Search Results (235)

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

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

Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple and heterogeneous clinical manifestations (e.g., skin lesions, kidney damage, neuropsychiatric dysfunction), that primarily affects women and whose etiology remains unclear. Various therapies that regulate and reduce the immune system activity are in use or are being developed; however, many of them have serious side effects. Therefore, new approaches are needed to maximize remission periods and reduce associated side effects. In this review, we summarize the currently recommended therapeutic strategies. Furthermore, we hypothesize that the combined use of drugs targeting various dysregulated cellular processes in SLE (i.e., cytokine production, neutrophil extracellular traps (NETs), phagocytosis) might have therapeutic potential, at least in some disease phenotypes. Preliminary data show that Toll-like receptors 7/8 (TLR 7/8) inhibition (e.g., Enpatoran) may reduce interferon-α (IFN-α) production by monocytes and NET formation by neutrophils. Our hypothesis is that future therapies combining compounds that modulate the three cellular processes might result in a better disease management as current therapies. Full article

Vasculitides are a heterogeneous group of disorders characterized by inflammation of blood vessel walls, leading to tissue ischemia and organ injury. Traditional inflammatory markers such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are widely used but lack diagnostic specificity. This has driven the search for more informative biomarkers across vasculitis subtypes. This review summarizes current evidence for validated and emerging biomarkers in large-, medium-, small-, and variable-vessel vasculitis, as well as single-organ vasculitis. Key analytes reflect systemic inflammation, such as serum amyloid A (SAA) and interleukin-6 (IL-6), as well as endothelial activation, complement pathways, neutrophil and macrophage activation, and organ-specific damage. Promising candidates include pentraxin-3 (PTX3) and matrix metalloproteinase-9 (MMP-9) in large-vessel vasculitis; N-terminal pro-B-type natriuretic peptide (NT-proBNP) and S100 proteins in Kawasaki disease; galactose-deficient immunoglobulin A1 (Gd-IgA1) and urinary angiotensinogen (AGT) in IgA vasculitis; and tissue inhibitor of metalloproteinases-1 (TIMP-1), S100 proteins, complement C3, and PTX3 in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Although these biomarkers provide mechanistic insight, most lack disease-specificity, external validation, or standardized assays. Future progress will require multicenter studies, harmonized testing, and integrated biomarker panels combined with imaging modalities to improve diagnosis, activity assessment, and monitoring. Full article

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases originating from hematopoietic stem cell transformation, characterized by the clonal proliferation of hematopoietic progenitors. A specific subset includes myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions, particularly involving PDGFR A or B, which are sensitive to TK inhibitor treatment. We report a case of a 21-year-old patient with a myeloproliferative/myelodysplastic neoplasm, presenting with hyperleukocytosis, anemia, thrombocytopenia, and elevated LDH. The peripheral blood smear showed hypogranular neutrophils, eosinophils, basophils, and myeloid precursors. The absence of BCR::ABL1 and mutations in JAK2, CALR, and MPL excluded common MPNs. Cytogenetic analysis revealed a rearrangement between chromosomes 5 and 14. FISH analysis confirmed an inverted insertion from chromosome 5 to chromosome 14, involving the PDGFRB gene. WGS and RNAseq identified a fusion between PDGFRB and CCDC88C, causing the constitutive activation of PDGFRB. The fusion gene was confirmed by sequencing. This allowed for targeted therapy with a tyrosine kinase inhibitor (TKI), leading to molecular remission monitored by RT-qPCR. This case highlights how a multidisciplinary approach can identify atypical transcripts in MPN, guiding targeted therapy with TK inhibitors, thus resulting in effective treatment and molecular remission. Full article

