Cold-induced urticaria in children: A multicenter, retrospective cohort study.

Background: Studies of cold-induced urticaria (ColdU) in pediatric patients are limited and not well characterized. Objective: The objective of the study was to investigate the characteristics of ColdU in children. Methods: A multicenter, retrospective chart review was performed in children ages ≤18 years diagnosed with ColdU at 11 pediatric allergy and immunology centers in Turkey between September 1, 2010, and August 31, 2022. Results: A total of 83 children with ColdU were included, 54.2% were girls, and the mean age of symptom onset was 8.8 years. The median duration of ColdU at the time of diagnosis was significantly higher in the girls than in the boys (1.0 years [0.0-13.8 years] versus 0.3 years [0.0-15.0 years]; p = 0.007). All the patients underwent an ice cube test, and 71.1% were found positive (typical ColdU). The mean ± standard deviation age of onset was significantly higher in the patients with typical ColdU versus atypical patients (9.4 ± 4.5 years versus 7.3 ± 4.5 years; p = 0.041). Swimming alone and in combination with the wind were significantly the most reported triggers in patients with cold-induced anaphylaxis (ColdA) when compared with patients with ColdU and with nonanaphylactic symptoms (70.0% versus 28.9% [p = 0.022], and 50.0% versus 4.1% [p < 0.001], respectively). Only patients with other chronic urticaria were found to be associated with the development of typical ColdU (p = 0.036). The median total serum immunoglobulin E (IgE) was significantly higher in typical ColdU than in atypical patients (72.5 IU/mL [3.86 - 2500 IU/mL] versus 30.0 IU/mL [0.83 - 1215 IU/mL]; p = 0.007); however, total serum IgE differences were not found to affect ColdU resolution between the two groups (p = 0.204). The resolution was documented in 30.4%. Conclusion: Those who were boys and had a positive ice cube test result could have an association with earlier onset of ColdU. Those swimming alone on a windy day were at highest risk for ColdA. It is still unclear what characteristics are associated with the resolution of ColdU, and this warrants further investigation.

Expanding the clinical and immunological phenotypes of PAX1-deficient SCID and CID patients.

Paired box 1 (PAX1) deficiency has been reported in a small number of patients diagnosed with otofaciocervical syndrome type 2 (OFCS2). We described six new patients who demonstrated variable clinical penetrance. Reduced transcriptional activity of pathogenic variants confirmed partial or complete PAX1 deficiency. Thymic aplasia and hypoplasia were associated with impaired T cell immunity. Corrective treatment was required in 4/6 patients. Hematopoietic stem cell transplantation resulted in poor immune reconstitution with absent naïve T cells, contrasting with the superior recovery of T cell immunity after thymus transplantation. Normal ex vivo differentiation of PAX1-deficient CD34+ cells into mature T cells demonstrated the absence of a hematopoietic cell-intrinsic defect. New overlapping features with DiGeorge syndrome included primary hypoparathyroidism (n = 5) and congenital heart defects (n = 2), in line with PAX1 expression during early embryogenesis. Our results highlight new features of PAX1 deficiency, which are relevant to improving early diagnosis and identifying patients requiring corrective treatment.

Primary Immunodeficiencies in Children Initially Admitted with Gastrointestinal/Liver Manifestations.

