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BackgroundHereditary angioedema (HAE) is a rare heritable disorder that is characterized by recurrent, circumscribed, nonpitting, nonpruritic, often painful subepithelial swellings of sudden unpredictable onset that generally fade during 48–72 h. Epidemiological data of hereditary angioedema patients in Belgium is lacking.MethodsWe set up a nation-wide, multicentric study involving the 8 Belgian hospitals known to follow-up patients with Type I and II HAE. All Belgium HAE patients were asked to fill out questionnaires that mainly covered demographic data, family history, and detailed information about diagnosis, treatment and burden of their Type I and II HAE.Results112 patients with type I or type II HAE could be included. Median delay between first symptoms and diagnosis was 7 years. 51% of patients had experienced pharyngeal or tongue swelling and 78% had experienced abdominal symptoms, both known to cause an important reduction in quality of life. 60% of symptomatic patients reported to receive long term prophylactic treatment. Human plasma-derived C1-esterase inhibitor concentrate was used by 56.3% of patients. 16.7% and 27.1% of patients used a 17-α-alkylated androgen and tranexamic acid as long term prophylactic therapy.ConclusionsWe present the first nation-wide epidemiological study regarding HAE in Belgium. Our data show that the morbidity of HAE is not to be underestimated. Knowledge and dissemination of this data is critical in raising awareness, encouraging development of therapies and optimising nationwide management.

Objective: Sublingual immunotherapy represents an efficient therapeutic tool for the management of latex allergic patients. Local and systemic adverse reactions are reported, and risk factors for those reactions are poorly understood. The aim of this study is to compare two different rush induction protocols (2-day and 3-day) in terms of safety and tolerability and effectiveness in reaching the maintenance dose.Methods: Twenty-three outpatients (F/M = 18:5; 5–64 years of age), with latex allergy were randomly assigned to: Group 1 (2-day) and Group 2 (3-day). Adverse reactions were classified by their type and severity.Results: Twenty-one subjects, 10 from Group 1 and 11 from Group 2, reached the maintenance dose, 70% of them without side effects. Seven adverse events were reported in Group 1: three were local (oral itching) and spontaneously remitted; four were systemic (Grade-2: two reactions; Grade-3: two reactions) and were effectively controlled with drugs. The protocol was interrupted in two cases because of recurrent reactions. No reactions were reported in Group 2. Age, gender, atopy, specific IgE, skin prick tests and sublingual challenge did not seem to influence the risk of side effects significantly. No significant modification of skin tests and specific IgE levels were reported in both groups. The cutaneous test turned negative in 16 patients, eight from Group 1 (80%) and eight from Group 2 (73%). The remaining patients (two from Group 1 and three from Group 2) showed a reduction of latex reactivity, in terms of symptom score (MIS: 2 vs. 0.5 in Group 1, 3 vs. 1 in Group 2).Conclusions: This study confirms the safety of rush induction. The 3-day protocol was better tolerated than the 2-day. Significant risk factors for the occurrence of adverse reactions were not identified. Only the type of protocol but not patient-related parameters seemed predictive of side-effects. [ABSTRACT FROM AUTHOR]

Patients with non-infectious systemic inflammation may suffer from one of many diseases, including hyperinflammation (HI), autoinflammatory disorders (AID), and systemic autoimmune disease (AI). Despite their clinical overlap, the pathophysiology and patient management differ between these disorders. We aimed to investigate blood biomarkers able to discriminate between patient groups. We included 44 patients with active clinical and/or genetic systemic inflammatory disease (9 HI, 27 AID, 8 systemic AI) and 16 healthy controls. We quantified 55 serum proteins and combined multiple machine learning algorithms to identify five proteins (CCL26, CXCL10, ICAM-1, IL-27, and SAA) that maximally separated patient groups. High ICAM-1 was associated with HI. AID was