BACKGROUND:Primary immunodeficiencies (PIDs) and eosinophilic gastrointestinal diseases (EGIDs) may share common underlying defects. However, no studies have investigated the frequency of PIDs among patients with EGIDs. In this study, we aimed to assess the frequency and spectrum of PIDs among our pediatric EGIDs patients. METHOD:Patients were prospectively evaluated over a two-year period. All patients were questioned according to ten warning signs of the Jeffrey Model Foundation. Routine laboratory tests and basic immunologic tests [serum immunoglobulin levels, isohemagglutinin titres, anti-HBs and anti-rubella Ig G titres] were performed on all participants. Advanced immunologic workup was performed in selected cases. All PID diagnoses were established according to the European Society for Immunodeficiencies' criteria. Electronic health records were screened for EGIDs' specific features, comorbidities, and previous laboratory tests. RESULTS:A total of 88 EGID patients [76% male, mean age: 12.02 years, 78 patients (88.6%) with EoE] were included. Fourteen patients were diagnosed with predominantly antibody deficiencies [unclassified antibody deficiency (n = 11), selective Ig A deficiency (n = 2), transient hypogammaglobulinemia of infancy (n = 1)]. Eighteen patients had abnormal Ig levels. Comparisons across the groups revealed no statistically significant differences in demographic, endoscopic, and pathologic features. Only topical swallowed budesonide unresponsiveness was significantly higher among cases with PID (p = .004). CONCLUSION:PIDs may not be rare among patients with EGIDs. JMF's warning signs alone may be insufficient to identify affected patients in this population; therefore, additionally, basic immunologic tests as first step and advanced evaluation in suspected cases may be appropriate. Neither the key diagnostic endoscopic and pathological features nor the presence of strictures reliably distinguish PIDs.
BACKGROUND:In our previous study, casein specific IgE (sIgE) was identified as the best predictor for heated milk (HM) tolerance. However, reaction severity and cumulative eliciting dose in oral food challenges (OFC) remain difficult to predict. The use of milk basophil activation test (BAT) and sIgE avidity has not been previously studied for this purpose in HM allergy without the presence of wheat matrix. Consequently, we aimed to investigate whether they could improve prediction of fresh milk (FM) and HM OFC outcomes, reaction severity, and cumulative eliciting dose. METHODS:1-18-year-old Finnish children with suspected IgE-mediated cow's milk allergy underwent OFCs with both FM (N = 160) and HM (N = 138). sIgE to milk and its allergens was measured. Milk BAT using whole blood and casein sIgE avidity measurements using a thiocyanate-based ELISA assay were performed. RESULTS:Milk BAT showed better performance in discriminating allergy and tolerance in FM OFCs (N = 57, area under the curve (AUC) 0.946) than in HM OFCs (N = 42, AUC 0.686). Casein sIgE avidity did not differ between HM allergic and tolerant children (N = 56). Neither assay was associated with reaction severity or cumulative eliciting dose in FM or HM OFCs. CONCLUSION:Milk BAT performed well in FM allergy prediction, while in HM OFCs its diagnostic accuracy was modest and did not exceed that of casein sIgE. Casein sIgE avidity did not improve prediction of FM or HM OFC outcome, reaction severity, or cumulative dose. The avidity assay was also inherently limited by the requirement for casein sIgE levels of >1kU/L.
OBJECTIVE:This study applied two-sample Mendelian randomization (MR) to elucidate causal relationships between sleep-related phenotypes and childhood asthma risk. METHODS:Instrumental variables for daytime napping, sleep disorders, chronotype, and fatigue were selected from European ancestry genome-wide association studies. Causal estimates were primarily derived using inverse-variance weighting (IVW), supplemented by sensitivity analyses including MR-Egger and MR-PRESSO. Instrument validity, heterogeneity, pleiotropy, and directionality were rigorously evaluated. RESULTS:IVW results demonstrated that genetic susceptibility to daytime napping (OR = 1.76; 95% CI: 1.07-2.88; p < .05), sleep disorders (OR = 1.35; 95% CI: 1.12-1.61; p < .05), and frequent fatigue (OR = 2.94; 95% CI: 1.61-5.38; p < .05) significantly increased asthma risk, whereas morning chronotype was protective (OR = 0.76; 95% CI: 0.61-0.98; p = .015). Sensitivity analyses supported these findings, with no evidence of pleiotropy or reverse causation. CONCLUSIONS:These results suggest that sleep behaviors causally influence childhood asthma risk and may represent modifiable targets for prevention and management.
