Editorial to the special issue “Environmental influences on childhood asthma”Back in 1892, Sir William Osler gave an accurate description of asthma as a disease that is associated with “spasm of the bronchial muscles, inflammation of the smaller bronchioles, bizarre and extraordinary variety of circumstances and cold infections, often running in families (1,2). This is basically a true reflection of our modern understanding of asthma which states that asthma is a complex genetic disorder that involves interactions between genetic and environmental factors.Since the human genetic makeup has not changed significantly in the last couple of decades, there is reason to believe that the overall increase in asthma prevalence (3) can be attributed to the changing environmental conditions of modern life. The role of environment in asthma is not limited to its role in the pathogenesis of the disease. Since it is currently not possible to change the genetic make-up of an individual underlying a complex genetic disorder such as asthma, modification of environmental conditions emerges as a significant tool for its treatment. Therefore, understanding the environmental factors that play an important role in asthma is crucial in understanding the disease pathogenesis as well as modification of factors that modulate the inception and progress of the disease as well as its treatment.Various studies published in the last years in the journal and included in this virtual issue have addressed these questions. Garcia-Serna et al. have found out that gestational exposure to traffic-related air pollutants (TRAP) may increase the pro-inflammatory and Th2-related cytokines in newborns which might influence immune system responses later in life (4). Similarly, Pesce et al. (5) have investigated the association between prenatal exposures to heavy metals and atopic diseases. The serum concentrations of lead, cadmium and manganese were assessed in maternal blood samples collected during pregnancy and in cord blood of 651 mother-children pairs. The authors have concluded that the levels of cadmium in cord blood were associated with greater risk of asthma at the age of 8. Baek et al. have documented that exposure to phthalates are associated with airway dysfunction in childhood and this effect was partially attributable to increased serum periostin levels (6). Regarding the association between the genes and environment, Theodorou et al. (7) have investigated the role of mitogen-activated protein kinase (MAPK) pathway in 232 children who were selected from two cross-sectional cohorts and one birth cohort study. They have isolated peripheral blood mononuclear cells (PBMC) from children with asthma along with healthy controls and stimulated them with farm-dust extracts or lipopolysaccharide. The results have shown that the children with asthma have expressed significantly less dual-specificity phosphatase-1 (DUSP1) which is the negative regulator of MAPK pathway. They have conclusively indicated the possible role of DUSP1 for future therapeutical interventions regarding the anti-inflammatory features of farming environments.In an effort to further elucidate the environmental factors that are central to our understanding of asthma, the journal has started a review series to provide a comprehensive picture on the role of environment on various aspect of asthma. Major subheadings includedBiodiversityUrban exposuresGene-environment interactionsFarm effectAir pollutionClimate changeAllergensDiet microbiome and obesityIn the virtual issue of the journal Tari Haahtela (8) has focused on the effect of biodiversity. Evidence supports that the immunomodulating roles of different micro-organisms may be protective for asthma and allergic diseases. The studies from the neighboring Finnish and Russian Karelia regions, which the author named as “the living laboratory”, have shown strong evidence for the central role of environment and lifestyle which modify the human microbiome, immune balance, and thus allergy and asthma risk. Diversity of the human microbiome as well as the diversity of the natural environment that we live in and more contact with the nature are important determinants of physical health.Grant et al. (9) have focused on the influence of urban exposures on childhood asthma. The authors have meticulously summarized and analyzed the results of previous studies which aimed to investigate the interaction between indoor allergens, microbes, indoor and outdoor pollutants, social determinants and childhood asthma along with the opportunities for intervention. Multiple environmental exposures and influences contribute to the increased incidence of asthma and excess asthma morbidity among children with asthma living in urban communities. Indoor pest allergen and mold exposures have been repeatedly linked to increased asthma diagnosis, symptoms, and exacerbations in urban children. However, studies in high-risk urban populations also found that early life pest allergen exposure, along with microbial and endotoxin exposure may be associated with a decreased risk of wheezing and asthma suggesting that the association is more complex than previously thought.Since asthma prevalence varies widely depending on the socio-economical level, changes to help reduce inequities and inequalities in social determinants of health such as poverty, housing disrepair, higher rates of obesity, and chronic stress may produce positive effects at the population-level.Hernandez-Pacheco et al (10) have reviewed the latest gene-environment interaction (GxE) studies in childhood asthma. They have summarized the role of various environmental exposures and the current state of knowledge on asthma genetics. The field of GxE in asthma has drastically evolved together with technological advances over the last years. However, despite reports on the effect of numerous environmental factors on childhood asthma, the availability of detailed and diverse exposure data is limited. Tobacco smoke remains to be the most accessible and extensively explored factor followed by traffic-related air pollution in GxE studies.Airway epithelium seems to be central in gene-environment interactions. The effect of the exposure to certain environmental factors early in life on the modification of the risk and severity of asthma later in childhood is partially dependent on the functionality and integrity of the airway epithelium. It is known that the environmental exposures can trigger an inflammatory response and the disruption of the barrier and mucociliary function.Although there are several methodological and conceptual challenges with GxE interaction studies, recent data have led to new insights into childhood asthma pathophysiology which is best exemplified by the 17q12-21 asthma locus. Some of the SNPs at this locus seem to be associated with the onset of childhood asthma, thereby highlighting the importance of age related factors in gene environment interactions.The need for longitudinal and functional studies which provide insights into the biological mechanisms underlying the observed associations between environmental exposures and epigenetic changes that modify the asthma risk is highlighted.Another extensively studied environmental factor that is associated with childhood as is the so called “farm effect”. Frei et al. (11) have summarized the current knowledge on how “farm effect” influences the immune homeostasis during the intrauterine period and in childhood with a focus on immune mechanisms induced by environmental microbial diversity and microbial components. Farming lifestyle factors including nutrition influence the immune homeostasis either by regulating the innate immune system or by induction of regulatory T cells or TH1. We see diversity as a significant factor also in the farm effect. Diversity of environmental microbes, the diversity of the gut microbiome, or the diversity of the nutrition emerge as significant factors.Paciencia et al. (12) investigated the association and mechanisms between air pollution and asthma in children along with the precautions that should be taken to reduce the burden of air pollution on asthma. Environmental conditions are not shared equally across the populations, regions, and settings where people live, work, and spend their time. Urban conditions and air quality are not only important features for national and local authorities to shape healthy cities and protect their citizens from environmental and health risks, but they also provide opportunities to mitigate inequalities in the most deprived areas where the environmental burden is highest. Actions to avoid exposure to indoor and outdoor air pollutants should be complementary at different levels –individual, local, and national levels – to take strong measures to protect children.Taken together, these reviews provide a very comprehensive coverage on the role of environmental factors on childhood asthma and suggest that efforts to modify these factors may have beneficial effects not only on the individual level but also at the population level.S. Tolga Yavuz1Ömer Kalayci2Philippe A. Eigenmann3

