Search Results (322)

This translational synthesis highlights the potential role of obesity-induced low-grade chronic inflammation in modulating clinical outcomes among patients with spondyloarthritis (SpA). Obesity transforms adipose tissue into a pro-inflammatory endocrine organ, where hypertrophic adipocytes release adipokines such as leptin alongside cytokines including TNF-α and IL-6, potentially contributing to macrophage polarization toward an M1 phenotype and activating NF-κB signaling pathways. This systemic immunometabolic priming may lower activation thresholds at the enthesis—the primary pathological site in SpA—potentially amplifying IL-23/IL-17 axis activity via Th17 bias, innate-like lymphocyte responses, and stromal–immune crosstalk under mechanical stress. Clinically, patients with SpA and obesity have been reported to demonstrate heightened disease activity (BASDAI, ASDAS), impaired function (BASFI), accelerated radiographic progression (syndesmophytes, enthesophytes), and diminished biologic response rates, potentially attributable to pharmacokinetic alterations (e.g., subtherapeutic TNF inhibitor levels) and pharmacodynamic resistance. Multisystem comorbidities, including non-alcoholic fatty liver disease, cardiovascular events, metabolic syndrome, sleep disturbances, and depression, further exacerbate morbidity and diminish quality of life. Therapeutic implications emphasize obesity as a modifiable disease modifier. Weight loss interventions, including hypocaloric diets, anti-inflammatory regimens (e.g., Mediterranean diet), multicomponent exercise, GLP-1 receptor agonists, and bariatric surgery, have been associated with reductions in inflammatory biomarkers, improved remission rates (MDA, DAPSA), and prolonged drug survival by restoring adipokine balance and disrupting mechano-inflammatory loops. Future randomized controlled trials should prioritize long-term evaluations of integrated multidisciplinary strategies that combine metabolic optimization with immunomodulatory therapies, addressing adherence challenges through psychological support and patient-tailored protocols, while elucidating dose–response relationships for GLP-1RAs and exercise in diverse SpA subtypes to establish precision management paradigms that mitigate cardiometabolic burden and improve holistic outcomes. Full article

Polycystic ovary syndrome (PCOS) is increasingly recognized as a complex, multi-system disorder involving interactions among metabolic dysfunction, chronic low-grade inflammation, and neuroendocrine dysregulation, rather than a condition confined to the ovary. While current management strategies primarily target symptomatic manifestations, such as menstrual irregularity, hyperandrogenism, and insulin resistance, they do not directly address the underlying integrative pathways linking the gut microbiome, cellular energy sensing, and hypothalamic reproductive control. This review proposes a mechanistic framework in which algae-derived bioactives modulate a gut–SIRT1–kisspeptin axis, thereby offering a systems-level perspective on PCOS pathophysiology and intervention. Gut dysbiosis in PCOS contributes to altered bile acid signaling, disrupted microbial metabolite profiles, and increased inflammatory tone, all of which may impair both metabolic and reproductive functions. Concurrently, reduced activity of the NAD⁺-dependent deacetylase SIRT1 has been documented across ovarian, endometrial, and metabolic tissues, linking energy imbalance to oxidative stress, inflammation, and impaired steroidogenesis. At the neuroendocrine level, dysregulated kisspeptin signaling contributes to abnormal gonadotropin-releasing hormone pulsatility and luteinizing hormone hypersecretion, key features of PCOS. Algae-derived compounds, including polysaccharides, phlorotannins, fucoidan, fucoxanthin, and microalgae bioactives, exhibit prebiotic, anti-inflammatory, and metabolic regulatory properties that intersect with these pathways, particularly through modulation of gut microbiota and activation of AMPK/SIRT1 signaling. The central proposition of this review is that algae-derived bioactives may act across interconnected biological layers: reshaping gut microbial ecology, restoring SIRT1-mediated metabolic balance, and retuning kisspeptin-driven neuroendocrine activity. While individual components of this axis are supported by substantial evidence, direct experimental validation of the complete pathway remains limited. Therefore, this framework is positioned as a translationally grounded but hypothesis-driven model that integrates currently fragmented findings into a coherent and testable paradigm. Future research should prioritize multi-level experimental and clinical studies that simultaneously assess microbiota composition, metabolic signaling, and reproductive neuroendocrine outcomes to establish the therapeutic potential of algae-based interventions in PCOS. Full article

