Search

Anaphylaxis is a serious systemic hypersensitivity reaction that is usually rapid in onset and may cause death. It is characterised by the rapid development of airway and/or breathing and/or circulation problems. Intramuscular adrenaline is the most important treatment, although, even in healthcare settings, many patients do not receive this intervention contrary to guidelines. The Resuscitation Council UK published an updated guideline in 2021 with some significant changes in recognition, management, observation and follow-up of patients with anaphylaxis. This is a concise version of the updated guideline., (© Royal College of Physicians 2022. All rights reserved.)

Background: The heterogeneity and lack of validation of existing severity scores for food allergic reactions limit standardization of case management and research advances. We aimed to develop and validate a severity score for food allergic reactions., Methods: Following a multidisciplinary experts consensus, it was decided to develop a food allergy severity score (FASS) with ordinal (oFASS) and numerical (nFASS) formats. oFASS with 3 and 5 grades were generated through expert consensus, and nFASS by mathematical modeling. Evaluation was performed in the EuroPrevall outpatient clinic cohort (8232 food reactions) by logistic regression with request of emergency care and medications used as outcomes. Discrimination, classification, and calibration were calculated. Bootstrapping internal validation was followed by external validation (logistic regression) in 5 cohorts (3622 food reactions). Correlation of nFASS with the severity classification done by expert allergy clinicians by Best-Worst Scaling of 32 food reactions was calculated., Results: oFASS and nFASS map consistently, with nFASS having greater granularity. With the outcomes emergency care, adrenaline and critical medical treatment, oFASS and nFASS had a good discrimination (receiver operating characteristic area under the curve [ROC-AUC]>0.80), classification (sensitivity 0.87-0.92, specificity 0.73-0.78), and calibration. Bootstrapping over ROC-AUC showed negligible biases (1.0 × 10 -6 -1.23 × 10 -3 ). In external validation, nFASS performed best with higher ROC-AUC. nFASS was strongly correlated (R 0.89) to best-worst scoring of 334 expert clinicians., Conclusion: FASS is a validated and reliable method to measure severity of food allergic reactions. The ordinal and numerical versions that map onto each other are suitable for use by different stakeholders in different settings., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Understanding risk factors for peanut allergy (PA) is essential to develop effective preventive measures., Objective: The objective was to ascertain associates and predictors of PA, and the relationship between PA and asthma severity., Methods: In a population-based birth cohort, we investigated the association between objectively confirmed PA with early-life environmental exposures, filaggrin (FLG)-loss-of-function mutations and other atopic disease. We then examined the association of PA with longitudinal trajectories of sensitization, wheeze and allergic comorbidities, which were previously derived using machine learning. Finally, we ascertained the relationship between PA and asthma severity., Results: PA was confirmed in 30/959 participants with evaluable data. In the multivariate analysis, eczema in infancy (OR = 4.4, 95% CI 1.5-13.2, p = 0.007), egg sensitization at age 3 years (OR = 9.7, 95% CI 3.3-29.9, p < 0.001) and early-life cat ownership (OR = 3.0, 95% CI 1.1-8.4, p = 0.04) were independent associates of PA. In the stratified analysis among 700 participants with genetic information, in children with early-life eczema there was no difference in FLG mutations between children with and without PA (3/18 [16.7%] vs. 42/220 [19.1%], p = 1.00). In contrast, among children without eczema, those with PA were almost eight times more likely to have FLG mutations (2/6 [33.3%] vs. 27/456 [5.9%], p = 0.049). We observed associations between PA and multiple allergic sensitization profiles derived using machine learning, with ~60-fold increase in risk among individuals assigned to multiple early sensitization. PA was significantly associated with persistent wheeze (but not other wheeze phenotypes), and with trajectories of atopic disease characterized by co-morbid persistent eczema and wheeze (but not with transient phenotypes). Children with PA were more likely to have asthma, but among asthmatics we found no evidence of an association between PA and asthma severity., Conclusions: Peanut allergy is associated with multiple IgE sensitization and early-onset persistent eczema and wheeze. FLG loss-of-function mutations were associated with peanut allergy in children without eczema., (© 2022 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Introduction: Oral immunotherapy (OIT) is effective at inducing desensitization in food-allergic individuals, and is a valid therapeutic option for those allergic to peanut, cow's milk and egg. However, there is a high rate of dose-related adverse events, and at least one fatality to OIT has been reported., Areas Covered: We provide an update on the broader framework of issues which will impact on the availability and uptake of OIT., Expert Opinion: The need for standardized products remains controversial. A licensed product exists for peanut-OIT, but OIT can also be safely achieved using peanut-containing foods at much lower cost. For other allergens, OIT can only be done with non-pharma products - something which has been done safely for over 2 decades. There is a need to develop personalized protocols for OIT, particularly for the 20% of patients unable to tolerate standard OIT. Cost-effectiveness is dependent on improved quality of life, but evidence for this is currently lacking, and is a key evidence gap. OIT is likely to be cost-effective, particularly if noncommercial products are used. There may be a trade-off: in patients with lower reaction thresholds, a commercial product may be needed for initial updosing, until a level of desensitization is achieved when they can be switched to natural food products.

Background: In diagnostic evaluation, it is necessary to assess the clinical impact of a new diagnostic as well as its diagnostic accuracy. The comparative interrupted time series design has been proposed as a quasi-experimental approach to evaluating interventions. We show how it can be used in the design of a study to evaluate a point-of-care diagnostic test for C-reactive protein in out-of-hours primary care services, to guide antibiotic prescribing among patients presenting with possible respiratory tract infection. This study consisted of a retrospective phase that used routinely collected monthly antibiotic prescribing data from different study sites, and a prospective phase in which antibiotic prescribing rates were monitored after the C-reactive protein diagnostic was introduced at some of the sites., Methods: Of 8 study sites, 3 were assigned to receive the diagnostic and 5 were assigned as controls. We obtained retrospective monthly time series of respiratory tract targeted antibiotic prescriptions at each site. Separate ARIMA models at each site were used these to forecast monthly prescription counts that would be expected in the prospective phase, using simulation to obtain a set of 1-year predictions alongside their standard errors. We show how these forecasts can be combined to test for a change in prescription rates after introduction of the diagnostic and estimate power to detect this change., Results: Fitted time series models at each site were stationary and showed second-order annual seasonality, with a clear December peak in prescriptions, although the timing and extent of the peak varied between sites and between years. Mean one-year predictions of antibiotic prescribing rates based on the retrospective time series analysis differed between sites assigned to receive the diagnostic and those assigned to control. Adjusting for the trend in the retrospective time series at each site removed these differences., Conclusions: Quasi-experimental designs such as comparative interrupted time series can be used in diagnostic evaluation to estimate effect sizes before conducting a full randomised controlled trial or if a randomised trial is infeasible. In multi-site studies, existing retrospective data should be used to adjust for underlying differences between sites to make outcome data from different sites comparable, when possible., (© 2022. The Author(s).)