Background/Objectives: Metachronous lung-limited oligometastatic disease represents a biologically heterogeneous state in which patient selection for pulmonary metastasectomy remains challenging. While systemic inflammation–nutrition indices have shown prognostic value across malignancies, their relevance in this strictly defined surgical setting is not well established. Methods: We conducted a retrospective single-center cohort study including 109 patients with isolated metachronous pulmonary recurrence who underwent curative intent R0 metastasectomy between September 2015 and April 2024. Preoperative systemic biomarkers, including neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), pan-immune-inflammation value (PIV), and monocyte-to-albumin ratio (MAR), were evaluated using receiver operating characteristic (ROC) analysis and multivariable Cox models to determine their association with overall survival (OS) and progression-free survival (PFS). Clinicopathological variables, such as lymph node involvement and metastatic burden, were incorporated into the adjusted models. Results: The median age of the cohort was 61 years (range, 29–82 years), and the sex distribution was balanced (48.6% female and 51.4% male), with 62.4% of patients being younger than 65 years. Among the systemic indices evaluated, monocyte-weighted biomarkers demonstrated the strongest prognostic performance. The MAR showed the highest discriminative ability for mortality (AUC, 0.749; p < 0.001), followed by the SIRI (AUC, 0.682; p = 0.007). In multivariable analyses, MAR independently predicted OS (p = 0.043) and PFS (p = 0.023), while SIRI independently predicted PFS (p = 0.043). Lymph node involvement remained the dominant adverse prognostic factor for both outcomes (p < 0.001); however, monocyte-weighted indices provided additional prognostic value beyond conventional anatomic criteria. Conclusions: Preoperative SIRI and MAR capture host immune–metabolic states that are relevant to postoperative trajectories and may refine risk stratification in candidates for pulmonary metastasectomy. These readily obtainable markers warrant prospective validation within biologically integrated selection frameworks. Full article

(1) Background: The clinical course of acute myocarditis in adolescents is heterogeneous, and reliable predictors of early functional changes remain limited, particularly in patients without severe systolic dysfunction. Routine hematologic parameters may reflect the early inflammatory response, but their prognostic relevance in pediatric non-fulminant myocarditis is poorly defined. This exploratory study aimed to assess whether admission inflammatory blood indices are associated with short-term changes in left ventricular systolic function in adolescents with acute myocarditis. (2) Methods: We retrospectively analyzed 44 adolescents (median age 16 years, 84% male) hospitalized with suspected acute non-fulminant myocarditis between 2020 and 2023. All patients had preserved or mildly reduced left ventricular ejection fraction (LVEF) at presentation. Clinical, laboratory, electrocardiographic, and echocardiographic data obtained at admission were analyzed. Changes in LVEF between the acute and post-acute phases during hospitalization were assessed using transthoracic echocardiography. Cardiac magnetic resonance imaging was performed in a subset of patients to support diagnosis but was not uniformly available for quantitative analysis. (3) Results: No in-hospital deaths occurred. A modest positive correlation was observed between neutrophil count at admission and improvement in LVEF during hospitalization (r = 0.348, p = 0.028). No significant associations were found between LVEF change and white blood cell count, lymphocyte count, monocyte count, neutrophil-to-lymphocyte ratio (NLR), troponin I, or NT-proBNP. (4) Conclusions: In adolescents with non-fulminant acute myocarditis and preserved or mildly reduced systolic function, admission neutrophil count was associated with short-term improvement in left ventricular ejection fraction. Given the retrospective design, limited sample size, and absence of mechanistic data, these findings should be interpreted as hypothesis-generating. Further prospective studies incorporating standardized cardiac magnetic resonance imaging and immunologic profiling are needed to clarify the clinical significance of this association. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition shaped by metabolic dysfunction, adipose tissue distribution, inflammatory activation, and body composition. Understanding how these factors interact across distinct clinical phenotypes is essential for improving diagnostic accuracy and risk stratification. This study aimed to compare metabolic, inflammatory, and elastographic profiles between MASLD subgroups defined by adipose tissue dysfunction (ATD) and obesity, and to identify pathways linking metabolic dysregulation to hepatic fibrosis. Methods: We conducted a cross-sectional observational study including 178 adult participants evaluated clinically, biochemically, and by bioimpedance and shear wave elastography. Participants ranged in age from 19 to 82 years. Patients were stratified into a non-MASLD control group and two MASLD subgroups: MASLD with ATD (G1) and MASLD with obesity (G2). Anthropometric data, lipid profile, glycemic markers, cytokines (IL-6, IL-10, TNF-α), liver stiffness, and non-invasive fibrosis indices were compared across groups using standard statistical testing. Results: Patients with MASLD showed higher liver stiffness, triglycerides, and IL-6/IL-10 levels than controls. Between MASLD phenotypes, the ATD group (G1) exhibited a more inflammatory and dysmetabolic profile, with significantly higher triglycerides, IL-6 levels, neutrophil counts, and creatinine, alongside trends suggesting early sarcopenic changes. In contrast, the obese phenotype (G2) demonstrated greater hepatic structural involvement, including higher liver stiffness and BMI, AST/ALT ratio and Diabetes (BARD) scores, despite more favorable inflammatory parameters. Several associations between liver stiffness, IL-6, and glycemic control approached but did not reach statistical significance. Conclusions: MASLD progression appears to follow two complementary but distinct mechanisms: an inflammatory, adipose dysfunction pathway dominated by IL-6 activation and early anabolic decline, and a metabolic-overload pathway driven by obesity. Phenotype-specific evaluation integrating inflammatory markers, metabolic indices, and elastographic parameters may improve risk stratification and inform personalized therapeutic strategies. Full article

