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Objective: To summarize the prevalence of Long COVID symptoms among the general population reported in published articles from the pre-omicron SARS-CoV2 era. This narrative review examined 21 symptoms. Methods: A PubMed/manual search returned 114 articles on general Long COVID symptoms. Manuscripts were excluded if they were not research studies, did not report symptom prevalence, or used a pediatric population. Ninety-eight studies were selected for review and fifty-nine met the criteria for inclusion. The risk of bias was assessed with the Hoy critical appraisal tool. Results: After excluding studies with a high risk of bias, meta-analysis of prevalence for 21 symptom categories ranged from 2.6–28.7% in studies based on surveys to 0.3–7.1% in studies based on electronic health record data. Conclusions: Long COVID symptom studies are limited by the variability in study design and representation of the general population. Further research is needed to effectively cluster symptoms in meaningful ways that enable focused treatment.

Long COVID comprises persistent symptoms that extend beyond four weeks post-SARS-CoV-2 infection. The potential association between long COVID and the endorsement of COVID-19 conspiracy theories has not been explored, particularly in Arab countries, where high endorsement of these theories has been reported. This study aimed to explore the association between endorsing COVID-19 conspiracy theories and the prevalence of self-reported long COVID symptoms among adults in Jordan and Kuwait in addition to other Arab countries. The study employed a cross-sectional design using Computer-Assisted Web Interviewing (CAWI), conducted in Arabic. Recruitment utilized convenience-based snowball sampling via social media and the survey was distributed in July 2024. Long COVID manifestations were assessed across ten recognized symptoms, and belief in conspiracy theories was measured using a five-point Likert scale across five items. The final study sample comprised 755 respondents, the majority of whom self-reported a history of confirmed COVID-19 diagnosis at least once (n = 493, 65.2%). The results indicated a neutral average attitude towards COVID-19 conspiracy theories (mean score = 15.18 ± 4.64 out of 30.00). Participants with high COVID-19 conspiracy theories scores were more likely to report high (aOR = 6.85, p < 0.001) or middle long COVID symptoms (aOR = 2.82, p = 0.008) compared to those with lower scores. Additional predictors of higher long COVID reporting included female sex, lower household income, frequent COVID-19 infections, and hospitalizations. The study results revealed a significant correlation between the endorsement of COVID-19 conspiracy theories and a higher frequency and magnitude of long COVID symptom reporting. The findings also highlighted the influence of sociodemographic factors and COVID-19 infection history on long COVID reporting, which suggests that public health strategies should address these factors to mitigate long COVID challenges effectively.

Approximately 31% of patients previously infected with SARS-CoV-2 are living with symptoms of long COVID in the United States. Long COVID significantly reduces quality of life and increases morbidity and disability; however, treatment options are limited. Enhanced External Counterpulsation (EECP) is an FDA-approved, non-invasive treatment for the management of cardiovascular symptoms with a mechanism of action which stimulates pathways that induce endothelial homeostasis, improving microvascular function, inflammation, and immune regulation, thereby potentially targeting the underlying etiology of long COVID. We recently reported that EECP improved symptoms in 231 patients with long COVID. Previous studies assessing the effects of EECP for long COVID have lacked a control group. As such, this analysis is the first comparing outcomes in patients with long COVID undergoing EECP (n = 33) to a non-treated group (control, n = 33). The patients were matched for baseline characteristics, and all patients completed patient-reported outcome assessments, including PROMIS Fatigue, the Duke Activity Status Index (DASI), and the Rose Dyspnea Scale (RDS), two times within a specified time interval. When comparing the average change from baseline in both groups, the EECP-treated patients’ improvement was significantly greater than the improvement in the control group across all measured endpoints, including PROMIS Fatigue (−15.0 ± 8.9 vs. −2.8 ± 5.9, p < 0.001) and DASI (+17.8 (11.8, 26.8) vs. +1.8 (−3.5, 5.5), p < 0.001), and there was an improvement of ≥1 in the RDS class (75.8% vs. 33.3%, p < 0.001). This study’s limitations include the small sample size and lack of information regarding concurrent treatments or interventions in the non-treated group; however, these preliminary data support EECP as a potential low-risk treatment option for patients with long COVID.

Knowledge about the underlying causes of the individual occurrence of symptoms during acute COVID-19 disease and during the post-acute sequelae of COVID-19 is limited. In a German COVID-19 follow-up study, we assessed whether elevated antibody responses to herpesviruses were associated with symptom occurrence in acute COVID-19 disease (n = 96 participants) and during 20 months of follow-up (n = 62 participants). Serum samples were analyzed for their antibodies to herpes simplex virus (HSV)-1 and -2, Epstein–Barr virus (EBV), and Cytomegalovirus (CMV) using fluorescent bead-based multiplex serology. The association of herpesvirus antibodies with symptom occurrence (fatigue, fever, dyspnea, decrease in taste, concentration problems) was assessed using multivariate logistic regression models. High EBV antibody levels were significantly associated with a more than fourfold increased odds of experiencing fatigue during acute COVID-19 disease and during follow-up. High CMV antibody levels were significantly associated with a more than threefold increased odds of experiencing concentration problems and a decrease in taste during the follow-up. The HSV-1 and -2 antibody levels were not elevated in the individuals that experienced symptoms. In conclusion, our findings indicate that herpesvirus infections, specifically EBV and CMV infections, might play a role in symptom development during acute and post-acute COVID-19 disease. It remains to be elucidated whether the elevated EBV and CMV antibodies determined in our study are indicators of herpesvirus reactivation.

Background/Objectives: Survival prospects following SARS-CoV-2 infection may extend beyond the acute phase, influenced by various factors including age, health conditions, and infection severity; however, this topic has not been studied in detail. Therefore, within this study, the mortality risk post-acute COVID-19 in the CRIT-COV-U cohort was investigated. Methods: Survival data from 651 patients that survived an acute phase of COVID-19 were retrieved and the association between urinary peptides and future death was assessed. Data spanning until December 2023 were collected from six countries, comparing mortality trends with age- and sex-matched COVID-19-negative controls. A death prediction classifier was developed and validated using pre-existing urinary peptidomic datasets. Results: Notably, 13.98% of post-COVID-19 patients succumbed during the follow-up, with mortality rates significantly higher than COVID-19-negative controls, particularly evident in younger individuals (

It is still unclear why certain individuals after viral infections continue to have severe symptoms. We investigated if predicting myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) development after contracting COVID-19 is possible by analyzing symptoms from the first two weeks of COVID-19 infection. Using participant responses to the 54-item DePaul Symptom Questionnaire, we built predictive models based on a random forest algorithm using the participants’ symptoms from the initial weeks of COVID-19 infection to predict if the participants would go on to meet the criteria for ME/CFS approximately 6 months later. Early symptoms, particularly those assessing post-exertional malaise, did predict the development of ME/CFS, reaching an accuracy of 94.6%. We then investigated a minimal set of eight symptom features that could accurately predict ME/CFS. The feature reduced models reached an accuracy of 93.5%. Our findings indicated that several IOM diagnostic criteria for ME/CFS occurring during the initial weeks after COVID-19 infection predicted Long COVID and the diagnosis of ME/CFS after 6 months.

