Search Results (317)

(1) Background: Sepsis is characterized by profound heterogeneity of immune responses, complicating biomarker-based prediction of clinical outcomes. Latent human cytomegalovirus (HCMV) infection is one of the strongest modulators of the human immune system and may influence cytokine-mediated signaling during sepsis. (2) Methods: In this post hoc analysis of 331 patients from the prospective multicenter SepsisDataNet.NRW cohort (German Clinical Trial Registry No. DRKS00018871), we quantified 13 serum cytokines on day 1 after sepsis diagnosis and determined HCMV IgG serostatus via ELISA. Using nested cross-validated logistic regression with exhaustive feature selection, we identified cytokine panels predictive of 30-day survival in the total cohort and in subgroups stratified by HCMV serostatus. (3) Results: In the total cohort, a four-cytokine panel (IL-6, IL-10, TNF-α, IL-12p70) predicted 30-day survival with a cross-validated area under the curve (AUC) of 0.66 [95% CI: 0.59–0.72]. Stratification by HCMV serostatus revealed distinct predictive profiles: in HCMV-seropositive patients, a two-cytokine model (IL-10, IL-23) achieved an AUC of 0.69 [95% CI: 0.61–0.77], whereas in seronegative patients, a model based on IL-8 and IL-17A failed to generalize (AUC = 0.47 [95% CI: 0.33–0.61]). Kaplan–Meier analysis confirmed a significant separation of survival curves for the HCMV-seropositive group (p < 0.001) but not for seronegative patients (p = 0.282). (4) Conclusions: HCMV serostatus defines an immunological context in which cytokine-based prediction of sepsis outcome becomes feasible. These data suggest that viral serostatus should be systematically incorporated into biomarker discovery and immunophenotyping approaches to improve the reproducibility and biological interpretability of sepsis endotyping. Full article

Background: T2 low asthma in children is an emerging yet underexplored endotype that challenges traditional views of type 2 inflammation. Recent data suggest that it is more prevalent than previously thought and is defined by low type 2 biomarkers, non-allergic clinical profiles, and strong associations with modifiable comorbidities such as obesity, passive smoke exposure, and recurrent respiratory infections. This phenotype often shows a poor response to standard inhaled corticosteroid therapy and T2-targeted biologics, underscoring the urgent need for improved diagnostic and therapeutic approaches. Methods: This narrative review conducted a literature search from PubMed and WoS databases (2020–2025), focusing on T2-low asthma defined by low blood eosinophils (<150–300/µL), FeNO (<20–25 ppb), and absent atopy in children under 18. Results: This review highlights the heterogeneity of T2-low asthma, including subtypes from neutrophilic/Th 17-high to paucigranulocytic airway remodeling and metabolic driven forms, as well as diagnostic challenges from biomarker supresssion by high-dose therapies. Pragmatic phenotyping algorithms using routine tests enable identification, directing comorbidity management over ineffective biologics. Conclusions: Systematic T2-low phenotyping in pediatric practice, alongside prospective studies and non-T2 therapy trials, promises precision medicine to enhance outcomes for these children, moving beyond eosinophil-centric care. Full article

