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Immediate drug-induced hypersensitivity reactions (IDHSRs) have conventionally been attributed to an immunoglobulin E (IgE)-mediated mechanism. Nevertheless, it has now been acknowledged that IDHSRs can also occur independently of IgE involvement. Non-IgE-mediated IDHSRs encompass the activation of effector cells, both mast cell-dependent and -independent and the initiation of inflammatory pathways through immunogenic and nonimmunogenic mechanisms. The IDHSRs involve inflammatory mediators beyond histamine, including the platelet-activating factor, which activates multiple cell types, including smooth muscle, endothelium, and MC, and evidence supports its importance in IgE-mediated reactions in humans. Clinically, distinguishing IgE from non-IgE mechanisms is crucial for future treatment strategies, including drug(s) restriction, readministration approaches, and pretreatment considerations. However, this presents significant challenges because certain drugs can trigger both mechanisms, and their presentations can appear similarly, ranging from mild to life-threatening symptoms. Thus, history alone is often inadequate for differentiation, and skin tests lack a standardized approach. Moreover, drug-specific IgE immunoassays have favorable specificity but low sensitivity, and the usefulness of the basophil activation test remains debatable. Lastly, no biomarker reliably differentiates between both mechanisms. Whereas non-IgE-mediated mechanisms likely predominate in IDHSRs, reclassifying most drug-related IDHSRs as non-IgE-mediated, with suggested prevention through dose administration adjustments, is premature and risky. Therefore, continued research and validated diagnostic tests are crucial to improving our capacity to distinguish between these mechanisms, ultimately enhancing patient care., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Early recognition of perioperative anaphylaxis, a life-threatening, usually IgE-mediated, immediate hypersensitivity, is essential, but bedside diagnosis is not always straightforward because clinical presentation may vary., Objectives: To describe early characteristics of perioperative immediate hypersensitivity, with special attention to cutaneous phenotypes, and identify risk factors for IgE-mediated allergy., Methods: We retrospectively analyzed data from adults with suspected perioperative immediate hypersensitivity who were investigated in two academic medical centers. Multivariable logistic regression was conducted to evaluate associations among patient, clinical, and paraclinical characteristics and IgE-mediated allergy., Results: Of 145 enrolled patients, 99 (68.3%) and 46 (31.7%) were respectively categorized in the IgE-mediated allergy and non-allergy groups. Cutaneous vasoconstriction phenotype (pallor, piloerection, thelerethism, and sweating with or without cyanosis) occurring within minutes (or even 1 minute) of drug exposure was strongly associated with IgE-mediated allergy (adjusted odds ratio [aOR] = 28.02; 95% CI, 4.41-305.18). IgE-mediated allergy was always life-threatening in this setting. Other early factors associated with allergy were low end-tidal carbon dioxide 25 mm Hg or less (aOR = 5.45; 95% CI, 2.39-26.45), low mean arterial pressure 60 mm Hg or less (aOR = 3.82; 95% CI, 1.28-17.31), and early cutaneous vasodilation (erythema, urticaria, and/or angioedema) (aOR = 2.78; 95% CI, 0.73-20.54). Late cutaneous vasodilation after restoration of hemodynamics corroborated the diagnosis of allergy (aOR = 23.67; 95% CI, 4.94-205.09). The best-fit model including three readily available variables (cutaneous phenotype involving the three modalities [reference lack of cutaneous signs], low mean arterial pressure, and low end-tidal carbon dioxide) had an area under the curve of 0.91., Conclusions: Cutaneous vasoconstriction phenotype is associated with the strongest risk of life-threatening allergy and thus may be regarded as pathognomonic of perioperative IgE-mediated anaphylaxis., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Carboplatin administration poses a risk of immediate hypersensitivity reactions (IHRs) that tend to increase with repeated administration and are mostly IgE-mediated., Objective: This study evaluated the usefulness of carboplatin-prescreening intradermal skin tests (IDTs)., Methods: Carboplatin-prescreening IDTs were routinely conducted in patients with a history of receiving six or more carboplatin cycles beginning in January 2021. The primary objective was to assess disparities in the incidence of unanticipated IHRs to carboplatin administration. We compared patients in the intervention group (from 2021 to 2022) and those who did not undergo prescreening IDTs under the same conditions (preintervention group, from 2019 to 2020). Secondary objectives included evaluating the sensitivity and specificity of the prescreening IDT and the incidence of carboplatin IHR according to the number of infusion cycles., Results: The intervention group was composed of 67 patients who were administered 347 carboplatin cycles whereas the preintervention group included 96 patients who were administered 464 carboplatin cycles. The risk of unanticipated carboplatin IHRs decreased by 83.2% in the intervention group compared with results in the preintervention group (preintervention group, 3.45%, n = 16 vs intervention group, 0.58%, n = 2; P = .005). The prescreening IDT showed a sensitivity and specificity of 77.78% and 99.41%, respectively. The risk of newly developed IHRs based on the number of carboplatin cycles was less than 1% (cycles 1-5), 2.11% (cycle 6), 3.90% (cycles 7-12), 2.90% (cycles 13-18), and 0.74% (cycles 19 and greater), respectively., Conclusions: Initiating carboplatin-prescreening IDTs from the seventh cycle on significantly reduced the risk of unanticipated IHRs., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The association between having older siblings and decreased risk for atopic symptoms is well-established. This has been interpreted as evidence for the microbiota hypothesis, i.e. that increased early-childhood microbial exposure caused by siblings protects from immune hypersensitivities. However, possible confounders of the association have received little attention. We used register data on Finnish cohorts born in 1995-2004 (N = 559,077) to assess medication purchases for atopic diseases: antihistamines, eczema medication, asthma medication and Epinephrine. We modelled the probability of atopic medication purchases at ages 0-15 by birth order controlling for important observed confounders and all unobserved genetic and environmental characteristics shared by siblings in a within-family fixed effects model. We further studied medication purchases among first-borns according to the age difference with younger siblings to assess whether having younger siblings in early childhood is beneficial. Having older siblings was associated with a lower probability of atopic medication purchases. Compared to first-borns, the probability was 10-20% lower among second-borns, 20-40% lower among third-borns, and 30-70% lower among subsequent children, depending on medication type. Confounding accounted for up to 75% of these differences, particularly for asthma and eczema medication, but significant differences by birth order remained across all medication types. Among first-borns, a smaller age difference with younger siblings was related to a lower likelihood of atopic medication use. Our results, based on designs that account for unobserved confounding, show that exposure to siblings in early childhood, protects from atopic diseases, and thus strongly support the microbiota hypothesis., (© 2024. The Author(s).)

