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Human Inborn Errors of Immunity (IEIs) encompass a clinically and genetically heterogeneous group of disorders, ranging from mild cases to severe, life-threatening types. Among these, Primary Immune Regulatory Disorders (PIRDs) constitute a subset of IEIs characterized by diverse clinical phenotypes, prominently featuring severe atopy, autoimmunity, lymphoproliferation, hyperinflammation, autoinflammation, and susceptibility to malignancies. According to the latest report from the International Union of Immunological Societies (IUIS), PIRDs arise from mutations in various genes including LYST, RAB27A, AP3B1, AP3D1, PRF1, UNC13D, STX11, STXBP2, FAAP24, SLC7A7, RASGRP1, CD70, CTPS1, RLTPR, ITK, MAGT1, PRKCD, TNFRSF9, SH2DIA, XIAP, CD27 (TNFRSF7), FAS (TNFRSF6), FASLG (TNFSF6), CASP10, CASP8, FADD, LRBA, STAT3, AIRE, ITCH, ZAP70, TPP2, JAK1, PEPD, FOXP3, IL2RA, CTLA4, BACH2, IL2RB, DEF6, FERMT1, IL10, IL10RA, IL10RB, NFAT5, TGFB1, and RIPK1 genes. We designed a targeted next-generation sequencing (TNGS) workflow using the Ion AmpliSeq™ Primary Immune Deficiency Research Panel to sequence 264 genes associated with IEIs on the Ion S5™ Sequencer. In this study, we report the identification of 38 disease-causing variants, including 16 novel ones, detected in 40 patients across 15 distinct PIRD genes. The application of next-generation sequencing enabled rapid and precise diagnosis of patients with PIRDs., (© 2024. The Author(s).)

Background: The time to acquisition of tolerance to unheated milk and regular egg after achievement of tolerance to baked goods is not known., Objective: To determine the time to acquisition of unheated-milk-regular-egg tolerance, after the tolerance of the baked forms, in children younger than 2 years., Methods: An initial oral food challenge with baked milk (BM) and baked egg (BE) was performed on patients who were reactive to unheated milk-regular egg, respectively. Patients who were BM-BE tolerant were offered unheated-milk-regular-egg challenges, and patients who were BM-BE reactive were offered BM-BE challenges at an average of 3-month intervals. Food-induced atopic dermatitis was included., Results: Thirty-six children with unheated-milk allergy (median age, 7.3 months [interquartile range (IQR), 6.0-13.5]) and 65 with regular-egg allergy (median age, 7 months [IQR, 5.8-11.0]) were included. Seven of 13 children who were BM tolerant acquired unheated-milk tolerance after a median 4.0 months (IQR, 2.0-7.0). Twelve of 23 children who were BM reactive acquired unheated-milk tolerance after a median 5.0 months (IQR, 3.0-8.0) after BM tolerance. Twenty-one of 29 children who were BE tolerant acquired regular-egg tolerance after a median 3.0 months (IQR, 1.0-6.0). Sixteen of 36 children who were BE reactive acquired regular-egg tolerance after a median 4.0 months (IQR, 2.0-6.8) after BE tolerance., Conclusion: Different tolerance rates were determined for baked products at different time points in the first 2 years of life. Unheated-milk-regular-egg allergy resolved in up to 65.5% and 75.5% of cases, respectively, in an average 4 to 5 months after acquisition of BM-BE tolerance. Baked-milk-baked-egg tolerance may be regarded as a precursor of tolerance., (Copyright © 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Several factors that increase the risk of severe food-induced anaphylaxis have been identified. Objective: We aimed to determine the demographic, etiologic, and clinical features of food-induced anaphylaxis in early childhood and also any other factors associated with severe anaphylaxis. Methods: We carried out a medical chart review of anaphylaxis cases from 16 pediatric allergy and immunology centers in Turkey. Results: The data of 227 patients with 266 food-induced anaphylaxis episodes were included in the study. The median (interquartile range) age of the first anaphylaxis episode was 9 months (6-18 months); 160 of these patients were boys (70.5%). The anaphylaxis episodes were mild in 75 cases (28.2%), moderate in 154 cases (57.9%), and severe in 37 cases (13.9%). The most frequent food allergens involved were cow's milk (47.4%), nuts (16.7%), and hen's egg (15.8%). Epinephrine was administered in only 98 (36.8%) of these anaphylaxis episodes. A logistic regression analysis revealed two statistically significant factors that were independently associated with severe anaphylaxis: the presence of angioedema and hoarseness during the anaphylactic episode. Urticaria was observed less frequently in patients who developed hypotension. In addition, confusion and syncope were associated with 25.9- and 44.6-fold increases, respectively, in the risk of concomitant hypotension. Conclusion: Cow's milk, nuts, and hen's egg caused the majority of mild and moderate-to-severe anaphylaxis episodes. The presence of angioedema and hoarseness in any patient who presents with a history of food-induced anaphylaxis should alert clinicians that the reaction may be severe. In addition, the presence of confusion, syncope, or stridor probably indicates concomitant hypotension.

