To the Editor,

Editorial Comment on “Atopic outcomes at 2 years in the CORAL cohort, born in COVID-19 lockdown”Sandoval-Ruballos, Mónica1, Carmen Riggioni2,3, Jon Genuneit41 Pediatric Allergy and Immunology Clinic, Guatemala, Guatemala.2Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.3Khoo Teck Puat-National University Children’s Medical Institute, National University Hospital, National University Health System, Singapore.4 Pediatric Epidemiology, Department of Pediatrics, Medical Faculty, Leipzig University, Leipzig, GermanyAtopic conditions have been on the rise globally, particularly in industrialized nations.(1) This phenomenon has spurred interest in the potential connection between the surge in allergic disorders and modern lifestyles characterized by reduced microbial exposure and increased hygiene practices. While the hygiene theory proposes that the early childhood microbial environment plays a pivotal role in shaping immune system development, reducing the risk of atopic conditions, more recent findings have emphasized the role of a defective epithelial barrier. This recent perspective suggests that the upsurge in agents damaging the epithelial barrier, associated with industrialization and modern living, is at the core of the escalation of allergic, autoimmune, and other chronic conditions. Notably, these effects may have intensified during the pandemic. (2) (3)The SARS-CoV-2 pandemic in early 2020 prompted various lockdowns and stringent hygiene measures, offering an intriguing opportunity to investigate the impact of these altered environmental factors on the prevalence of atopic conditions. The CORAL study is a longitudinal observational project, following 365 infants born in Ireland, during the initial pandemic period (March-May 2020) from enrollment to 24 months of age. (4) The authors compared the occurrence of allergic diseases with a pre-pandemic Irish cohort (BASELINE study 2008-2011). (5) This investigation aims to shed light on the pandemic’s potential impact on infant allergic disease development.At first glance, the CORAL cohort exhibited higher rates of atopic dermatitis (AD) at both 12 and 24 months compared to BASELINE. However, this finding may reflect a gradual increase in AD incidence within their population, given that the BASELINE cohort was born about one decade earlier. Alternatively, the early-life environment during the lockdowns may have played a role. In addition, the authors delineated three patterns of AD. A more severe AD phenotype was noted among infants with persistent AD diagnosis at 24 months, and AD-persistent infants were more likely to be sensitized. This observation aligns with prior studies, highlighting the significance of severity, and atopic sensitization as relevant determinants of AD prognosis.(6)While AD rates were higher in the CORAL cohort, they exhibited lower rates of food sensitization and allergy compared to BASELINE, particularly significant in peanut sensitization and egg allergy, with a non-significant trend towards lower peanut allergy. Importantly, parents received complementary feeding advice at 6 months, emphasizing early peanut introduction. Therefore, these outcomes may be attributed to recommended early allergen introduction, along with other factors like increased breastfeeding, fewer infections during the first 12 months (7), lower antibiotic exposure, and sustained dietary allergen exposure during lockdown. The relevance of early allergen introduction, especially for peanut and egg, has gained prominence in international guidelines more recently, owing to accumulating evidence underscoring its role in directly reducing the development of food allergy (8).At 24 months, antibiotic usage and childcare outside home increased AD likelihood potentially linked to decreased infection rates and antibiotic use in children not attending daycare, preserving microbiota integrity. Intriguingly, despite more AD cases in children attending daycare, they exhibited lower allergic sensitization rates. Aeroallergen sensitization at 24 months was more pronounced among children cared for solely at home, thus reflecting environmental influence. From a theoretical perspective, it is plausible that the lockdown measures, which led to a substantial increase in indoor confinement, may have resulted in heightened exposure to indoor allergens,(9) consequently leading to higher sensitization rates. Furthermore, allergic sensitization at 12 and 24 months was associated with AD at both time points and with asthma diagnosis at 24 months.Despite its valuable insights, the CORAL study has limitations, including a small cohort size and potential selection bias, as it represented only 12% of eligible children. Here, high breastfeeding rates and low parental smoking rates may limit generalizability. Additionally, the small sample size might hinder the identification of associations that might be evident in larger cohorts.Other studies conducted during the pandemic have primarily focused on assessing the impact on allergic conditions during lockdowns. They have often reported positive effects of interventions such as hygiene, mask usage, and social distancing in reducing air pollution and lowering infection rates, potentially resulting in a reduced impact on allergic conditions (10). The CORAL study stands out among these studies due to its specific objective of evaluating the effect of lockdowns on the incidence of allergic diseases. Finally, it provides valuable insights into how the pandemic have influenced the health of infants born during this period. While the increased incidence of AD initially raises concerns, the lower rates of food sensitization and allergies suggest the positive effects of evolving allergy practices, particularly early allergen introduction. Furthermore, the beneficial impacts of lockdown, such as increased breastfeeding and reduced antibiotic use, may outweigh the anticipated risks associated with reduced early-life microbial exposures.This study enhances our understanding of the real-world impact of early-life environments on allergic disease risk. Continuous monitoring of the CORAL cohort into later childhood will reveal the lasting consequences of being born during the pandemic. These findings underscore the intricate interplay between environmental factors, infant health, and the development of allergies in a rapidly evolving landscape of healthcare practices.