Background: In the absence of a clear clinical history of reaction, diagnosis of cashew allergy using skin prick tests (SPT) or cashew-specific IgE requires a high number of oral food challenges (OFC). By using Ana o 3 sIgE alone, or a two-step diagnostic algorithm using cashew sIgE followed by Ana o 3 sIgE, there is a reduced need for OFC. We aimed to perform a cost comparison for both of these approaches compared to cashew SPT alone. Methods: Pooled individual level data from 6 studies was used to determine diagnostic accuracy and OFC rate. Two studies used cashew SPT (n=567, 198 allergic), with 95% positive and negative predictive values of ≥12mm and <3mm. Four studies were included in the pathways for Ana o 3 sIgE alone or a 2-step algorithm incorporating cashew and Ana o 3 sIgE (n=271, 156 allergic). Cut-offs used were ≥8.5kUA/L and ≤0.1kUA/L for cashew sIgE and ≥0.35kUA/L and ≤0.1kUA/L for Ana o 3 sIgE. Costs were constructed based on unit prices from hospital inpatient admissions, expenses incurred by families, individual patient data on allergic reaction types and rates and adrenaline autoinjector carriage, applying a health system perspective. Results: Modelled data through the Ana o 3 pathway resulted in a 46.43% cost reduction (\euro307,406/1000 patients) compared to using cashew SPT alone (\euro573,854/1000 patients). The 2-step algorithm resulted in a 44.94% cost reduction compared to SPT alone (\euro315,952.82/1000 patients). Both the Ana o 3 pathway and 2-step algorithm resulted in a 79-80% reduction in OFCs compared to SPT. Conclusions: Using Ana o 3 as a standalone test for cashew allergy diagnosis or a 2-step algorithm incorporating cashew sIgE and Ana o 3 sIgE is accurate and results in a large reduction in both OFCs and health system costs compared to cashew SPT alone.

Whether you benefit from high-quality urban environments, such as those rich in green and blue spaces, that may offer benefits to allergic and respiratory health depends on where you live and work. Environmental inequality, therefore, results from the unequal distribution of the risks and benefits that stem from interactions with our environment. Within this perspective, this article reviews the evidence for an association between air pollution caused by industrial activities, traffic, disinfection-by-products and tobacco/e-cigarettes and asthma in children. We also discuss the proposed mechanisms by which air pollution increases asthma risk, including environmental epigenetic regulations, oxidative stress, and damage, disrupted barrier integrity, inflammatory pathways, and enhancement of respiratory sensitization to aeroallergens. Environmental air pollution is a major determinant of childhood asthma, but magnitude of effect is not shared equally across the population, regions, and settings where people live, work, and spend their time. Improvement of the exposure assessment, a better understanding of critical exposure time windows, underlying mechanisms, and drivers of heterogeneity may improve the risk estimates. Urban conditions and air quality are not only important features for national and local authorities to shape healthy cities and protect their citizens from environmental and health risks, but they also provide opportunities to mitigate inequalities in the most deprived areas where the environmental burden is highest. Actions to avoid exposure to indoor and outdoor air pollutants should be complementary at different levels – individual, local, and national levels – to take effective measures to protect children who have little or no control over the air they breathe.