Background/Objectives: Kawasaki’s disease (KD) is a leading cause of heart disease in children. The multisystem inflammatory syndrome (MIS) associated with the SARS-CoV-2 virus is similar to KD. The etiologies of KD and MIS are unknown. Both diseases are associated with pathogens and immunizations. Methods: The Vaccine Adverse Event Reporting System (VAERS) was retrospectively examined for etiology insights into both KD and MIS. Results: Statistically significant, elevated AE MIS safety signals were observed for several COVID-19 Pfizer-BioNTech manufacturing lots. Elevated AE MIS normalized frequencies were observed in children of all ages. Immediate-onset AE KD safety signals were detected for specific vaccines and coadministered combinations of these vaccines (including specific live, attenuated virus vaccines and other specific vaccines) for young infants; a subset of these safety signals has a male sex bias, whereas others appear to be unbiased. Conclusions: Both KD and MIS are hypothesized to involve two activation pathways. The first pathway is hypothesized to involve high titers of immune complexes that activate Fc receptors on mast cells, platelets, and other immune cells. Immune complex titers higher than primary immune response levels are hypothesized to be required to activate low-affinity IgGFcγR2α receptors on immune cells and platelets. IVIG treatment is hypothesized to directly compete with immune complex binding to FcγR2α receptors. The second hypothesized pathway is proposed to directly activate mast cells and other immune cells without involving immune complexes and Fc receptors; lack of Fc receptor competition by immune complexes is hypothesized as a possible explanation for IVIG nonresponders for KD and MIS, worthy of future studies. The proposed etiology models for both KD and MIS may be consistent with being novel mast cell activation syndromes (MCAS). MIS is hypothesized to be KD-associated with the SARS-CoV-2 virus or the COVID-19 spike protein (MIS-V). Full article

Preeclampsia is a pregnancy-specific multisystem disorder and a major cause of maternal and perinatal morbidity and mortality worldwide. This narrative review summarizes current evidence on the principal risk factors and pathophysiological mechanisms involved in its development. The disease is best explained by the two-stage model: in stage 1, inadequate trophoblast invasion and incomplete spiral artery remodeling lead to placental hypoperfusion, hypoxia, and oxidative stress; in stage 2, the hypoxic placenta releases anti-angiogenic and pro-inflammatory factors, including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), which trigger systemic endothelial dysfunction and the maternal clinical syndrome. The review highlights the central role of angiogenic imbalance, immune dysregulation, and chronic inflammation in disease progression. Particular emphasis is placed on maternal risk factors such as primiparity, advanced maternal age, obesity, diabetes mellitus, chronic hypertension, multiple pregnancy, prior preeclampsia, genetic susceptibility, and epigenetic regulation. We also emphasize the contribution of microRNAs in relation to placental hypoxia, trophoblast invasion, angiogenesis, endothelial injury and microchimerism to the development of preeclampsia. The review also examines the role of T helper 1 (Th1)/Th2/Th17/regulatory T cells (Treg) imbalance and uterine natural killer cell dysfunction at the maternal–fetal interface. Improved understanding of these interconnected mechanisms may support earlier diagnosis, better risk stratification, and the development of targeted preventive and therapeutic strategies. Full article

Cirrhosis is no longer viewed solely as an isolated hepatic disorder but rather as a complex multisystemic disease that affects cardiovascular, renal, pulmonary, metabolic, and immune systems. One of its most clinically relevant but under-recognized consequences is cardiac dysfunction, manifesting as cirrhotic cardiomyopathy, portopulmonary hypertension, right ventricular (RV) failure, and impaired myocardial strain. Oxidative stress (OS) has recently emerged as a fundamental mechanistic link between hepatic fibrogenesis and myocardial remodeling, acting through mitochondrial injury, NADPH oxidase activation, nitric oxide dysregulation, iron-mediated ferroptosis, and inflammatory cytokines. These alterations lead to diastolic dysfunction, autonomic imbalance, myocardial fibrosis, electrophysiological abnormalities (including QTc prolongation), and impaired RV–pulmonary artery coupling. Redox biomarkers such as malondialdehyde (MDA), NOX2-derived peptides, GSH/GSSG ratio, sST2, NT-proBNP, and 8-isoprostanes hold promise in detecting early subclinical cardiac involvement in cirrhosis. Novel antioxidant therapies, including mitochondrial-targeted molecules, NOX inhibitors, and ferroptosis blockers, may improve myocardial remodeling and hemodynamic stability. This review explores the central role of redox imbalance in the cardiohepatic syndrome and its potential utility in diagnosis, monitoring, and therapy. Full article

