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Background: The generic 36-item Short-Form Health Survey (SF-36v2) has been used to assess health related quality of life in adult patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) even though it has not yet been validated for use in this specific disease.Objective: This study aims to validate the SF-36v2 for use in adult patients with C1-INH-HAE.Results: There was a very low item non-response rate (1-3.4%), with a high ceiling effect in 25/35 items and a low floor effect in 3/35 items. A moderate ceiling effect was observed in 5/8 dimensions of the SF-36v2, whereas no floor effect was noticed in any of the dimensions. Internal consistency was good to excellent with Cronbach's alpha coefficient ranging between 0.82 and 0.93 for the different dimensions. Construct validity was good: seven out of the 8 hypotheses defined on clinical criteria were confirmed, discriminant validity assessment showed significant differences among patients with different C1-INH-HAE severity, convergent validity showed a good correlation among the physical and mental component summaries of the SF-36v2 and the HAE-QoL total score (0.45 and 0.64 respectively, P < 0.001). Test-retest reliability was high with intraclass correlation coefficient varying from 0.758 to 0.962. The minimal clinically important difference was calculated by distribution methods and small differences in the domain scores and in the component summaries scores were shown to be meaningful.  CONCLUSIONS: The psychometric properties of the SF-36v2 show it can be a useful tool to assess HRQoL in adult patients with C1-INH-HAE, although with some content validity limitation.Methods: The psychometric properties of the SF-36v2 were evaluated in an international setting based on responses from 290 adult C1-INH-HAE patients in 11 countries. [ABSTRACT FROM AUTHOR]

Background: In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT., Methods: 1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms., Results: 285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3-4 vs. 11% [n = 78 of 709] with Grade 1-2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3-4 vs. 0.001% [n = 78] in Grade 1-2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01)., Conclusions: By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment., Objective: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE)., Methods: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022)., Results: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms., Conclusion: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care., (Copyright © 2024. Published by Elsevier Inc.)

Background: Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants., Objective: To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks., Methods: We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2., Results: A total of 58 worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction., Conclusions: This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of five key outcomes., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter- and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor MR declared a past co-authorship with the author GP., (Copyright © 2024 Porebski, Dziadowiec, Rybka, Kitel and Kwitniewski.)

Mast cells (MCs) are immune cells that reside in tissues; particularly in the skin, and in the gastrointestinal and respiratory tracts. In recent years, there has been considerable interest in the Mas-Related G Protein-Coupled Receptor X2 (MRGPRX2), which is present on the surface of MCs and can be targeted by multiple exogenous and endogenous ligands. It is potentially implicated in non-IgE-mediated pseudoallergic reactions and inflammatory conditions such as asthma or atopic dermatitis. In this paper, we review natural products and herbal medicines that may potentially interact with MRGPRX2. They mainly belong to the classes of polyphenols, flavonoids, coumarins, and alkaloids. Representative compounds include rosmarinic acid, liquiritin from licorice extract, osthole, and sinomenine, respectively. While evidence-based medicine studies are still required, these compounds have shown diverse effects, such as antioxidant, analgesic, anti-inflammatory, or neuroprotective. However, despite potential beneficial effects, their use is also burdened with risks of fatal reactions such as anaphylaxis. The role of MRGPRX2 in these reactions is a subject of debate. This review explores the literature on xenobiotic compounds from herbal medicines that have been shown to act as MRGPRX2 ligands, and their potential clinical significance.

Hereditary angioedema (HAE) is a rare genetic disease. It is characterized by recurrent attacks of angioedema. Evidence to what extent it affects patient functioning is limited in the pediatric population. We aimed to determine the clinical characteristics and management of Polish children with HAE and to measure the health-related quality of life (HRQoL) of these patients. This cross-sectional study was conducted among 21 pediatric patients and their caregivers, as well as 21 respective controls randomly selected from the general population. During routine follow-up visits, standardized pediatric quality of life questionnaires (PedsQL TM 4.0) were administered to all caregivers and adolescents (≥13 years). Caregivers also completed a structured medical interview regarding the clinical characteristics and treatment of children with HAE during the previous six months. During this period, 57% of patients had low (group I), 24% moderate (group II), and 19% high (group III) HAE activity, corresponding to ≥10 attacks per 6 months. None of the patients received long-term prophylaxis. The children in group III had a lower HRQoL than other groups and controls on all dimensions of the PedsQL TM 4.0. The lowest scores in all groups were observed in the emotional functioning domain. Our data demonstrate that the burden of HAE on the quality of life of pediatric patients and their families encompasses a wide range of daily functioning.

