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Background No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. Methods We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. Results Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P

The last decade has seen an unprecedented pace of change, particularly of clinical research in atopic dermatitis (AD). This review summarizes some key discoveries. Over the last 10 years, nearly half of all studies investigated the efficacy and safety of novel therapeutic agents, particularly biologics and small molecules. Clear demonstration of benefit in clinical trials with no significant safety concerns provided strong evidence leading to subsequent Food and Drug Administration approval and routine use of the anti-IL-4 receptor alpha antagonist dupilumab in patients 6 months and older, the selective Janus kinase 1 (JAK1) inhibitors upadacitinib for patients 12 years and older and abrocitinib, the IL-13 antagonist tralokinumab, and the JAK1/2 inhibitor baricitinib for adults 18 years and older. Several other drugs are in the pipeline. Other areas under the spotlight have been trials of skin moisturizers and probiotics in the prevention of AD, investigating the role of filaggrin and skin barrier function and the role of skin and gut microbiome, with Staphylococcus aureus second immunoglobulin-binding protein having been found to uniquely trigger allergic skin responses in AD. Skin microbiome, epidermal metabolites/structural components, and local inflammatory biomarkers are now commonly assessed using genomic and proteomic analysis of tape strips rather than more invasive biopsy to identify factors such as C-C motif chemokine ligand-17 that correlate with disease severity and response to therapy. Overall, the last decade has ushered in a new and exciting era in our understanding, diagnosis, and treatment of this common allergic skin disease.

Current systemic treatments for children younger than 6 years with moderate-to-severe atopic dermatitis that is uncontrolled with topical therapies might have suboptimal efficacy and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. We aimed to evaluate efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis.This randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial was conducted in 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were aged 6 months to younger than 6 years, with moderate-to-severe atopic dermatitis (Investigator's Global Assessment [IGA] score 3-4) diagnosed according to consensus criteria of the American Academy of Dermatology, and an inadequate response to topical corticosteroids. Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (bodyweight ≥5 kg to15 kg: 200 mg; bodyweight ≥15 kg to30 kg: 300 mg) every 4 weeks plus low-potency topical corticosteroids (hydrocortisone acetate 1% cream) for 16 weeks. Randomisation was stratified by age, baseline bodyweight, and region. Patient allocation was done via a central interactive web response system, and treatment allocation was masked. The primary endpoint at week 16 was the proportion of patients with IGA score 0-1 (clear or almost clear skin). The key secondary endpoint (coprimary endpoint for the EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Primary analyses were done in the full analysis set (ie, all randomly assigned patients, as randomly assigned) and safety analyses were done in all patients who received any study drug. This study was registered with ClinicalTrials.gov, NCT03346434.Between June 30, 2020, and Feb 12, 2021, 197 patients were screened for eligibility, 162 of whom were randomly assigned to receive dupilumab (n=83) or placebo (n=79) plus topical corticosteroids. At week 16, significantly more patients in the dupilumab group than in the placebo group had IGA 0-1 (23 [28%] vs three [4%], difference 24% [95% CI 13-34]; p0·0001) and EASI-75 (44 [53%] vs eight [11%], difference 42% [95% CI 29-55]; p0·0001). Overall prevalence of adverse events was similar in the dupilumab group (53 [64%] of 83 patients) and placebo group (58 [74%] of 78 patients). Conjunctivitis incidence was higher in the dupilumab group (four [5%]) than the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation.Dupilumab significantly improved atopic dermatitis signs and symptoms versus placebo in children younger than 6 years. Dupilumab was well tolerated and showed an acceptable safety profile, similar to results in older children and adults.Sanofi and Regeneron Pharmaceuticals.

Dedicator of cytokinesis (DOCK) proteins play a central role in actin cytoskeleton regulation. This is highlighted by the DOCK2 and DOCK8 deficiencies leading to actinopathies and immune deficiencies. DOCK8 and DOCK11 activate CDC42, a RHO-GTPase involved in actin cytoskeleton dynamics, among many cellular functions. The role of DOCK11 in human immune disease has been long suspected but has never been described so far. We studied eight male patients, from seven unrelated families, with hemizygous DOCK11 missense variants leading to reduced DOCK11 expression. The patients were presenting with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Patients' platelets exhibited abnormal ultrastructural morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls. Lastly, in line with the patients' autoimmune manifestations, we also observed abnormal regulatory T cells (Tregs) phenotype with profoundly reduced FOXP3 and IKZF2 expression. Moreover, we found a reduced T cell proliferation and an impaired STAT5B phosphorylation upon IL2 stimulation of the patients' lymphocytes. In conclusion, DOCK11 deficiency is a new X-linked immune-related actinopathy leading to impaired CDC42 activity and STAT5 activation, and associated with abnormal actin cytoskeleton remodeling as well as Tregs phenotype culminating in immune dysregulation and severe early-onset autoimmunity.