Proton pump inhibitors (PPIs) are invaluable therapeutic options in a variety of dyspeptic diseases. In addition to their well-known risk profile, PPI consumption is related to food and environmental allergies, dysbiosis, osteoporosis, as well as immediate and delayed hypersensitivity reactions (HSRs). The latter, although a rare event, around 1%-3%, due to the extraordinarily high rate of prescription and consumption of PPIs are related to a substantial risk. In this Position Paper, we provide clinicians with practical evidence-based recommendations for the diagnosis and management of HSRs to PPIs. Furthermore, the unmet needs proposed in the document aim to stimulate more in-depth investigations in the topic., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Immediate drug hypersensitivity reactions (IDHRs) are a burden for patients and the health systems. This problem increases when taking into account that only a small proportion of patients initially labelled as allergic are finally confirmed after an allergological workup. The diverse nature of drugs involved will imply different interactions with the immunological system. Therefore, IDHRs can be produced by a wide array of mechanisms mediated by the drug interaction with specific antibodies or directly on effector target cells. These heterogeneous mechanisms imply an enhanced complexity for an accurate diagnosis and the identification of the phenotype and endotype at early stages of the reaction is of vital importance. Currently, several endophenotypic categories (type I IgE/non-IgE, cytokine release, Mast-related G-protein coupled receptor X2 (MRGPRX2) or Cyclooxygenase-1 (COX-1) inhibition and their associated biomarkers have been proposed. A precise knowledge of endotypes will permit to discriminate patients within the same phenotype, which is crucial in order to personalise diagnosis, future treatment and prevention to improve the patient's quality of life., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Local anesthetic (LA) drugs are commonly used in clinical practice to provide effective analgesia, including in dentistry and minor surgical procedures. The perception of a high risk of allergy in daily applications leads to the referral of atopic patients and those with other drug allergies to allergy clinics for the evaluation of allergic reactions to LA. The aim of this study was to determine who should be referred to the allergy clinic for LA allergy testing, assess the frequency of LA allergy in pediatric patients, and identify the negative predictive value of skin tests in diagnosis., Methods: January 2017-July 2023, the clinical and laboratory data, as well as the results of drug allergy tests, of patients referred to our pediatric allergy clinic by dentists and physicians performing minor surgical procedures with suspected LA allergy were retrospectively evaluated., Results: Our study included a total of 153 patients, comprising 84 girls (54.9%) and 69 boys (45.1%), with a mean age of 8.9 (±3.3) years. The most common reason for referral was a history of non-LA drug allergies (n = 66, 43.2%), followed by asthma (n = 25, 16.3%). Hypersensitivity reactions (HRs) with LA were most commonly associated with articaine (n = 7, 4.8%), followed by lidocaine (n = 6, 4.1%). When intradermal tests were evaluated, 17 patients (11.1%) had a positive test result. The positivity for lidocaine was 70.6% (n = 12), and prilocaine was 29.4% (n = 5). Subcutaneous provocation was administered to 109 patients (71.2%), and one patient exhibited local erythema and swelling with prilocaine., Conclusion: Although LA allergy is a rare occurrence, consultations of this nature are frequently requested from allergy clinics in real life. Considering the negative predictive value of skin tests performed with LA drugs, the reaction rate appears to be low in patients with atopy or other drug allergies. It is crucial for all relevant healthcare professionals to be knowledgeable about the appropriate approach to suspected LA allergies to avoid unnecessary tests. To the best of our knowledge, our study is the most comprehensive work in the literature that evaluates the results of diagnostic tests in children referred with a suspicion of LA allergy., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: There is no accepted grading system classifying the severity of immediate reactions to drugs., Objective: The purpose of this article is to present a proposed grading system developed through the consensus of drug allergy experts from the United States Drug Allergy Registry (USDAR) Consortium., Methods: The USDAR investigators sought to develop a consensus severity grading system for immediate drug reactions that is applicable to clinical care and research., Results: The USDAR grading scale scores severity levels on a scale of 0 to 4. A grade of no reaction (NR) is used for patients who undergo challenge without any symptoms or signs, and it would confirm a negative challenge result. A grade 0 reaction is indicative of primarily subjective complaints that are commonly seen with both historical drug reactions and during drug challenges, and it would suggest a low likelihood of a true drug allergic reaction. Grades 1 to 4 meet the criteria for a positive challenge result and may be considered indicative of a drug allergy. Grade 1 reactions are suggestive of a potential immediate drug reaction with mild symptoms. Grade 2 reactions are more likely to be immediate drug reactions of moderate severity. Grade 3 reactions have features suggestive of a severe allergic reaction, whereas grade 4 reactions are life-threatening reactions such as anaphylactic shock and fatal anaphylaxis., Conclusion: This proposed grading schema for immediate drug reactions improves on prior schemata by being developed specifically for immediate drug reactions and being easy to implement in clinical and research practice., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Allergic bronchopulmonary aspergillosis (ABPA) develops in the presence or absence of asthma, either atopic or nonatopic. We have tried to explore the essential components in the pathogenesis of the disease, which are either consistent and variable according to the presence and type of asthma., Methods: Non-cystic fibrosis ABPA cases satisfying Asano's criteria were extracted from a prospective registry of ABPA and related diseases in Japan between 2013 and 2023. According to the type of preceding asthma, ABPA was classified into three groups: ABPA sans asthma (no preceding asthma), ABPA with atopic asthma, and ABPA with nonatopic asthma. Exploratory and confirmatory factor analyses were performed to identify the components that determined the clinical characteristics of ABPA., Results: Among 106 cases of ABPA, 25 patients (24%) had ABPA sans asthma, whereas 57 (54%) and 24 (23%) had ABPA with atopic and nonatopic asthma, respectively. Factor analysis identified three components: allergic, eosinophilic, and fungal. Patients with atopic asthma showed the highest scores for the allergic component (p < .001), defined by total and allergen-specific IgE titers and lung opacities, and the lowest scores for the fungal component defined by the presence of specific precipitin/IgG or positive culture for A. fumigatus. Eosinophilic components, including peripheral blood eosinophil counts and presence of mucus plugs/high attenuation mucus in the bronchi, were consistent among the three groups., Conclusion: The eosinophilic component of ABPA is considered as the cardinal feature of ABPA regardless of the presence of preceding asthma or atopic predisposition., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Amoxicillin (AX) combined or not with clavulanic acid (CLV) is frequently involved in IgE-mediated reactions. Drug provocation test (DPT) is considered as the gold standard for diagnosis, although contraindicated in high-risk patients. Basophil activation test (BAT) can help diagnose immediate reactions to