Background: Despite a better understanding of the epidemiology, pathogenesis, and management of patients with anaphylaxis, there remain knowledge gaps. Enumerating and prioritizing these gaps would allow limited scientific resources to be directed more effectively., Objective: We sought to systematically describe and appraise anaphylaxis knowledge gaps and future research priorities based on their potential impact and feasibility., Methods: We convened a 25-member multidisciplinary panel of anaphylaxis experts. Panelists formulated knowledge gaps/research priority statements in an anonymous electronic survey. Four anaphylaxis themed writing groups were formed to refine statements: (1) Population Science, (2) Basic and Translational Sciences, (3) Emergency Department Care/Acute Management, and (4) Long-Term Management Strategies and Prevention. Revised statements were incorporated into an anonymous electronic survey, and panelists were asked to rate the impact and feasibility of addressing statements on a continuous 0 to 100 scale., Results: The panel generated 98 statements across the 4 anaphylaxis themes: Population Science (29), Basic and Translational Sciences (27), Emergency Department Care/Acute Management (24), and Long-Term Management Strategies and Prevention (18). Median scores for impact and feasibility ranged from 50.0 to 95.0 and from 40.0 to 90.0, respectively. Key statements based on median rating for impact/feasibility included the need to refine anaphylaxis diagnostic criteria, identify reliable diagnostic, predictive, and prognostic anaphylaxis bioassays, develop clinical prediction models to standardize postanaphylaxis observation periods and hospitalization criteria, and determine immunotherapy best practices., Conclusions: We identified and systematically appraised anaphylaxis knowledge gaps and future research priorities. This study reinforces the need to harmonize scientific pursuits to optimize the outcomes of patients with and at risk of anaphylaxis., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Although there is a general perception that the prevalence of food allergy is increasing, data supporting this are limited. Food is the least common cause of fatal anaphylaxis, and fortunately, it is a very rare event; however, it is also unpredictable. There is widespread consensus that severe reactions cannot be predicted in a clinically meaningful way. Certain food triggers are more frequently associated with fatal anaphylaxis than others. In observational studies, peanut and tree nuts account for at least 30% to 50% of fatalities, with seafood and cow's milk also associated with fatal reactions. Fatal food-induced anaphylaxis is most likely to occur during adolescence and young adulthood, although the reasons for this are unclear. International guidelines agree that intramuscular (IM) epinephrine is the treatment of choice for managing food-triggered anaphylaxis and has a good safety profile when given by the IM route. However, fatalities still occur despite the timely administration of epinephrine. Food-allergic individuals must navigate a world that requires daily vigilance for allergens and preparedness for allergic reactions. Although the actual risk of fatal reactions is minimal, it is not zero, and severe reactions are unpredictable. Clinicians need to help patients better understand the very low but real risk of fatal reaction and enable them to lead as normal a life as possible through appropriate education, safety netting, and risk reduction., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Anaphylaxis is a medical emergency with adrenaline acknowledged as the first-line therapy. It is therefore important that patients have access to self-injectable adrenaline in the community. Manufacturers have been requested by European Medicine Regulators to generate pharmacokinetic data for these autoinjector devices. For the first time, these data provide an insight into how individual devices work in different populations, and how they compare. We undertook a thorough literature search and also accessed grey literature, using searches of medicine regulators' websites and freedom of information requests. The data demonstrate that it takes at least 5-10 min to achieve early peak plasma concentration for most devices. The specific autoinjector device seems to be the most important determinant of pharmacokinetics, with different devices giving rise to different plasma adrenaline profiles. Needle length does not seem to be the most important factor; rather, the force and speed of injection (which varies from one device to another) is likely to be of greater importance. In general, peak plasma adrenaline concentration is lower and time-to-peak concentration longer with increased skin-to-muscle depth. However, it is difficult to draw conclusions with the current available data, due to a lack of head-to-head comparisons, small numbers of study participants and the failure to acknowledge the biphasic nature of intramuscular adrenaline absorption for analysis purposes., (wileyonlinelibrary.com/journal/cea.)

Regional and national legislation mandates the disclosure of "priority" allergens when present as an ingredient in foods, but this does not extend to the unintended presence of allergens due to shared production facilities. This has resulted in a proliferation of precautionary allergen ("may contain") labels (PAL) that are frequently ignored by food-allergic consumers. Attempts have been made to improve allergen risk management to better inform the use of PAL, but a lack of consensus has led to variety of regulatory approaches and nonuniformity in the use of PAL by food businesses. One potential solution would be to establish internationally agreed "reference doses," below which no PAL would be needed. However, if reference doses are to be used to inform the need for PAL, then it is essential to characterize the hazard associated with these low-level exposures. For peanut, there are now published data relating to over 3000 double-blind, placebo-controlled challenges in allergic individuals, but a similar level of evidence is lacking for other priority allergens. We present the results of a rapid evidence assessment and meta-analysis for the risk of anaphylaxis to a low-level allergen exposure for priority allergens. On the basis of this analysis, we propose that peanut can and should be considered an exemplar allergen for the hazard characterization at a low-level allergen exposure., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There are increasing global data relating to prevalence of food allergy and food-induced anaphylaxis; however, this is often based on surrogate measures of sensitization rather than objective symptoms at food challenge. In terms of protecting food-allergic consumers from reactions, to our knowledge, there has been no global survey assessing geographic differences in the proportion of anaphylaxis triggered by specific foods., Objective: We sought to identify common triggers for food-induced anaphylaxis and how these vary from country to country., Methods: Systematic review of relevant reports published between January 2010 and November 2020. Results were reported following PRISMA guidelines. Publications were screened and data extracted by 2 independent reviewers, and the risk of bias was assessed., Results: Sixty-five studies (encompassing 41 countries and all 6 regions as defined by the Food and Agriculture Organization of the United Nations) were included. Significant regional variations in the most common triggers of food anaphylaxis were seen; however, in general, there was good agreement between local legislative requirements for allergen disclosure and the most common allergens for each region or nation., Conclusions: Local legislation for allergen disclosure generally reflects those allergens commonly responsible for food anaphylaxis. Cow's milk and crustaceans appear to cause a higher proportion of anaphylaxis compared to peanut in some regions., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is no current consensus on assigning severity to food-induced allergic reactions, for example, to assess the efficacy of allergen immunotherapy. Existing severity scores lack the capability to