Early Childhood Atopic Phenotypes and the Development of Allergic Respiratory DiseaseTo the Editor,Pediatric atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disorder that affects up to 20% of children worldwide1. Often the earliest sign of atopy, AD has been recognized as the start of the “atopic march”, described as the progression of AD to allergic respiratory diseases (ARD) including asthma and allergic rhinitis2. Although these atopic conditions often share a common T2 enriched pathway influenced by both genetic and environmental factors, not all children with AD have subsequent risk of ARD. Additionally, recent investigations dispute the theory that the temporal progression of the atopic march occurs in a sequential pattern3. Early AD can facilitate allergen sensitization due to a dysfunctional skin barrier4. Both aeroallergen and food sensitization has been associated with risk of ARD5, but it is less clear whether AD may partially mediate that risk. Additionally, food allergy has been recognized to be part of the atopic march, however its role in the march to ARD is less well identified. It is also unclear how these risks may appear in ethnically diverse populations. Distinct atopic phenotypes may better predict risk of ARD. Our objective was to identify whether associations between early food sensitization, aeroallergen sensitization, or food allergy (FA) and the subsequent risk of ARD by age 10 was modified by the development of early AD by age 2 years.We analyzed data from our racially and socioeconomically diverse birth cohort, Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) that enrolled pregnant women 21–45 years of age and their offspring. Recruitment period was from September 2003–December 2007. Eligibility and recruitment are described in previous publications 6 and all study protocols were approved by the Henry Ford Health System Institutional Review Board.Offspring sensitization to aeroallergens (Alternaria, cat, cockroach, dog, Dermatophagoides farina, ragweed, timothy grass), milk, egg, or peanut was determined at 2 years of age by sIgE≥0.35 IU/mL and skin prick testing (SPT; wheal size ≥3 mm larger than the saline control defined a positive test). As sensitization does not always translate to clinical allergy, we also formed an algorithm to determine those most likely to have true IgE-mediated food allergy7. Two allergists reviewed subjects with at least one of the following criteria: (1) at least one food (milk, egg or peanut) with sIgE ≥0.35 IU/mL; (2) a positive SPT; or (3) parental report of infant symptoms potentially related to food allergy plus at least one sIgE >0.10 IU/mL. To standardize classifying infants to the presence of IgE-mediated food allergy (IgE-FA), physicians were asked to combine professional experience with investigator-developed protocols based on the Guidelines for the Diagnosis and Management of Food Allergy in the United States8. A third allergist independently reviewed and ruled on discordant decisions. Data on asthma and AR by age 10 diagnosed by the study physician was collected using clinical history, physical exam, spirometry, and methacholine test.Adjusted relative risk (aRR) was calculated using Poisson regression with robust error variance and following adjustment for sex, child’s race, parental history of asthma, parental history of AR, BMI z-score at age 2, delivery mode, 1-month breastfeeding status, prenatal indoor dog exposure, prenatal indoor cat exposure, and 1-month daycare status.Of the 1258 mother-child