beta-lactams, although controversy exists regarding the best activation marker. We have performed a real-life study in a prospective cohort to analyze the real value of BAT as diagnostic tool and the best activation marker, CD63 and CD203c, for the evaluation of immediate reactions to these drugs., Methods: We prospectively evaluated patients with a clinical suspicion of immediate reactions after AX or AX-CLV administration during a 6-year period. The allergological work-up was done following the EAACI recommendations. BAT was performed in all patients using CD63 and CD203c as activation markers., Results: In AX-allergic patients, both activation markers, CD63 and CD203c, showed similar SE values (48.6% and 46.7%, respectively); however, specificity was of 81.1% and 94.6%, respectively, with CD203c showing good positive predictive value and like-hood ratio. In CLV-allergic patients, CD203c showed higher SE (50%) than CD63 (42.9%), maintaining the same value of SP (80%). Combining the results of both markers can slightly increase the sensitivity (51.4% for AX and 54.8% for CLV), although decreasing the specificity (79.7% and 73%, respectively). Interestingly, all patients with an anaphylactic shock showed a positive BAT to CLV using CD203c., Conclusions: BAT using CD203c showed a good confirmatory power, especially for AX allergy. Placing BAT as a first step in the diagnostic procedure can help reduce the need of performing a complete allergological work-up in 46.6% of patients, diminishing the risk of reinducing allergic reactions., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Polyethylene glycol (PEG) allergy has been recently observed after COVID-19 mRNA vaccination. We present a case of a patient with a history of two hospitalisations for unexplained recurrence of immediate-type hypersensitivity reactions and anaphylaxis who was diagnosed with PEG allergy in early childhood. Subsequently, he was instructed to avoid using PEG-containing daily necessities and drugs. However, in middle childhood, he presented with immediate-type hypersensitivity reactions after taking PEG-free antibiotics. The prick test was positive for the whole drug but negative for its active ingredient. PEG can cross-react with compounds with a C-C-O skeleton as analogue substances; accordingly, the presence of a substance with a similar skeleton in the additive may have been the causative factor. Our findings indicate that patients with PEG allergy may experience immediate-type hypersensitivity reactions to analogue substances., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of Review: Serum tryptase, a mast cell marker, provides clues for the mechanism, severity, and management of drug hypersensitivity induced by immunoglobulin E dependent or independent mast cell activation., Recent Findings: The interpretation of serum tryptase levels has been challenged during the last 2 years by major advances in tryptase genetics and their rapid incorporation into clinical practice. On the contrary, new pathophysiological insight into nonmast cell-dependent immediate hypersensitivity has been gained., Summary: This review provides up-to-date information on the pathophysiology and recommended use and interpretation of tryptase in the context of drug hypersensitivity reactions as a function of their endotype., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Local anesthetics (LA) are commonly used in procedures and in topical agents for pain management. With the increasing use of LA drugs, the management of LA reactions is more frequently encountered in the office and in operating rooms. True allergic reactions involving IgE-mediated reactions and anaphylaxis are rare; they have only been identified in case reports and account for less than 1% of adverse LA reactions. Most reactions are non-allergic or are a result of hypersensitivity to other culprits such as preservatives, excipients, or other exposures. LA reactions that are misclassified as true allergies can lead to unnecessary avoidance of LA drugs or delays in surgical procedures that require their use. A detailed history of prior LA reactions is the first and most crucial step for understanding the nature of the reaction. Reactions that are suspicious for an immediate hypersensitivity reaction can be evaluated with skin prick and intradermal testing with subsequent graded challenge. Reactions that are suspicious for a delayed hypersensitivity reaction can be evaluated with patch testing., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Gadolinium based contrast agents (GBCAs) are safe compounds globally used in magnetic resonance imaging (MRI). However, in last years it has been detected an increase of immediate hypersensitivity reactions (IHRs) to them. Diagnosis of IHRs to GBCAs is based on clinical symptoms, skin tests (STs) and drug provocation test (DPT). But DPTs are not without risks, thus it is important to implement an in vitro alternative method such as the basophil activation test (BAT). We described the clinical validation of the BAT using ROC curves from a control population formed by 40 healthy individuals without previous reactions to any contrast agents and 5 patients suffering from IHRs to GBCAs. Four patients presented IHRs to gadoteric acid (GA) as the culprit agent and another one to gadobutrol (G). Basophil reactivity was measured in percentage of CD63 expression and in stimulation index (SI). The optimal cut-off with the highest sensitivity (S) and specificity (E) for the GA was of 4.6% at 1:100 dilution (S = 80% and E = 85%; AUC = 0.880, p = 0.006). For the SI with GA, the cut-off of highest sensitivity and specificity was of 2.79 at 1:100 dilution (S = 80% and E = 100%; AUC = 0.920, p = 0.002). Sensitivity did not show differences between STs regarding the BAT (p < 0.05). Moreover, the BAT was able to detect one case with IHR to GA which had negative STs. Therefore, the BAT is a useful method in diagnosis of IHRs to GBCAs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Chlorhexidine generally has a good safety profile. However, allergic reactions are reported with increasing frequency. In China, it is rarely reported, and its characteristics are unknown. The purpose of this study was to summarize the experience of a Chinese allergy center with chlorhexidine allergy., Methods: The authors retrospectively reviewed all patients who underwent chlorhexidine allergy testing in the Allergy Center of West China Hospital, Sichuan University (Chengdu, China), in the period February 2018 to May 2022 (n = 43 patients) and included the patients diagnosed with chlorhexidine allergy for analysis., Results: Ten patients who were diagnosed by skin prick and serum-specific immunoglobulin E tests were included. They experienced a total of 30 allergic reactions to chlorhexidine (mean ± SD, 3.0 ± 1.3). Five patients experienced six allergic reactions (6 of 30, 20%) during general or local anesthesia, and they may have been exposed to chlorhexidine via different routes. Only one allergic reaction (1 of 30, 3%) was recorded with exposure via a mouthwash. The other 23 allergic reactions (23 of 30, 77%) were caused via a skin disinfectant; the route of exposure was IV cannulation in 22 allergic reactions (22 of 23, 96%) and broken skin in one allergic reaction (1 of 23, 4%). The symptoms included a quick onset and great severity. Two patients (2 of 10, 20%) had been accidentally re-exposed to chlorhexidine after diagnosis., Conclusions: This study conducted in China showed that the majority of reactions to chlorhexidine were attributed to skin disinfectants, and IV cannulation was the most common exposure route; in general, however, chlorhexidine allergy was easily overlooked. The potential allergenicity of chlorhexidine used for skin preparation before IV cannulation or should be considered in patients who develop allergic reactions perioperatively., (Copyright © 2023, the American Society of Anesthesiologists. All Rights Reserved.)