Background/Objectives: Insulin resistance and ambulatory blood pressure monitoring (ABPM) abnormalities represent distinct but interrelated pathways contributing to cardiovascular risk. The triglyceride–glucose (TyG) index reflects metabolic burden, whereas arterial load—captured through arterial stiffness, blood pressure variability, and morning surge—reflects hemodynamic instability. Whether the coexistence of these domains identifies a particularly high-risk ambulatory phenotype remains unclear. To evaluate the independent and combined effects of metabolic burden (TyG) and arterial load on circadian blood pressure pattern and short-term systolic blood pressure variability. Methods: This retrospective cross-sectional study included 294 adults who underwent 24 h ABPM. Arterial load was defined using three ABPM-derived indices (high AASI, high SBP-ARV, high morning surge). High metabolic burden was defined as TyG in the upper quartile. The “double-high” phenotype was classified as high TyG plus high arterial load. Primary and secondary outcomes were non-dipping pattern and high SBP variability. Multivariable logistic regression and Firth penalized models were used to assess independent associations. Predictive performance was evaluated using ROC analysis. Results: The double-high phenotype (n = 15) demonstrated significantly higher nighttime SBP, reduced nocturnal dipping, and markedly elevated BP variability. It was the strongest independent predictor of non-dipping (adjusted OR = 42.0; Firth OR = 11.73; both p < 0.001) and high SBP variability (adjusted OR = 41.7; Firth OR = 26.29; both p < 0.001). Arterial load substantially improved model discrimination (AUC = 0.819 for non-dipping; 0.979 for SBP variability), whereas adding TyG to arterial load produced minimal incremental benefit. Conclusions: The coexistence of elevated TyG and increased arterial load defines a distinct hemodynamic endotype characterized by severe circadian blood pressure disruption and exaggerated short-term variability. While arterial load emerged as the principal determinant of adverse ambulatory blood pressure phenotypes, TyG alone demonstrated limited discriminative capacity. These findings suggest that TyG primarily acts as a metabolic modifier, amplifying adverse ambulatory blood pressure phenotypes predominantly in the presence of underlying arterial instability rather than serving as an independent discriminator. Integrating metabolic and hemodynamic domains may therefore improve risk stratification and help identify a small but clinically meaningful subgroup of patients with extreme ambulatory blood pressure dysregulation. Full article

Background: Severe asthma exacerbations (SAEs) significantly contribute to asthma-related morbidity, mortality, and healthcare burden. Despite therapeutic advances, a subset of patients remains exacerbation-prone. This review aims to summarize current evidence on risk factors, phenotypes, and biomarkers associated with SAEs, and explore personalized strategies for their acute management. Methods: We conducted a comprehensive literature review focusing on clinical, inflammatory, and environmental drivers of SAE. Special attention was given to Type 2 (T2) biomarkers—blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO)—as tools for phenotyping and treatment guidance. Emerging evidence on the use of biologics during exacerbations was also analyzed. Results: SAEs are heterogeneous in etiology and inflammatory profile. Respiratory infections, allergen exposure, obesity, and comorbidities increase exacerbation risk. T2-high SAEs respond well to corticosteroids and biologics, whereas T2-low SAEs show limited treatment benefit. BEC and FeNO reliably predict exacerbation risk and corticosteroid responsiveness. Recent case reports suggest potential roles for anti-IL-5 and anti-thymic stromal lymphopoietin (TSLP) biologics in acute care. Conclusions: Biomarker-guided management of SAEs may enhance therapeutic precision and avoid overtreatment. Integrating phenotypic (observable characteristics) and endotypic (biological markers) assessment into acute care could improve patient outcomes and optimize resource use. Prospective trials are needed to confirm these approaches. Full article

Nonsteroidal anti-inflammatory drugs (NSAIDs) can exacerbate urticaria and/or angioedema in up to 30% of patients with chronic urticaria (CU), representing a distinct subtype characterized by heightened inflammation and leukotriene-driven pathophysiology. MicroRNAs (miRNAs) are post-transcriptional regulators that modulate immune and inflammatory responses. This study aimed to identify differentially expressed miRNAs (DEMs) according to NSAID hypersensitivity status and to elucidate their molecular networks in CU. Serum miRNA profiles were analyzed in 14 NSAID-exacerbated CU (NECU) and 16 NSAID-tolerant CU (NTCU) patients using an Affymetrix GeneChip^® miRNA 4.0 Array. DEMs were identified (fold difference > 1.5, p < 0.05), and validated targets were retrieved from the multiMiR database for network construction and Gene Ontology enrichment analyses. NECU patients exhibited a higher frequency of angioedema and systemic corticosteroid use than NTCU patients. Eight DEMs were identified, including upregulated miR-5001-5p, miR-4270, and miR-6869-5p, and downregulated miR-6511b-5p, miR-2277-5p, and miR-378h in NECU. Network integration revealed AGO2-BTG2-LMNB2, NFIC-ZZZ3, and NUFIP2-GLG1 as central clusters, implicating dysregulation of mRNA decay and inflammatory signaling pathways. Reduced miR-6511b-5p expression may derepress BRG1, enhancing chromatin accessibility for inflammatory and leukotriene-synthetic genes. Distinct miRNA signatures differentiate NECU from NTCU, implying a miR-5001-5p/miR-6511b-5p–mRNA decay axis that links impaired post-transcriptional regulation with leukotriene-driven inflammation in CU. These findings highlight candidate miRNAs as potential biomarkers for disease endotyping and therapeutic stratification. Full article

