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Tree nut (TN) and seed allergies are frequent, and their prevalence appears to be on the rise. Allergic reactions associated with these foods are more frequently severe, and these allergies tend to persist into adulthood, consequently affecting quality of life. In this review, we summarize recent advances in diagnostic modalities and management strategies for TN/seed-allergic patients.Clinical manifestations of TN and seed allergy range from asymptomatic sensitization to severe anaphylactic reactions. The use of emerging diagnostic tools such as component resolved diagnostics (CRD) and the basophil activation test (BAT) can help better predict clinical reactivity, the latter being currently reserved for research settings. Strict avoidance of all TN is generally not required, as most patients can tolerate select TN despite co-sensitization. Oral immunotherapy (OIT) is a promising alternative treatment instead of complete avoidance of culprit allergens, as it can safely increase the allergy threshold.Our recent understanding of co-reactivity between various TN and seeds has shaped management opportunities, including select TN introduction and optimization of OIT, two strategies which may improve quality of life. There is a need for better minimally invasive diagnostic methods for TN and seed allergy, with CRD and BAT being promising tools.

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Colorectal cancer is driven by mutations that activate canonical WNT/β-catenin signaling, but inhibiting WNT has significant on-target toxicity, and there are no approved therapies targeting dominant oncogenic drivers. We recently found that activating a β-catenin–independent branch of WNT signaling that inhibits GSK3-dependent protein degradation induces asparaginase sensitivity in drug-resistant leukemias. To test predictions from our model, we turned to colorectal cancer because these cancers can have WNT-activating mutations that function either upstream (i.e., R-spondin fusions) or downstream (APC or β-catenin mutations) of GSK3, thus allowing WNT/β-catenin and WNT-induced asparaginase sensitivity to be unlinked genetically. We found that asparaginase had little efficacy in APC or β-catenin–mutant colorectal cancer, but was profoundly toxic in the setting of R-spondin fusions. Pharmacologic GSK3α inhibition was sufficient for asparaginase sensitization in APC or β-catenin–mutant colorectal cancer, but not in normal intestinal progenitors. Our findings demonstrate that WNT-induced therapeutic vulnerabilities can be exploited for colorectal cancer therapy.Significance:Solid tumors are thought to be asparaginase-resistant via de novo asparagine synthesis. In leukemia, GSK3α-dependent protein degradation, a catabolic amino acid source, mediates asparaginase resistance. We found that asparaginase is profoundly toxic to colorectal cancers with WNT-activating mutations that inhibit GSK3. Aberrant WNT activation can provide a therapeutic vulnerability in colorectal cancer.See related commentary by Davidsen and Sullivan, p. 1632.This article is highlighted in the In This Issue feature, p. 1611

Current recommendations for the management of penicillin allergy are to perform penicillin skin testing (PST) with penicilloyl-polylysine (PPL) and benzylpenicillin (BP) prior to drug challenge with amoxicillin. However, the role of PST is increasingly questioned in the pediatric setting. To resolve the question of PST’s diagnostic accuracy, consecutive children with a history of non-life-threatening penicillin allergy referred to a tertiary-care allergy center were recruited to undergo double-blinded PST with PPL and BP prior to drug provocation to amoxicillin. Five of 158 participants (3.2%) presented with an immediate or accelerated reaction upon amoxicillin challenge, none of which were severe. Only one of these had positive PST (20%), compared to 15 of 153 amoxicillin tolerant participants (9.8%). The sensitivity and specificity of PST with PPL and BP for reacting upon amoxicillin challenge were 20% (95% CI: 0.5–71.6%) and 90% (95% CI: 84.4–94.4%), respectively. These results argue against the routine use of PST as a preliminary step to drug provocation with amoxicillin in this population, as it is unlikely to significantly alter pre-test probability of reacting to challenge.

Severe combined immunodeficiency (SCID) comprises rare inherited disorders of immunity that require definitive treatment through hematopoietic cell transplantation (HCT) or gene therapy for survival. Despite successes of allogeneic HCT, many SCID patients experience incomplete immune reconstitution, persistent T-cell lymphopenia, and poor long-term outcomes.We hypothesized that CD4We analyzed markers of exhaustion in blood samples from 61 SCID patients at a median of 10.4 years after HCT.Compared to post-HCT SCID patients with normal CD4Recipients of unconditioned HCT for SCID may develop late post-HCT T-cell exhaustion as a result of diminished production of T-lineage cells. Elevated expression of inhibitory receptors on their T cells may be a biomarker of poor long-term T-cell reconstitution.

The advantage of the newer biological therapies is that the immunosuppressive effect is targeted, in contrast, to the standard, traditional immunomodulatory agents, which have a more global effect. However, there are unintended targets and consequences, even to these "precise" therapeutics, leading to acquired or secondary immunodeficiencies. Besides depleting specific cellular immune subsets, these biological agents, which include monoclonal antibodies against biologically relevant molecules, often have broader functional immune consequences, which become apparent over time. This review focuses on acquired B-cell immunodeficiency, secondary to the use of B-cell depleting therapeutic agents. Among the many adverse consequences of B-cell depletion is the risk of hypogammaglobulinemia, failure of B-cell recovery, impaired B-cell differentiation, and risk of infections. Factors, which modulate the outcomes of B-cell depleting therapies, include the intrinsic nature of the underlying disease, the concomitant use of other immunomodulatory agents, and the clinical status of the patient and other co-existing morbidities. This article seeks to explore the mechanism of action of B-cell depleting agents, the clinical utility and adverse effects of these therapies, and the relevance of systematic and serial laboratory immune monitoring in identifying patients at risk for developing immunological complications, and who may benefit from early intervention to mitigate the secondary consequences. Though these biological drugs are gaining widespread use, a harmonized approach to immune evaluation pre-and post-treatment has not yet gained traction across multiple clinical specialties, because of which, the true prevalence of these adverse events cannot be determined in the treated population, and a systematic and evidence-based dosing schedule cannot be developed. The aim of this review is to bring these issues into focus, and initiate a multi-specialty, data-driven approach to immune monitoring.

