of COVID-19 and PASC.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with systemic inflammation and vascular injury, which contribute to the development of acute respiratory syndrome (ARDS) and the mortality of COVID-19 infection. Moreover, multiorgan complications due to persistent endothelial dysfunction have been suspected as the cause of post-acute sequelae of SARS-CoV-2 infection. Therefore, elucidation of the vascular inflammatory effect of SARS-CoV-2 will increase our understanding of how endothelial cells (ECs) contribute to the short- and long-term consequences of SARS-CoV-2 infection. Here, we investigated the interaction of SARS-CoV-2 spike protein with human ECs from aortic (HAoEC) and pulmonary microvascular (HPMC) origins, cultured under physiological flow conditions. We showed that the SARS-CoV-2 spike protein triggers prolonged expression of cell adhesion markers in both ECs, similar to the effect of TNF-α. SARS-CoV-2 spike treatment also led to the release of various cytokines and chemokines observed in severe COVID-19 patients. Moreover, increased binding of leucocytes to the endothelial surface and a procoagulant state of the endothelium were observed. Transcriptomic profiles of SARS-CoV-2 spike-activated HPMC and HAoEC showed prolonged upregulation of genes and pathways associated with responses to virus, cytokine-mediated signaling, pattern recognition, as well as complement and coagulation pathways. Our findings support experimental and clinical observations of the vascular consequences of SARS-CoV-2 infection and highlight the importance of EC protection as one of the strategies to mitigate the severe effects as well as the possible post-acute complications of COVID-19 disease.

Post-COVID-19 syndrome (PCS) is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-associated chronic condition characterized by long-term violations of physical and mental health. People with type 2 diabetes (T2D) are at high risk for severe COVID-19 and PCS.

The current study aimed to define the predictors of PCS development in people with T2D for further planning of preventive measures and improving patient outcomes.

The data were collected through the national survey targeting persons with T2D concerning the history of COVID-19 course and signs and symptoms that developed during or after COVID-19 and continued for more than 12 weeks and were not explained by an alternative diagnosis. In total, 469 patients from different regions of Ukraine were enrolled in the study. Among them, 227 patients reported PCS development (main group), while 242 patients did not claim PCS symptoms (comparison group). Stepwise multivariate logistic regression and probabilistic neural network (PNN) models were used to select independent risk factors.

Based on the survey data, 8 independent factors associated with the risk of PCS development in T2D patients were selected: newly diagnosed T2D (OR 4.86; 95% CI 2.55-9.28; p<0.001), female sex (OR 1.29; 95% CI 0.86-1.94; p=0.220), COVID-19 severity (OR 1.35 95% CI 1.05-1.70; p=0.018), myocardial infarction (OR 2.42 95% CI 1.26-4.64; p=0.002) and stroke (OR 3.68 95% CI 1.70-7.96; p=0.001) in anamnesis, HbA1c above 9.2% (OR 2.17 95% CI 1.37-3.43; p=0.001), and the use of insulin analogs (OR 2.28 95% CI 1.31-3.94; p=0.003) vs human insulin (OR 0.67 95% CI 0.39-1.15; p=0.146). Although obesity aggravated COVID-19 severity, it did not impact PCS development. In ROC analysis, the 8-factor multilayer perceptron (MLP) model exhibited better performance (AUC 0.808; 95% CІ 0.770-0.843), allowing the prediction of the risk of PCS development with a sensitivity of 71.4%, specificity of 76%, PPV of 73.6% and NPV of 73.9%.

Patients who were newly diagnosed with T2D, had HbA1c above 9.2%, had previous cardiovascular or cerebrovascular events, and had severe COVID-19 associated with mechanical lung ventilation were at high risk for PCS.

The World Health Organization declared the coronavirus disease 2019 (COVID-19) pandemic on March 11, 2020. Since then, researchers have been investigating the efficacy and side effects of its medication, up until now. From the viewpoint of Persian medicine, some medications such as antihistamines may cause retention of secretions and lead to exacerbation and spread of the disease in the body. There are studies with conflicting results regarding the effectiveness of antihistamines in COVID-19. Systematic reviews found a lack of data on beneficial effect of antihistamine-decongestant-analgesic combinations for the common cold and a limited short-term effect of antihistamines on severity of overall symptoms. This prospective cohort study was designed to investigate the relationship between the use of antihistamines and the severity of COVID-19 symptoms. Three hundred patients with a diagnosis of COVID-19 participated in the study in Shiraz, Iran from December 4, 2021 until January 24, 2022. The interviews were conducted via phone call by a single interviewer. Patients were followed weekly for 4 weeks. We collected information by using a data collection form, containing demographic information, underlying disease, COVID-19 symptoms, treatment methods, medications, and a list of antihistamines and herbs that might have been used. Generalized estimating equations were applied to assess the relationship between the severity of COVID-19 and the use of antihistamines, taking into account potential confounding factors such as time and herbal consumption. The difference in the severity of COVID-19 disease in antihistamine users compared to nonusers was not significant in 4 weeks despite the higher baseline severity in nonusers. The comparison of two groups of antihistamine users and nonusers showed that there was a significant difference (p = 0.001) regarding the use of herbal medicines.