pairs enrolled in WHEALS, 347 had sufficient data for analyses (Supplemental Figure 1). Demographics are shown in Table 1. The overall rate of early AD by age 2 years was 25.4% (88 out of 347 subjects). Supplemental Table 1 shows the overall rates of asthma and allergic rhinitis by age 10 by 2-year AD status. AD by age 2 years significantly modified the association between FA at 3-5 years and the risk of ever having asthma by age 10 (p=0.027) (Figure 1). In the absence of AD, FA to milk, egg, or peanut was associated with an increased risk of ever having asthma (aRR 3.36(1.71, 6.58), p<0.001), while no difference was observed in the presence of AD (aRR 1.24(0.57, 2.68), p=0.99). Food sensitization in the absence of AD was associated with increased risk of ever asthma (aRR 2.04(1.03, 4.05), p=0.038), but was not associated with ever AR (aRR 1.10(0.81, 1.48), p=0.97). Food sensitization in the presence of AD was not associated with ever asthma (aRR 0.89(0.45,1.78), p=0.99) or ever allergic rhinitis (aRR 1.45(0.97-2.16), p=0.078).In terms of aeroallergen sensitization, AD by age 2 did not significantly modify the association between aeroallergen sensitization at age 2 and the risk of ARD by age 10. This was true for aeroallergen sensitization overall and when sub-analyzed by seasonal versus perennial (Table 2, Figure 1). However, among those without AD by age 2, perennial aeroallergen sensitization was associated with an increased risk of ever having asthma by age 10 (aRR 2.15 (1.06, 4.36), p=0.031). This association was not significant for those with AD by age 2 (aRR 1.68 (0.78, 3.63), p=0.26).Our findings among a racially and socioeconomically diverse birth cohort suggest that early AD modifies the relationship between FA and the risk of ever having asthma by age 10. However, the association between FA and increased risk of ever having asthma was only seen among those without AD by age 2, which does not support the previously reported atopic progression of disease as described by the atopic march. This held true after correcting for several environmental and parental factors that may increase risk of ARD in our cohort. Our findings may represent a distinct atopic phenotype more characteristic among non-White subgroups, as our cohort is 67% self-identified Black. Previous reports have highlighted the differences in AD phenotypes among ethnically diverse subgroups9. Additionally, recent reports highlight atopic trajectories differ among White and Black children, with Black children more likely to have asthma without FA, AR, or allergen sensitization10. Due to sample size, we were unable to assess the differing trajectories in whites versus blacks. However, because our cohort is composed of 64.8% black children, we believe that black race may be contributing to the outcomes of our study as previous studies have reported atopic trajectories that are different in Black children10. Future studies investigating these endotypes that differ by ethnicity would be beneficial to identify potential immunological markers that would guide therapies for ethnically diverse populations and allow appropriate anticipatory guidance.Keywords : Atopic march, atopic dermatitis, food allergy, food sensitization, aeroallergen sensitization, asthma, allergic rhinitisKey message: Identifying early atopic phenotypes may help identify later ARD risk. This study reiterates that the “march” is not always a chronological process, but rather a complex relationship between heterogenous allergic phenotypes.