Race is a Modifier between Parental Allergy and Food Allergy in OffspringAmy A. Eapen, MD, MS*1, Erica Ridley MD*1, Alexandra R. Sitarik MS2, Christine Joseph PhD2, Christian Nageotte, MD1, Rana Misiak, MD1, Dennis Ownby MD3, Christine Johnson PhD2, Edward Zoratti MD1, Haejin Kim MD1.1Division of Allergy and Clinical Immunology, Henry Ford Health System, Detroit, Michigan2Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan3Department of Pediatrics, Augusta University, Augusta, Georgia.*Dr. Eapen and Dr. Ridley are listed as co-first authorsCorresponding author: Amy A. Eapen, MD, One Ford Place, 4B Detroit, MI 48202; Telephone (313) 971-6182; Fax (313) 876-2094; E-mail: [email protected]: Grants from the National Institute of Allergy and Infectious Diseases (R01 A1051598 and P01 A1089473) and the Fund for Henry Ford Hospital.Financial disclosure : There are no financial disclosures of conflicts of interest.Word count: 1191Keywords : Food allergy, race, parental allergy, total IgETo the Editor,Studies indicate associations between maternal allergy and development of food allergy in their offspring1, with higher food allergy risk among those with more than one first degree relative with allergic disease2. However, unnecessary food avoidance among children of allergic parents has important implications since diverse diets in children may decrease risk for food allergy, and early food introduction with foods such as peanut, can be protective for food allergy3. We sought to assess the association between parental allergic markers and offspring food sensitization and clinical allergy to milk, egg, or peanut.We analyzed data from the racially and socioeconomically diverse population birth cohort, Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) that enrolled pregnant women between 21 to 45 years of age and their offspring following recruitment between September 2003 to December 2007. Details regarding the cohort have been previously published4,5. Institutional Review Board (IRB) approval was obtained for all aspects of the study.Parental factors assessed included questionnaire responses regarding history of allergy or asthma; maternal total IgE and maternal serum allergen specific IgE (sIgE) levels during pregnancy or one month postpartum were also evaluated. Atopy was defined as at least one sIgE ≥ 0.35 IU/mL to eight allergens (dust mite, dog, cat, grass, ragweed,Alternaria , egg, cockroach). Maternal asthma, atopic dermatitis, and food allergy were determined by questionnaire. Due to a paucity of paternal data, only paternal asthma was assessed.Offspring sensitization to milk, egg, or peanut was determined at 2 years of age by sIgE≥ 0.35 IU/mL and also skin prick testing (SPT; wheal size ≥3 mm larger than the saline control defined a positive test). As sensitization to foods does not translate to clinical allergy in all cases, we formed an algorithm to determine those most likely to have true IgE-mediated food allergy6. A consensus panel of allergists determined food allergy status in offspring based on review of the aforementioned data and abstracted chart informations as previously described7. Briefly, infant data were forwarded to the panel only if more than one of the following criteria were met for milk, egg, or peanut allergens: (1) 1 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 specific IgE greater than 0.10 IU/mL. To enhance standardization in 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.Logistic regression models of parental variables with each outcome were fit. Interaction terms were added to logistic regression models to assess differences in associations based on race, (p<0.10 was considered a significant interaction). Predicted probabilities were used to construct receiver operating characteristic (ROC) curves and calculate area-under-the-curve (AUC) values.Of 1258 maternal-child pairs, 761 had sufficient data for analysis (Supplemental Figure el). Participant characteristics indicated that families not lost to follow up had higher household incomes, as well as higher maternal education, and a higher proportion of mothers who were married, kept pets, and breastfed the child. rates (Table e1).Associations between parental variables and physician panel determination of food allergy are shown in Table 1. After adjusting for child race, seven out of eight parental characterics of the were significant or of borderline signficance. However, the maximum AUC for ROC curves for any individual variable was 0.54 (maternal total IgE), indicating poor prognostic value (Supplemental Table e2). Maternal atopy, multi-sensitization, and total IgE significantly interacted with race (p=0.012, 0.092, 0.068, respectively) indicating strong associations among African American (AA) children only (Table 1). For example, maternal atopy in non-AA children was not associated with food allergy, but was highly associated among AA children (OR [95% CI]=3.56 [1.55, 9.66], p=0.006).Maternal current asthma was also associated with childhood food allergy (OR [95% CI]=2.27 [1.02, 4.71], p=0.034), and patterns varied by race with history of maternal asthma associated with food allergy only in non-AA children (OR [95% CI]= 4.92 [1.22, 17.14], p=0.015), and current asthma among AA children (OR [95% CI]=2.64 [1.10, 5.92], p=0.022; Table 1).Combined, parental variables only modestly impacted food allergy ROC analyses resulting in an AUC of 0.66. However, the ROC curves differed by race (non-AA AUC 0.36 vs AA AUC 0.71, p=0.002) as shown in Figure 1.Apart from food allergy, parental variables were analysed for associations with offspring sensitization (positive sIgE or SPT) to peanut, milk, or egg at age 2 years. Maternal atopy, multi-sensitization, and total IgE were associated with offspring positive food sIgE sensitization to at least one food. Analysis stratified by race indicated these associations were significant only among AA children. (Supplemental Table e3). Furthermore, maternal current asthma was associated with food sIgE sensitization only among non-AA children (OR [95% CI]=4.90 [1.69, 16.20], p=0.005). ROC curves were significantly different between AA and non-AA children (p=0.036) but predictive ability remained poor in both (AUC 0.55 and 0.44 respectively as in supplemental Figure e2).Maternal multisensitization, total IgE and current asthma, and paternal asthma were statistically significantly associated with any positive food SPTs only among AA children. (Supplemental Table e4). Additionally, race modified the relationship between maternal atopy and SPTs (p=0.039); AA children of atopic mothers had elevated odds of food SPT positivity (OR [95% CI]=1.96 [1.15, 3.45], p=0.016). Despite ROC differences by race (p=0.015; Figure e3), parental variables again had minimal predictive ability.The importance of genetic factors in food allergy is supported by twin studies showing higher concordance of peanut allergy among monozygotic compared with dizygotic twins (64.3% and 6.8%, respectively)9. In addition, heritability among parents and offspring for overall food sensitization have been reported1. However, our report indicates parental variables related to allergy have poor predictive ability for offspring food sensitization. The results from the physician panel demonstrate a moderate degree of risk and capability of predicting food allergy in offspring from parents having clinical characteristics of allergy.We previously reported similar food allergy prevalence for milk, egg, and peanut in AA and non-AA children7. We report here that the inherited risk as measures by parental allergic variables and predictive ability of parental allergic variables on food allergy development in offspring varies by race and is more strongly associated with clinical food allergy versus sensitization, among AA children. The potential mechanisms behind this racial discrepancy are require further studies.Potential study limitations include the physician panel to determine clinical food allergy status as opposed to performing oral food challenges. These challenges are time consuming and impractical to implement in large epidemiological studies10. Another limitation is that non-AA children included multiple ethnicites, which was done to preserve sample size. These groups may have different incidences of disease, and risk may vary. Finally, included and excluded WHEALS participants differed by demographic variables, so findings may not be generalizable to the target population.Parental allergy and atopy, although associated with offspring food allergy, is only a weak predictor and depends upon race. Further studies of familial factors contributing to food allergy and these disparities are needed to precisely identify children at risk for food allergy.Amy A. Eapen, MD, MS*1, Erica Ridley MD*1, Alexandra R. Sitarik MS2, Christine Joseph PhD2, Christian Nageotte, MD1, Rana Misiak, MD1, Dennis Ownby MD3, Christine Johnson PhD2, Edward Zoratti MD1, Haejin Kim MD1.1Division of Allergy and Clinical Immunology2Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan3Department of Pediatrics, Augusta University, Augusta, Georgia.*Dr. Eapen and Dr. Ridley are listed as co-first authors

