Plasma Extracellular Vesicles Derived from Pediatric COVID-19 Patients Modulate Monocyte and T Cell Immune Responses Based on Disease Severity.

BACKGROUND: The COVID-19 pandemic has caused significant morbidity and mortality globally. The role of plasma-derived extracellular vesicles (EVs) in pediatric COVID-19 patients remains unclear. METHODS: We isolated EVs from healthy controls (n = 13) and pediatric COVID-19 patients (n = 104) with varying severity during acute and convalescent phases using serial ultracentrifugation. EV effects on healthy PBMCs, naïve CD4+ T cells, and monocytes were assessed through in vitro assays, flow cytometry, and ELISA. RESULTS: Our findings indicate that COVID-19 severity correlates with diverse immune responses. Severe acute cases exhibited increased cytokine levels, decreased IFNγ levels, and lower CD4+ T cell and monocyte counts, suggesting immunosuppression. EVs from severe acute patients stimulated healthy cells to express higher PDL1, increased Th2 and Treg cells, reduced IFNγ secretion, and altered Th1/Th17 ratios. Patient-derived EVs significantly reduced proinflammatory cytokine production by monocytes (p < .001 for mild, p = .0025 for severe cases) and decreased CD4+ T cell (p = .043) and monocyte (p = .033) populations in stimulated healthy PBMCs. CONCLUSION: This study reveals the complex relationship between immunological responses and EV-mediated effects, emphasizing the impact of COVID-19 severity. We highlight the potential role of plasma-derived EVs in early-stage immunosuppression in severe COVID-19 patients.

Clinical features, severity, and immunological changes during venom immunotherapy in children and adults.

Background: Hymenoptera venom allergy (HVA) is among the most common causes of severe allergic reactions worldwide. Objective: To investigate clinical features and factors that affect the severity of HVA and to determine the alterations in immunologic biomarkers after venom immunotherapy (VIT). Methods: Seventy-six adults and 36 children were prospectively investigated. We analyzed specific immunoglobulin E (sIgE) and sIgG4 levels of venom extracts and components (rApi m1, rApi m10, rVes v1, rVes v5, rPol d5) before and after the first year of VIT. Results: Although cardiovascular symptoms were more common in adults (p < 0.001), the skin was the most affected organ in children (p = 0.009). Serum basal tryptase (sBT) levels were higher in the adults than the children (p < 0.001). The absence of urticaria (odds ratio [OR] 4.208 [95% confidence interval {CI}, 1.395-12.688]; p = 0.011) and sBT ≥ 5.2 ng/mL (OR 11.941 [95% CI, 5.220-39.733]; p < 0.001) were found as the risk factors for grade IV reactions. During VIT, changes in sIgE levels were variable. In the Apis VIT group, we observed remarkable increases in sIgG4 levels in Apis extract and rApi m1 but not in Api m10. Vespula extract, rVes v1, and rVes v5 sIgG4 levels were significantly increased in Vespula VIT group, we also detected significant increases in the Polistes extract and rPol d5 sIgG4 levels, which were not observed in the Apis VIT group. In the patients who received both Apis and Vespula VIT, increases in sIgG4 levels were observed for both venoms. Conclusion: Adults and children can have different clinical patterns. After 1 year, VIT induced a strong IgG4 response. Although Apis immunotherapy (IT) induced Apis sIgG4, excluding Api m10, Vespula IT induced both Vespula and Polistes sIgG4.

The contribution of milk substitutes to the nutritional status of children with cow's milk allergy.

BACKGROUND: The impact of alternative milk substitutes on the nutritional status of children with cow's milk allergy (CMA), the prevailing cause of food allergies, is unresolved. METHODS: A cross-sectional study was performed in children older than 2 years with IgE-mediated CMA. Patients' clinical characteristics, anthropometric measurements, dietary intake (by 3-day food diary), and biochemical markers of nutritional status were assessed. RESULTS: One hundred two children with CMA (68.6% boys; median age, 3.7 years; 51% multiple food allergies) were evaluated. 44.1% of the children consumed plant-based beverages (PBB), 19.6% therapeutic formula and 36.3% did not consume any milk substitutes. In all age groups, dietary calcium, riboflavin, and vitamin D intake of those who did not use milk substitutes were lower than those who consumed formula or PBB (p < .01). Also in the 2-3 years old age group, dietary zinc (p = .011) and iron intake (p = .004) of the formula-fed group was higher. Formula-fed patients had higher levels of 25-OH vitamin D (µg/L) and serum vitamin B12 (ng/L) than PBB-fed patients (respectively; p < .001, p = .005) and those who did not consume any milk substitute (p < .001). Patients of all ages who did not utilize a milk substitute failed to obtain an adequate amount of dietary calcium. CONCLUSION: The use of milk substitutes positively affects dietary calcium, riboflavin, and vitamin D intake in CMA, but their contribution is variable. Those who do not use milk substitutes are at greater risk inadequate of dietary calcium intake. Personalized nutritional advice, given the clinical diversity and the impact of individual differences, is required.