Pinus halepensis (Aleppo pine) nuts induced anaphylaxis: a case seriesGabrielle Doré-Brabant1, Joëlle Bouchard2, Louis Marois2 and Aubert Lavoie21 Department of Pediatrics, CHU de Québec - Université Laval, Québec, Canada.2 Department of Allergy and Immunology, CHU de Québec - Université Laval, Québec, Canada.

Comment on Platts-Mills T, Caraballo L, Jacquet A, Zarzuk J. Dust mite allergy. In: Dramburg S, Hilger C, Santos AF, de Las Vecillas L, Aalberse RC, Acevedo N, et al. EAACI Molecular Allergology User’s Guide 2.0. Pediatr Allergy Immunol. 2023 Mar;34 Suppl. 28:e13854.

Pre-school wheeze is very common and often difficult to treat. Most children do not require any investigations, only a detailed history and physical examination to ensure an alternative diagnosis is not being missed; the differential diagnosis, and hence investigation protocols for the child in whom a major illness is suspected, shows geographical variation. The pattern of symptoms may be divided into episodic viral and multiple trigger to guide treatment, but the pattern of symptoms must be re-assessed regularly. However, symptom patterns are a poor guide to underlying pathology. Attention to the proper use of spacers, and adverse environmental exposures such as tobacco smoke exposure, is essential. There are no disease-modifying therapies, so therapy is symptomatic. This paper reviews recent advances in treatment, including new data on the place of leukotriene receptor antagonists, prednisolone for acute attacks of wheeze and antibiotics, based on new attempts to understand the underlying pathology in a way that is clinically practical.

DisseminatedMycobacterium fortuitum infection in a young girl withIFN-γR1 defect masquerading as histiocytosisArchan Sila, Suprit Basua, Jhumki Dasa, Sunil Sethib, Debajyoti Chatterjee c, Pandiarajan Vignesha, Deepti Suria, Ankur Kumar Jindala*aAllergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India- 160012bDepartment of Medical Microbiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India- 160012cDepartment of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India- 160012

Introduction: Following the “hygiene hypothesis” and the increase in prevalence of atopic diseases such as allergic rhinitis, a plethora of studies have investigated the role of sibship composition as a protective factor, but findings are conflicting. Aim: To synthesize the global literature linking birth order and sibship size (number of siblings) to the risk of allergic rhinitis. Methods: Fifteen databases were systematically searched, with no restrictions on publication date or language. Observational studies with defined sibship composition (birth order or sibship size) as exposure and allergic rhinitis or allergic rhinoconjunctivitis (self-reported or clinically diagnosed) as outcome were eligible. Study selection, data extraction, and quality assessment was performed independently in pairs. Relevant data were summarized in tables. Comparable numerical data were analyzed using meta-analysis with robust variance estimation (RVE). Results: Seventy-six reports with >2 million subjects were identified. Being second- or later-born child was associated with protection against both current (pooled risk ratio [RR] 0.79, 95%CI 0.73-0.86) and ever (RR 0.77, 95%CI 0.68-0.88) allergic rhinitis. Having siblings, regardless of birth order, was associated with a decreased risk of current allergic rhinitis (RR 0.89, 95% CI 0.83-0.95) and allergic rhinoconjunctivitis (RR 0.92, 95%CI 0.86-0.98). These effects were unchanged across age, time period, and geographical regions. Conclusion: Our findings indicate that primarily, a higher birth order, and to a lesser extent the number of siblings, is associated with a lower risk of developing allergic rhinitis.

Clinical Letter to the EditorConflict of interests’ statement: No potential conflict of interest is declared for any of the authorsTitle: Hemophagocytic lymphohistiocytosis in an adolescent withNLRP12 -related autoinflammatory disorder, a case report

Background: Due to the recency of the postbiotic field, there are no head-to-head postbiotic studies investigating its biotherapeutic potential for atopic dermatitis (AD). No network meta-analysis (NMA) has yet been conducted to synthesize relevant studies to compare postbiotic interventions for AD. Objective: To assess the comparative efficacy and safety of postbiotic strains for treating pediatric AD. Methodology: This is an NMA of randomized controlled studies that evaluate postbiotics in treating pediatric AD. Systematic search of databases and registers from inception to November 30, 2022. Three authors independently performed the search, screening, appraisal using the Cochrane risk of bias tool version 2 and data extraction. Data analysis was done using STATA14 software. Results: There were 9 studies that evaluated 8 postbiotic preparations. Lactobacillus rhamnosus IDCC 3201 (LR) ranked highest in the efficacy outcome. Compared to placebo, LR may be effective in reducing symptoms of atopic dermatitis both in the main analysis (SMD -0.53, 95%CI -1.02 to -0.04) and sensitivity analysis involving studies that used SCORAD (MD -5.52, 95% CI -10.46 to -0.58), based on low-certainty evidence. Based on moderate-certainty evidence, LR probably does not increase the risk of adverse events (RR 0.97, 95% CI 0.79 to 1.21). Although Lactobacillus paracasei GM080 (LP2) ranked highest in the safety outcome, it may not reduce AD symptoms compared to placebo (SMD -0.03, 95% CI -0.37 to 0.32) based on low-certainty evidence. Conclusion: LR showed significant benefits for children with AD, based on low-certainty evidence. Further investigation on LR is recommended.