Background: Food allergy is a disease with a diverse and variable natural history, and some patients may react to two or more food antigens. This study aimed to classify and characterize the long-term prognosis of infantile-onset, immediate-type food allergies in children, focusing on three major antigens in Japan: egg, milk, and wheat. Methods: All children visited to our hospital with food allergies, including suspected cases, were prospectively registered in our medical database. From this database, infants who had immediate-type symptoms or were sensitized to above three antigens were included. Cox regression analysis and repeated-measures latent class analysis were performed to reveal risk factors and tolerance patterns for food allergies. Results: Of 2,830 patients registered in the database, we included 915 patients with immediate-type food allergy symptoms and 276 sensitized asymptomatic patients in this study. The number of patients with immediate-type symptoms to egg, milk, and wheat was 609, 443, and 235, respectively. The number of patients with multiple food allergies was 302. Ratios of acquiring tolerance to egg, milk, and wheat at the age of 6 years were 74%, 69%, and 75%, respectively. Latent class analysis revealed 10 classes of prognosis for food allergies, including five with multiple food allergies. The largest class was transient egg allergy alone (21.4%), and there were severe cases of persistent allergy to three major allergens (3.2%). Conclusions: This study demonstrated the prognosis of food-allergy classes in Japan, including multiple food allergies, with 10 classes with its own characteristics.

Background Household studies are crucial for understanding the transmission of SARS-CoV-2 infection, which may be underestimated from PCR testing of respiratory samples alone. We aim to combine assessment of household mitigation measures; nasopharyngeal, saliva and stool PCR testing; along with mucosal and systemic SARS-CoV-2 specific antibodies, to comprehensively characterise SARS-CoV-2 infection and transmission in households. Methods Between March and September 2020, we obtained samples from 92 participants in 26 households in Melbourne, Australia, in a 4-week period following onset of infection with ancestral SARS-CoV-2 variants. Results The secondary attack rate was 36% (24/66) when using nasopharyngeal swab (NPS) PCR positivity alone. However, when respiratory and non-respiratory samples were combined with antibody responses in blood and saliva, the secondary attack rate was 76% (50/66). SARS-CoV-2 viral load of the index case and household isolation measures were key factors that determine secondary transmission. In 27% (7/26) of households, all family members tested positive by NPS for SARS-CoV-2 and were characterised by lower respiratory Ct-values than low transmission families (Median 22.62 vs 32.91; IQR 17.06 to 28.67 vs 30.37 to 34.24). High transmission families were associated with enhanced plasma antibody responses to multiple SARS-CoV-2 antigens and the presence of neutralising antibodies. Three distinguishing saliva SARS-CoV-2 antibody features were identified according to age (IgA1 to Spike 1, IgA1 to nucleocapsid protein (NP), suggesting that adults and children generate distinct mucosal antibody responses during the acute phase of infection. Conclusion Utilising respiratory and non-respiratory PCR testing, along with measurement of SARS-CoV-2 specific local and systemic antibodies, provides a more accurate assessment of infection within households and highlights some of the immunological differences in response between children and adults.

Background: World-wide incidence and prevalence of both asthma and type 1 diabetes mellitus (T1DM) in children has been increasing in past decades. Association between the two diseases has been found in some but not other studies. Objective: We conducted a meta-analysis to verify such an association, and bidirectional Mendelian randomization analysis to examine the potential cause-effect relationships. Methods: Three databases (PubMed, Embase and Web of Science) were searched from their inception to February 1, 2021. Pooled hazard ratios (HR) or odds ratios (OR), and 95% confidence intervals, were calculated. Associations between single-nucleotide polymorphisms with childhood asthma and T1DM were selected based on genome-wide association studies. The outcome datasets were obtained from FinnGen study. We used the inverse variance-weighted, weighted median and MR-Egger methods to estimate causal effects. To assess robustness and horizontal pleiotropy, MR-Egger regression and MR pleiotropy residual sum and outlier test was conducted. Results: In meta-analysis, childhood asthma was associated with an increased risk of T1DM (HR=1.30, 95% CI 1.05-1.61, P=0.014), whereas T1DM was not associated with the risk of asthma (HR=0.98, 95% CI 0.64-1.51, P=0.941; OR=0.84, 95% CI 0.65-1.08, P=0.168). MR analysis indicated increased genetic risk of T1DM in children with asthma (OR=1.308; 95% CI 1.030-1.661; P =0.028). Analysis using the IVW method indicated not associated between T1DM and genetic risk of asthma (OR=1.027, 95%CI 0.970-1.089, P=0.358). Conclusion: Both meta-analysis and MR study suggested that childhood asthma was a risk factor for T1DM. No epidemiological or genetic evidence for an association of T1DM with asthma incidence. Further studies could be carried out to leverage this newfound insight into better clinical and experimental research in asthma and T1DM. Further studies could be carried out to leverage this newfound insight into better clinical and experimental research in asthma and T1DM.

We describe a case of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) to multiple CFTR modulators and piperacillin in an 8 year old female with CF. To our knowledge this is the first reported case of delayed type, T-cell mediated hypersensitivity to multiple CFTR modulators described in literature. Our findings suggest possible cross-reactivity between CFTR modulators or multiple sensitisations, which should be taken into account in similar cases.