discriminate between non-anaphylaxis reactions of different severities. Attempts are ongoing to develop a more discriminatory score, which should ideally be data-driven and validated in multiple cohorts., Objective: To undertake an exercise using best-worst scaling (BWS) to define a potential gold standard against which severity scoring of food-induced allergic reactions can be refined., Methods: We undertook a global survey to better understand how health care professionals rate the severity of food-induced allergic reactions, using BWS methodology. Respondents were given a number of patient case vignettes describing real-world allergic reactions and asked to select the pair that, in their opinion, reflected the maximum difference in severity. Responses were then modeled and a preference score (representing severity) determined for each scenario. Scenarios were also scored using existing published scoring systems and the scores compared with the BWS score using Spearman r correlation and Cohen kappa. Given the differences in definitions of anaphylaxis globally, we also evaluated differences in BWS ranking depending on the geographical location of respondents., Results: We received 334 complete responses, 183 (55%) from Europe and 65 (20%) from North America. Perception of severity of some reactions appeared to be affected by geographical location. The comparison of BWS ranking with current grading systems identified significant issues that varied from one grading system to another, such as prominence to some symptoms (eg, vomiting) that skew grading when using scoring systems not designed for food allergy. In general, current scoring systems poorly discriminate against more mild symptoms and often overestimate their severity., Conclusions: These data provide a methodology free of user scale bias to help define a potential, consensus-driven gold standard that can be used to guide and validate the development of improved grading systems to score food-induced allergic symptoms and highlight areas for education where there is the potential to miscategorize severity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Regulatory bodies recommend that all patients at risk of anaphylaxis be prescribed 2 epinephrine autoinjectors, which they should carry at all times. This is in contrast to some guidelines. The proportion of anaphylaxis reactions that are treated with multiple doses of epinephrine has not been systematically evaluated., Objective: Our aim was to undertake a systematic review and meta-analysis of published studies reporting epinephrine treatment for anaphylaxis in which data relating to the number of doses administered were available., Methods: We searched the Medline, Embase, and Cochrane databases for relevant studies reporting at least 10 anaphylaxis events (due to food or venom) from 1946 until January 2020. Data were extracted in duplicate for the meta-analysis, and the risk of bias was assessed. The study was registered under the PROSPERO identifier CRD42017069109., Results: A total of 86 studies (36,557 anaphylaxis events) met the inclusion criteria (20 of the studies [23%] were prospective studies; 64 [74%] reported reactions in the community, and 22 [26%] included food challenge data). Risk of bias was assessed as low in 50 studies. Overall, 7.7% of anaphylaxis events from any cause (95% CI = 6.4-9.1) were treated with multiple doses of epinephrine. When only epinephrine-treated reactions for which subsequent doses were administered by a health care professional were considered, 11.1% of food-induced reactions (95% CI = 9.4-13.2) and 17.1% of venom-induced reactions (95% CI = 11.3-25.0) were treated with more than 1 epinephrine dose. Heterogeneity was moderate to high in the meta-analyses, but at sensitivity analysis this estimate was not affected by study design or anaphylaxis definition., Conclusion: Around 1 in 10 anaphylaxis reactions are treated with more than 1 dose of epinephrine., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Food hypersensitivity (FHS), including food allergy, coeliac disease and food intolerance, is a major public health issue. The Food Standards Agency (FSA), an independent UK Government department working to protect public health and consumers' wider interests in food, sought to identify research priorities in the area of FHS., Methods: A priority setting exercise was undertaken, using a methodology adapted from the James Lind Alliance-the first such exercise with respect to food hypersensitivity. A UK-wide public consultation was held to identify unanswered research questions. After excluding diagnostics, desensitization treatment and other questions which were out of scope for FSA or where FSA was already commissioning research, 15 indicative questions were identified and prioritized by a range of stakeholders, representing food businesses, patient groups, health care and academia, local authorities and the FSA., Results: 295 responses were received during the public consultation, which were categorized into 70 sub-questions and used to define 15 key evidence uncertainties ('indicative questions') for prioritization. Using the JLA prioritization framework, this resulted in 10 priority uncertainties in evidence, from which 16 research questions were developed. These could be summarized under the following 5 themes: communication of allergens both within the food supply chain and then to the end consumer (ensuring trust in allergen communication); the impact of socio-economic factors on consumers with FHS; drivers of severe reactions; mechanism(s) underlying loss of tolerance in FHS; and the risks posed by novel allergens/processing., Discussion: In this first research prioritization exercise for food allergy and FHS, key priorities identified to protect the food-allergic public were strategies to help allergic consumers to make confident food choices, prevention of FHS and increasing understanding of socio-economic impacts. Diagnosis and treatment of FHS was not considered in this prioritization., (© 2021 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background and Aims: There is a lack of basic science data on the effect of dexmedetomidine on the hypoxic chemosensory reflex with both depression and stimulation suggested. The primary aim of this study was to assess if dexmedetomidine inhibited the cellular response to hypoxia in rat carotid body glomus cells, the cells of the organs mediating acute hypoxic ventilatory response (AHVR). Additionally, we used a small sample of mice to assess if there was any large influence of subsedative doses of dexmedetomidine on AHVR., Material and Methods: In the primary study, glomus cells isolated from neonatal rats were used to study the effect of 0.1 nM ( n = 9) and 1 nM ( n = 13) dexmedetomidine on hypoxia-elicited intracellular calcium [Ca 2% ]i influx using ratiometric fluorimetry. Secondarily, whole animal unrestrained plethysmography was used to study AHVR in a total of 8 age-matched C57BL6 mice, divided on successive days into two groups of four mice randomly assigned to receive sub-sedative doses of 5, 50, or 500 μg.kg -1 dexmedetomidine versus control in a crossover study design (total n = 12 exposures to drug with n = 12 controls)., Results: There was no effect of dexmedetomidine on the hypoxia-elicited increase in [Ca 2% ]i in glomus cells (a mean ± SEM increase of 95 ± 32 nM from baseline with control hypoxia, 124 ± 41 nM with 0.1 nM dexmedetomidine; P = 0.514). In intact mice, dexmedetomidine had no effect on baseline ventilation during air-breathing (4.01 ± 0.3 ml.g -1 .min -1 in control and 2.99 ± 0.5 ml.g -1 .min -1 with 500 μg.kg -1 dexmedetomidine, the highest dose; P = 0.081) or on AHVR (136 ± 19% increase from baseline in control, 152 ± 46% with 500 μg.kg -1 dexmedetomidine, the highest dose; P = 0.536)., Conclusion: Dexmedetomidine had no effect on the cellular responses to hypoxia. We conclude that it unlikely acts via inhibition of oxygen sensing at the glomus cell. The respiratory chemoreflex effects of this drug remain an open question. In our small sample of intact mice, hypoxic chemoreflex responses and basal breathing were preserved., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Anaesthesiology Clinical Pharmacology.)

Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval [95% CI] 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Vaccine hesitancy-defined by the World Health Organization (WHO) as a "delay in acceptance or refusal of vaccines despite availability of vaccination services"-is not a recent phenomenon. Historical records indicate that vaccine hesitancy existed by the 18th century in Europe and even resulted in violent riots. The drivers of vaccine hesitancy have evolved over the last 200 years but not, perhaps, as much as one might expect. More problematic are the means by which concerns over vaccine hesitancy are communicated by a new landscape of digital communication, generating what has been described as an "infodemic" in which an overabundance of information-both factual and misinformation-contributes to hesitancy. In this review, we discuss the background and current drivers of vaccine hesitancy and the evidence base for strategies to combat this. We highlight the important role the allergy/immunology community could have in working to mitigate vaccine hesitancy, particularly with respect to the current coronavirus disease 2019 (COVID-19) pandemic., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer-BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines., Methods: Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139., Findings: Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation., Interpretation: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines., Funding: UK Vaccine Task Force and National Institute for Health Research., Competing Interests: Declaration of interests MDS acts on behalf of the University of Oxford as an investigator on studies funded or sponsored by vaccine manufacturers, including AstraZeneca, GlaxoSmithKline, Pfizer, Novavax, Janssen, Medimmune, and MCM. He receives no personal financial payment for this work. JSN-V-T is seconded to the Department of Health and Social Care, England. AMC and DMF are investigators on studies funded by Pfizer and Unilever. They receive no personal financial payment for this work. AF is a member of the Joint Committee on Vaccination and Immunisation and chair of the WHO European Technical Advisory Group of Experts on Immunisation. He is an investigator or provides consultative advice on clinical trials and studies of COVID-19 vaccines produced by AstraZeneca, Janssen, Valneva, Pfizer, and Sanofi, and of other vaccines from these and other manufacturers, including GlaxoSmithKline, VPI Pharmaceuticals, Takeda, and Bionet Asia. He receives no personal remuneration or benefits for any of this work. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust as an investigator or provides consultative advice on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Sanofi, Medimmune, Merck, and Valneva. He receives no personal financial payment for this work. PTH acts on behalf of St George's University of London as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, Novavax, and Valneva. He receives no personal financial payment for this work. CAG acts on behalf of University Hospitals Birmingham NHS Foundation Trust as an investigator on clinical trials and studies of COVID-19 and other vaccines funded or sponsored by vaccine manufacturers, including Janssen, Pfizer, AstraZeneca, Novavax, CureVac, Moderna, and Valneva. He receives no personal financial payment for this work. VL acts on behalf of University College London Hospitals NHS Foundation Trust as an investigator on clinical trials of COVID-19 vaccines funded or sponsored by vaccine manufacturers including Pfizer, AstraZeneca, and Valneva. He receives no personal financial payment for this work. TL is named as an inventor on a patent application covering the ChAd vaccine and is an occasional consultant to Vaccitech, unrelated to this work. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. All other authors declare no competing interests., (Crown Copyright © 2021 Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Background: There is increasing interest in the use of eliciting doses (EDs) to inform allergen risk management. The ED can be estimated from the distribution of threshold doses for allergic subjects undergoing food challenges within a specified population. Estimated ED 05 values for cow's milk (the dose expected to cause objective allergic symptoms in 5% of the milk-allergic population) range from 0.5 mg to 13.9 mg cow's milk protein. We undertook a single-dose challenge study to validate a predicted ED 05 for cow's milk of 0.5 mg protein., Methods: Participants were recruited from 4 clinical centres. Predetermined criteria were used to identify patients reacting to 0.5 mg cow's milk protein (approximately 0.015 mL of fresh cow's milk). Children over 1 year underwent formal challenge to cow's milk to confirm clinical reactivity., Results: 172 children (median age 6.0 (IQR 0.7-11) years, 57% male) were included in this analysis. Twelve (7.0%, 95% CI 3.7%-11.9%) children experienced objective symptoms that met the predetermined criteria. One participant had mild anaphylaxis that responded to a single dose of adrenaline, the remainder experienced only mild symptoms with no treatment required. We did not identify any baseline predictors of sensitization that were associated with objective reactivity to the single-dose challenge using 0.5 mg cow's milk protein., Conclusions: These data support an estimated ED 05 for cow's milk of 0.5 mg protein. Values for ED 05 above 0.5 mg for cow's milk protein proposed for allergen risk management need to be reviewed., (© 2021 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Objective: To assess the impact of anaphylaxis on health-related quality of life (HRQL) and self-efficacy in food-allergic patients undergoing in-hospital food challenge., Design: Secondary analysis of a randomised controlled trial., Setting: Specialist allergy centre., Patients: Peanut-allergic young people aged 8-16 years., Interventions: Double-blind, placebo-controlled food challenge to peanut, with HRQL and self-efficacy assessed using validated questionnaire, approximately 2 weeks prior to and 2 weeks after challenge. Where possible, anaphylaxis was treated with self-injected adrenaline (epinephrine)., Main Outcome Measures: Change in HRQL and self-efficacy., Results: 56 participants had reactions at food challenge, of whom 16 (29%) had anaphylaxis. Overall, there was an improvement in HRQL (mean 2.6 points (95% CI 0.3 to 4.8); p=0.030) and self-efficacy (mean 4.1 points (95% CI 2.4 to 5.9); p<0.0001), independent of whether anaphylaxis occurred. Parents also reported improved HRQL (mean 10.3 points (95% CI 5.9 to 14.7); p<0.0001). We found evidence of discordance between the improvement in HRQL and self-efficacy as reported by young people and that perceived by parents in their child., Conclusions: Anaphylaxis at food challenge, followed by self-administration of injected adrenaline, was associated with an increase in HRQL and self-efficacy in young people with peanut allergy. We found no evidence that the occurrence of anaphylaxis had a detrimental effect. Young people should be encouraged to self-administer adrenaline using their autoinjector device to treat anaphylaxis at in-hospital challenge., Trial Registration Number: NCT02149719., Competing Interests: Competing interests: PT has received research funding for studies of food desensitisation from the Medical Research Council, Imperial/NIHR Biomedical Research Centre, Jon Moulton Charity Trust and Action Medical Research and has acted a principle investigator for commercial studies of food immunotherapy sponsored by Aimmune Therapeutics and DBV Technologies. DC is an employee of DBV Technologies. The other authors declare that they have no conflicts of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Food-allergic patients are routinely prescribed 2 epinephrine autoinjectors (EAIs). The cost-effectiveness of this strategy is unknown., Objective: To evaluate the cost-effectiveness of routinely prescribing all patients 2 EAI devices versus a risk-stratified approach (2 EAIs prescribed only for patients with a risk factor)., Methods: Markov models compared universal versus risk-stratified approaches on the basis of either a previous medical history of anaphylaxis (PMH-ana) or anaphylaxis requiring multiple epinephrine doses (multi-epi). Cohorts of children with peanut allergy were evaluated over an 80-year time horizon from both US and UK societal and health care perspectives. Models assumed prescribing a second EAI provided a baseline 10-fold risk reduction versus anaphylaxis-related fatality and hospitalization. Cost-effectiveness threshold was $100,000/quality-adjusted life-year (QALY)., Results: From a US perspective, universal prescription of 2 EAIs to all patients with peanut allergy was not cost-effective in the base case versus risk stratification by PMH-ana. Universal prescription of 2 EAIs was associated with an incremental cost of $10,696,036/QALY versus the PMH-ana strategy, and $17,514,558/QALY versus the multi-epi strategy. However, the universal strategy became cost-effective versus a multi-epi strategy when single EAI costs were less than $80, second epinephrine dose requirements more than 25.5%, anaphylaxis hospitalization costs more than $18,453, annual anaphylaxis risk more than 76.5%, or anaphylaxis hospitalization rate more than 74.9%. From a UK perspective, universally prescribing 2 EAIs was also not cost-effective (incremental cost of $4,132,440/QALY vs PMH-ana and $6,208,227/QALY vs multi-epi) at single device costs more than $18., Conclusions: At current EAI prices and low rates of needing 2 devices, limiting the second EAIs to patients with PMH-ana is more cost-effective than routinely prescribing 2 EAIs to all patients (particularly in resource-constrained settings)., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Eliciting doses (EDs) (eg, ED 01 or ED 05 values, which are the amounts of allergen expected to cause objective symptoms in 1% and 5% of the population with an allergy, respectively) are increasingly being used to inform allergen labeling and clinical management. These values are generated from food challenge, but the frequency of anaphylaxis in response to these low levels of allergen exposure and their reproducibility are unknown., Objective: Our aim was to determine (1) the rate of anaphylaxis in response to low-level peanut exposure and (2) the reproducibility of reaction thresholds (and anaphylaxis) at food challenge., Methods: We conducted a systematic review and individual participant data meta-analysis of studies that reported at least 50 individuals with peanut allergy reacting to