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Background Omalizumab has been shown to improve the safety and feasibility of oral immunotherapy (OIT), but the optimal dosage strategy is unknown. Objective Our aim was to identify determinants of omalizumab dose–related efficacy in the context of OIT. Methods The study sample consisted of a clinical cohort of 181 patients treated with omalizumab-enabled oral immunotherapy at 3 centers. Patients received omalizumab for at least 2 months before an initial food escalation (IFE) with a mix of up to 6 allergens. Progression through IFE steps was assessed with survival analysis. Continued food dose tolerance with omalizumab weaning was also documented. Results Omalizumab dosage per weight alone was strongly associated with progression through the IFE (χ2 = 28.18; P Conclusion In the context of OIT and IgE-mediated disease, omalizumab dosages should be adjusted for body weight alone, independently of total IgE level. The fraction of allergen-specific/total IgE may be useful to predict patients at greater risk of food dosing reactions subsequent to weaning.

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.

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.

Epigallocatechin-3-gallate (EGCG) is a candidate therapeutic for Down syndrome (DS) phenotypes based on in vitro inhibition of DYRK1A, a triplicated gene product of Trisomy 21 (Ts21). Consumption of green tea extracts containing EGCG improved some cognitive and behavioral outcomes in DS mouse models and in humans with Ts21. In contrast, treatment with pure EGCG in DS mouse models did not improve neurobehavioral phenotypes. This study tested the hypothesis that 200 mg/kg/day of pure EGCG, given via oral gavage, would improve neurobehavioral and skeletal phenotypes in the Ts65Dn DS mouse model. Serum EGCG levels post-gavage were significantly higher in trisomic mice than in euploid mice. Daily EGCG gavage treatments over three weeks resulted in growth deficits in both euploid and trisomic mice. Compared to vehicle treatment, EGCG did not significantly improve behavioral performance of Ts65Dn mice in the multivariate concentric square field, balance beam, or Morris water maze tasks, but reduced swimming speed. Furthermore, EGCG resulted in reduced cortical bone structure and strength in Ts65Dn mice. These outcomes failed to support the therapeutic potential of EGCG, and the deleterious effects on growth and skeletal phenotypes underscore the need for caution in high-dose EGCG supplements as an intervention in DS.

Background Previous proof-of-concept studies have shown that a short course of omalizumab can safely accelerate the oral immunotherapy schedule for multiple allergens simultaneously. Considering the high cost of medication, the dose-related efficacy of omalizumab at decreasing the duration of oral immunotherapy up-dosing phase must be objectively quantified before cost–benefit analyses can be performed. The primary objective of this trial will be to compare the efficacy of 2 omalizumab dosages to placebo at decreasing time-to-maintenance dose during a symptom-driven multi-food OIT protocol. Methods A total of 90 participants aged 6 to 25 with multiple food allergies (3 or more) will be enrolled at four sites in Canada. Participants will be randomized to: (A) Omalizumab 8 mg/kg per month (n = 36); (B) Omalizumab 16 mg/kg per month (n = 36); or (C) Placebo (n = 18). Study drug will be administered at full dosage for 12 weeks, then progressively tapered at 50% dosage (8 mg/kg vs 4 mg/kg vs placebo) for 4 weeks and at 25% dosage (4 mg/kg vs 2 mg/kg vs placebo) for another 4 weeks. After a pre-treatment period of 8 weeks, participants will undergo an initial food escalation (IFE) to an OIT mix containing 3 allergens and start daily home dosing with biweekly increases until a target daily maintenance of 1500 mg protein is achieved. The amount escalated at each visit will vary based on treatment tolerance according to a standardized up-dosing algorithm. Participants will be followed for at least 12 months following the initial food escalation. The primary endpoint will be time from IFE to the target maintenance dose of 1500 mg protein. Time-to-event analytic methods, including the log-rank test, will be used to compare the 3 arms. Discussion This trial uses a novel pragmatic approach to compare OIT with omalizumab to OIT without omalizumab in a blinded manner, which allows to single out the effect of this anti-IgE medication on treatment effectiveness speed without the recourse to predetermined schedules. The innovative patient-centered up-dosing algorithm allows to maximise treatment effectiveness speed without compromising patient safety, regardless of whether the patient is on omalizumab or not. This study will also provide novel prospective data to inform on the optimal and most cost-effective dosage for this indication. Trial registration ClinicalTrials.gov, NCT04045301, Registered 5 August 2019, https://clinicaltrials.gov/ct2/show/NCT04045301

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.