The recent global COVID-19 pandemic has had a profound and enduring impact, resulting in substantial loss of life. The scientific community has responded unprecedentedly by investigating various aspects of the crisis, particularly focusing on the acute phase of COVID-19. The roles of the viral load, cytokines, and chemokines during the acute phase and in the context of patients who experienced enduring symptoms upon infection, so called Post-Acute Sequelae of COVID-19 or PASC, have been studied extensively. Here, in this review, we offer a virologist’s perspective on PASC, highlighting the dynamics of SARS-CoV-2 viral loads, cytokines, and chemokines in different organs of patients across the full clinical spectrum of acute-phase disease. We underline that the probability of severe or critical disease progression correlates with increased viral load levels detected in the upper respiratory tract (URT), lower respiratory tract (LRT), and plasma. Acute-phase viremia is a clear, although not unambiguous, predictor of PASC development. Moreover, both the quantity and diversity of functions of cytokines and chemokines increase with acute-phase disease severity. Specific cytokines remain or become elevated in the PASC phase, although the driving factor of ongoing inflammation found in patients with PASC remains to be investigated. The key findings highlighted in this review contribute to a further understanding of PASC and their differences and overlap with acute disease.

(1) Background: Data on persisting symptoms after SARS-CoV-2 infection in children and adolescents are conflicting. Due to the absence of a clear pathophysiological correlate and a definitive diagnostic test, the diagnosis of Long COVID currently rests on consensus definitions only. This review aims to summarise the evidence regarding Long COVID in children and adolescents, incorporating the latest studies on this topic. (2) Methods: We designed a comprehensive search strategy to capture all relevant publications using Medline via the PubMed interface, with the initial literature search conducted in April 2023. To be included, publications had to present original data and include >50 participants with Long COVID symptoms aged between 0 and18 years. (3) Results: A total of 51 studies met the inclusion criteria, with most studies originating from Europe (n = 34; 66.7%), followed by the Americas (n = 8; 15.7%) and Asia (n = 7; 13.7%). Various study designs were employed, including retrospective, cross-sectional, prospective, or ambispective approaches. Study sizes varied significantly, with 18/51 studies having fewer than 500 participants. Many studies had methodological limitations: 23/51 (45.1%) studies did not include a control group without prior COVID-19 infection. Additionally, a considerable number of papers (33/51; 64.7%) did not include a clear definition of Long COVID. Other limitations included the lack of PCR- or serology-based confirmation of SARS-CoV-2 infection in the study group. Across different studies, there was high variability in the reported prevalence of Long COVID symptoms, ranging from 0.3% to 66.5%, with the majority of studies included in this review reporting prevalences of approximately 10–30%. Notably, the two studies with the highest prevalences also reported very high prevalences of Long COVID symptoms in the control group. There was a relatively consistent trend for Long COVID prevalence to decline substantially over time. The prevalence of Long COVID appeared to differ across different paediatric age groups, with teenagers being more commonly affected than younger children. Furthermore, data suggest that children and adolescents are less commonly affected by Long COVID compared to adults. In children and adolescents, Long COVID is associated with a very broad range of symptoms and signs affecting almost every organ system, with the respiratory, cardiovascular, and neuropsychiatric systems being most commonly affected. (4) Conclusions: The heterogeneity and limitations of published studies on Long COVID in children and adolescents complicate the interpretation of the existing data. Future studies should be rigorously designed to address unanswered questions regarding this complex disease.

This review investigates links between post-acute sequelae of SARS-CoV-2 infection (PASC), post-infection viral persistence, mitochondrial involvement and aberrant innate immune response and cellular metabolism during SARS-CoV-2 infection. Advancement of proteomic and metabolomic studies now allows deeper investigation of alterations to cellular metabolism, autophagic processes and mitochondrial dysfunction caused by SARS-CoV-2 infection, while computational biology and machine learning have advanced methodologies of predicting virus–host gene and protein interactions. Particular focus is given to the interaction between viral genes and proteins with mitochondrial function and that of the innate immune system. Finally, the authors hypothesise that viral persistence may be a function of mitochondrial involvement in the sequestration of viral genetic material. While further work is necessary to understand the mechanisms definitively, a number of studies now point to the resolution of questions regarding the pathogenesis of PASC.

Long COVID (post-acute sequelae of COVID-19—PASC) is a consequence of infection by SARS-CoV-2 that continues to disrupt the well-being of millions of affected individuals for many months beyond their first infection. While the exact mechanisms underlying PASC remain to be defined, hypotheses regarding the pathogenesis of long COVID are varied and include (but are not limited to) dysregulated local or systemic inflammatory responses, autoimmune mechanisms, viral-induced hormonal imbalances, skeletal muscle abnormalities, complement dysregulation, novel abzymes, and long-term persistence of virus and/or fragments of viral RNA or proteins. This review article is based on a comprehensive review of the wide range of symptoms most often observed in long COVID and an attempt to integrate that information into a plausible hypothesis for the pathogenesis of PASC. In particular, it is proposed that long-term dysregulation of the gut in response to viral persistence could lead to the myriad of symptoms observed in PASC.

There is limited long-term evidence on the effects of COVID-19 on vascular injury between male and female sex. An adult cohort of COVID-19 survivors (COVID+) and confirmed SARS-CoV-2 antibody-negative participants (COVID-) were prospectively enrolled. COVID+ participants who have documented the presence of persistent symptoms four weeks following infection were considered to have post-acute sequelae of COVID-19 (PASC). Non-invasive, FDA-approved EndoPAT (Endo-PAT2000) was used for endothelial assessment. COVID-(n = 94) were 1:1 propensity score matched to COVID+ (n = 151) on baseline covariates including sex. Among COVID+, 66.2% (n = 100) had PASC. Higher levels of coagulation marker, D-dimer (p = 0.001), and gut permeability marker, zonulin (p = 0.001), were associated with female sex. Estimated differences in augmentation index (AI) between COVID− (0.9 ± 17.2) and COVID+ (8.4 ± 15.7; p = 0.001) and between female and male sex (12.9 ± 1.9; p < .0001) were observed. Among COVID+ with PASC, the average AI (10.5 ± 1.6) was 9.7 units higher than COVID− (p < .0001) and 6.2 units higher compared to COVID+ with no PASC (p = 0.03). COVID+ PASC+ female sex had the highest AI (14.3 ± 1.9). The effects of SARS-CoV-2 infection on vascular function varies across strata of sex and female sex in the post-acute phase of COVID-19 have the worse arterial elasticity (highest AI).

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant health concern, particularly for patients with chronic kidney disease (CKD). This study investigates the long-term outcomes of individuals with CKD who were infected with COVID-19, focusing on their health status over a three-year period post-infection. Data were collected from both CKD and non-CKD patients who survived SARS-CoV-2 infection and were followed for three years as part of a research study on the impact, prognosis, and consequences of COVID-19 infection in CKD patients. In this prospective cohort study, we analyzed clinical records, laboratory findings, and patient-reported outcomes assessed at intervals during follow-up. The results indicated no permanent changes in renal function in any of the groups analyzed, although patients without CKD exhibited faster recovery over time. Furthermore, we examined the effect of RAAS-blocker therapy over time, finding no influence on PASC symptoms or renal function recovery. Regarding PASC symptoms, most patients recovered within a short period, but some required prolonged follow-up and specialized post-recovery management. Following up with patients in the post-COVID-19 period is crucial, as there is still insufficient information and evidence regarding the long-term effects, particularly in relation to CKD.

Long COVID (LC), also referred to as Post COVID-19 Condition, Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), and other terms, represents a complex multisystem disease persisting after the acute phase of COVID-19. Characterized by a myriad of symptoms across different organ systems, LC presents significant diagnostic and management challenges. Central to the disorder is the role of low-grade inflammation, a non-classical inflammatory response that contributes to the chronicity and diversity of symptoms observed. This review explores the pathophysiological underpinnings of LC, emphasizing the importance of low-grade inflammation as a core component. By delineating the pathogenetic relationships and clinical manifestations of LC, this article highlights the necessity for an integrated approach that employs both personalized medicine and standardized protocols aimed at mitigating long-term consequences. The insights gained not only enhance our understanding of LC but also inform the development of therapeutic strategies that could be applicable to other chronic conditions with similar pathophysiological features.

The infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated not only with the development of acute disease but also with long-term symptoms or post-acute sequelae of SARS-CoV-2 (PASC). Multiple lines of evidence support that some viral antigens and RNA can persist for up to 15 months in multiple organs in the body, often after apparent clearance from the upper respiratory system, possibly leading to the persistence of symptoms. Activation of the immune system to viral antigens is observed for a prolonged time, providing indirect evidence of the persistence of viral elements after acute infection. In the gastrointestinal tract, the persistence of some antigens could stimulate the immune system, shaping the local microbiota with potential systemic effects. All of these interactions need to be investigated, taking into account predisposing factors, multiplicity of pathogenic mechanisms, and stratifying populations of vulnerable individuals, particularly women, children, and immunocompromised individuals, where SARS-CoV-2 may present additional challenges.

Background: Coronavirus disease 2019 (COVID-19) can lead to persistent and debilitating symptoms referred to as Post-Acute sequelae of SARS-CoV-2 infection (PASC) This broad symptomatology lasts for months after the acute infection and impacts physical and mental health and everyday functioning. In the present study, we aimed to evaluate the prevalence and predictors of long-term impairment of working ability in non-elderly people hospitalised for COVID-19. Methods: This cross-sectional study involved 322 subjects hospitalised for COVID-19 from 1 March 2020 to 31 December 2022 in the University Hospital of Bari, Apulia, Italy, enrolled at the time of their hospital discharge and followed-up at a median of 731 days since hospitalization (IQR 466–884). Subjects reporting comparable working ability and those reporting impaired working ability were compared using the Mann-Whitney test (continuous data) and Fisher’s test or Chi-Square test (categorical data). Multivariable analysis of impaired working ability was performed using a logistic regression model. Results: Among the 322 subjects who were interviewed, 184 reported comparable working ability (57.1%) and 134 reported impaired working ability (41.6%) compared to the pre-COVID-19 period. Multivariable analysis identified age at hospital admission (OR 1.02, 95% CI 0.99 to 1.04), female sex (OR 1.90, 95% CI 1.18 to 3.08), diabetes (OR 3.73, 95% CI 1.57 to 9.65), receiving oxygen during hospital stay (OR 1.76, 95% CI 1.01 to 3.06), and severe disease (OR 0.51, 95% CI 0.26 to 1.01) as independent predictors of long-term impaired working ability after being hospitalised for COVID-19. Conclusions: Our findings suggest that PASC promotes conditions that could result in decreased working ability and unemployment. These results highlight the significant impact of this syndrome on public health and the global economy, and the need to develop clinical pathways and guidelines for long-term care with specific focus on working impairment.

Background: The effect of COVID-19 infection versus the indirect effect of the pandemic on body composition remains unclear. This study investigates the long-term changes in body composition in COVID-19 survivors compared to a contemporary control group. Method: This is a prospective study involving adults who underwent a pre-pandemic whole-body DXA scan (DXA#1) between 2017 and 2019. Participants were asked to return for a repeat whole-body DXA scan (DXA#2) after the pandemic. Detailed data were collected including their medical and COVID-19 history. Inflammation markers and fasting lipids were measured. For those participants who experienced a COVID-19 infection between the two DXAs, DXA#2 was acquired at least one year after COVID-19 infection. Results: Overall, 160 adults were enrolled; 32.5% females, 51.8% non-white, with mean age of 43.2 years. Half (n = 80) of the participants experienced a COVID-19 infection between their two DXA scans (COVID-19+ group), and the other half had never had COVID-19. COVID-19-negative participants displayed an increase in annualized trunk fat (g) [922.5 vs. 159.7; p = 0.01], total fat (g) [1564.3 vs. 199.9; p = 0.2], and LBM (g) [974.9 vs. −64.5; p = 0.0002] when compared to the COVID-19+ group. However, among the COVID-19+ group, no differences were seen in annualized trunk fat, total fat mass, or LBM between those with PASC and without (p > 0.05). Conclusion: During the pandemic, both the COVID-19 survivors and the COVID-19-negative group exhibited increases in weight, total fat, and trunk fat, likely associated with pandemic-linked lifestyle modifications. However, only COVID-19 survivors displayed a decline in lean body mass over the same period, regardless of PASC symptoms.

We completed a retrospective review of data collected by the JH-CROWN consortium based on ICD10 codes for a hospitalized cohort. The severity and prevalence of COVID-19 and development of PASC within heritable connective tissue diseases were unknown; however, clinical observation suggested a thorough examination was necessary. We compared rates of disease severity, death, and PASC in connective tissue diseases versus the entire cohort as well as in diabetes and hypertension to determine if connective tissue disease was a risk factor. Of the 15,676 patients in the database, 63 (0.40%) had a connective tissue disease, which is elevated relative to the distribution in the population, suggesting a higher risk of severe disease. Within these 63 patients, 9.52% developed PASC compared to 2.54% in the entire cohort (p < 0.005). Elucidation of populations at high risk for severe disease and development of PASC is integral to improving treatment approaches. Further, no other study to date has examined the risk in those with connective tissue diseases and these data support a need for enhanced awareness among physicians, patients, and the community.

Long COVID, also referred to as Post-Acute Sequelae of COVID (PASC), is probably triggered during SARS-CoV-2 infection and acute COVID-19 by SARS-CoV-2 Spike-protein binding and hyper-activating the cell-membrane expressed Receptor for Advance Glycation End-products (mRAGE) and Toll-Like Receptor 4 (TLR4). SARS-CoV-2 infects lung monocytes by Spike binding to mRAGE (not ACE2). During acute COVID-19, high levels of IL-6 hyper-stimulate S100A8/A9 expression and secretion. Although no viral protein nor mRNA can be detected in half of long COVID (PASC) patients, there is a significant elevation of serum levels of IL-1b, IL-6, TNFa, and S100A8/A9. It appears that a pathological pro-inflammatory feedback loop (the TLR4/RAGE-loop) is established during acute COVID-19, which is maintained by S100A8/A9 > RAGE/TLR4 chronic inflammatory signalling, even after SARS-CoV-2 has been cleared from the body. During long COVID/PASC, Ca2+-binding protein S100A8/A9 chronically stimulates TLR4/RAGE-signalling to induce chronic expression of IL-1b, IL-6 and TNFa. Secreted IL-6 binds to its IL-6R receptor on the surface of other cells and signals via STAT3 and C/EBPb for more S100A8/A9 expression. Secreted IL-1b binds to its receptor IL-1R on other cells, and signals via NFkB for more mRAGE and TLR4 expression. New S100A8/A9 can bind and activate cell-surface mRAGE and TLR4 to stimulate expression of more IL-1b, IL-6 and TNFa. This process establishes a pathogenic pro-inflammatory TLR4/RAGE-loop: IL-1b + IL-6 > IL-1R + IL-6R > TLR4/mRAGE + S100A8/A9 > IL-1b + IL-6, which generates multi-organ inflammation that persists in the blood vessels, the brain, the liver, the heart, the kidneys, the gut and the musculo-skeletal system, and is responsible for all the complex pathologies associated with long COVID/PASC. Chronic expression of IL-1, IL-6 and TNFa is critical for the maintenance of the TLR4/RAGE-loop and persistence of long COVID/PASC. Ezrin peptides are inhibitors of IL-1, IL-6, IL-8 and TNFa expression, so are now being investigated as potential therapy for long COVID/PASC. There is preliminary anecdotal evidence of symptomatic relief (not confirmed yet by formal clinical trials) from a few long COVID/PASC patient volunteers, after treatment with ezrin peptide therapy.