peanut at double-blind, placebo-controlled food challenge (DBPCFC) and were published between January 2010 and September 2020. Risk of bias was assessed by using National Institute for Clinical Excellence methodologic checklists., Results: A total of 19 studies were included (covering a total of 3151 participants, 534 of whom subsequently underwent further peanut challenge). At individual participant data meta-analysis, 4.5% (95% CI, 1.9% to 10.1%) of individuals reacted to 5 mg or less of peanut protein with anaphylaxis (moderate heterogeneity [I 2  = 57%]). Intraindividual thresholds varied by up to 3 logs, although this variation was limited to a half-log change in 71.2% (95% CI, 56.2% to 82.6%) of individuals. In all, 2.4% (95% CI, 1.1% to 5.0%) of patients initially tolerated 5 mg of peanut protein but then reacted to this dose at subsequent challenge (low heterogeneity [I 2  = 16%]); none developed anaphylaxis., Conclusion: Around 5% of individuals reacting to an ED 01 or ED 05 level of exposure to peanut might develop anaphylaxis in response to that dose. This equates to 1 and 6 anaphylaxis events per 2500 patients exposed to an ED 01 or ED 05 dose, respectively, in the broader population of individuals with peanut allergy., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Clinical reactions to Oral Food Challenge (OFC) in peanut-allergic individuals have been well-characterised, but rates and phenotypes of symptom recurrence beyond the first hour after objective symptoms are less well-characterised., Objective: To evaluate the rate of new-onset symptoms occurring at least 1 h after stopping OFC in peanut-allergic children and adults undergoing peanut-OFC., Methods: We prospectively collected data relating to adverse events following positive reactions at double-blind, placebo-controlled food challenges (DBPCFC) to peanut in children and adults evaluated for eligibility to participate in two clinical trials (NCT02149719, NCT02665793). The trials included people aged 8 to 45 with primary, IgE-mediated peanut allergy at DBPCFC. The challenge protocol included consumption of a light meal 1 h after reaction., Results: A total of 121 participants (64 children, 57 adults) had immediate, objective symptoms at DBPCFC, 25 (17 children, 8 adults) with anaphylaxis. Thirty-three (27%) had progression or recurrence of symptoms ≥ 1 h after objective clinical reaction, of whom 8 developed anaphylaxis. In 23 cases, the onset of new symptoms was associated with consumption of a light meal. In eight cases, symptoms were limited to a symptomatic postural fall in blood pressure noted in preparation for discharge, without any other new features of an allergic reaction., Conclusions & Clinical Relevance: Progressive or new-onset symptoms ≥1 h following initial allergic reaction at OFC are common and can include orthostatic hypotension. Recurrent symptoms may be temporally associated with food consumption., (© 2021 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

The Resuscitation Council UK has updated its Guideline for healthcare providers on the Emergency treatment of anaphylaxis. As part of this process, an evidence review was undertaken by the Guideline Working Group, using an internationally-accepted approach for adoption, adaptation, and de novo guideline development based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence to decision (EtD) framework, referred to as GRADE-ADOLOPMENT. A number of significant changes have been made, which will be reflected in the updated Guideline. These include: emphasis on repeating intramuscular adrenaline doses after 5 min if symptoms of anaphylaxis do not resolve; corticosteroids (e.g. hydrocortisone) no longer being routinely recommended for the emergency treatment of anaphylaxis; interventions for reactions which are refractory to initial treatment with adrenaline; a recommendation against the use of antihistamines for the acute management of anaphylaxis; and guidance relating to the duration of observation following anaphylaxis, and timing of discharge., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The United Kingdom has a national immunization programme which includes annual influenza vaccination in school-aged children, using live attenuated influenza vaccine (LAIV). LAIV is given annually, and it is unclear whether repeat administration can affect immunogenicity. Because LAIV is delivered intranasally, pre-existing local antibody might be important. In this study, we analysed banked samples from a study performed during the 2017/18 influenza season to investigate the role of pre-existing influenza-specific nasal immunoglobulin (Ig)A in children aged 6-14 years. Nasopharyngeal swabs were collected prior to LAIV immunization to measure pre-existing IgA levels and test for concurrent upper respiratory tract viral infections (URTI). Oral fluid samples were taken at baseline and 21-28 days after LAIV to measure IgG as a surrogate of immunogenicity. Antibody levels at baseline were compared with a pre-existing data set of LAIV shedding from the same individuals, measured by reverse transcription-polymerase chain reaction. There was detectable nasal IgA specific to all four strains in the vaccine at baseline. However, baseline nasal IgA did not correlate with the fold change in IgG response to the vaccine. Baseline nasal IgA also did not have an impact upon whether vaccine virus RNA was detectable after immunization. There was no difference in fold change of antibody between individuals with and without an URTI at the time of immunization. Overall, we observed no effect of pre-existing influenza-specific nasal antibody levels on immunogenicity, supporting annual immunization with LAIV in children., (© 2021 British Society for Immunology.)

Background and Aims: The term "Food Allergy" refers to a complex global health problem with a wide spectrum of severity. However, a uniform definition of severe food allergy is currently missing. This systematic review is the preliminary step towards a state-of-the-art synopsis of the current evidence relating to the severity of IgE-mediated food allergy; it will inform attempts to develop a consensus to define food allergy severity by clinicians and other stakeholders., Methods: We undertook a mixed-methods systematic review, which involved searching 11 international biomedical databases for published studies from inception to 31 December 2019. Studies were independently screened against pre-defined eligibility criteria and critically appraised by established instruments. The substantial heterogeneity of included studies precluded meta-analyses and, therefore, narrative synthesis of quantitative and qualitative data was performed., Results: We found 23 studies providing eligible primary data on symptom-specific severity of food allergic reactions, and 31 previously published symptom-severity scoring systems referred to food allergic reactions. There were seven studies which assessed quality-of-life measures in patients (and family members) with different food allergy severity and two studies that investigated the economic burden of food allergy severity. Overall, the quality and the global rating of all included studies were judged as being moderate., Conclusions: There is heterogeneity among severity scoring systems used and even outcomes considered in the context of severity of food allergy. No score has been validated. Our results will be used to inform the development of an international consensus to define the severity of food allergy., Systematic Review Registration: A protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) database with the registration number CRD42020183103 (https://www.crd.york.ac.uk/prospero/#recordDetails)., Competing Interests: The following authors declared no potential interests: Ignacio J Ansotegui; Stefania Arasi; Shahd Daher; Alessandro Fiocchi; Ulugbek Nurmatov; Stavros Petrou; Graham Roberts; Mario Sánchez-Borges; Luciana Kase Tanno; Marta Vazquez Ortiz; Gary Wing-Kin Wong. Some of the authors have professional affiliations related to the content of the systematic review as set out below: Audrey Dunn-Galvin: consultancy fee from Aimmune and DBV; Paul J Turner: grants from UK 10.13039/501100000265Medical Research Council, 10.13039/501100013342NIHR/Imperial BRC, JM Charitable Foundation and UK 10.13039/501100000354Food Standards Agency; personal fees from UK Food Standards Agency, DBV Technologies, ILSI Europe and Allergenis, non-financial support from Aimmune Therapeutics; Sayantani B Sindher: supported by 10.13039/100000002NIH grants. Involved in clinical trials with Regeneron, Aimmune Therapeutics, DBV Technologies, Adare Pharmaceuticals, Sanofi, Novartis; Ruchi Gupta: grants from The 10.13039/100000002National Institute of Health (NIH) (R21 ID # AI135705, R01 ID# AI130348, U01 ID # AI138907), Rho Inc., Stanford Sean N. Parker Center for Allergy Research, UnitedHealth Group, Thermo Fisher Scientific, Genentech, and the National Confectioners Association (NCA); is employed by Ann & Robert H. Lurie Children's Hospital of Chicago; is a Professor of Pediatrics at Northwestern University; and serves as a medical consultant/advisor for Before Brands, Kaléo Inc., Genentech, ICER, FARE, Aimmune Therapeutics, and DBV Technologies; Philippe Eigenmann: Research grants and support: Ulrich Muller Gierock Foundation, 10.13039/100011033ThermoFisher Scientific; Consultant: DBV technologies, Nesté, Danone, Novartis, Abbott; Speaking engagements: ThermoFisher Scientific, ALK, Abbott; Stock options: DBV technologies; Anna Nowak-Wegrzyn: Grant/Research/Clinical Trial Support: DBV Technologies; ITN/NIAID; 10.13039/100004324Astellas Pharmaceutical; 10.13039/100004339Sanofi-Aventis [Future therapies for food allergy]. International FPIES Association [FPIES, unpaid advisor]. Consultant/Advisory Boards: Gerber Nutrition Institute; Merck. Speaking engagements: Nestle, Thermofisher Scientific; Montserrat Fernandez-Rivas: research grants from the Spanish Government (10.13039/501100003329MINECO, ISCIII) for the project SOLMILK, ARADyAL network and PI19/01095; consultancy fees from Aimmune, DBV, Novartis, SPRIM; lecture fees from ALK, Allergy Therapeutics, Diater, GSK, HAL Allergy, Thermofisher Scientific; Brian P Vickery: Employment: Pediatric Institute of Emory University + Children's Healthcare of Atlant; Consultant/Advisor: Aimmune Therapeutics; AllerGenis, LLC; Food Allergy Research and Education (FARE); Reacta Biosciences; Grant support: NIH-NIAID; 10.13039/100006423FARE; 10.13039/100004328Genentech; Clinical investigator: Aimmune; DBV Technologies; Regeneron; Motohiro Ebisawa: lecture fees: DBV technologies and Mylan., (© 2021 The Authors.)