Background: In children younger than 2 years, studies evaluating the value of skin prick tests (SPTs) and specific immunoglobulin E (sIgE) results to predict persistence or resolution of egg allergy (EA) are limited. In addition, the value of egg yolk (EY) sIgE and fresh egg (FE) SPTs has not been well characterized., Objective: To investigate the optimal decision points (ODPs) for outgrowing allergy with SPTs and sIgE tests for egg allergen preparations., Methods: SPTs for FE, egg white (EW), and EY, sIgE tests for EW and EY, and oral food challenges (OFCs) were performed in children with suspected EA. Reactive patients strictly avoided all dietary egg. After 1 year, EA was reevaluated with addition OFCs, SPTs, and sIgE tests., Results: A total of 81 children (median age, 7 months; age range, 2-24 months) were enrolled. Notably, 4 children with a history of anaphylaxis and 60 of 77 children with a positive challenge result underwent egg elimination. The 1-year follow-up OFC test was performed on 59 children. A total of 27 reacted to egg. No persistent patient had a follow-up SPT result for FE of 4 mm or less (positive predictive values of 100% and negative predictive value of 56% for outgrowth). The diameters of the initial SPT for FE decreased 50% or more in half of the patients who outgrew EA. The ODPs for outgrowing allergy for follow-up sIgE tests for EY and EW were 2.1 kU/L or less (positive predictive value of 86.2%) and 4.0 kU/L or less (positive predictive value of 84.6%), respectively., Conclusion: A SPT diameter for FE of 4 mm or less and sIgE values of 2.1 kU/L or less for EY and 4.0 kU/L or less for EW have a good positive predictive value for outgrowth of EA in children younger than 2 years., (Copyright © 2020. Published by Elsevier Inc.)

Background: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. The long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established., Objective: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations., Methods: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry., Results: The mean age of the patients was 13.4 ± 7.9 years, and the follow-up period was 3.4 ± 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. The long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy., Conclusions: Long-term abatacept therapy is effective in most patients with LRBA deficiency., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The oral provocation test (OPT) with culprit drug is the gold standard in the diagnosis of nonsteroidal anti-inflammatory drug hypersensitivity (NSAID-H). Some authors have proposed that the total number of OPTs required to diagnose NSAID-H is much lower with acetyl salicylic acid (ASA) provocations, regardless of patients' reaction history, and less time consuming., Objective: This study aims to evaluate the total number of OPTs required to confirm NSAID-H according to the drugs (ASA or culprit NSAID) used in the initial OPT., Methods: The study included patients with a history of NSAID-H. Data on the demographic and clinical features, coexisting chronic or allergic disease, and laboratory results were collected from medical records. The drug used for the initial OPT (ASA or culprit NSAID), results of the OPT, and the total number of OPTs were reviewed., Results: We included 56 children with suspected hypersensitivity reaction to NSAIDs. NSAID-H was confirmed in 21 children (37.5%). We calculated that if all OPTs were performed with culprit drugs as an initial choice, the number of OPTs required for diagnosis would be 3 or more in 85.7% of positive cases. The number of episodes was an independent risk factor for NSAID-H by multiple logistic regression analysis (odds ratio, 4.3; 95% confidence interval, 1.48-12.24; P = .007)., Conclusion: Performing an initial OPT with ASA regardless of patients' reaction history can result in much lower numbers of OPT to diagnose NSAID-H and can improve patient compliance., (Copyright © 2019 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Limited studies conducted on children <2 years old and/or involving a skin prick test (SPT) for fresh milk (FM) have examined the predictive value of allergometric tests for outgrowth of cow's milk allergy (CMA). We investigated the optimal decision points for outgrowth (ODP fo ) with SPT for commercial cow's milk extract (CE) and FM and specific immunoglobulin E (sIgE) levels for milk proteins to predict outgrowing allergy in children <2 years old., Methods: SPTs for CE and FM, tests for sIgEs (cow's milk, casein, α-lactoalbumin, β-lactoglobulin) and oral food challenges (OFC) were performed in children referred for evaluation of suspected CMA, and 15 months after diagnosis., Results: Fifty-one children (median age, 7.5 months; range, 2-23 months) were enrolled. Five had a history of anaphylaxis and 26 of 48 children with a positive initial challenge underwent milk elimination. The last OFC was performed in 28 children of whom 13 reacted to milk. The initial SPT responses to CE and FM and milk sIgE levels of the patients with persistent CMA were higher at diagnosis, with ODP fo of 7mm, 9mm, and 10.5kU/L, respectively; these values remained higher with ODP fo of 4mm, 11mm, and 10.5kU/L at the last OFC., Conclusion: Higher initial SPTs for FM and CE and higher initial sIgE levels for cow's milk proteins are associated with a reduced likelihood of outgrowth. Initial milk sIgE level <10.5kU/L and initial SPT for fresh milk <9mm are related to the acquisition of tolerance in the follow-up period., (Copyright © 2019 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)