Revisión This review article incorporates information from the 4th Global Meningococcal Initiative summit meeting. Since the introduction of stringent COVID-19 infection control and lockdown measures globally in 2020, there has been an impact on IMD prevalence, surveillance, and vaccination compliance. Incidence rates and associated mortality fell across various regions during 2020. A reduction in vaccine uptake during 2020 remains a concern globally. In addition, several Neisseria meningitidis clonal complexes, particularly CC4821 and CC11, continue to exhibit resistance to antibiotics, with resistance to ciprofloxacin or beta-lactams mainly linked to modifications of gyrA or penA alleles, respectively. Beta-lactamase acquisition was also reported through horizontal gene transfer (blaROB-1) involving other bacterial species. Despite the challenges over the past year, progress has also been made on meningococcal vaccine development, with several pentavalent (serogroups ABCWY and ACWYX) vaccines currently being studied in late-stage clinical trial programmes. Medical writing support was funded by Sanofi Pasteur. Sí

Patients with atopic dermatitis (AD) have an increased risk of infection, including skin infections. Previous studies in children aged 6–11 years and adolescents showed that dupilumab is not associated with an increased risk of overall infections and is associated with a lower incidence of skin infections compared with a placebo. This post-hoc analysis reports the impact of dupilumab treatment on infections, including skin infections, in children aged 6 months to 5 years with moderate-to-severe AD. In LIBERTY AD PRESCHOOL, a double-blind, placebo-controlled trial (NCT03346434, part B), children aged 6 months to 5 years with moderate-to-severe AD (Investigator’s Global Assessment score ≥3) were randomized 1 : 1 to subcutaneous dupilumab every 4 weeks (200 mg if baseline weight was ≥5 to

Background and ObjectivePrevious studies of dupilumab for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents, and severe atopic dermatitis in children aged 6 to < 12 years demonstrate no clinically important changes in laboratory parameters. The objective of this study was to assess laboratory outcomes in children aged 6 months to < 6 years with moderate-to-severe atopic dermatitis treated with dupilumab.MethodsIn this randomized, placebo-controlled, phase III trial of dupilumab, 161 children aged 6 months to < 6 years with moderate-to-severe atopic dermatitis were enrolled from 31 sites in Europe and North America and randomized 1:1 to receive subcutaneous placebo or dupilumab (5 kg to < 15 kg: 200 mg; 15 kg to < 30 kg: 300 mg) every 4 weeks plus topical corticosteroids for 16 weeks. Hematology, serum chemistry, and urinalysis assessments were analyzed on blood and urine samples collected at screening and weeks 4 and 16; descriptive statistics are provided.ResultsNo clinically meaningful changes in laboratory parameters were observed. While two cases of eosinophilia and one case each of neutropenia and leukocytosis were reported as treatment-emergent adverse events in the dupilumab plus topical corticosteroids group, these events were not associated with clinical symptoms and did not lead to treatment discontinuation or study withdrawal.ConclusionsThese results suggest that routine laboratory monitoring of children aged 6 months to < 6 years treated with dupilumab plus topical corticosteroids is not required. Limitations of this study include short study duration, and exclusion of patients with abnormalities in laboratory test results at screening.

Previous studies of dupilumab for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents, and severe atopic dermatitis in children aged 6 to12 years demonstrate no clinically important changes in laboratory parameters. The objective of this study was to assess laboratory outcomes in children aged 6 months to 6 years with moderate-to-severe atopic dermatitis treated with dupilumab.In this randomized, placebo-controlled, phase III trial of dupilumab, 161 children aged 6 months to6 years with moderate-to-severe atopic dermatitis were enrolled from 31 sites in Europe and North America and randomized 1:1 to receive subcutaneous placebo or dupilumab (5 kg to 15 kg: 200 mg; 15 kg to 30 kg: 300 mg) every 4 weeks plus topical corticosteroids for 16 weeks. Hematology, serum chemistry, and urinalysis assessments were analyzed on blood and urine samples collected at screening and weeks 4 and 16; descriptive statistics are provided.No clinically meaningful changes in laboratory parameters were observed. While two cases of eosinophilia and one case each of neutropenia and leukocytosis were reported as treatment-emergent adverse events in the dupilumab plus topical corticosteroids group, these events were not associated with clinical symptoms and did not lead to treatment discontinuation or study withdrawal.These results suggest that routine laboratory monitoring of children aged 6 months to 6 years treated with dupilumab plus topical corticosteroids is not required. Limitations of this study include short study duration, and exclusion of patients with abnormalities in laboratory test results at screening.ClinicalTrials.gov: NCT03346434, part B.Atopic dermatitis (AD) is a chronic, inflammatory skin disease that often causes itchy rashes. To reduce persistent AD signs and symptoms, patients may need to take medications that require laboratory monitoring. This can add to treatment burden, especially among infants and children. Dupilumab is a drug that specifically targets key molecules that underlie AD and has been tested in several clinical trials, now in patients 6 months and older. Studies in adults, adolescents, and children as young as 6 years of age with moderate-to-severe AD have shown that dupilumab can be used without the need for regular laboratory tests. In this study, the authors analyzed blood and urine samples collected during a clinical trial of dupilumab in 161 infants and children aged 6 months to 5 years with moderate-to-severe AD. Routine laboratory tests revealed no clinically meaningful changes in patients’ blood and urine following treatment with dupilumab. In general, the laboratory results in these patients were similar to those in adults, adolescents, and children aged 6–11 years treated with dupilumab. Taken together, these findings suggest that dupilumab can be used for the continuous treatment of moderate-to-severe AD without the need for routine laboratory monitoring.

