Skin prick test in milk allergic patients undergoing oral immunotherapy: Does the milk form used for skin tests matter?

SPT is the most commonly used confirmatory test for an IgE-mediated milk allergy. However, food SPTs are not standardized. We aimed to assess the accuracy of SPTs with extract, diluted, and undiluted milk to detect desensitization in children with milk allergy undergoing OIT. Children with milk allergy undergoing OIT and controls were recruited from Montreal Children's Hospital (MCH), British Columbia Children's Hospital (BCCH) and The Hospital for Sick Children (SickKids). Participants in the active arm received a weekly increase in milk until 200 ml of pure milk was tolerated. SPT using milk extract (Omega), diluted 2% milk (1:10), and undiluted milk was done at the study entry and when 200 ml of pure milk was reached. Participants in the control arm had SPT at study entry and 12 months later before they entered the active arm. Among 53 children who reached 200 ml, the median age was 12 years and 54.7% were males. The mean decrease in wheal size at 200 ml from the baseline was 3.78 mm (95%CI, 2.55-5.01), 5.05 mm (95% CI, 3.68-6.41), and 5.05 mm (95% CI, 3.29-6.80) for milk extract, diluted and undiluted milk respectively. Among 32 controls, the median age was 10 years and 62.5% were males. There was no significant change in wheal diameter over a one-year period regardless of the skin test method. Response to extract behaved similarly to whole food (Diluted and undiluted) and thus can be used to follow sensitization in the context of a desensitization program.

Resistance determinants and their genetic context in enterobacteria from a longitudinal study of pigs reared under various husbandry conditions.

Pigs are major reservoirs of resistant Enterobacteriaceae that can reach humans through consumption of contaminated meat or vegetables grown in manure-fertilized soil. Samples were collected from sows during lactation and their piglets at five time points spanning the production cycle. Cefotaxime-resistant bacteria were quantified and isolated from feed, feces, manures and carcasses of pigs reared with penicillin-using or antibiotic-free husbandries. The isolates were characterized by antibiotic susceptibility testing, whole genome sequencing and conjugation assays. The extended spectrum ß-lactamase (ESBL) phenotype was more frequent in isolates originating from antibiotic-free animals, while the bacteria isolated from penicillin-using animals were on average resistant to a greater number of antibiotics. The ESBL-encoding genes identified were bla CTX-M-1, bla CTX-M-15 and bla CMY-2 and they co-localised on plasmids with various genes encoding resistance to ß-lactams, co-trimoxazole, phenicols and tetracycline, all antibiotics used in pig production. Groups of genes conferring the observed resistance and the mobile elements disseminating multidrug resistance were determined. The observed resistance to ß-lactams was mainly due to the complementary actions of penicillin-binding proteins, an efflux pump and ß-lactamases. Most resistance determinants were shared by animals raised with or without antimicrobials. This suggests a key contribution of indigenous enterobacteria maternally transmitted along the sow lineage, regardless of antimicrobial use. It is unclear if the antimicrobial resistance observed in the enterobacteria populations of the commercial pig herds studied were present before the use of antibiotics, or the extent to which historical antimicrobial use exerted a selective pressure defining the resistant bacterial populations in farms using penicillin prophylaxis.Importance: Antimicrobial resistance is a global threat that needs to be fought on numerous fronts along the One Health continuum. Vast quantities of antimicrobials are used in agriculture to ensure animal welfare and productivity, and are arguably a driving force for the persistence of environmental and food-borne resistant bacteria. This study evaluated the impact of conventional, organic and other antibiotic-free husbandry practices on the frequency and nature of antimicrobial resistance genes and multidrug resistant enterobacteria. It provides knowledge about the relative contribution of specific resistance determinants to observed antibiotic resistance. It also showed the clear co-selection of genes coding for extended-spectrum beta-lactamases and genes coding for the resistance to antibiotics commonly used for prophylaxis or in curative treatments in pig operations.

Determinants of omalizumab dose-related efficacy in oral immunotherapy: Evidence from a cohort of 181 patients.

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 < .0001), whereas the standard dosage per weight and total IgE level used for asthma was not (χ2 = 0.001; P = .97). When the values at time of IFE were estimated through pharmacokinetics and pharmacodynamics simulation, IFE outcome was best predicted by a model that includes levels of free allergen-specific IgE and their interaction with blocking omalizumab-IgE complexes and free omalizumab levels in serum (χ2 = 65.84; degrees of freedom [df] = 2; P < .0005). The occurrence of immediate-type reactions to food dosing subsequent to weaning of omalizumab was associated with a greater ratio of specific IgE level to total IgE level at baseline (geometric mean 0.39 vs 0.16 in those without symptom; P < .0001). 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.

Correction to: Protocol for a double-blind, randomized controlled trial on the dose-related efficacy of omalizumab in multi-food oral immunotherapy.