Individuals with Down syndrome (DS) display distinctive skeletal morphology compared to the general population, but disparate descriptions, methodologies, analyses, and populations sampled have led to diverging conclusions about this unique skeletal phenotype. As individuals with DS are living longer, they may be at a higher risk of aging disorders such as osteoporosis and increased fracture risk. Sexual dimorphism has been suggested between males and females with DS in which males, not females, experience an earlier decline in bone mineral density (BMD). Unfortunately, studies focusing on skeletal health related to Trisomy 21 (Ts21) are few in number and often too underpowered to answer questions about skeletal development, resultant osteoporosis, and sexual dimorphism, especially in stages of bone accrual. Further confounding the field are the varied methods of bone imaging, analysis, and data interpretation. This review takes a critical look at the current knowledge of DS skeletal phenotypes, both from human and mouse studies, and presents knowledge gaps that need to be addressed, differences in research methodologies and analyses that affect the interpretation of results, and proposes guidelines for overcoming obstacles to understand skeletal traits associated with DS. By examining our current knowledge of bone in individuals with Ts21, a trajectory for future studies may be established to provide meaningful solutions for understanding the development of and improving skeletal structures in individuals with and without DS.

Children with trisomy 21 (Down syndrome [DS]) have a 130-fold increased incidence of Hirschsprung disease (HSCR), a developmental defect in which the enteric nervous system (ENS) is missing from the distal bowel (i.e., distal bowel is aganglionic). Treatment for HSCR is surgical resection of aganglionic bowel, but many children have bowel problems after surgery. Postsurgical problems, such as enterocolitis and soiling, are especially common in children with DS. To determine how trisomy 21 affects ENS development, we evaluated the ENS in 2 DS mouse models, Ts65Dn and Tc1. These mice are trisomic for many chromosome 21 homologous genes, including Dscam and Dyrk1a, which are hypothesized to contribute to HSCR risk. Ts65Dn and Tc1 mice have normal ENS precursor migration at E12.5 and almost normal myenteric plexus structure as adults. However, Ts65Dn and Tc1 mice have markedly reduced submucosal plexus neuron density throughout the bowel. Surprisingly, the submucosal neuron defect in Ts65Dn mice is not due to excess Dscam or Dyrk1a, since normalizing copy number for these genes does not rescue the defect. These findings suggest the possibility that the high frequency of bowel problems in children with DS and HSCR may occur because of additional unrecognized problems with ENS structure.

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.

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 There is no recent systematic review on the risk of cross-reactivity to cephalosporins and carbapenems in penicillin-allergic patients despite many new studies on the subject. All past reviews have several limitations such as not including any patient with a T-cell–mediated penicillin allergy. Objectives To determine the risk of cross-reactivity to cephalosporins and carbapenems in patients with a proven IgE- or T-cell–mediated penicillin allergy. To measure the association between R1 side chain similarity on cephalosporins and penicillins and the risk of cross-reactivity. Methods MEDLINE and EMBASE were searched from January 1980 to March 2019. Studies had to include at least 10 penicillin-allergic subjects whose allergy had been confirmed by a positive skin test (ST) or drug provocation test (DPT) result. Cross-reactivity had to be assessed to at least 1 cephalosporin or carbapenem through ST or DPT. Both random-effects and fixed-effect models were used to combine data. A bioinformatic model was used to quantify the similarity between R1 side chains. Results Twenty-one observational studies on cephalosporin cross-reactivity involving 1269 penicillin-allergic patients showed that the risk of cross-reactivity varied with the degree of similarity between R1 side chains: 16.45% (95% CI, 11.07-23.75) for aminocephalosporins, which share an identical side chain with a penicillin (similarity score = 1), 5.60% (95% CI, 3.46-8.95) for a few cephalosporins with an intermediate similarity score (range, 0.563-0.714), and 2.11% (95% CI, 0.98-4.46) for all those with low similarity scores (below 0.4), irrespective of cephalosporin generation. The higher risk associated with aminocephalosporins was observed whether penicillin allergy was IgE- or T-cell–mediated. Eleven observational studies on carbapenem cross-reactivity involving 1127 penicillin-allergic patients showed that the risk of cross-reactivity to any carbapenem was 0.87% (95% CI, 0.32-2.32). Conclusions Although it remains possible that these meta-analyses overestimated the risk of cross-reactivity, clinicians should consider the increased risk of cross-reactivity associated with aminocephalosporins, and to a lesser extent with intermediate-similarity-score cephalosporins, compared with the very low risk associated with low-similarity-score cephalosporins and all carbapenems when using beta-lactams in patients with a suspected or proven penicillin allergy.

