MHC class II deficiency: Clinical, immunological, and genetic insights in a large multicenter cohort.

BACKGROUND: Major Histocompatibility Complex Class II (MHC-II) deficiency, a combined immunodeficiency, results from loss of Human Leukocyte Antigen class II expression on antigen-presenting cells. Currently, hematopoietic stem cell transplantation (HSCT) stands as the sole curative approach, though factors influencing patient outcomes remain insufficiently explored. OBJECTIVE: Our aim was to elucidate the clinical, immunological, and genetic profiles associated with MHC-II deficiency and identify prognostic indicators that affect survival rates. METHODS: In this multicenter retrospective analysis, we gathered data from 35 patients diagnosed with MHC-II deficiency across 12 centers in Turkey. We recorded infection histories, gene mutations, immune cell subsets, and surface MHC-II expression on blood cells. We conducted survival analyses to evaluate the impact of various factors on patient outcomes. RESULTS: Predominant symptoms observed were pneumonia (n=29, 82.9%), persistent diarrhea (n=26, 74.3%), and severe infections (n=26, 74.3%). The RFXANK gene mutation (n=9) was the most frequent, followed by mutations in RFX5 (n=8), CIITA (n=4), and RFXAP (n=2) genes. Patients with RFXANK mutations presented with later onset and diagnosis compared to those with RFX5 mutations (p=0.0008 and p=0.0006, respectively), alongside a more significant diagnostic delay (p=0.020). A notable founder effect was observed in 5 patients with a specific RFX5 mutation (c.616G>C). The overall survival rate for patients was 28.6% (n=10), showing a significantly higher proportion in individuals with HSCT (n=8, 80%). Early demise (p=0.006) and higher CD8+ T-cell counts were observed in patients with the RFX5 mutations compared to RFXANK-mutant patients (p=0.006 and p=0.009, respectively). CONCLUSION: The study delineates the genetic and clinical panorama of MHC-II deficiency, emphasizing the prevalence of specific gene mutations such as RFXANK and RFX5. These insights facilitate early diagnosis and prognosis refinement, significantly contributing to the management of MHC-II deficiency.

Allergen-specific B cell responses in oral immunotherapy-induced desensitization, remission, and natural outgrowth in cow's milk allergy.

BACKGROUND: Antigen-specific memory B cells play a key role in the induction of desensitization and remission to food allergens in oral immunotherapy and in the development of natural tolerance (NT). Here, we characterized milk allergen Bos d 9-specific B cells in oral allergen-specific immunotherapy (OIT) and in children spontaneously outgrowing cow's milk allergy (CMA) due to NT. METHODS: Samples from children with CMA who received oral OIT (before, during, and after), children who naturally outgrew CMA (NT), and healthy individuals were received from Stanford biobank. Bos d 9-specific B cells were isolated by flow cytometry and RNA-sequencing was performed. Protein profile of Bos d 9-specific B cells was analyzed by proximity extension assay. RESULTS: Increased frequencies of circulating milk allergen Bos d 9-specific B cells were observed after OIT and NT. Milk-desensitized subjects showed the partial acquisition of phenotypic features of remission, suggesting that desensitization is an earlier stage of remission. Within these most significantly expressed genes, IL10RA and TGFB3 were highly expressed in desensitized OIT patients. In both the remission and desensitized groups, B cell activation-, Breg cells-, BCR-signaling-, and differentiation-related genes were upregulated. In NT, pathways associated with innate immunity characteristics, development of marginal zone B cells, and a more established suppressor function of B cells prevail that may play a role in long-term tolerance. The analyses of immunoglobulin heavy chain genes in specific B cells demonstrated that IgG2 in desensitization, IgG1, IgA1, IgA2, IgG4, and IgD in remission, and IgD in NT were predominating. Secreted proteins from allergen-specific B cells revealed higher levels of regulatory cytokines, IL-10, and TGF-ß after OIT and NT. CONCLUSION: Allergen-specific B cells are essential elements in regulating food allergy towards remission in OIT-received and naturally resolved individuals.