Background The Food Allergy Quality of Life Questionnaire Parent Form (FAQLQ-PF) is the most widely used quality of life questionnaire in food allergy. The objective of this study was to develop a mapping algorithm to convert FAQLQ-PF scores into health state utilities. Methods The Short-Form Six-Dimensions version 2 (SF-6Dv2) and FAQLQ-PF questionnaires were collected from an academic center oral immunotherapy referral cohort. Utility estimates were derived from the SF-6Dv2 using the food allergy preference set. Candidate mapping algorithm models were developed using seven regression methods starting from either the total average score, the average scores of each of the three domains or the individual item scores of FAQLQ-PF. The process was repeated twice, including only section A, common to all age groups, or including all age-applicable sections of the FAQLQ-PF. The mean absolute error (MAE) and root mean squared error (RMSE) were used to select the best fitting model. An independent cohort from a previous national online survey was used for external validation. Results In the index cohort, 1000 of 1257 respondents had completed both questionnaires. The lowest MAE (0.0791) and RMSE (0.1020) were recorded when entering individual item scores in a categorical regression model. The model including only FAQLQ-PF section A was found to be most consistent when tested in the external validation cohort (n=248) (MAE of 0.0898). Conclusion The FAQLQ-PF was mapped onto SF-6Dv2 utilities with good predictive accuracy in two independent cohorts. This will enable calculation of health utility for cost-effectiveness analyses in food allergy.

Rituximab is a B-cell depleting agent used in B-cell malignancies and autoimmune diseases. A subset of adult patients may develop prolonged and symptomatic hypogammaglobulinemia following rituximab treatment. However, this phenomenon has not been well delineated in the pediatric population.This study sought to determine the prevalence, risk factors, and clinical significance of hypogammaglobulinemia following rituximab therapy in children.This was a multicenter, retrospective cohort study that extracted clinical and immunological data from pediatric patients who received rituximab.The cohort comprised 207 patients (median age, 12.0 years). Compared to baseline values, there was a significant increase in hypogammaglobulinemia post-rituximab therapy, with an increase in prevalence of hypo-IgG (28.7%-42.6%; P = .009), hypo-IgA (11.1%-20.4%; P = .02), and hypo-IgM (20.0%-62.0%; P .0001). Additionally, low IgG levels at any time post-rituximab therapy were associated with a higher risk of serious infections (34.4% vs 18.9%; odds ratio, 2.3; 95% CI, 1.1-4.8; P = .03). Persistent IgG hypogammaglobulinemia was observed in 27 of 101 evaluable patients (26.7%). Significant risk factors for persistent IgG hypogammaglobulinemia included low IgG and IgA levels pre-rituximab therapy. Nine patients (4.3%) within the study were subsequently diagnosed with a primary immunodeficiency, 7 of which received rituximab for autoimmune cytopenias.Hypogammaglobulinemia post-rituximab treatment is frequently diagnosed within the pediatric population. Low IgG levels are associated with a significant increase in serious infections, and underlying primary immunodeficiencies are relatively common in children receiving rituximab, thus highlighting the importance of immunologic monitoring both before and after rituximab therapy.

Non-immunoglobulin E-mediated gastrointestinal food allergic disorders (non-IgE-GI-FA) include food protein-induced enterocolitis syndrome (FPIES), food protein-induced enteropathy (FPE) and food protein-induced allergic proctocolitis (FPIAP), which present with symptoms of variable severity, affecting the gastrointestinal tract in response to specific dietary antigens. The diagnosis of non-IgE-GI-FA is made clinically, and relies on a constellation of typical symptoms that improve upon removal of the culprit food. When possible, food reintroduction should be attempted, with the documentation of symptoms relapse to establish a conclusive diagnosis. Management includes dietary avoidance, nutritional counselling, and supportive measures in the case of accidental exposure. The prognosis is generally favorable, with the majority of cases resolved before school age. Serial follow-up to establish whether the acquisition of tolerance has occurred is therefore essential in order to avoid unnecessary food restriction and potential consequent nutritional deficiencies. The purpose of this review is to delineate the distinctive clinical features of non-IgE-mediated food allergies presenting with gastrointestinal symptomatology, to summarize our current understanding of the pathogenesis driving these diseases, to discuss recent findings, and to address currents gaps in the knowledge, to guide future management opportunities.

