Search Results (244)

Post-acute sequelae of SARS-CoV-2 infection (PASC), also referred to as Long COVID, affects millions worldwide and is characterized by persistent fatigue, reduced immune fitness, and mood disturbances. The aim of the current study was to identify if immune fitness, mood, fatigue, and quality of life prior to SARS-CoV-2 infection could predict PASC fatigue severity. A retrospective cross-sectional survey was conducted among 299 Dutch PASC patients. Participants completed validated measures of immune fitness, fatigue (assessed with both the Fatigue Severity Scale and a single-item scale), mood (including stress, anxiety, depression, hostility, loneliness, and happiness) and quality of life for the three months prior to SARS-CoV-2 infection. The same assessments were made for the month before survey completion (i.e., during PASC). Correlational and regression analyses were conducted to identify possible predictors of PASC fatigue severity. Participants were predominantly female (90%): mean age 44.1 (SD 11.2) years. Both assessments of PASC fatigue did not correlate significantly with the prior SARS-CoV-2 assessments of immune fitness, fatigue, mood, and quality of life. The regression analyses revealed no significant predictors for PASC fatigue severity. In conclusion, immune fitness, fatigue, mood and quality of life prior to SARS-CoV-2 infection were not identified as independent predictors of PASC fatigue severity. Full article

Long COVID (LC), also referred to as post-acute sequelae of SARS-CoV-2 infection, is characterized by persistent symptoms originating 3 months following acute COVID-19, lasting for at least two months and frequently affecting individuals who initially experienced mild to moderate disease. The clinical spectrum is heterogeneous, involving respiratory, cardiovascular, neurological, renal, gastrointestinal, and endocrine systems, thereby posing substantial diagnostic and therapeutic challenges. Despite extensive investigation, the precise immunopathogenic mechanisms underlying LC remain incompletely defined. Accumulating evidence suggests that LC is driven by a multifactorial interplay of persistent viral antigen reservoirs, chronic immune activation, dysregulated innate and adaptive immune responses, autoimmunity, endothelial dysfunction, microvascular injury, and aberrant tissue repair. These systemic immune perturbations manifest variably across different organs, contributing to the diverse clinical phenotypes observed. However, mechanistic clarity is hindered by heterogeneity in study designs, limited longitudinal data, and the absence of standardized immunological profiling. This narrative review provides integrative insights into the immunopathogenesis of LC, synthesizing current evidence on systemic immune dysregulation and organ-specific immunological mechanisms. A conceptual framework is proposed to facilitate a structured understanding of this complex syndrome and to guide future research toward targeted immunomodulatory strategies. Full article

Context/Objectives: In patients with COPD (chronic obstructive pulmonary disease), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection represents an overlap of viral injury on a lung already affected by pathological mucus, altered mucociliary clearance, chronic inflammation, and impaired antiviral immunity. Methods: A focused narrative review (2020–2025) was conducted using clinical, experimental, and consensus evidence. The evidence was synthesized qualitatively, with priority given to cohort studies, meta-analyses, and mechanism-focused studies with clinical relevance. Results: Mucus obstruction (“mucus plugs”) is frequent in COPD (41–67%) and is associated with unfavorable outcomes. COPD also increases the risk of post-COVID respiratory sequelae. Bacterial coinfection at presentation is uncommon (3–5%), whereas secondary bacterial infections are more frequent (14–18%), especially in severe disease requiring intensive care, where VA-LRTI/VAP (ventilator-associated lower respiratory tract infection/ventilator-associated pneumonia) become predominant. Sepsis, whether viral or mixed, reflects disease severity and may contribute to functional decline and susceptibility to reinfections; however, the concept of a post-acute “sepsis legacy” in COPD after COVID-19 should currently be regarded as a clinically plausible but still emerging hypothesis rather than an established COPD-specific outcome. During recovery, acute exacerbation risk rises to 5.6% versus 3.9%, peaking in the first 30 days after severe disease (aHR ≈ 8.14). Persistent dyspnea and reduced DLCO (diffusing capacity for carbon monoxide) suggest ARDS-related injury, tissue remodeling, and microvascular dysfunction. Conclusions: In COPD, post-COVID respiratory sequelae result from the interaction of mucus, immunity, and infectious/sepsis-related complications. The first post-discharge month is a critical period requiring careful risk stratification and targeted follow-up. Full article