Background: Long COVID has become a central public health concern. This study characterized the effectiveness of BNT162b2 BA.4/5 bivalent COVID-19 vaccine (bivalent) against long COVID symptoms. Methods: Symptomatic US adult outpatients testing positive for SARS-CoV-2 were recruited between 2 March and 18 May 2023. Symptoms were assessed longitudinally using a CDC-based symptom questionnaire at Week 4, Month 3, and Month 6 following infection. The odds ratio (OR) of long COVID between vaccination groups was assessed by using mixed-effects logistic models, adjusting for multiple covariates. Results: At Week 4, among 505 participants, 260 (51%) were vaccinated with bivalent and 245 (49%) were unvaccinated. Mean age was 46.3 years, 70.7% were female, 25.1% had ≥1 comorbidity, 43.0% prior infection, 23.0% reported Nirmatrelvir/Ritonavir use. At Month 6, the bivalent cohort had 41% lower risk of long COVID with ≥3 symptoms (OR: 0.59, 95% CI, 0.36–0.96, p = 0.034) and 37% lower risk of ≥2 symptoms (OR: 0.63, 95% CI, 0.41–0.96, p = 0.030). The bivalent cohort reported fewer and less durable symptoms throughout the six-month follow-up, driven by neurologic and general symptoms, especially fatigue. Conclusions: Compared with unvaccinated participants, participants vaccinated with the bivalent were associated with approximately 40% lower risk of long COVID and less symptom burden over the six-month study duration.

Patients suffering from chronic fatigue syndrome (CFS) or post-COVID syndrome (PCS) exhibit a reduced physiological performance capability. Impaired mitochondrial function and morphology may play a pivotal role. Thus, we aimed to measure the muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity and assess mitochondrial morphology in CFS and PCS patients in comparison to healthy controls (HCs). Mitochondrial OXPHOS capacity was measured in permeabilized muscle fibers using high-resolution respirometry. Mitochondrial morphology (subsarcolemmal/intermyofibrillar mitochondrial form/cristae/diameter/circumference/area) and content (number and proportion/cell) were assessed via electron microscopy. Analyses included differences in OXPHOS between HC, CFS, and PCS, whereas comparisons in morphology/content were made for CFS vs. PCS. OXPHOS capacity of complex I, which was reduced in PCS compared to HC. While the subsarcolemmal area, volume/cell, diameter, and perimeter were higher in PCS vs. CFS, no difference was observed for these variables in intermyofibrillar mitochondria. Both the intermyofibrillar and subsarcolemmal cristae integrity was higher in PCS compared to CFS. Both CFS and PCS exhibit increased fatigue and impaired mitochondrial function, but the progressed pathological morphological changes in CFS suggest structural changes due to prolonged inactivity or unknown molecular causes. Instead, the significantly lower complex I activity in PCS suggests probably direct virus-induced alterations.

The post-acute sequelae of COVID-19 (PASC) is a complex condition. While there are emerging studies on its effects in adults, there is scarce research regarding the long-term effects of COVID-19 infection among youth. Several researchers have likened long-haul COVID-19 to chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and postural orthostatic tachycardia syndrome (POTS). In adults, the prognosis for these diagnoses is less promising than that in youth; however, there is currently very little information available on the presentation of youth with PASC. A better understanding of the specific symptom presentation for youth diagnosed with PASC is necessary. Retrospective chart reviews were conducted collecting demographic data, COVID-19 symptoms and disease progression, and vaccination status. Additional data on referrals to a PASC treatment program and appointments attended were collected. Overall, data suggested that youth present with less severe PASC symptoms than adults, and the role of vaccination is unclear. These youth are often not referred to treatment programs. More exploration is necessary to continue to build an understanding of how best to aid youth diagnosed with PASC.

Background/objectives: Survival prospects following SARS-CoV-2 infection may extend beyond the acute phase, influenced by various factors including age, health conditions, and infection severity; however, this topic has not been studied in detail. Therefore, within this study, the mortality risk post-acute COVID-19 in the CRIT-COV-U cohort was investigated., Methods: Survival data from 651 patients that survived an acute phase of COVID-19 were retrieved and the association between urinary peptides and future death was assessed. Data spanning until December 2023 were collected from six countries, comparing mortality trends with age- and sex-matched COVID-19-negative controls. A death prediction classifier was developed and validated using pre-existing urinary peptidomic datasets., Results: Notably, 13.98% of post-COVID-19 patients succumbed during the follow-up, with mortality rates significantly higher than COVID-19-negative controls, particularly evident in younger individuals (<65 years). These data for the first time demonstrate that SARS-CoV-2 infection highly significantly increases the risk of mortality not only during the acute phase of the disease but also beyond for a period of about one year. In our study, we were further able to identify 201 urinary peptides linked to mortality. These peptides are fragments of albumin, alpha-2-HS-glycoprotein, apolipoprotein A-I, beta-2-microglobulin, CD99 antigen, various collagens, fibrinogen alpha, polymeric immunoglobulin receptor, sodium/potassium-transporting ATPase, and uromodulin and were integrated these into a predictive classifier (DP201). Higher DP201 scores, alongside age and BMI, significantly predicted death., Conclusions: The peptide-based classifier demonstrated significant predictive value for mortality in post-acute COVID-19 patients, highlighting the utility of urinary peptides in prognosticating post-acute COVID-19 mortality, offering insights for targeted interventions. By utilizing these defined biomarkers in the clinic, risk stratification, monitoring, and personalized interventions can be significantly improved. Our data also suggest that mortality should be considered as one possible symptom or a consequence of post-acute sequelae of SARS-CoV-2 infection, a fact that is currently overlooked.

Persistent or recurrent cardiovascular symptoms have been identified as one of the hallmarks of long-COVID or post-acute sequelae of SARS-CoV-2 infection (PASC). The purpose of this study was to determine the prevalence and extent of cardiac abnormalities in patients referred for cardiac MRI due to clinical evidence of PASC. To investigate this, two tertiary care hospitals identified all patients who were referred for cardiac MRI under the suspicion of PASC in a 2-year period and retrospectively included them in this study. Patients with previously known cardiac diseases were excluded. This resulted in a total cohort of 129 patients (63, 51% female; age 41 ± 16 years). The majority of patients (57%) showed normal cardiac results. No patient had active myocarditis or an acute myocardial infarction. However, 30% of patients had evidence of non-ischemic myocardial fibrosis, which exceeds the prevalence in the normal adult population and suggests that a possible history of myocarditis might explain persistent symptoms in the PASC setting.