Micro-RNAs (miRNAs) are short, non-coding RNA molecules regulating genes’ expression. Studies published over last years demonstrated that they play an important role in allergic diseases by regulating humoral and cellular immunity, cytokine secretion and epithelium function. Some of them seem potential non-invasive biomarkers facilitating diagnosis of the most common allergic diseases, such as allergic rhinitis (miR-21, miR-126, miR-142-3p, miR-181a, miR-221), asthma (miR-16, miR-21, miR-126, miR-146a, miR-148a, miR-221, miR-223) and atopic dermatitis (miR-24, miR-124, miR-155, miR-191, miR-223, miR-483-5p), or objectively assessing severity of inflammation and endotype of the disease. In spite of the large body of literature available, its scientific value is limited due to the small numbers of study participants, heterogeneity of populations enrolled, and diverse methodology. Some studies have revealed significant changes in miRNAs’ profile in the course of allergen immunotherapy. Tolerance induction is associated with processes controlled by miRNAs: enhanced activity of Treg cells and increased production of tolerogenic IL-10 and TGF-β. Thus, miRNAs may be candidates as biomarkers of successful immunotherapy. Finally, they are also possible therapeutic agents or targets of therapies based on antagomirs blocking their activity. However, so far no studies are available that demonstrate efficacy in overcoming delivery barriers, tissue targeting or drugs’ safety. As a consequence, despite promising results of in vitro and animal model studies, translation into human therapeutic agents is uncertain. Full article

Autoantibodies have long been regarded as passive reflections of immune dysregulation in connective tissue diseases (CTDs). Recent advances in systems immunology and molecular pathology have fundamentally redefined them as active molecular fingerprints that delineate distinct disease endophenotypes with predictive power for clinical trajectories and therapeutic responses. Rather than mere epiphenomena, autoantibodies encode precise information about dominant immune pathways, organ tropism, and pathogenic mechanisms. This review synthesizes emerging evidence that autoantibody repertoires—defined by specificity, structural properties, and functional characteristics—stratify patients beyond traditional clinical taxonomy into discrete pathobiological subsets. Specific signatures such as anti-MDA5 in rapidly progressive interstitial lung disease, anti-RNA polymerase III in scleroderma renal crisis, and anti-Ro52/TRIM21 in systemic overlap syndromes illustrate how serological profiles predict outcomes with remarkable precision. Mechanistically, autoantibody pathogenicity is modulated by immunoglobulin isotype distribution, Fc glycosylation patterns, and tissue-specific receptor expression—variables that determine whether an antibody functions as a biomarker or pathogenic effector. The structural heterogeneity of autoantibodies, shaped by cytokine microenvironments and B-cell subset imprinting, creates a dynamic continuum between pro-inflammatory and regulatory states. The integration of serological, transcriptomic, and imaging data establishes a precision medicine framework: autoantibodies function simultaneously as disease classifiers and therapeutic guides. This endophenotype-driven approach is already influencing trial design and patient stratification in systemic lupus erythematosus, systemic sclerosis, and inflammatory myopathies, and is reshaping both clinical practice and scientific taxonomy in CTDs. Recognizing autoantibodies as endophenotypic determinants aligns disease classification with pathogenic mechanism and supports the transition towards immunologically informed therapeutic strategies. Full article