OMALIZUMAB MAY FACILITATE DRUG DESENSITIZATION IN PATIENTS FAILING STANDARD PROTOCOLSTo the Editor,Nephrotic syndrome (NS) is a common glomerular disorder in children, for which steroids are the first-line treatment. While most children with NS respond to steroid therapy, 20% of children are resistant to steroids. Some children with steroid-responsive NS develop a frequently relapsing or steroid-dependent course and experience significant side effects of steroid therapy. Alternative medications such as calcineurin inhibitors, mycophenolate mofetil, cyclophosphamide, and rituximab, an anti-CD20 monoclonal antibody, are being considered for such patients with difficult-to-treat NS (1,2).Hypersensitivity reactions to monoclonal antibodies are quite limited in clinical practice, such as the release of cytokines that occur during intravenous infusion. However, IgE-mediated reactions may also occur. Life-threatening IgE-mediated reactions such as anaphylaxis lead to discontinuation of treatment or conversion to a less beneficial treatment. Rapid drug desensitization (RDD) is a therapeutic option that allows continuation of treatment with the causative drug (3). Omalizumab is a recombinant humanized anti-IgE monoclonal antibody. Treatment indications include severe asthma and idiopathic chronic urticaria. However, the efficacy of omalizumab has also been described in food allergy, as a bridge to oral immunotherapies, atopic dermatitis, idiopathic anaphylaxis, and mastocytosis (4). Previous studies have reported the use of omalizumab for rapid desensitization to chemotherapeutic agents (5). Here, we describe a patient with steroid-resistant NS who developed anaphylaxis on the first infusion of rituximab and subsequent type 1 hypersensitivity reactions during desensitization trials with rituximab using 12-, 16-, and 20-step protocols.A 4-year-old boy diagnosed with steroid-resistant NS and unresponsive to calcineurin inhibitors, either cyclosporine A or tacrolimus, and in their combination with mycophenolate mofetil, received rituximab. After premedication with methylprednisolone at a dose of 2 mg/kg, rituximab 375 mg/m2 was administered intravenously. During the infusion, he developed anaphylaxis (vomiting and dyspnea). The infusion was stopped and intramuscular epinephrine was administered, and a 12-step rapid desensitization protocol was planned for further infusions (Table 1). He was premedicated with H1 blockers and systemic steroids. However, the patient developed breakthrough reactions (urticaria) that required additional antihistamines at the 4th step. Infusion was resumed at a slower rate. Ten minutes after re-administration, generalized urticaria and angioedema developed. Montelukast was administered according to ENDA/EAACI recommendations for rapid desensitization in drug allergy (6). After 7 days, the protocol was modified to administer 375 mg/m2 rituximab in 16 steps with premedication (Table 2). The patient developed generalized urticaria and angioedema again at the 4th step. The next week, the desensitization protocol was designed with 375 mg/m2 rituximab in 20 steps (Table 3). Again, generalized urticaria and angioedema occurred in the 2nd step. A skin prick test was performed 3 weeks after the initial reaction. During the skin prick test, the patient developed generalized urticaria.In the absence of alternative treatment options for NS, desensitization with omalizumab treatment was suggested to prevent hypersensitivity reactions to rituksimab. Omalizumab (patient weight: 17.5 kg; total IgE:71 UI /ml; dose: 150 mg/ every 2 weeks) was added to treatment. The last omalizumab dose was administered 1 day before the following desensitization. After premedication, 375 mg/m2rituximab was administered in 20 steps. In the 5th step, the patient developed local urticaria requiring an antihistamine. The infusion was resumed and successfully completed. Under omalizumab treatment, the patient was administered 375 mg/m2 rituximab for the second time in a 20-step protocol. After the 6th dose, the interval of omalizumab treatment was changed to every 4 weeks. The rituximab dose was then increased to 750 mg/m2 at the third infusion. After premedication, the 20-step desensitization protocols were successfully applied in the following days.Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen on the surface of B cells and causes elimination of B lymphocytes by complement- and antibody-dependent cellular cytotoxicity for 6-12 months (2). Efficacy has also been demonstrated in the treatment of steroid-resistant NS (7). Rituximab is one of the most common biologic agents with infusion-related reactions. Rituximab-associated hypersensitivity reactions can be classified as infusion-related reactions, cytokine release, IgE-mediated/non-IgE-mediated hypersensitivity reactions, mixed reactions, type 3 and type 4 hypersensitivity reactions (8).Omalizumab is a recombinant humanized IgG1 monoclonal antibody and prevents degranulation in effector cells by specifically binding to the FceRI receptor site of free IgE, causing a decrease in the level of free IgE in serum, and causing downregulation of FceRI receptors (9). Omalizumab has previously been used as a co-adjuvant in RDD along with insulin, the enzyme elosulfase alpha, chemotherapeutic agents, and aspirin (9). In a randomized, double-blind, placebo-controlled trial by Lang et al, desensitization was achieved after 16 weeks treatment with omalizumab. In other case reports, omalizumab treatment was generally started 7-14 days before RDD; only in one case report was the first omalizumab dose given 4 days before RDD (9). In previous studies, omalizumab dosing in allergic asthma was based on patient weight and total IgE. In our case, we administered 6 doses of omalizumab (150 mg/dose) every two weeks before desensitization and continued treatment once a month until completion of rituximab therapy. In patients with successful RDD on omalizumab, RDD steps can be reduced on subsequent infusions. Arroaberran et al. (10) presented a patient who tolerated elosulfase alpha enzyme without desensitization after omalizumab treatment.In conclusion, omalizumab may facilitate desensitization protocols and allow continuation of the preferred treatment.1Hatice Betul Gemici Karaaslan,