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naive CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ss repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978), Projekt DEAL; German Federal Ministry of Education and Research (BMBF) [01GM0896, 01GM1111B, 01GM1517C, 01EO1303, 01ZZ1801B]; EU [HEALTHF2-2008-201549]; Novartis; GlaxoSmithKline; LFB; UCB UK; Plasma Protein Therapeutics Association (PPTA),; Care-for-Rare Foundation; PROimmune e.V; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [39087428]; UK National Institute of Health Research; Great Ormond Street Hospital Biomedical Research Centre, Open Access funding enabled and organized by Projekt DEAL. The ESID Registry was supported by the German Federal Ministry of Education and Research (BMBF 01GM0896, 01GM1111B, 01GM1517C, 01EO1303 and 01ZZ1801B) EU grant no. HEALTHF2-2008-201549 (EURO-PADnet), the pharmaceutical companies Novartis, GlaxoSmithKline, LFB, and UCB UK, the Plasma Protein Therapeutics Association (PPTA), the Care-for-Rare Foundation, PROimmune e.V, LFB, and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence StrategyEXC 2155 RESIST-Project ID 39087428. EGD is supported by the UK National Institute of Health Research and the Great Ormond Street Hospital Biomedical Research Centre.

Introduction: Children with autoimmune diseases often require treatment with systemic immunosuppressives. Efficacy and safety of vaccination, particularly live-attenuated viral vaccines in these pa...

Extensive activation of mast cells is the major switch that triggers systemic anaphylaxis, resulting in the subsequent release of anaphylactic mediators into circulation. We previously demonstrated that rapid changes in oxygen tension lead to mast cell degranulation, and the released tryptase triggers retinal angiogenesis in a murine oxygen-induced retinopathy model. However, whether a rapid shift from hyperoxia to normoxia (relative hypoxic stress) is a risk factor for systemic anaphylaxis remains unknown. In this study, we demonstrated that the relative hypoxia stress induces systemic mast cell activation via transient receptor potential ankyrin 1 (TRPA1) channels, which immediately leads to hypothermia and increased vascular permeability in adult mice. Although mast cell–deficient or TRPA1-deficient mice did not exhibit anaphylactic symptoms following a rapid sift to normoxia, preinjection with bone marrow–derived cultured mast cells (BMCMCs) derived from wild-type TRPA1-expressing mice restored anaphylactic responses. In addition, we found that the rapid reductions in oxygen tension in a culture atmosphere triggered the degranulation of BMCMCs derived from wild-type TRPA1-expressing mice but not that of BMCMCs derived from TRPA1-deficient mice. In human LAD2 mast cells, the relative hypoxic stress led to the degranulation, which was suppressed by the addition of a TRPA1 inhibitor. Gradual reductions from hyperoxia to normoxia led to no anaphylactic symptoms. Our results demonstrated that TRPA1-triggered mast cell degranulation is a novel pathway that induces anaphylactic shock without Ag–Ab reactions. These findings introduce a potential role for oxygen in inducing mast cell–dependent anaphylaxis and highlight the need to reconsider chronic pure oxygen therapy for anoxic diseases.

Meningococcal disease caused by Neisseria meningitidis is a major cause of meningitis and septicemia with high rates of morbidity and mortality worldwide. MenACWY-TT and MenACWY-CRM197 are meningoc...