Frequent mislabelled causal relationship between drug hypersensitivity reactions and culprit drugs reinforces the need for an accurate diagnosis. The systematic reviews and meta-analyses of in vitro assays published so far focused on immediate reactions and the most severe delayed reactions, while the most frequent drug-induced delayed reactions-nonsevere exanthemas-have been underestimated. We aim to fill this gap. A systematic review of studies on in vitro assays used in the diagnosis of nonsevere drug-induced delayed reactions was conducted following the methodology of Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies Statement. The EMBASE and PubMed databases were searched. We have included 33 studies from which we extracted the data, then performed meta-analysis where possible, or synthesised the evidence narratively. The quality of the analysed studies was assessed with the QUADAS-2 tool. The tests identified the most frequently were lymphocyte transformation test (LTT), ELISpot, and ELISA. In the meta-analysis carried out for LTT in reactions induce by beta-lactams, the pool estimate of sensitivity and specificity amounted to 49.1% (95% CI: 14.0%, 85.0%) and 94.6% (95% CI: 81.7%, 98.6%), respectively. The studies showed heterogeneity in study design and laboratory settings, which resulted in a wide range of specificity and sensitivity of testing., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Szymon Drygala et al.)

Oral drug provocation tests (DPT) are the basic diagnostic tool for the detection of hypersensitivity to non-opioid analgesics and for selecting a safe alternative for a patient. They are of great practical importance due to their common use, but the data on the follow-up of patients after negative DPT are still very scarce. We examined the further fate of 164 such adult patients after negative NSAID or paracetamol tests and analyzed which excipients in the studied drugs they could be exposed to after the diagnostic workup. A structured medical interview was performed 32.9 months (mean) after the provocation tests. Of the 164 patients, 131 (79.9%) retook the tested drug and 12 developed another hypersensitivity reaction, giving the estimated negative predictive value of 90.8%. These reactions were induced by acetylsalicylic acid, paracetamol, meloxicam, and diclofenac, and were clinically similar to the initial ones (most commonly urticaria and angioedema). There are 93 generics of these drugs on the local market, containing a total of 33 excipients for which hypersensitivity reactions have been reported. All available generics contain such excipients. Thirty-one patients (20.1%) did not take the previously tested drug again, most often because it was not needed or because they were afraid of another reaction. DPT with analgesics has a high diagnostic performance. A minority of patients had relapsed after reexposure. One of the underestimated reasons for this may be drug excipients provoking a reaction, so it is advisable to use exactly the same medical product that has been negatively tested. Many patients avoid reexposure to a given drug, despite negative tests, therefore very reliable patient education in connection with DPT is highly needed.

