Characteristics of food allergy in children: National multicenter study

Conference: Congress of the European-Academy-of-Allergy-and-Clinical-Immunology (EAACI) Location: Lisbon, PORTUGAL Date: JUN 01-05, 2019Background : Food allergies impose a significant burden on the life of the child and the family. In this study, to determine the demographic characteristics of food allergies, we investigated the characteristics of patients with food allergies in different regions of Pediatric Allergy- Immunology departments in Turkey. Method : Turkey ' s National Study of Allergy and Clinical Immunology Society has conducted a Study Group on Food Allergies. 25 centers participated in this multicenter, cross- sectional and descriptive study.European Academy of Allergy and Clinical Immunolog

Management of Systemic Hypersensitivity Reactions to Gonadotropin-Releasing Hormone Analogues during Treatment of Central Precocious Puberty

Background:Besides local reactions, systemic hypersensitivity reactions such as urticaria, anaphylaxis, serum sickness and Henoch-Schonlein purpura (HSP) have been reported during gonadotropin-releasing hormone (GnRH) analogue treatment.Aim:To present the clinical presentation of 9 cases with systemic hypersensitivity reactions to GnRH analogues and discuss the management of such reactions based on our experience.Patients and Methods:Nine of 232 (3.8%) patients with central precocious puberty receiving GnRH analogue treatment had systemic hypersensitivity reactions in 4 years' period. Six patients had a type 1 hypersensitivity reaction (generalized hives, pruritus, and/or edema) to triptorelin acetate (TA), 2 patients to leuprolide acetate (LA), and 1 patient to both medications who also developed anaphylaxis to LA during intradermal test (IDT). Another patient on TA had skin lesions suggestive of HSP. GnRH analogue treatment was discontinued in 2 patients after discussion with the parents. Treatment was changed to another GnRH analogue preparation in 6 patients and was maintained with the same medication with antihistamines and corticosteroid premedication in 1 patient. None of the patients developed new reactions after these precautions.Conclusion:Systemic hypersensitivity reactions should be carefully evaluated and cross-reaction to the other GnRH analogues should be kept in mind. Discontinuation of GnRH analogue is always an option. However, if continuation of GnRH analogue is elected, we recommend switching to an alternative GnRH analogue, which should be considered only after a skin prick test (SPT) and IDT. In the lack of the possibility to perform SPT and IDT, injections may be administered under strict medical supervision in a well-equipped facility to manage anaphylaxis. We discuss additional options in situations where alternative GnRH analogues are unavailable, which enabled us to continue treatment in most cases without further problems

Monogenic early-onset lymphoproliferation and autoimmunity: the natural history of stat3 gof syndrome

Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. 1 Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD42CD82) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. Conclusion: : STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome. (J Allergy Clin Immunol 202

Glucocorticoid Receptor-β is Downregulated by Vitamin D Treatment in Children with Low Vitamin D Levels but Not in Allergic Asthma

Background: Vitamin D (VitD) enhances the anti-inflammatory effects of glucocorticoids (GC) in vitro. It was hypothesized that VitD3 (colecalciferol) treatment could have an impact on the expression of glucocorticoid receptors (GRs) in a group of children with low VitD levels, with or without asthma. Methods: Asthmatic children and healthy controls, all with low serum VitD levels (25-hydroxyvitamin D [25(OH)D] level <30ng/mL) were recruited. VitD3 treatment at a dose of 300,000IU was given orally. Blood samples were obtained at admission and 1 month after the treatment to examine serum 25(OH)D levels and the relative gene expression (RGE) of GR-α and -β in peripheral blood mononuclear cells. Results: Twenty-four children with asthma (Mage 11.1±2.1 years) and 14 healthy controls (Mage 11.5±1.7 years) were studied. The expression of GR-β was significantly higher in the control group at baseline compared with those with asthma (p=0.006). With VitD3 treatment, there was a decrease in GRβ expression at 1 month in the control group (p=0.05), but not in the asthma group. When analyzing the change in the relative expression of GRβ (change in 1st month to baseline), the decrease in GRβ was significantly higher in the control group compared with the asthma group (p=0.002). A negative correlation was detected between the change in the asthma control test score (ACT) and the change in 25(OH)D values (r=-0.51, p=0.01). Conclusion: VitD3 supplementation led to a decrease in the expression of GRβ in control subjects with low baseline VitD levels, whereas no such change was observed in asthmatic children. Meanwhile, better asthma control was achieved by VitD3 treatment, possibly through mechanisms not related to GR expression. © Copyright 2015, Mary Ann Liebert, Inc. 2015

Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K

Class IA phosphatidylinositol 3-kinases (PI3K), which generate PIP3 as a signal for cell growth and proliferation, exist as an intracellular complex of a catalytic subunit bound to a regulatory subunit. We and others have previously reported that heterozygous mutations in PIK3CD encoding the p110δ catalytic PI3K subunit cause a unique disorder termed p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) disease. We report four patients from three families with a similar disease who harbor a recently reported heterozygous splice site mutation in PIK3R1, which encodes the p85α, p55α, and p50α regulatory PI3K subunits. These patients suffer from recurrent sinopulmonary infections and lymphoproliferation, exhibit hyperactive PI3K signaling, and have prominent expansion and skewing of peripheral blood CD8+ T cells toward terminally differentiated senescent effector cells with short telomeres. The PIK3R1 splice site mutation causes skipping of an exon, corresponding to loss of amino acid residues 434–475 in the inter-SH2 domain. The mutant p85α protein is expressed at low levels in patient cells and activates PI3K signaling when overexpressed in T cells from healthy subjects due to qualitative and quantitative binding changes in the p85α–p110δ complex and failure of the C-terminal region to properly inhibit p110δ catalytic activity