Background Aminoacyl tRNA synthetases/ligases (ARSs) are highly conserved enzymes involved in attaching amino acids to tRNA promoting protein synthesis. Although deficiencies of ARSs localized to the mitochondria classically present with neuropathology, the clinical features of cytosolic ARS deficiencies are more variable. They have previously been associated with neonatal hepatitis, but never with early-onset inflammatory bowel disease. Case summary A nine-year-old Bangladeshi boy presented with neonatal liver failure and deranged clotting, transaminitis and cholestasis. His parents were first cousins. Two older brothers and a sister were well. The patient suffered from loose stools from early infancy which became more troublesome and persistent from five years old with ten bloody motions a day. Repeated endoscopies showed persistent pancolitis, which was refractory to mesalazine, corticosteroids, azathioprine, sirolimus and anti-TNF (adalimumab) therapy, but has improved recently with subcutaneous methotrexate.Whole Genome Sequencing revealed a novel pathogenic missense variant (c.290A > G) in the cytosolic isoleucyl-tRNA synthetase gene, leading to an amino acid substitution (p.Asp97Gly). Pathogenic variants in other genes associated with inflammatory bowel disease (IBD) (ADAM17, EGFR, FOXP3, IL10RA, IL10RB, IL21R, NCF4, STAT3) were excluded. Cytokine assays demonstrated markedly elevated IL-2, IL-5, IL-13, IL-9 and IL-10 by the patient's CD4+ T-cells, while IL-17A, IL-17F, IFNβ were lower, and TNFα not significantly different when compared to healthy controls. Conclusion This case report provides evidence that recessive mutations in cytosolic isoleucyl-tRNA synthetase are a novel monogenic cause of IBD, which should be considered, particularly in infants and children with a history of neonatal hepatitis and very early-onset IBD poorly responsive to treatment.

Background and aims Monogenic forms of inflammatory bowel disease (IBD) illustrate the essential roles of individual genes in pathways and networks safeguarding immune tolerance and gut homeostasis. Methods To build a taxonomy model we assessed 165 disorders. Genes were prioritized based on penetrance of IBD and disease phenotypes were integrated with multi-omics datasets. Monogenic IBD genes were classified by: (1) overlapping syndromic features; (2) response to hematopoietic stem cell transplantation; (3) bulk RNA-seq of 32 tissues; (4) single-cell RNA-seq of >50 cell subsets from the intestine of healthy individuals and IBD patients (pediatric and adult), and (5) proteomes of 43 immune subsets. The model was validated by addition of newly identified monogenic IBD defects. As a proof-of-concept, we explore the intersection between immunometabolism and antimicrobial activity for a group of disorders (G6PC3/SLC37A4). Results Our quantitative integrated taxonomy defines the cellular landscape of monogenic IBD gene expression across 102 genes with high and moderate penetrance (81 in the model set and 21 genes in the validation set). We illustrate distinct cellular networks, highlight expression profiles across understudied cell types (e.g., CD8+ T cells, neutrophils, epithelial subsets and endothelial cells) and define genotype-phenotype associations (perianal disease and defective antimicrobial activity). We illustrate processes and pathways shared across cellular compartments and phenotypic groups and highlight cellular immunometabolism with mTOR activation as one of the converging pathways. There is an overlap of genes and enriched cell-specific expression between monogenic and polygenic IBD. Conclusion Our taxonomy integrates genetic, clinical and multi-omic data; providing a basis for genomic diagnostics and testable hypotheses for disease functions and treatment responses.

Background Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing. Objectives We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles. Methods Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants. Results Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked–like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein. Conclusion These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.

Primary complement deficiencies are a complex and diverse group of over 20 distinct inherited immunodeficiency disorders. They make up 2–5% of all primary immunodeficiencies. These diseases can be divided into three broad groups. Classical pathway defects (C1, C2, C4) are associated with an increased risk of invasive pneumococcal infection and, in the case of C1q deficiency, an 80% risk of SLE-like immune complex disease. C1q deficiency has a 20% mortality rate in the first 20 years of life. Terminal complement defects (C5–C9) are largely associated with an increased risk of invasive meningococcal disease. Infection risk can be partly mitigated by vaccination. A third group includes deficiency (C3 loss of function, Factor B, properdin) or dysregulation of the C3 activity (C3 gain of function, Factor H, Factor I, membrane cofactor protein), the latter leads to endothelial damage and renal disease (aHUS or membranoproliferative glomerulonephritis) with a high risk of renal failure requiring dialysis. For most patients with primary complement deficiencies, CH50 and AH50 rather than C3 and C4, should be requested as the initial screening test. Management varies, ranging from augmenting pneumococcal and meningococcal antibody responses by immunization, antibiotic prophylaxis, immunosuppressants and HSCT for C1q deficiency, and anti-C5 monoclonal therapy for patients with aHUS.

Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval [95% CI] 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.