Background: Corticosteroids, which are anti-inflammatory and immunosuppressive agents used for the treatment of various diseases including allergic disorders, can induce immediate and delayed hypersensitivity reactions. Although these reactions are not common, due to the wide usage of corticosteroid medications, corticosteroid hypersensitivity reactions are clinically important., Objective: In this review, we summarise the prevalence, pathogenetic mechanism, clinical manifestations, risk factors, diagnostic and therapeutic approach for corticosteroid-induced hypersensitivity reactions., Methods: An integrative review of the literature was conducted using PubMed searches (mainly large cohort-based studies) regarding the different aspects of corticosteroid hypersensitivity., Results: Hypersensitivity reactions to corticosteroids can be immediate or delayed and can follow all modes of corticosteroid administration. Prick and intradermal skin tests are useful diagnostic tools for immediate hypersensitivity reactions, patch tests are useful for delayed hypersensitivity reactions. According to the diagnostic tests an alternative (safe) corticosteroid agent should be administered., Conclusion: Physicians of all medical disciplines should be aware that corticosteroids can cause (paradoxically) immediate or delayed allergic hypersensitivity reactions. The diagnosis of such allergic reactions is challenging since it is often difficult to distinguish between hypersensitivity reactions and deterioration of the basic inflammatory disease (e.g., worsening of asthma or dermatitis). Thus, a high index of suspicion is needed in order to identify the culprit corticosteroid.

Background: In light of the pandemic of spurious penicillin allergy, correct diagnosis of amoxicillin (AX) allergy is of great importance. The diagnosis of immediate hypersensitivity reactions relies on skin tests and specific IgE, and although reliable, these are not absolutely predictive. Therefore, drug challenges are needed in some cases, which contain the risk of severe reactions. Safe in vitro diagnostics as an alternative for the drug challenge in the diagnostic workup of AX allergy would be more than welcome to fill this gap. In this respect, the basophil activation test (BAT) has shown potential, but its clinical reliability is doubtful., Objective: To investigate the reliability of the BAT to AX and determining its exact place in the diagnostic algorithm of AX allergy., Methods: BAT for AX was performed in 70 exposed control individuals and 66 patients diagnosed according to the European Academy of Allergy and Clinical Immunology guidelines for AX allergy. Upregulation of both CD63 and CD203c was flow-cytometrically assessed., Results: Analyses revealed that 1370 μmol/L and 685 μmol/L were the most discriminative stimulation concentrations for CD63 and CD203c upregulation, respectively, and a diagnostic threshold of 9% for positivity for both markers was identified. At these concentrations, sensitivity and specificity for CD63 upregulation were 13% and 100%, respectively, and for CD203c upregulation, 23% and 98%., Conclusions: BAT with dual analysis of CD63 and CD203c is of poor performance to document AX allergy. The sensitivity is too low to let it occupy a prominent role in the diagnostic algorithm., (Copyright © 2022. Published by Elsevier Inc.)

Background: The burden of occupational hand eczema in hairdressers is high, and (partly strong) allergens abound in the hair cosmetic products they use., Objectives: To systematically review published evidence concerning contact allergy to an indicative list of active ingredients of hair cosmetics, namely, p-phenylenediamine (PPD), toluene-2,5-diamine (PTD), persulfates, mostly ammonium persulfate (APS), glyceryl thioglycolate (GMTG), and ammonium thioglycolate (ATG), concerning the prevalence of sensitization, particularly in terms of a comparison (relative risk; RR) between hairdressers and non-hairdressers., Methods: Following a PROSPERO-registered and published protocol, eligible literature published from 2000 to February 2021 was identified, yielding 322 publications, and extracted in standardized publication record forms, also considering risk of bias., Results: Based on 141 publications, the contact allergy prevalence to PPD was 4.3% (95% CI: 3.8-4.9%) in consecutively patch tested patients. Other ingredients were mostly tested in an aimed fashion, yielding variable, and partly high contact allergy prevalences. Where possible, the RR was calculated, yielding an average increased sensitization risk in hairdressers of between 5.4 (PPD) and 3.4 (ATG). Additional evidence related to immediate-type hypersensitivity, experimental results, exposures, and information from case reports was qualitatively synthesized., Conclusions: An excess risk of contact allergy is clearly evident from the pooled published evidence from the last 20 years. This should prompt an improvement in working conditions and product safety., (© 2022 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Immediate drug hypersensitivity reactions (DHRs) are historically thought to be because of immunoglobulin E (IgE) cross-linking, causing mast cell degranulation and release of mediators like tryptase and histamine. With the increasing use of monoclonal antibodies, it has become apparent that some patients present atypical features during immediate DHRs, including occurrence in initial exposure, a lack of urticaria and angioedema, and the presence of fever, chills, rigors and musculoskeletal pain as the predominant symptoms. This observation led to the recognition of a novel phenotype of immediate DHRs called cytokine release syndrome (CRS). Other types of immediate DHRs include infusion-related reactions (which present similarly to CRS), and mixed reactions (which share overlapping features of both type 1 reactions and CRS). Desensitization to culprit drugs can be a lifesaving option in patients who develop immediate DHRs to first-line treatment. Whereas robust data are supporting the safety and efficacy of drug desensitization, breakthrough reactions can still occur and CRS seems to be a more common cause than type 1 reactions. Tryptase has been the only available biomarker for immediate DHRs and is associated with type 1 reactions. Emerging evidence consistently found the association between increased serum interleukin 6 level and DHR-related CRS, suggesting that interleukin 6 can be a novel biomarker, in addition to tryptase, to distinguish various types of DHRs. In the era of precision medicine, phenotyping and endotyping hypersensitivity reactions to chemotherapy and monoclonal antibodies using validated biomarkers should be part of routine drug allergy care., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The susceptibility of the atopic population to respiratory infections (RI) has not been fully elucidated. This susceptibility is attributed to the immune dysregulation that characterizes atopic diseases. Although, the exact mechanisms involved are not fully understood, there is evidence that shows that the maturation of innate immunity progresses differently in patients with atopy. Objective: The aim of the study was to evaluate the susceptibility to viral RIs (VRI) based on the number and duration of them in different age groups in subjects with atopy and subjects without atopy. Methods: Seventy-eight subjects (39 healthy and 39 with atopy) were included in the study. All the subjects were evaluated by a specialist and defined as being atopic if they had a clinical history and/or symptoms compatible with any allergic diseases and relevant sensitizations. Epidemiologic data were recorded based on a standardized questionnaire, which included recording habits, conditions, and living environment as well as the history of viral infections during the last year. Results: In our population, children with atopy were found to be more susceptible to viral RIs than children without atopy (p = 0.02), whereas there was no difference in susceptibility between healthy adults and adults with atopy (18-45 years old). More specifically, the atopic age group 2-5 years old showed the higher susceptibility to VRIs. Conclusion: This study provided evidence that children with atopy, especially at ages 2-5 years old, had more numerically and prolonged RIs than did the subjects without atopy. These clinical findings support the hypothesis of distracted maturation of innate immunity in subjects with atopy.

