Maria Oana Săsăran

Background: Interleukin-33 (IL-33) is an epithelial-derived member of the IL-1 cytokine family that functions as an alarmin and signals through the ST2 receptor, upstream of type 2 inflammation. Together with thymic stromal lymphopoietin (TSLP) and IL-25, it constitutes an epithelial alarmin triad that orchestrates barrier-related immune responses. Despite substantial mechanistic data, the specific role of IL-33 as a biomarker and therapeutic target in pediatric food-related allergic disease remains insufficiently defined. Objective: This systematic review aims to synthesize current evidence on serum and tissue IL-33 in pediatric IgE-mediated food allergy and eosinophilic gastrointestinal disorders (EGIDs), to delineate its association with disease severity, clinical phenotype and oral immunotherapy (OIT) outcomes, and to critically appraise the IL-33/ST2 axis as a candidate biomarker and therapeutic target within the broader epithelial alarmin network. Methods: A systematic search of PubMed/MEDLINE, Web of Science, Scopus and the Cochrane Library (2010–2026) identified pediatric clinical studies quantifying IL-33 or IL-33/ST2 in food allergy or EGIDs, alongside murine and in vitro studies directly interrogating IL-33-dependent mechanisms in food allergy models. Eligible studies were screened and extracted according to predefined PICO criteria. Results: Fourteen studies fulfilled the inclusion criteria (four pediatric clinical cohorts, ten direct preclinical murine or in vitro studies). Across murine models, keratinocyte-derived IL-33 consistently activated a skin-to-gut axis driving intestinal mast-cell expansion and IgE-independent food anaphylaxis, which was abrogated by genetic or pharmacologic ST2 blockade. In a small case-control study of nine children with eosinophilic gastroenteritis, serum IL-33 and TSLP were increased during active disease and declined after dietary elimination. In pediatric eosinophilic esophagitis, IL-33 was increased in tissue but not consistently in serum. Conversely, serum IL-33 demonstrated limited discriminatory value in IgE-mediated food allergy. Conclusions: IL-33 emerges as a context-dependent yet non-redundant component of the epithelial alarmin circuitry in pediatric food-related allergic disease, as candidate biomarker of epithelial inflammation in pediatric EGIDs. However, current clinical evidence is limited and requires validation in larger prospective cohorts.

Background: Small intestinal bacterial overgrowth (SIBO) and intestinal methanogen overgrowth (IMO) are heterogeneous conditions with poorly standardized antibiotic treatment. This review assessed clinical and test-based outcomes of SIBO therapy, phenotype-specific response, recurrence, and pediatric evidence on the same subject. Methods: PubMed/MEDLINE, Scopus, and Web of Science Core Collection were searched for English-language human studies published between January 2000 and April 2026. Randomized, non-randomized interventional, and observational studies evaluating antibiotic-based treatment for SIBO or methane-positive/IMO phenotypes were included. Owing to substantial heterogeneity, findings were synthesized narratively. Results: Thirty-nine studies were included. Rifaximin was the most frequently studied antibiotic, although outcomes varied considerably. In the only direct three-antibiotic comparison, metronidazole achieved the highest breath-test normalization, whereas rifaximin provided greater improvement in abdominal pain and bloating and fewer adverse events. Rifaximin plus neomycin showed the strongest comparative signal in methane-positive/IMO phenotypes. Clinical and test-based outcomes were frequently discordant, and pediatric evidence remained sparse and inconsistent. Conclusion: No antibiotic was universally superior. In adults, rifaximin appears to offer the most favorable overall balance between symptom improvement and tolerability, whereas metronidazole may achieve higher breath-test normalization in selected patients. Rifaximin plus neomycin showed the strongest comparative signal in methane-positive/IMO phenotypes. Evidence is insufficient to identify a preferred pediatric regimen. Treatment success should integrate symptoms, objective response, tolerability, recurrence, and patient phenotype.

Background and objective: Polymorphisms of the vitamin D receptor (VDR) gene have been studied in relation to various diseases, including infections. This narrative review aims to summarize the role of VDR polymorphisms in the susceptibility towards pediatric infectious diseases, as well as in their complications. Methods: We conducted a narrative review of the available literature data (PubMed/MEDLINE, Web of Science and Google Scholar databases) published until January 31 ^st , 2026. Search keywords included “VDR” AND “child” AND “respiratory tract infection” OR “gastroenteritis” OR “diarrhea” OR “urinary tract infection”. Results: A total number of 21 studies complied to the inclusion and exclusion criteria. FokI remains the most intensely studied polymorphism of the VDR gene in relation to pediatric infections and its genotypes are differentially expressed in relation to infections of the respiratory tract requiring hospitalization. There are no studies available analyzing the impact of VDR gene polymorphisms in acute infectious diarrhea, but two studies have shown so far that children who are carriers of particular genotypes of the ApaI, FokI and/or BsmI polymorphisms are more predisposed towards developing urinary tract infections. Data on pediatric/neonatal sepsis is scarce, limited to three studies which have shown inconsistent, contradictory findings. Conclusions: Future studies are warranted to validate or infirm the role of VDR gene polymorphisms in the prediction of pediatric infectious disease incidence and outcomes. The heterogeneity of available studies, given by the different age groups, ethnicity of populations enrolled and geographical locations greatly influences available results and their interpretation.