The treatment journey of children with moderate to severe atopic dermatitis in Türkiye: unmet needs.

BACKGROUND: Atopic dermatitis (AD) substantially burdens individuals, families, and healthcare systems. We aimed to document the treatment journey of pediatric patients with moderate-to-severe AD in a referral center based in our country. METHODS: This retrospective study reviewed patients aged 1-18 years diagnosed with AD, seeking systemic treatment recommendations from the "pediatric allergy and dermatology multidisciplinary team meeting". RESULTS: Over the 14-month study period, 30 (12.5%) of 240 AD patients were evaluated in the pediatric dermato-allergy team meetings. The median age of the patients was 13.66 years (Q1-Q3: 7.94-17.27), of whom 60% were male. The median annual healthcare visits for AD were 4 (Q1-Q3: 1.00-8.75). Among the study group, 70% were sensitized to aeroallergens, and admission markers included total IgE (median: 1980 IU/mL, Q1-Q3: 794.50-5446), and eosinophil counts (median: 650, Q1-Q3: 275-1275). All patients utilized intermittent and/or continuous topical corticosteroids (CS), with 56.6% employing short-term/long-term topical tacrolimus. Over the past two years, systemic CSs were utilized in 93.3% of the patients, whereas 57.1% received more than one course. Approximately 43.3% of the patients agreed to receive systemic cyclosporine treatment, with only 30.8% benefiting and 3.3% reporting adverse effects (hypertrichosis and cellulitis). Three patients self-funded dupilumab, all benefiting without adverse effects. Omalizumab, mycophenolate mofetil and narrow-band  ultraviolet (UV) treatments were used in one patient each, with limited benefit observed. Health insurance did not grant approval for a Janus kinase inhibitor for one patient. CONCLUSIONS: Managing moderate to severe AD is complex and costly, considering disease heterogeneity, comorbidities, care pathways, and health system challenges. Addressing the unmet needs should be a priority in Türkiye's healthcare systems.

Recognition of nuts and seeds in children with/without food allergies and their mothers: A reflection of culinary culture.

BACKGROUND: Nuts and seeds are among the leading causes of food allergy. Effective food allergy management hinges on the ability to identify and avoid relevant foods. AIM: To evaluate the nut/seed recognition ability in both children and mothers. METHODS: Primary caregivers (mothers) and their children (6-18 years old) with/without food allergies were shown photographs of nuts/seeds, and their products with visible/hidden allergens to assess their ability to recognize accurately. RESULTS: A total of 196 children and 184 mothers participated. The median ages of the children and mothers were 7.6 (6.8-10) and 37.8 (33.1-41.5) years, respectively. Over 75% of the children/adolescents and over 90% of the mothers accurately identified the kernel forms of nuts/seeds, except pine nuts. Walnuts, hazelnuts, almonds, and cashews were the most accurately recognized kernel forms by both populations. Generally, the kernel forms were recognized 5-20% more accurately than their in-shell forms, followed by products with visible and hidden forms, respectively. Some Turkish culinary-specific products with visible/hidden allergens were recognized as frequently as the kernel/in-shell forms by both study groups. Although there was a similar recognition pattern between study groups and subgroups (nut/seed allergy, other food allergy, controls), higher rates of recognition were found in mothers than in their children and adolescents than in schoolchildren. CONCLUSION: In Eastern Mediterranean region, nuts and sesame seeds are highly recognized by both mothers and their children. Accurate identification of these foods is likely a culinary feature, but not the result of increased awareness. More information is needed on whether this ability reduces the risk of exposure.

Understanding of lipid transfer protein sensitization patterns and its clinical significance in children.