Hematopoietic stem cell transplantation from unrelated donors in children with DOCK8 deficiency

DIDS is a unique form of combined immune deficiency characterized by an unusual susceptibility to cutaneous viral infections, severe allergies with eosinophilia and elevated immunoglobulin E titers, autoimmunity, and cancer. HSCT is considered the standard of care for this deadly disease. We have retrospectively analyzed the outcome of allogeneic HSCT from unrelated donors in patients with DIDS. Data from four patients, with five transplants, are presented. All patients received transplants from unrelated donors' BM, except for one patient who received a cord blood transplant. The conditioning regimens were based on myeloablative protocols for BM derived transplants; a NM regimen was pursued for the patient who received a cord blood transplant, which resulted in graft rejection. Although recurrent pneumonia and skin infections resolved immediately after transplantation, all patients subsequently developed human herpesvirus infection, including cutaneous herpetic lesions, cytomegalovirus reactivation, and zona zoster, which could be attributed to the use of ATG. Despite the presence of serious morbidities prior to transplantation, all patients recovered successfully. DIDS can be successfully treated with allogeneic HSCT from unrelated donors following a myeloablative conditioning regimen, with a reasonable safety profile

Functional reprogramming of regulatory T cells in the absence of Foxp3

Regulatory T cells (T-reg cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest an effector T (T-eff) cell-like phenotype. We demonstrate that Foxp3 deficiency dysregulates metabolic checkpoint kinase mammalian target of rapamycin (mTOR) complex 2 (mTORC2) signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient T-reg cells ameliorated disease in a Foxo1 transcription factor-dependent manner. Rictor deficiency re-established a subset of T-reg cell genetic circuits and suppressed the T-eff cell-like glycolytic and respiratory programs, which contributed to immune dysregulation. Treatment of T-reg cells from patients with FOXP3 deficiency with mTOR inhibitors similarly antagonized their T-eff cell-like program and restored suppressive function. Thus, regulatory function can be re-established in Foxp3-deficient T-reg cells by targeting their metabolic pathways, providing opportunities to restore tolerance in T-reg cell disorders

Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28

The attitudes of patients' parents receiving allergen-specific immunotherapy against anaphylaxis

Objective: Allergen immunotherapy (AIT) employs incremental amounts of an antigen to selected patients to promote clinical tolerance towards the offending allergen. The adverse reactions to AIT include local side effects such as induration in the field of application, itching and hyperemia, or systemic side effects such as shortness of breath, urticaria, hypotension, abdominal pain, vomiting and anaphylaxis. It is important that patients receiving AIT and their parents know about possible adverse reactions and can intervene when necessary. We aimed to assess the knowledge and attitudes towards anaphylaxis of the caregivers/parents of allergic children who receive subcutaneous immunotherapy (SCIT). Materials and Methods: We gathered information using a structured questionnaire on the subject demographics and clinical information as regards the type of allergies and symptoms; and employed specific questions to capture information on the knowledge and attitudes of the patients’ parents about the symptoms and management strategies of anaphylaxis and the use of an epinephrine autoinjector. All pediatric allergy patients’ parents who were received SCIT between 2016 and 2019 at the Yeditepe University Hospital’s pediatric allergy clinic were included in the study. Results: We studied 101 participants who completed the questionnaire. The median age of the patients receiving SCIT was 12.0 (minmax, 5.0-17.0) years, and 52.5% of the study group were boys. Only less than half of the subjects had some idea about anaphylaxis. Seventy-eight percent had no idea that food might lead to anaphylaxis. Seventy percent of the participants did not expect SCIT to cause anaphylaxis; 6% had no idea about this anaphylaxis at all. Most of the parents did not know how to react to anaphylaxis and the majority had no clue about the epinephrine autoinjector. Conclusion: We identified important knowledge gaps among the parents of children receiving SCIT about anaphylaxis or its management. We emphasize the necessity of educating the parents of children receiving SCIT on anaphylaxis as well as the application of epinephrine autoinjectors when indicated

The middle east and north africa diagnosis and management guidelines for inborn errors of immunity

Human inborn errors of immunity (IEI) are a group of 485 distinct genetic disorders affecting children and adults. Signs and symptoms of IEI are heterogeneous, and accurate diagnosis can be challenging and depends on the available human expertise and laboratory resources. The Middle East and North Africa (MENA) region has an increased prevalence of IEI because of the high rate of consanguinity with a predominance of autosomal recessive disorders. This area also exhibits more severe disease phenotypes compared with other regions, probably due to the delay in diagnosis. The MENA-IEI registry network has designed protocols and guidelines for the diagnosis and treatment of IEI, taking into consideration the variable regional expertise and resources. These guidelines are primarily meant to improve the care of patients within the region, but can also be followed in other regions with similar patient populations