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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.

Eosinophilia is common in children and may be caused by various disorders. Large-cohort studies, including mild cases, are limited in children. This study aimed to reveal underlying etiologies of childhood eosinophilia and to create a diagnostic algorithm. Children (< 18 years) with absolute eosinophil counts (AECs) ≥ 0.5 × 10 9 /L were reviewed from medical files. Clinical characteristics and laboratory values were recorded. Patients were grouped based on the severity of eosinophilia as mild (0.5-1.5 × 10 9 /L), moderate (≥ 1.5 × 10 9 /L) and severe (≥ 5.0 × 10 9 /L). An algorithm was formed to evaluate these patients. We included 1178 children with mild (80.8%), moderate (17.8%) and severe eosinophilia (1.4%). The most common reasons of eosinophilia were allergic diseases (80%), primary immunodeficiency (PID) (8.5%), infectious diseases (5.8%), malignancies (0.8%) and rheumatic diseases (0.7%). Only 0.3% of children presented with idiopatic hypereosinophilic syndrome. Allergic diseases and PIDs were the most common etiologies in mild/moderate and severe groups, respectively. The median duration of eosinophilia was 7.0 (3.0-17.0) months in the study population and was the shortest in severe cases (2.0 (2.0-5.0) months). Multiple logistic regression analysis demonstrated food allergy [OR:1.866, 95%CI:1.225-2.842, p = 0.004] and PIDs [OR:2.200, 95%CI:1.213-3.992, p = 0.009] as independent factors for childhood eosinophilia. A diagnostic algorithm including mild form was presented for childhood eosinophilia.    Conclusion: Eosinophilia was frequently determined due to secondary causes; allergic diseases in mild/moderate eosinophilia, PIDs in severe group. Etiology of eosinophilia was diverse, and an algorithm concerning the severity of eosinophilia would be practical and rational. What is Known: • In children, eosinophilia is common, and mild eosinophilia occurs frequently. • Malignancies presents frequently with severe eosinophilia. What is New: • Primary immunodeficiencies were not a rare cause of eosinophilia, especially in countries such as the Middle East and eastern Mediterranean countries, where the countries consanguineous marriages are common, and should be investigated in children with eosinophilia who do not have allergic or infectious diseases. • In literature, there are many algorithms about childhood hypereosinophilia. However, mild eosinophilia is extremely important in children. Because all patients with malignancy and most of the patients with rheumatic diseases presented with mild eosinophilia. Therefore, we proposed an algorithm for childhood eosinophilia that includes mild eosinophilia besides moderate and severe cases., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Serine/threonine kinase-4 (STK4) deficiency is an autosomal recessive combined immunodeficiency., Objective: We aimed to define characteristic clinical and laboratory features to aid the differential diagnosis and determine the most suitable therapy., Methods: In addition to nine STK4 deficiency patients, we reviewed 15 patients from the medical literature. We compared B lymphocyte subgroups of the cohort with age-matched healthy controls., Results: In the cohort, median age at symptom onset and age at diagnosis were 6 years 8 months (range, 6-248 months) and 7 years 5 months (range, 6-260 months), respectively. The main clinical findings were infections (in all nine patients [9 of 9]), autoimmune or inflammatory diseases (7 of 9), and atopy (4 of 9). CD4 lymphopenia (9 out 9), lymphopenia (7 out 9), intermittent eosinophilia (4 out 9), transient neutropenia (3 out 9), low IgM (4 out 9), and high IgE (4 out 9) were common. Decreased recent thymic emigrants, naive and central memory T cells, but increased effector memory T cells were present. The increase in plasmablasts (P = .003) and decrease in switched memory B cells (P = .022) were significant. When 24 patients are analyzed, cutaneous viral infections (n = 20), recurrent pneumonia (n = 18), Epstein Barr virus-associated lymphoproliferation (n = 11), atopic dermatitis (n = 10), autoimmune cytopenia (n = 7), and lymphoma (n = 6) were frequent. Lymphopenia, CD4 lymphopenia, high IgG, IgA, and IgE were common laboratory characteristics., Conclusions: The differential diagnosis with autosomal recessive hyper-IgE syndrome is crucial. Because, atopy and CD4 lymphopenia are common in both diseases. Immunoglobulins, antibacterial, and antiviral prophylaxis are the mainstays of treatment. Clinicians may use immunomodulatory therapies during inflammatory or autoimmune complications. However, more data are needed to recommend hematopoietic stem cell transplantation as a safe therapy., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. Certain gene loci are pointed out in several studies in CVID patients. Until now, monogenic defects have been identified in only 2-10% of CVID patients; therefore, association of the disease with HLA alleles may be important for elucidating immunological and genetic mechanisms behind CVID. The aim of this study is to investigate the relationship between CVID and HLA alleles., Methods: HLA class I/II alleles were analyzed in 65 patients with CVID and alleles that may be related to disease susceptibility were determined by comparing with 300 healthy controls. We also evaluated HLA allele frequencies in CVID patients with gastrointestial system (GIS) involvement and autoimmune manifestations., Results: When compared with controls, frequencies of B*27, B*35, C*04, and DRB1*04 alleles were significantly different in patients with CVID ( p < .05). Frequencies of C*12, DRB1*13, and DRB1*15 alleles were more frequent in controls, indicating protective alleles ( p < .05). There was a statistically significant difference for DQ2 and DQ8 haplotypes between patients with GIS involvement and controls., Conclusion: In comparison with literature, distinctive HLA alleles found in our study may originate from the diversity in gene pool between the populations. These data may provide clues for disease susceptibility.