Purpose: The gastrointestinal system is the most commonly affected organ, followed by the lungs, in patients with primary immunodeficiency disease (PID). Hence, it is common for children with PIDs to present with gastrointestinal symptoms. We aimed to analyze the clinical and histopathological findings of patients who were initially admitted to pediatric gastroenterology/hepatology clinics and subsequently diagnosed with PIDs to identify the clinical clues for PIDs. Methods: The demographic, laboratory, and histopathological findings, treatment modality, and outcomes of patients initially admitted to the pediatric gastroenterology/hepatology unit and subsequently diagnosed with PIDs were recorded. Results: The study included 24 patients (58.3% male; median age [range]: 29 [0.5-204] months). Common clinical presentations included chronic diarrhea (n=8), colitis (n=6), acute hepatitis (n=4), and acute liver failure (n=2). The association of autoimmune diseases, development of malignant diseases, and severe progression of viral diseases was observed in 20.8%, 8.3%, and 16.6% of the patients, respectively. Antibody deficiency was predominantly diagnosed in 29.2% of patients, combined immunodeficiency in 20.8%, immune dysregulation in 12.5%, defects in intrinsic and innate immunity in 4.2%, autoinflammatory disorders in 8.3%, and congenital defects of phagocytes in 4.2%. Five patients remained unclassified (20.8%). Conclusion: Patients with PIDs may initially experience gastrointestinal or liver problems. It is recommended that the association of autoimmune or malignant diseases or severe progression of viral diseases provide pediatric gastroenterologists some suspicion of PIDs. After screening using basic laboratory tests, genetic analysis is mandatory for a definitive diagnosis.

Atypical Localization of Eczema Discriminates DOCK8 or STAT3 Deficiencies from Atopic Dermatitis.

PURPOSE: Autosomal recessive dedicator of cytokinesis 8 (DOCK8-/-) and autosomal dominant signal transducer and activator of transcription 3 (STAT3-/+) deficiencies are inborn errors of immunity (IEI) disorders present with the classic features of eczema and create a dilemma during differentiation from atopic dermatitis (AD). Therefore, an appropriate approach is required for eczema to diagnose DOCK8-/- and STAT3-/+ early. Here, we described a set of clinical and immunological variables, including atypical AD localizations and lymphocyte subsets, to differentiate DOCK8-/- or STAT3-/+ from AD. METHODS: This multicenter study involved 100 patients with DOCK8-/- and STAT3-/+ and moderate/severe AD. We recruited disease manifestations, including detailed localizations of eczema, infections, and allergy. Principle component analysis (PCA) was used to discriminate DOCK8-/- or STAT3-/+ from AD. RESULTS: There were 43 patients with DOCK8-/-, 23 with STAT3-/+, and 34 with AD. Pneumonia, severe infections, mucocutaneous candidiasis, and skin abscesses were commonly observed in DOCK8 and STAT3 deficiencies. Atypical skin involvement with neonatal rash, retro auricular, axillary, sacral, and genital eczema discriminate DOCK8-/- and STAT3-/+ from AD with high specificity ranges between 73.5 and 94.1% and positive predictive index ranges between 55 and 93.1%. Together with using absolute numbers of CD3+, CD4+, and CD8+ T cells, the combined clinical and laboratory features showed perfect differentiation between DOCK8-/- or STAT3-/+ and AD via PCA. CONCLUSIONS: The described features can be easily implemented by physicians providing early diagnosis of DOCK8 and STAT3 deficiencies.

A Novel Interleukin 17 Receptor A Mutation in a Child with Chronic Mucocutaneous Candidiasis and Staphylococcal Skin Infections.

OBJECTIVE: Chronic mucocutaneous candidiasis leads to persistent or recurrent fungal infections of the nail, skin, oral, and genital mucosa. Impaired interleukin 17-mediated immunity is a cause of chronic mucocutaneous candidiasis. We aimed to show the pathogenicity of a novel interleukin 17 receptor A mutation through functional studies. MATERIALS AND METHODS: After next-generation sequencing analysis showed the interleukin 17 receptor A variant, we confirmed the variant by Sanger sequencing and functional validation of the variant by flow cytometry. RESULTS: We present the case of a 6-year-old male patient who presented with recurrent oral and genital Candida infections and eczema. He had staphylococcal skin lesions, fungal susceptibility, and eczema. The patient carried a novel homozygous nonsense [(c.787C> T) (p.Arg263Ter)] mutation in the interleukin 17 receptor A gene. Sanger sequencing confirmed the variant and revealed the segregation of the variant in the family. We used flow cytometry to detect interleukin 17 receptor A protein expression in peripheral blood mononuclear cells from patients and measured Th17 cell percentage. We observed low interleukin 17 receptor A protein expression in patient peripheral blood mononuclear cells, decreased CD4+ interleukin 17+ cell percentage, and decreased interleukin 17F expression in CD4+ cells compared to healthy controls. CONCLUSIONS: Innate immune defects may lead to chronic recurrent fungal and bacterial infections of the skin, mucosa, and nails. Generally, genetic and functional analysis is needed in addition to basic immunological tests.