Drug hypersensitivity is increasing worldwide as the consumption of drug is increasing. Many clinical presentations of drug hypersensitivity are complex and take place in the setting of illness and/or polypharmacotherapy. To review the most recent findings in the diagnosis and management of immediate drug hypersensitivity reactions. Studies were selected based on their relevance, originality and date of publication. The understanding of endotypes, biomarkers and phenotypes has improved the categorization of immediate hypersensitivity reactions. In this review, we discussed the short- and long-term management of anaphylaxis with a special focus on in vivo and in vitro diagnostic methods. Moreover, the clinical management of drug-induced anaphylaxis, the role of hidden allergens and the importance of delabeling are discussed. Endophenotyping is crucial to correctly diagnose and treat patients with immediate drug hypersensitivity reactions, preventing future episodes through drug desensitization., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Ibuprofen is the most common culprit drug causing nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity in children. We aimed to evaluate the frequency, clinical characteristics, and risk factors of confirmed ibuprofen allergy in children presenting with a history of suspected immediate type ibuprofen-induced hypersensitivity reactions., Methods: We evaluated 50 (35 M, 15 F) children with a median age of 7 years, who were referred to our clinic with suspected immediate ibuprofen hypersensitivity. Patients were subjected to a diagnostic work up including drug provocation tests (DPTs) with the culprit drug. Reactions were classified according to the European Academy of Allergy and Clinical Immunology Task Force recommendations for pediatric patients. Proven ibuprofen allergic patients underwent DPT to find a safe alternative drug., Results: Ibuprofen allergy was confirmed in 34% (n: 17) of children; 9 patients were diagnosed by DPTs and 8 patients diagnosed based on their histories. Angioedema was the most common clinical manifestation (n: 30, 60%). Among patients with proven ibuprofen allergy, 7 of them were classified as cross-intolerant. Cross-intolerance reactions were further classified as NSAID-exacerbated cutaneous disease (n = 1) and NSAID-induced urticaria/angioedema/anaphylaxis (n = 6). As an alternative drug, paracetamol was safely tolerated, whereas 1 patient developed angioedema and urticaria with nimesulide. Older age and male gender were identified as independent risk factors for immediate-type ibuprofen allergy., Conclusion: DPTs should be performed to confirm or exclude ibuprofen allergy in children and to find safe alternative drugs. Male gender and older age are risk factors for ibuprofen allergy. NSAID-induced hypersensitivity reactions in the pediatric population cannot be well defined using the adult classification system., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: Data on beta-lactam hypersensitivity (BLH) are mainly focused on immediate or mild nonimmediate reactions in the ambulatory setting, but limited in patients with concurrent illness and moderate-to-severe nonimmediate reactions in the hospitalized setting., Objective: To investigate the entire spectrum of BLH in Thai tertiary hospital., Methods: Clinical characteristics of 357 patients with suspected BLH were evaluated in a 7-year period. Culprit drug identification was performed in 335 patients by combined skin testing, in vitro testing, or drug provocation tests., Results: The predominant BLH presentations were non-immunoglobulin (Ig)E-mediated reactions with severe cutaneous adverse reactions of 18.9%, and BLH status was definitively confirmed in 18.1%. The most common verified culprits were cephalosporins (34.8%), particularly in hypersensitivity type IV reactions. Natural penicillins were the main implicated drugs in 48.5% of ambulatory patients. In contrast, cephalosporins and carbapenems were the main implicated drugs in hospitalized patients. Non-IgE-mediated anaphylaxis and serum sickness-like reaction remained diagnostically challenged. New generations of beta-lactams, hospitalized patients, recent allergic history, and underlying malignancies or autoimmune diseases were associated with increased BLH risk., Conclusion: At present, cephalosporins are the leading causes of BLH, particularly in non-IgE-mediated reactions. More research on the verification of non-IgE hypersensitivity reactions from new generations of beta-lactams should be better emphasized., Clinical Trial Registration: The registry was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, and listed on ClinicalTrials.gov (Identifier: NCT01667055; https://www., Clinicaltrials: gov/ct2/show/NCT01667055)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Beta-lactam (BL) antibiotics are the most often involved drugs in allergic reactions. Mild cutaneous reactions such as maculopapular exanthema or urticaria are the most common presenting complaints of BL allergy in the pediatric population. However, it can be challenging to distinguish BL-induced allergy from reactions due to infections or other reasons. In this study, we aimed to determine the clinical characteristics and potential risk factors of true BL allergy in children with suspected mild cutaneous reactions to BLs., Methods: We evaluated children who were admitted to our pediatric allergy clinic with suspected BL allergy in between January 2015 and March 2020. Patients with a history suggestive of immediate and non-immediate mild cutaneous reactions were included in the study. The oral challenge test (OCT) with the culprit drug was performed on all patients to confirm the diagnosis., Results: Two hundred fourteen (119 male and 95 female) patients with a median age of 4.9 years were evaluated. BL allergy was confirmed in 10.7% (23) of the patients, according to the OCT results. Most of the proven allergic reactions were of the immediate type (73.9%), and urticaria was the most common presenting complaint (60.8%) in proven BL-allergic patients. The negative predictive value of penicillin-G skin testing was 89.7% for immediate-type penicillin allergy and 93.4% for non-immediate reactions. Also, positive predictive value of penicillin-G skin testing was 50% for immediate and 25% for non-immediate reactions. In the multivariate logistic regression analysis, a history of proven drug allergy (Exp (B): 7.76, 95% CI: 1.88-31.97, p = 0.005) was found to be the risk for BL allergy., Conclusion: This study highlighted that OCTs should be performed to confirm the diagnosis in patients suspected of immediate and non-immediate mild cutaneous reactions to BLs and remove the overestimated "BL allergy" label. In these patients, a history of proven drug allergy might be a risk factor for true BL allergy., (© 2023 S. Karger AG, Basel.)