[This corrects the article DOI: 10.1186/s13223-020-00419-z.].

Protocol for a double-blind, randomized controlled trial on the dose-related efficacy of omalizumab in multi-food oral immunotherapy.

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.

Epicutaneous peanut patch device for the treatment of peanut allergy.

INTRODUCTION: Food allergy prevalence has increased in recent decades, which has mobilized efforts to develop treatment alternatives. Epicutaneous immunotherapy (EPIT) is a novel method that involves transdermal administration of peanut allergen with the objective to induce tolerance. Recent clinical trials have shown its efficacy at increasing the eliciting dose in children with a favorable safety profile. Areas covered: This review covers the proposed mechanism of action of EPIT in murine models and humans, efficacy and safety data from clinical trials with peanut EPIT, and a discussion on its potential role in the future management of peanut allergy. Expert opinion: With the recent completion of pivotal trials for peanut EPIT and upcoming marketing, the main question for clinicians and food allergic patients is how to define its role in the management of peanut allergy and how it compares to oral immunotherapy (OIT). Like OIT, EPIT seems to promote immunological tolerance over time. However, EPIT could lack the rapid mast-cell desensitization induced by the progressive intake of food in OIT, which explains differences in short-term outcomes and safety profiles. Head-to-head and long-term comparison of real-life efficacy with regards to sustained unresponsiveness will help define its place in the food allergy arsenal.

Adverse Events in Oral Immunotherapy for the Desensitization of Cow's Milk Allergy in Children: A Randomized Controlled Trial.

BACKGROUND: This study focuses on the side effects of cow's milk oral immunotherapy (CM-OIT) using consensus definitions of food-induced anaphylaxis. OBJECTIVE: To evaluate the risk of allergic reactions (ARs) and to identify risk factors associated with higher risk of anaphylactic ARs (AARs) during CM-OIT in children. METHODS: Clinical charts of children receiving CM-OIT were carefully reviewed. ARs were defined as single-organ ARs, and AARs were defined as involvement of 2 organ systems and/or hypotension in response to CM protein. Descriptive statistics were used to represent demographics, occurrence, reaction characteristics, and comorbidities. Poisson analysis was performed to evaluate risk factors associated with AARs. RESULTS: Among 41 children undergoing CM-OIT, 11 discontinued the treatment (N = 26.8%). The mean age at challenge was 12.1 years (standard deviation [SD], 3.6) and half were male (56.1%). The mean number of AARs per patient was 6.0 (SD, 3.5) versus a mean of 17.4 (SD, 11.9) non-AARs per patient. Among withdrawals from OIT, the mean number of AARs per patient was 8.3 versus 5.1 in nonwithdrawals. AARs were more frequent in children with higher specific IgE (sIgE) for α-lactalbumine and casein at baseline (1.11 [95% confidence interval (CI): 1.01, 1.22] and 1.01 [1.0, 1.03], respectively). Children with resolved eczema and higher sIgE for ß-lactoglobuline at baseline (0.13 [95% CI: 0.04, 0.46] and 0.96 [95% CI: 0.94, 0.99], respectively) were less likely to develop AARs. CONCLUSIONS: Although the majority of ARs during OIT are nonanaphylactic, AARs occur frequently. Children with higher sIgE for α-lactalbumine and casein at baseline seem to be at higher risk for AARs during OIT.

Prevalence of Hypersensitivity Reactions in Children Associated with Acetaminophen: A Systematic Review and Meta-Analysis.

BACKGROUND: Acetaminophen is the most commonly used antipyretic in children. However, there are limited data assessing hypersensitivity reactions related to acetaminophen usage. OBJECTIVES: To conduct a systematic review to characterize reported reactions to acetaminophen in adults and children, and perform a meta-analysis to assess the prevalence of acetaminophen hypersensitivity in children with a suspected acetaminophen allergy. METHODS: We performed a systematic review of studies reporting hypersensitivity reactions to acetaminophen by searching 2 electronic databases. From the selected studies, we included those assessing the prevalence of acetaminophen hypersensitivity by performing oral challenge in our meta-analysis. RESULTS: Eighty-five studies were included in the systematic review, assessing a total of 1,030 participants. Immediate (within 1 h of exposure) hypersensitivity reactions were reported in > 25% of the articles, while cutaneous nonimmediate reactions were similarly reported in about 25% of the articles. The remaining articles reported Steven-Johnson syndrome/toxic epidermal necrolysis, fixed drug eruptions, and cross-intolerance reactions. Five pediatric studies were included in our meta-analysis. The prevalence of acetaminophen hypersensitivity reaction among children undergoing oral challenge was 10.1% (95% confidence interval 4.5-15.5). CONCLUSION: Future studies assessing the risk of immediate and nonimmediate hypersensitivity reactions to acetaminophen and elucidating the mechanism of acetaminophen hypersensitivity reactions are required.