Artemis deficiency: A large cohort including a novel variant with increased radiosensitivity.

BACKGROUND: Artemis deficiency is an autosomal recessive disorder characterized by a combined immunodeficiency with increased cellular radiosensitivity. In this review, the clinical and genetic characteristics of 15 patients with DCLRE1C variants are presented. METHODS: The demographic, clinical, immunologic, and genetic characteristics of patients with confirmed DCLRE1C variants diagnosed between 2013 and 2023 were collected retrospectively. Three patients were evaluated for radiosensitivity by the Comet assay, compared with age- and sex-matched healthy control. RESULTS: Seven patients who had severe infections in the first 6 months of life were diagnosed with T-B-NK+ SCID (severe combined immunodeficiency). Among them, four individuals underwent transplantation, and one of those died due to post-transplant complications in early life. Eight patients had hypomorphic variants. Half of them were awaiting a suitable donor, while the other half had already undergone transplantation. The majority of patients were born into a consanguineous family (93.3%). Most patients had recurrent sinopulmonary infections (73.3%), and one patient had no other infection than an acute respiratory infection before diagnosis. Two patients (13.3%) had autoimmunity in the form of autoimmune hemolytic anemia. Growth retardation was observed in only one patient (6.6%), and no malignancy was detected in the surviving 11 patients during the median (IQR) of 21.5 (12-45) months of follow-up. Three patients who had novel variants exhibited increased radiosensitivity and compromised DNA repair, providing a potential vulnerability to malignant transformation. CONCLUSION: Early diagnosis, radiation avoidance, and careful preparation for transplantation contribute to minimizing complications, enhancing life expectancy, and improving the patient's quality of life.

The relationships between language, functional hearing, social, and motor development skills in children with early cochlear implants.

PURPOSE: The purpose of this study was to investigate the relations between functional hearing, language, social, bilateral coordination and manual dexterity skills in children with early cochlear implants (CIs). METHODS: Thirty children with CIs were included in this study. The manual dexterity and bilateral coordination development of the participants were evaluated with Manual Dexterity and Bilateral Coordination subtests of Bruininks-Oseretsky Motor Proficiency-2 (BOT-2). Their language skills were assessed by the Test of Early language Development-3. To assess the functional hearing of participants the Functioning After Pediatric Cochlear Implantation scale (FAPCI) was administered their caregivers. Also, the Social Skills Evaluation Scale was administered to participants' teachers to asses their social skills. RESULTS: There were significant correlations between participants' receptive and expressive language skills, Manual Dexterity, and FAPCI scores (p < 0.05). There were also significant relationships between the SSES and FAPCI scores of the participants (p < 0.05). However, the Bilateral Coordination subtest did not show any significant correlation with any of the measurements (p > 0.05). CONCLUSION: The results suggest that the language, manual dexterity and functional hearing abilities of children with CIs are closely related. Although, there were no significant correlations between all of the measurement, it is important to look beyond hearing and speech evaluations to assess the whole child.

Auditory performance and language skills in children with auditory brainstem implants and cochlear implants.

PURPOSE: This study aims to evaluate school-age language skills and auditory performance in different listening situations in children with cochlear implants and auditory brainstem implants. METHOD: The study included 60 children between the ages of 5 and 9 years with cochlear implants (CI) and auditory brainstem implants (ABI). The volunteer children were divided into two groups: bimodal CI-ABI and bilateral CI users. Test of Language Development: Primary (TOLD-P:4), which assesses components of language such as phonology, morphology, syntax and semantics, was used to evaluate school-age language skills. Children's Auditory Performance Scale (CHAPS) was used to measure their listening performance in quiet, noisy, multi-stimulus environments and their auditory attention and memory skills in daily life. The correlations between language and auditory performance were analyzed and compared between the two groups. RESULTS: Children with ABI showed poorer performance in school-age language skills and auditory performance in different listening environments (p < 0.05). Significant correlations were between school-age language skills and auditory performance (p < 0.05). CONCLUSION: Improved auditory performance is crucial for the development of school-age language skills. To improve auditory performance in children with ABI in different listening environments, assistive listening devices, acoustic environmental arrangements, informative activities, etc., should be used.