Introduction: Hypocalcemia represents a major cause of seizures in children in the absence of fever or infections. Hypovitaminosis D, usually associated with a lack of proper prophylactic regimens, can trigger those events. This case series aims to highlight two cases of hypocalcemic seizures in infants, attributed to severe vitamin D deficiency, with the aim of raising awareness regarding the importance of vitamin D prophylaxis. A narrative review of the literature is also provided, which highlights similar reported cases. Methods: We hereby report two cases of male infants (aged 4 months and 5 months) who presented to the emergency department of a tertiary pediatric center with seizures in the absence of fever or infections. Diagnostic work-ups revealed low levels of total serum calcium and ionic calcium deficiency. The cause of the hypocalcemia turned out to be severe vitamin D deficiency in both cases, caused by complete absence of vitamin D supplements since birth and during maternal pregnancy. In both cases, combined oral calcium and vitamin D supplementation led to complete resolution of symptoms and restoration of normal calcium levels. A comprehensive review of the literature is also provided, which focuses on pediatric studies and case reports that analyzed the prevalence, particularities, and outcomes of hypocalcemic seizures related to vitamin D deficiency. Articles including subjects with congenital or endocrine disorders that could have caused hypocalcemia were ruled out. Results: After accessing the full-length form of each article and applying the inclusion and exclusion criteria, 27 articles were included, namely 14 studies and 13 case reports. Hypocalcemic seizures caused by vitamin D deficiency are more common in infants, are usually linked to maternal hypovitaminosis D, and have a higher prevalence in developing countries. Most of the case reports depicting hypocalcemic seizures were distinguished through very low vitamin D levels. Conclusions: These case series emphasize the importance of vitamin D supplementation for the prevention of hypocalcemia, which constitutes a major metabolic cause of seizures in infancy. Nevertheless, maternal vitamin D supplementation during pregnancy is the only factor that can ensure the presence of satisfactory deposits in the newborn and prevent hypovitaminosis D-related complications.

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Early-onset neonatal sepsis (EONS) remains a challenging diagnosis in clinical practice, with limited available paraclinical data. This study aims to analyze the utility of two cytokines determined from the umbilical cord blood (UCB) of newborns and from maternal blood, IL-6 and IL-8, for the early and accurate diagnosis of EONS. The study population was divided into a study group (50 patients with confirmed EONS) and control group (50 patients with sepsis risk factors, without a confirmed infection). UCB IL levels were significantly higher in the study group for both IL-6 (44.28 ± 23.10 pg/mL versus 5.54 ± 4.14 pg/mL, p < 0.01) and IL-8 (15.48 ± 7.56 versus 5.31 ± 2.58 pg/mL, p < 0.01). For the distinction between confirmed EONS and healthy controls with risk factors, cut-off levels of > 16.34 pg/mL were identified for IL-6 and of > 7.59 pg/mL for IL-8, respectively. UCB IL-6 and IL-8 levels correlated with neonatal leukocyte, neutrophil, lymphocyte levels, as well as with the leukocyte index. Maternal IL-6 and IL-8 levels did not differ significantly between the two study groups and did not corelate with their UCB homologues. Maternal levels of IL-6 and IL-8 could not predict EONS, in contradistinction to UCB IL-6 and IL-8 levels, that seem to be useful in the early stratification and diagnosis of EONS among term neonates. Future research, expanded on wider neonatal cohorts is warranted to deliver more information regarding the utility of UCB ILs into daily clinical practice, for precocious identification of populations at risk of developing EONS.

Type 1 Diabetes (T1D) is a complex autoimmune disorder characterized by immune-mediated destruction of pancreatic β cells, driven by genetic susceptibility and modulated by environmental factors, notably the gut microbiome. Dysbiosis, manifested as reduced microbial diversity, perturbations in the Firmicutes/Bacteroidetes ratio, and compromised short-chain fatty acid production, contributes to T1D pathogenesis through mechanisms involving immune system dysregulation and heightened intestinal permeability. Emerging evidence indicates a relationship between the gut and oral microbiomes, as well as the potential influence of the virome and mycobiome. This narrative review synthesizes the current literature on the intricate interplay between the gut microbial ecosystem, the host immune response, and the development of T1D, highlighting the potential for targeted microbiome-based interventions to ameliorate disease progression. A more nuanced understanding of these multi-kingdom interactions is essential for developing precise therapeutic strategies to prevent or delay T1D onset and to improve patient outcomes through restoration of immune tolerance and gut homeostasis.