characterized by an increase in SAA and decrease in CXCL10 levels. A trend for higher CXCL10 and statistically lower SAA was observed in patients with systemic AI. Principal component analysis and unsupervised hierarchical clustering confirmed separation of disease groups. Logistic regression modelling revealed a high statistical significance for HI (P = 0.001), AID, and systemic AI (P < 0.0001). Predictive accuracy was excellent for systemic AI (AUC 0.94) and AID (0.91) and good for HI (0.81). Further research is needed to validate findings in a larger prospective cohort. Results will contribute to a better understanding of the pathophysiology of systemic inflammatory disorders and can improve diagnosis and patient management., Competing Interests: Declarations Competing Interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Ten percent of the population is labeled as allergic to penicillin(s), when in fact 90% of these labels are inappropriate. Recent studies have shown that inpatient delabeling by a direct drug challenge (dDC) is safe in low-risk patients. However, there is a need for outpatient and nonallergist delabeling., Objective: To assess the safety of delabeling low-risk adults by means of dDC in primary care., Methods: We searched the MEDLINE, Embase, and Cochrane Library databases from inception to March 15, 2022 (updated June 5, 2023) for studies performing dDC in adults in primary care or other outpatient settings. Two researchers independently screened studies for eligibility. The data extraction and critical appraisal were performed by 1 reviewer, and we pooled the results in a meta-analysis., Results: Of 2138 results, 12 studies (1070 participants) were eligible for inclusion. Three studies evaluated delabeling in primary care and 9 studies in an outpatient hospital setting. There were no critical adverse events during dDC. No reaction occurred in 97.13% of the 1070 patients, who previously labeled as penicillin-allergic, and were safely delabeled. Ten patients (<1%) developed an immediate reaction: 3 had self-limiting reactions and 7 needed antihistaminics, steroids, epinephrine, and/or salbutamol., Conclusions: No serious allergic reactions are observed during direct amoxicillin challenge in adults in an outpatient setting. However, with the exception of 1 recent report, these studies are of low to moderate quality. Nonspecialist delabeling is promising, but further research is required on correct risk stratification and safety assessment in large cohort studies evaluating dDC in primary care., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Hypersensitivity reactions (HR) are common in mastocytosis. However, little is known about triggers and risk factors. The registry of the European Competence Network on Mastocytosis (ECNM) enables reliable studies in a larger cohort of mastocytosis patients. We assessed prevalence, triggers and risk factors of HR in adults with mastocytosis in the ECNM registry., Methods: Data were collected in 27 ECNM centers. We analyzed potential triggers (Hymenoptera venoms, food, drug, inhalant and others) and risk factors at diagnosis and during follow-up. The study group consisted of 2485 adults with mastocytosis, 1379 women (55.5%) and 1106 men (44.5%). Median age was 48.2 years (range 18-91 years)., Results: Nine hundred and forty eight patients (38.1%) reported one or more HR`. Most common triggers were Hymenoptera venoms in cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), whereas in advanced SM (advSM), most common elicitors were drugs, including nonsteroidal anti-inflammatory agents and penicillin. In multivariate analyses, tryptase level < 90 ng/mL, <15% infiltration by mast cells in bone marrow biopsy-sections, and diagnosis of ISM were identified as independent risk factors for HR. For drug-induced HR, prominent risk factors were advSM and high tryptase levels. New reactions were observed in 4.8% of all patients during 4 years follow-up., Conclusions: HR are mainly triggered by Hymenoptera venoms in patients with CM and ISM and by drugs in patients with advSM. Tryptase levels <90 ng/mL, mast cell bone marrow infiltration <15%, and WHO category ISM are predictors of HR. New HR occur in 4.8% of all patients within 4 years., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Purpose