Chronic rhinitis is induced by endotype-diverse inflammatory processes, which complicates effective therapeutic management. According to the current principles of personalized medicine, which also apply to the management of rhinological disorders, the best therapeutic results can be achieved after targeted treatment preceded by analysis of the patient’s endotype. Analysis of immune and cellular mechanisms allows for the use of biological treatment, and its effects provide new information on inflammatory processes in the nasal mucosa. The effects of biological treatment may be particularly interesting in the case of mixed endotypes, which pose a difficult therapeutic challenge. In eosinophilic asthma co-occurring with allergic rhinitis, as well as in eosinophilic asthma associated with non-allergic rhinitis, eosinophils represent a key effector cell population driving the underlying type 2-mediated inflammatory response. The aim of this study is to analyze the efficacy of anti-IL5 or anti-ILR5 therapy in patients with severe eosinophilic asthma and persistent allergic or non-allergic rhinitis. Methods: In this single-center real-life study, the authors analyzed the effects of biological treatment on rhinological symptoms in patients over the age of 18 with severe uncontrolled eosinophilic bronchial asthma with coexisting persistent allergic or non-allergic rhinitis treated with mepolizumab or benralizumab. In all patients, the otolaryngologist performed anterior rhinoscopy. Evaluation of rhinological symptoms and quality of life in patients treated with anti-IL5 or anti-IL5 therapy before and six months after biological treatment was performed using the TNSS and SNOT-22 scales. Results: In total, 67 patients with eosinophilic severe bronchial asthma were included in the study; among them 39 (58.2%) suffered from persistent allergic rhinitis and 28 (41.8%) suffered from chronic non-allergic rhinitis. After six months of treatment, higher absolute differences for SNOT and TNSS were observed in the persistent allergic rhinitis group. Conclusions: Biological treatment with mepolizumab and benralizumab may reduce the severity of rhinological symptoms in both endotypes of inflammation. However, higher therapeutic benefits were observed in patients with co-existing persistent allergic rhinitis. It was demonstrated that, in addition to IgE-mediated responses, the eosinophil represented an important component of the inflammatory reaction in allergic rhinitis. Full article

B-cells and plasmablasts have emerged as central organizers of autoimmune pathogenesis, extending far beyond their classical role as antibody-producing cells to orchestrate immune circuits, tissue microenvironments, and therapeutic trajectories. Advances in single-cell technologies, high-dimensional cytometry, and B-cell receptor sequencing have uncovered a dynamic continuum of B-cell differentiation programs that drive clinical heterogeneity across systemic autoimmune diseases. Plasmablasts, in particular, have gained recognition as highly responsive sensors of immune activation: they expand during flares, encode interferon-driven and extrafollicular responses, and correlate with disease severity. Autoantibody profiles, long viewed as static diagnostic signatures, are now understood as durable molecular footprints of distinct B-cell pathways. In this review, we propose an endotype-based framework integrating B-cell circuits with clinical phenotypes, illustrate therapeutic decision-making through mechanistic case vignettes, and outline future strategies combining immunomonitoring, multi-omics, and precision therapeutics. We further address translational challenges and discuss complementary approaches, including T-cell modulation, FcRn inhibition, and antigen-specific tolerization. Full article

Heart failure with preserved ejection fraction (HFpEF) accounts for about half of heart failure cases and is linked to aging, obesity, diabetes, and multimorbidity, yet disease-modifying therapies remain limited. A major barrier is heterogeneity: HFpEF comprises overlapping inflammatory, fibrotic, cardiometabolic, and hemodynamic/vascular endophenotypes embedded within systemic cardiorenal and cardiohepatic cross-talk, which conventional metrics such as left ventricular ejection fraction (LVEF), natriuretic peptides (NPs), and standard imaging capture incompletely. In this narrative review, we synthesize clinical, mechanistic, and trial data to describe HFpEF endophenotypes and their multi-organ interactions; critically appraise why traditional diagnostic and enrollment strategies contributed to neutral outcomes in landmark trials; and survey emerging cardiovascular multi-omics studies. We then outline an integrative systems-biology framework that applies (i) within-layer analyses and cross-layer integration, (ii) network-based driver nomination and biomarker discovery, and (iii) target nomination to link molecular programs with circulating markers and candidate therapies. Finally, we discuss practical challenges in implementing multi-omics HFpEF research and highlight future directions such as artificial intelligence (AI)-enabled multi-omics integration, cross-organ profiling, and biomarker-guided, endotype-enriched platform trials. Collectively, these advances position HFpEF as a proving ground for precision cardiology, in which therapies are matched to molecularly defined disease programs rather than ejection-fraction cutoffs alone. Full article