Background: Long COVID presents a novel and emerging public health challenge. As the first point of contact, general practitioners (GPs) play a key role in diagnosing and coordinating the care of patients presenting with post-acute sequelae of COVID-19 (PASC), despite a lack of experience. This study aimed to identify the main difficulties encountered by GPs in Franche-Comté, France, in managing adult outpatients with long COVID. Methods: We conducted a cross-sectional survey using an anonymous online questionnaire, which contained 21 questions and was distributed to GPs in Franche-Comté, France. The survey assessed definition, diagnostic and therapeutic challenges in managing long COVID. Results: Among the 410 questionnaires distributed, 90 general practitioners (GPs) responded (response rate: 21.9%). The mean age of participants was 34 ± 10 years, and 64.4% were women (n = 58). Regarding knowledge of long COVID, three participants (3.3%) did not recognize it as a distinct clinical entity, while more than half (58.9%, n = 53) reported insufficient knowledge. The main challenges identified were therapeutic management (76.7%, n = 69) and diagnosis (75.6%, n = 68). Only 4.5% of respondents (n = 4) reported no difficulty in defining post-acute sequelae of SARS-CoV-2 infection (PASC). The most frequently reported diagnostic difficulty was distinguishing long COVID from differential diagnoses (93.3%, n = 83/89), particularly fibromyalgia (94.3%, n = 83/88). Only 37.1% of participants (n = 33/89) reported actively following up patients with PASC. During initial management, the main challenge was the difficulty in objectively assessing patients’ complaints using available diagnostic tools (80.7%, n = 67/83). Additionally, a large majority of GPs reported difficulties in addressing patients’ questions (86.7%, n = 72/83) and managing associated anxiety disorders (75.9%, n = 63/83). Conclusions: These findings highlight the immediate need to enhance GP training in Franche-Comté, France, in dealing with long COVID. Improvements such as harmonizing long COVID definitions, testing diagnoses, and strengthening interdisciplinary coordination are essential to provide coherent and patient-centered care for this disease. Full article

Background/Objectives: While acute cardiac injury during COVID-19 is well-documented, the long-term risk of new-onset heart failure (HF) in survivors remains a critical clinical concern. This study aims to quantify the risk of new-onset heart failure during a 25 months prognostic follow-up period following recovery from SARS-CoV-2. Methods: We conducted a systematic review and meta-analysis of nine high-quality studies (n > 400,000 survivors) in accordance with PRISMA 2020 guidelines. Databases including PubMed/MEDLINE and Scopus were searched through January 2026. A quantitative meta-analysis was performed on six studies using a random-effects model to pool adjusted hazard ratios (aHR). Results: The pooled analysis revealed a significant 35% increased risk of new-onset heart failure following COVID-19 recovery (aHR 1.35; 95% CI: 1.14–1.60; p = 0.001). Significant heterogeneity was observed (I² = 92.62%), reflecting diverse risk profiles among survivors. The risk was most pronounced in immunocompromised kidney transplant recipients (aHR 2.32) and younger adults under the age of 65 (aHR 1.53). Subclinical myocardial damage, characterized by reduced left ventricular longitudinal strain, was identified even in survivors who experienced mild initial infections. Conclusions: COVID-19 recovery serves as a significant independent risk factor for chronic heart failure, emphasizing that cardiovascular impact extends far beyond the acute phase. These findings necessitate the implementation of structured cardiovascular monitoring and biomarker screening for at least one year post-infection to address this emerging chronic disease burden. Full article

