Pediatric Allergy and Immunology in North America - An introductionBianca Olivieri1,2, Ayobami Akenroye3, Carmen Riggioni4,5, Philippe Eigenmann6

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Reply to Wang et al.To the Editor,We sincerely appreciate the thoughtful response from Wang et al.1, regarding our recent study2. We are grateful for the effort the authors put into expressing potential limitations of our work, as such comments enrich the dialogue in the emerging intersection of pediatric healthcare and health geography. In this interdisciplinary field, constructive discourse is essential to refining methodologies and fostering collaborations that drive innovative solutions. We welcome the opportunity to address their concerns and engage further in this important conversation.Firstly, we acknowledge that a more diverse study sample would have been beneficial. The overall patient population in our health system are diverse across race, ethnicity, language, illness, environmental exposures, and geography. However, the nature of this single center study, as Wang et al. correctly point out, is that our patient study population are less diverse, particularly, in overall geographic composite index measures such as the Social Vulnerability Index (SVI) and Child Opportunity Index (COI). Notably, our study sample represents a group with particularly high scores on SVI and lower scores on COI. That said, a multicenter study involving patients from other health systems would indeed help us further understand the association between SVI or COI and the risk for pediatric intensive care unit (PICU) admission for status asthmaticus. Scaling out to a multicenter study using patient addresses and spatially granular data can be challenging due to the need to protect patient privacy3. Establishing the partnerships, information sharing infrastructure, and processes necessary to conduct a more comprehensive multicenter study is an ongoing area of focus for our team. We are committed to advancing this critical work.Secondly, we acknowledge that a large percentage of patients at the time of our study have reported race and ethnicity values of “other” or “unknown.” Unfortunately, this can be common across health systems with diverse patient populations. Despite the Meaningful Use mandate by the Centers for Medicare and Medicaid Services requiring the collection of race and ethnicity values in electronic health records (EHR), many health systems lack comprehensive race and ethnicity data for their patient populations4. While sub-optimal, there are multiple reasons for responses of “other” and “unknown.” For one, EHRs were traditionally designed with limited race and ethnicity options for patients to choose from, leading to an oversimplification of race and ethnicity categories. Limited options and discrete choices may not always reflect the identity of patients4. Not to mention, directly asking patients how they identify is difficult because the conversation can be uncomfortable for all those involved4. Also, the value of race and ethnicity data for research may not always be fully understood by healthcare professionals and patients leading to subpar data collection4. Still, it is worth noting that since our study was completed, our health system has conducted a large systemic effort to improve the collection of race and ethnicity data. For instance, patients are given more options to self-identify their race and ethnicity with better processes in place during clinic appointments to facilitate data collection. Efforts to minimize missing race and ethnicity data for health disparities research and other health system applications continues to be an important work for all healthcare systems.Thirdly, we concur that other factors, including the residential environment, air pollution, and indoor allergens are important considerations in pediatric healthcare and respiratory diseases. The exposome encompasses a wide array of factors that are associated with asthma5. As we work toward improving our understanding of addressing pediatric health, future work will integrate the physical, social, and environment as key drivers of health. A more holistic approach to understanding this extended environment as it relates to patient health can unlock a better understanding of health and open opportunities to create meaningful and effective interventions. Linking individual environmental factor data remains a key focus for this team.We are thankful for the insightful comments provided by Wang et al. Response to research work provides us all with the opportunity to engage in thoughtful discourse amongst our colleagues to drive research and healthcare forward. Our study of PICU admissions for status asthmaticus is ongoing and a part of a growing work in progress. We share the same ideals Wang et al. express, but more importantly, we share the same desire to advance the health of children everywhere through research.Alicia Adiwidjaja, BS1,2Justin Jones, MD1Patrick Ross, MD1,3Matthew Keefer, MD1,3Margaret J Klein, MS1Jonathan M. Tan, MD MPH MBI1,2,31Children’s Hospital Los Angeles, Los Angeles, California, USA2University of Southern California Spatial Sciences Institute, Los Angeles, California, USA3University of Southern California Keck School of Medicine, Los Angeles, California, USAConflicts of InterestJonathan Tan receives research grant funding from the Anesthesia Patient Safety Foundation, Foundation for Anesthesia Education and Research, and the Southern California Environmental Health Sciences Center. Jonathan Tan is a consultant for GE HealthCare, Edwards Lifesciences, and Medtronic. Jonathan Tan is on the Board of Directors for the Society for Pediatric Anesthesia.ReferencesWang C, Tian H, Shang J. Comment on Justin Jones et al.Pediatric Allergy and Immunology. 2024.Jones J, Klein MJ, Adiwidjaja A, Ross P, Keefer M, Tan JM. The association between composite measures of social vulnerability and PICU admission for status asthmaticus. Pediatric Allergy and Immunology. 2024;35(11). doi:https://doi.org/10.1111/pai.14278. PMID: 39526837. U.S. Department of Health and Human Services. Summary of the HIPAA Privacy Rule. 2003.Diallo MS, Tan JM, Heitmiller ES, Vetter TR. Achieving Greater Health Equity: An Opportunity for Anesthesiology. Anesth Analg. 2022 Jun 1;134(6):1175-1184. doi: 10.1213/ANE.0000000000005937. Epub 2022 Feb 2. PMID: 35110516.Guillien, A., Cadiou, S., Slama, R., & Siroux, V. (2021). The Exposome Approach to Decipher the Role of Multiple Environmental and Lifestyle Determinants in Asthma. International Journal of Environmental Research and Public Health, 18(3), 1138. https://doi.org/10.3390/ijerph18031138