Background: Lipid transfer proteins (LTP) are the most common food allergens in the Mediterranean region. Objective: The study aimed to investigate co-sensitization patterns and cluster relationships between LTP allergen molecules across a broad range of allergen-specific sensitization patterns, and clinical outcomes in eastern Mediterranean children. Methods: Among 496 children evaluated for multiple sensitizations with multiplex testing, 105 children (21%) with 16 different LTP sensitizations were analyzed. Clinical reactivity was examined based on clear-cut history of immunoglobulin E mediated symptoms (oral allergy syndrome [OAS], systemic reactions, and anaphylaxis). Results: All children included were sensitive to food LTPs, but 56% were sensitive to pollen LTPs. The number of children with OAS and clinical reactivity was 12 and 59, respectively, and no cofactors were reported. The most common sensitizations were Pru p 3 (74%) and Cor a 8 (66%). Significant correlations were observed in the heatmap between the LTP molecules other than Par j 2 and Tri a 14. Overall, clinical reactivity was associated with increased age and number of LTP molecule positivity. Conclusion: In the eastern Mediterranean region, 21% of children with multiple food and/or pollen sensitizations were found to have LTP sensitization; however, almost half reported clinical reactivity. The hierarchical pathway highlights that distinct LTP allergen molecules can act as primary sensitizers. Clinical reactivity is linked to increasing numbers of LTP molecule positivity and increasing age.

Mite allergen sensitization patterns in Turkish children: Age-related changes and molecular correlations.

BACKGROUND: Mites are ubiquitous aeroallergens found worldwide. Elucidating individual mite allergen sensitization patterns provides critical insights for managing allergic diseases. This study aimed to investigate molecular allergen (MA) sensitization patterns across different age groups and explore cluster relationships among mite-sensitized children. METHODS: We analyzed 76 children who exhibited sensitization to at least one of the 17 distinct mite MAs through microarray testing. RESULTS: Dermatophagoides farinae exhibited a slightly higher prevalence of sensitization compared with Dermatophagoides pteronyssinus. Der p 1/2 and Der f 1/2 demonstrated an almost 40% sensitization rate, while Der p 10/Blo t 10, Der p 20, Der p 23, and Gly d 2/Lep d 2 displayed an approximately 20% sensitization rate. Sensitization levels and ratios increased significantly with age for Der p 23 but showed numerical rises for other MAs, except for Der p 10/Blo t 10. The presence of various types of atopic diseases had only a minimal impact on sensitization profiles. Strong correlations emerged between Der f 2 and Der p 2, Der p 10 and Blo t 10, Der p 21 and Blo t 5, as well as Gly d 2 and Lep d 2. Hierarchical cluster analysis substantiated these relationships. Der p 10 and its homolog Blo t 10-sensitive patients (15/76) were mostly seen as mono sensitization(12/15). Ten patients exhibited monosensitization to Der p 20, suggesting a possible association with scabies infection. CONCLUSION: In children, mite sensitization diversity and levels increased with age. The presence of significant correlations/cluster relationships among these sensitizations underscores homologies among specific MAs.

Systemic treatments in atopic dermatitis in children.

Atopic dermatitis (AD) is a very common skin disease caused by inflammatory reactions, in which the main symptoms of severe itching and recurrent eczema diminish quality of life. As epidermal barrier function and the immune system play a critical role in atopic dermatitis, promoting IgE-mediated sensitization can be the main targets of AD treatment. The goal of AD treatment should be to eliminate the symptoms and obtain longterm eczema control with a multi-step approach adapted to the severity of the disease. Basic management for all patients comprises the use of moisturisers and avoiding triggers. While topical therapy is effective for most children diagnosed with AD, there may also be children who require systemic therapy. The aim of this paper was to present an extensive review of the systemic agents commonly used in childhood atopic dermatitis which mainly target cutaneous inflammation.

Cupressus arizonica: an emerging aeroallergen for East Mediterranean children.

Background/aim: Cupressus sempervirens is a tree native to the Mediterranean region. We aimed to investigate the frequency of sensitization/allergy to Cupressus arizonica pollen, which is not native to Anatolia. Materials and methods: Patients aged 5-18 years who underwent respiratory allergy screening in Türkiye's largest referral center over a 1-year period were reviewed retrospectively for a diagnostic study of Cupressus allergy. Results: Of 246 patients, 207 (67.6% male) with a median age of 11.7 (IQR 9.2-15) years were found to be aeroallergen-sensitive and C. arizonica (32%) was the second most common sensitivity after grass pollen (83.6%). In the C. arizonica-sensitive subgroup, only 3% (2/67) were monosensitive, and grass (77.6%), cat (38.8%), and weeds (38.8%) were the most common co-sensitivities. Cup a 1 specific IgE (sIgE) was measured in 26 patients with C. arizonica sensitivity and all were found to be positive. A nasal allergen challenge (NAC) was performed for 44 of 67 patients with C. arizonica sensitivity, and 13 of 44 patients had a positive outcome (NAC+) at the highest two extract concentrations. The Cupressus wheal sizes and Cup a 1 sIgE levels of the NAC+ subgroup were higher than those of the NAC- subgroup but reached significance only for wheal size [6 (5-7.5) vs. 4.5 (4-6), p=0.004]. The NAC+ subgroup reported more frequent nasal discharge, congestion, and eye symptoms than the NAC- subgroup during the relevant pollen season. Conclusion: C. arizonica sensitivity has increased in the East Mediterranean region, similarly to North Mediterranean data, and this is associated with the presence of allergy both clinically and in laboratory findings. C. arizonica should be included in the aeroallergen screening panels of children from the East Mediterranean.