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major cause of sudden death and a frequent finding in forensic practice. Correctly estimating thrombus age is crucial to reconstruct the temporal relationship among clinical events, therapeutic decisions, and death, and also to distinguish unavoidable complications from possible diagnostic or management errors. This narrative review summarizes current macroscopic, histological, immunohistochemical, and molecular criteria for thrombus dating, integrating evidence from autopsy studies, experimental models, and clinical research. Because of the inherent heterogeneity of thrombi and postmortem changes, classical morphology frequently does not provide sufficiently precise timing, although it does allow a broad distinction between acute, subacute, and chronic thrombi. A more precise temporal characterization has recently been made possible by the introduction of immunohistochemical and molecular markers, such as neutrophils and NETs, macrophage markers, fibrinolytic system components, metalloproteinases, inflammatory cytokines, autophagy markers, aquaporins, and pro-resolving pathways. In order to improve diagnostic accuracy, a combined evaluation of these characteristics seems promising in differentiating clinically relevant time windows (within 3 days, 3–10 days, 10–21 days, and >21 days). Molecular profiling combined with advanced histopathology may eventually enable more consistent and repeatable thrombus dating standards and enhance the forensic assessment of VTE-related fatalities. Full article

While the distinct roles of lymphocyte populations are well characterized in adaptive immunity, the phenotypic and functional diversity of innate immune cells is less explored. In recent years, subsets of monocytes have gained attention, as prominent shifts in population frequencies have been observed in disease states such as cancer. This narrative review summarizes current knowledge of the distribution and functional differences among the three major monocyte subsets (classical, intermediate, non-classical) in tumor settings. It includes rare populations, such as neutrophil-like, CD56+, and Tie2-expressing monocytes. Scientific evidence indicates that the phenotypical and functional heterogeneity of monocyte subsets determines their roles in either preventing cancer development or supporting the progression of disease through a remarkable diversity of mechanisms. Of note, alterations in the distribution of monocyte subsets and their functional reprogramming have been identified as drivers of cancer progression. While changes in monocyte frequencies have limited diagnostic biomarker potential for cancer detection, they may reflect the progression of disease and response to therapy. Based on subset-specific properties, distinct monocyte populations are increasingly recognized as promising targets of cancer immunotherapy. Yet novel strategies targeting monocyte populations must consider the risk of treatment reversal given the high plasticity of these cells. Full article