Reply to Wei-Zhen Tang, MD; Wei-Ze Xu, MD; and Tai-Hang Liu, PhD.Vincent Ojwang’ 1,2, Bright I. Nwaru2,3,4, Hanna-Mari Takkinen 2,5,6, Suvi M. Virtanen 2, 5, 6, 7Department of Community Health and Behavioral Sciences, School of Medicine, Masinde Muliro University of Science and Technology, Kakamega, KenyaFaculty of Social Sciences, Health Sciences Unit, Tampere University, Tampere, FinlandKrefting Research Centre, Institute of Medicine, University of Gothenburg, Gothenburg, SwedenWallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, SwedenDepartment of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, FinlandTampere University Hospital, Wellbeing Services County of Pirkanmaa, Tampere, FinlandCenter for Child Health Research, Tampere University and Tampere University Hospital, Tampere, Finland

Introduction Diet diversity (DD) in infancy may be protective for early food allergy (FA) but there is limited knowledge about how DD incorporating consumption frequency influences FA risk. Methods Three measures of DD were investigated in 2060 infants at 6 and/or 9 months of age within the NorthPop Birth Cohort Study; a weighted DD score based on intake frequency, the number of introduced foods, and the number of introduced allergenic foods. In multivariable logistic regression models based on directed acyclic graphs, associations to parentally reported physician diagnosed FA at 9- and 18-months age were estimated, including sensitivity- and stratified analyses. Results High weighted DD scores (24-31p) at 9 months of age was associated with a 61% decreased FA risk at age 18 months [OR (95% CI) = 0.39 0.18-0.88] compared with infants with the lowest DD scores (0-17p). The association remained significant after exclusion of early FA cases. Having introduced 13-14 foods at age 9 months, independent of consumption frequency, was associated to a 45% decreased FA risk [OR (95% CI) = 0.55 (0.31-0.98)] compared to having introduced 0-10 foods. When stratifying, results remained only for children with no FA history in the family. No association was seen between reduced FA risk and DD measured at 6 months of age or having introduced more allergenic foods in infancy. Conclusion A diverse diet at 9 months of age may prevent FA at 18 months and results underscore the need for additional investigations on the impact of consumption frequency in infancy.