BACKGROUND:Oral food challenge (OFC) protocols in food protein-induced enterocolitis syndrome (FPIES) often select starting doses with consideration of prior reaction severity, implying that dose may influence reaction intensity; however, patient-level evidence linking antigen dose to reaction profiles remains limited. OBJECTIVE:To characterize threshold heterogeneity and compare clinical reaction profiles between diagnostic and reactive threshold OFCs within individual patients. METHODS:In this prospective study, 54 infants with OFC-confirmed FPIES (egg yolk, 36; cow's milk, 18) underwent threshold characterization at 0.001 g/kg (ultra-low) and 0.01 g/kg (low); all had previously reacted at a diagnostic OFC (median 0.38 g/kg). For the 30 reacting at a threshold challenge, the primary endpoint was objective reaction intensity (vomiting, examination signs); treatment intensity and a composite burden category were supporting measures. RESULTS:Of 54 patients, 12 (22%) reacted at 0.001 g/kg, 18 (33%) at 0.01 g/kg, and 24 (44%) tolerated both. Among the 30 threshold reactors, reactions were objectively milder than at the diagnostic OFC: median vomiting 2 (IQR 2-3) versus 4 (4-6) (p < .001), pallor 27% versus 63% (p = .019), decreased activity 43% versus 80% (p = .007). No ICG-defined severe features (hypotension/shock, severe lethargy) occurred at either OFC. Treatment intensity was also lower (intravenous fluid and prolonged observation each 27% versus 67%; both p < .001). CONCLUSION:Reactions at ultra-low and low threshold doses were objectively milder than at diagnostic doses within patients, while clinically meaningful reactions still occurred. These findings support systematic threshold assessment beginning at 0.001 g/kg, independent of diagnostic OFC clinical burden.
BACKGROUND:Behavioral problems and asthma in childhood are considered related despite the debatable causal relationship and unknown mechanisms. We investigated whether early-life behavioral problem trajectories affect the risk of childhood asthma and ascertained potential DNA-methylation mechanisms. METHODS:Based on two independent birth cohorts, this study included 1041 and 1647 children aged 6-10 and 6-7 years in the Cohort for Childhood Origin of Asthma and Allergic Diseases (COCOA) study and Panel Study on Korean Children (PSKC), wherein asthma was defined by a physician's diagnosis and parental questionnaire, respectively. The Korean version of the Child Behavior Checklist (CBCL) was administered at ages 2-6 years. The CBCL trajectories were identified using a latent generalized mixture model. Blood samples from 7-year-old participants were used for DNA-methylation profiling and quantifying metabolites and proteins. RESULTS:Trajectories with high internalizing behavioral problem scores in preschool age were significantly associated with childhood-onset asthma. Increased CBCL anxiety/depression scores at age 2 (COCOA) and somatization scores at ages 4 and 6 (COCOA and PSKC) significantly increased the risk of asthma symptoms and current asthma. In an exploratory sub-study, DNA-methylation analysis suggested hypomethylation of HAL and MAD1L1 in children with co-occurring asthma and behavioral problems, accompanied by higher HAL protein and lower circulating histidine. CONCLUSION:Early-life internalizing behavioral problem trajectories precede childhood asthma, which may be mediated by methylation, especially of HAL and MAD1L1.