The clinical manifestation study of post-acute sequelae of SARS-CoV-2 infection (PASC) has shown a lack of knowledge regarding its morphology and pathogenesis. The aim of this research was to investigate morphological manifestations of PASC in the myocardium. Materials and Methods: The study included 38 patients requiring endomyocardial biopsy (EMB) during the post-acute phase of coronavirus infection and a control group including patients requiring EMB prior to the SARS-CoV-2 pandemic. The patients’ clinical and laboratory data were analyzed. Histological examination and immunohistochemistry (IHC) of the myocardial tissue was conducted with antibodies to CD3, CD68, HLA-DR, MHC1, C1q, VP1 enteroviruses, spike protein SARS-CoV-2, Ang1, von Willebrand factor (VWF), and VEGF. The morphometric analysis included counting the mean number of inflammatory infiltrate cells per mm2 and evaluating the expression of SARS-CoV-2 spike protein, HLA-DR, MHC1, C1q, Ang1, VWF, and VEGF using a scoring system. If the expression of SARS-CoV-2 spike protein was >3 points, an additional IHC test with antibodies to ACE2, CD16 as well as RT-PCR testing of the myocardial tissue were performed. For two patients, immunofluorescence tests of the myocardial tissue were performed using antibody cocktails to SARS-CoV-2 spike protein/CD16, SARS-CoV-2 spike protein/CD68, CD80/CD163. The statistical data analysis was carried out using the Python programming language and libraries such as NumPy, SciPy, Pandas, and Matplotlib. Results: The study demonstrated a significant increase in the number of CD68+ macrophages in the myocardium of PASC patients compared to patients who did not have a history of COVID-19 (p = 0.014 and p = 0.007 for patients with and without myocarditis, respectively), predominantly due to M2 macrophages. An increase in the number of CD68+ macrophages was more frequently observed in patients with shorter intervals between the most recent positive SARS-CoV-2 PCR test and the time of performing the EMB (r = −0.33 and r = −0.61 for patients with and without myocarditis, respectively). The expression scores of Ang1, VEGF, VWF, and C1q in PASC patients did not significantly differ from those in EMB samples taken before 2019. Conclusion: The myocardium of PASC patients demonstrated a significant increase in the number of CD68+ macrophages and a decrease in the expression of markers associated with angiopathy. No evidence of coronavirus-associated myocarditis was observed in any PASC patient.

Recent studies have strengthened the evidence for Epstein–Barr Virus (EBV) as an important contributing factor in the development of multiple sclerosis (MS). Chronic inflammation is a key feature of MS. EBV+ B cells can express cytokines and exosomes that promote inflammation, and EBV is known to be reactivated through the upregulation of cellular inflammasomes. Inflammation is a possible cause of the breakdown of the blood–brain barrier (BBB), which allows the infiltration of lymphocytes into the central nervous system. Once resident, EBV+ or EBV-specific B cells could both plausibly exacerbate MS plaques through continued inflammatory processes, EBV reactivation, T cell exhaustion, and/or molecular mimicry. Another virus, SARS-CoV-2, the cause of COVID-19, is known to elicit a strong inflammatory response in infected and immune cells. COVID-19 is also associated with EBV reactivation, particularly in severely ill patients. Following viral clearance, continued inflammation may be a contributor to post-acute sequelae of COVID-19 infection (PASC). Evidence of aberrant cytokine activation in patients with PASC supports this hypothesis. If unaddressed, long-term inflammation could put patients at risk for reactivation of EBV. Determining mechanisms by which viruses can cause inflammation and finding treatments for reducing that inflammation may help reduce the disease burden for patients suffering from PASC, MS, and EBV diseases.

The expansive and rapid spread of the SARS-CoV-2 virus has resulted in a global pandemic of COVID-19 infection and disease. Though initially perceived to be acute in nature, many patients report persistent and recurrent symptoms beyond the infectious period. Emerging as a new epidemic, “long-COVID”, or post-acute sequelae of coronavirus disease (PASC), has substantially altered the lives of millions of people globally. Symptoms of both COVID-19 and PASC are individual, but share commonality to established respiratory viruses, which include but are not limited to chest pain, shortness of breath, fatigue, along with adverse metabolic and pulmonary health effects. Nutrition plays a critical role in immune function and metabolic health and thus is implicated in reducing risk or severity of symptoms for both COVID-19 and PASC. However, despite the impact of nutrition on these key physiological functions related to COVID-19 and PASC, the precise role of nutrition in COVID-19 infection and PASC onset or severity remains to be elucidated. This narrative review will discuss established and emerging nutrition approaches that may play a role in COVID-19 and PASC, with references to the established nutrition and clinical practice guidelines that should remain the primary resources for patients and practitioners.

With a growing number of patients entering the recovery phase following infection with SARS-CoV-2, understanding the long-term neurological consequences of the disease is important to their care. The neurological complications of post-acute sequelae of SARS-CoV-2 infection (NC-PASC) represent a myriad of symptoms including headaches, brain fog, numbness/tingling, and other neurological symptoms that many people report long after their acute infection has resolved. Emerging reports are being published concerning COVID-19 and its chronic effects, yet limited knowledge of disease mechanisms has challenged therapeutic efforts. To address these issues, we review broadly the literature spanning 2020–2022 concerning the proposed mechanisms underlying NC-PASC, outline the long-term neurological sequelae associated with COVID-19, and discuss potential clinical interventions.

The recent global COVID-19 pandemic has had a profound and enduring impact, resulting in substantial loss of life. The scientific community has responded unprecedentedly by investigating various aspects of the crisis, particularly focusing on the acute phase of COVID-19. The roles of the viral load, cytokines, and chemokines during the acute phase and in the context of patients who experienced enduring symptoms upon infection, so called Post-Acute Sequelae of COVID-19 or PASC, have been studied extensively. Here, in this review, we offer a virologist's perspective on PASC, highlighting the dynamics of SARS-CoV-2 viral loads, cytokines, and chemokines in different organs of patients across the full clinical spectrum of acute-phase disease. We underline that the probability of severe or critical disease progression correlates with increased viral load levels detected in the upper respiratory tract (URT), lower respiratory tract (LRT), and plasma. Acute-phase viremia is a clear, although not unambiguous, predictor of PASC development. Moreover, both the quantity and diversity of functions of cytokines and chemokines increase with acute-phase disease severity. Specific cytokines remain or become elevated in the PASC phase, although the driving factor of ongoing inflammation found in patients with PASC remains to be investigated. The key findings highlighted in this review contribute to a further understanding of PASC and their differences and overlap with acute disease.

(1) Background: Data on persisting symptoms after SARS-CoV-2 infection in children and adolescents are conflicting. Due to the absence of a clear pathophysiological correlate and a definitive diagnostic test, the diagnosis of Long COVID currently rests on consensus definitions only. This review aims to summarise the evidence regarding Long COVID in children and adolescents, incorporating the latest studies on this topic. (2) Methods: We designed a comprehensive search strategy to capture all relevant publications using Medline via the PubMed interface, with the initial literature search conducted in April 2023. To be included, publications had to present original data and include >50 participants with Long COVID symptoms aged between 0 and18 years. (3) Results: A total of 51 studies met the inclusion criteria, with most studies originating from Europe (n = 34; 66.7%), followed by the Americas (n = 8; 15.7%) and Asia (n = 7; 13.7%). Various study designs were employed, including retrospective, cross-sectional, prospective, or ambispective approaches. Study sizes varied significantly, with 18/51 studies having fewer than 500 participants. Many studies had methodological limitations: 23/51 (45.1%) studies did not include a control group without prior COVID-19 infection. Additionally, a considerable number of papers (33/51; 64.7%) did not include a clear definition of Long COVID. Other limitations included the lack of PCR- or serology-based confirmation of SARS-CoV-2 infection in the study group. Across different studies, there was high variability in the reported prevalence of Long COVID symptoms, ranging from 0.3% to 66.5%, with the majority of studies included in this review reporting prevalences of approximately 10-30%. Notably, the two studies with the highest prevalences also reported very high prevalences of Long COVID symptoms in the control group. There was a relatively consistent trend for Long COVID prevalence to decline substantially over time. The prevalence of Long COVID appeared to differ across different paediatric age groups, with teenagers being more commonly affected than younger children. Furthermore, data suggest that children and adolescents are less commonly affected by Long COVID compared to adults. In children and adolescents, Long COVID is associated with a very broad range of symptoms and signs affecting almost every organ system, with the respiratory, cardiovascular, and neuropsychiatric systems being most commonly affected. (4) Conclusions: The heterogeneity and limitations of published studies on Long COVID in children and adolescents complicate the interpretation of the existing data. Future studies should be rigorously designed to address unanswered questions regarding this complex disease.