Editorial comment on “Current options in the management of tree nut allergy: A

Allergic diseases such as asthma, atopic dermatitis and food allergies are a burgeoning health challenge in the Asia-Pacific region. Compounding this, the region has become increasingly susceptible to the impacts of climate change. The region has weathered extreme precipitation, intense heat waves, and dust storms over the recent decades. While the effects of environmental and genetic factors on allergic diseases are well understood, prevailing gaps in understanding the complex interactions between climate change and these factors remain. We aim to provide insights into the various pathways by which climate change influences allergic diseases in the Asia-Pacific population. We outline practical steps that allergists can take to reduce the carbon footprint of their practice on both a systemic and patient-specific level. We recommend that allergists optimise disease control to reduce the resources required for each patient's care, which contributes to reducing greenhouse gas emissions. We encourage the responsible prescription of metered dose inhalers by promoting the switch to dry powder inhalers for certain patients, at each clinician's discretion. We also recommend the utilisation of virtual consultations to reduce patient travel while ensuring that evidence-based guidelines for rational allergy management are closely adhered to. Finally, eliminating unnecessary testing and medications will also reduce greenhouse gas emissions in many areas of medical care.

Background: Association of early pregnancy body mass index (BMI) and maternal gestational weight gain (GWG), and asthma and allergic disease in children is unclear. Methods: We analyzed data from 3,176 mother-child pairs in a prospective birth cohort study. Maternal anthropometric measurements in the first and last antenatal clinic visits were obtained through post-delivery questionnaires to calculate early pregnancy BMI and maternal GWG. Asthma and allergic diseases in children by the age of 5 years was assessed using a validated questionnaire. Furthermore, serum samples were analyzed for IgE antibodies to eight allergens. We applied Cox proportional hazards and logistic regression analyses to estimate the association of early pregnancy BMI and maternal GWG (as continuous variables and categorized into quarters), and asthma, atopic eczema, atopic sensitization, and allergic rhinitis in children. Results: Early pregnancy BMI and maternal GWG were not associated with asthma and allergic disease in children when analyzed as continuous variables. Compared to the first quarter (GWG <0.32 kg/week), mothers in the third quarter (GWG 0.42-0.52 kg/week) had children with higher odds of developing atopic eczema (adjusted OR 1.49, 95% CI [1.13-1.96]) by age 5 years. Conclusion: The association of early pregnancy BMI and maternal GWG and asthma and allergic disease in children is inconsistent. High maternal GWG may be associated with increased odds of atopic eczema.

Hereditary angioedema (HAE) is a rare, life-threatening genetic disorder characterized by acute, recurrent and unpredictable episodes of cutaneous or submucosal angioedema, mediated by bradykinin, due to C1 inhibitor (C1INH) abnormalities in the vast majority of cases. The epidemiology of the disease is poorly documented in children. Clinical manifestations usually appear during childhood or early adolescence. Classical signs, preceded by prodromal symptoms in 50 % of cases, include transient, localized, non-pitting, non-pruritic swelling of deep dermal/subcutaneous or mucosal/submucosal tissues, leading to oedema of the extremities, face, lips, tongue, trunk and genitals, recurring gastrointestinal symptoms and laryngeal edema possibly causing asphyxiation and death. Diagnosis is often delayed due to low awareness in the medical community, and particularly challenging in case of isolated abdominal crises or atypical presentation and in neonates or infants. It relies on biological tests (measurement of serum/plasma levels of C1INH function, C1INH protein, and C4), genetic testing in selected cases, and imaging for differential diagnosis of acute abdominal crises. Main differential diagnosis for peripheral oedema is mast cell-mediated oedema that accounts for 95 % of angioedema in clinical practice. Quality of life can be significantly impaired. Disease management includes treatment of attacks, short-term and long-term prophylaxis, psychological support, avoidance of triggers, patients’ and parents’ education and coordination of all stakeholders, ideally within a specialized healthcare network. New plasma kallikrein inhibitors, namely lanadelumab (subcutaneous route) and berotralstat (oral route) have facilitated long-term prophylaxis thanks to improved usability.