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. TARC levels differ between patients and healthy controls. The presence of atopy has not been shown to affect these markers. © 2021 Codon Publications. Published by Codon Publications., Competing Interests: The authors declare no conflict of interest. Hacettepe University Scientific Research Projects Coordination Unit provided financial support to this study and TARC kit was received with this financial support.

Background: Pistachio and cashew nut, which belong to the same botanical family, are tree nuts that induce serious allergic reactions., Objective: We aimed to determine the predictive factors for pistachio and cashew nut reactivity during oral food challenge (OFC)., Methods: A total of 112 pistachio and/or cashew nut sensitized children, aged 58.45 (IQR:40.38-88.32) months, were included. Cutoff values and probability curves for skin prick test (SPT), sIgE, sIgE/Total IgE that predict reactivity were determined for pistachio and cashew nut. Additionally, a diagram was created that can be useful while making a decision for OFC based on SPT and sIgE values., Results: A total of 73 patients underwent OFC with pistachio and/or cashew nut. Twelve children with current anaphylaxis history were not challenged and accepted as allergic. SPT was the only predictive factor for positive pistachio/ cashew nut OFC. According to area under curve (AUC) analysis, SPT was more predictive than sIgE and sIgE/Total IgE both for pistachio and cashew nut. Optimal cutoff values according to "Youden index" for pistachio SPT, sIgE, and sIgE/ Total IgE were 7.25 mm, 4.14 kUA/L, and 1.32%, respectively. And those values for cashew nut SPT, sIgE, and sIgE/Total IgE were 6.25 mm, 1.125 kUA/L, and 3.30%, respectively. The diagram showed that SPT predicted the reactivity together with sIgE better than only the SPT values., Conclusion: SPT was the best predictor for reactivity both for pistachio and cashew nut. Combined use of SPT and sIgE may improve the prediction of reactivity at pistachio and cashew nut OFCs in children.