To the EditorReply to Stefano Miceli SopoFirst of all we want to thank for giving us an opportunity to reply to this correspondence (1), acknowledging the correspondence authors important point about the recommendation of introducing well-cooked, but not raw or uncooked pasteurized hen’s egg as part of complementary feeding.We agree that the evidence-base is sparse, with just two trials about cooked egg contributing to the low to moderate certainty evidence in our review (2) and guideline (3). These studies were in different populations (4, 5). We highlighted these points in the guideline, and the subgroup analysis from the Perkin study (6) was used only as supporting material, and for estimating the amount of egg that could be used. It is correct that the Natsume study included infant at higher risk due to eczema, but that was the case for both groups, and outcome was assessed by controlled challenges as described in the systematic review (2).As set out in the guideline, the process took into account expert insight weighing up benefits and harms, costs, feasibility, standard practice and patient preferences, in addition to published evidence. Weighing up all of these factors, the task force decided that the potential benefits outweighed potential harms in the case of well-cooked egg. One relatively large study found a 29% absolute decrease in the proportion of high risk infants with egg allergy at 1 year when very small amounts of egg were introduced (RR 0.22, 95% CI 0.08 to 0.54) (4). And two trials found no adverse effects (4, 5). It is likely feasible for many families to introduce well-cooked egg as part of complementary feeding, including in baked goods. The potential benefits do not outweigh the harms for uncooked egg, so the task force did not suggest trying this approach.The task force included representatives from many countries and specialties, and followed a robust process when reviewing evidence and debating potential recommendations. As the correspondence authors note, this recommendation is in line with other key guidelines. Whilst the correspondence authors may not agree with specific recommendations, the process used to debate and vote on them was systematic and took into account perspectives from across the world, including those from organisations representing patients and their families. Furthermore, a public consultation process sought feedback prior to publication, which further reinforced consensus about this recommendation.As is the case with all guidelines, the EAACI food allergy prevention guideline provides suggestions for clinicians to consider, alongside the needs of individual patients and local contexts and customs. The guideline is not prescriptive and does not override clinical judgement ad individual circumstances. Given the lack of likely harm, the convenience of this approach and best available evidence to date, the task force stands by its suggestion that clinicians in countries where egg allergy is an issue discuss with families the potential and desire to introduce small amounts of well-cooked egg into the infant diet when appropriate as part of complementary feeding. This need not be from the beginning of complementary therapy and the amounts may be very small.The guideline suggests half of a well-cooked, small egg twice a week, which may be in the form of a hard-boiled egg, well-cooked egg pasta, bread or baked goods, for example (p. 850). There is no evidence of significant harm, and it is likely that infants in many parts of the world may be exposed to egg in their diet anyway. There is no need to avoid this to prevent egg allergy, and in the opinion of the EAACI task force, introducing it may have benefits.Susanne Halken, Professor a, ProfessorAntonella Maria Muraro b, ProfessorGraham Roberts c, ProfessorDebra de Silva d, ProfessorOn behalf of On behalf of the EAACI Prevention Guideline Task Forcea Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, DenmarkbDepartment of Women and Child Health, Food Allergy Referral Centre Veneto Region, Padua University Hospital, Padua, Italyc Clinical and Experimental Sciences and Human Development in Health, Faculty of Medicine, University of Southampton, Southampton, UK. NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK. The David Hide Asthma and Allergy Research Centre, St Mary’s Hospital, Newport, UKdThe Evidence Centre Ltd, London, UKReferencesStefano Miceli Sopo, Dario Sinatti, Francesco Mastellone, Giulia Bersani, Mariannita Gelsomino. Comment on Halken et al. Pediatr Allergy Immunol . 2022de Silva D, Halken S, Singh C, et al. Preventing food allergy in infancy and childhood: systematic review of randomised controlled trials. Pediatr Allergy Immunol . 2020;31(7):813-826Halken S, Muraro A, de Silva D, et al. EAACI guideline: Preventing the development of food allergy in infants and young children (2020 update). Pediatr Allergy Immunol. 2021;32(5):843-858.Natsume O, Kabashima S, Nakazato J, et al. Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. Lancet. 92 2017;389(10066):276-286.Perkin MR, Logan K, Tseng A, et al. Randomized trial of introduction of allergenic foods in breast-fed infants. N Engl J Med. 2016;374(18):1733-1743.Perkin MR, Logan K, Bahnson HT, et al. Efficacy of the enquiring About Tolerance (EAT) study among infants at high risk of developing food allergy. J Allergy Clin Immunol. 2019;144(6):1606-1614.

Threshold and safe ingestion dose among infants sensitized to hen’s eggMasatoshi Mitomori,a Noriyuki Yanagida,aMakoto Nishino,a Kyohei Takahashi,aKen-ichi Nagakura,a Kiyotake Ogura,aMari Takei,b Sakura Sato,b Motohiro EbisawabaDepartment of Pediatrics, National Hospital Organization, Sagamihara National Hospital, Kanagawa, JapanbClinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, Kanagawa, JapanRunning title: Threshold and safe ingestion dose of egg

Background: Genetic areas of FOXP3 TSDR, HLA-G upstream of CpG island 96, CpG41 and CpG73 islands of the HLA‐DRB1 and HLA-DQB1 genes respectively, previously documented to display immune modulatory properties, were subjected to epigenetic/genetic analysis to assess their influence in IgE-mediated food allergy (FA) development in children. Methods: 64 orally challenged and IgE- tested food allergic subjects together with 44 controls were recruited. Targeted pyrosequencing analysis, to detect DNA methylation status and genetic variations was utilized and experimental results obtained were analysed by statistical software platform and correlated to clinical data. Also, transcription factor (TF) binding sites at study areas were unmasked by the JASPAR prediction database. Results: Parents’ smoking was significantly correlated with aberrant methylation patterns, regardless food allergic or control status. HLA-G promoter region showed a trend for hypomethylation in food allergic subjects, with one of the CG sites displaying significantly decreased methylation values. Rs1233333, residing within HLA-G promoter region preserved a protective role towards DNA methylation. Variable methylation patterns were recorded for CpG41 of the HLA‐DRB1 gene and hypermethylation of the region was significantly correlated with the presence of (Single Nucleotide Polymorphisms) SNPs. TFs’ recognition sites, located at studied genetic areas and exerting pivotal regulatory biological roles, are potentially affected from divergent DNA methylation status. Conclusions: We propose that HLA-G expression is triggered by food derived allergens, providing a TregFoxP3-/HLA-G+ subpopulation generation and direct immune-tolerance. Furthermore, clear evidence is provided for the underlying co-operation of genetic polymorphisms with epigenetic events, mainly at CpG41 island of HLA-DRB1 gene, which need an extended investigation and elucidation.

Allergy related outcomes at 12 months in the CORAL Birth cohort of Irish children born during the first COVID 19 lockdown.Word count: 1248, References: 10

Background Cold urticaria (coldU) is associated with substantial morbidity and risk of fatality. Data on coldU in children are sparse. We aimed to evaluate the clinical characteristics, management, risk of associated anaphylaxis, and resolution rate of coldU in a pediatric cohort. Additionally, we sought to compare these metrics to children with chronic spontaneous urticaria (CSU). Methods We prospectively enrolled children with coldU from 2013-2021 in a cohort study at the Montreal Children’s Hospital and an affiliated allergy clinic. Data for comparison with participants with solely CSU were extracted from a previous study. Data on demographics, comorbidities, severity of presentation, management, and laboratory values were collected at study entry. Patients were contacted yearly to assess for resolution. Results Fifty-two children with cold urticaria were recruited, 51.9% were female and the median age of symptom onset was 9.5 years. Most patients were managed with second generation H1-antihistamines (sgAHs). Well-controlled disease on sgAHs was negatively associated with concomitant CSU (adjusted odds ratio (aOR)=0.69 [95%CI: 0.53, 0.92]). Elevated eosinophils were associated with cold-induced anaphylaxis (coldA) (aOR=1.38 [95%CI: 1.04, 1.83]), which occurred in 17.3% of patients. The resolution rate of coldU was 4.8 per 100 patient-years, which was lower than that of CSU (adjusted hazard ratio=0.43 [95%CI: 0.21, 0.89], P<10-2). Conclusion Pediatric coldU bears a substantial risk of anaphylaxis and a low resolution rate. Absolute eosinophil count and co-existing CSU may be useful predictive factors.