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Background Consumption of raw cow’s milk has repeatedly been shown to protect from asthma, allergies, and respiratory infections. As raw milk bears potential health hazards, it cannot be recommended for prevention. Therefore, we performed an intervention study with microbially safe but otherwise minimally processed cow’s milk. Here we describe feasibility and safety of the trial. Methods The MARTHA trial (DRKS00014781) was set up as a double-blind randomized intervention in a population residing in Bavaria. Infants from 6 to 36 months of age consumed minimally processed cow’s milk (intervention arm) or ultra-heat-treated (UHT) semi-skimmed milk (comparator arm). Results At the age of 6 to 12 months, 260 infants were enrolled, with 72% having a family history of atopy. The extensive screening system for milk consumption and symptoms suggestive of adverse events was well accepted with 22,988 completed weekly surveys and an average completion of 82% surveys sent out. The children consumed the study milk on average on 457 days (61% of intervention days). The intervention proved to be safe without any case of milk allergy or milk intolerance under the intervention in both arms. All 6 cases of serious adverse events were unrelated to milk. The most common reason was unscheduled hospitalization of more than 3 days. Conclusions The intervention with minimally processed milk and the study instruments proved feasible. During the age of 6 to 36 months, there was no increased risk of milk allergy in a population with a substantial proportion of family history of atopy.

The recognition of constipation as a possible non-Immunoglobulin E (IgE) mediated allergic condition is challenging because functional constipation (unrelated to food allergies) is a common health problem with a reported worldwide prevalence rate of up to 32.2% in children. However, many studies in children report challenge proven cow’s milk allergy and constipation as a primary symptom, have found that between 28-78% of children improve on a cow’s milk elimination diet. Due to the paucity of data and a focus on IgE mediated allergy, not all food allergy guidelines list constipation as a symptom of food allergy. Yet, it is included in all cow’s milk allergy guidelines available in English language. The Exploring Non- IgE Mediated Allergy(ENIGMA) Task Force (TF) of the European Academy for Allergy and Clinical Immunology (EAACI) considers in this paper constipation in the context of failure of standard treatment and discuss the role of food allergens as culprit in constipation in children. This position paper has used the Delphi approach in reaching consensus on both diagnosis and management, as currently published data is insufficient to support a systematic review.

Background: It is necessary to evaluate the parental ability to achieve nutritional adequacy while avoiding allergens for children with food allergies (FA), yet this area is currently understudies. Our study aimed to develop and validate the Parental Self-Efficacy Scale for Dietary Management of Children with Food Allergies (PSED-FA). Methods: PSED-FA was developed through a literature review and semi-structured interviews, refined by a panel of five allergists and five dietitians, and validated using responses from caregivers of children with FA. The construction of the tool involved exploratory factor analysis (EFA), confirmatory factor analysis for model fit, and evaluation of internal consistency using Cronbach’s alpha. Convergent and divergent validity were assessed using the average variance extracted (AVE), maximum shared variance (MSV), and average shared variance (ASV). Results: Participants included nine focus interview groups, with 114 individuals in the validation group. Egg whites (55.2 %), tree nuts (35.2%), and peanuts (22.8%) were the most common allergens. The EFA identified three factors: preparing allergen-free meals, knowledge of nutrition management, and management of food restrictions. The goodness of fit of our model met all the criteria. The tool showed high internal consistency (overall Cronbach’s alpha: 0.902) and met the criteria for both convergent (AVE >0.5) and divergent validity (AVE >MSV and ASV). Conclusion: This study validated a reliable and effective tool for assessing parental self-efficacy in managing the dietary needs of children with FA. This tool can aid health professionals in evaluating parental confidence and identifying areas for improving dietary management in children with FA.

Background: Basophil activation test (BAT) or the mast cell activation test (MAT) are two in vitro tests that are currently being studied in food allergy as diagnostic tools as an alternative to oral food challenges (OFCs). We conducted a meta-analysis on BAT and MAT assessing their specificity and sensitivity in diagnosing peanut allergy. Methods: Six databases were searched for studies on patients suspected of having peanut allergy. Studies using BAT or MAT to peanut extract and/or component as diagnostic tools with results given in percentage of CD63 activation were included in this meta-analysis. Study quality was evaluated with the QUADAS-2 tool. Results: On the eleven studies identified, eight focused exclusively on children, while three included a mixed population of adults and children. Only one study provided data on MAT, precluding us from conducting a statistical analysis. The diagnostic accuracy of BAT was higher when stimulated with peanut extract rather than Ara h2 with a pooled specificity of 96% (95% CI: 0.89-0.98) and sensitivity of 0.86 (95% CI: 0.74-0.93). The sensitivity and specificity of BATs in discriminating between allergic and sensitized patients was studied as well with pooled analysis revealing a sensitivity of 0.86 (95% CI: 0.74; 0.93) and a specificity of 0.97 (95% CI: 0.94, 0.98). Conclusion: BATs, when stimulated with peanut extracts, exhibit a satisfactory sensitivity and specificity for the diagnosis of peanut allergy and can help to discriminate between allergic individuals and those only sensitized to peanut. More investigations on the potential for MATs diagnostic methods are warranted.