Background: Immediate hypersensitivity reactions to penicillins are often labeled on the basis of a similar set of symptoms, but a key feature of these reactions that can be reproduced in diagnostic testing may be the timing of a reaction in relation to the dose administration., Objective: To determine whether the timing of a reaction in response to the last dose of a penicillin would predict the results of diagnostic testing., Methods: We evaluated 1074 patients by performing skin tests, serum specific IgE assays (ImmunoCAP), and challenges. Patients who were evaluated by us more than 6 months after their reactions and found negative were reevaluated within 2 to 4 weeks., Results: Patients who had reacted within 1 hour after the first dose, within 1 hour after subsequent doses, more than 1 hour to within 6 hours after the first dose, or more than 1 hour to within 6 hours after subsequent doses were classified as group A (758 individuals), B (92), C (67), or D (157), respectively. Penicillin hypersensitivity was diagnosed in 707 patients (65.8%) by skin tests (407 patients, 57.6%), ImmunoCAP (47, 6.6%), both tests (232, 32.8%), or challenges (21, 3%). A conversion to allergy-test positivity occurred in 7 of 10 patients with anaphylactic reactions and in 1 of 28 patients with other reactions who were reevaluated after negative challenges. The rate of penicillin-allergic patients in groups A, B, C, and D was 85%, 35.9%, 35.8%, and 3.8%, respectively. Only 1 of 107 patients reporting cutaneous reactions lasting more than 1 day had positive results to allergy tests., Conclusions: IgE-mediated hypersensitivity can be diagnosed by skin tests in about 70% of subjects who react within 1 hour (eg, patients from groups A and B). This hypersensitivity can be lost over time, as demonstrated by the negativization of allergy tests in follow-up studies. In subjects with anaphylactic reactions, however, it is advisable to not consider this phenomenon definitive. In fact, a conversion to allergy test positivity can be observed in up to 20% of such subjects retested after negative challenges., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Iodinated contrast media produce non-immediate hypersensitivity reactions (NIHR). The goal of this prospective study was to determine the utility of skin tests and the subsequent tolerance to negative skin-tested iodinated contrasts in patients with NIHR caused by iomeprol., Methods: Prick and intradermal tests with iomeprol, iopamidol, iopromide, and iobitridol were performed in all patients. IV challenge with the causative contrast (iomeprol in 90%) was made if skin tests were negative. In case of a positive skin test with the causal contrast, or a positive challenge test with it, IV challenge test with an alternative, negative skin-tested contrast was performed in all patients., Results: Skin tests were positive in 47.6% (20/42) of patients with NIHR induced by iomeprol. Of the 66 challenge tests performed with negative skin-tested iodinated contrasts, tolerance was confirmed in 35 (53%): 32 iomeron, 2 iobitridol, 1 iopamidol. Cross-reactivity between iomeprol and iopamidol was 22% (4/20 in patients with positive skin tests and 5/21 in patients with negative skin tests)., Conclusions: Sensitivity of the skin tests was less than 50% NIHRs due to iomeprol, while the negative predictive value of skin tests in patients who tolerated challenges with alternative contrasts (mainly iopamidol) was 53% (35 tolerated out of 66 performed). The cross-reactivity between iomeprol and iopamidol is high., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Allergic reactions to the coronavirus disease 2019 (COVID-19) vaccines have raised concerns, particularly as repeated doses are required. Skin tests with the vaccines excipient were found to be of low value, whereas the utility of skin tests with the whole vaccine is yet to be determined., Objective: To evaluate a panel of skin tests and the outcomes of subsequent doses of immunization among subjects who suffered an immediate allergic reaction to the BioNTech (BNT162b2) COVID-19 vaccine., Methods: Between March and December 2021, patients who experienced symptoms consistent with immediate allergic reactions to the BNT162b2 vaccine and were referred to the Sheba Medical Center underwent skin testing with polyethylene glyol (PEG)-containing medicines, Pfizer-BNT162b2, and Oxford-AstraZeneca vaccine (AZD1222). Further immunization was performed accordingly and under medical observation., Results: A total of 51 patients underwent skin testing for suspected allergy to the COVID vaccines, of which 38 of 51 (74.5%) were nonreactive, 7 of 51(13.7%) had no skin sensitization but suffered a clinical reaction during skin testing (mainly cough), and 6 of 51 (11.7%) exhibited immediate skin sensitization. Both skin sensitization and cough during testing were related to a higher use of adrenaline following immunization (P = .08 and P = .024, respectively). Further immunization with the BNT162b2 vaccine was recommended unless sensitization or severe reaction to previous immunization was evident. The latter were referred to be tested/receive the alternative AZD1222 vaccine. Ten patients underwent skin testing with AZD1222: 2 of 10 (20%) demonstrated skin sensitization to both vaccines; thus, 8 of 10 were immunized with the AZD1222, of which 2 of 8 (25%) had allergic reactions., Conclusions: Immediate allergic reactions to COVID-19 vaccines are rare but can be severe and reoccur. Intradermal testing with the whole vaccine may discriminate sensitized subjects, detect cross-sensitization between vaccines, and enable estimation of patients at higher risk., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Following intravenous contrast medium (CM) injection, a small proportion of patients acquires hypersensitivity reactions that occur either immediately or non-immediately (delayed). Although it is now claer that even oral applied CMs are able to cause adverse reactions, many radiologists as well as physicians of other disciplines, still believe that CM-application via the gastrointestinal route does not induce hypersensitivity reactions. Since this kind of misinterpretation may harm the patient, education on this topic is still necessary. Therefore, we describe a case who acquired a delayed hypersensitivity reaction following the oral intake of a non-ionic iodinated CM.