Aim Outpatient workload for paediatric specialities across a region, let alone within a specific centre is usually difficult to gauge. We aimed to develop an online database for recording and assessing workload in real-time. Method The University of Manchester in conjunction with the North West Paediatric Allergy Network developed and implemented a secure database utilising an online-system of live recording and collation of the workload and outcomes of children with allergies presenting to 21 paediatric secondary and tertiary centres across the whole North West of England and North Wales seeing children with allergies. Results In a 9-month period from January to September 2019, 3,600 patient events were recorded across the two regions. 34% were new patients, 53% follow-up patients, 5% telephone consultations and 8% did not attend their appointments. Eighty one percent of children had suffered immediate hypersensitivity reactions, of which 85% were children with food allergies. The ‘big four’ food allergies accounting for 81% of all children with food allergies were milk, egg, peanut and tree nuts. Only 19% of patients were discharged after their clinic appointment, while the remainder were followed up, 19% of whom were put forward for a formal food challenge to confirm their allergies. Fourteen percent of children were either on oral immunosuppressants or biologics (1%) or immunotherapy (oral immunotherapy for food allergies (9%), subcutaneous or sublingual immunotherapy for aeroallergies (4%)). Conclusion Our online system for recording and collating of clinical workload and outcomes allows for immediate review of the number and types of allergies children suffered across the regions. Comparisons in terms of efficiency and outlies were easily detected. The data allowed us to develop business cases to meet current demands, as well as management pathways to streamline allergy management.

The glucose-6-phosphatase catalytic subunit 3 (G6PC3) encodes a ubiquitously expressed enzyme that regulates cytoplasmic glucose availability. Loss-of-function biallelic G6PC3 mutations cause severe congenital neutropenia and a diverse spectrum of extra-hematological manifestations, among which inflammatory bowel disease (IBD) has been anecdotally reported. Neutrophil function and clinical response to granulocyte colony-stimulating factor (G-CSF) and hematopoietic stem cell transplantation (HSCT) were investigated in 4 children with G6PC3 deficiency-associated IBD. G6PC3 deficiency was associated with early-onset IBD refractory to treatment with steroids and infliximab. The symptoms of IBD progressed despite G-CSF treatment. In vitro studies on the patients’ blood showed that neutrophils displayed higher levels of activation markers (CD11b, CD66b, and CD14), excessive IL-8 and reactive oxygen species, and increased apoptosis and secondary necrosis. Secondary necrosis was exaggerated after stimulation with Escherichia coli and could be partially rescued with supplemental exogenous glucose. HSCT led to normalization of neutrophil function and remission of gastrointestinal symptoms. We conclude that neutrophils in G6PC3 deficiency release pro-inflammatory mediators when exposed to gut bacteria, associated with intestinal inflammation, despite treatment with G-CSF. HSCT is an effective therapeutic option in patients with G6PC3 deficiency-associated IBD refractory to immune suppressants.

Background Children aged ≥ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16‐week, randomized, placebo‐controlled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)‐4/IL‐13 signalling, significantly improved signs and symptoms with acceptable safety; longer‐term safety and efficacy data are lacking. Objectives To report the pharmacokinetic profile and long‐term safety and efficacy of dupilumab in children (aged ≥ 6 to < 12 years) with severe AD. Methods Children (aged ≥ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, open‐label, ascending‐dose, sequential cohort study and subsequent open‐label extension (OLE) study. Patients received single‐dose dupilumab 2 or 4 mg kg−1 followed by 8‐week pharmacokinetic sampling, then 2 or 4 mg kg−1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were dupilumab concentration–time profile and treatment‐emergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PP‐NRS) score. Results Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, target‐mediated pharmacokinetics characterized dupilumab concentrations (week 24–48 mean serum concentrations: 2 mg kg−1, 61–77 mg L−1; 4 mg kg−1, 143–181 mg L−1). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kg−1, 47%; 4 mg kg−1, 56%) and AD exacerbation (29% and 13%, respectively). Single‐dose dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PP‐NRS improved by −37%/−33% and −17%/−20% at week 2 (phase IIa) and −92%/−84% and −70%/−58% at week 52 (OLE), respectively. Conclusions These safety and efficacy results support the use of dupilumab as a continuous long‐term treatment for children aged ≥ 6 to < 12 years with severe AD.

Background Pollen and house dust mite (HDM) subcutaneous immunotherapy (SLIT) and pollen subcutaneous immunotherapy (SCIT) are effective therapies for children with allergic rhinoconjunctivitis (AR). There are no previous direct comparative studies investigating quality of life (QoL) of all three immunotherapy regimes. The aim of this study was to compare QoL and safety in children receiving these immunotherapies for AR. Methods Demographic characteristics, Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and Visual Analogue (VAS) scores were assessed in 249 children undergoing HDM and pollen immunotherapy at a UK specialist paediatric centre between 2007 and 2019. Results All three immunotherapy regimes led to a > 50% improvement in QoL and VAS after 3 years of therapy, with significant improvements by the end of the first year (p