Long-term prognosis after low-dose peanut challenge for patients with history of anaphylaxisNobuko Akamatsu, MD, PhD1,2, Ken-ichi Nagakura, MD, PhD1, Sakura Sato, MD3, Noriyuki Yanagida, MD, PhD1,3,*, Motohiro Ebisawa, MD, PhD3 1Department of Pediatrics, National Hospital Organization, Sagamihara National Hospital, Kanagawa, Japan2Department of Pediatrics and Adolescent Medicine, Tokyo Medical University Hospital, Tokyo, Japan3Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, Kanagawa, JapanRunning title: Prognosis after low-dose peanut challenge*Corresponding author: Noriyuki Yanagida, MD, PhDDepartment of Pediatrics, National Hospital Organization, Sagamihara National Hospital,18-1, Sakuradai, Minami-ku, Sagamihara, Kanagawa 252-0392, JapanE-mail: [email protected] count: 1190Number of figures: 2 Number of tables: 0Conflict of interest: Motohiro Ebisawa and Sakura Sato have received speaker honoraria from Viatris. All other authors declare that they have no conflicts of interest.Financial support: This paper has not received any financial support.Keywords : low-dose oral food challenge, peanut, food allergy, low-dose-tolerant, tolerant, pediatric, anaphylaxisTo the Editor,Peanuts cause severe allergic reactions, and only 20% of peanut-allergic patients acquire tolerance.1 Peanut oral food challenge (OFC) has a high risk of severe symptoms such as anaphylaxis, and OFC is avoided in children with an immediate history, especially with a history of anaphylaxis.1Peanut-allergic patients and their guardians have a lower quality of life because of worry that anaphylaxis may occur at any time.2 Low-dose OFC may be useful to manage children with a history of anaphylaxis,3 but it has not been used to evaluate prognosis. This study investigated long-term prognosis after low-dose peanut OFC for patients with a history of immediate reactions, including anaphylaxis.We retrospectively analyzed participants with a history of immediate symptoms due to peanut ingestion, who received baseline low-dose OFC with 133 mg of peanut protein from August 2013–August 2017 at Sagamihara National Hospital (Figure 1), and evaluated two-year tolerance acquisition.We defined tolerance as passing an OFC with 795 mg protein (medium-dose OFC) and ingesting more than 795 mg protein without symptoms at home; consuming this dose enables cessation of strict avoidance in daily life. We defined baseline low-dose OFC negative patients as the low-dose-tolerant group and positive patients as the low-dose-reactive group. The low-dose-tolerant group was instructed to consume 133 mg at home twice a week. Then, based on guardians’ preference, patients received a medium-dose OFC every 6 months or gradually increased peanut ingestion to 795 mg at home under a physician’s direction. The low-dose-reactive group completely avoided peanuts and received low-dose OFC every 6 months. When the low-dose-reactive group passed low-dose OFC, they received medium-dose OFC (Supplementary Figure 1).Anaphylaxis was defined according to the World Allergy Organization Guidelines.4 OFC protocol is described in the supplementary information.5 The percentage of patients who acquired tolerance within two years was estimated using Kaplan-Meier curves. The co-factors for tolerance acquisition were analyzed using Cox regression analysis. Multivariate analysis was performed on the results of low-dose OFC, total IgE, peanut-specific IgE (Pn-sIgE), and history of peanut-related anaphylaxis. SPSS (version 27.0; SPSS Inc., Chicago, IL) was used for all analyses; p <0.05 was considered statistically significant. The Ethics Committee of The Sagamihara National Hospital (2016-015) approved the study according to the Helsinki Declaration. Written informed consent was obtained from all patients’ guardians.Fifty-three patients (median age, 7.1 years) were enrolled; 43% had a history of anaphylaxis. The median Pn-sIgE level was 20.7 (interquartile range 7.0–57.5) kUA/L. The median Ara h 2-specific IgE level was 10.4 (4.98–28.3) kUA/L. The median thresholds of past immediate symptoms were 26.6 mg (13.3–133) (Supplementary Table 1).Twenty-one patients (40%) passed the low-dose OFC and were defined as the low-dose-tolerant group, and 32 (60%) failed and were defined as the low-dose-reactive group (Supplementary Table 1); 35% of patients with a history of anaphylaxis passed the low-dose OFC. During low-dose OFC, oral mucosal symptoms were most common (72%), then gastrointestinal (63%) and respiratory symptoms (63%). Three patients required intramuscular adrenaline (Supplementary Table 2). When the low-dose-tolerant patients ingested low-dose peanuts at home, six (29%) had mild reactions like oral and throat discomfort; most reactions resolved naturally and did not require medical attention.In the low-dose-tolerant group, 13 patients (62%) acquired tolerance within 