Background: Immunomodulatory proteins in human milk (HM) can shape infant immune development. However, strategies to modulate their levels are currently unknown. This study investigated whether maternal prebiotic supplementation alters the levels of immunomodulatory proteins in HM. Methods: The study was nested within the SYMBA double-blind randomised controlled trial (ACTRN12615001075572), which is investigating the effects of maternal prebiotic (scGOS/lcFOS) supplementation from <21 weeks gestation during pregnancy until 6-months postnatal during lactation on child allergic disease risk. Mother-child dyads receiving prebiotics (n=46) or placebo (n=54) were included in this study. We measured the levels of 24 immunomodulatory proteins in HM collected at 2, 4 and 6 months. Results: Cluster analysis showed that the overall immunomodulatory protein composition of milk samples from both groups was similar. Prebiotic-supplemented women had decreased levels of TGF-β1 at 2 months, IgG1 at 4 months and sCD14 at 6 months (p=0.03, 0.03 and 0.04, respectively). IL-5 levels were increased in the prebiotic group compared to the control group at 4 and 6 months (p=0.02 and 0.04, respectively). After adjustment for multiple comparisons, the statistical differences between the prebiotic and placebo groups were no longer present (p>0.05). Conclusion: This study is the first to comprehensively trial scGOS/lcFOS intake during pregnancy and indicate potentially altered levels of immunomodulatory proteins in HM. Future research will elucidate the significance of change in milk content in immunomodulatory compounds in the prevention of allergy risk (and beyond), filling a major gap in dietary advice to pregnant and/or lactating women.

A large and growing corpus of epidemiologic studies suggests that the population-level burden of pediatric FA is not equitably distributed across major sociodemographic groups, including race, ethnicity, household income, parental educational attainment, sex). As is the case for more extensively studied allergic disease states such as asthma and atopic dermatitis) epidemiologic data suggest that FA may be more prevalent among certain populations experiencing lower socioeconomic status (SES), particularly those with specific racial and ethnic minority backgrounds living in highly urbanized regions. Emerging data also indicate that these patients may also experience more severe FA-related physical health, psychosocial and economic outcomes relating to chronic disease management. However, many studies that have identified sociodemographic inequities in FA burden are limited by cross-sectional designs that are subject to numerous biases, which can reduce the epidemiologic utility of the resulting estimates. Compared to cross-sectional study designs or cohorts that are recruited during childhood, birth cohorts can offer advantages relative to other study designs when investigators seek to understand causal relationships between exposures occurring during the prenatal or postnatal period and the atopic disease status of individuals later in life. Numerous birth cohorts have been established across recent decades, which include evaluation of food allergy-related outcomes, and a subset of these also have measured sociodemographic variables that, together, have the potential to shed light on the existence and possible etiology of sociodemographic inequities in food allergy. This manuscript attempts to survey the current state of this birth cohort literature and draw insights regarding what is currently known, and what further information can potentially be gleaned from thoughtful examination and further follow-up of ongoing birth cohorts across the globe.