Background: Food protein-induced allergic proctocolitis (FPIAP) is a non-immunoglobulin E (IgE)-mediated food allergy, which presents with bloody mucoid stool in infants. Although IgE-mediated allergy and sensitizations to offending foods have been described in other non-IgE-mediated food allergies, it has not been investigated in FPIAP., Objective: To investigate IgE-mediated allergy and sensitization to offending foods in FPIAP., Methods: Patients (n = 204) were retrospectively recruited and grouped as FPIAP (n = 180; FPIAP with or without the symptoms of IgE-mediated food hypersensitivity to offending and nonoffending foods at initial consultation), FPIAP-IgE sensitization to offending foods (n = 17), and FPIAP-transition to IgE-mediated allergy to offending foods (n = 7). The study was performed in accordance with the protocol approved by the local ethical committee of the Hacettepe University., Results: The median age of onset of symptoms and the development of tolerance was 2 months (interquartile range [IQR], 1.0-3.0) and 12 months (IQR, 10.0-14.0), respectively, and of the patients with skin prick test or serum specific IgE tests (n = 196), 38 (19.4%) had evidence of IgE sensitization to offending foods at the initial consultation or during follow-up; 17 (8.6%) had IgE sensitization, 7 (3.6%) indicated a transition to IgE-mediated allergy to FPIAP-induced foods. The median age of tolerance development of the FPIAP-transition group (19 months, IQR, 18.0-29.0) was significantly later than that of the FPIAP group (11 months, IQR, 10.0-14.0; P < .001) and the FPIAP-IgE sensitization group (11.0 months, IQR, 9.5-12.0; P < .001). Tolerance was observed within the study period in almost all the patients., Conclusion: Children with FPIAP may have sensitization or develop IgE-mediated allergy over time to offending foods. In addition, IgE sensitization in FPIAP does not have an unfavorable effect on tolerance development; however, the transition to an IgE-mediated phenotype may delay tolerance for a brief time., (Copyright © 2020 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive immune responses with high mortality. We aimed to define mortality-related parameters in HLH secondary to primary immunodeficiency (PID). A total of 28 patients with HLH between the years 2013 and 2017 were enrolled in the study. The patients were evaluated in 2 groups including PID with hypopigmentation (n=7) (Chédiak-Higashi syndrome [CHS] and Griscelli syndrome type 2 [GS2]) and other PIDs (n=21). The median age of the study population was 23 (4.3 to 117.0) months at the time of the diagnosis of HLH. Central nervous system involvement was recorded in 7 (GS2/CHS patients [n=4], other PIDs [n=3], P=0.026), and death was observed in 9 patients (GS2/CHS patients [n=1], other PIDs [n=8], P=0.371). Five patients (3 GS2/CHS and 2 other PID patients) underwent hematopoietic stem cell transplantation. Low serum albumin level was the only variable associated with the mortality and albumin levels less than the cut-off value of 3.07 g/dL increased mortality 5.8 times in patients with HLH secondary to PID. We presented a single-center experience consisting of patients with HLH secondary to PID with a mortality rate of 32.1%. Hypoalbuminemia was the only risk factor to increase the overall mortality rate of HLH.

Objectives Severe congenital neutropenia (SCN) is a primary immunodeficiency (PID) characterized by persistent severe neutropenia, recurrent infections, and oral aphthous lesions. Severe congenital neutropenia is caused by various genetic defects such as ELANE, GFI, HAX-1, JAGN1, SRP54, and glucose-6 phosphatase catalytic subunit 3 (G6PC3) deficiency. Clinical features of the patients with G6PC3 deficiency vary from neutropenia to several systemic features in addition to developmental delay. Case presentation In this report, we presented three unrelated patients diagnosed with G6PC3 deficiency. All these patients had short stature, prominent and superficial vascular tissue, cardiac abnormalities (Atrial septal defect (secondary), mitral valve prolapse with mitral insufficiency, pulmonary hypertension) and lymphopenia. Patient 1 (P1) and 2 (P2) had urogenital abnormalities, P2 and P3 had thrombocytopenia. Conclusions We have shown that lymphopenia and CD4 lymphopenia do not rarely accompany to G6PC3 deficiency. Characteristic facial appearance, systemic manifestions, neutropenia could be the clues for the diagnosis of G6PC3 deficiency.