Background: Early in the pandemic, we established COVID-19 Recovery and Engagement (CORE) Clinics in the Bronx and implemented a detailed evaluation protocol to assess physical, emotional, and cognitive function, pulmonary function tests, and imaging for COVID-19 survivors. Here, we report our findings up to five months post-acute COVID-19. Methods: Main outcomes and measures included pulmonary function tests, imaging tests, and a battery of symptom, physical, emotional, and cognitive assessments 5 months post-acute COVID-19. Findings: Dyspnea, fatigue, decreased exercise tolerance, brain fog, and shortness of breath were the most common symptoms but there were generally no significant differences between hospitalized and non-hospitalized cohorts (p > 0.05). Many patients had abnormal physical, emotional, and cognitive scores, but most functioned independently; there were no significant differences between hospitalized and non-hospitalized cohorts (p > 0.05). Six-minute walk tests, lung ultrasound, and diaphragm excursion were abnormal but only in the hospitalized cohort. Pulmonary function tests showed moderately restrictive pulmonary function only in the hospitalized cohort but no obstructive pulmonary function. Newly detected major neurological events, microvascular disease, atrophy, and white-matter changes were rare, but lung opacity and fibrosis-like findings were common after acute COVID-19. Interpretation: Many COVID-19 survivors experienced moderately restrictive pulmonary function, and significant symptoms across the physical, emotional, and cognitive health domains. Newly detected brain imaging abnormalities were rare, but lung imaging abnormalities were common. This study provides insights into post-acute sequelae following SARS-CoV-2 infection in neurological and pulmonary systems which may be used to support at-risk patients and develop effective screening methods and interventions.

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant health concern, particularly for patients with chronic kidney disease (CKD). This study investigates the long-term outcomes of individuals with CKD who were infected with COVID-19, focusing on their health status over a three-year period post-infection. Data were collected from both CKD and non-CKD patients who survived SARS-CoV-2 infection and were followed for three years as part of a research study on the impact, prognosis, and consequences of COVID-19 infection in CKD patients. In this prospective cohort study, we analyzed clinical records, laboratory findings, and patient-reported outcomes assessed at intervals during follow-up. The results indicated no permanent changes in renal function in any of the groups analyzed, although patients without CKD exhibited faster recovery over time. Furthermore, we examined the effect of RAAS-blocker therapy over time, finding no influence on PASC symptoms or renal function recovery. Regarding PASC symptoms, most patients recovered within a short period, but some required prolonged follow-up and specialized post-recovery management. Following up with patients in the post-COVID-19 period is crucial, as there is still insufficient information and evidence regarding the long-term effects, particularly in relation to CKD.

The coronavirus disease 2019 (COVID-19) pandemic began in January 2020 in Wuhan, China, with a new coronavirus designated SARS-CoV-2. The principal cause of death from COVID-19 disease quickly emerged as acute respiratory distress syndrome (ARDS). A key ARDS pathogenic mechanism is the “Cytokine Storm”, which is a dramatic increase in inflammatory cytokines in the blood. In the last two years of the pandemic, a new pathology has emerged in some COVID-19 survivors, in which a variety of long-term symptoms occur, a condition called post-acute sequelae of COVID-19 (PASC) or “Long COVID”. Therefore, there is an urgent need to better understand the mechanisms of the virus. The spike protein on the surface of the virus is composed of joined S1–S2 subunits. Upon S1 binding to the ACE2 receptor on human cells, the S1 subunit is cleaved and the S2 subunit mediates the entry of the virus. The S1 protein is then released into the blood, which might be one of the pivotal triggers for the initiation and/or perpetuation of the cytokine storm. In this study, we tested the hypothesis that the S1 spike protein is sufficient to activate inflammatory signaling and cytokine production, independent of the virus. Our data support a possible role for the S1 spike protein in the activation of inflammatory signaling and cytokine production in human lung and intestinal epithelial cells in culture. These data support a potential role for the SARS-CoV-2 S1 spike protein in COVID-19 pathogenesis and PASC.

An increasing body of evidence in the literature is reporting the feasibility of using medical ozone as a possible alternative and adjuvant treatment for COVID-19 patients, significantly reducing hospitalization time, pro-inflammatory indicators, and coagulation markers and improving blood oxygenation parameters. In addition to the well-described ability of medical ozone in counteracting oxidative stress through the upregulation of the main anti-oxidant and scavenging enzymes, oxygen–ozone (O2–O3) therapy has also proved effective in reducing chronic inflammation and the occurrence of immune thrombosis, two key players involved in COVID-19 exacerbation and severity. As chronic inflammation and oxidative stress are also reported to be among the main drivers of the long sequelae of SARS-CoV2 infection, a rising number of studies is investigating the potential of O2–O3 therapy to reduce and/or prevent the wide range of post-COVID (or PASC)-related disorders. This narrative review aims to describe the molecular mechanisms through which medical ozone acts, to summarize the clinical evidence on the use of O2–O3 therapy as an alternative and adjuvant COVID-19 treatment, and to discuss the emerging potential of this approach in the context of PASC symptoms, thus offering new insights into effective and safe nonantiviral therapies for the fighting of this devastating pandemic.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystemic disease characterized by a complex, incompletely understood etiology. Methods: To facilitate future clinical and translational research, a multicenter German ME/CFS registry (MECFS-R) was established to collect comprehensive, longitudinal, clinical, epidemiological, and laboratory data from adults, adolescents, and children in a web-based multilayer-secured database. Results: Here, we present the research protocol and first results of a pilot cohort of 174 ME/CFS patients diagnosed at two specialized tertiary fatigue centers, including 130 (74.7%) adults (mean age 38.4; SD 12.6) and 43 (25.3%) pediatric patients (mean age 15.5; SD 4.2). A viral trigger was identified in 160/174 (92.0%) cases, with SARS-CoV-2 in almost half of them. Patients exhibited severe functional and social impairment, as reflected by a median Bell Score of 30.0 (IQR 30.0 to 40.0) and a poor health-related quality of life assessed with the Short Form-36 health survey, resulting in a mean score of 40.4 (SD 20.6) for physical function and 59.1 (SD 18.8) for mental health. Conclusions: The MECFS-R provides important clinical information on ME/CFS to research and healthcare institutions. Paired with a multicenter biobank, it facilitates research on pathogenesis, diagnostic markers, and treatment options. Trial registration: ClinicalTrials.gov NCT05778006.

The infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated not only with the development of acute disease but also with long-term symptoms or post-acute sequelae of SARS-CoV-2 (PASC). Multiple lines of evidence support that some viral antigens and RNA can persist for up to 15 months in multiple organs in the body, often after apparent clearance from the upper respiratory system, possibly leading to the persistence of symptoms. Activation of the immune system to viral antigens is observed for a prolonged time, providing indirect evidence of the persistence of viral elements after acute infection. In the gastrointestinal tract, the persistence of some antigens could stimulate the immune system, shaping the local microbiota with potential systemic effects. All of these interactions need to be investigated, taking into account predisposing factors, multiplicity of pathogenic mechanisms, and stratifying populations of vulnerable individuals, particularly women, children, and immunocompromised individuals, where SARS-CoV-2 may present additional challenges.

Post-acute sequelae of SARS-CoV-2 (PASC), or long COVID syndrome, is emerging as a major health issue in patients with previous SARS-CoV-2 infection. Symptoms commonly experienced by patients include fatigue, palpitations, chest pain, dyspnea, reduced exercise tolerance, and “brain fog”. Additionally, symptoms of orthostatic intolerance and syncope suggest the involvement of the autonomic nervous system. Signs of cardiovascular autonomic dysfunction appear to be common in PASC and are similar to those observed in postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. In this review, we report on the epidemiology of PASC, discuss current evidence and possible mechanisms underpinning the dysregulation of the autonomic nervous system, and suggest nonpharmacological and pharmacological interventions to treat and relieve symptoms of PASC-associated dysautonomia.