Background Penicillin allergy is the most frequent drug allergy, among which aminopenicillins are reputed for causing delayed rashes in children, particularly in the context of viral infections. Despite a negative allergy evaluation, a significant proportion of individuals continue to avoid penicillin antibiotics for fear of an allergic reaction. Objective To evaluate the safety and efficacy of a 5-day challenge to amoxicillin and the proportion of subsequent use of amoxicillin. Methods Pediatric patients with a history of a reaction to amoxicillin were prospectively recruited in the study. All patients were challenged, and those with negative immediate challenges underwent an ambulatory 5-day challenge to amoxicillin to rule out nonimmediate reactions. Patients were called 2 years after their initial allergy evaluation to assess subsequent amoxicillin use and tolerance. Results One hundred thirty children with a history of amoxicillin allergy underwent a graded drug provocation test (DPT) to amoxicillin. Three patients had a positive immediate challenge, 3 had a positive nonimmediate challenge, and 2 were equivocal. Of the 122 patients with a negative challenge, 114 (93.4%) were reached 2 years after their initial allergy evaluation: 75 had used antibiotics since, of which only 1 (1.3%) had refused to reuse amoxicillin because of fear of an allergic reaction. Finally, the 5-day DPT resulted in a 24.1% decrease in future penicillin avoidance compared with classical single-dose graded DPT performed for 1 day in a historical cohort (P Conclusion The 5-day challenge is a safe and effective way to rule out nonimmediate amoxicillin allergy, and it ensures better compliance with future penicillin use.

Aim Childhood immune thrombocytopenia (ITP) has been associated with low bleeding rates and a high frequency of spontaneous remission. Although current guidelines suggest that most patients are just observed, children still receive platelet-enhancing therapies for fear of bleeding complications. We hypothesised that a standardised protocol with a step-down approach would reduce hospitalisation and treatment use. Method A retrospective chart review was performed on patients diagnosed with acute ITP between January 2010 and December 2014, before (n = 54) and after (n = 37) the standardised protocol, which was introduced in January 2013. Management and events during the first 3 months following diagnosis were recorded. Results The protocol resulted in a 34% decrease in the hospitalisation rate (p < 0.001) at diagnosis. Prednisone treatment duration at diagnosis was also significantly reduced (13.1 versus 5.8 days, p = 0.004). Children over 3 years of age were 3.8 times less likely to be hospitalised (95% CI 1.94–7.61) and 2.3 times less likely to receive treatment (95% CI 1.2–4.3). There was no difference in the rate of persistent ITP (38% versus 30%, p = 0.43) or serious bleeding complications (7% versus 5%, p = 0.70). Conclusion Our ITP management protocol significantly reduced hospitalisation rates and length of prednisone treatment without any increase in disease complications.

Colorectal cancer is driven by mutations that activate canonical WNT/β-catenin signaling, but inhibiting WNT has significant on-target toxicity, and there are no approved therapies targeting dominant oncogenic drivers. We recently found that activating a β-catenin–independent branch of WNT signaling that inhibits GSK3-dependent protein degradation induces asparaginase sensitivity in drug-resistant leukemias. To test predictions from our model, we turned to colorectal cancer because these cancers can have WNT-activating mutations that function either upstream (i.e., R-spondin fusions) or downstream (APC or β-catenin mutations) of GSK3, thus allowing WNT/β-catenin and WNT-induced asparaginase sensitivity to be unlinked genetically. We found that asparaginase had little efficacy in APC or β-catenin–mutant colorectal cancer, but was profoundly toxic in the setting of R-spondin fusions. Pharmacologic GSK3α inhibition was sufficient for asparaginase sensitization in APC or β-catenin–mutant colorectal cancer, but not in normal intestinal progenitors. Our findings demonstrate that WNT-induced therapeutic vulnerabilities can be exploited for colorectal cancer therapy. Significance: Solid tumors are thought to be asparaginase-resistant via de novo asparagine synthesis. In leukemia, GSK3α-dependent protein degradation, a catabolic amino acid source, mediates asparaginase resistance. We found that asparaginase is profoundly toxic to colorectal cancers with WNT-activating mutations that inhibit GSK3. Aberrant WNT activation can provide a therapeutic vulnerability in colorectal cancer. See related commentary by Davidsen and Sullivan, p. 1632. This article is highlighted in the In This Issue feature, p. 1611

Fixed drug eruption (FDE) is a distinctive type of delayed drug hypersensitivity that presents with dermal inflammation of limited involvement recurring at the same location upon exposure to the culprit drug. It is typically characterized by an erythematous single lesion with sharp margins, even though multiple-site involvement can also occur. Appropriate testing to confirm diagnosis is still debated, although graded drug provocation test (DPT) seems to be more sensitive (1). Drugs most frequently associated with FDE include analgesics, antimalarials, barbiturates and antibiotics, including amoxicillin (2, 3). However, the evaluation of cross-reactivity of the culprit drug to others agents with similar chemical structure has been poorly studied. We present here a rare case of FDE to amoxicillin reproducible with a DPT in which we also assessed cross-reactivity with other beta-lactams both with and without identical lateral chains. This article is protected by copyright. All rights reserved.