Background: The aim of RApid community Point-of-care Testing fOR COVID-19 (RAPTOR-C19) is to assess the diagnostic accuracy of multiple current and emerging point-of-care tests (POCTs) for active and past SARS-CoV2 infection in the community setting. RAPTOR-C19 will provide the community testbed to the COVID-19 National DiagnOstic Research and Evaluation Platform (CONDOR)., Methods: RAPTOR-C19 incorporates a series of prospective observational parallel diagnostic accuracy studies of SARS-CoV2 POCTs against laboratory and composite reference standards in patients with suspected current or past SARS-CoV2 infection attending community settings. Adults and children with suspected current SARS-CoV2 infection who are having an oropharyngeal/nasopharyngeal (OP/NP) swab for laboratory SARS-CoV2 reverse transcriptase Digital/Real-Time Polymerase Chain Reaction (d/rRT-PCR) as part of clinical care or community-based testing will be invited to participate. Adults (≥ 16 years) with suspected past symptomatic infection will also be recruited. Asymptomatic individuals will not be eligible. At the baseline visit, all participants will be asked to submit samples for at least one candidate point-of-care test (POCT) being evaluated (index test/s) as well as an OP/NP swab for laboratory SARS-CoV2 RT-PCR performed by Public Health England (PHE) (reference standard for current infection). Adults will also be asked for a blood sample for laboratory SARS-CoV-2 antibody testing by PHE (reference standard for past infection), where feasible adults will be invited to attend a second visit at 28 days for repeat antibody testing. Additional study data (e.g. demographics, symptoms, observations, household contacts) will be captured electronically. Sensitivity, specificity, positive, and negative predictive values for each POCT will be calculated with exact 95% confidence intervals when compared to the reference standard. POCTs will also be compared to composite reference standards constructed using paired antibody test results, patient reported outcomes, linked electronic health records for outcomes related to COVID-19 such as hospitalisation or death, and other test results., Discussion: High-performing POCTs for community use could be transformational. Real-time results could lead to personal and public health impacts such as reducing onward household transmission of SARS-CoV2 infection, improving surveillance of health and social care staff, contributing to accurate prevalence estimates, and understanding of SARS-CoV2 transmission dynamics in the population. In contrast, poorly performing POCTs could have negative effects, so it is necessary to undertake community-based diagnostic accuracy evaluations before rolling these out., Trial Registration: ISRCTN, ISRCTN14226970.

Background: The coronavirus disease 2019 pandemic imposed multiple restrictions on health care services., Objective: To investigate the impact of the pandemic on Allergy & Immunology (A&I) services in the United Kingdom., Methods: A national survey of all A&I services registered with the Royal College of Physicians and/or the British Society for Allergy and Clinical Immunology was carried out. The survey covered staffing, facilities, personal protective equipment, appointments & patient review, investigations, treatments, and research activity. Weeks commencing February 3, 2020 (pre-coronavirus disease), April 6, 2020, and May 8, 2020, were used as reference points for the data set., Results: A total of 99 services participated. There was a reduction in nursing, medical, administrative, and allied health professional staff during the pandemic; 86% and 92% of A&I services continued to accept nonurgent and urgent referrals, respectively, during the pandemic. There were changes in immunoglobulin dose and infusion regimen in 67% and 14% of adult and pediatric services, respectively; 30% discontinued immunoglobulin replacement in some patients. There was a significant (all variables, P ≤ .0001) reduction in the following: face-to-face consultations (increase in telephone consultations), initiation of venom immunotherapy, sublingual and subcutaneous injection immunotherapy, anesthetic allergy testing, and hospital procedures (food challenges, immunoglobulin and omalizumab administration); and a significant increase (P ≤ .0001) in home therapy for immunoglobulin and omalizumab. Adverse clinical outcomes were reported, but none were serious., Conclusions: The pandemic had a significant impact on A&I services, leading to multiple unplanned pragmatic amendments in service delivery. There is an urgent need for prospective audits and strategic planning in the medium and long-term to achieve equitable, safe, and standardized health care., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Food allergy is the most common cause of anaphylaxis. Changes in posture during acute reactions can trigger fatal outcomes, but the impact of allergic reactions on the cardiovascular system in nonfatal reactions remains poorly understood., Objective: Our aim was to systematically evaluate changes in cardiovascular function during acute allergic reactions to peanut., Methods: Participants underwent double-blind placebo-controlled food challenge to peanut as part of a clinical trial. Changes in hemodynamic parameters (heart rate, stroke volume, blood pressure, and peripheral blood flow) and electrocardiogram findings during food challenges were assessed using noninvasive continuous monitoring., Results: A total of 57 adults (median age 24 years [interquartile range = 20-29]), 53% of whom were female, participated; 22 (39%) had anaphylaxis. Acute reactions were associated with significant changes in stroke volume (mean decrease of 4.2% [95% CI = 0.8-7.6; P = .03]), heart rate (mean increase 11.6% [95% CI = 8.4-14.8; P < .0001]), and peripheral blood flow (mean increase 19.7% [95% CI = 10.8-28.6; P < .0001]), irrespective of reaction severity. These changes were reproduced at a subsequent repeat peanut challenge in 26 participants, and could be reversed with administration of intravenous fluids which resulted in faster resolution of abdominal symptoms., Conclusions: In this first detailed human study of cardiovascular changes during food-induced allergic reactions, we found evidence for significant fluid redistribution, independent of reaction severity. This provides a sound rationale for optimizing venous return during significant allergic reactions to food. Finally, these data provide a new paradigm for understanding severity in anaphylaxis, in which poor outcomes may occur as a result of a failure in compensatory mechanisms., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Vaccines against COVID-19 (and its emerging variants) are an essential global intervention to control the current pandemic situation. Vaccines often cause adverse events; however, the vast majority of adverse events following immunization (AEFI) are a consequence of the vaccine stimulating a protective immune response, and not allergic in etiology. Anaphylaxis as an AEFI is uncommon, occurring at a rate of less than 1 per million doses for most vaccines. However, within the first days of initiating mass vaccination with the Pfizer-BioNTech COVID-19 vaccine BNT162b2, there were reports of anaphylaxis from the United Kingdom and United States. More recent data imply an incidence of anaphylaxis closer to 1:200,000 doses with respect to the Pfizer-BioNTech vaccine. In this position paper, we discuss the background to reactions to the current COVID-19 vaccines and relevant steps to mitigate against the risk of anaphylaxis as an AEFI. We propose a global surveillance strategy led by allergists in order to understand the potential risk and generate data to inform evidence-based guidance, and thus provide reassurance to public health bodies and members of the public., Competing Interests: Dr. Ansotegui reports personal fees from Mundipharma, Roxall, Sanofi, MSD, Faes Farma, Hikma, UCB, Astra Zeneca, Stallergenes, Abbott, and Bial, outside