BACKGROUND:Food allergies (FA) are a growing public health concern affecting family wellbeing. While previous research has focused largely on school-aged children, limited evidence exists regarding families of infants and toddlers. This study examined the quality of life (QoL) in families with children aged up to 3 years with food allergies in Cyprus and sought to identify modifiable factors that may inform strategies to improve family QoL. METHODS:A sequential explanatory mixed-methods design was used. Quantitative data were collected from mothers of 100 children with FA diagnosis by either a consultant allergist or consultant paediatrician using the Food Allergy Quality of Life Questionnaire-Parent Form, translated and culturally adapted into Greek. Semi-structured interviews were conducted with 12 mothers and analysed using thematic analysis. Findings were integrated using a joint display. RESULTS:Mean FAQLQ-PF scores indicated mild-moderate quality-of-life impairment; however, notable burden was observed in domains related to fear of unfamiliar foods, dietary restriction and social participation. Moderate-high concern regarding accidental ingestion (76%) and severe reactions (77%) was common. Qualitative findings highlighted sustained parental vigilance, restructuring of daily routines around food safety and emotional strain associated with diagnostic uncertainty. Mothers also described variability in clinical guidance and limited societal awareness, particularly in childcare and public food environments. Integration revealed predominantly convergent findings. In one area of complementarity, qualitative data revealed extensive daily caregiving effort underlying low quantitative activity limitation scores. One area of silence was identified where a quantitative construct was not reflected in interview narratives, suggesting that structured and open-ended methods capture different dimensions of the caregiving experience. CONCLUSION:In our sample, families of infants and toddlers with FA in Cyprus experience persistent emotional and practical challenges despite moderate QoL impairment. Parental stress is driven primarily by risk perception, social restrictions and variability in clinical guidance. Standardised early management and improved community awareness may enhance family adaptation during this critical period.
BACKGROUND:Prenatal exposure to ambient air pollution has been associated with early-life allergic outcomes; however, underlying biological mechanisms remain incompletely understood. METHODS:A total of 101 mother-infant pairs were ultimately included in this prospective birth cohort study. Maternal exposure to ambient air pollutants was assigned to geocoded residential addresses using spatiotemporal models. Allergic symptoms were defined as cumulative caregiver-reported symptoms occurring from birth to 6 months and assessed at the 6-month follow-up. DNA methylation in naïve CD4+ T cells was analyzed in a subset of 30 cord blood samples using targeted bisulfite sequencing. Associations were evaluated using regression models, and statistical mediation analysis was performed under a counterfactual-based approach. RESULTS:Higher first-trimester exposure to PM10 (adjusted odds ratio [AOR], 2.27; 95% confidence interval [CI], 1.09-4.98) and NO2 (AOR, 2.11; 95% CI, 1.02-4.53) was associated with an increased likelihood of allergic symptoms within the first 6 months of life. In addition, third-trimester exposure to PM2.5 components, including sulfate (SO4 2-), nitrate (NO3 -), and ammonium (NH4 +), was positively associated with these outcomes. DNA methylation at a CpG site within the PRKACB promoter showed statistical evidence consistent with a potential mediating role in the association between third-trimester sulfate exposure and allergic symptoms. Functional assays supported the regulatory relevance of this locus. CONCLUSIONS:Prenatal ambient air pollution exposure was associated with early-life allergic symptoms, and cord blood DNA methylation at the PRKACB locus may represent a potential molecular mechanism underlying these associations. These findings are exploratory and require confirmation in larger studies.
BACKGROUND:Allergic rhinitis is the most common chronic disease in children. Information on efficacy and safety of oral allergic rhinitis treatments in children is scarce. We aimed to comprehensively evaluate the efficacy and safety of oral medications for allergic rhinitis in children. METHODS:We performed a systematic review, searching three bibliographic databases and clinicaltrials.gov for randomized controlled trials assessing the use of oral antihistamines (OAH) or leukotriene receptor antagonists (LTRA) in children (<12 years old) with seasonal or perennial allergic rhinitis. Evaluated outcomes included the Total Nasal Symptom Score (TNSS), the Total Ocular Symptom Score (TOSS), the Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ), development of adverse or serious adverse events, and withdrawals due to adverse events. We performed network meta-analysis at both class and individual treatment levels. Certainty in the body of evidence was assessed using the GRADE approach for network meta-analysis. RESULTS:We included eight primary studies with 906 participants. Overall, OAH were more effective against placebo in improving the TNSS (mean difference (MD) = -1.60; 95%CI = -2.25 to -0.95). On the other hand, OAH+LTRA did not demonstrate additional benefit over OAH in improving the TNSS (MD = -0.15; 95% CI = -1.18 to 0.88), and there were no important differences between individual OAH. Evidence on the TOSS was not found. No significant differences in the frequency of adverse events were observed. Certainty of evidence was low or very low for most comparisons. CONCLUSIONS:Oral treatments for allergic rhinitis appear to be effective and safe in children. However, evidence is scarce and the quality of evidence is mostly low. We performed a systematic review of randomised controlled trials assessing oral medications for allergic rhinitis in children and reporting results on nasal symptoms, ocular symptoms, quality of life and adverse events. Oral antihistamines (OAH) were found to be better than placebo, and OAH + oral leukotriene receptor antagonists (OLTRA) were not found to be better than OAH. We identified trivial differences between different OAH.