There has been extensive progress in understanding the cellular and molecular mechanisms of inflammation and immune regulation in allergic diseases of the skin and lungs during the last few years. Asthma and atopic dermatitis (AD) are typical diseases of type 2 immune responses. interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin are essential cytokines of epithelial cells that are activated by allergens, pollutants, viruses, bacteria, and toxins that derive type 2 responses. Th2 cells and innate lymphoid cells (ILC) produce and secrete type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13. IL-4 and IL-13 activate B cells to class-switch to IgE and also play a role in T-cell and eosinophil migration to allergic inflammatory tissues. IL-13 contributes to maturation, activation, nitric oxide production and differentiation of epithelia, production of mucus as well as smooth muscle contraction, and extracellular matrix generation. IL-4 and IL-13 open tight junction barrier and cause barrier leakiness in the skin and lungs. IL-5 acts on activation, recruitment, and survival of eosinophils. IL-9 contributes to general allergic phenotype by enhancing all of the aspects, such as IgE and eosinophilia. Type 2 ILC contribute to inflammation in AD and asthma by enhancing the activity of Th2 cells, eosinophils, and their cytokines. Currently, five biologics are licensed to suppress type 2 inflammation via IgE, IL-5 and its receptor, and IL-4 receptor alpha. Some patients with severe atopic disease have little evidence of type 2 hyperactivity and do not respond to biologics which target this pathway. Studies in responder and nonresponder patients demonstrate the complexity of these diseases. In addition, primary immune deficiency diseases related to T-cell maturation, regulatory T-cell development, and T-cell signaling, such as Omenn syndrome, severe combined immune deficiencies, immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and DOCK8, STAT3, and CARD11 deficiencies, help in our understanding of the importance and redundancy of various type 2 immune components. The present review aims to highlight recent advances in type 2 immunity and discuss the cellular sources, targets, and roles of type 2 mechanisms in asthma and AD.

International audience; Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. The CTPS1 T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T cell leukemia fully abolished cell proliferation. Expression of CTPS1 T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT CTPS1. This indicates that CTPS1 T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1 T566Dfs26X is completely attributable to protein instability. This study supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.

Background Children with severe atopic dermatitis (AD) have limited treatment options. Objective We report efficacy and safety of dupilumab + topical corticosteroids (TCS) in children aged 6–11 years with severe AD inadequately controlled with topical therapies. Methods In this double-blind, 16-week, phase 3 trial (NCT03345914), 367 patients were randomized 1:1:1 to 300mg dupilumab every 4 weeks (300mg-q4w), a weight-based regimen of dupilumab every 2 weeks (100mg-q2w, baseline weight

Background Hereditary alpha-tryptasemia (HAT) is a genetic trait caused by an increased alpha-tryptase tryptase alpha/beta 1 gene copy number. Basal serum mast cell tryptase (MCT) level is typically greater than or equal to 8.0 ng/mL. Objectives To study the clinical disease spectrum of HAT and determine its UK prevalence. Methods Droplet digital PCR was used to determine tryptase alpha/beta 1 copy number in 432 DNA samples from an unselected UK birth cohort and in 70 patients referred with a basal MCT level greater than 8 ng/mL. Baseline MCT concentrations and clinical presentation were also assessed in 4283 samples sent to a regional immunology laboratory. Results Duplication in alpha copy number was present in 5% of the unselected British birth cohort, with all affected individuals having a basal MCT level of greater than or equal to 8.0 ng/mL. Basal MCT levels of greater than or equal to 8.0 ng/mL were also found in 5% of the 4283 individuals referred for MCT testing because of clinical symptoms. In 70 patients confirmed to have HAT (79% with a duplication; 21% with a higher alpha gene copy number), urticaria/angioedema (51%), skin flushing (41%), food intolerances (39%), and altered bowel habits (36%) were common presenting complaints. However, clinical manifestations were not more common in patients with gene triplications or quintuplications than in those with duplications. Some immediate family members with the same genetic trait and high basal MCT levels were asymptomatic. Conclusions Five percent of people in the United Kingdom may have HAT. The diagnosis should be considered when basal MCT level is greater than or equal to 8 ng/mL. HAT has variable clinical penetrance. It may modify the expression of multifactorial allergic diseases rather than directly cause specific phenotypes.