The COVID-19 pandemic has led to an unprecedented global health crisis, with millions recovering from acute infection but experiencing lingering symptoms, collectively referred to as post-acute sequelae of COVID-19 (PASC), or “long COVID.” While the precise mechanisms underlying long COVID remain elusive, one hypothesis gaining traction is the persistence of viral reservoirs in various tissues. Despite evidence of viral RNA and proteins detected in post-acute patients, the concept of viral reservoirs in the context of long COVID remains a subject of debate. This review explores the current scientific evidence for the existence of persistent SARS-CoV-2 in human tissues beyond the acute infection phase, focusing on the molecular mechanisms by which the virus may evade immune surveillance. We examine the role of immune dysregulation, chronic inflammation, and viral persistence in tissues such as the lungs, heart, brain, and gut. Additionally, we explore how these persistent viral elements may be associated with ongoing symptoms in long COVID and discuss the biological plausibility of these links. Finally, we discuss the clinical implications of viral persistence in post-COVID care, potential therapeutic strategies, and the need for further research to resolve the open questions surrounding this phenomenon. Full article

Long COVID is the disease entity triggered and potentially driven by SARS-CoV-2 infection. It is an heterogeneous condition characterized by dozens of different symptoms, signs and sequelae, which can affect all organs and body systems and evolve over the disease course. Clinical manifestations of Long COVID can vary from individual to individual and across the broader patient population. Pathology can range from asymptomatic and subclinical manifestations to fatal outcomes. Over 400 million people worldwide are estimated to suffer, or have suffered, from Long COVID, making the sequelae of SARS-CoV-2 infection one of the greatest public health challenges of the 21st century. This article provides an updated overview of epidemiology, definitions, main concepts and terminology for Long COVID. It also summarizes key evidence of pathology and disease mechanisms in major organs and body systems, such as the immune system, cardiovascular system, endothelium, heart, lungs, central nervous system, peripheral nervous system, gastrointestinal system, hapatobiliary system, pancreas and kidney. Heterogeneity in manifestations, potential risk of death and the degree of disability in several disease subsets call for timely diagnosis of each Long COVID types and a fuller understanding of their pathophysiological underpinnings. Further research is recommended to better understand pathobiology, develop effective clinical trials, and identify treatments and scalable biomarkers. Full article

Infectious diseases remain a major cause of mortality and disability worldwide. This burden is driven, in part, by antimicrobial resistance (AMR) and the re-emergence of epidemic and pandemic threats, underscoring the need for translational research to address knowledge gaps exposed by recent pandemics. Despite significant advances enabled by antibiotics and antivirals, their effectiveness is increasingly constrained by resistance development, limited pathogen spectra, and prolonged development timelines that fail to keep pace with rapidly shifting epidemiology. Diagnostic limitations impede timely pathogen identification and hinder the development of treatment regimens informed by pathogen mechanisms of action. Severe infections frequently involve dysregulated host responses, including hyperinflammation, inflammasome activation, and endothelial or immunothrombotic injury, which may progress to sepsis, immunoparalysis, or chronic sequelae, highlighting the limitations of pathogen-centered paradigms. Conventional biomarkers and culture-based microbiology are often slow or nonspecific, while molecular assays may not reliably distinguish colonization from active infection or capture host-response heterogeneity shaped by age, immune competence, and disease stage. This review synthesizes mechanistic and translational insights across three interrelated axes: (i) host–pathogen interactions, with a focus on innate immune sensing networks (e.g., Toll-like receptors, inflammasomes, RIG-I-like receptors, and cGAS-STING) and microbial replication and immune evasion strategies; (ii) clinical and public health implications, spanning acute organ dysfunction syndromes, post-acute infection syndromes, and AMR-driven health system strain; and (iii) emerging therapeutics along a continuum of pathogen-, virulence-, host-, and immune-directed approaches. Emphasis is placed on anti-virulence therapeutics, bacteriophage therapy, monoclonal antibodies, and engineered immune modalities within frameworks of quantitative translational pharmacology and implementation science. Finally, an integrative conceptual framework encompassing mechanistic phenotypes, host-response diagnostics, and stage-adapted therapeutic combinations is proposed to guide rational intervention across endemic infections and future pandemic preparedness. Full article