Asthma is a common chronic disease in children, contributing to significant morbidity and healthcare utilization worldwide. The integration of artificial intelligence (AI) and machine learning (ML) into pediatric asthma care is rapidly advancing, offering new opportunities for early diagnosis, risk stratification, and personalized management. AI-driven tools can analyze complex clinical, genetic, and environmental data to identify asthma phenotypes and endotypes, predict exacerbations, and support timely interventions. In pediatric populations, these technologies enable non-invasive diagnostic approaches, remote monitoring through wearable devices, and improved medication adherence via smart inhalers and digital health platforms. Despite these advances, challenges remain, including the need for pediatric-specific datasets, transparency in AI decision-making, and careful attention to data privacy and equity. The integration of AI in pediatric asthma care and into the clinical decision system can offer personalized treatment plans, reducing the burden of the disease both for patients and health professionals. This is a narrative review on the applications of AI and ML in pediatric asthma care. Full article

The concept of united airway disease (UAD) highlights the bidirectional relationship between inflammatory disorders of the upper airways—such as allergic rhinitis and chronic rhinosinusitis with or without nasal polyps (CRSwNP/CRSsNP)—and lower airway diseases, most notably asthma. This paradigm is supported by epidemiological, embryological, and immunological evidence demonstrating that airway inflammation represents a single, interconnected process rather than isolated compartmental pathology. Central to many UAD phenotypes is type 2 (T2) inflammation, driven by cytokines including IL-4, IL-5, and IL-13, and mediated by effector cells such as eosinophils and group 2 innate lymphoid cells (ILC2s). Epithelial barrier dysfunction often serves as the initiating trigger for this shared inflammatory cascade by production of TSLP, IL-25 and IL-33. Optimal diagnosis and management of UAD require an integrated, multidisciplinary framework. Clinical evaluation remains essential for patient characterization but must be complemented by pheno-endotypic assessment using imaging (CT), allergy testing, biomarker profiling (FeNO, blood eosinophils, IgE), and pulmonary function testing (spirometry, impulse oscillometry). Therapeutic strategies are layered, targeting both symptom control and inflammation across airway compartments. Standard approaches include intranasal and inhaled corticosteroids as well as saline irrigations, while severe T2-high disease increasingly benefits from biologic therapies (anti-IL-5/IL-5R, anti-IL-4R, anti-TSLP), which reduce dependence on systemic corticosteroids and surgical interventions such as endoscopic sinus surgery (ESS). Emerging precision-medicine models, particularly the “treatable traits” approach, further underscore the need to view the airway as a unified system. Collectively, these insights reinforce the clinical imperative of addressing upper and lower airway disease as a continuum, ensuring that inflammation in one district is neither overlooked nor treated in isolation. Full article

Background: Galectin-10 (Gal-10), the main constituent of Charcot–Leyden crystals, is a recognized marker of eosinophilic inflammation, yet its role in nasal mucosal remodeling in Seasonal Allergic Rhinitis (SAR) remains poorly defined. Methods: Gal-10, IL-5, MUC5AC, and IFN-γ were analyzed in Nasal lavage (NL) samples from children with SAR by ELISA. Unsupervised clustering and discriminant analyses were applied. The functional effects of Gal-10 were investigated ex vivo using a 3D epithelial–mesenchymal trophic unit (EMTU) model stimulated with NL containing high, low, or depleted Gal-10 levels. EMT (epithelial–mesenchymal transition) markers (vimentin, E-cadherin, SNAIL1) and MUC5AC secretion were assessed by immunohistochemistry, Western blot, and ELISA. Results: Gal-10 levels in NL positively correlated with IL-5 and MUC5AC and inversely with IFN-γ. Clustering analysis identified distinct SAR endotypes, with Gal-10 showing the highest discriminative power. In the 3D EMTU model, high Gal-10 NL induced increased vimentin and SNAIL1 expression and enhanced MUC5AC secretion, effects attenuated after Gal-10 depletion. Conclusions: Gal-10 is associated with Th2-type inflammation, mucus hypersecretion, and early epithelial–mesenchymal transition in pediatric SAR, supporting its role as a mediator of nasal mucosal remodeling and a potential therapeutic target Full article