Many publications have reported that acute COVID-19 infection can cause autonomic dysfunction. In this series, we described seven patients who had recurrent fever after acute COVID-19 infection, and the possible pathophysiological basis is autonomic dysfunction.

This was a retrospective study conducted at the Qilu Hospital of Shandong University from January 2023 to March 2023. Patients who were hospitalized in the Department of Infectious Diseases with a diagnosis of fever of unknown origin.

Between January and March 2023, a total of seven patients with autonomic dysfunction in post-COVID condition, who had recurrent fever accompanied by electrolyte imbalances and other manifestations of autonomic dysfunction. The median age of these patients was relatively high, and they were mostly indoor workers with comorbidities such as diabetes and chronic hypertension. Physical cooling and correction of electrolyte imbalances with medication were effective treatments.

The COVID-19 infection can lead to autonomic dysfunction, which manifests not only as tachycardia and blood pressure abnormalities, but may also be the pathophysiological mechanism underlying recurrent fever in post-COVID cases.

The SARS-CoV-2 pandemic has resulted in 762 million infections worldwide from 2020 to date, of which approximately ten percent are suffering from the effects after infection in 2019 (COVID-19) [1, 40]. In Germany, it is now assumed that at least one million people suffer from post-COVID condition with long-term consequences. These have been previously reported in diseases like Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS). Symptoms show a changing variability and recent surveys in the COVID context indicate that 10-30 % of outpatients, 50 to 70% of hospitalised patients suffer from sequelae. Recent data suggest that only 13% of all ill people were completely free of symptoms after recovery [3, 9]. Current hypotheses consider chronic inflammation, mitochondrial dysfunction, latent viral persistence, autoimmunity, changes of the human microbiome or multilocular sequelae in various organ system after infection. Hyperbaric oxygen therapy (HBOT) is applied since 1957 for heart surgery, scuba dive accidents, CO intoxication, air embolisms and infections with anaerobic pathogens. Under hyperbaric pressure, oxygen is physically dissolved in the blood in higher concentrations and reaches levels four times higher than under normobaric oxygen application. Moreover, the alternation of hyperoxia and normoxia induces a variety of processes at the cellular level, which improves oxygen supply in areas of locoregional hypoxia. Numerous target gene effects on new vessel formation, anti-inflammatory and anti-oedematous effects have been demonstrated [74]. The provision of intermittently high, local oxygen concentrations increases repair and regeneration processes and normalises the predominance of hyperinflammation. At present time only one prospective, randomized and placebo-controlled study exists with positive effects on global cognitive function, attention and executive function, psychiatric symptoms and pain interference. In conclusion, up to this date HBO is the only scientifically proven treatment in a prospective randomized controlled trial to be effective for cognitive improvement, regeneration of brain network and improvement of cardiac function. HBOT may have not only theoretical but also potential impact on targets of current pathophysiology of Post COVID condition, which warrants further scientific studies in patients.

Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency, marked by hypogammaglobulinemia, poor antibody responses, and increased infection susceptibility. The COVID-19 pandemic provided a unique opportunity to study the effects of prolonged viral infections on the immune responses of CVID patients. Here we use single-cell RNA-seq and spectral flow cytometry of peripheral blood samples before, during, and after SARS-CoV-2 infection showing that COVID-19 CVID patients display a persistent type I interferon signature at convalescence across immune compartments. Alterations in adaptive immunity include sustained activation of naïve B cells, increased CD21low B cells, impaired Th1 polarization, CD4+ T central memory exhaustion, and increased CD8+ T cell cytotoxicity. NK cell differentiation is defective, although cytotoxicity remains intact. Monocytes show persistent activation of inflammasome-related genes. These findings suggest the involvement of intact humoral immunity in regulating these processes and might indicate the need for early intervention to manage viral infections in CVID patients.

The physical performance and functional status of individuals with long COVID may be altered. Health resort treatment comprises balneology, exercises, physical medicine modalities, and climate therapy. Complex treatment in a sanatorium may have a positive effect on long COVID patients. This study assessed functional status, physical performance, and fatigue in people with long COVID that qualified for the health resort treatment and its efficacy in this group of patients.