of the Review: With increased access and decriminalization of cannabis use, cases of IgE-dependent cannabis allergy (CA) and cross-reactivity syndromes have been increasingly reported. However, the exact prevalence of cannabis allergy and associated cross-reactive food syndromes (CAFS) remains unknown and is likely to be underestimated due to a lack of awareness and insufficient knowledge of the subject among health care professionals. Therefore, this practical roadmap aims to familiarize the reader with the early recognition and correct management of IgE-dependent cannabis-related allergies. In order to understand the mechanisms underlying these cross-reactivity syndromes and to enable personalized diagnosis and management, special attention is given to the molecular diagnosis of cannabis-related allergies., Recent Findings: The predominant signs and symptoms of CA are rhinoconjunctivitis and contact urticaria/angioedema. However, CA can also present as a life-threatening condition. In addition, many patients with CA also have distinct cross-reactivity syndromes, mainly involving fruits, vegetables, nuts and cereals. At present, five allergenic components of Cannabis sativa (Can s); Can s 2 (profilin), Can s 3 (a non-specific lipid protein), Can s 4 (oxygen-evolving enhancer protein 2 oxygen), Can s 5 (the Bet v 1 homologue) and Can s 7 (thaumatin-like protein) have been characterized and indexed in the WHO International Union of Immunological Sciences (IUIS) allergen database. However, neither of them is currently readily available for diagnosis, which generally starts by testing crude extracts of native allergens. The road to a clear understanding of CA and the associated cross-reactive food syndromes (CAFS) is still long and winding, but well worth further exploration., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Anaphylaxis is a common feature of patients with mastocytosis, particularly with Hymenoptera venoms. Hence, it is hypothesized that patients with mastocytosis may have an increased susceptibility to developing drug-induced anaphylaxis (DIA). Patients and medical practitioners are therefore concerned when there is a need to use various drugs. However, this issue has not been systematically investigated., Objective: To investigate the prevalence and clinical characteristics of anaphylaxis to various types of drugs among patients with mastocytosis., Methods: A retrospective study was conducted among 470 consecutive patients (18 years and older) with confirmed clonal mast cell diseases recruited from 2 independent mastocytosis reference centers. All patients underwent a comprehensive, individualized allergy workup with evaluation of the (self)reported drug hypersensitivity., Results: The overall prevalence of DIA was 6.3%, accounting for one-third of the confirmed drug hypersensitivity reactions. Nonsteroidal anti-inflammatory drugs were the most common elicitors of DIA (56%), followed by perioperative agents (23%) and antibiotics (13%). Anaphylactic reactions were severe in most cases, with 43% of patients experiencing hypotensive syncope. All drug-related hypersensitivity reactions occurred before mastocytosis was diagnosed., Conclusions: The prevalence of DIA in mastocytosis tends to be higher than in the general population, but is overall low. However, its severity is more pronounced. Our results suggest that patients with mastocytosis with a previous reaction to drugs should undergo a thorough allergy workup. Well-tolerated drugs can be further used without specific precautions., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis and 575 patients enrolled within the German Registry on Eosinophils and Mast Cells were analyzed. For screening and diagnosis of SM, tryptase was identified as the most specific serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase, β2-microglobulin, lactate dehydrogenase (LDH), albumin, vitamin B12, and C-reactive protein (P < .001). With regard to subvariants of AdvSM, an elevated LDH of ≥260 U/L was associated with multilineage expansion (leukocytosis, r = 0.37, P < .001; monocytosis, r = 0.26, P < .001) and the presence of an associated myeloid neoplasm (P < .001), whereas tryptase levels were highest in mast cell leukemia (MCL) vs non-MCL (308μg/L vs 146μg/L, P = .003). Based