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., (Copyright © 2019 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

Common variable immunodeficiency (CVID) results in defective B cell differentiation and impaired antibody production and is the most common symptomatic primary immunodeficiency. Our aim was to evaluate the correlation among B cell subgroups, κ-deleting recombination excision circle (KREC) copy numbers, and clinical and immunological data of the patients with CVID, and evaluate the patients according to classifications currently available to define the role of KREC copy numbers in the diagnosis of CVID. KREC analysis was performed using a quantitative real-time polymerase chain reaction assay, and B cell subgroups were measured by flow cytometry. The median age of the patients (n = 30) was 25 (6-69) years. Parental consanguinity ratio was 33%. The median age at diagnosis was 15 (4-59), and follow-up period was 6 (1-37) years. CD19 + and CD4 + cell counts at the time of diagnosis were low in 66.7% and 46.7% of the patients, respectively. CD19 + cell counts were positively correlated with KREC copy numbers in patients and healthy controls. CD19 + cell counts and KREC copy numbers were significantly reduced in CVID patients compared to healthy controls as expected. KRECs are quantitative markers for B cell defects. We found low CD4 + cell numbers, recent thymic emigrants, and lymphopenia in some of the patients at diagnosis, which reminds the heterogeneity of CVID's etiology. In this study, a positive correlation was shown between CD19 + cell counts and KREC copy numbers. Low KREC copy numbers indicated B cell deficiency; however, high KREC copy numbers were not sufficient to rule out CVID.

Background: Food protein-induced allergic proctocolitis (FPIAP) is a non-immunoglobulin E (IgE) mediated food allergy that typically presents with blood-mixed mucoid stool. Objective: To identify the predictors that affect the tolerance development in infants with FPAIP and laboratory as well as clinical differences between patients with early and with late tolerance. Methods: A total of 185 infants with FPIAP were included. The patients were grouped and analyzed based on laboratory tests and clinical characteristics. Results: The median (interquartile range [IQR]) age of onset of symptoms was 2.0 months (1.0-3.0 months). Symptoms began in severe cases in patients (n = 23) at a younger median (IQR) age (1.5 months [0.7-2.0 months]) than the group with nonsevere presentation (median 2.0 months [IQR 1.5-3.0 months]) (p < 0.001). The frequency of neutropenia (<1500/mm³) (p = 0.045) and eosinophilia (450 mm³) (p = 0.018) was increased in severe cases. Concomitant IgE-related food allergy (odds ratio [OR] 3.595 [95% confidence interval {CI}, 1.096-11.788], p = 0.035), non-IgE-mediated multiple food allergy (OR 3.577 [95% CI, 1.595-8.018], p = 0.002), feeding with cow's milk-based formula (at least once during infancy) (OR 2.517 [95% CI, 1.188-5.333], p = 0.016), and late complementary feeding (OR 5.438 [95% CI, 2.693-10.981], p < 0.001) were the predictors for late tolerance development. The estimated optimal cutoff value for introduction of complementary foods for the resolution of allergy was 5.5 months, with 69.4% sensitivity, 74.4% specificity, and an area under the curve of 0.737 (95% CI, 0.626-0.812) (p < 0.001). Conclusion: This study showed that the early introduction of complementary feeding accelerates tolerance development in FPAIP. A longer duration of an elimination diet has no impact on the resolution of allergy. Physicians should consider conservative avoidance measures and earlier introduction of complementary feeding in FPIAP.

Background: Anaphylaxis is a sudden, severe, and potentially life-threatening allergic reaction, affecting a portion of allergic patients. Adrenaline is the first-line medication for anaphylaxis and available in many parts of the world as adrenaline autoinjectors (AAIs)., Objective: Aim of this study was to determine attitudes and knowledge levels of patients/parents regarding the use of AAIs, frequency, and rate of appropriate AAI use and to give a standardized and better education by improving on mistakes during administration., Method: 190 patients aged 1-18 years who were prescribed AAIs for any reason between 2012 and 2017 in Hacettepe University Pediatric Allergy Unit. Demographic data were collected during face-to-face interview or by telephone. Parents completed a mini-survey regarding use, carriage, and storage of AAI., Results: Some 190 patients (64.7% male) aged 7.83 (4.99-12.08) years, median (inter-quartile), were included in the study. The indications for AAI prescription were food allergy (78.9%); venom allergy (14.2%); idiopathic anaphylaxis (3.7%); mastocytosis (2.1%); and drug allergy (1.0%). One-fourth of AAI-prescribed patients experienced anaphylaxis requiring the use of AAI within the past five years. However, only 30% of the patients dared to use AAI; only three-quarters of whom had managed to use it correctly., Conclusion: After prescription of AAI and initial training, patients and parents' concerns and fears should be taken into consideration and necessary support should be provided. At every opportunity and each clinical visit, not only should training sessions be repeated but also the patients and parents should be psychologically supported., (Copyright © 2019 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

