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

Abstract: Background: The European Academy of Allergy and Clinical Immunology’s (EAACI) is updating the Guidelines on Food Allergy Diagnosis. We aimed to undertake a systematic review of the literature with meta-analyses to assess the accuracy of diagnostic tests for IgE-mediated food allergy. Methods: We searched three databases (Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID)) for diagnostic test accuracy studies published between 1 st October 2012 and 30 th June 2021 according to a previously published protocol (CRD42021259186). We independently screened abstracts, extracted data from full-texts, and assessed risk of bias with QUADRAS 2 tool in duplicate. Meta analyses were undertaken for food-test combination where 3 or more studies were available. Results: 149 studies comprising 24,489 patients met the inclusion criteria and were generally heterogeneous. 60.4% of studies were in children ≤12 years of age, 54.3% undertaken in Europe, ≥95% conducted in a specialized pediatric or allergy clinical setting and all included oral food challenge in at least a percentage of enrolled patients, in 21.5% DBPCFC. Skin prick test (SPT) with fresh cow’s milk and raw egg had high sensitivity (90% and 94%) for milk and cooked egg allergies. Specific IgE to individual components had high specificity: Ara h 2 had 92%, Cor a 14 95%, Ana o 3 94%, casein 93%, ovomucoid 92/91% for the diagnosis of peanut, hazelnut, cashew, cow’s milk and raw/cooked egg allergies, respectively. BAT was highly specific for the diagnosis of peanut (90%) and sesame (93%) allergies. Conclusions: SPT and specific IgE to extracts had high sensitivity whereas specific IgE to components and BAT had high specificity to support the diagnosis of individual food allergies. PROSPERO registration: CRD42021259186 Funding: European Academy of Allergy (EAACI).

Multisystem inflammatory syndrome in children (MIS-C) is a rare, but severe complication of coronavirus disease 2019 (COVID-19). It develops approximately four weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and involves hyperinflammation with multisystem injury, commonly progressing to shock. The exact pathomechanism of MIS-C is not known, but immunological dysregulation leading to cytokine storm plays a central role. In response to the emergence of MIS-C, the European Academy of Allergy and Clinical Immunology (EAACI) established a task force (TF) within the Immunology Section in May 2021. With the use of an online Delphi process, TF formulated clinical statements regarding immunological background of MIS-C, diagnosis, treatment, follow-up, and the role of COVID-19 vaccinations. MIS-C case definition is broad, and diagnosis is made based on clinical presentation. The immunological mechanism leading to MIS-C is unclear and depends on activating multiple pathways leading to hyperinflammation. Current management of MIS-C relies on supportive care in combination with immunosuppressive and/or immunomodulatory agents. The most frequently used agents are systemic steroids and intravenous immunoglobulin. Despite good overall short-term outcome, MIS-C patients should be followed-up at regular intervals after discharge, focusing on cardiac disease, organ damage, and inflammatory activity. COVID-19 vaccination is a safe and effective measure to prevent MIS-C. In anticipation of further research, we propose a convenient and clinically practical algorithm for managing MIS-C developed by the Immunology Section of the EAACI.

Background: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of updating the guidelines on the diagnosis and management of food allergy. The existing guidelines are based on a systematic review of the literature until 30th September 2012. Therefore, a new systematic review must be undertaken to inform the new guidelines. This systematic review aims to assess the accuracy of index tests to support the diagnosis of IgE-mediated food allergy. Methods: The databases Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID) will be searched for diagnostic test accuracy studies from 1st October 2012 to 30th June 2021. Inclusion and exclusion criteria will be used to select appropriate studies. Data from these studies will be extracted and tabulated, and then reviewed for risk of bias and applicability using the QUADAS-2 tool. All evaluation will be done in duplicate. Studies with a high risk of bias and low applicability will be excluded. Meta-analysis will be performed if there are three or more studies of the same index test and food. Results: A protocol for the systematic review and meta-analyses is presented and was registered using Prospero prior to commencing the literature search. Discussion: Oral food challenges are the reference standard for diagnosis but involve considerable risks and resources. This protocol for systematic review aims to assess the accuracy of various tests to diagnose food allergy, which can be useful in both clinical and research settings.