the submitted work. Dr. Cardona reports personal fees from ALK, Allergy Therapeutics, LETI, Thermofisher, Merck, Astrazeneca, and GSK, outside the submitted work. Former chair of the WAO Anaphylaxis Committee. Member of the working group of the EAACI anaphylaxis guidelines. Chair of the SLAAI anaphylaxis Committee. Dr. Campbell is a part-time employee of DBV Technologies and reports grants from National Health and Medical Research Council of Australia and personal fees from Allergenis, Westmead Fertility Centre, and Financial Markets Foundation for Children. Dr. Ebisawa reports personal fees from Mylan, outside the submitted work. Dr. El-Gamal has nothing to disclose. Dr. Fineman has nothing to disclose. Dr. Geller has nothing to disclose. Dr. Gonzalez-Estrada has nothing to disclose. Dr. Greenberger reports personal fees from Wolters Kluwer book, Wolters Kluwer Uptodate, and Allergy Therapeutics, outside the submitted work; and Expert testimony: Legal on anaphylaxis. Dr. Leung has nothing to disclose. Dr. Levin has nothing to disclose. Dr Muraro reports grants and personal fees from Aimmune and personal fees from DVB, Mylan, ALK and Nestle outside the submitted work. Dr. Sanchez Borges has nothing to disclose. Dr. Senna has nothing to disclose. Dr. Sheikh has nothing to disclose. Dr. Tanno has nothing to disclose. Dr. Thong has nothing to disclose. Dr. Turner reports grants from UK Medical Research Council, NIHR/Imperial BRC, UK Food Standards Agency, End Allergies Together, Jon Moulton Charity Trust; personal fees and non-financial support from Aimmune Therapeutics, DBV Technologies and Allergenis, personal fees and other from ILSI Europe and UK Food Standards Agency, outside the submitted work; current Chairperson of the WAO Anaphylaxis Committee, and joint-chair of the Anaphylaxis Working group of the UK Resuscitation Council. Dr. Worm reports other from Allergopharma GmbH & Co. KG, other from ALK-Abelló Arzneimittel GmbH, other from Mylan Germany GmbH, other from Leo Pharma GmbH, other from Sanofi-Aventis Deutschland GmbH, other from Regeneron Pharmaceuticals, other from DBV Technologies S.A, other from Stallergenes GmbH, other from HAL Allergie GmbH, other from Bencard Allergie GmbH, other from Aimmune Therapeutics UK Limited, other from Actelion Pharmaceuticals Deutschland GmbH, other from Novartis AG, other from Biotest AG, other from AbbVie Deutschland GmbH & Co. KG, other from Lilly Deutschland GmbH, outside the submitted work., (© 2021 The Author(s).)

Epidemiological studies have been pivotal in advancing understanding of the etiology of food allergy and in guiding the development of evidence-based guidelines for food allergy prevention and clinical management. In recent years, as research into the population-level distribution and determinants of food allergy has accumulated, data indicate that substantial differences in food allergy outcomes and management exist across racial/ethnic and other socioeconomic strata. This clinical commentary aims to provide a review of existing epidemiological studies and shed valuable light on the disparate burden of food allergy. Emerging methods to quantify environmental exposure and food allergy outcomes are detailed, as are specific areas in which future research is warranted. We also highlight the role that epidemiology plays in advancing health equity and provide a framework as to how it can effectively inform health policy at all phases of the policy cycle-from initial population health assessment to the evaluation and refinement of specific health policies (ie, national guidelines to promote earlier introduction of peanut-containing foods for allergy prevention)., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The term "Food Allergy" refers to a complex global health problem with a wide spectrum of severity. However, a uniform definition of severe food allergy is currently missing. This systematic review is the preliminary step towards a state-of-the-art synopsis of the current evidence relating to the severity of IgE-mediated food allergy; it will inform attempts to develop a consensus to define food allergy severity by clinicians and other stakeholders., Methods: We will undertake a systematic review, which will involve searching international biomedical databases for published studies. Studies will be independently screened against pre-defined eligibility criteria and critically appraised by established instruments. Data will be descriptively and, if possible and applicable, quantitatively synthesised., Ethics and Dissemination: This study does not require any specific ethical approval since it is a systematic review. We plan to report results from this systematic review in a peer reviewed journal. These results will be used to inform the development of an international consensus to define severe food allergy. Author's potential conflicts of interest are clearly stated., Prospero Registration Number: CRD42020183103., Competing Interests: The following authors declared no potential interests: Ignacio J Ansotegui; Stefania Arasi; Shahd Daher; Alessandro Fiocchi; Ulugbek Nurmatov; Stavros Petrou; Graham Roberts; Mario Sánchez-Borges; Luciana Kase Tanno; Marta Vazquez Ortiz; Gary Wing-Kin Wong. Some of the authors have professional affiliations related to the content of the systematic review as set out below: Audrey Dunn-Galvin: consultancy fee from Aimmune and DBV; Motohiro Ebisawa: lecture fees: DBV technologies and Mylan; Philippe Eigenmann: Research grants and support: Ulrich Muller Gierock Foundation, 10.13039/100011033ThermoFisher Scientific; Consultant: DBV technologies, Nesté, Danone, Novartis, Abbott; Speaking engagements: ThermoFisher Scientific, ALK, Abbott; Stock options: DBV technologies; Montserrat Fernandez-Rivas: research grants from the Spanish Government (10.13039/501100003329MINECO, 10.13039/501100004587ISCIII) for the projectos SOLMILK, ARADyAL network and PI19/01095; consultancy fees from Aimmune, DBV, Novartis, SPRIM; lecture fees from ALK, Allergy Therapeutics, Diater, GSK, HAL Allergy, Thermofisher Scientific. Ruchi Gupta: grants from 10.13039/100000002The National Institute of Health (NIH) (R21 ID # AI135705, R01 ID# AI130348, U01 ID # AI138907), Rho Inc., Stanford Sean N. Parker Center for Allergy Research, UnitedHealth Group, 10.13039/100011033Thermo Fisher Scientific, 10.13039/100004328Genentech, and the National Confectioners Association (NCA); is employed by Ann & Robert H. Lurie Children's Hospital of Chicago; is a Professor of Pediatrics at Northwestern University; and serves as a medical consultant/advisor for Before Brands, Kaléo Inc., Genentech, ICER, FARE, Aimmune TherapeuticsAimmune Therapeutics, and DBV Technologies; Anna Nowak-Wegrzyn: Grant/Research/Clinical Trial Support: DBV Technologies; 10.13039/100000060ITN/NIAID; 10.13039/100004324Astellas Pharmaceutical; Sanofi-Aventis [Future therapies for food allergy]. International FPIES Association [FPIES, unpaid advisor]. Consultant/Advisory Boards: Gerber Nutrition Institute; Merck. Speaking engagements: Nestle, Thermofisher Scientific; Sayantani B Sindher: supported by 10.13039/100000002NIH grants. Involved in clinical trials with Regeneron, Aimmune Therapeutics, DBV Technologies, Adare Pharmaceuticals, Sanofi, Novartis; Paul J Turner: grants from UK Medical Research Council, NIHR/Imperial BRC, JM Charitable Foundation and UK Food Standards Agency; personal fees fromUK Food Standards Agency, DBV Technologies, ILSI Europe and Allergenis, non-financial support from Aimmune Therapeutics; Brian P Vickery: Employment: Pediatric Institute of Emory University + Children's Healthcare of Atlant; Consultant/Advisor: Aimmune Therapeutics; AllerGenis, LLC; Food Allergy Research and Education (FARE); Reacta Biosciences; Grant support: Immune Tolerance Network; 10.13039/100000060NIH-NIAID; 10.13039/100006423FARE; 10.13039/100004328Genentech; Clinical investigator: Aimmune; DBV Technologies; Regeneron., (© 2020 Published by Elsevier Inc. on behalf of World Allergy Organization.)