The ability of cells to tolerate amino acid starvation is fundamental to survival under stress. Some cancer cells are vulnerable to asparagine depletion, which is exploited therapeutically using asparaginase. We recently found that Wnt pathway activation induces a profound therapeutic vulnerability to asparaginase in acute leukemia and in colorectal cancer (Hinze et al., In press; Hinze et al., 2019). This effect is mediated by a β-catenin independent branch of Wnt signaling termed Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits GSK3-dependent protein degradation. Asparaginase resistance is uniquely dependent on GSK3α because its inhibition fully phenocopied Wnt-induced sensitization to asparaginase (p < 0.0001), whereas selective GSK3β inhibition had no effect (p=ns). This is surprising because GSK3α and GSK3β are closely related paralogs thought to be redundant for many of their biologic functions. Thus, we set out to define why asparaginase resistance is selectively dependent on GSK3α activity. To define the GSK3α domains responsible for asparaginase resistance, we tested whether resistance could be restored by expression of a series of GSK3 alleles in which the N-terminal, kinase, and C-terminal domains of GSK3α and GSK3β were swapped in various configurations. Fusing the N-terminus of GSK3α to the kinase and C-terminal domains of GSK3β fully restored asparaginase resistance in GSK3α depleted T-ALL (p Citation Format: Laura Hinze, Sabine Schreek, Andre Zeug, Evgeni Ponimaskin, Roxane Labrosse, James Degar, Beat Bornhauser, Jean-Pierre Bourquin, Martin Stanulla, Alejandro Gutierrez. Spatial sequestration of GSKα as a cellular response to amino acid starvation [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PR06.

Background: Current recommendations for the management of penicillin allergy are to perform penicillin skin testing (PST) with penicilloyl-polylysine (PPL) and benzylpenicillin (BP) prior to drug challenge with amoxicillin. However, the diagnostic accuracy of PST is increasingly questioned. Methods: Consecutive children with a history of penicillin allergy referred to a tertiary-care allergy center were recruited to undergo double-blinded PST with PPL and BP prior to drug provocation to amoxicillin. EMBASE and MEDLINE were searched through April 2019 for all studies on the diagnostic accuracy of PST for immediate or accelerated reaction to amoxicillin. Bi-variate random-effect model was used to combine data in a meta-analysis of sensitivity and specificity stratified for agents used for PST or drug provocation test. Results: The prospective study was discontinued after the interim analysis due to futility of PST. Five of 158 participants (3.2%) presented with an immediate or accelerated reaction upon amoxicillin challenge, none of which were severe. Only one of these had positive PST (20%), compared to 15 of 153 penicillin tolerant participants (9.8%). Systematic review identified 10 eligible studies. All were found at risk of interpretation bias and three of verification bias. The summary sensitivity and specificity of PST with PPL and BP for reacting on amoxicillin challenge were 17.6% (95%CI: 5.8-42.4) and 94.7% (95%CI: 89.9-97.3), respectively. Conclusions: These results strongly argue against the routine use of PST as a preliminary step to drug provocation with amoxicillin, as it is unlikely to significantly alter pre-test probability of reacting to challenge. Funding Statement: This study was enabled by grant support from the Canadian Allergy, Asthma and Immunology Foundation and philanthropic donation from the Seigneur Family Foundation. Declaration of Interests: The authors declare no conflict of interest related to the study. PB reports personal fees from Novartis, Pfizer, Sanofi, ALK and Aralez Pharmaceuticals, as well as grants from DBV technologies, Regeneron and Sanofi outside the submitted work. KS reports personal fees from Novartis outside the submitted work. ADR reports grants from Merck and ALK outside the submitted work. Ethics Approval Statement: All patients signed informed consent forms prior to their enrollment and the study received approval from the institution’s ethics committee (CHUSJ-2013-495-3635).

Background Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, infections, autoimmunity and lymphoma. Gene therapy (GT) using autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplant for patients who lack well matched donors, avoiding graft-versus-host-disease. An initial experience with gene therapy using a γ-retroviral vector showed correction of hematological defects in 9/10 patients, but was aggravated by development of leukemia in 7 of them. We report the outcomes of a phase I/II clinical trial in which 5 WAS patients underwent GT using a self-inactivating lentiviral (SIN-LV) vector expressing the human WAS cDNA under the control of a 1.6kB fragment of the human WAS promoter. Subjects and Methods Five patients with severe WAS (clinical score 3-5) were enrolled at a median age of 1.8 years (1.4 - 8 years) at a single pediatric tertiary care center. WAS protein (WASP) was absent or markedly decreased in 2 and 3 subjects, respectively. Purified CD34+ cells from mobilized peripheral blood (n = 4) or both mobilized peripheral blood and bone marrow (n = 1) were transduced ex-vivo with the SIN-LV vector and re-infused after conditioning with busulfan (target AUC of 70-80 mg*h/L) and fludarabine (120mg/m2). The median dose of CD34+ cells infused was 9.8 x 106 cells/kg (6.3 - 24.9 x 106 cells/kg) with a mean vector copy number (VCN) of 1.7 copies/cell in CD34+ cells (0.54 - 3.37). In addition to eczema, thrombocytopenia and WAS-related infections in all patients, two subjects also had autoimmunity pre-GT, manifested as skin vasculitis and autoimmune cytopenias. Results All 5 subjects were alive and well at median follow-up of 4.8 years (2.5 - 5.9 years). Multi-lineage vector gene marking was sustained over time. All subjects had improvement or resolution of eczema and none have had any intercurrent severe infectious events. WASP expression measured by flow cytometry in T cells was increased over baseline in all patients, but remained below normal levels and correlated with VCN and cell dose received. Proliferation of T cells in response to anti-CD3, which was initially defective in 4/5 patients, improved post-GT. Humoral immune deficiency was also ameliorated, as evidenced by independence from Ig replacement and vaccine responses in those tested. All subjects remained platelet transfusion-free and none have had severe bleeding events. Platelet levels increased to >50 x 103 cells/uL in two patients with a VCN ≥2 in transduced stem cells and myeloid VCN ~1 copy/cell in neutrophils; the other 3 subjects sustained platelet counts No severe GT-related adverse events have occurred to date. Replication-competent lentivirus was not detected. Analysis of integration site distributions in five subjects showed reconstitution to be highly polyclonal, with no clones expanded to >20% of the transgene-marked cell population. To date, there have been no malignancies reported, either related to GT or WAS itself. Conclusion In summary, our data confirm and extend the safety and efficacy of GT in correcting disease manifestations associated with WAS, as seen in other studies using SIN-LV. Higher VCN in the drug product and in transduced stem cells correlated with better reconstitution of platelets and myeloid function. In contrast to other groups, we found in our study that patients with poor lymphocyte reconstitution post-GT may be at risk of ongoing autoimmunity despite high-level gene marking. Disclosures London: ArQule, Inc: Consultancy; United Therapeutics: Consultancy. Despotovic:Novartis: Research Funding; Amgen: Research Funding; Dova: Honoraria. Forbes:Takeda: Consultancy. Galy:Genethon: Employment. Williams:Novartis: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Other: License of certain IP relevant to hemoglobinopathies. Potential for future royalty/milestone income. Received payment in past through BCH institutional licensing agreement., Research Funding; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder, potential for future royalty/milestone income, Research Funding; Alerion Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder. OffLabel Disclosure: CliniMACS technology for CD34+ cell selection