Language, cognitive, and speech in noise perception abilities of children with cochlear implants: a comparative analysis by implantation period and bilateral versus unilateral cochlear implants.

PURPOSE: The purpose of this study was to compare the language, cognitive, and speech in noise (SiN) perception abilities of children with cochlear implants (CIs) to those of their peers with NH by grouping them according to their implantation period (12-18 months/19-24 months) and unilateral/bilateral CI use. METHODS: The sample comprised 50 children with cochlear implants (CIs) and 20 children with normal hearing (NH), ages 6-9 years. Children's language, cognitive, and speech in noise (SiN) perception skills were assessed. RESULTS: Children with CIs between 12 and 18 months and 19 and 24 months performed more poorly than children with NH on language, verbal memory (VM), verbal-short-term memory (V-STM), verbal working memory (V-WM), rapid naming, and speech in noise (SiN) perception abilities measures (p < 0.001). In addition, children with CIs between 19 and 24 months performed worse on rapid naming and V-WM tasks than children with CIs between 12 and 18 months (p < 0.017). Children with unilateral and bilateral CI performed more poorly than children with NH on language, VM, V-STM, V-WM, rapid naming, and SiN perception abilities assessments (p < 0.001). Additionally children with unilateral CI users performed poorly than children with bilateral CI users on SiN perception (p < 0.017). CONCLUSIONS: In children with congenital hearing loss (CHL), cochlear implantation between 12 and 18 months or sequential bilateral implantation is not sufficient for these children to perform like their NH peers in language, cognitive, and SiN perception abilities. In addition, intervention approaches should focus not only on increasing language skills, but also on cognitive abilities.

The validity and reliability of Turkish version of the children's home inventory for listening difficulties - (C.H.I.L.D) questionnaire.

OBJECTIVE: This study aimed to investigate the validity and reliability of the Turkish version of the Children's Home Inventory for Listening Difficulties - (C.H.I.L.D) questionnaire. METHODS: The study included 121 children with cochlear implants and their families aged 3-12 years and 171 children with normal hearing and their families. Confirmatory factor analysis (C.F.A.) was used to assess construct validity, Cronbach's alpha was used to analyze internal consistency and test-retest reliability was also investigated. RESULTS: The reliability coefficients of the entire C.H.I.L.D family member (C.H.I.L.D-FM) and children version (C.H.I.L.D-C) were 0.983, 0.978, and Cronbach's coefficients were 0.992, 0.992, and the corrected item-total correlations increased from 0.989 to 0.994 and from 0.988 to 0.994, respectively. The scale's construct validity was excellent, according to the CFA analyses. The goodness-of-fit indexes (for the parent's version 0.892 and for the child's version 0.867) demonstrated a good fit for the single-factor construct, with only the normed fit index revealing an acceptable fit. CONCLUSION: The Turkish version of the C.H.I.L.D is a reliable and valid evaluation test for children and their family members.

Drug Allergy in Children: Adverse Reactions after Skin Testing.