Egg is an ubiquitous allergen found in many food products. Current food allergy guidelines recognize the importance of consultation with a registered dietitian to ensure nutritional adequacy. However, there is a lack of evidence on its impact on the implementation of allergen avoidance strategies. Taking advantage of a well-characterized cohort of influenza vaccination in egg-allergic children (n=397), we tested the hypothesis that real-life professional dietary advice was associated with a decrease in accidental reactions to egg in allergic children with retrospective questionnaires. Lack of consultation with a dietitian was associated with a 1.89-fold increase in the risk of accidental reactions to egg (confidence interval: 1.47–2.42). The only other independent variable that predicted reactions was having had a history of acute reaction to egg prior diagnosis (relative risk=2.02; confidence interval: 1.64–3.00). These findings support the usefulness of referral to a food allergy-specialized dietitian at time of diagnosis in order to prevent future accidental reactions to egg.

Background Prescribing antibiotics to patients with a history of penicillin allergy is common in clinical practice. Opting for non-beta-lactam antibiotics has its inconveniences and is often unnecessary, because most of these patients are in fact not allergic. Objective This study aimed to determine how physicians in a large Canadian tertiary-care academic hospital without allergists on staff treat patients with a history of penicillin allergy. Methods A retrospective study was conducted during a 1-year period among all patients hospitalized in the intensive care unit, coronary care unit, and internal medicine wards. Files of patients with a record of penicillin allergy were reviewed to assess the need for antibiotics during their hospitalization and the decision-making process underlying the choice of antibiotic. The additional costs of alternative antibiotics were calculated. Results The files of 1738 patients admitted over a 1-year period were hand reviewed. A history of penicillin allergy was found in 172 patients (9.9%). The allergic reaction was described in only 30% of cases and left unmentioned in 20.7%. Beta-lactam antibiotics were used on 56 occasions despite a history of penicillin allergy. The use of alternative antibiotics in place of the beta-lactam standard of care carried an additional cost of $15,672 Canadian. Conclusion Alleged penicillin allergy is common among hospitalized patients and leads to substantial additional costs. Poor documentation of penicillin allergy likely reflects a lack of knowledge on this issue in the medical community, which impairs optimal treatment of these patients. Increased education on this matter is needed, and allergists on staff could be part of the solution.

Background Atopic dermatitis (AD) is a common skin disease of childhood which may cause debilitating symptoms and greatly impair the quality of life of the patient and his relatives [1]. Treatment of chronic AD usually focuses on topical regimen of emolients and immunosuppressants, although systemic immunosuppressive therapy is sometimes required in more severe cases. Omalizumab is a humanized monoclonal anti- IgE antibody that binds at the high-affinity receptor (FceRI) binding site that has revealed some potential in the treatment of severe and recalcitrant AD [2]. Case Here, we present the case of a 11-years-old girl who has been under treatment with Omalizumab for the past five years. The patient first presented at 2 months of age with a global and severe AD involving. She was severely atopic with total IgE levels of 121,000, mild asthma, and multiple food allergies. Treatment with oral prednisone, cyclosporin, azathioprine and intravenous immunoglobulins did not improve her skin symptoms significantly. She was hospitalised multiple times for skin infections attributed to the disease and immunosuppressive medication. Treatment with Omalizumab was initiated at 6 years of age. Four months later, SCORAD index improved significantly. Since, her follow-up has been almost free of any remarkable event and treatment with Omalizumab has been well tolerated.

Egg specific IgE levels are frequently used in combination with skin-prick tests to guide clinical decisions and to monitor egg allergy evolution in children. We compared both Immulite and ImmunoCAP egg specific IgE assays in egg allergic children, and found a linear correlation between both assays with a mean Immulite:ImmunoCAP ratio of 3. This is relevant information for clinicans wishing to estimate values from one assay to the other, as most literature has been published using the ImmunoCAP system.