Adverse COVID-19 outcomes in immune deficiencies: Inequality exists between subclasses.

BACKGROUND: Genetic deficiencies of immune system, referred to as inborn errors of immunity (IEI), serve as a valuable model to study human immune responses. In a multicenter prospective cohort, we evaluated the outcome of SARS-CoV-2 infection among IEI subjects and analyzed genetic and immune characteristics that determine adverse COVID-19 outcomes. METHODS: We studied 34 IEI patients (19M/15F, 12 [min: 0.6-max: 43] years) from six centers. We diagnosed COVID-19 infection by finding a positive SARS-CoV-2 PCR test (n = 25) and/or a lung tomography scoring (CORADS) ≥4 (n = 9). We recorded clinical and laboratory findings prospectively, fitted survival curves, and calculated fatality rates for the entire group and each IEI subclass. RESULTS: Nineteen patients had combined immune deficiency (CID), six with predominantly antibody deficiency (PAD), six immune dysregulation (ID), two innate immune defects, and one in the autoinflammatory class. Overall, 23.5% of cases died, with disproportionate fatality rates among different IEI categories. PAD group had a relatively favorable outcome at any age, but CIDs and IDs were particularly vulnerable. At admission, presence of dyspnea was an independent risk for COVID-related death (OR: 2.630, 95% CI; 1.198-5.776, p < .001). Concerning predictive roles of laboratory markers at admission, deceased subjects compared to survived had significantly higher CRP, procalcitonin, Troponin-T, ferritin, and total-lung-score (p = .020, p = .003, p = .014, p = .013, p = .020; respectively), and lower absolute lymphocyte count, albumin, and trough IgG (p = .012, p = .022, p = .011; respectively). CONCLUSION: Our data disclose a highly vulnerable IEI subgroup particularly disadvantaged for COVID-19 despite their youth. Future studies should address this vulnerability and consider giving priority to these subjects in SARS-Cov-2 therapy trials.

Food-induced anaphylaxis in early childhood and factors associated with its severity.

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.

Proven Food-Induced Acute Urticaria and Predictive Factors for Definitive Diagnosis in Childhood.

BACKGROUND: Urticaria can be the only sign of a food allergy or can be seen together with other signs and symptoms of a food allergy. OBJECTIVE: To determine the demographic, etiologic, and clinical features of food-induced acute urticaria in childhood. METHODS: Patients suspected of food-induced acute urticaria were included in this prospective cross-sectional multicenter study. RESULTS: Two hundred twenty-nine urticaria cases were included in this study. Seventeen patients who did not meet the inclusion criteria of the study were excluded. Of the 212 included cases, 179 (84.4%) were diagnosed with definitive food-induced acute urticaria. The most common foods causing acute urticaria were cow's milk, hen's eggs, and nuts in 56.4, 35.2, and 19% of cases, respectively. The positive predictive value of a history of milk-induced acute urticaria together with a milk-specific IgE >5 kU/L for cow's milk-induced acute urticaria was 92% (95% CI: 81-96%). A history of cow's milk-induced and/or hen's egg-induced acute urticaria was consistent with a definitive diagnosis of food-induced urticaria (Chen's kappa: 0.664 and 0.627 for milk and eggs, respectively). Urticaria activity scores were higher in patients with food-induced acute urticaria (p = 0.002). CONCLUSION: Cow's milk, hen's eggs, and nuts were the most common allergens in the etiology of childhood food-induced acute urticaria. Although the urticaria activity score provides guidance for diagnosis, an oral food challenge is often essential for the definitive diagnosis of a patient with a history of food-induced acute urticaria.