Asparaginase is an antileukemic enzyme that depletes the nonessential amino acid asparagine, but resistance is a common clinical problem whose biologic basis is poorly understood. We recently found that Wnt-induced inhibition of glycogen synthase kinase 3 (GSK3) profoundly sensitizes drug-resistant leukemias to asparaginase (Hinze et al, Cancer Cell, 2019;35:664). This effect is mediated by a β-catenin independent branch of Wnt signaling termed Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits GSK3-dependent protein ubiquitination and proteasomal degradation (Acebron et al, Mol Cell, 2014;54:663). Thus, asparaginase-resistant leukemias rely on catabolic protein degradation as an alternative source of amino acids to survive asparaginase therapy. Asparaginase resistance is selectively mediated by GSK3α, because its genetic or pharmacologic inhibition fully phenocopied Wnt-induced sensitization to asparaginase (p < 0.0001), whereas selective inhibition of GSK3β had no effect. This is surprising because GSK3α and GSK3β are closely related paralogs thought to be redundant for many of their biologic functions. Thus, our objective was to define why asparaginase resistance is selectively dependent on GSK3α activity. To define the GSK3 domains responsible for asparaginase resistance, we leveraged the fact that selective depletion of GSK3α induces profound sensitization to asparaginase, and this effect is rescued by expression of a cDNA encoding GSK3α, but not GSK3β. We thus tested whether asparaginase resistance could be restored by expression of a series of GSK3 alleles in which the N-terminal, kinase, and C-terminal domains of GSK3α and GSK3β were swapped in various configurations. This revealed that asparaginase resistance is dependent on the N-terminal domain of GSK3α, whereas the kinase and the C-terminal domain were interchangeable. Fusing the N-terminus of GSK3α to the kinase and C-terminal domains of GSK3β fully restored asparaginase resistance in GSK3α depleted T-ALL (p < 0.0001) and AML cells (p < 0.0001). By contrast, fusing the N-terminus of GSK3β to the kinase and C-terminus of GSK3α had no discernible effect on response to asparaginase (p = n.s.). To investigate how the N-terminus of GSK3α regulates asparaginase response, we first applied structural prediction algorithms. This revealed that the N-terminal domain of GSK3α is a low-complexity (or prion-like) domain predicted to be intrinsically disordered, features associated with liquid-liquid phase separation. Phase separation is an increasingly recognized feature of cell biology that allows cells to concentrate components of important biochemical reactions in so-called membraneless organelles, thus promoting high-catalytic efficiency. Indeed, immunofluorescence confocal microscopy revealed that GSK3α, but not GSK3β, translocates into cytoplasmic bodies in response to asparagine depletion (p < 0.0001). The cytoplasmic GSK3a bodies were membraneless, as assessed by a proteinase K protection assay, and appeared to be distinct from known phase-separated compartments such as stress granules, P-bodies and aggresomes. However, cytoplasmic GSK3α bodies colocalized with the heat shock protein 70 (HSP70), K48-linked ubiquitin and the proteasome, suggesting that these bodies function in protein unfolding, ubiquitination and degradation. Indeed, genetic depletion of either GSK3α or HSP70 blocked formation of phase-separated GSK3α bodies (p < 0.0001) and induced asparaginase sensitivity (p < 0.0001). To explore the clinical relevance of GSK3α body formation in response to asparagine starvation, we tested a panel of matched asparaginase resistant vs. sensitive T-ALL, AML and B-ALL patient-derived xenografts (PDXs), and found that the ability of GSK3α to undergo phase separation significantly correlated with resistance to asparaginase in T-ALL, B-ALL and AML (Figure 1, p < 0.0001). Our data support a model in which inducible phase separation of GSK3α and heat shock proteins represents a previously unrecognized response to amino acid starvation that concentrates the cellular machinery for protein degradation, thus allowing efficient catalysis of this alternative source of amino acids in response to amino acid starvation. Disclosures Chiosis: Samus Therapeutics: Equity Ownership, Patents & Royalties: Intellectual rights to the PU-FITC assay. Stevenson:Celgene: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership. Bourquin:Servier: Other: Travel support.