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., (Copyright © 2019 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Tree nut (TN) allergies are the most common cause of fatal anaphylaxis and generally are ongoing food allergies throughout life. Objective: To investigate the predicting factors for TN anaphylaxis in children. Methods: Children with TN allergy were divided into anaphylactic and nonanaphylactic groups, those who had an anaphylactic reaction with at least one type of TN and those with any type of reaction other than anaphylaxis with TNs, respectively. Children with TN allergies were evaluated for the predictors of anaphylaxis by using multivariate logistic regression analysis. Results: A total of 184 children (ages 4.9 years; 3.2-6.9 years) with TN allergy were included in the study. Of these, 90 experienced an anaphylactic type of reaction on exposure to at least one type of TNs. Comparisons of the two groups showed that concomitant asthma, skin-prick test, specific immunoglobulin E, total immunoglobulin E, and serum basal tryptase (sBT) levels were significantly higher in the anaphylactic group compared with the nonanaphylactic group. In multivariate analysis, female gender (odds ratio [OR] 4.905 [95% confidence interval {CI}, 1.266-19.001], p = 0.021), sBT levels (OR 2.287 [95% CI, 1.431-3.654], p < 0.001), concomitant egg white allergy (OR 4.135 [95% CI, 1.016-16.481], p = 0.048), and concomitant asthma (OR 3.874 [95% CI, 1.109-13.526], p = 0.034) were risk factors for anaphylaxis. The optimal cutoff value for sBT was 2.06 ng/mL, with a sensitivity of 85.9% and a specificity of 69%, as well as an area under the curve 0.810 (95% CI, 0.717-0.903, p < 0.001). The sBT levels of 1.94 ng/mL and 5.30 ng/mL predicted clinical reactivity at 50% and 95% probabilities. Conclusion: Different aspects, including gender, higher mast cell load and/or activation, and a stronger atopic background ( e.g., coexisting egg allergy, asthma), contributed to the development of anaphylactic reactions to TNs in children.

Hyper-IgE syndromes comprise a group of inborn errors of immunity. STAT3-deficient hyper-IgE syndrome is characterized by elevated serum IgE levels, recurrent infections and eczema, and characteristic skeletal anomalies. A loss-of-function biallelic mutation in IL6ST encoding the GP130 receptor subunit (p.N404Y) has very recently been identified in a singleton patient (herein referred to as P N404Y ) as a novel etiology of hyper-IgE syndrome. Here, we studied a patient with hyper-IgE syndrome caused by a novel homozygous mutation in IL6ST (p.P498L; patient herein referred to as P P498L ) leading to abrogated GP130 signaling after stimulation with IL-6 and IL-27 in peripheral blood mononuclear cells as well as IL-6 and IL-11 in fibroblasts. Extending the initial identification of selective GP130 deficiency, we aimed to dissect the effects of aberrant cytokine signaling on T-helper cell differentiation in both patients. Our results reveal the importance of IL-6 signaling for the development of CCR6-expressing memory CD4 + T cells (including T-helper 17-enriched subsets) and non-conventional CD8 + T cells which were reduced in both patients. Downstream functional analysis of the GP130 mutants (p.N404Y and p.P498L) have shown differences in response to IL-27, with the p.P498L mutation having a more severe effect that is reflected by reduced T-helper 1 cells in this patient (P P498L ) only. Collectively, our data suggest that characteristic features of GP130-deficient hyper-IgE syndrome phenotype are IL-6 and IL-11 dominated, and indicate selective roles of aberrant IL-6 and IL-27 signaling on the differentiation of T-cell subsets., (Copyright© 2019 Ferrata Storti Foundation.)