Background/Objectives: In recent years, the recognition that type 2 inflammation plays a leading role in CRSwNP has enabled the more tailored treatment of the disease through improved patient endotyping. We studied 45 patients with severe CRSwNP who were treated with dupilumab or mepolizumab. The aim was to evaluate the efficacy of these treatments on endoscopic, clinical and patient reported parameters, and to assess whether nasal cytology could be useful for identifying responsive patients and monitoring their response to biologic drugs. Methods: Follow-up visits were scheduled at baseline (T0), and at 3 (T3), 6 (T6), 12 (T12), and 24 months (T24). At each visit, patients underwent blood analysis, nasal endoscopy, and nasal scraping for cytology. They also completed the SNOT-22 questionnaire, a visual analog scale (VAS) for nasal obstruction and smell perception, and the Asthma Control Test (ACT) test in cases of concomitant asthma. Results: Biological therapy demonstrated broad efficacy in disease management, based on both clinical and cytological findings. The Nasal Polyp Score, SNOT-22 questionnaire, VAS scores for nasal obstruction and smell, and ACT score showed progressive improvement. Blood eosinophil counts and total IgE levels also decreased over time (T0 vs. T24: p = 0.008 and p < 0.001, respectively). At nasal cytology, a reduction in eosinophil cell count and in the mixed mast cell–eosinophil pattern during treatment with both biologics were observed (T0 vs. T24: p < 0.001). Positive effects were typically recorded within six months of treatment and were sustained after two years. Conclusions: Although the histological evaluation of infiltrated tissues remains the gold standard for assessing mucosal eosinophilia, nasal cytology appears to be a simpler, non-invasive, and repeatable method for evaluating local eosinophilia. Identifying endotypes and assessing the severity of inflammation are crucial for predicting the efficacy of different treatment options. Full article

Background/Objective: Early hemodynamic instability in sepsis arises from endothelial dysfunction and vasoplegia before capillary leakage and organ failure occur. Albumin administration guided by serum concentration or shock criteria has not improved outcomes. This review synthesized evidence supporting an early, physiology-guided framework for albumin and norepinephrine use in pre-δ vasoplegic sepsis. Methods: A narrative synthesis of experimental and clinical studies examined endothelial injury, sepsis phenotypes, hemodynamic monitoring, biochemical markers, and intravascular albumin mass. Evidence from phenotype cohorts was integrated to construct a physiology-based therapeutic framework. Results: The δ phenotype consistently emerged as a vasoplegic, hyperinflammatory endotype with hypoalbuminemia, elevated lactate, and the highest mortality. Studies showed 20–25% of patients with community-acquired sepsis exhibit early vasoplegia, with low systemic vascular resistance and high cardiac output. Mass-balance analyses showed intravascular albumin mass declines early in sepsis, correlate inversely with fluid balance, and predict mortality. These findings suggest early low-dose norepinephrine may stabilize perfusion pressure, while albumin use should follow intravascular albumin mass trajectories. A dynamic exclusion concept proposes withholding albumin during capillary leak and reintroducing it when intravascular albumin mass stabilizes. Conclusions: Albumin therapy in sepsis should shift from late concentration-based to early physiology-guided endothelial protection. Monitoring intravascular albumin mass, lactate, and fluid balance may guide targeted norepinephrine and albumin use before δ-type endothelial failure occurs. This framework needs phenotype-stratified validation. Full article