Infantile atopic dermatitis: Serum vitamin D, zinc and TARC levels and their relationship with disease phenotype and severity

Background Several markers that influence the clinical course of atopic dermatitis (AD) have been investigated so far. Thymus and activation regulated chemokine (TARC) – a Th2-related cytokine – increase in various atopic diseases. It has been shown that vitamin D affects Treg cells and immune responses. Zinc as an essential trace element for cell–cell interactions, cellular differentiation, and proliferation. However, the effect of these markers on infantile AD and disease severity are mostly unknown. Objective The aim of this study was to investigate the relationship between TARC, vitamin D, zinc levels, and the disease severity in infants with AD. Method AD patients (n = 160) with age and sex that matched healthy controls (n = 79) were included in the study. The diagnosis of AD was made based on the Hanifin–Rajka criteria. The objective SCORAD index was used for the assessment of disease severity. Results A total of 160 patients (male 71.9%) with AD were included in the study. The median age of onset of symptoms was 2 (1.0–3.5) months. The lesions initially started on face 76.9%, neck 6.9%, extremities 7.5%, and body 8.8%. Nearly 40% of the patients were found to be atopic. Food allergy was found in 39.4%. The median of objective SCORAD index was 27.5 (17.5–40) in the study group. The TARC levels of AD patients were higher than control group [1803 pg/ml (1006– 3123) vs 709 pg/ml (504–1147), p < 0.001] There was a significant correlation between objective SCORAD scores and TARC values in subjects with AD (r = 0.363, p < 0.001). As the severity of AD increased, vitamin D levels decreased (p for trend 0.015) and TARC values increased (p for trend < 0.001). Serum zinc levels did not change with the severity of the disease. The presence of atopy did not have an influence on serum TARC, zinc, and vitamin D levels. Conclusion In infants with AD, disease severity is positively related with TARC levels; and inversely proportional to vitamin D levels (AU)

Oral food challenge in IgE mediated food allergy in eastern Mediterranean children

Background: The oral food challenge (OFC) in IgE mediated food allergy causes anxiety both in parents and in patients due to its inherent risks. Objective: Documentation of the rate, spectrum, and predictors of positive reactions is instructive. Methods: Children, who underwent OFC between January 1, 2017 and December 31, 2019 were analyzed. Results A total of 1361 OFCs in 613 cases were reviewed. Most of them were performed in preschool children (≤2 years 50%) and 55% of them had more than one OFC. Mainly considered food groups were cow’s milk (31.8%), hen’s egg (28.5%), tree nuts (20%), legumes (7%), seeds (4.9%), and wheat (2.7%). The overall OFC positivity was 9.6%, whereas 6.7% with cow’s milk, 4.9% with hen’s egg, 16.1% with tree nuts, 21.6% with wheat, and 32.8% with seeds. The severity scoring revealed grade I (24.4%), II (45.8%), and III (29.7%) reactions. Fifty (38%) cases required epinephrine and four cases required hospitalization. OFCs with sesame seeds (odds ratio [OR]: 7.747, [confidence interval (CI) 95%: 4.03–14.90]), wheat (OR: 3.80, [CI: 1.64–8.84]), and tree nuts (OR: 2.78, [CI: 1.83–4.23]) predicted a positive OFC while a concomitant asthma (OR: 3.61 [CI: 1.27–10.28]) was more likely to elicit anaphylaxis. Conclusion In OFC practice, priority is given to basic nutritional sources and the most frequent food allergens, where preschool children with multiple sensitizations are the primary subjects. Increased risks of positive reactions with sesame, tree nut, and wheat and increased risk of anaphylaxis with concomitant asthma should be considered while performing OFC (AU)

The impact of skin prick testing on pain perception and anxiety in children and parents