Purpose: This review summarizes the current scope of understanding associated with two common post-infectious complications associated with COVID-19 infection: Multi-System Inflammatory Syndrome in Children (MIS-C) and Post-Acute Sequelae of SARS-CoV-2 infection (PASC). It identifies current gaps in the knowledge and issues that may limit the ability to fill these gaps. This review provides a framework to drive continued research., Methods: A comprehensive review of the current literature was performed, identifying seminal articles describing the emergence of MIS-C and PASC, and works from the literature focused on the clinical implications and pathophysiologic understanding of these disorders., Findings: Although pediatric patients experienced few severe cases of acute COVID-19 infection, the burden of disease from post-infectious sequelae is substantial. Mortality is low, but morbidity is significant. There are still numerous unknowns about the pathophysiology of both MIS-C and PASC; however, with widespread immunity developing after increased vaccination and prior infection, it may be difficult to perform adequate prospective studies to answer pathophysiologic questions. Long-term sequalae of MIS-C seem to be minimal whereas, by definition, PASC is an ongoing problem and may be severe., Implications: The rapid sharing of information regarding novel conditions such as MIS-C and PASC are key to interventions related to future post-infectious sequelae outside of those stemming from COVID-19. Although MIS-C seems unlikely to return as a clinical condition in substantial numbers, there is still significant learning that can be gleaned from existing patients about general aspects of epidemiology, equity, and pathophysiology. There is significant morbidity associated with PASC and additional resources need to be dedicated to determining appropriate and effective therapies moving forward.

Background: Long COVID has become a central public health concern. This study characterized the effectiveness of BNT162b2 BA.4/5 bivalent COVID-19 vaccine (bivalent) against long COVID symptoms., Methods: Symptomatic US adult outpatients testing positive for SARS-CoV-2 were recruited between 2 March and 18 May 2023. Symptoms were assessed longitudinally using a CDC-based symptom questionnaire at Week 4, Month 3, and Month 6 following infection. The odds ratio (OR) of long COVID between vaccination groups was assessed by using mixed-effects logistic models, adjusting for multiple covariates., Results: At Week 4, among 505 participants, 260 (51%) were vaccinated with bivalent and 245 (49%) were unvaccinated. Mean age was 46.3 years, 70.7% were female, 25.1% had ≥1 comorbidity, 43.0% prior infection, 23.0% reported Nirmatrelvir/Ritonavir use. At Month 6, the bivalent cohort had 41% lower risk of long COVID with ≥3 symptoms (OR: 0.59, 95% CI, 0.36-0.96, p = 0.034) and 37% lower risk of ≥2 symptoms (OR: 0.63, 95% CI, 0.41-0.96, p = 0.030). The bivalent cohort reported fewer and less durable symptoms throughout the six-month follow-up, driven by neurologic and general symptoms, especially fatigue., Conclusions: Compared with unvaccinated participants, participants vaccinated with the bivalent were associated with approximately 40% lower risk of long COVID and less symptom burden over the six-month study duration.

The post-acute sequelae of COVID-19 (PASC) is a complex condition. While there are emerging studies on its effects in adults, there is scarce research regarding the long-term effects of COVID-19 infection among youth. Several researchers have likened long-haul COVID-19 to chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and postural orthostatic tachycardia syndrome (POTS). In adults, the prognosis for these diagnoses is less promising than that in youth; however, there is currently very little information available on the presentation of youth with PASC. A better understanding of the specific symptom presentation for youth diagnosed with PASC is necessary. Retrospective chart reviews were conducted collecting demographic data, COVID-19 symptoms and disease progression, and vaccination status. Additional data on referrals to a PASC treatment program and appointments attended were collected. Overall, data suggested that youth present with less severe PASC symptoms than adults, and the role of vaccination is unclear. These youth are often not referred to treatment programs. More exploration is necessary to continue to build an understanding of how best to aid youth diagnosed with PASC.

Despite the prevalence of dysautonomia in people with Long COVID, it is currently unknown whether Long COVID dysautonomia is routinely accompanied by structural or functional cardiac alterations. In this retrospective observational study, the presence of echocardiographic abnormalities was assessed. Left ventricular (LV) chamber sizes were correlated to diagnostic categories and symptoms via standardized patient-reported outcome (PRO) questionnaires. A total of 203 individuals with Long COVID without pre-existing cardiac disease and with available echocardiograms were included (mean age, 45 years; 67% female). Overall, symptoms and PRO scores for fatigue, breathlessness, quality of life, disability, anxiety and depression were not different between those classified with post-COVID dysautonomia (PCD, 22%) and those unclassified (78%). An LV internal diameter at an end-diastole z score < -2 was observed in 33 (16.5%) individuals, and stroke volume (SV) was lower in the PCD vs. unclassified subgroup (51.6 vs. 59.2 mL, 95% C.I. 47.1-56.1 vs. 56.2-62.3). LV end-diastolic volume (mean diff. (95% CI) -13 [-1--26] mL, p = 0.04) and SV (-10 [-1--20] mL, p = 0.03) were smaller in those individuals reporting a reduction in physical activity post-COVID-19 infection, and smaller LVMI was weakly correlated with worse fatigue (r = 0.23, p = 0.02). The majority of individuals with Long COVID report shared symptoms and did not demonstrate cardiac dysfunction on echocardiography.

The aims of this study were to analyze cytokine profiles in patients with COVID-19, gain insights into the immune response during acute infection, identify cytokines associated with disease severity and post-COVID complications, and explore potential biomarkers for prognosis and therapeutic targets. Using a multiplex analysis, we studied the cytokine pattern in 294 acute COVID-19 and post-COVID patients with varying severities of infection. Our findings revealed that disease severity was associated with elevated levels of IL-15, IL-8, and fractalkine. Severe/extremely severe forms in comparison with mild/moderate disease were associated with MCP-1, IFNa2, IL-7, IL-15, EGF, IP-10, IL-8, Eotaxin, FGF-2, GROa, sCD40L, and IL-10. The key cytokines of post-COVID are FGF-2, VEGF-A, EGF, IL-12(p70), IL-13, and IL-6. By the sixth month after recovering from a coronavirus infection, regardless of disease severity, some patients may develop complications such as arterial hypertension, type 2 diabetes mellitus, glucose intolerance, thyrotoxicosis, atherosclerosis, and rapid progression of previously diagnosed conditions. Each complication is characterized by distinct cytokine profiles. Importantly, these complications can also be predicted during the acute phase of the coronavirus infection. Understanding cytokine patterns can aid in predicting disease progression, identifying high-risk patients, and developing targeted interventions to improve the outcomes of COVID-19.