Editorial comment on the Special Issue “Omics in Food Allergy”Riccardo Castagnoli1,2, Ivan Taietti1,2,*, Agnes Sze-Yin Leung3, Philippe Eigenmann41. Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, Pavia, Italy2. Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy3. Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, China4. Pediatric Allergy Unit, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Geneva, SwitzerlandORCID:Riccardo Castagnoli: 0000-0003-0029-9383Ivan Taietti: 0000-0002-0372-523XAgnes Sze-Yin Leung: 0000-0001-8249-4478Philippe Eigenmann: 0000-0003-1738-1826Corresponding author:Ivan Taietti, MD;Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy.ivan.taietti@gmail.com; +39 340 7092400.Food allergy (FA), defined as an adverse reaction to food mediated by the immune system, is a significant public health issue with increasing prevalence over the past decades. Although FA affects up to 10% of children, the precise mechanisms underlying FA development and persistence remain inadequately understood1. Food immunotherapy has been successful in increasing the threshold of tolerance in individuals with persistent FA (desensitization), and in a subset, sustained unresponsiveness (remission) can be achieved. A combination of environmental and genetic factors is considered to be involved in the tolerance induction to food allergens. However, to date, it has been difficult to fully dissect the complexity of the biological determinants involved in FA.The emergence of “omics” sciences, including genomics, transcriptomics, proteomics, and metabolomics, is revolutionizing the basic and translational research approach, allowing for the comprehensive study of biological processes through analyzing and integrating multiple datasets from various biological perspectives.Moreover, epigenetic studies that evaluate the role of gene expression modifiers are deepening our understanding of the interaction between genetic predisposition and environmental influences.The Special Issue “Omics in Food Allergy” aims to present current knowledge and future perspectives in the field of FA through the lenses of omics sciences.Chun et al. and Lehmann et al. provide a detailed overview of epigenetic mechanisms involved in FA, including DNA methylation and microRNA (miRNAs)2,3. DNA methylation refers to the covalent addition of a methyl group, typically to a cytosine in a CpG dinucleotide in DNA. This limits access for transcription, frequently in the promoter region, leading to reduced gene expression. Moreover, miRNAs are small RNAs transcribed from intergenic or intronic genomic loci that decrease gene expression by mRNA degradation and translational inhibition. Of note, Chun et al. described two different approaches in investigating FA mechanisms: (i) the epigenome-wide research approach and (ii) candidate-gene investigations. The epigenome-wide research approach identified genomic regions differently methylated and regulated, involved in FA causation, antigen presentation, T cell development, and reaction severity. Candidate-gene investigations focused on Th1, Th2, T regulatory, and innate genes of interest in FA, highlighting the importance of methylation changes in specific candidate genes. In this context, for cow’s milk allergy (CMA), the attention is focused on novel genetic loci involved in Th1/Th2 differentiation pathways and potential B-cell dysfunction4. Of note, miRNA seems to be involved in CMA as demonstrated by the downregulation of mi193a-5p, a post-transcriptional regulator of IL-4 expression, in infants with CMA5. Moreover, methylation levels in peripheral blood mononuclear cells for IL-4, IL-5, IL-10, and IFN-γ negatively correlate with their respective serum cytokine concentrations and vary according to CMA status (active, resolved, or non-CMA). Finally, Chun et al. reviewed ongoing research aimed at finding DNA methylation predictors of food challenges. Initial work based on the concept of epigenetic markers as biomarkers of disease and treatment demonstrated promise for applying DNA methylation markers to potentially improve how we assess and manage patients with FA, but further validation in larger cohorts and work to practically translate such biomarkers to clinical practice is advocated2.Metabolomics may reflect the integration of genetic, transcriptomic, and proteomic variations with environmental factors, thus reflecting molecular processes of diseases. A metabolome approach would facilitate the identification of surrogate metabolite markers correlating with the disease activity and prognosis. Lee et al. reported an updated overview of metabolomics’s current application in the FA field. Alterations to the gut microbiota induced by Western dietary patterns are likely to profoundly affect host immunity and play a significant role in FA. Metabolites of interest include short-chain fatty acids (SCFAs), bile acid metabolites, and tryptophan metabolites due to their essential roles in normal immune development and homeostasis. SCFAs appear to be reduced in FA patients. Of note, it has been shown that bacterial SCFAs could protect against FA as a consequence of a high-fiber diet in mice. Accordingly, a reduction in Bifidobacterium during infancy, with a consequent reduction in SCFA levels is associated with an increased risk of allergy6. In peanut allergy, oral dysbiosis, reduced