2 years, including five patients with a history of anaphylaxis, whereas in the low-dose-reactive group, one patient (3%), with no history of anaphylaxis, acquired tolerance (p <0.001) (Figure 2). In the low-dose-reactive group, 6% of patients passed low-dose OFC within two years.The predictive factors of failure to acquire tolerance have been positive reactions to low-dose OFC (crude hazard ratios of total IgE, Pn-sIgE: 0.37 [95% confidence interval 0.15–0.94, p =0.04), and log (Pn-sIgE) 2.23 [1.01–4.92], p =0.048) (Supplementary Table 3). In 23 patients with a history of anaphylaxis, five (22%) acquired tolerance. In 30 patients with no history of anaphylaxis, nine (30%) acquired tolerance. History of anaphylaxis did not significantly affect tolerance acquisition (Supplementary Figure 2).This is the first report showing that low-dose OFC can be undergone relatively safely with tolerance acquisition in some peanut-allergic patients, including patients with a history of anaphylaxis. Patients with a history of anaphylaxis have a lower quality of life because of worry that anaphylaxis may occur at any time.6 Therefore, these results are significant because if patients realize that low-dose peanuts can be ingested, complete avoidance becomes unnecessary, and tolerance acquisition could be assessed. The low-dose-reactive group was less likely to develop tolerance and required careful follow-up to prevent accidental ingestion.Previous studies of long-term prognosis after peanut OFC excluded patients with a history of anaphylaxis,1 therefore, their tolerance acquisition based on the results of OFC was unknown. In our current study, more than half of patients in low-dose-tolerant groups acquired tolerance within two years, even those with a history of anaphylaxis. Furthermore, one-fifth of patients with a history of anaphylaxis tolerated peanuts, and there was no significant difference between patients with and without a history of anaphylaxis in acquiring tolerance. Therefore, passing low-dose OFC could be considered to assess tolerance acquisition, regardless of the history of anaphylaxis.It has been reported that peanut OFC is high risk because it often causes anaphylaxis and other serious symptoms.1 In the previous studies of peanut OFC, subjects have no history of anaphylaxis or as few as 10%, while this study had 40%, but the occurrence of anaphylaxis in OFC was comparable.1,7 Furthermore, there is a report of a group of subjects, 83% of whom had a history of anaphylaxis, and all patients reacted with anaphylaxis in OFC.8 It has been reported that the incidence of anaphylaxis with OFC was higher with progression up to the total OFC ingested.7 Therefore this study suggests that low-dose OFC is relatively safe in patients with a history of anaphylaxis.Recently, some trials of low-dose oral immunotherapy showed that ingesting low-dose peanuts (133-300 mg) could induce immunological changes and allow the intake of larger amounts.9Similarly, daily ingestion of low-dose wheat is effective in increasing consumption dose and preventing accidental symptoms, even in patients with a history of anaphylaxis.10 Therefore, twice weekly ingestion of 133 mg in the low-dose-tolerant group may yield oral tolerance. In addition, few serious reactions were observed in the low-dose-tolerant group during the subsequent at-home dose escalation in this study.This study has several limitations. First, 33 subjects were excluded because their two-year course could not be tracked. Although the excluded and included patients’ backgrounds were similar (Supplementary Table 4), predictors of tolerance acquisition, such as anaphylaxis may be different with more subjects. Second, there was a lack of information on several points. Although at-home intake methods were unified, the frequency of home peanut intake and adherence was unknown. Additionally, we couldn’t confirm thresholds of past immediate symptoms in 25% of subjects. However, the median thresholds were 26.6 mg in 75% of subjects who were able to assess the threshold. Therefore, we assume that thresholds in the remaining children were similar.For peanut-allergic patients with a history of anaphylaxis, low-dose OFC is relatively safe and effective in the assessment of tolerance acquisition. Low-dose OFC results may effectively stratify peanut-allergic patients with anaphylaxis history with good and poor tolerance acquisition to select optimal management plans.Nobuko Akamatsu, MD, PhD1,2, Ken-ichi Nagakura, MD, PhD1, Sakura Sato, MD3, Noriyuki Yanagida, MD, PhD1,3, Motohiro Ebisawa, MD, PhD3,1Department of Pediatrics, National Hospital Organization, Sagamihara National Hospital, Kanagawa, Japan2Department of Pediatrics and Adolescent Medicine, Tokyo Medical University Hospital, Tokyo, Japan3Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, Kanagawa, Japan