BACKGROUND:Eosinophilic oesophagitis (EoE) is a chronic immune-mediated disease in which oesophageal microbiota may vary according to disease activity and treatment. We aimed to characterise oesophageal microbiota in treatment-naïve children with EoE before and after proton pump inhibitor (PPI) therapy, and to assess spatial variability along the oesophagus. METHODS:In this multicentre longitudinal study, oesophageal biopsies were obtained from proximal-mid and distal oesophagus of treatment-naïve children with newly diagnosed EoE at baseline and after standardised PPI induction therapy, and from non-EoE controls. Microbiota composition was analysed using 16S rRNA gene sequencing. Alpha and beta diversity, differential taxonomic abundance and associations with eosinophilic inflammation and treatment response were assessed. RESULTS:Oesophageal microbiota profiles differed between active EoE, post-treatment EoE and non-EoE controls. Active EoE showed higher alpha diversity, particularly in the presence of moderate-to-severe eosinophilic inflammation. Microbial diversity and composition were largely consistent between proximal-mid and distal oesophageal regions. Active EoE was associated with enrichment of inflammation-related taxa, including Fusobacteriota and Bacteroidota, and genera such as Neisseria, Fusobacterium and Prevotella. PPI induction therapy was associated with reduced alpha diversity and compositional shifts characterised by increased Firmicutes and reduced inflammation-associated genera, irrespective of histological response. Specific taxa were enriched in non-responders post-treatment. CONCLUSIONS:Children with EoE exhibit an oesophageal microbiota profile associated with disease activity and largely stable across oesophageal regions. PPI therapy was associated with microbiota compositional changes irrespective of histological response, supporting a dynamic interaction between treatment, inflammation and the oesophageal microbial ecosystem.
BACKGROUND:The timing of clinically meaningful benefit after pediatric sublingual immunotherapy (SLIT) across allergic multimorbidity patterns remains uncertain. We evaluated early and longitudinal response to SLIT in routine care. METHODS:This retrospective longitudinal cohort included patients aged 3-17 years who received individualized liquid-drop SLIT and met prespecified adherence and treatment-persistence criteria. Assessments were performed at baseline and months 6, 12, 18, 24, and 36. The primary outcome was achievement of the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) minimal clinically important difference (MCID; increase ≥0.5 points) at month 6. RESULTS:Among 1208 patients, 1095 had asthma and 954 allergic rhinitis. Overall, 666/1095 (60.8%) achieved month-6 PAQLQ MCID: 515/671 (76.8%) with asthma plus allergic rhinitis (Asthma+AR), 103/254 (40.6%) with allergic asthma without AR, and 48/170 (28.2%) with asthma, AR, and atopic dermatitis (Asthma+AR + AD). Compared with allergic asthma without AR, adjusted odds of response were higher for Asthma+AR (adjusted odds ratio 4.73, 95% CI 3.47-6.45) and lower for Asthma+AR + AD (0.52, 95% CI 0.34-0.80). By month 36, mean PAQLQ increased by 1.42 points, rhinitis-related quality-of-life scores decreased by 1.89 points, FeNO decreased by 15.7 ppb, and prescribed inhaled corticosteroid dose decreased by 92.6%. CONCLUSION:Early response to pediatric SLIT differed across clinical allergic multimorbidity patterns, although outcomes continued to improve through 36 months in this selected adherent and treatment-persistent cohort.