A retrospective review of the medical records of 116 patients (66 women and 50 men) undergoing health resort treatment for long COVID in 2021 at the Rehabilitation Hospital and Sanatorium "Gwarek" in Goczałkowice-Zdrój (Poland) was conducted. Data were collected between March and May 2024. Their functional status, physical performance, and level of fatigue were assessed twice: before and after the treatment.

After the health resort treatment, their physical performance (10.41 points ± 1.84 points vs. 11.57 points ± 0.94 points; p < 0.00001) and functional status (2.13 points ± 0.88 points vs. 1.23 points ± 0.62 points; p < 0.00001) improved. Their fatigue (4.83 points ± 2.38 points vs. 2.15 points ± 1.31 points; p < 0.00001) level was diminished after the treatment.

Fatigue was of moderate intensity in the long COVID patients that qualified for the health resort treatment. Most of the long COVID patients reported mild functional limitations, whereas their physical performance was undisturbed. Health resort treatment improved functioning in patients with persistent COVID-19 symptoms by reducing fatigue, improving their functional capacity and physical performance. It should be recommended as a supplement to the standard treatment because of its complexity.

Post-COVID syndrome (PCS) is characterized by a polymorphism of symptoms with hypothetical pathophysiological mechanisms. Here, we aimed to analyze the profile of inflammatory cytokines in patients with PCS and to study the relationship between this profile, the clinical symptoms as well as the endothelial function in PCS.

Our analytical study involved all eligible patients (n = 66) with PCS included from April 2021 to December 2021. The serum concentration of cytokines IFN-γ, IL-1α, IL-1β, IL-6, IL-8, IL-10, IL-12p70, IL-27, IP-10, MCP-1 and TNF-α was quantified by flow cytometry. Endothelial function was explored by assessing microvascular flow and reactivity using thermal probes. A comparative study was carried out according to the presence of each PCS symptom.

The average age of our patients was 55.9 ± 16.2 years. The sex ratio was 0.69. Forty-one patients (62%) presented with a severe form of acute infection. The most frequently reported symptoms were dyspnea (67%), fatigue (50%), and memory problems (32%). Fifty-seven patients (86%) had endothelial dysfunction. The majority of patients had increased levels of IP-10 (100%), IL-8 (95%), IFN-γ (95%), MCP-1 (80%), and TNF-α (70%). The serum concentration of IL-10 was below the threshold of quantification in 89% of subjects. The severe form of acute infection was associated with elevated IL-10, MCP-1, and IL-27. Increased IL-6 and IL-27 levels were associated with fatigue while IL-8 concentrations were higher in patients who reported dyspnea. Elevation of IL-8 level was more common in patients with profound impairment of endothelial function.

Our results further support the presence of endothelial dysfunction in PCS and show an elevation of pro-inflammatory cytokines with a downmodulation of the IL-10- anti-inflammatory response. In addition, immuno-clinical phenotypes emerge, such as an inflammatory profile mediated by IL-6 and IL-27 in fatigue and IL-8 in dyspnea. The identification of immuno-clinical phenotypes would allow a better understanding of the pathophysiology of PCS symptoms.

The corona virus (SARS-CoV-2) pandemic and the resulting long-term neurological complications in patients, known as long COVID, have renewed interest in the correlation between viral infections and neurodegenerative brain disorders. While many viruses can reach the central nervous system (CNS) causing acute or chronic infections (such as herpes simplex virus 1, HSV-1), the lack of a clear mechanistic link between viruses and protein aggregation into amyloids, a characteristic of several neurodegenerative diseases, has rendered such a connection elusive. Recently, we showed that viruses can induce aggregation of purified amyloidogenic proteins via the direct physicochemical mechanism of heterogeneous nucleation (HEN). In the current study, we show that the incubation of HSV-1 and SARS-CoV-2 with human cerebrospinal fluid (CSF) leads to the amyloid aggregation of several proteins known to be involved in neurodegenerative diseases, such as APLP1 (amyloid β precursor like protein 1), ApoE, clusterin, α2-macroglobulin, PGK-1 (phosphoglycerate kinase 1), ceruloplasmin, nucleolin, 14-3-3, transthyretin, and vitronectin. Importantly, UV-inactivation of SARS-CoV-2 does not affect its ability to induce amyloid aggregation, as amyloid formation is dependent on viral surface catalysis via HEN and not its ability to replicate. Additionally, viral amyloid induction led to a dramatic drop in the soluble protein concentration in the CSF. Our results show that viruses can physically induce amyloid aggregation of proteins in human CSF and result in soluble protein depletion, thus providing a potential mechanism that may account for the association between persistent and latent/reactivating brain infections and neurodegenerative diseases.