Background: Previous studies reported controversial results regarding the association between allergic disorders and ADHD/ASD. The aim of this article is to investigate whether allergic disorders are associated with ADHD/ASD in a large cohort of pediatric patients. Methods: A retrospective study using the pediatric (0-18 year) database (ICD-9-CM codes) of Clalit Health Services during the years (2000-2018). Diagnosis of all disorders was made by specialist physicians. Results: 117,022 consecutive non-selective allergic children diagnosed with one or more allergic disorder (asthma, rhinitis. conjunctivitis, skin, food, or drug allergy) and 116,968 non-allergic children were enrolled to our study. The mean follow-up period was 11±6 years. The presence of allergic disorders in early childhood (mean age of allergic diagnosis 4.5± 4.3 years) in boys as well as in girls, significantly increased the risk to develop ADHD (O.R 2.45, CI 2.39-2.51; P<0.0001), ASD (O.R 1.17, CI 1.08-1.27; P<0.0001) or both ADHD+ASD (O.R 1.5, CI 1.35-1.79; P<0.0001). Children with more than one allergic comorbidity revealed a much higher risk. In a multivariable analysis (adjusted for age at study entry, number of yearly visits and gender) the risk of allergic children to develop ADHD and ADHD+ASD, but not ASD alone, remained significantly higher. Conclusion: Allergic disorder in early childhood significantly increased the risk to develop ADHD, and to a less extend ASD, in later life.

Background: Cross-reactivity between wheat and other cereals is an essential issue in the management of wheat allergy. Few studies have reported in vitro cross-reactivity in immediate-type wheat allergy. This study aimed to examine cross-reactivity of the three fractions (albumin/globulin, gliadin, and glutenin fractions) among cereals in children with wheat allergy. Methods: Sera from 128 children with immediate-type wheat allergy were collected. We measured specific immunoglobulin E (sIgE) levels against each fraction of wheat, barley, and rye by using an enzyme-linked immunosorbent assay (ELISA). Cross-reactivities of each fraction among wheat, barley, and rye were examined via inhibition ELISA. Results: All subjects were sensitized to all the fractions of wheat, and also those of barley and rye. The wheat sIgE levels were significantly higher than those of barley and rye in all the fractions (p ≤ 0.001) and were significantly correlated with sIgE levels to them in each fraction (r = 0.887–0.969, p < 0.001). On inhibition ELISA, wheat inhibited the IgE binding to most of the solid phases at the lower protein levels compared to barley and rye in all fractions. Conclusions: In children with immediate-type wheat allergy, sensitization to all the three fractions of wheat was observed. In addition, they showed sensitization to barley and rye caused by in vitro cross-reactivity with wheat in each fraction. When managing children with wheat allergy, sensitization to barley and rye caused by the cross-reactivities should be considered.