A rare but potentially fatal hyperinflammatory disease that develops following SARS-CoV-2 infection is called multisystem inflammatory syndrome in children (MIS-C). Mucocutaneous manifestations are common and frequently overlap with other pediatric inflammatory illnesses, including Kawasaki disease, and may serve as early diagnostic indicators. We describe a 6-year-old girl who was previously healthy but was hospitalized in the pediatric intensive care unit due to a high-grade fever, toxic appearance, and quickly progressing mucocutaneous symptoms, such as bilateral non-purulent conjunctivitis and broad maculopapular rash. Myocardial dysfunction, severe anemia and thrombocytopenia, respiratory failure necessitating mechanical ventilation, and hypotensive shock complicated the clinical course. Laboratory tests showed positive SARS-CoV-2 serology and significantly increased inflammatory markers. Several microbiological tests came up negative. Bacterial sepsis and Kawasaki diseases were not included. A diagnosis of MIS-C was made based on clinical, laboratory, and epidemiological data. In addition to supportive intensive care, the patient received systemic corticosteroids and intravenous immunoglobulin. After two weeks, she was released in a stable condition after gradually improving clinically and biochemically. This instance emphasizes how crucial it is to identify noticeable mucocutaneous manifestations as early warning signs of MIS-C. Immunomodulatory therapy must be started as soon as possible in order to minimize serious consequences and enhance the prognosis of afflicted infants. Full article

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-system illness with heterogeneity that complicates identifying the pathophysiology, biomarkers, and therapeutic targets. Evidence indicates the importance of immune dysregulation, including the complement system, in ME/CFS. This study investigates the contribution of genetic drivers to potential dysregulation of the complement pathway in ME/CFS. We used protein quantitative trait loci (pQTL) analyses, adjusted for covariates using linear and logistic regression, to identify genetic variants significantly associated with plasma complement protein levels in a study sample identified from the general population (50 ME/CFS and 121 non-fatigued). ME/CFS patients carrying certain pQTLs exhibited dysregulation of the alternative complement pathway, which defined an inflammatory subgroup with a high C3/low Bb profile and established a genetic link to dysregulation of the alternative complement pathway. Six of the significant pQTLs were also associated with fatigue-related phenotypes in the UK Biobank, four of which were complement-associated, providing some validation in an independent population. Our findings highlight a mechanism by which risk alleles contribute to ME/CFS heterogeneity, providing evidence of a genetic basis for complement dysregulation in a subset of patients. This approach could identify pathway-focused subgroups in ME/CFS and related illnesses to inform personalized approaches to diagnosis and treatment. Full article

Background and Objectives: Early identification of cardiac dysfunction in multi-system inflammatory syndrome in children (MIS-C) is crucial for effective management. Our primary objective was to predict left ventricular systolic dysfunction (LVSD) through a multicenter collaborative assessing admission laboratory data and echocardiogram findings. Methods: Laboratory and clinical data were collected by retrospective chart review from a cohort of pediatric patients admitted and treated for MIS-C in our institutions. Laboratory data including absolute lymphocyte count, albumin, sedimentation rate, C-reactive protein, procalcitonin, d-dimer, fibrinogen, ferritin, interleukin-6 level, and lymphocyte subsets (T, B and NK quantitation, TBNK) were collected. We built a LASSO logistic regression model to predict which MIS-C patients would have left ventricular systolic dysfunction LVSD using only laboratory data obtained within the first 24 h of admission. Results: Of the 1474 MIS-C patients evaluated, 297 had LVSD. The linear kinetic analysis found differences in albumin, lymphocyte count, C-reactive proteins and fibrinogen for systolic dysfunction patients, and of these C-reactive proteins, fibrinogen and procalcitonin were more predictive earlier. The best model for coronary artery abnormalities (CAAs) performed poorly, with a mean cross-validated AUC of 0.57. The model performed well with a cross-validated AUC of 0.845. Conclusions: This model identified widely available biomarkers to successfully predict systolic dysfunction in MIS-C patients. Those at high risk of systolic dysfunction had higher peak laboratory values for C-reactive protein, fibrinogen, and procalcitonin early on. A regularized logistic regression model was validated to provide excellent discrimination for LVSD. Full article

Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) are pediatric inflammatory conditions with overlapping mucocutaneous features that may complicate early diagnosis. We performed a narrative review of the literature to characterize and compare cutaneous manifestations reported in children with KD and MIS-C and to assess their diagnostic relevance. Published studies describing dermatologic findings in patients aged 0–18 years were reviewed. The analysis revealed a broad heterogeneity of skin manifestations in both conditions, ranging from classic polymorphous rash and acral erythema to atypical presentations, including annular, psoriasiform, vesiculobullous, urticarial, and erythema nodosum-like lesions. Reactivation at Bacillus Calmette–Guérin vaccination sites and associated mucocutaneous findings, such as conjunctivitis and oral changes, emerged as supportive diagnostic clues, particularly for incomplete KD. Considerable overlap in cutaneous phenotypes between KD and MIS-C was observed, especially in patients with persistent fever and systemic inflammation, highlighting the risk of diagnostic delay. These findings underscore the importance of recognizing atypical dermatologic patterns as part of an integrated diagnostic approach, as delayed identification may increase the risk of cardiovascular complications. Early recognition of cutaneous clues can support timely initiation of immunomodulatory therapy and improve clinical outcomes. Full article

Kaposi’s Sarcoma-associated herpesvirus (KSHV) and Epstein–Barr virus (EBV) are oncogenic gammaherpesviruses with high prevalence in sub-Saharan Africa. Both viruses are typically acquired during childhood, establishing lifelong latency. While viral reactivation into the lytic cycle has been mainly studied in adult HIV-infected populations—and more recently in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-infection—the dynamics of KSHV and EBV infection in children remain poorly understood. Here, we characterize pediatric patients (n = 175; median age 4.6 years; IQR 2.0–8.3) presenting with inflammatory conditions during the COVID-19 pandemic in South Africa (from July 2020 to February 2024). Including a healthy, non-inflammatory control group, we found widespread exposure to SARS-CoV-2 (70.9% seropositivity), with 72.6% of the children being seropositive for EBV and 19.4% for KSHV. There were no significant differences in seroprevalence between children with inflammatory conditions and healthy controls for any of these viruses, although SARS-CoV-2 antibody titers were significantly higher in the inflammatory group, while EBV immune responses were lower in children presenting with inflammation. Among the KSHV-seropositive children, no active viremia was detected (as determined by the absence of viral DNA in the peripheral blood). In contrast, 34.4% of EBV-seropositive children had detectable EBV viral load, with a modestly higher proportion in the inflammatory group. However, EBV viral load levels were comparable between children diagnosed with Multisystem Inflammatory Syndrome in Children (MIS-C), Kawasaki Disease (KD), and other inflammatory conditions. Logistic regression analyses revealed that increasing age was significantly associated with higher risk of SARS-CoV-2 and EBV seropositivity, but not KSHV. Notably, the risk of EBV DNA detection in the peripheral blood decreased with age. In summary, this study suggests effective immunological control of gammaherpesvirus infections in HIV-negative paediatric patients, even in the presence of inflammatory conditions that might otherwise trigger viral reactivation. Full article