Food allergy is an important health issue that affects up to 8 % of the population. The management of allergic patients involves allergen avoidance and prompts the treatment of accidental reactions, as no curative treatment is available so far in routine practice. Oral immunotherapy (OIT) is a promising therapeutic alternative, but it is associated with frequent allergic reactions and cost-effectiveness issues. In hopes of reducing such reactions, a number of trials have used omalizumab, an anti-IgE monoclonal humanized antibody, as adjunctive therapy in OIT. The allergens studied in these omalizumab-enabled OIT trials include peanuts, milk, eggs, or mixes of multiple foods. In this article, we review the major findings from these studies and discuss potential benefits and issues related to omalizumab-enabled OIT. Results from the previous trials suggest that the use of omalizumab could potentially lead to safer and more efficient OIT protocols, by reducing the number and severity of reactions, and increasing allergen tolerance threshold. While more evidence is needed with regard to the maintenance of the long-term tolerance after OIT, omalizumab’s potential immunomodulatory role could be of benefit. More studies are needed to further document this new indication for omalizumab.

A1 Role of fibrocytes in allergic rhinitis Marie-Ève Côté, Marie-Ève Boulay, Sophie Plante, Jamila Chakir, Louis-Philippe Boulet A2 Patterns of aeroallergens sensitization in Northern Alberta Hanan Ahmed, Maria-Beatriz Ospina, Kyriaki Sideri, Harissios Vliagoftis A3 Addressing acceptable risk for adolescents with Food-Induced Anaphylaxis (FIA) Sara F. Johnson, Roberta L. Woodgate A4 Outcomes of matched related and unrelated bone marrow transplantation after reduced-toxicity conditioning for children suffering from Chronic Granulomatous Disease Guilhem Cros, Pierre Teira, Sonia Cellot, Henrique Bittencourt, Helene Decaluwe, Marie France Vachon, Michel Duval, Elie Haddad A5 Outcomes of patients with severe combined immunodeficiency (SCID) prior to and after initiation of newborn screening for SCID in Ontario Vy H.D. Kim, Anne Pham-Huy, Eyal Grunebaum A6 Detection of regulatory B cells in the airways of subjects with asthma John-Paul Oliveria, Stephanie Phan, Mark W. Tenn, Damian Tworek, Steven G. Smith, Adrian J. Baatjes, Caitlin D. Obminski, Caroline E. Munoz, Tara X. Scime, Roma Sehmi, Gail M Gauvreau A7 Characterization of IgE-expressing B cells in the airways and peripheral blood of allergic asthmatic subjects John-Paul Oliveria, Stephanie Phan, Mark W. Tenn, Brittany M Salter, Steven G Smith, Caitlin D Obminski, Caroline E Munoz, Abbey Schlatman, Tara X Scime, Rick Watson, Roma Sehmi, Gail M Gauvreau A8 Pregnancy: could it be a risk factor for primary immunodeficient patients Roya Sherkat, Razieh Khoshnevisan, Saba Sheikhbahaei A9 Clinical experience with Octagam: a Canadian retrospective chart review Stephen Betschel, Richard Warrington, Robert Schellenberg A10 Kounis syndrome secondary to contrast media with inferior ST elevations and bilateral ischemic stroke Michael N Fein, Jean-Philippe Pelletier A11 Honey bee venom immunotherapy ineffective in bumble bee-induced anaphylaxis: case report and review of literature Manstein Kan, Robert Schellenberg A12 Delayed immune reconstitution occurring after multiple immune complications of hematological stem cell transplantation for a leaky SCID Roxane Labrosse, Guilhem Cros, Pierre Teira, Henrique Bittencourt, Helene Decaluwe, Michel Duval, Elie Haddad A13 Comparison of Three Case Reports of Acquired Angioedema: presentation, management and outcome Raymond Mak, James Loh, Amin Kanani A14 Sitagliptin-associated angioedema not related to concurrent use of ARB or ACE inhibitor Dominik A. Nowak, Paul K. Keith A15 Sneddon-Wilkinson subcorneal pustular dermatosis associated with an IgA monoclonal gammopathy Daniel Pannozzo, Dominik A. Nowak, Hermenio C. Lima A16 Omalizumab can be effective in patients with allergic bronchopulmonary aspergillosis Diana Pham, Hoang Pham, Gonzalo G. Alvarez, Istvan T. Bencze, Krishna B. Sharma, Mark Smith, Shawn Aaron, Jennifer Block, Tara Keays, Judith Leech, David Schneidermen, Jodi Cameron, Jennifer Forgie, Alicia Ring, John W. O’Quinn, Stephanie Santucci, William H. Yang A17 Efficacious use of omalizumab in the treatment of cystic fibrosis Diana Pham, Hoang Pham, Ena Gaudet, Shawn Aaron, Stephanie Santucci, William H. Yang A18 HAE with normal C1-INH with inconsistent response to C1 esterase inhibitor infusion but reliably responsive to icatibant Hoang Pham, Stephanie Santucci, William H. Yang A19 Anaphylaxis reaction to