The coronavirus disease 2019 (COVID-19) pandemic has been associated with a wide range of neurological complications, among which persistent cognitive impairment and memory deficits are increasingly recognized as key symptoms of the post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID). Although clinical and epidemiological studies have documented these symptoms across diverse patient populations, the underlying neurobiological mechanisms remain incompletely understood. Growing evidence from human studies, neuropathological analyses, and experimental models indicates that neuroimmune and inflammatory processes plays a central role in COVID-19-associated cognitive dysfunction. As the brain’s resident immune cells, microglia are vital for synaptic health, neuroplasticity, and memory, yet these processes may be compromised after SARS-CoV-2 infection. Systemic inflammation, blood–brain barrier (BBB) disruption, endothelial injury, and cytokine signaling can induce sustained microglial activation and priming, leading to inflammasome activation, complement-mediated synaptic remodeling, oxidative stress, and impaired hippocampal neurogenesis. These processes collectively disrupt neural circuits involved in learning and memory and may underlie the persistent “brain fog” reported by COVID-19 survivors. This review synthesizes clinical, biomarker, neuroimaging, and mechanistic evidence linking SARS-CoV-2 infection to microglia-mediated neuroinflammation and memory impairment. In contrast to prior reviews that broadly describe neuroinflammation in COVID-19, we integrate multidimensional evidence into a microglia-centric immunovascular framework that highlights converging pathogenic pathways underlying cognitive symptoms. We further discuss emerging biomarkers of glial activation and evaluate current and prospective therapeutic strategies targeting microglial and neuroimmune pathways. Understanding the role of microglial dysregulation in post-COVID cognitive impairment may facilitate the development of targeted interventions to mitigate long-term neurological consequences of COVID-19. Full article

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can cause persistent, multisystem complications collectively termed long COVID. Cardiovascular sequelae are among the most clinically significant yet remain incompletely characterized. This review aimed to synthesize current evidence on objective cardiovascular outcomes in long COVID and explore underlying mechanisms. Methods: A systematic review was conducted using PubMed, Scopus, and Web of Science for studies published between January 2020 and March 2024. Search terms included “COVID-19,” “long COVID,” “post-acute sequelae,” “cardiovascular,” “echocardiography,” “biomarkers,” and “imaging.” Only studies reporting at least one cardiovascular outcome, defined as either objectively measured parameters (e.g., echocardiography, cardiac biomarkers, ECG findings, or vascular function indices) or clinically relevant cardiovascular symptoms during follow-up, were included. From 412 identified records, ten recent, high-quality studies with a primary cardiovascular focus were selected. This systematic review was conducted in accordance with the PRISMA 2020 guidelines. Results: Long COVID is associated with subclinical myocardial dysfunction, arrhythmias, endothelial injury, vascular stiffness, and a prothrombotic state. Reported findings included reduced left ventricular ejection fraction, impaired global longitudinal strain, increased arterial stiffness, elevated cardiac biomarkers, new-onset hypertension, and persistent ECG changes, even in non-hospitalized patients without prior cardiovascular disease. Proposed mechanisms include myocardial inflammation, endothelial dysfunction, renin–angiotensin–aldosterone system dysregulation, autonomic imbalance, and chronic inflammation. Secondary bacterial and fungal infections were noted in critically ill survivors but did not fully explain the breadth or persistence of symptoms. Conclusions: Long COVID is a heterogeneous entity with substantial cardiovascular implications across all levels of acute disease severity. Early detection through longitudinal monitoring, standardized definitions, and multidisciplinary care is essential to reduce long-term cardiovascular risk. Full article