Mast cell activation (MCA) is common and occurs in a number of pathologic conditions, including IgE-dependent and independent allergic reactions, atopic disorders, autoimmune processes, and mastocytosis. In a subset of patients, no underlying disease and no known trigger of MCA are found. When the symptoms are severe, systemic, and recurrent, and accompanied by a diagnostic increase in the serum tryptase level or other mast cell mediators, an MCA syndrome (MCAS) may be diagnosed. In these patients, the symptoms typically respond to drugs suppressing MCA, mediator production in mast cells, or mediator effects. In each case, diagnostic consensus criteria must be fulfilled to diagnose MCAS. In other patients, MCA may be local, less severe, or less acute, or may be suspected but not confirmed, so that the diagnostic criteria of MCAS are not fulfilled. In these patients, it may be difficult to prove MCA, for example, by measuring multiple mast cell mediators or basophil activation, the latter as a surrogate of IgE-dependent hypersensitivity. However, validated diagnostic criteria for implicating suspected MCA behind such conditions are lacking, even if some of these conditions have recently been assigned to an International Classification of Diseases-10-Clinical Modification code (ICD-10-CM). In this article, we discuss diagnostic features and criteria and propose a ICD-10-CM-adjusted classification for disorders associated with MCA, herein referred to as MCA disorders (MCADs), with special emphasis on the delineation between confirmed MCAS, MCAD not fulfilling MCAS criteria, and suspected MCAD that is not present. In addition, we discuss the discrimination between overt MCAD and predisposing conditions, such as atopic states, mastocytosis, and hereditary alpha tryptasemia., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: A male patient aged 81, with a history of atrial fibrillation, pacemaker implantation and hip replacement was admitted due to pneumonia. Subsequent Methicillin Sensitive Staphylococcus Aureus (MSSA) bacteremia and septic arthritis of his prosthetic joint was diagnosed, and treated with Oxacillin. Two weeks later, an exanthematous rash appeared, involving most of his body surface, evolving to blisters that dried up and led to extensive exfoliation of the skin, consistent with a delayed type hypersensitivity drug reaction. Other possible etiologies for this rash were ruled out. Antibiotic treatment was changed to Cefalexin, assuming that there is no cross reactivity between penicillins and cephalosporins, regarding late drug reactions. Thereafter, the rash subsided, but his renal function deteriorated and interstitial nephritis due to a hypersensitivity reaction to cephalosporin was diagnosed. Hypersensitivity to penicillins and other beta-lactam antibiotics is reported by 10% of the population, only 1/10 of them are verified using standardized allergic testing (1-3). Delayed type hypersensitivity to beta-lactams is more common than immediate type allergy. It evolves days and weeks following exposure to the offending drug. Late responses are classified as type II- IV hypersensitivities, type IV being the most prevalent (4-7). We present a patient who developed two distinct delayed type phenomena to two different beta lactam antibiotics during the same hospitalization. The possibility of a hypersensitivity reaction should rise in the differential diagnosis of the deteriorating patient most notably as such might be life threatening on the one hand, and reversible, after drug withdrawal, on the other hand.

Diagnosis of type I hypersensitivity reactions (IgE-mediated reactions) to penicillins is based on clinical history, skin tests (STs), and drug provocation tests (DPTs). Among in vitro complementary tests, the fluoro-enzyme immunoassay (FEIA) ImmunoCAP ® (Thermo-Fisher, Waltham, MA, USA) is the most widely used commercial method for detecting drug-specific IgE (sIgE). In this study, we aimed to analyze the utility of ImmunoCAP ® for detecting sIgE to penicillin G (PG) and amoxicillin (AX) in patients with confirmed penicillin allergy. The study includes 139 and 250 patients evaluated in Spain and Italy, respectively. All had experienced type I hypersensitivity reactions to penicillins confirmed by positive STs. Additionally, selective or cross-reactive reactions were confirmed by DPTs in a subgroup of patients for further analysis. Positive ImmunoCAP ® results were 39.6% for PG and/or AX in Spanish subjects and 52.4% in Italian subjects. When only PG or AX sIgE where analyzed, the percentages were 15.1% and 30.4%, respectively, in Spanish patients; and 38.9% and 46% in Italian ones. The analysis of positive STs showed a statistically significant higher percentage of positive STs to PG determinants in Italian patients. False-positive results to PG (16%) were detected in selective AX patients with confirmed PG tolerance. Low and variable sensitivity values observed in a well-defined population with confirmed allergy diagnosis, as well as false-positive results to PG, suggest that ImmunoCAP ® is a diagnostic tool with relevant limitations in the evaluation of subjects with type I hypersensitivity reactions to penicillins.

Emerging evidence suggests that vicarious racial experiences of discrimination may negatively influence child health. Few studies have focus on childhood asthma symptoms and potential moderators of such relationship., Methods: We used two population-based cross-sectional studies from the Social Change Allergy and Asthma in Latin America project in Salvador, Brazil. A total of 1003 children and mothers interviewed in 2006 were included, of whom 873 were reached again in 2013. Vicarious racial discrimination was assessed in mothers by applying the Experiences of Discrimination scale. Data on wheeze and environmental exposures were collected with standardized questionnaires. Levels of allergen-specific IgE were measured to identify atopy. Generalized estimating equations were used to estimate the association between maternal discrimination and wheezing and asthma phenotypes. Interaction terms were evaluated to identify whether mothers' mental health and family social support modified such associations., Results: Children whose mothers reported racial discrimination had greater odds of have asthma symptoms (OR 1.75; 95% CI 1.15-2.67) and non-atopic asthma (OR 1.92; 95% CI 1.09-3.40). When we considered effect modification by social support, we found a higher ORs when the level of social support was lower (OR 2.43; 95% IC 1.19-4.97) than when the level of social support was higher (OR 1.12; CI 0.64-1.96)., Conclusion: Maternal discrimination was associated with asthma symptoms and with non-atopic phenotype among their children. Enjoying wider social support network appears to buffer the effect on asthmatic symptoms. Intervention on childhood asthma needs to incorporate strategies that target the family., (© 2021. W. Montague Cobb-NMA Health Institute.)