lactase enzyme Mathew R. Voisin, Rozita Borici-Mazi A20 Risk of solid tumor malignancies in patients with primary immune deficiency Kateryna Vostretsova, Donald F. Stark A21 Is it time to adopt the chromogenic assay for measuring C1 esterase inhibitor function in patients with HAE Type 2? Elizabeth Yeboah, Paul K. Keith A22 Emergency department visits for anaphylaxis and allergic reactions Michelle Martin-Rhee, Cheryl Gula, Clare Cheng, Geoff Paltser A23 START: Susceptibility To food Allergies in a Registry of Twins Alizée Dery, Ann Clarke, Kari Nadeau, Laurie Harada, Kimberley Weatherall, Celia Greenwood, Denise Daley, Yuka Asai, Moshe Ben-Shoshan A24 Qualifying the diagnostic approach employed by allergists when managing patients with self-diagnosed non-celiac gluten sensitivity (NCGS) Lee Horgan, Teresa Pun A25 Retrospective analysis on the agreement between skin prick test and serum food specific IgE antibody in adults with suspected food allergy Ling Ling, Maria B. Ospina, Kyriaki Sideri, Harissios Vliagoftis A26 Staple food hypersensitivity from infancy to adolescence: a report from the BAMSE cohort Jennifer L.P. Protudjer, Mirja Vetander, Marianne van Hage, Ola Olén, Magnus Wickman, Anna Bergström A27 Evaluating the impact of supervised epinephrine autoinjector administration during food challenges on perceived parent confidence Timothy Teoh, Christopher Mill, Tiffany Wong, Ingrid Baerg, Angela Alexander, Kyla J. Hildebrand, John Dean, Boris Kuzeljevic, Edmond S. Chan A28 Local immunoglobulin production to Aspergillus fumigatus cystic fibrosis Jonathan Argeny, Mia Gona-Hoepler, Petra Fucik, Edith Nachbaur, Saskia Gruber, Reto Crameri, Andreas Glaser, Zsolt Szépfalusi, Claudio Rhyner, Thomas Eiwegger A29 Extract consumption with skin prick test (SPT) devices Greg. Plunkett, Brad Mire A30 Evaluation of our cases with nonsteroidal anti-inflammatory drug reactions Mehtap Yazicioglu, Ceren Can, Gokce Ciplak A31 Reasons for referral and final diagnoses in a tertiary care pediatric allergy clinic Victoria E. Cook, Kyla J. Hildebrand, Elodie Portales-Casamar, Christopher Mill, Edmond S. Chan A32 Internist referral practices for inpatients with self-reported penicillin allergies at a tertiary care teaching hospital Michael N Fein, Emil P Nashi A33 Assessing the risk of reactions in children with a negative oral challenge after a subsequent use of amoxicillin Sofianne Gabrielli, Christopher Mill, Marie-Noel Primeau, Christine Lejtenyi, Elena Netchiporouk, Alizee Dery, Greg Shand, Moshe Ben-Shoshan A34 Validity of self-reported penicillin allergies Erica Hoe, Joel Liem A35 Effectiveness of allergy-test directed elimination diets in eosinophilic esophagitis Jason K. Ko, David J.T. Huang, Jorge A. Mazza A36 Allergy testing and dietary management in pediatric eosinophilic esophagitis (EoE): A retrospective review of a tertiary Canadian centre’s experience Mary McHenry, Anthony Otley,Wade Watson A37 Visualizing the impact of atopic and allergic skin disease Dominik A. Nowak, John N. Kraft A38 Cystic fibrosis with and without nasal polyposis in pediatric patients: a cross-sectional comparative study Mihaela Paina, Ahmed A. Darwish Hassan, Delia Heroux, Lynn Crawford, Gail Gauvreau, Judah Denburg, Linda Pedder, Paul K. Keith A39 Evaluation of macrolide antibiotic hypersensitivity: the role of oral challenges in children Bahar Torabi, Marie-Noel Primeau, Christine Lejtenyi, Elaine Medoff, Jennifer Mill, Moshe Ben-Shoshan A40 Venom allergy testing: is a graded approach necessary? Jaclyn A. Quirt, Xia Wen, Jonathan Kim, Angel Jimenez Herrero, Harold L. Kim A41 The role of oral challenges in evaluating cephalosporin hypersensitivity reactions in children Magdalena J. Grzyb, Marie-Noël Primeau, Christine Lejtenyi, Elaine Medoff, Jennifer Mill, Moshe Ben-Shoshan A42 Breastfeeding and infant wheeze, atopy and atopic dermatitis: findings from the Canadian Healthy Infant Longitudinal Development Study Meghan B. Azad, Zihang Lu, Allan B. Becker, Padmaja Subbarao, Piushkumar J. Mandhane, Stuart E. Turvey, Malcolm R. Sears, the CHILD Study Investigators A43 IL33 DNA methylation in bronchial epithelial cells is associated to asthma Anne-Marie Boucher-Lafleur, Valérie Gagné-Ouellet, Éric Jacques, Sophie Plante, Jamila Chakir, Catherine Laprise A44 NRF2 mediates the antioxidant response to organic dust-induced oxidative stress in bronchial epithelial cells Michael Chen, Toby McGovern, Mikael Adner, James G. Martin A45 The effects of perinatal distress, immune biomarkers and mother-infant interaction quality on childhood atopic dermatitis (rash) at 18 months Nela Cosic, Henry Ntanda, Gerald Giesbrecht, Anita