Pattern recognition receptors (PRRs), receptors of the innate immune system, are important in interaction with pathogens. Caspase Recruitment Domain-containing protein 9 (CARD9), a member of PRRs, is an intracellular adaptor protein important in fungal defense. CARD9 deficiency causes a rare primary immunodeficiency (PID) characterized by superficial and deep fungal infections. We report a 17year-old female with a homozygous nonsense mutation in CARD9, who presented with severe cerebral fungal infection of the central nervous system. She was also found to have an heterozygous NLRP12 mutation, which may have had add-on effect on the severity of the infection., (Copyright © 2018. Published by Elsevier Inc.)

Background: Although data on anaphylaxis in the general population exist for different allergens, there is still lack of detailed etiologic data on drug-induced anaphylaxis (DIA), particularly in children., Objective: To define the etiology of DIA, to determine the accuracy of drug-related anaphylaxis histories, along with the severity and culprit drug associations among individuals <18 years old., Methods: Patients with a history of drug hypersensitivity reaction (DHR) referred to our center between January 2012 and February 2016 were included. After the collection of European Network for Drug Allergy questionnaire results, initial skin tests and/or provocation tests were performed for the offending drug., Results: Among 561 children and adolescents referred due to a suspected DHR, 113 (19%) (median age [interquartile range], 9.6 years [5.4-13.8 years]; 55% boys) had anaphylaxis in their history. At the end of diagnostic evaluation of the patients, 84 (74% of the patients with a history of DIA) were actually hypersensitive to the offending drug. Major drugs that resulted in DIA were antibiotics (33%), nonsteroidal anti-inflammatory drugs (25%), and chemotherapeutics (19%). The majority of patients reported grade 2 (moderate) (45%) and grade 3 (severe) (33%) anaphylactic reactions. A history of systemic illness (41.7 versus 7.1%; p = 0.001), concomitant intake of other drugs regularly (36.9 versus 10.3%; p = 0.007), and the use of chemotherapeutics as the culprit drug (19 versus 0%; p = 0.011) were more frequent, whereas the use of antibiotics was less frequent (34.5 versus 75.9%; p < 0.001) among patients with actual DIA compared to drug tolerant patients., Conclusion: Three-fourths of the children and adolescents referred due to a suspected history of DIA were found to actually be drug hypersensitive. Prediagnosed systemic illness and different types of drugs would have an impact on the risk of DIA; however, atopic disease or a family history of drug hypersensitivity did not have an impact on actual DIA.

Background: There is little information regarding the etiology and natural course of chronic spontaneous urticaria (CSU) in childhood., Objective: To investigate the etiology, prognosis, and the factors associated with the prognosis of CSU in children., Method: Data from children with CSU who had been diagnosed between 1992 and 2015 were analyzed. A telephone interview was done to assess the current status of these patients. Remission was defined as the disappearance of urticaria for >6 months., Results: A total of 222 children with CSU were evaluated. The median age of symptom onset was 8.8 years (interquartile range [IQR], 4.6-12.3 years), median duration of urticaria was 23 months (IQR, 7-48 months), and the median sum of the daily urticaria activity score of 7 consecutive days (UAS7) was 28 (IQR, 21-42). Accompanying angioedema was reported by 107 patients (48.2%), whereas 27.1% of the study population had autoantibody positivity. Autologous serum skin testing results were positive in 43 (34.1%); skin-prick testing results revealed atopy in 55 children (27.9%). Parasites (4.8%), pollen sensitization (1.5%), food allergy (0.9%), urinary tract infection (0.9%), and Hashimoto thyroiditis (0.5%) were determined as etiologic factors of CSU. The patients were followed up for a median time of 15 months (IQR, 5-36.5 months). Remission was observed in 10.6, 29.3, and 44.5% of the patients in 1, 3, and 5 years, respectively. In multivariate regression analysis, a UAS7 of >28 at admission was found to be a risk factor for persistence of urticaria (odds ratio 6.22 [95% confidence interval, 1.54-25.15; p = 0.010)., Conclusion: The etiology of CSU in children was mostly idiopathic despite detailed investigation. In childhood, the natural course of CSU was favorable, and nearly half of the patients recovered after 5 years of disease duration. A high UAS7 at admission seemed to be a significant risk factor for the persistence of symptoms.