INTRODUCTION: Skin tests are one of the most widely used diagnostic tools for suspected drug allergies in children. Studies on systemic reactions occurring during skin testing with allergens have mostly been conducted in pediatric and adult patient groups together. However, data on adverse reactions including allergic reactions after drug skin tests in children are scarce. It is aimed to determine the adverse reactions after skin test in children with suspected drug allergy. METHODS: Patients who underwent a drug skin test due to the suspicion of drug allergy between May 2017 and June 2020 were evaluated, retrospectively. Data about adverse reactions seen after skin testing at the testing area in the clinic were analyzed. RESULTS: The study included 1,073 children (585 [54.5%] boys and 488 [45.5%] girls) with a median age of 7.5 years. A total of 12 (1.1%) reactions were detected after skin testing, and 4 (0.4%) of them were allergic reactions. Of the allergic reactions, three were anaphylaxis and one was urticaria. Two of the reactions (1 anaphylaxis and 1 urticaria) were detected after the skin prick test and the remaining 2 were detected after intradermal test. Three of the nonallergic reactions were considered as vasovagal reactions and seven were considered as nonspecific and anxiety-related reactions. CONCLUSION: Although drug skin tests were generally well-tolerated and adverse reactions were rare, severe allergic reactions including anaphylaxis may ensue. Skin tests should be necessarily performed in clinical settings in experienced centers.

Evaluation of language, attention, and memory skills in children with auditory brainstem implants.

PURPOSE: This study aimed to evaluate attention, memory, and language skills in children with auditory brainstem implants and cochlear implants. METHODS: This study included 20 children with auditory brainstem implants (ABI) and 20 cochlear implanted (CI) children between the ages of 6 years and 8 years 11 months and their families. "Test of Language Development: Primary (TOLD-P:4)" was used to assess language skills, "STROOP Test, Visual-Aural Digit Span (VADS) test, and Cancellation Test" were used to evaluate attention and memory skills. In addition, the functional outcomes of hearing skills in daily life were scored by "Auditory Behavior in Everyday Life (ABEL) scale". The significance level was determined as 0.05. RESULTS: Children with ABI showed lower language skills than children with CI in terms of TOLD-P:4 language test scores, STROOP sub-test completion times, and the VADS and Cancellation test scores (p < 0.05). In addition, statistically significant correlations were found between language, attention, memory skills, and auditory behavior scale. CONCLUSIONS: This study is one of the limited numbers of studies investigating cognitive processes in children with ABI. Since attention and memory are correlated with language skills, it is recommended that the development of cognition should be considered in follow-up and intervention approaches of children with ABI and/or CI.

Working Memory, Attention Skills and Language Proficiency in Children with Unilateral and Bilateral Cochlear Implants.

BACKGROUND: Previous studies observed that children with cochlear implants (CIs) have poor language, working memory, and attention skills. The ability to perform cognitive tasks, such as attention and memory, plays a crucial role in the academic achievement and everyday life of children with hearing impairment. PURPOSE: This study aimed to evaluate and compare the effects of age at the time of implantation and bilateral hearing on cognitive skills, such as language development, working memory, and selective attention, among children with CIs. RESEARCH DESIGN: Language skills were assessed using the Test of Language Development-Primary: Fourth Edition (TOLD-P:4), working memory using the Visual-Aural Digit Span Test-Revised Form (VADS-R), and selective attention skills using the Stroop Test TBAG Form. STUDY SAMPLE: A total of 58 participants, comprised of 21 children with early unilateral CIs (before 2 years), 18 children with late unilateral CIs (after 2 years), and 19 children with bilateral CIs, between the ages of 6 and 9 years, were included in the study. DATA COLLECTION AND ANALYSIS: According to the age at the time of implantation and whether or not the participant was unilaterally or bilaterally implanted, the mean scores, percentage values, and resultant scores of the participants were calculated using the Mann-Whitney U test. The number of repeated backward digit spans for the VADS-R test, completion times, number of errors and corrections for the Stroop test, raw scores, scaled scores corresponding to raw scores at the relevant age, descriptive terms for the TOLD-P:4 test, and within-group comparisons for all tests were examined. RESULTS: There were significant differences in language, working memory, and attention skills between individuals with early and late unilateral cochlear implantation, whereas there were no significant differences in many subtests between individuals with early unilateral and bilateral cochlear implantation. CONCLUSION: These findings demonstrate the importance of early cochlear implantation and bilateral hearing on the development of cognitive processes, such as language development, selective attention, and memory skills, which are important factors that may contribute to children's academic performance and overall success.