Radiocontrast media (RCM) are common elicitors of immediate and nonimmediate hypersensitivity reactions, manifesting predominantly as urticaria/anaphylaxis or exanthems, respectively. In the minority of patients with immediate hypersensitivity reactions to RCM allergy is demonstrated by positive skin tests. However, data show that assessment by an allergist/immunologist is beneficial for managing patients with previous immediate and nonimmediate hypersensitivity reactions. For future RCM-enhanced examinations in patients with previous reactions, structurally different, skin test-negative preparations should be applied. The efficacy of this strategy is confirmed by drug provocation tests or exposures confirming or excluding RCM hypersensitivity and demonstrating tolerability of alternative RCM., Competing Interests: Disclosure No conflict of interest, no funding., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In evaluating adverse drug reactions (ADRs), patch tests (PTs), skin prick tests (SPTs), and intradermal tests (IDTs) are useful tools for identifying responsible drugs and finding safe alternatives. Their diagnostic value depends on the clinical features of the ADR and on the drug tested. PTs have a good sensitivity in assessing acute generalized exanthematous pustulosis and drug rash with eosinophilia and systemic symptoms. SPTs done with all drugs except opiates are used for immediate hypersensitivity reactions. IDTs seem sensitive for immediate hypersensitivity reactions to beta-lactam antibiotics, iodinated contrast media, heparins, general anesthetics, and platinum salts., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To explore the value of total IgE in the diagnosis of atopy in children and adolescents. Methods: This cross-sectional study analyzed data from the National Health and Nutrition Examination Survey from 2005-2006 included measurement of total and specific IgE levels and allergy questions for 6-19 year old children and adolescents. According to the results of specific IgE, participants were divided into the atopic or non- atopic group. Based on questionnaire, participants were divided into the rhinitis or non-rhinitis group. To compare the difference of total IgE between groups. The relationship between total IgE and atopy was analyzed. The value of total IgE in the diagnosis of atopy was analyzed by ROC curve. Results: ①The geometric mean total IgE level in the non-atopic subjects and the atopic subjects were 24.4 kU/L and 153.1 kU/L, respectively. The difference between the two groups was statistically significant（ P <0.01）. ②In logistic regression analyses, we observed the adjusted odds ratio（OR） for atopy with a 10-fold increase in total IgE level was 17.6[95% CI ：14.1-22.3], statistically significant changes（ P <0.01）. ③The area under the receiver operator characteristic curve（AUC） of total IgE for diagnosing atopy in the total population were 0.857. The specificity and sensitivity of total IgE at the optimal cutoff of 54.3 kU/L on the ROC curve for diagnosing atopy were76.4%, and 80.0%, respectively. At the optimal cutoff of 54.6 kU/L for diagnosing atopy in the population with rhinitis, AUC, specificity, and sensitivity were 0.888, 86.7% and 77.0%, respectively. At the optimal cutoff of 59.0 kU/L for diagnosing atopy in the population with non-rhinitis, AUC, specificity, and sensitivity were 0.841, 74.8% and 78.6%, respectively. ④The diagnostic specificity of atopy increased with total IgE, while the sensitivity decreased. Conclusion: There was a close relationship between total IgE and atopy. Total IgE level can be used to discriminates children and adolescents with and without atopy., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Background: Cefazolin is a common trigger of perioperative anaphylaxis. The diagnostic approach is controversial because the optimal concentration for skin testing is uncertain, drug provocation tests (DPTs) are contraindicated in severe reactions, and in vitro tests are not thoroughly validated., Objective: We aimed to characterize a large number of patients reporting cefazolin allergic reactions and to analyze the diagnostic role of in vivo and in vitro tests., Methods: We prospectively evaluated patients with suspicion for allergic reactions to cefazolin by clinical history, skin tests (STs), and, if negative, DPT. In a subgroup of patients, basophil activation test (BAT) and radioallergosorbent test were done before allergologic workup was performed and the final diagnosis was achieved., Results: We evaluated 184 patients, 76 of whom were confirmed as allergic (41.3%), 90 were nonallergic (48.9%), and 18 were nonconfirmed (9.8%). All patients reporting anaphylactic shock and most reporting anaphylaxis were confirmed to be allergic (P < .001). Forty allergic patients (52.6%) were confirmed by STs, 22 by DPT (28.9%), and 14 by clinical history (18.4%). All subjects manifesting exanthemas and pruritus were nonallergic. The BAT sensitivity was 66.7% when CD63 and CD203c were combined as activation markers. Six of 8 patients with negative STs and positive DPT had a positive BAT., Conclusions: Patients allergic to cefazolin often reported severe immediate-type reactions. Skin tests enabled a diagnosis in half of patients when using cefazolin at 20 mg/mL. Unfortunately, DPT could not be performed in all patients owing to reaction severity, which makes BAT a promising diagnostic tool. Further research is needed to clarify the underlying mechanisms, especially in severe reactions., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Inborn errors of immunity are traditionally best known for enhancing susceptibility to infections. However, allergic inflammation, among other types of immune dysregulation, occurs frequently in patients with inborn errors of immunity. As such, the term primary atopic disorders (PADs) was recently coined to describe the group of heritable monogenic allergic disorders. It is becoming increasingly important for clinicians to recognize that allergic diseases such as food allergy, atopic dermatitis, and allergic asthma are expressions of misdirected immunity, and in patients who present with severe, early-onset, or coexisting allergic conditions, these can be indications of an underlying PAD. Identifying monogenic allergic disease through next-generation sequencing can dramatically improve outcomes by allowing the use of precision-based therapy targeting the patient's underlying molecular defect. It is therefore imperative that clinicians recognize PADs to be able to provide informed therapeutic options and improve patient outcomes. Here, we summarize the clinical features commonly seen with each of the currently known PADs, identify clinical warning signs that warrant assessment for PADs, and lastly, discuss the benefits of timely diagnosis and management of these conditions., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Dysregulated mast cell-mediated inflammation and/or activation have been linked to a number of human diseases, including asthma, anaphylaxis, chronic spontaneous urticaria, and mast cell activation syndromes. As a major mast cell granule protein, tryptase is a biomarker commonly used in clinical practice to diagnose mast cell-associated disorders and -mediated reactions, but its mechanistic roles in disease pathogenesis remains incompletely understood. Here, we summarize recent advances in the understanding of human tryptase genetics and the effects that different genetic composition may have on the quaternary structure of tetrameric mature tryptases. We also discuss how these differences may impact clinical phenotypes including allergic inflammation, immediate hypersensitivity, and others seen in patients with mast cell-associated disorders. With the increased application of next-generation sequencing, we foresee that human genetic approaches will be a major focus of understanding human tryptase functions in various human mast cell disorders and in new therapeutic development., (Copyright © 2021. Published by Elsevier Ltd.)

Meatal stenosis (MS) is known as one of the most frequent complications of circumcision. In the present study, we aimed to find any possible relationship between MS and allergic disorders. A total of 36 children with a mean±SD age of 5.84±2.03 years were referred with MS and an atopic background even in themselves or in one of their family members (Group A). There were also age-matched controls with a mean±SD age of 5.70±2.17 years who were referred to our center with allergic symptoms and no urinary complaints (Group B, n=17). The RIDA qLine allergy and allergy explorer (ALEX) tests were performed for all patients to find possible allergen sensitization. Laboratory findings revealed that IgE-sensitization to the main food and aeroallergens in Group A (with the chief complaint of MS in whom a mild atopic condition was found during concise medical history taking) were very similar to the control group with no significant difference (except for ryegrass which was higher in the control group). Although total IgE level was considerably higher in group B compared to group A, food sensitization to cow's milk and ß-lactoglobulin was higher in asthmatic patients of group A compared to the controls. It seems that not all patients with MS should be considered as a complication of circumcision and undergo a surgical procedure for correction of the stenosis. Further investigations are required to determine the role of concise medical history taking and proper treatment of the allergic disorder to reduce failed surgical attempts in atopic boys with MS.