Background: The aim of this study was to identify patient clusters based on acute symptom profiles and individual characteristics most likely to develop pediatric post-acute sequelae of SARS-CoV-2 infection (PASC), as well as clusters among patients with PASC based on post-acute sequelae and associated characteristics. Methods: This multicenter cohort study in 12 Italian pediatric units enrolled patients aged 0–17 years within three months of a laboratory-confirmed SARS-CoV-2 infection. Participants who completed at least two surveys developed by the ISARIC over one year were analyzed. PASC was defined per WHO criteria. Multiple Correspondence Analysis and Hierarchical Clustering were performed. Results: Of 1137 children enrolled, 850 (76%) completed at least two surveys. The most prevalent age group was older children (6–11 years) (46%); adolescents (12–17) and young children (0–5) were numerically similar. Males were more represented (51.9%), except for the adolescent group (45.1%). PASC occurred in 32.8% of participants, with the distribution of sequelae types varying by age. Clustering in COVID-19 cases identified three clusters: young children mainly presented with respiratory symptoms and with a higher risk of hospitalization, while older children were spared in both acute and post-acute phases. Adolescents, particularly females, reported more pronounced acute symptoms and developed PASC more frequently. Clustering analysis of cases with PASC identified three clusters, confirming these age-related patterns. Young children still exhibited respiratory sequelae, and older children confirmed good recovery with minimal complications, while adolescents, especially females, remained the most affected subgroup, reporting persistent neuropsychological sequelae such as fatigue and insomnia. Conclusions: Findings support age-tailored follow-up, emphasizing respiratory monitoring for young children and targeted neuropsychological care for adolescents, particularly girls. Full article

Vitamin D is a secosteroid hormone traditionally recognized for its role in bone and mineral metabolism, but it is increasingly understood to also function as an important immunomodulator influencing susceptibility to and outcomes of infectious diseases. This narrative review summarizes current evidence on the immunological, clinical, and preventive effects of vitamin D in the context of novel coronavirus disease (COVID-19), post-acute sequelae of SARS-CoV-2 infection (long COVID), and influenza. Mechanistically, vitamin D enhances innate immune defenses through the induction of antimicrobial peptides, including cathelicidin and defensins, and modulates adaptive immunity by suppressing maladaptive Th1/Th17 responses while promoting regulatory T-cell activity. Observational studies have frequently associated vitamin D deficiency with more severe COVID-19 outcomes; however, these associations may be influenced by confounding factors and reverse causality. Some meta-analyses suggest that vitamin D supplementation reduced rates of intensive care unit admission and ventilatory support, particularly among older adults and individuals with low baseline serum 25-hydroxyvitamin D concentrations. Emerging evidence also indicates that inadequate vitamin D status may be associated with an increased risk and symptom burden of long COVID, although causality has not been established. In the case of influenza, a limited number of randomized controlled trials (RCTs) and meta-analyses report a modest but statistically significant reduction in infection risk, especially with daily or weekly vitamin D supplementation in populations with low baseline vitamin D levels. Clinical guidelines consistently recommend maintaining adequate vitamin D status for general health but do not endorse high-dose vitamin D as a treatment for COVID-19 due to inconsistent trial findings. Overall, vitamin D should not be considered a standalone therapeutic agent; rather, maintaining sufficient vitamin D levels represents a low-risk, potentially beneficial strategy to support immune resilience against respiratory viral infections. Full article

