Background: Tree nut allergy is usually life-long and potentially life-threatening. Standard of care consists of strict avoidance of the culprit nut and symptomatic treatment of accidental reactions. Objective: To evaluate the potential therapeutic options for desensitization of patients with IgE-mediated tree nut allergy, focusing on, but not limited to, immunotherapy. Methods: We systematically searched three bibliographic databases for studies published until July 2022 for active treatments of IgE-mediated allergy to tree nuts (walnut, hazelnut, pistachio, cashew, and almond) with allergen-specific immunotherapy (AIT) using oral (OIT), sublingual (SLIT), epicutaneous (EPIT) or subcutaneous (SCIT) delivery, or with other disease-modifying treatments. Results: We included 17 studies (three randomized, double-blinded, placebo-controlled, five quasi-experimental prospective cohorts, five prospective cohorts, two retrospective cohorts, and two case reports. Three studies investigated sublingual immunotherapy, five investigated oral immunotherapy to a single tree nut, and six used multi-food oral immunotherapy with (four) or without (two) omalizumab. The remaining studies investigated the effectiveness of monoclonal antibodies in multi-food allergic patients, including patients with a tree nut allergy. The heterogeneity of the studies prevented pooling and meta-analysis. Conclusion: Even though strict avoidance remains the standard of care for patients with tree nut allergy, alternative approaches have been tested in clinical trials and real-life studies. These new concepts require further investigation with more well-designed studies including well-characterized nut allergic patients before implementing them in daily clinical practice.

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.

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: There has been increasing interest in elucidating the relationship between adenoid hypertrophy (AH) and allergic rhinitis (AR). However, the impact of aeroallergen sensitization patterns on children concurrently experiencing AH and AR remains unclear. Methods: Patients aged 2-8 years (January 2019 to December 2022) with nasal symptoms were assessed for allergies, adenoid size and respiratory viral infection history. The levels of serum total immunoglobulin E (IgE) and specific IgE and flexible nasal endoscopy were performed. We analyzed the relationship between AH and sensitization patterns and lymphocyte subpopulations in adenoid samples using flow cytometry. Results: 5281 children were enrolled in our cohort. 56.5% of children was diagnosed with AR and 48.6% with AH. AR was more prevalent in AH children compared to nAR. Compared to non-sensitized, those with AR polysensitized to molds had a higher prevalence of AH (adjusted OR 1.61, 95%CI 1.32-1.96) and a greater occurrence of two or more respiratory viral infections, particularly in cases with adenoidectomy. In AH-AR children, adenoid tissues showed reduced frequencies and corrected absolute counts of regulatory T cells (Tregs), activated Tregs, class-switched memory B cells (CSMB), natural killer (NK) T cells and NK subpopulations compared to AH-nAR children. Polysensitization in AH-AR children correlated with lower CSMB frequencies. Conclusion: Polysensitivity to molds significantly increased the risk of AH in children with AR. Adenoids of AR children demonstrated less number of B cells, NK cells and Treg cells with an effector/memory phenotype, which was closely linked to sensitization models and respiratory viral infection, particularly concerning CSMB.

Background: Viral wheeze is an important risk factor for asthma, which comprises several respiratory phenotypes. We sought to understand if the etiology of early life wheezing illnesses relates to childhood respiratory and asthma phenotypes. Methods: Data were collected prospectively on 429 children in the Urban Environment and Childhood Asthma (URECA) birth cohort study through age 10 years. We identified wheezing illnesses and the corresponding viral etiology (PCR testing of nasal mucus) during the first three years of life. Six phenotypes of respiratory health were identified at 10 years of age based on trajectories of wheezing, allergic sensitization, and lung function. We compared etiology of early wheezing illnesses on these respiratory phenotypes and the development of asthma. Results: In the first three years of life, at least one virus was detected in 324 (67%) of the 483 wheezing episodes documented in the study cohort. Using hierarchical partitioning we found that non-viral wheezing episodes accounted for the greatest variance on asthma diagnosed at both 7 and 10 years of age (8.0% and 5.8% respectively). Rhinovirus wheezing illnesses explained the most variance on respiratory phenotype outcome followed by non-viral wheezing episodes (4.9% and 3.9% respectively) at 10 years of age. Conclusion and Relevance: Within this high-risk urban-residing cohort early life, non-viral wheezing episodes were frequently identified and associated with asthma development. Though rhinovirus wheezing illnesses had the greatest association with phenotype outcome, the specific etiology of wheezing episode in early life provided limited information about subsequent wheezing phenotypes.

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.

A document by Hugo Gagnon. Click on the document to view its contents.

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.

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.

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.

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.

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

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