The clinical manifestation study of post-acute sequelae of SARS-CoV-2 infection (PASC) has shown a lack of knowledge regarding its morphology and pathogenesis. The aim of this research was to investigate morphological manifestations of PASC in the myocardium., Materials and Methods: The study included 38 patients requiring endomyocardial biopsy (EMB) during the post-acute phase of coronavirus infection and a control group including patients requiring EMB prior to the SARS-CoV-2 pandemic. The patients' clinical and laboratory data were analyzed. Histological examination and immunohistochemistry (IHC) of the myocardial tissue was conducted with antibodies to CD3, CD68, HLA-DR, MHC1, C1q, VP1 enteroviruses, spike protein SARS-CoV-2, Ang1, von Willebrand factor (VWF), and VEGF. The morphometric analysis included counting the mean number of inflammatory infiltrate cells per mm 2 and evaluating the expression of SARS-CoV-2 spike protein, HLA-DR, MHC1, C1q, Ang1, VWF, and VEGF using a scoring system. If the expression of SARS-CoV-2 spike protein was >3 points, an additional IHC test with antibodies to ACE2, CD16 as well as RT-PCR testing of the myocardial tissue were performed. For two patients, immunofluorescence tests of the myocardial tissue were performed using antibody cocktails to SARS-CoV-2 spike protein/CD16, SARS-CoV-2 spike protein/CD68, CD80/CD163. The statistical data analysis was carried out using the Python programming language and libraries such as NumPy, SciPy, Pandas, and Matplotlib., Results: The study demonstrated a significant increase in the number of CD68+ macrophages in the myocardium of PASC patients compared to patients who did not have a history of COVID-19 ( p = 0.014 and p = 0.007 for patients with and without myocarditis, respectively), predominantly due to M2 macrophages. An increase in the number of CD68+ macrophages was more frequently observed in patients with shorter intervals between the most recent positive SARS-CoV-2 PCR test and the time of performing the EMB (r = -0.33 and r = -0.61 for patients with and without myocarditis, respectively). The expression scores of Ang1, VEGF, VWF, and C1q in PASC patients did not significantly differ from those in EMB samples taken before 2019., Conclusion: The myocardium of PASC patients demonstrated a significant increase in the number of CD68+ macrophages and a decrease in the expression of markers associated with angiopathy. No evidence of coronavirus-associated myocarditis was observed in any PASC patient.

Persistent or recurrent cardiovascular symptoms have been identified as one of the hallmarks of long-COVID or post-acute sequelae of SARS-CoV-2 infection (PASC). The purpose of this study was to determine the prevalence and extent of cardiac abnormalities in patients referred for cardiac MRI due to clinical evidence of PASC. To investigate this, two tertiary care hospitals identified all patients who were referred for cardiac MRI under the suspicion of PASC in a 2-year period and retrospectively included them in this study. Patients with previously known cardiac diseases were excluded. This resulted in a total cohort of 129 patients (63, 51% female; age 41 ± 16 years). The majority of patients (57%) showed normal cardiac results. No patient had active myocarditis or an acute myocardial infarction. However, 30% of patients had evidence of non-ischemic myocardial fibrosis, which exceeds the prevalence in the normal adult population and suggests that a possible history of myocarditis might explain persistent symptoms in the PASC setting.

PAirwise Sequence Comparison (PASC) is a tool that uses genome sequence similarity to help with virus classification. The PASC tool at NCBI uses two methods: local alignment based on BLAST and global alignment based on Needleman-Wunsch algorithm. It works for complete genomes of viruses of several families/groups, and for the family of Filoviridae, it currently includes 52 complete genomes available in GenBank. It has been shown that BLAST-based alignment approach works better for filoviruses, and therefore is recommended for establishing taxon demarcation criteria. When more genome sequences with high divergence become available, these demarcations will most likely become more precise. The tool can compare new genome sequences of filoviruses with the ones already in the database, and propose their taxonomic classification.

With a growing number of patients entering the recovery phase following infection with SARS-CoV-2, understanding the long-term neurological consequences of the disease is important to their care. The neurological complications of post-acute sequelae of SARS-CoV-2 infection (NC-PASC) represent a myriad of symptoms including headaches, brain fog, numbness/tingling, and other neurological symptoms that many people report long after their acute infection has resolved. Emerging reports are being published concerning COVID-19 and its chronic effects, yet limited knowledge of disease mechanisms has challenged therapeutic efforts. To address these issues, we review broadly the literature spanning 2020-2022 concerning the proposed mechanisms underlying NC-PASC, outline the long-term neurological sequelae associated with COVID-19, and discuss potential clinical interventions.

Chronic olfactory dysfunction after SARS-CoV-2 infection occurs in approximately 10% of patients with COVID-19-induced anosmia, and it is a growing public health concern. A regimen of olfactory training and anti-neuroinflammatory therapy with co-ultramicronized palmitoylethanolamide with luteolin (um-PEA-LUT) has shown promising results in clinical trials; however, approximately 15% of treated patients do not achieve full recovery of a normal olfactory threshold, and almost 5% have no recovery. Disease-modifying therapies (DMTs), which are used to treat autoimmune neuroinflammation in multiple sclerosis (MS), have not been studied for treating persistent inflammation in refractory post-COVID-19 smell disorder. This study evaluated COVID-19-related smell loss and MS-related smell loss, comparing the responses to different therapies. Forty patients with MS and 45 reporting post-COVID-19 olfactory disorders were included in the study. All patients underwent nasal endoscopy and were evaluated by using validated Sniffin' Sticks testing. The patients with long COVID were treated for three months with um-PEA-LUT plus olfactory training. The patients with MS were treated with DMTs. Olfactory functions before and after treatment were analyzed in both groups. At the experimental endpoint, 13 patients in the COVID-19 group treated with um-PEA-LUT had residual olfactory impairment versus 10 patients in the MS group treated with DMTs. The severity of the persistent olfactory loss was lower in the MS group, and the patients with MS treated with IFN-beta and glatiramer acetate had the preservation of olfactory function. These data provide a rationale for considering prospective trials investigating the efficacy of DMTs for post-COVID-19 olfactory disorders that are refractory to um-PEA-LUT with olfactory training. This study is the first to consider the role of DMT in treating refractory post-viral olfactory loss in patients with long COVID.

The purpose of this article is to review the evidence of similar symptomatology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC). Reanalysis of data from a study by Jason comparing symptom reports from two groups of ME/CFS and PASC patients shows a notably similar symptomatology. Symptom scores of the PASC group and the ME/CFS group correlated 0.902 (p < 0.0001) across items. The hypothesis is presented that ME/CFS and PASC are caused by a chronic state of multisystemic disequilibrium including endocrinological, immunological, and/or metabolic changes. The hypothesis holds that a changed set point persistently pushes the organism towards a pathological dysfunctional state which fails to reset. To use an analogy of a thermostat, if the ‘off switch’ of a thermostat intermittently stops working, for periods the house would become warmer and warmer without limit. The hypothesis draws on recent investigations of the Central Homeostasis Network showing multiple interconnections between the autonomic system, central nervous system, and brain stem. The hypothesis helps to explain the shared symptomatology of ME/CFS and PASC and the unpredictable, intermittent, and fluctuating pattern of symptoms of ME/CFS and PASC. The current theoretical approach remains speculative and requires in-depth investigation before any definite conclusions can be drawn.

Post-acute sequelae of coronavirus disease 19 (COVID-19) (PASC) describe a wide range of symptoms and signs involving multiple organ systems occurring after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, representing a growing health problem also in the world of sport and the athletic population. Patients with PASC have new, returning, or persisting symptoms four or more weeks after the infection. Among the most frequent symptoms, patients complain of fatigue, dyspnea, exercise intolerance, and reduced functional capacity that interfere with everyday life activity. The role of exercise programs in PASC patients will be identified, and upcoming studies will establish the magnitude of their benefits. However, the benefits of exercise to counteract these symptoms are well known, and an improvement in cardiopulmonary fitness, functional status, deconditioning, and quality of life can be obtained in these patients, as demonstrated in similar settings. Based on this background, this review aims to summarise the current evidence about the PASC syndrome and the benefit of exercise in these patients and to provide a practical guide for the exercise prescription in PASC patients to help them to resume their functional status, exercise tolerance, prior activity levels, and quality of life, also considering the athletic population and their return to play and sports competitions.