oral SCFA levels, and increased oral mucosal Th2 cytokine secretion characterize patients affected, and low fecal SCFAs at a young age could raise the risk of developing FA. Bile acid levels in stool seem to be involved in FA development and persistence, but blood level measurements are advocated to better characterize their role. Moreover, sphingolipids may modulate the function of invariant natural killer T cells and contribute to maintaining intestinal balance and protecting against FA through the modulation of the mast cells’ responsiveness. Sphingolipid dysmetabolism is involved in FA development as a consequence of immune dysregulation in modulating the differentiation of regulatory T cells and Th17 cells that is relevant in FA. Interestingly, some fecal sphingolipids seem to confer protection against FA while reduction of other of them seems to be associated with increased risk of FA, likewise the reduction in serum sphingolipids. Unfortunately, no definitive evidence is available to distinguish whether the sphingolipids modulating this FA effect are dietary or microbial-derived. Metabolites of tryptophan from kynurenine and indole pathways are linked to the function of the intestinal barrier and mucosal immune responses (mainly T regulatory cells) and contribute to intestinal homeostasis. A reduction in these pathways is linked to multiple FA in children. To date, the role of omega-3-polyunsaturated fatty acids metabolites is not clearly defined in FA. However, 17-hydroxy-docosahexaenoic acid (17-HDHA) has been reported to inhibit IgE production by B cells and to suppress the differentiation of naïve B cells into IgE-secreting cells7.The gut microbiome (GM) and its metabolic product, as previously mentioned, play an important role in FA development. TheBifidobacteriaceae family and bacteria of theLactobacillales order are consistently reported lower in CMA children. At the same time, the Firmicutes phylum, primarily associated with the Clostridia class, is consistently increased in mice and human studies. It seems discordant with the observation that infants with resolved CMA were reported to have enrichedClostridia class at 3-6 months but with non-conclusive data. However, Savova et al. showed that GM with enriched Clostridiaclass, reduced Lactobacillales order, and reducedBifidobacterium genus is associated with CMA in early life. Emerging evidence shows that prebiotics, probiotics, and symbiotics, may be a promising adjuvant in promoting tolerance acquisition. ElevatedBifidobacterium genus and reduced Clostridia class members were consistently observed post-treatment with Bifidobacteriumstrains probiotics or after lactose-supplemented extensively hydrolyzed formula (EHF) treatment strategy but with decreased levels ofLactobacillus genus in those treated with Bifidobacteriumstrains probiotics. Gaps remain in understanding the relationship between microbiome and immune response and between transcriptomics (including genes related to the immune response) and GM. In vivo ,Bifidobacterium bifidum has been shown to reduce allergy symptoms, lower serum IgE and raise IgG2 levels, decrease the pro-inflammatory cytokines (TNFα, IL- 1β, and IL-6), and increase the anti-inflammatory cytokine IL-10 in CMA-patients8. Recently, fiber diet has been shown to modulate the disease course of FA through diet-driven changes in the GM9. It is necessary to conduct further research on the impact of GM on FA development and persistence.Lastly, oral immunotherapy (OIT) may provide an active treatment that enables to increase the amount of food that the patient can intake without reaction during treatment (i.e., desensitization), and reduces the risk of potential life-threatening allergic reaction in the event of accidental ingestion10 Unfortunately, there are still significant gaps in understanding the immune mechanisms following OIT, but increasing knowledge about transcriptional pathways associated with its outcomes is available to date11. Ashley et al.12 show that OIT-induced remission of FA is linked to the anergic T cell state mediated by anergy of memory T cells associated with mantained T regulatory cell activity. Suppression of the Th2 transcriptional signals in Th2A-like cells was linked to desensitization following OIT. Moreover, the dampened Th2 and Th1 signatures in effector cells are linked with FA remission, while baseline inflammatory signals in Th1 and Th17 effector cells were associated with poorer outcomes following OIT. Type I interferons were recently identified as potential regulators of remission following OIT because of their key role in the suppression of the Th2 antigen response through regulatory action on GATA3 and the high-affinity IgE receptor. Moreover, an early transient increase in TGF-β producing cells one year into treatment seems to be associated with good clinical outcomes. In addition, persistent activation of FOXP3, expressed by T regulatory cells, may be a critical requirement for lasting persistence of remission12.Comprehensive multi-omics studies are essential to understand FA mechanistically, as highlighted by this Special Issue. “Omics” studies of FA are of great interest as they allow for a thorough understanding of the complexity of FA development and therapeutic outcomes. This has a fundamental impact on approaches to precision medicine.

Letter to the Editor