Single-cell sequencing (scRNA-seq) has emerged as a pivotal technology for deciphering the complex cellular heterogeneity and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC), positioning it as a critical tool for informing novel therapeutic strategies. This review explores how scRNA-seq reveals diverse cellular subpopulations and their functional roles within the PDAC TME, including malignant epithelial cells with transitional phenotypes, heterogeneous cancer-associated fibroblasts (CAFs), functionally distinct immune cells such as tumor-associated neutrophils (TANs) and macrophages (TAMs), and actively participating neural components like Schwann cells. These cellular constituents form specialized functional units that drive tumor progression, immune evasion, neural invasion, and therapy resistance through metabolic reprogramming, immunosuppressive signaling, and cellular plasticity. The review further examines technological advances in single-cell sequencing from 2023 to 2025, focusing on sample preprocessing innovations, multi-omics integration (combining transcriptomics with epigenomics and proteomics), spatial resolution enhancements, and customized computational tools that address PDAC-specific challenges. Clinically, single-cell sequencing enables precise cellular subtyping, identification of novel biomarkers, and development of personalized therapeutic approaches, including combination therapies targeting specific cellular subpopulations and their interactions. Despite these advances, significant challenges remain in standardizing clinical applications such as liquid biopsy for early detection and tumor microenvironment assessment for diagnostic staging, validating biomarkers like CLIC4, GAS2L1, Cytokeratins, Vimentin and N-cadherin in circulating tumor cells, and comprehensively integrating multi-omics data. Future research focusing on both technology refinement and biological validation will be essential for translating single-cell insights into improved diagnostic and therapeutic outcomes for pancreatic cancer. Full article

Background: Systemic inflammation plays a pivotal role in heart failure (HF) progression, yet no meta-analysis has synthesized prospective cohort data on interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and neutrophil-to-lymphocyte ratio (NLR) as prognostic biomarkers. Objectives: To quantify the independent prognostic value of IL-6, hs-CRP, and NLR for mortality and HF-related outcomes across HF phenotypes. Methods: Following PRISMA and MOOSE guidelines, we searched PubMed, Embase, Scopus, Web of Science, and CENTRAL from January 2014 to October 2025 for prospective cohorts reporting adjusted hazard ratios (HRs). Random-effects meta-analysis pooled HRs; heterogeneity was assessed via I² statistic, with subgroup and sensitivity analyses for robustness. Quality was evaluated using Newcastle–Ottawa Scale (NOS) and GRADE. Results: Thirteen cohorts (n ≈ 19,000) were included. Elevated IL-6 (five studies) was associated with increased all-cause mortality and composite outcomes (low-moderate heterogeneity, I² < 35%). hs-CRP (five studies) showed similar prognostic strength, with trajectories amplifying risk. NLR (three studies) independently predicted adverse events with negligible heterogeneity. Associations persisted across HFrEF and HFpEF, acute/chronic settings, and geographic regions, independent of natriuretic peptides and comorbidities (NOS median 8/9; GRADE moderate-to-high). Conclusions: IL-6, hs-CRP, and NLR are robust, independent prognostic biomarkers in HF, supporting their integration into clinical risk stratification and inflammation-targeted therapies. PROSPERO: CRD420251207035. Full article

Diabetic macular edema (DME) is a leading cause of vision loss in patients with diabetes. While VEGF-driven vascular permeability is central to its pathogenesis, inflammation plays a complementary and pivotal role in disease progression, morphological heterogeneity, and treatment response. Readily available blood cell-derived inflammatory indices, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), monocyte-to-high-density lipoprotein cholesterol ratio (MHR), monocyte-to-lymphocyte ratio (MLR), platelet-to-neutrophil ratio (PNR), and pan-immune-inflammation value (PIV), as well as platelet measures (MPV, PDW), have been investigated as low-cost markers of systemic inflammation in DME. Specifically, comparative studies have reported that an NLR ≥ 2.26 can effectively distinguish DME from non-DME with 85% sensitivity and 74% specificity. Elevated NLR is more associated with serous retinal detachment. Moreover, a baseline NLR ≤ 2.32 has been linked to a better anatomical response to treatment. This narrative review summarizes the evidence regarding these biomarkers’ diagnostic and prognostic utility and highlights their associations with OCT morphotypes and anti-VEGF responsiveness. We propose that multi-marker panels integrated with OCT features may enhance risk stratification and help personalize therapy, but emphasize that prospective, multi-center validation and harmonized thresholds are required before routine clinical application. Full article