Background/Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children presents with a heterogeneous clinical spectrum, whereas multisystem inflammatory syndrome in children (MIS-C) is a distinct immunological entity characterized by a hyperinflammatory phenotype and a distinct biological architecture. Identifying routine biomarkers with early discriminatory utility is essential for rapid differentiation between MIS-C and coronavirus disease 2019 (COVID-19). Methods: We conducted a retrospective comparative study of 144 pediatric patients with COVID-19 or MIS-C admitted to a single specialized medical center. The analyses integrated classical statistical methods, Benjamini–Hochberg false discovery rate correction (FDR), penalized regression models, and machine learning algorithms to identify biomarkers with discriminative value, using only routine laboratory tests. Results: MIS-C was associated with an intense inflammatory profile, characterized by increases in C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), lymphopenia, and selective electrolyte disturbances, highlighting a coherent biological architecture. In contrast, COVID-19 showed limited associations with traditional inflammatory markers. Predictive models identified a stable core of biomarkers with excellent performance in Random Forest analysis (area under the curve, AUC = 0.95), and reproducible thresholds (CRP ~3.7 mg/dL, NLR ~3.3, PLR ~376; potassium ~4.2 mmol/L). These findings were independently confirmed using penalized Ridge regression, where the reduced model achieved superior discrimination compared to the full 13-variable model (AUC = 0.93 vs. 0.89) and maintained stable performance under internal cross-validation, reinforcing the clinical relevance of this compact biomarker panel. Conclusions: MIS-C is clearly distinguished from COVID-19 by a specific and reproducible immunological signature. The identified biomarkers may represent a potential foundation for the development of simple clinical algorithms for pediatric triage and risk stratification, opening the prospect of a simplified scoring tool applicable in emergency settings. Full article

Influenza is typically framed as an acute respiratory infection, yet accumulating evidence suggests that—like SARS-CoV-2—it may trigger persistent, multi-organ morbidity consistent with a post-acute infection syndrome (“long flu”). Leveraging the nationwide FinnGen registry infrastructure, we conducted a temporally stratified disease-wide association study (DWAS) to map antecedent risk factors and long-term sequelae following clinically diagnosed influenza and COVID-19. We assembled an exposed cohort comprising 9204 individuals with influenza (ICD-10 J09–J11) and 4258 individuals with COVID-19 (ICD-10 U072) recorded in specialist inpatient/outpatient care between 1998 and 2021, and an unexposed comparator cohort of 420,005 individuals with no recorded influenza or pneumonia (J09–J18) across their available medical history. Across harmonized clinical endpoints, we fitted age- and sex-adjusted Cox proportional hazards models and controlled for multiple testing using a stringent false discovery rate threshold (FDR-adjusted p < 0.001), further interrogating temporal persistence within 1-, 5-, and 15-year windows. The DWAS revealed that both infections are associated with broad, system-spanning disease signatures extending beyond the respiratory tract, including circulatory, neurological, metabolic, musculoskeletal, digestive, mental/behavioural, ocular, and oncologic endpoints. Predisposition analyses demonstrated that infection risk is concentrated in individuals with substantial pre-existing multimorbidity, most prominently cardiovascular disease, alongside cardiometabolic, respiratory, renal, neuropsychiatric, and inflammatory conditions. Post-infection analyses identified a durable burden of incident multi-system morbidity after influenza, with particularly robust and persistent cardiovascular and neurological signatures—encompassing thromboembolic disease and major adverse cardiovascular outcomes, as well as migraine, neurodegenerative disorders, and depression—together with metabolic and renal sequelae that, in subsets, extended across multi-year horizons. Collectively, these longitudinal findings reframe influenza as a systemic event embedded within a chronic disease continuum, motivate recognition of “long flu” as a clinically meaningful post-viral risk landscape, and support intensified prevention and risk-stratified surveillance strategies alongside analogous efforts for long COVID. Full article