Drug-induced enterocolitis syndrome with paracetamol (acetaminophen) in a 12-month-old-old boy B.Pascalab, B.Evrardac, E.Merlinbc, C.Egronb, B.Bonnetac, E.Michaudba Service d’immunologie, hôpital Gabriel Montpied, Clermont-ferrand, Franceb Service de pédiatrie générale, hôpital Estaing, Clermont-ferrand, Francec Université Clermont Auvergne, Clermont ferrand, FranceTo the Editor,Drug-induced enterocolitis syndrome (DIES) is a new clinical presentation similar to food protein-induced enterocolitis syndrome (FPIES). It was described for the first time in 2014 by Novembre et al.(1). More and more cases have been described since and clinical diagnostic criteria have recently been proposed. (2)A 12-month-old boy was referred to our Pediatric Allergy Unit for a suspected drug hypersensitivity. At age 10 months, he was admitted to the pediatric emergency room for vomiting and fever, previously treated with two intake of intrarectal paracetamol (15 mg/kg every 6 hours), the last one 4 hours before admission. He had no previous history (and no allergic history). During the initial examination, we observed asthenia, paleness, no fever (after antipyretics) and tachycardia, followed by four episodes of mucus vomiting without diarrhea. An occlusive syndrome was suspected. Given the hemodynamic disorders, continued fluid resuscitation was performed. Blood tests showed an isolated hyperleukocytosis with neutrophils (11.08 G/L). Eosinophils (0.210 G/L), lymphoid cells (7.25 G/L), the ionogramm and CRP (4.9 mg/L) were normal. Blood gas revealed a compensated respiratory alkalosis (lactates 2.2 mmol/L, methemoglobinemia 1.3%). No tryptase or specific IgE test was performed. Abdominal ultrasound was normal. Microbiological workup was negative. The next day, he was still irritable with several night vomiting episodes. He was discharged with some clinical improvement (diagnosed viral disease).By questioning the parents, they noticed that their child presented digestive disorders’ events at home since birth, which coincided with the 5 times intake of Paracetamol, twice orally and then intrarectally. The symptoms appeared systematically from the first intake. In the child’s medical history, we found no rhythmicity related to meals or other etiologies. His father has a well-known pollen and Penicillin allergies. By reviewing the emergency room observations (Figure 1), we noticed systematic digestive disorders approximately 3h to 6h after each paracetamol intake, explaining the moderate initial clinical improvement.Four months later, skin prick tests (10 mg/mL) and intradermal tests (0.1 mg/mL) were negative. The drug oral challenge (Table 1) was positive: repeated vomiting, marked pallor, lethargy, and crying without cutaneous or respiratory symptoms 2 hours after the last paracetamol intake. Rehydration and corticosteroid therapy brought a complete clinical recovery. No mast cell degranulation was observed (normal tryptase levels: 6.6 µg/L to 6.2 µg/L 1 hour after reaction). There was no infectious context or other confounding factors on the day of the challenge test.We inferred a drug-induced enterocolitis syndrome (DIES) caused by paracetamol, in the absence of other plausible causes. This child’s reaction met the various major and minor criteria described (3), independently of the dosage form, formally implicating paracetamol (Table 2). Therefore, the assay of specific immunoglobulins and the performance of a basophils activation test were not performed.Based on all these observations, we decided to propose an alternative treatment with ibuprofen, if the child had fever and eliminate cross allergy, confirmed by a negative challenge test. We will follow the child and perhaps propose another Paracetamol challenge test, in a few years, to assess possible cure of the syndrome. Since the provocation test, parents kept paracetamol excluded, the child no longer presented any digestive disorder. Prognosis of the DIES is actually unknown. Oral challenge seems to be indeed the only useful test to confirm or exclude DIES (3). In contrast, skin tests don’t provide conclusive evidence to diagnose DIES, as for FPIES.This is the first clinical presentation of DIES with paracetamol. Similar cases following antibiotic intakes (including amoxicillin) and only one for pantoprazole have been described, with similar clinical and biological manifestations (2). DIES is a clinical entity more frequent in a pediatric population, described with a minimum age of 2 years old, but adult cases are more and more reported in the literature. The patient is therefore younger than the cases described in the literature.Currently, it is considered in the literature that DIES is a syndrome equivalent to FPIES but with allergens of a different nature, respectively drug versus food. FPIES is a non-IgE mediated gastrointestinal food allergy (prevalence 1%), symptoms depend on the frequency of food exposure. FPIES affects infants and young children, diagnosis is clinical, and there are no specific biomarkers. In the literature, there were two kinds of FPIES being described: chronic FPIES occurs when food consumption is regular, symptoms (chronic diarrhea, vomiting, weight loss..) resolve with a period of avoidance, and acute FPIES occurs with occasional consumption of food and can have severe symptoms which may lead to shockSimilarly, DIES present specific criteria of non-IgE-mediated hypersensitivity, based only on the presence of typical symptoms (Table 2). However, to date, acute or chronic forms have not yet been described.Although its clinical manifestations can be severe and lead to hypovolemic shock, DIES pathophysiology is still not well understood. There is also no validated biomarker. According to Powell and al (4), neutrophilia has been recognized as a common finding in patients presenting with acute FPIES for a long time. The increase of the eosinophil cationic protein (ECP) in stool samples from 24 and 48 h after the reaction was also described. (5) Many cases of FPIES will be probably described in the coming years, maybe with new different drugs. This diagnosis should be considered in the event of a recurrent digestive disorder, at any age.To date, several unanswered questions need to be addressed. Clinicians must be known for example if DIES is a transient or persistent trouble. Further studies may allow to find the origin, evolution and treatment of DIES.In conclusion, we reported the first DIES induced by PARACETAMOL, with tolerance to IBUPROFEN, confirmed by oral challenge test. Until now, it is the youngest patient case report and the first for PARACETAMOL.Keywords: children; drug hypersensitivity reactions; drug-induced enterocolitis syndrome; drug allergy; antipyreticReferences1. Drug-Induced Enterocolitis Syndrome (DIES) Elio Novembre, Francesca Mori, Simona Barni, Neri Pucci,2. Mori F, Liccioli G, Fuchs O et al. Drug-induced enterocolitis syndrome: Similarities and differences compared with food protein-induced enterocolitis syndrome. Pediatr Allergy Immunol. 2021 Mar 2.3. Van Thuijl AOJ, Landzaat LJ, Liem O, et al. Drug-induced enterocolitis syndrome (DIES): A clinical entity that deserves more awareness. Ann Allergy Asthma Immunol. 2019 May;122(5):538-539.4. G K Powell. Enterocolitis in low-birth-weight infants associated with milk and soy protein intolerance J Pediatr. 1976 May;88(5):840-4.5. Freundt Serpa NP, Sánchez-Morillas L, Jaqueti Moreno P, González-Gutiérrez ML, Cimarra M, Cerecedo I, Fernández-Rivas M. Drug-Induced Enterocolitis Syndrome Due to Amoxicillin-Clavulanic Acid With Good Tolerance to Penicillin. J Investig Allergol Clin Immunol. 2020;30(4):301-302. doi: 10.18176/jiaci.0500. Epub 2020 Feb 25. PMID: 32101171.

Increased prevalence of Autoimmune Diseases in Children with Chronic Spontaneous UrticariaMichelle Le, MD1, Lydia Zhang MD2, Sofianne Gabrielli MSc2, Connor Prosty BSc, MD(c)1, Laura May Miles LLM, MD(c)2, Elena Netchiporouk, MD, MSc1, Sharon Baum, MD3, Shoshana Greenberger, MD3, Luis F. Ensina, MD, MSc, PhD4, Fatemeh Jafarian, MD1, Xun Zhang, PhD5, Moshe Ben-Shoshan, MD, MSc21Division of Dermatology, McGill University, Montreal, QC, Canada2Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, McGill University Health Centre, Montreal, QC, Canada3Department of Dermatology, Chaim Sheba Medical Center, Tel-Aviv University, Sackler School of Medicine, Tel Hashomer, Israel4Department of Pediatrics, Federal University of São Paolo, Brazil5Centre for Outcome Research and Evaluation, Research Institute of McGill University Health Centre, Montreal, QC, CanadaCorrespondence: Michelle Le, M.D., 1001 Decarie Blvd, Montréal, Québec, H4A 3J1 email: [email protected] type: LetterManuscript word count: 981References : 10Tables : 1Figures: NoneFunding sources : NoneConflicts of interest: None declaredIRB Approval Status : Reviewed and approved by McGill University Health Centre; approval 12-255GEN