Background/Objectives: This study aimed to characterize dendritic cell (DC) heterogeneity, immune associations, and prognostic relevance across three TP53-mutated tumor entities—high-grade serous ovarian cancer (HGSOC), triple-negative breast cancer, and endometrial cancer—focusing on plasmacytoid DCs (pDCs) in HGSOC. Methods: RNA-sequencing and clinical data of 603 patients from The Cancer Genome Atlas were analyzed. DC subset abundance was assessed for cDC progenitor, conventional DC type 1 (cDC1), conventional DC type 2 (cDC2), plasmacytoid DC (pDC), and mature DC by marker gene signatures. Differences in DC scores across tumors were analyzed using Kruskal–Wallis. Survival analyses were performed using Kaplan–Meier and Cox regression. Spearman’s correlation was used to determine associations between parameters. Results: HGSOC showed the lowest pDC abundance, yet high pDC scores were independently associated with shorter PFS (HR = 1.55, 95% CI: 1.05–2.27; p = 0.027), representing the only DC-subset-related prognostic signal observed across tumor types. pDCs correlated positively with neutrophils and negatively with monocytes, and pDCs, cDC2s, and cDC progenitors correlated inversely with TMB. No consistent link was found between pDC and TP53 mutation classes. However, tumors harboring specific TP53 mutations within established hotspot regions exhibited significantly lower pDC levels (p = 0.015). Conclusions: Our findings reveal distinct DC infiltration patterns and highlight the immunological vulnerability of TP53-mutated HGSOC. pDCs appear to exert a tumor-promoting, immune-evasive role, suggesting that DC function depends on their programming and tumor context. Selective targeting of DC subsets may offer novel therapeutic opportunities in TP53-mutated, low-TMB cancers. Full article

Background/Objectives: Sepsis-associated liver injury (SALI) is a critical and often early complication of sepsis, defined by distinct hyper-inflammatory and immunosuppressive phases that shape patient phenotypes. Methods: Characterizing these phases establishes a foundation for immunomodulation strategies tailored to individual immune responses, as discussed subsequently. Results: The initial inflammatory response activates pathways such as NF-κB and the NLRP3 inflammasome, leading to a cytokine storm that damages hepatocytes and is frequently associated with higher SOFA scores and a higher risk of 28-day mortality. Kupffer cells and infiltrating neutrophils exacerbate hepatic injury by releasing proinflammatory cytokines and reactive oxygen species, thereby causing cellular damage and prolonging ICU stays. During the subsequent immunosuppressive phase, impaired infection control and tissue repair can result in recurrent hospital-acquired infections and a poorer prognosis. Concurrently, hepatocytes undergo significant metabolic disturbances, notably impaired fatty acid oxidation due to downregulation of transcription factors such as PPARα and HNF4α. This metabolic alteration corresponds with worsening liver function tests, which may reflect the severity of liver failure in clinical practice. Mitochondrial dysfunction, driven by oxidative stress and defective autophagic quality control, impairs cellular energy production and induces hepatocyte death, which is closely linked to declining liver function and increased mortality. The gut-liver axis plays a central role in SALI pathogenesis, as sepsis-induced gut dysbiosis and increased intestinal permeability allow bacterial products, including lipopolysaccharides, to enter the portal circulation and further inflame the liver. This process is associated with sepsis-related liver failure and greater reliance on vasopressor support. Protective microbial metabolites, such as indole-3-propionic acid (IPA), decrease significantly during sepsis, removing key anti-inflammatory signals and potentially prolonging recovery. Clinically, SALI most commonly presents as septic cholestasis with elevated bilirubin and mild transaminase changes, although conventional liver function tests are insufficiently sensitive for early detection. Novel biomarkers, including protein panels and non-coding RNAs, as well as dynamic liver function tests such as LiMAx (currently in phase II diagnostics) and ICG-PDR, offer promise for improved diagnosis and prognostication. Specifying the developmental stage of these biomarkers, such as identifying LiMAx as phase II, informs investment priorities and translational readiness. Current management is primarily supportive, emphasizing infection control and organ support. Investigational therapies include immunomodulation tailored to immune phenotypes, metabolic and mitochondrial-targeted agents such as pemafibrate and dichloroacetate, and interventions to restore gut microbiota balance, including probiotics and fecal microbiota transplantation. However, translational challenges remain due to limitations of animal models and patient heterogeneity. Conclusion: Future research should focus on developing representative models, validating biomarkers, and conducting clinical trials to enable personalized therapies that modulate inflammation, restore metabolism, and repair the gut-liver axis, with the goal of improving outcomes in SALI. Full article