Neurodevelopment is a dynamic and multifactorial process, critical in the early stages of life, involving the formation of neural networks, the establishment of synapses, and the maturation of cognitive, social and emotional circuits. In this context, the gut microbiome emerges as an essential regulator of neurodevelopment, exerting influences through multiple biochemical and immunological mechanisms that define the “gut-brain axis”. The microbiota modulates neurodevelopment by regulating neurotransmitters (serotonin, dopamine, GABA), the production of microbial metabolites, including short-chain fatty acids, the modulation of inflammatory cytokines, and vagal signaling to the central nervous system. Recent evidence highlights the role of microbiota in modulating microglia, synaptogenesis, dendritic maturation, and neuronal plasticity, emphasizing how these processes are influenced by microbial activity rather than providing a comprehensive treatise on plasticity itself. Gut microbiota disturbances, or dysbiosis, have been associated with various neuropsychiatric and neurodevelopmental disorders, contributing to cognitive, behavioral, and emotional dysfunctions. This article summarizes, in a narrative manner, the main dysbiosis patterns identified in these disorders and the biological mechanisms by which the microbiome influences neuronal development and function, including immune–neuronal interactions, metabolomic modulation, and neuroendocrine signaling. Finally, emerging directions of intervention aimed at adjusting the microbial profile, such as dietary adjustment, the use of probiotics, prebiotics, symbiotics, and fecal microbiota transplantation, are presented with the aim of positively influencing neurodevelopment and preventing or ameliorating associated dysfunctions. This review emphasizes the need for longitudinal, rigorous, and controlled clinical trials to validate the efficacy of microbiota modulation strategies and to substantiate their integration into individualized pediatric management protocols.

Background: Neonatal Ebstein’s anomaly (EA) is a severe condition with significant hemodynamic instability and early myocardial dysfunction, where abnormal right-heart geometry limits conventional echocardiography and highlights the value of myocardial deformation imaging. Methods: We conducted a single-center retrospective observational study including 16 neonates with EA and 26 healthy neonates. All subjects underwent comprehensive transthoracic echocardiography during the neonatal period. Conventional two-dimensional imaging and speckle-tracking echocardiography (STE) were used to assess biventricular and biatrial myocardial deformation. Deformation parameters were compared between groups, and receiver operating characteristic (ROC) curve analysis evaluated diagnostic performance. Results: Neonates with EA demonstrated significant structural remodeling and severe biventricular and biatrial dysfunction compared with controls. Speckle-tracking showed markedly reduced right ventricular longitudinal strain (LS) in all segments (all, p < 0.001), particularly in free-wall and four-chamber views. Left ventricular (LV) global LS (GLS) was significantly reduced in neonates with EA compared with controls (−14.53% vs. −22.32%, p < 0.001), indicating early involvement of LV myocardial function in the neonatal period. Atrial reservoir, conduit, and contractile strain were severely impaired in both atria (all, p < 0.001). ROC analysis revealed excellent diagnostic accuracy, especially for LVGLS (AUC 0.919) and right atrial contractile strain (AUC 0.958). Conclusions: STE enables the early detection of extensive biventricular and biatrial myocardial dysfunction in neonatal EA, including abnormalities not fully captured by conventional echocardiographic parameters, thereby providing significant incremental diagnostic value.

Background: Ventricular function assessments in Fontan patients remain challenging. Ejection fraction (EF) lacks sensitivity for early dysfunction, and the roles of strain and advanced imaging in systemic left ventricle (LV) physiology are not fully defined. We aimed to compare (i) LV and atrial strain indices between pediatric Fontan patients with preserved EF (P-LVEF) versus reduced EF (R-LVEF) and (ii) echocardiographic global longitudinal strain, segmental longitudinal strain indices, and conventional 2D and 3D echocardiographic parameters through cardiac morphology. Methods: Pediatric patients with Fontan circulation and systemic LV morphology underwent clinical, hemodynamic, and multimodality echocardiographic evaluation, including 2D/3D parameters, global and segmental LV strain, and left atrial strain. Outcomes were analyzed according to EF status and congenital morphology. Significant results from multiple comparisons were followed by post hoc analysis, where appropriate. Results: Patients with a reduced EF exhibited a worse clinical status, a higher pulmonary vascular resistance index, and greater systemic congestion compared with those with a preserved EF. Conventional 2D indices showed no significant differences between the two studied groups except for LV end-systolic volume (ESV) (p = 0.0315) and LV end-systolic longitudinal diameter (ESL) (p = 0.0024), which showed higher values in the R-LVEF group. Although the relative frequency of impaired deformation was higher in Fontan patients with an unbalanced atrioventricular canal compared with the Fontan patients with a tricuspid atresia + pulmonary stenosis + ventricular septal defect, the difference did not reach statistical significance (p = 0.1365). Most segmental longitudinal strain values were not significantly different across patients with different cardiac morphology, except for the basal anterior segment and apical inferoseptal segment (p < 0.05). Conclusions: In pediatric Fontan patients with systemic LV morphology, a reduced EF was associated with a worse clinical and hemodynamic status. Conventional echocardiographic indices showed a limited ability to differentiate between the compared groups. Although no statistically significant differences were detected between pediatric Fontan patients with preserved EF and reduced EF, LV and atrial strain indices provided complementary information on ventricular–atrial interactions and myocardial deformation. These findings are exploratory and warrant confirmation in larger, prospective studies.