Summary Background Dupilumab (monoclonal antibody inhibiting IL‐4/IL‐13 signalling) is approved for use in adolescents aged ≥ 12 years with inadequately controlled moderate‐to‐severe atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16‐week, randomised, placebo‐controlled phase III trial in adolescents (NCT03054428). Objectives To characterize the pharmacokinetics of dupilumab, and long‐term safety and efficacy in adolescents. Methods This was a global, multicentre, phase IIa, open‐label, ascending‐dose, sequential cohort study with a phase III open‐label extension (OLE) in adolescents with moderate‐to‐severe AD. In the phase IIa study, patients received one dupilumab dose (2 mg kg−1 or 4 mg kg−1) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8‐week safety follow‐up. Patients then enrolled in the OLE, continuing 2 mg kg−1 or 4 mg kg−1 dupilumab weekly. Primary end points were dupilumab concentration–time profile and incidence of treatment‐emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI). Results Forty adolescents received dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target‐mediated pharmacokinetics. Mean ± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L−1 and 161 ± 60 mg L−1 for 2 mg kg−1 and 4 mg kg−1, respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kg−1], 47% [4 mg kg−1]) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction −34% ± 20% (2 mg kg−1) and −51% ± 29% (4 mg kg−1)]. With continuing treatment, EASI scores improved further [week 52: −85% ± 12% (2 mg kg−1) and −84% ± 20% (4 mg kg−1)]. Conclusions In adolescents with moderate‐to‐severe AD, dupilumab's pharmacokinetic profile was similar to that in adults. These 52‐week safety and efficacy data support long‐term use of dupilumab in this patient population. What's already known about this topic? Adolescents with moderate‐to‐severe atopic dermatitis (AD) have high unmet medical need, with significant disease burden and limited treatment options.Dupilumab (monoclonal antibody against interleukin‐4 receptor α) is approved for the treatment of adolescents with moderate‐to‐severe AD who are inadequately responsive to standard of care (U.S.A.) or candidates for systemic therapy (European Union).A 16‐week, randomized, placebo‐controlled phase III trial in adolescents demonstrated significant improvements in AD signs/symptoms with an acceptable safety profile. What does this study add? These studies demonstrate the long‐term safety and efficacy of dupilumab in adolescents with moderate‐to‐severe AD for up to 52 weeks of treatment, thus extending and reinforcing the findings from the 16‐week dupilumab phase III trial.The data from these studies also support the use of dupilumab in combination with current standard of care (topical corticosteroids), which was not evaluated in the 16‐week phase III monotherapy trial., Linked Comment: https://doi.org/10.1111/bjd.18627. https://doi.org/10.1111/bjd.18661 available online

Mast cells are typically linked to immediate hypersensitivity and anaphylaxis. This review looks beyond this narrow role, focusing on how these cells have evolved and diversified via natural selection promoting serine protease gene duplication, augmenting their innate host defence function against helminths and snake envenomation. Plasticity of mast cell genes has come at a price. Somatic activating mutations in the mast cell growth factor KIT gene causes cutaneous mastocytosis in young children, and systemic mastocytosis with a more guarded prognosis in adults who may also harbor other gene mutations with oncogenic potential as they age. Allelic TPSAB1 gene duplication associated with higher basal mast cell tryptase is possibly one of the commonest autosomal dominantly inherited multi‐system diseases affecting the skin, gastrointestinal tract, circulation, musculoskeletal system and affect.Mast cells are also establishing a new‐found importance in severe asthma, and in remodelling of blood vessels in cancer and atherosclerotic vascular disease. Furthermore, recent evidence suggests that mast cells sense changes in oxygen tension, particularly in neonates, and that subsequent degranulation may contribute to common lung, eye and brain diseases of prematurity classically associated with hypoxic insults. One hundred and forty years since Paul Ehrlich's initial description of “mastzellen”, this review collates and highlights the complex and diverse roles that mast cells play in health and disease