on multivariable analysis, the hazard-risk weighted assignment of 1 point to LDH (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.1-4.0; P = .018) and 1.5 points each to β2-microglobulin (HR, 2.7; 95% CI, 1.4-5.4; P = .004) and albumin (HR, 3.3; 95% CI, 1.7-6.5; P = .001) delineated a highly predictive 3-tier risk classification system (0 points, 8.1 years vs 1 point, 2.5 years; ≥1.5 points, 1.7 years; P < .001). Moreover, serum chemistry parameters enabled further stratification of patients classified as having an International Prognostic Scoring System for Mastocytosis-AdvSM1/2 risk score (P = .027). In conclusion, serum chemistry profiling is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In the past two decades, we witnessed the evolution of the basophil activation test (BAT) from mainly research applications to a potential complementary diagnostic tool to document IgE-dependent allergies. However, BAT presents some technical weaknesses. Around 10%-15% of tested patients are non-responders, BAT can be negative immediately post-reaction and the use of fresh basophils, ideally analysed within 4 h of collection, restricts the number of tests that can be performed per sample. The need for fresh basophils is especially limiting when conducting batch analyses and interlaboratory comparisons to harmonize BAT methodology. These limitations significantly hinder the wider application of BAT and urge the development of alternative testing, such as the mast cell activation test (MAT). The essential difference between BAT and MAT is the heterogeneity of the starting material used to perform the assays. Mast cells are tissue-resident, so cannot be easily accessed. Current alternative sources for functional studies are generating primary human mast cells, differentiated from donor progenitor cells, or using immortalized mast cell lines. Hence, the methodological approaches for MAT are not only vastly different from BAT, but also different among MAT protocols. This review summarizes the advantages and disadvantages of BAT and MAT assays, dedicating special attention to elucidating the key differences between the cellular sources used and provides an overview of studies hitherto performed comparing BAT and MAT in the diagnosis of IgE-mediated food and drug allergies., (© 2024 John Wiley & Sons Ltd.)

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: Rocuronium is a major cause of perioperative hypersensitivity (POH). Skin tests (STs) and quantification of specific immunoglobulin E antibodies (sIgEs) can yield incongruent results. In such difficult cases, the basophil activation test (BAT) can be helpful. Here, we evaluated the passive mast cell activation test (pMAT) as a substitute of BAT as part of the diagnostic tests for rocuronium allergy., Methods: Sera from patients with a suspected POH reaction potentially related to rocuronium were included. All patients had a complete diagnostic investigation, including STs, quantification of sIgEs to morphine and rocuronium, and BAT. For execution of pMAT, human mast cells were generated from healthy donor peripheral blood CD34 + progenitor cells and sensitised overnight with patient sera., Results: In total, 90 sera were studied: 41 from ST + sIgE + patients, 13 from ST - sIgE - patients, 20 from ST + sIgE - patients, and 16 from ST - sIgE + patients. According to BAT results, patients were further allocated into subgroups. Of the 38 BAT + patients, 25 (66%) showed a positive pMAT as well. Of the 44 BAT - patients, 43 (98%) also showed a negative pMAT. Mast cells that were not passively sensitised did not respond to rocuronium., Conclusions: We show that the pMAT, in many cases, can substitute for BAT in the diagnosis of rocuronium hypersensitivity and advance diagnosis in difficult cases with uncertain ST or sIgE results when BAT is not locally available., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at birth persisted over time, with normal memory αβ and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αβ T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αβ T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αβ T cells, autoimmune conditions were more frequent in these patients compared with the general population.

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.)