Vaccines are essential public health tools with a favorable safety profile and prophylactic effectiveness that have historically played significant roles in reducing infectious disease burden in populations, when the majority of individuals are vaccinated. The COVID-19 vaccines are expected to have similar positive impacts on health across the globe. While serious allergic reactions to vaccines are rare, their underlying mechanisms and implications for clinical management should be considered to provide individuals with the safest care possible. In this review, we provide an overview of different types of allergic adverse reactions that can potentially occur after vaccination and individual vaccine components capable of causing the allergic adverse reactions. We present the incidence of allergic adverse reactions during clinical studies and through post-authorization and post-marketing surveillance and provide plausible causes of these reactions based on potential allergenic components present in several common vaccines. Additionally, we review implications for individual diagnosis and management and vaccine manufacturing overall. Finally, we suggest areas for future research.

Background This systematic review used the GRADE approach to compile evidence to inform an anaphylaxis guideline from the European Academy of Allergy and Clinical Immunology (EAACI). Methods We searched five bibliographic databases from 1946 to 20 April 2020 for studies about the diagnosis, management and prevention of anaphylaxis. We included 50 studies with 18,449 participants: 29 randomised controlled trials, seven controlled clinical trials, seven consecutive case series and seven case-control studies. Findings were summarised narratively because studies were too heterogeneous to conduct meta-analysis. Results It is unclear whether the NIAID/FAAN criteria or Brighton case definition are valid for immediately diagnosing anaphylaxis due to the very low certainty of evidence. Adrenaline is the cornerstone of first-line emergency management of anaphylaxis but, due to ethical constraints, little robust research has assessed its effectiveness . Newer models of adrenaline autoinjectors may slightly increase the proportion of people correctly using the devices and reduce time to administration. Face-to-face training for laypeople may slightly improve anaphylaxis knowledge and competence in using autoinjectors. Adrenaline prophylaxis prior to snake bite anti-venom may reduce anaphylaxis but the impact of prophylactic corticosteroids and antihistamines is uncertain. There was insufficient evidence about the impact of other anaphylaxis management strategies. Conclusions Anaphylaxis is a potentially life-threatening condition but, due to practical and ethical challenges, there is a paucity of robust evidence about how to diagnose and manage it.

In December 2019, China reported the first cases of the coronavirus disease 2019 (COVID-19). This disease, caused by the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), has developed into a pandemic. To date it has resulted in ~5.6 million confirmed cases and caused 353,334 related deaths worldwide. Unequivocally, the COVID-19 pandemic is the gravest health and socio-economic crisis of our time. In this context, numerous questions have emerged in demand of basic scientific information and evidence-based medical advice on SARS-CoV-2 and COVID-19. Although the majority of the patients show a very mild, self-limiting viral respiratory disease, many clinical manifestations in severe patients are unique to COVID-19, such as severe lymphopenia and eosinopenia, extensive pneumonia, a “cytokine storm” leading to acute respiratory distress syndrome, endothelitis, thrombo-embolic complications and multiorgan failure. The epidemiologic features of COVID-19 are distinctive and have changed throughout the pandemic. Vaccine and drug development studies and clinical trials are rapidly growing at an unprecedented speed. However, basic and clinical research on COVID-19-related topics should be based on more coordinated high-quality studies. This paper answers pressing questions, formulated by young clinicians and scientists, on SARS-CoV-2, COVID-19 and allergy, focusing on the following topics: virology, immunology, diagnosis, management of patients with allergic disease and asthma, treatment, clinical trials, drug discovery, vaccine development and epidemiology. Over 140 questions were answered by experts in the field providing a comprehensive and practical overview of COVID-19 and allergic disease.