Background: Anaphylaxis, which is rare, has been reported after COVID-19 vaccination, but its management is not standardized., Method: Members of the European Network for Drug Allergy and the European Academy of Allergy and Clinical Immunology interested in drug allergy participated in an online questionnaire on pre-vaccination screening and management of allergic reactions to COVID-19 vaccines, and literature was analysed., Results: No death due to anaphylaxis to COVID-19 vaccines has been confirmed in scientific literature. Potential allergens, polyethylene glycol (PEG), polysorbate and tromethamine are excipients. The authors propose allergy evaluation of persons with the following histories: 1-anaphylaxis to injectable drug or vaccine containing PEG or derivatives; 2-anaphylaxis to oral/topical PEG containing products; 3-recurrent anaphylaxis of unknown cause; 4-suspected or confirmed allergy to any mRNA vaccine; and 5-confirmed allergy to PEG or derivatives. We recommend a prick-to-prick skin test with the left-over solution in the suspected vaccine vial to avoid waste. Prick test panel should include PEG 4000 or 3500, PEG 2000 and polysorbate 80. The value of in vitro test is arguable., Conclusions: These recommendations will lead to a better knowledge of the management and mechanisms involved in anaphylaxis to COVID-19 vaccines and enable more people with history of allergy to be vaccinated., (© 2022 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Existing evidence indicates that modifier genes could change the phenotypic outcome of the causal SERPING1 variant and thus explain the expression variability of hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE). To further examine this hypothesis, we investigated the presence or absence of 18 functional variants of genes encoding proteins involved in the metabolism and function of bradykinin, the main mediator of C1-INH-HAE attacks, in relation to three distinct phenotypic traits of patients with C1-INH-HAE, i.e., the age at disease onset, the need for long-term prophylaxis (LTP), and the severity of the disease. Genetic analyses were performed by a validated next-generation sequencing platform. In total, 233 patients with C1-INH-HAE from 144 unrelated families from five European countries were enrolled in the study. Already described correlations between five common functional variants [ F12 -rs1801020, KLKB1 -rs3733402, CPN1 -rs61751507, and two in SERPING1 (rs4926 and rs28362944)] and C1-INH-HAE severity were confirmed. Furthermore, significant correlations were found between either the age at disease onset, the LTP, or the severity score of the disease and a series of other functional variants ( F13B -rs6003, PLAU -rs2227564, SERPINA1 -rs28929474, SERPINA1 -rs17580, KLK1 -rs5515, SERPINE1 -rs6092, and F2 -rs1799963). Interestingly, correlations uncovered in the entire cohort of patients were different from those discovered in the cohort of patients carrying missense causal SERPING1 variants. Our findings indicate that variants other than the SERPING1 causal variants act as independent modifiers of C1-INH-HAE severity and could be tested as possible prognostic biomarkers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Parsopoulou, Loules, Zamanakou, Csuka, Szilagyi, Kompoti, Porebski, Psarros, Magerl, Valerieva, Staevska, Obtulowicz, Maurer, Speletas, Farkas and Germenis.)

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is a rare disease characterized by recurrent swellings. This study aims to determine (i) the clinical characteristics of the HAE patient population from Poland, and (ii) real-life patients' treatment practices. A cross-sectional study involved 138 adult HAE patients (88 females, 50 males) treated in six regional HAE centers in Poland. Consecutive patients during routine follow-up visits underwent a structured medical interview on the clinical characteristics of the course and treatment of HAE attacks within the last six months. A total of 118 of 138 patients was symptomatic. They reported in total 2835 HAE attacks predominantly peripheral and abdominal, treated with plasma-derived C1-INH (61.4%), icatibant (36.7%) and recombinant C1-INH (1.9%). An amount of 116 patients carried the rescue medication with them while traveling, and 74 patients self-administrated on demand treatment. There were twice as many symptomatic women ( n = 78) as there were men ( n = 40). Women treated their HAE attacks significantly more often than men. Older patients (≥65 years) reported a longer delay in diagnosis, and practiced the self-administration of rescue medication less frequently in comparison to other patients. Clinical features of the surveyed population are similar to other European, but not Asian, HAE patient groups. Self-administration still remains an unmet medical need. Some distinct HAE patients may require special attention due to the severe course of the disease (females) or a delay in diagnosis (the elderly).

In patients with drug hypersensitivity reactions, confirmation of causality frequently facilitates decision on a continuation or withdrawal of a given treatment. Unfortunately, identification of the culprit drug often proves difficult. In vivo methods possess well-known disadvantages like low sensitivity of skin tests or the risk of relapse during drug provocation tests. Therefore, laboratory assays are of great interest as they may improve causal diagnosis without putting patients at risk. In this article, the mechanistic principles and methodological issues of the enzyme-linked immunospot (ELISpot) assay were recapped the context of drug hypersensitivity reactions. A review of ELISpot application in causal diagnosis of drug hypersensitivity was based on literature search. The main findings are: (i) ELISpot assay has a good performance in the detection of drug-specific response. (ii) ELISpot results seem to be not substantially impacted by the type of drug or phenotype of the reaction. (iii) Testing within 30 days since the episode of drug hypersensitivity reaction shows a better performance than in later recovery phase. (iv) Data from pediatric population are too scarce to draw any conclusions. (v) Differences in laboratory protocols and in criteria used in the assessment of ELISpot plates along with the issue of the technical feasibility and reproducibility may limit the use of this assay in the routine diagnostic of drug hypersensitivity reactions., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objectives : Over-the-counter availability and a good safety profile make paracetamol one of the most common analgesics in developed countries but also the leading cause of liver failure due to overdose. The objectives of the study were to identify modifiable risk factors for severe hepatotoxicity following paracetamol overdose in adults. Materials and Methods : A retrospective cohort study involved the consecutive adult patients hospitalized in a toxicological center over a period of seven years due to paracetamol overdose. Complete medical datasets of laboratory and anamnestic variables were analyzed and validated by means of logistic regression model. Results : A total of 185 patients entered the study, including 25 individuals who developed severe hepatotoxicity (plasma aminotransferases levels above 1000 UI/L) and 31 individuals with mild to moderate liver injury (plasma aminotransferases levels above upper normal range, but below 1000 UI/L). In the univariable analysis, significant hepatotoxicity risk factors were male gender, alcohol abuse, an ingested paracetamol dose, and a timespan from ingestion to hospital admission. The later one was the only significant risk factor in the multivariable model (adjusted odds ratio 1.08; 95% CI: 1.03-1.12). Conclusions : A delay in hospital admission, resulting in a delayed administration of disease-specific treatment outweighs any other known risk factors of paracetamol-induced hepatotoxicity.