Purpose of Review: Provide an overview of the expanding landscape of mast cell (MC)-targeting treatments in mast cell activation syndromes (MCAS)., Recent Findings: Tyrosine-kinase inhibitors (TKIs) targeting wild-type and mutated KIT can efficiently induce MC depletion. Avapritinib and midostaurin can also temper IgE-mediated degranulation. Avapritinib has been recently approved by the FDA for the treatment of indolent systemic mastocytosis (ISM). Targeting activation pathways and inhibitory receptors is a promising therapeutic frontier. Recently, the anti Siglec-8 antibody lirentelimab showed promising results in ISM. MCAS is a heterogeneous disorder demanding a personalized therapeutic approach and, especially when presenting as anaphylaxis, has not been formally captured as outcome in prospective clinical trials with TKI. Long-term safety of TKI needs to be addressed. New drugs under investigation in diseases in which non-neoplastic MCs play a pivotal role can provide important inputs to identify new efficient and safe treatments for MCAS., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite the low prevalence of each rare disease, the total burden is high. Patients with rare diseases encounter numerous barriers, including delayed diagnosis and limited access to high-quality treatments. In order to tackle these challenges, the European Commission launched the European Reference Networks (ERNs), cross-border networks of healthcare providers and patients representatives. In parallel, the aims and structure of these ERNs were translated at the federal and regional levels, resulting in the creation of the Flemish Network of Rare Diseases. In line with the mission of the ERNs and to ensure equal access to care, we describe as first patient pathways for systemic sclerosis (SSc), as a pilot model for other rare connective and musculoskeletal diseases. Consensus was reached on following key messages: 1. Patients with SSc should have multidisciplinary clinical and investigational evaluations in a tertiary reference expert centre at baseline, and subsequently every three to 5 years. Intermediately, a yearly clinical evaluation should be provided in the reference centre, whilst SSc technical evaluations are permissionably executed in a centre that follows SSc-specific clinical practice guidelines. In between, monitoring can take place in secondary care units, under the condition that qualitative examinations and care including interactive multidisciplinary consultations can be provided. 2. Patients with early diffuse cutaneous SSc, (progressive) interstitial lung disease and/or pulmonary arterial hypertension should undergo regular evaluations in specialised tertiary care reference institutions. 3. Monitoring of patients with progressive interstitial lung disease and/or pulmonary (arterial) hypertension will be done in agreement with experts of ERN LUNG.

Tryptase has proven to be a very useful and specific marker to demonstrate mast cell activation and degranulation when an acute (i.e., within 4 h after the event) and baseline value (i.e., at least 24 h after the event) are compared and meet the consensus formula (i.e., an increase of 20% + 2). The upper limit of normal determined by the manufacturer is 11.4 ng/mL; however, this boundary has been the subject of debate. According to ECNM and AIM experts, the normal range of baseline tryptase should be 1 to 15 ng/mL. A genetic trait, hereditary alpha tryptasemia, characterized by an increased alpha coding TPSAB1 copy number is associated with a baseline value above 8 ng/mL. Elevated tryptase can also be found in chronic kidney disease, obesity, and hematological neoplasms. A tryptase > 20 ng/mL serves as a minor criterion to diagnose systemic mastocytosis and an increase in tryptase > 20% + 2 during an acute event is a required criterion in the diagnosis of mast cell activation syndrome. The goal of this review is to demonstrate the (in)significance of tryptase using some clinical vignettes and to provide a practical guide on how to manage and interpret an elevated tryptase level.

Introduction: Hereditary angioedema (HAE) is a rare disorder characterized by unpredictable painful and potentially life-threatening swelling episodes. The international WAO/EAACI guideline on the diagnosis and management of HAE was recently updated and provides up-to-date guidance for the management of. In this paper, we assessed to what extent the Belgian clinical practice was aligned with the revised guideline, and whether there were opportunities to optimise Belgian clinical practice in HAE., Methods: We compared the updated international guideline for HAE with information we acquired on Belgian clinical practice, a Belgian patient registry and expert opinion analysis. The Belgian patient registry was developed with the involvement of eight Belgian reference centers for HAE patients. Eight Belgian experts, physicians in the participating centers, included patients in the patient registry and participated in the expert opinion analysis., Results: The main action points to further optimise the Belgian clinical practice of HAE are Work towards total disease control and normalize patients' life by considering the use of new and innovative long-term prophylactic treatment options; (2) inform C1-INH-HAE patients about new long-term prophylactic therapies; (3) assure the availability of on-demand therapy for all C1-INH-HAE patients; (4) implement a more universally used assessment including multiple aspects of the disease (e.g. quality of life assessment) in daily clinical practice; and (5) continue and expand an existing patient registry to assure continued data availability on C1-INH-HAE in Belgium., Conclusions: In light of the updated WAO/EAACI guideline, five action points were identified and several other suggestions were made to optimise the Belgian clinical practice in C1-INH-HAE.