Evaluation of the triggers and the treatment models of anaphylaxis in pediatric patients.

OBJECTIVE: Anaphylaxis is an acute, life-threatening systemic hypersensitivity reaction. We aimed to evaluate the demographic and clinical characteristics of patients presenting with anaphylaxis, as well as triggers and risk factors, and to determine the rate of adrenaline auto-injector (AAI) usage. METHODS: The study was planned in the pediatric allergy outpatient clinic over a 1-year period. The data of children diagnosed with anaphylaxis were evaluated retrospectively; demographic characteristics, causes of anaphylaxis, and treatment modalities were recorded in the created study form. RESULTS: Eighty children (29 females) with a median age of 6.5 years (range: 1 month-17 years) were evaluated. The most common triggers were foods under 2 years of age (73%), and drugs (70%) above 2 years of age. Nearly half of the anaphylaxis episodes (n=41, 51.3%) occurred at home. Cutaneous and respiratory symptoms were the most commonly reported complaints (98.8%). The median age of the patients at the first attack with severe anaphylaxis (n=29, 36.3%) was significantly higher than the rest (p:0.007). The age at onset of the reaction (p:0.006) and occurrence of the reaction in hospital conditions (p<0.001) were determined to be significant risk factors for severe anaphylaxis. Most of them received antihistamines (95.7%) and corticosteroids (91.3%), while 78.3% received adrenaline. Only 9.5% of patients with recurrent episodes of anaphylaxis used AAIs. CONCLUSION: Foods in infants and drugs in older children were the leading causative allergens of anaphylaxis. The most common clinical manifestations were respiratory and cutaneous symptoms. The older age at onset of the reaction and the occurrence of the reaction in hospital conditions were determined to be significant risk factors for severe anaphylaxis. It was determined that the frequency of AAI use was low among patients and their families.

Evaluation of musical emotion perception and language development in children with cochlear implants.

OBJECTIVES: While the primary purpose of cochlear implant (CI) fitting is to improve individuals' receptive and expressive skills, musical emotion perception (MEP) is generally ignored. This study assesses the MEP and language skills (LS) of children using CI. METHODS: 26 CI users and 26 matched healthy controls between the ages of 6 and 9 were included in the study. The Test of Language Development (TOLD) was applied to evaluate the LS of the participants, and the Montreal Emotion Identification Test (MEI) was applied to evaluate the MEP. RESULTS: MEI test scores and all subtests of TOLD were statistically significantly lower in the CI group. Also, there was a statistically significant and moderate correlation between the listening subtest of TOLD and the MEI test. CONCLUSIONS: MEP and language skills are poor in children with CI. Although language skills are primarily targeted in CI performance, improving MEP should also be included in rehabilitation programs. The relationship between music and the TOLD's listening subtest may provide evidence that listening skills can be improved by paying attention to the MEP, which is frequently ignored in rehabilitation programs.

Therapeutic modalities and clinical outcomes in a large cohort with LRBA deficiency and CTLA4 insufficiency.

BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency (LRBA-/-) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) insufficiency (CTLA4+/-) are mechanistically overlapped diseases presenting with recurrent infections and autoimmunity. The effectiveness of different treatment regimens remains unknown. OBJECTIVE: Our aim was to determine the comparative efficacy and long-term outcome of therapy with immunosuppressants, CTLA4-immunoglobulin (abatacept), and hematopoietic stem cell transplantation (HSCT) in a single-country multicenter cohort of 98 patients with a 5-year median follow-up. METHODS: The 98 patients (63 LRBA-/- and 35 CTLA4+/-) were followed and evaluated at baseline and every 6 months for clinical manifestations and response to the respective therapies. RESULTS: The LRBA-/- patients exhibited a more severe disease course than did the CTLA4+/- patients, requiring more immunosuppressants, abatacept, and HSCT to control their symptoms. Among the 58 patients who received abatacept as either a primary or rescue therapy, sustained complete control was achieved in 46 (79.3%) without severe side effects. In contrast, most patients who received immunosuppressants as primary therapy (n = 61) showed either partial or no disease control (72.1%), necessitating additional immunosuppressants, abatacept, or transplantation. Patients with partial or no response to abatacept (n = 12) had longer disease activity before abatacept therapy, with higher organ involvement and poorer disease outcomes than those with a complete response. HSCT was performed in 14 LRBA-/- patients; 9 patients (64.2%) showed complete remission, and 3 (21.3%) continued to receive immunosuppressants after transplantation. HSCT and abatacept therapy gave rise to similar probabilities of survival. CONCLUSIONS: Abatacept is superior to immunosuppressants in controlling disease manifestations over the long term, especially when started early, and it may provide a safe and effective therapeutic alternative to transplantation.

Defective Treg generation and increased type 3 immune response in leukocyte adhesion deficiency 1.

In 15 Turkish LAD-1 patients and controls, we assessed the impact of pathogenic ITGB2 mutations on Th17/Treg differentiation and functions, and innate lymphoid cell (ILC) subsets. The percentage of peripheral blood Treg cells, in vitro-generated induced Tregs differentiated from naive CD4+ T cells were decreased despite the elevated absolute counts of CD4+ cells in LAD-1 patients. Serum IL-23 levels were elevated in LAD-1 patients. Post-curdlan stimulation, LAD-1 patient-derived PBMCs produced more IL-17A. Additionally, the percentages of CD18-deficient Th17 cells expanded from total or naïve CD4+ T cells were higher. The blood ILC3 subset was significantly elevated in LAD-1. Finally, LAD-1 PBMCs showed defects in trans-well migration and proliferation and were more resistant to apoptosis. Defects in de novo generation of Tregs from CD18-deficient naïve T cells and elevated Th17s, and ILC3s in LAD-1 patients' peripheral blood suggest a type 3-skewed immunity and may contribute to LAD-1-associated autoimmune symptoms.

Risk Factors of Challenge-Proven Beta-Lactam Allergy in Children with Immediate and Non-Immediate Mild Cutaneous Reactions.

INTRODUCTION: Beta-lactam (BL) antibiotics are the most often involved drugs in allergic reactions. Mild cutaneous reactions such as maculopapular exanthema or urticaria are the most common presenting complaints of BL allergy in the pediatric population. However, it can be challenging to distinguish BL-induced allergy from reactions due to infections or other reasons. In this study, we aimed to determine the clinical characteristics and potential risk factors of true BL allergy in children with suspected mild cutaneous reactions to BLs. METHODS: We evaluated children who were admitted to our pediatric allergy clinic with suspected BL allergy in between January 2015 and March 2020. Patients with a history suggestive of immediate and non-immediate mild cutaneous reactions were included in the study. The oral challenge test (OCT) with the culprit drug was performed on all patients to confirm the diagnosis. RESULTS: Two hundred fourteen (119 male and 95 female) patients with a median age of 4.9 years were evaluated. BL allergy was confirmed in 10.7% (23) of the patients, according to the OCT results. Most of the proven allergic reactions were of the immediate type (73.9%), and urticaria was the most common presenting complaint (60.8%) in proven BL-allergic patients. The negative predictive value of penicillin-G skin testing was 89.7% for immediate-type penicillin allergy and 93.4% for non-immediate reactions. Also, positive predictive value of penicillin-G skin testing was 50% for immediate and 25% for non-immediate reactions. In the multivariate logistic regression analysis, a history of proven drug allergy (Exp (B): 7.76, 95% CI: 1.88-31.97, p = 0.005) was found to be the risk for BL allergy. CONCLUSION: This study highlighted that OCTs should be performed to confirm the diagnosis in patients suspected of immediate and non-immediate mild cutaneous reactions to BLs and remove the overestimated "BL allergy" label. In these patients, a history of proven drug allergy might be a risk factor for true BL allergy.