Cytidine triphosphate (CTP) synthase 1 is responsible for the catalytic conversion of uridine triphosphate (UTP) to CTP in lymphocytes. This reaction is important for the biosynthesis of nucleic acids, playing a key role in lymphocyte function and turnover. Lack of this enzyme due to mutation in CTPS gene is associated with impaired capacity of activated T and B-lymphocytes to proliferate in response to antigen-induced activation. Patients with this mutation all have ancestors from the North West of England and present in the first decade of life with severe acute and chronic herpes virus infections and recurrent infections with encapsulated bacteria. There is a high risk of EBV-driven lymphoma. This is a potentially life-threatening primary immune deficiency (PID) and long-term survival has not been reported. We report on 11 patients with CTPS1 mutations who underwent hematopoietic stem cell transplant (HSCT) at three UK centres (London, Manchester and Newcastle). The molecular diagnosis was made pre-HSCT in six patients and retrospectively in five patients who had undergone HSCT for previously undiagnosed life-threatening PID. All patients had the same homozygous NM_001905.3: c.1692-1G>C mutation (rs145092287) mutation and all the parents were heterozygous carriers. This mutation is known to lead to an abnormal transcript lacking exon 18 and complete lack of protein expression. Six patients had an affected 39 sibling. Patient 1 had 2 affected siblings who died of infection and hemophagocytic lymphohistiocytosis (HLH) in early childhood and patient 2 also had a sibling who died of overwhelming VZV and EBV infections before diagnosis. Pre-transplant features are summarized in Table 1. Systemic viral infections were seen in all patients, with acute and chronic EBV infections in nine patients, four suffering from EBV-driven lymphoproliferative disease (LPD) (two CNS and one lung) and one with EBV-driven HLH. Four patients had severe chickenpox. Five patients presented with chronic diarrhea. Four patients with EBV-driven LPD received rituximab and three EBV-specific cytotoxic T-lymphocytes (CTLs) (two pre-transplant and one post-transplant). The age of the patients at transplant ranged from 15 months to 17 years. The source of stem cells was peripheral blood (PB) in seven patients, bone marrow (BM) in three and cord blood (CB) in one. Eight received matched (10/10) donor stem cells, two had 1/10 mismatches and one received a haploidentical 6/10 transplant from his father as there were no suitable matched donor (Table 2). All but one received conditioning with fludarabine in combination with treosulfan (n=3), melphalan (n=4), treosulfan and thiotepa (n=1, the non-reduced intensity conditioning (RIC) protocol) or low dose busulfan (n=2)3 one received treosulfan and cyclophosphamide. All but one patient received serotherapy with alemtuzumab (n=8) or anti T cell globulin (ATG) (n=2). CD34+ cell dose ranged from 0.4 - 16.1 x 106/kg. Neutrophil engraftment (≥0.5 x 109 51 /L) occurred between day 11- 23 post-transplant. Ten had 100% CD3 donor engraftment and one had 76% in last follow up. Eight patients are alive with post-HSCT follow-up of 8 months to 22 years. All surviving patients have discontinued immunosuppression and six are off immunoglobulin replacement therapy. Patient 4 died 76 days post-HSCT following EBV CNS reactivation leading to obstructive hydrocephalus. She was treated with external ventricular drainage and three doses of 2 x 106 55 EBV-CTLs but died of multi-organ failure 4 56 . Patient 7 developed intractable gut inflammation due to a combination of adenovirus and CMV colitis and chronic graft versus host disease (cGvHD) and died at day +290 despite treatment with ganciclovir and cidofovir for the viral infections and corticosteroids, ciclosporin, tacrolimus and infliximab as anti-inflammatory drugs. Patient 8 developed mild acute skin GvHD post-transplant, but later suffered from intractable chronic skin GvHD (but no gut or liver disease) unresponsive to corticosteroids and extracorporeal photophoresis. Twelve months post-transplantation he developed a tremor and altered mental state progressing to coma and died 15 months post-transplant. Brain biopsy and magnetic resonance (MR) scan performed prior to death were indicative of progressive multifocal leukoencephalopathy (PML), although no JC, BK or astrovirus were isolated from cerebrospinal fluid (CSF) or brain tissue. CTPS1 deficiency is a serious life-limiting immunodeficiency with a high risk of death from VZV and EBV in the first decade of life. Seven (41%) of 17 patients worldwide with CTPS1 deficiency have died, three post and four prior to HSCT (one from fulminant VZV and the other three from fulminant EBV LPD). These deaths were prior to clinical availability of rituximab. However, mild clinical phenotype has previously been described. HSCT can be curative but is not without potential risks and complications. Kucuk et al also reported two siblings with this mutation who had successful transplantation. The current report is the largest series of children with CTPS1 deficiency who have undergone HSCT.The overall survival post-HSCT in this series was 72% which is slightly lower than seen after HSCT for other combined PIDs. Pre-transplantation, extra-nodal EBV-driven LPD of the brain and lung as well as fulminant VZV pneumonitis requiring ventilation in intensive care are major risks. The post-transplantation course can be challenging to even the specialist centres because of re-activation of EBV and other herpes viruses, particularly in the brain and gastrointestinal tract, but also because of the risk of unusually severe skin and gut cGvHD, the latter which may be partly fuelled by ongoing underlying low grade chronic viral infection. Both patients that developed fatal GvHD had transplants from 9/10 matched unrelated donors. Viral reactivation can be observed prior to donor T-lymphocyte engraftment post-transplant and perhaps virus-specific CTLs may be helpful in some of these patients. There is no doubt that HSCT can be curative in this condition and we recommend early transplantation before the onset of end-organ damage and for patients without fully matching family or unrelated donors, the consideration of ex-vivo T-cell depletion strategies.

Mast cells are classically thought to play an important role in protection against helminth infections and in the induction of allergic diseases; however, recent studies indicate that these cells also contribute to neovascularization, which is critical for tissue remodeling, chronic inflammation, and carcinogenesis. Here, we demonstrate that mast cells are essential for sprouting angiogenesis in a murine model of oxygen-induced retinopathy (OIR). Although mouse strains lacking mast cells did not exhibit retinal neovascularization following hypoxia, these mice developed OIR following infusion of mast cells or after injection of mast cell tryptase (MCT). Relative hypoxia stimulated mast cell degranulation via transient receptor potential ankyrin 1. Subsequent surges in MCT stimulated retinal endothelial cells to produce monocyte chemotactic protein-1 (MCP1) and angiogenic factors, leading to sprouting angiogenesis. Mast cell stabilizers as well as specific tryptase and MCP1 inhibitors prevented the development of OIR in WT mice. Preterm infants with early retinopathy of prematurity had markedly higher plasma MCT levels than age-matched infants without disease, suggesting mast cells contribute to human disease. Together, these results suggest therapies that suppress mast cell activity should be further explored as a potential option for preventing eye diseases and subsequent blindness induced by neovascularization.