A biomarker is a defined characteristic measured as an indicator of normal, biologic, pathogenic processes, or biological responses to an exposure or intervention. Diagnostic biomarkers are used to detect a disease or a subtype of a disease; monitoring biomarkers are measured serially to assess a medical condition; response biomarkers are used to check biologic response following a medical intervention; predictive biomarkers are used to identify patients who are more likely to respond to a medical intervention; and prognostic biomarkers are used to assess the future likelihood of a clinical event. Although biomarkers have been extensively investigated and validated in many diseases and pathologies, very few are currently useful for the diagnosis, evaluation of disease activity, and treatment of hereditary angioedema (HAE). Pathophysiologic pathways involved in HAE reveal a plethora of molecules from the complement, coagulation, and fibrinolysis systems or from the vascular endothelium, which may serve as biomarkers. The most promising candidates, together with their laboratory readout systems, should be evaluated with regard to their analytical and clinical validity and utility. To be highly specific, such biomarkers should be linked to the pathomechanisms of HAE, particularly the bradykinin-generating cascade. Additionally, major advances in high-throughput omics-based technologies may facilitate the discovery of new candidate biomarkers in the future. This review will cover the existing as well as future potential biomarkers that will support the diagnosis, monitor disease activity, and can be used to assess the efficacy of new avenues of therapy of HAE and other forms of angioedema., (© 2021. The Author(s).)

The genetic alteration underlying the great majority of primary angioedema with normal C1 inhibitor (nl-C1-INH-HAE) cases remains unknown. To search for variants associated with nl-C1-INH-HAE, we genotyped 133 unrelated nl-C1-INH-HAE patients using a custom next-generation sequencing platform targeting 55 genes possibly involved in angioedema pathogenesis. Patients already diagnosed with F12 alterations as well as those with histaminergic acquired angioedema were excluded. A variant pathogenicity curation strategy was followed, including a comparison of the results with those of genotyping 169 patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE), and only filtered-in variants were studied further. Among the examined nl-C1-INH-HAE patients, carriers of neither the ANGPT1 p.Ala119Ser nor the KNG1 p.Met379Lys variant were found, whereas the PLG p.Lys330Glu was detected in four (3%) unrelated probands (one homozygote). In total, 182 different variants were curated, 21 of which represented novel mutations. Although the frequency of variants per gene was comparable between nl-C1-INH-HAE and C1-INH-HAE, variants of the KNG1 and XPNPEP1 genes were detected only in nl-C1-INH-HAE patients (six and three, respectively). Twenty-seven filtered variants in 23 different genes were detected in nl-C1-INH-HAE more than once, whereas 69/133 nl-C1-INH-HAE patients had compound heterozygotes of filtered variants located in the same or different genes. Pedigree analysis was performed where feasible. Our results indicate the role that alterations in some genes, like KNG1 , may play in disease pathogenesis, the complex trait that is possibly underlying in some cases, and the existence of hitherto unrecognized disease endotypes.