[Analysis of IFN-γR1 (CD119) and IL-12Rß1 (CD212) Deficiency by Flow Cytometry]. / IFN-γR1 (CD119) ve IL-12Rß1 (CD212) Eksikliginin Akan Hücre Ölçer ile Analizi.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare primary immune deficiency (PID). IL-12Rß1 deficiency is the most frequently observed of more than 16 genetic defects that have been identified for MSMD. Genetic and immunological tests are remarkable in the diagnosis of PID. In this study, it was aimed to determine the expression of IFN-γR1 and IL-12Rß1 in patients with MSMD, their relatives, and healthy individuals and to evaluate the importance of flow cytometry as a fast and reliable method in the diagnosis of MSMD. IFN-γR1 and IL-12Rß1 expression levels were analyzed in 32 volunteers including six patients, six relatives, and 20 healthy individuals. The normal range of IFN-γR1 and IL-12Rß1 levels among healthy individuals were determined. IL-12Rß1 expression level in lymphocytes was found to be low in one patient's relative, and less than 1% in three patients and in one patient's relative. It was observed that the IL-12Rß1 expression levels of the patient with STAT1 deficiency were increased compared to the healthy individuals. No difference was found in the expression levels of IFN-γR1 and IL-12Rß1 in one patient, but IFN-γR1 expression was decreased in one patient compared to healthy individuals. Our results show that the determination of IL-12Rß1 and IFN-γR1 deficiencies by flow cytometry can be used as a rapid and reliable method for the diagnosis of MSMD. The use of this method as a screening test will enable early diagnosis especially in patients whose genetic diagnosis has not been confirmed and clinically compatible with MSMD. In addition, it is thought that IL-12Rß1 and IFN-γR1 range data obtained from healthy individuals will be considered as a reference source in routine and research studies to be conducted with MSMD.

Hypersensitivity to Ibuprofen: Real-Life Experience in Children with History of Suspected Immediate Reactions.

INTRODUCTION: Ibuprofen is the most common culprit drug causing nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity in children. We aimed to evaluate the frequency, clinical characteristics, and risk factors of confirmed ibuprofen allergy in children presenting with a history of suspected immediate type ibuprofen-induced hypersensitivity reactions. METHODS: We evaluated 50 (35 M, 15 F) children with a median age of 7 years, who were referred to our clinic with suspected immediate ibuprofen hypersensitivity. Patients were subjected to a diagnostic work up including drug provocation tests (DPTs) with the culprit drug. Reactions were classified according to the European Academy of Allergy and Clinical Immunology Task Force recommendations for pediatric patients. Proven ibuprofen allergic patients underwent DPT to find a safe alternative drug. RESULTS: Ibuprofen allergy was confirmed in 34% (n: 17) of children; 9 patients were diagnosed by DPTs and 8 patients diagnosed based on their histories. Angioedema was the most common clinical manifestation (n: 30, 60%). Among patients with proven ibuprofen allergy, 7 of them were classified as cross-intolerant. Cross-intolerance reactions were further classified as NSAID-exacerbated cutaneous disease (n = 1) and NSAID-induced urticaria/angioedema/anaphylaxis (n = 6). As an alternative drug, paracetamol was safely tolerated, whereas 1 patient developed angioedema and urticaria with nimesulide. Older age and male gender were identified as independent risk factors for immediate-type ibuprofen allergy. CONCLUSION: DPTs should be performed to confirm or exclude ibuprofen allergy in children and to find safe alternative drugs. Male gender and older age are risk factors for ibuprofen allergy. NSAID-induced hypersensitivity reactions in the pediatric population cannot be well defined using the adult classification system.