Background Skin prick testing (SPT) is a major diagnostic tool in patients with allergic symptoms. The testing process may involve pain, anxiety, and stress on children and parents. Objective We aimed to measure the level of pain and anxiety before and after SPT in children and parents, and tried to identify predictive factors. Methods The children underwent SPT and parents completed the State Trait Anxiety Inventory (STAI) S-Anxiety before and after SPT, T-Anxiety before SPT. The study nurse completed Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) scores (<5 years) or Wong-Baker FACES Pain Rating Scale (VAS), (≥5 years) after the SPT, in order to quantify pain. Results A total of 523 children (5.3 [2.8–9.1] [median, interquartile range] years old, 59.5% male) were evaluated. Parent gender was a predominant factor for anxiety, as mothers had a higher pre-test STAI (S-Anxiety) score, STAI (T-Anxiety), and post-test STAI (S-Anxiety) score than fathers (p < 0.001). Pre-test STAI (S-Anxiety) scores of parents decreased with increasing age (for 0–<5 years, 5–<12 years, and ≥12 years; [p for trend = 0.016]). The children tested on the back had higher VAS scores compared with the ones tested on the forearm [2[0–4] vs 2[0–2], [p = 0.005]). Risk factors determining higher general anxiety STAI (T-Anxiety) scores above the median were female sex for the parent (OR = 1.68; 95% CI [1.10–2.57]; p = 0.017), and parent’s education level being greater than or equal to high school level (OR = 1.83; 95% CI [1.27–2.64]; p = 0.001). Conclusion SPT may cause anxiety and pain in a subgroup of children particularly in younger age, and if performed on the back. Anxiety levels were higher in mothers, and in parents with high education levels (AU)

Phenotypical characterization of tree nuts and peanut allergies in east Mediterranean children

INTRODUCTION/OBJECTIVES: The characteristics of tree nuts (TNs) and peanut (PN) allergies vary in different regions of the world. We aim to identify the characteristics of TNs/PN allergies in Turkish children. Patients and METHODS: A total of 227 children [4.8 (3.2-6.8) years] with TN and/or PN allergies were included. The phenotypical features of TNs/PN allergic children and the risk factors for multiple TNs/PN allergies were evaluated. RESULTS: Allergy to TNs/PN developed at a median age of 12.0 (10.0-18.0) months. The most common TNs/PN responsible for food allergies were the hazelnut (63.9%) and the pistachio (54.6%). Of TNs/PN allergic children, 54.2% experienced reactions with at least two types of. Current ages 6-10 years [OR:2.455, 95% CI:1.255-4.852, p = 0.009] and family history of atopy [OR:2.156, 95% CI:1.182-3.932, p = 0.012] were the risk factors for multiple TNs/PN allergies. Most of the patients with cashew nut and pistachio allergies exhibited co-sensitization and co-allergy to both of these TNs/PN. Although the rarest TNs/PN allergy was seen with almond, the possibility of allergy to other TNs or PN was highly increased in the patients with almond allergy compared to other TNs/PN. CONCLUSIONS: Children with TNs/PN allergy living in an East Mediterranean region differ from the counterparts living in Western countries by an earlier age of onset of the TNs/PN allergy symptoms, increasing possibility to have multiple TNs/PN allergy at older ages, and different spectrum of TN/PN allergies (hazelnut followed by pistachio/cashew) that all indicate the consumption habits which are important determinants of TN/PN allergy development

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Predictive factors for progression to chronicity or recurrence after the first attack of acute urticaria in preschool-age children

Introduction and objectives: Preschool-aged group is frequently affected by urticaria, and infections are the most frequently documented factors that cause acute urticaria in children. This prospective study was designed to investigate the underlying factors of acute urticaria in under five-year-old children and to describe predictive factors for progression to chronicity or recurrence after the first attack. Patients and methods: Children younger than five years of age with acute urticaria were recruited between July 2015 and July 2016. Patients (n = 83) were grouped into those below and above two years of age. In order to assess the risk factors for progression to chronicity or recurrence, logistic regression analysis was performed. Results: Upper respiratory tract infection was the most common detectable reason for acute urticaria (49.4%). Herpes Simplex Virus type 1 was significantly isolated in the cases with the manifestation of an acute single-episode urticaria (p = 0.042). Angioedema and food allergy were predominantly observed under two years old (p = 0.001, p = 0.006 respectively). A positive relationship was determined between the duration of urticaria and chronicity (r = 0.301, p = 0.006). The absence of atopic dermatitis (OR: 6.95, 95% CI: 1.35-35.67, p = 0.020), negative Herpes virus serology (OR: 4.25, 95% CI: 0.83-21.56, p = 0.040), and unknown etiology (OR: 3.30, 95% CI: 1.12-9.71, p = 0.030) were the independent risk factors for recurrent urticaria. Conclusions: Preschool-aged children with acute urticaria should be evaluated for infections at the time of admission. Patients with unknown etiology, negative Herpes virus serology, absence of atopic dermatitis, and long lasting urticaria should be followed up for chronicity and recurrence

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