A proper allergy work-up, based on the gold standard drug provocation test (DPT), usually rules out suspected drug hypersensitivity in children. These tests are generally open, given their high efficiency compared to double-blind placebo-controlled DPTs. Although their negative predictive value is excellent, no studies have calculated their positive predictive value, highly dependent on the prevalence of the disease. Most studies have found a rate of less than 5% to 10% of true beta-lactam hypersensitivity in children. Given this low prevalence (pre-test probability), a few false positive results can significantly reduce the estimated positive predictive value. False positives may arise from the nocebo effect during the test, including nocebo by proxy, or from observer bias, which depends on professional expertise and organizational circumstances. Some studies have found a high rate of tolerance on a second DPT in children who failed the first, but these results may be affected by the interval between the two tests, of a year or more in most cases, reflecting a loss of hypersensitivity over time. Taking into account the low rate of positive DPTs, with commonly mild reactions, we suggest confirming non-severe positive DPTs with a second provocation performed soon after the first, especially in the case of beta-lactam antibiotics, in order to improve the diagnostic accuracy, de-label more patients, and achieve a better estimation of true drug hypersensitivity prevalence.

Currently available vaccines are safe but, potentially, any vaccine can cause an allergic reaction and albeit very rare, anaphylaxis can occur. Although its rarity, the precise diagnostic management of a suspected anaphylaxis post-vaccination is of paramount importance due to the risk of a potential serious reactions after re-exposure, while, a misdiagnosis might lead to an increase in the number of children that interrupt vaccinations resulting in an unjustifiably individual and collective risk of loss of protection against immune preventable diseases. Especially, in the light that most cases of suspected allergy to a vaccine are not effectively confirmed in up to 85% of the patients referred for an allergy evaluation and patients can continue vaccination with the same formulation and tolerance of the booster doses The patient assessment has to be done by an allergist or an immunologist expert in the vaccine field to select subjects at risk of allergic reactions and to perform the correct procedures for vaccine hypersensitivity diagnosis and management, in order to guarantee safe immunization practices. Aim of this review is to provide a practical and safe management in the clinical settings of the allergic patient which have to undergo immunization practices, both to manage children with a suspected allergic reaction to a vaccine both children with history of allergy to a vaccine component.

Early life exposure to antibiotics and laxatives in relation to infantile atopic eczemaSarah El-Heis 1 DMSarah R Crozier1,2 PhDNicholas C Harvey1,3 PhDEugene Healy4 PhDKeith M Godfrey1,3,5 FMedSci1 Medical Research Council Lifecourse Epidemiology Centre, University of Southampton,Southampton, UK2 NIHR Applied Research Collaboration Wessex, Southampton Science Park, Innovation Centre, Southampton, UK3 NIHR Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK4 Dermatopharmacology, Faculty of Medicine, University of Southampton, Southampton, UK5 Developmental Sciences, University of Southampton, Southampton, UK