Background: Acute kidney injury (AKI) is increasingly recognised in children with acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C), yet the long-term renal consequences in younger paediatric populations remain unclear. Most studies focus on acute illness or mixed-age cohorts, with limited data specific to children aged 0–12 years. Objectives: This study aimed to systematically identify, evaluate, and synthesise evidence on post-acute (≥30 days) and long-term (≥90 days) kidney outcomes following SARS-CoV-2 infection or MIS-C in children aged 0–12 years, including chronic kidney disease (CKD), eGFR decline, proteinuria, haematuria, hypertension, and need for kidney replacement therapy. Methods: We searched MEDLINE, Embase, CINAHL, and PubMed (December 2019–30 November 2025), following PRISMA 2020 guidelines and a registered PROSPERO protocol (CRD420251241949). Observational studies reporting kidney outcomes ≥30 days post-infection in children aged 0–12 years were included. Risk of bias was assessed using the Newcastle–Ottawa Scale or ROBINS-I. Owing to heterogeneity and absence of ≥3 comparable datasets, a narrative synthesis was performed. Results: Seven studies met inclusion criteria (five MIS-C cohorts, two acute COVID-19 cohorts). Only a subset provided extractable data specific to children aged 0–12 years. Follow-up ranged from 30 days to 12 months; four studies reported outcomes ≥ 180 days. Across all studies, no incident CKD, sustained eGFR decline, or kidney replacement therapy were reported among children completing long-term follow-up; however, most long-term outcome data were derived from MIS-C cohorts with median ages around 8–11 years that included some adolescents, rather than exclusively children aged 0–12 years. One MIS-C study reported long-term hypertension in 14% of children. A cross-sectional Italian cohort of mild COVID-19 demonstrated hyperfiltration, proteinuria, and microhaematuria at ~3 months, though chronicity could not be assessed due to absence of baseline values. A large US EHR-based cohort identified increased CKD risk after COVID-19 in the broader < 21-year population; however, 0–12-year-specific event counts were not reported, preventing quantitative synthesis for young children. Conclusions: Evidence on long-term kidney outcomes after SARS-CoV-2 infection in children aged 0–12 years remains limited, and only a small subset of studies provided extractable, age-specific data. On the other hand, MIS-C cohorts generally show favourable renal recovery, small sample sizes, lack of control groups, and short follow-up restrict confidence in these findings. Large paediatric EHR studies suggest potential long-term renal risk in broader paediatric populations, highlighting the need for age-stratified, prospective cohorts with serial eGFR, urine studies, and blood pressure assessments. Until definitive evidence emerges, structured renal follow-up may be warranted for children with AKI or MIS-C during COVID-19. Full article

Background: Vogt–Koyanagi–Harada (VKH) is a multisystem autoimmune disease that ophthalmologists often encounter first. The condition is caused by an immune response against tyrosinase-related proteins in pigment cells (melanocytes) of the uvea, inner ear, meninges, and skin, and the process may be triggered by genetic and environmental factors. Although much is known about the disease, establishing an accurate and timely diagnosis still requires a multidisciplinary team and strong clinical expertise. Treatment demands early and aggressive anti-inflammatory therapy with corticosteroids, often prolonged and combined with immunosuppressive or biological agents. Aim: The present article aims to present three unique cases of patients with VKH syndrome, diagnosed and monitored by Ophthalmologists using standard imaging techniques over the course of five years, to demonstrate the unusual manifestations of the already rare syndrome and to improve the general knowledge of the disease among Ophthalmology specialists. Methods: Three different patients with various subjective symptoms and unique clinical signs went through observation in University Specialized Eye Hospital for Active Treatment—Varna. Results: The three clinical cases presented diagnostic challenges, the key role of imaging studies and the importance of thorough medical history taking. Conclusions: The prognosis in VKH is variable—timely diagnosis and treatment are essential to reduce the risk of recurrence and chronic progression of the disease. Full article

Posterior Reversible Encephalopathy Syndrome (PRES) is a rare but potentially reversible neurological manifestation associated with Multisystem Inflammatory Syndrome in Children (MIS-C). We report an eight-year-old boy who developed PRES secondary to MIS-C following asymptomatic SARS-CoV-2 exposure. The patient presented with fever, seizures, decreased consciousness, and visual disturbances. MRI revealed characteristic bilateral parieto-occipital and posterior temporal cortical–subcortical hyperintensities, while CT scans were normal. The patient achieved full neurological recovery with corticosteroid therapy, blood pressure control, and supportive management. This case underscores the importance of early MRI in detecting PRES when clinical or CT findings are inconclusive, emphasizing the need for heightened awareness among pediatric clinicians to prevent irreversible neurological sequelae. Full article