Background: Anaphylaxis is a severe, systemic hypersensitivity reaction that can be potentially life-threatening. Anaphylaxis during oral food challenge is not uncommon and can usually be effectively managed with intramuscular adrenaline as first line treatment. Although very rare, fatal anaphylaxis during in-hospital food challenge has been reported., Objective: We describe our experience of cases of refractory anaphylaxis at in-hospital challenge and propose a framework for escalation of treatment in such cases using intravenous infusion of adrenaline which has been adopted for widespread use elsewhere., Methods: We present four patients who all experienced severe life-threatening anaphylaxis, refractory to intramuscular adrenaline treatment, during supervised oral food challenges. Patient data were collected from contemporaneous notes, and patient consent was obtained., Results: In all four cases, the anaphylaxis reactions were amenable to treatment with low-dose intravenous adrenaline, with no reported adverse effects., Conclusion and Clinical Relevance: These cases demonstrate the need for clinicians undertaking higher risk allergen challenges to be able to manage cases of severe anaphylaxis refractory to intramuscular adrenaline, and to consider a framework for managing these reactions. While peripheral intravenous adrenaline infusions should always be initiated only in conjunction with expert input, the protocol suggested is simple enough to be undertaken within the hospital environment while more experienced support is obtained., (© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: Tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral ribonucleic acid (RNA) using reverse transcription polymerase chain reaction (RT-PCR) are pivotal to detecting current coronavirus disease (COVID-19) and duration of detectable virus indicating potential for infectivity., Methods: We conducted an individual participant data (IPD) systematic review of longitudinal studies of RT-PCR test results in symptomatic SARS-CoV-2. We searched PubMed, LitCOVID, medRxiv, and COVID-19 Living Evidence databases. We assessed risk of bias using a QUADAS-2 adaptation. Outcomes were the percentage of positive test results by time and the duration of detectable virus, by anatomical sampling sites., Results: Of 5078 studies screened, we included 32 studies with 1023 SARS-CoV-2 infected participants and 1619 test results, from - 6 to 66 days post-symptom onset and hospitalisation. The highest percentage virus detection was from nasopharyngeal sampling between 0 and 4 days post-symptom onset at 89% (95% confidence interval (CI) 83 to 93) dropping to 54% (95% CI 47 to 61) after 10 to 14 days. On average, duration of detectable virus was longer with lower respiratory tract (LRT) sampling than upper respiratory tract (URT). Duration of faecal and respiratory tract virus detection varied greatly within individual participants. In some participants, virus was still detectable at 46 days post-symptom onset., Conclusions: RT-PCR misses detection of people with SARS-CoV-2 infection; early sampling minimises false negative diagnoses. Beyond 10 days post-symptom onset, lower RT or faecal testing may be preferred sampling sites. The included studies are open to substantial risk of bias, so the positivity rates are probably overestimated.

Substantial progress has been made in characterising the risk associated with exposure to allergens in food. However, absence of agreement on what risk is tolerable has made it difficult to set quantitative limits to manage that risk and protect allergic consumers effectively. This paper reviews scientific progress in the area and the diverse status of allergen management approaches and lack of common standards across different jurisdictions, including within the EU. This lack of regulation largely explains why allergic consumers find Precautionary Allergen Labelling confusing and cannot rely on it. We reviewed approaches to setting quantitative limits for a broad range of food safety hazards to identify the reasoning leading to their adoption. This revealed a diversity of approaches from pragmatic to risk-based, but we could not find clear evidence of the process leading to the decision on risk acceptability. We propose a framework built around the criteria suggested by Murphy and Gardoni (2008) for approaches to defining tolerable risks. Applying these criteria to food allergy, we concluded that sufficient knowledge exists to implement the framework, including sufficient expertise across the whole range of stakeholders to allow opinions to be heard and respected, and a consensus to be achieved., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The degree to which different volatile anesthetics depress carotid body hypoxic response relates to their ability to activate TASK potassium channels. Most commonly, volatile anesthetic pairs act additively at their molecular targets. We examined whether this applied to carotid body TASK channels., Methods: We studied halothane and isoflurane effects on hypoxia-evoked rise in intracellular calcium (Ca2+i, using the indicator Indo-1) in isolated neonatal rat glomus cells, and TASK single-channel activity (patch clamping) in native glomus cells and HEK293 cell line cells transiently expressing TASK-1., Results: Halothane (5%) depressed glomus cell Ca2+i hypoxic response (mean ± SD, 94 ± 4% depression; P < 0.001 vs. control). Isoflurane (5%) had a less pronounced effect (53 ± 10% depression; P < 0.001 vs. halothane). A mix of 3% isoflurane/1.5% halothane depressed cell Ca2+i response (51 ± 17% depression) to a lesser degree than 1.5% halothane alone (79 ± 15%; P = 0.001), but similar to 3% isoflurane alone (44 ± 22%; P = 0.224), indicating subadditivity. Halothane and isoflurane increased glomus cell TASK-1/TASK-3 activity, but mixes had a lesser effect than that seen with halothane alone: 4% halothane/4% isoflurane yielded channel open probabilities 127 ± 55% above control, versus 226 ± 12% for 4% halothane alone (P = 0.009). Finally, in HEK293 cell line cells, progressively adding isoflurane (1.5 to 5%) to halothane (2.5%) reduced TASK-1 channel activity from 120 ± 38% above control, to 88 ± 48% (P = 0.034)., Conclusions: In all three experimental models, the effects of isoflurane and halothane combinations were quantitatively consistent with the modeling of weak and strong agonists competing at a common receptor on the TASK channel., (Copyright © 2020, the American Society of Anesthesiologists, Inc. All Rights Reserved.)