BACKGROUND Severe Pediatric Allergic Asthma (SPAA) induces a huge economic burden in terms of direct, indirect and intangible costs. The use of omalizumab for the treatment of these patients has produced a significant improvement in several clinical outcomes, but at the same time, the cost for the management of the disease has also increased. The aim of this report was to evaluate whether the use of omalizumab is cost-effective. METHODS A sample of 426 children with SPAA from the ANCHORS study was used to calculate the Incremental Cost Effectiveness Ratio (ICER) for the avoidance of Moderate to Severe Exacerbations (MSE), and also for the improvement in childhood Asthma Control Test (c-ACT) or the Asthma Control Questionnaire (ACQ5). We retrospectively collected data of health encounters and drug consumption before and up to six years after the beginning of the treatment with omalizumab. RESULTS The ICER per avoided MSE was \euro2,107 after one year, and it consistently decreased to \euro656 in those followed up to six years. Similarly, the ICER for the Minimally Important Difference in control tests showed a decrease from \euro2,059 to \euro380 per each 0.5 points of improvement in ACQ5, and from \euro3,141 to \euro2,322 per each 3 points improvement in c-ACT, at years 1 and 6 respectively. CONCLUSION The use of OMZ is a cost-effective option for most children with uncontrolled SPAA, mainly those who have frequent exacerbations, showing progressively reduced costs in successive years of treatment.

Sesame is a potentially potent allergen that can trigger skin, gastrointestinal, and respiratory tract symptoms, and anaphylaxis. Only 20% to 30% of sesame-allergic children develop tolerance. The prevalence of sesame allergy depends on local diets and ranges from 0.1% to 0.9%. A high risk of accidental exposure to sesame has resulted in mandatory food labeling in many countries. More than half of patients with sesame allergy are also allergic to peanut/tree nuts. Serum specific IgE testing with a quantitative Ses i 1 component can be performed safely and has higher clinical specificity and better positive predictive value for oral food challenge (OFC) than whole sesame extract or skin prick testing (SPT). Compared with SPT or OFC, in vitro Ses i 1 testing requires no special techniques and carries no risk of reactions. Diagnosis of suspected sesame allergy begins with a thorough history and physical examination. A positive sesame extract test (≥0.1 kU A/L) should prompt further testing. In patients with a high probability of reacting, results of component testing may facilitate a decision about performing an OFC. In a Japanese study of OFC and Ses i 1, there was a 5% probability of a positive OFC with Ses i 1 sIgE levels <0.13 kU A/L, and a 50% probability of a positive OFC with levels >32.0 kU A/L. Most patients could safely consume sesame if sIgE levels were <0.13 kU A/L. Ses i 1 testing can be used to guide appropriate management (avoidance, emergency medication, and oral immunotherapy).

Background: Cow’s milk allergy can result in anaphylactic reactions. The estimated prevalence of cow’s milk allergy in developed countries ranges from 0.5% to 3% at age 1 year. Objective: Our objective was to perform a systematic review and, if possible, a meta-analysis to assess the frequency of fatal and recurrent anaphylaxis induced by cow’s milk. Methods: We searched PubMed/MEDLINE, EMBASE, and the Web of Science for studies that had assessed fatal and recurrent anaphylaxis induced by cow’s milk for the population of a country or at least an administrative region. Our review included cohort, cross-sectional, and registry studies that had assessed the incidence or prevalence of recurrent anaphylaxis or the incidence of fatal anaphylaxis due to cow’s milk. Results: The pooled prevalence of recurrence (PR) for at least an episode of anaphylaxis was 26.98% (3.41-155.19). Teymourpour et al (Iran) reported the highest PR (53.10%); the 2 studies with the lowest PR were from France (5.16 and 0.42 respectively) (p<0.01). Nine studies on fatal anaphylaxis were selected (41 deaths) and found to be highly heterogeneous (I 2=75.91%). Levy et al and Bassagio et al reported the highest incidence rate (IR 0.15 and 0.6 deaths per million persons-year). Conclusion: The PR of anaphylaxis was approximately one quarter of patients with anaphylaxis due to cow’s milk, while deaths from anaphylaxis caused by cow’s milk were very rare, although some studies report rates as high as 15 times the lowest IR.

Early childhood allergy prevention behaviours: trends in Germany from 2015 to 2020