Background: Cardiac arrhythmias are a frequent complication of acute SARS-CoV-2 infection. However, their long-term prevalence and clinical determinants among patients with post-COVID-19 syndrome, especially those previously hospitalized, remain poorly defined. Objectives: To assess the prevalence and types of arrhythmias in long COVID patients following hospitalization and to identify associated clinical risk factors. Methods: In this cross-sectional study, 53 patients previously hospitalized with confirmed COVID-19 were evaluated ≥3 months post-infection. All participants underwent a standardized clinical assessment, 12-lead electrocardiography, and 24 h Holter monitoring. Logistic and Cox regression analyses were performed to identify predictors of arrhythmia. Results: Arrhythmias were identified in 41.5% (n = 22) of patients. Atrial fibrillation (32%) was the most frequent arrhythmia, followed by sinus bradycardia (27%) and sinus tachycardia (18%). Age (OR 1.06, 95% CI 1.01–1.10, p = 0.01) and length of hospital stay (OR 1.1, 95% CI 1.01–1.2, p = 0.04) were independently associated with arrhythmia. Biguanide (metformin) therapy was inversely associated with the occurrence of arrhythmia (Exp(B) = 0.017, p = 0.008). Dyspnea (82.4%) and palpitations (41.5%) were the most commonly reported symptoms. Conclusions: Arrhythmias are common in patients with long COVID following severe disease. Advanced age and prolonged hospitalization are significant risk factors, while biguanide use may offer a protective effect. These findings underscore the need for targeted cardiac surveillance in this population. Full article

COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is clinically defined by persistent symptoms that endure beyond acute infection and affect multiple organ systems, including the immune, cardiopulmonary, neurological, and metabolic axes. The underlying mechanisms remain poorly resolved, limiting the development of targeted diagnostics and therapeutics. MicroRNAs (miRNAs), as key post-transcriptional regulators of gene expression, control inflammatory networks, antiviral responses, mitochondrial bioenergetics, and fibrotic pathways, all of which are implicated in long COVID pathogenesis. Recent studies show durable changes in circulating miRNA signatures months after recovery from the acute phase, suggesting a role in maintaining chronic immune activation and metabolic dysfunction. Importantly, circulating miRNAs are stable, quantifiable in biofluids, and reflect systems-level dysregulation, positioning them as promising biomarker candidates for patient stratification, symptom clustering, and disease monitoring. Moreover, miRNA-directed interventions, such as mimics and antagomiRs, represent an emerging precision-medicine strategy to correct sustained molecular disturbances. This review summarizes current evidence linking miRNAs to long COVID, highlights their biomarker potential, and discusses therapeutic avenues that may help advance mechanism-based interventions for this globally emerging chronic condition. Full article

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can develop as post-vaccination syndrome (PVS) or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). In our prior retrospective study, most patients with PVS who developed ME/CFS had vitamin D insufficiency or deficiency. We evaluated the efficacy of vitamin D replacement therapy guidance for ME/CFS symptom improvement in patients with vitamin D insufficiency or deficiency. Methods: This open-label randomized controlled trial enrolled 91 participants with ME/CFS as PVS or PASC and serum 25(OH) vitamin D < 30 ng/mL across five clinical sites. Participants were randomized 1:1 to intervention (active vitamin D preparation plus vitamin D replacement therapy guidance: 25 μg daily supplementation, dietary counseling, sun exposure, and exercise) or control (active vitamin D preparation alone) for 12 weeks. The primary endpoint was the change in ME/CFS symptom count from screening to Week 12. Results: Mean symptom change was −6.7 in the intervention group versus −1.2 in the control group (between-group difference −5.6; 95% CI: −7.2, −3.9; p < 0.001). Serum 25(OH) vitamin D improved from 18.6 to 27.1 ng/mL in the intervention group, while the control group showed a decreasing trend (between-group difference 10.2 ng/mL; 95% CI: 7.9, 12.5). Achievement of <8 symptoms (i.e., no longer meeting ME/CFS diagnostic criteria) was significantly higher in the intervention group, with 16 participants achieving this threshold compared to 1 in the control group (p < 0.001). Subgroup analyses showed consistent benefit in both PVS (n = 56) and PASC (n = 29) cohorts. Conclusions: Vitamin D replacement therapy guidance significantly reduced ME/CFS symptoms along with improvement of serum 25(OH) vitamin D levels in patients with vitamin D insufficiency or deficiency who developed ME/CFS as PVS or PASC. Full article