Kozyrskyj, Nicole Letourneau A46 Examining the immunological mechanisms associated with cow’s milk allergy Bassel Dawod, Jean Marshall A47 Tryptase levels in children presenting with anaphylaxis to the Montréal Children’s Hospital Sarah De Schryver, Michelle Halbrich, Ann Clarke, Sebastian La Vieille, Harley Eisman, Reza Alizadehfar, Lawrence Joseph, Judy Morris, Moshe Ben-Shoshan A48 Secondhand tobacco smoke exposure in infancy and the development of food hypersensitivity from childhood to adolescence Laura Y. Feldman, Jesse D. Thacher, Inger Kull, Erik Melén, Göran Pershagen, Magnus Wickman, Jennifer L. P. Protudjer, Anna Bergström A49 Combined exposure to diesel exhaust and allergen enhances allergic inflammation in the bronchial submucosa of atopic subjects Ali Hosseini, Tillie L. Hackett, Jeremy Hirota, Kelly McNagny, Susan Wilson, Chris Carlsten A50 Comparison of skin-prick test measurements by an automated system against the manual method Saiful Huq, Rishma Chooniedass, Brenda Gerwing, Henry Huang, Diana Lefebvre, Allan Becker A51 The accurate identification and quantification of urinary biomarkers of asthma and COPD through the use of novel DIL- LC-MS/MS methods Mona M. Khamis, Hanan Awad, Kevin Allen, Darryl J. Adamko, Anas El-Aneed A52 Systemic immune pathways associated with the mechanism of Cat-Synthetic Peptide Immuno-Regulatory Epitopes, a novel immunotherapy, in whole blood of cat-allergic people Young Woong Kim, Daniel R. Gliddon, Casey P. Shannon, Amrit Singh, Pascal L. C. Hickey, Anne K. Ellis, Helen Neighbour, Mark Larche, Scott J. Tebbutt A53 Reducing the health disparities: online support for children with asthma and allergies from low-income families Erika Ladouceur, Miriam Stewart, Josh Evans, Jeff Masuda, Nicole Letourneau, Teresa To, Malcolm King A54 Epigenetic association of PSORS1C1 and asthma in the Saguenay-Lac-Saint-Jean asthma study Miriam Larouche, Liming Liang, Catherine Laprise A55 IL-33 induces cytokine and chemokine production in human mast cells Stephanie A. Legere, Ian D. Haidl, Jean-Francois Legaré, Jean S. Marshall A56 Reference ranges for lung clearance index from infancy to adolescence for Canadian population Zihang Lu, Malcolm Sears, Theo J. Moraes, Felix Ratjen, Per Gustafsson, Wendy Lou, Padmaja Subbarao A57 Kingston Allergy Birth Cohort: cohort profile and mother/child characteristics to age 2 Michelle L. North, Elizabeth Lee, Vanessa Omana, Jenny Thiele, Jeff Brook, Anne K. Ellis A58 Cow’s milk protein specific IgE, IgA and IgG4 as a predictor of outcome in oral immunotherapy Tanvir Rahman, Duncan Lejtenyi, Sarah De Schryver, Ryan Fiter, Ciriaco Piccirillo, Moshe Ben-Shoshan, Bruce Mazer A59 Age of peanut introduction and development of reactions and sensitization to peanut Elinor Simons, Allan B. Becker, Rishma Chooniedass, Kyla Hildebrand, Edmond S. Chan, Stuart Turvey, Padmaja Subbarao, Malcolm Sears A60 Multi-omic blood biomarker signatures of the late phase asthmatic response Amrit Singh, Casey P. Shannon, Young Woong Kim, Mari DeMarco, Kim-Anh Le Cao, Gail M. Gauvreau, J. Mark FitzGerald, Louis-Philippe Boulet, Paul M. O’Byrne, Scott J. Tebbutt A61 Early life gut microbial alterations in children diagnosed with asthma by three years of age Leah T. Stiemsma, Marie-Claire Arrieta, Jasmine Cheng, Pedro A. Dimitriu, Lisa Thorson, Sophie Yurist, Boris Kuzeljevic, Diana L. Lefebvre, Padmaja Subbarao, Piush Mandhane, Allan Becker, Malcolm R. Sears, Kelly M. McNagny, Tobias Kollmann, the CHILD Study Investigators, William W. Mohn, B. Brett Finlay, Stuart E. Turvey A62 The relationship between food sensitization and atopic dermatitis at age 1 year in a Canadian birth cohort Maxwell M. Tran, Diana L. Lefebvre, Chinthanie F. Ramasundarahettige, Allan B. Becker, Wei Hao Dai, Padmaja Subbarao, Piush J. Mandhane, Stuart E. Turvey, Malcolm R. Sears A63 Allergen inhalation enhances Toll-like receptor-induced thymic stromal lymphopoietin receptor expression by hematopoietic progenitor cells in mild asthmatics Damian Tworek, Delia Heroux, Seamus N. O’Byrne, Paul M. O’Byrne, Judah A. Denburg A64 The Allergic Rhinitis Clinical Investigator Collaborative – replicated eosinophilia on repeated cumulative allergen challenges in nasal lavage samples Laura Walsh, Mena Soliman, Jenny Thiele, Lisa M. Steacy, Daniel E. Adams, Anne K. Ellis A65 The CHILD Study: optimizing subject retention in pediatric longitudinal cohort research Linda Warner, Mary Ann Mauro, Robby Mamonluk, Stuart E. Turvey A66 Differential expression of C3a and C5a in allergic asthma ChenXi Yang, Amrit Singh, Casey P. Shannon, Young Woong Kim, Ed M. Conway, Scott J. Tebbutt