Background: In about 5% of patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) no mutation in the SERPING1 gene is detected., Methods: C1-INH-HAE cases with no mutation in the coding region of SERPING1 after conventional genotyping were examined for defects in the intronic or untranslated regions of the gene. Using a next-generation sequencing (NGS) platform targeting the entire SERPING1, 14 unrelated C1-INH-HAE patients with no detectable mutations in the coding region of the gene were sequenced. Detected variants with a global minor allele frequency lower than the frequency of C1-INH-HAE (0.002%), were submitted to in silico analysis using ten different bioinformatics tools. Pedigree analysis and examination of their pathogenic effect on the RNA level were performed for filtered in variants., Results: In two unrelated patients, the novel mutation c.-22-155G > T was detected in intron 1 of the SERPING1 gene by the use NGS and confirmed by Sanger sequencing. All bioinformatics tools predicted that the variant causes a deleterious effect on the gene and pedigree analysis showed its co-segregation with the disease. Degradation of the mutated allele was demonstrated by the loss of heterozygosity on the cDNA level. According to the American College of Medical Genetics and Genomics 2015 guidelines the c.-22-155G > T was curated as pathogenic., Conclusions: For the first time, a deep intronic mutation that was detected by NGS in the SERPING1 gene, was proven pathogenic for C1-INH-HAE. Therefore, advanced DNA sequencing methods should be performed in cases of C1-INH-HAE where standard approaches fail to uncover the genetic alteration., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) is a rare genetic disease that runs in the family. As a result of the disease, acute swellings of the subcutaneous tissue and mucous membranes of the digestive and respiratory systems, including the larynx, occur. Any attack of the disease involving the throat and larynx is particularly dangerous and requires knowledge of clinical determinants of the disease and its proper management., Materials and Methods: The study included adult consecutive HAE-C1INH patients having follow-up visits in our centre. The group was examined with a structured clinical questionnaire, concerning the last 6 months and focusing particularly on laryngeal swelling attacks., Results: 55 subjects (F/M - 35/20, age range - 18-76) were included in the study. Laryngeal attacks occurred in 19 individuals (34.5%): 1-3, 4-6, and ≥7 attacks in 9, 8 and 2 patients, respectively, two of whom required intubation. In comparison to other patients, subjects with laryngeal attacks were characterised by significantly more frequent: (1) facial attacks, (2) severe disease activity, (3) the occurrence of female patients, (4) mental stress as a trigger of attacks. All patients with laryngeal attacks had a rescue medication at home and 15/19 (78%) patients could use it at home. Most of them used plasma-derived C1-inhibitor 17/19 (89.5%) and icatibant, 8/19 (42.1%)., Discussion: HAE-C1INH patients with laryngeal attacks require particular attention. Proper training regarding the identification of these patients, adequate management, access to emergency services and emergency drugs are essential to ensure the safety of subjects with this localization of HAE-C1INH attacks.

Paracetamol is a popular and easily available drug which is used world-wide as analgesic, antipyretic agent. Hypersensitivity reactions to this drug involve a wide range of symptoms of various importance for patient management. The EudraVigilance (EV) database serves as a system for monitoring adverse events (AE) due to drug intake. We retrospectively recorded AE reports for "paracetamol" reported from 1 January 2007 to 1 October 2018 which fulfilled the category of "serious" in EV. For further analysis the retrieved AE reports were selected according to the keywords corresponding to hypersensitivity symptoms. We included in the study 4589 AE reports with 9489 particular AEs. 24.2% of all the AE reports concerned children. The most often reported symptoms were "angioedema," "rash" and "urticaria" (each of them with a frequency of >10% in the AE reports). An important group of AEs were oedema reported as being located in the head, neck or respiratory tract. We recorded 58 AE reports with fatal outcomes, including 9 Stevens-Johnson syndrome/toxic epidermal necrolysis cases (SJS/TEN), 10 anaphylactic reactions, 21 cases of hepatic failure and a further 18 cases which occurred for other reasons. SJS/TEN, acute generalized exanthematous pustulosis and drug reaction with eosinophilia and systemic symptoms were reported 129, 42 and 25 times, respectively. Prodromes and symptoms of potentially life-threating SJS/TEN appeared in 286 of the AE reports. 380 AE reports pointed to a diagnosis of anaphylaxis. To improve patient safety, healthcare professionals, including pharmacists, can identify warning signs of severe hypersensitivity reactions to paracetamol.

The human ortholog MRGPRX2 and the mice ortholog, Mrgprb2 are activated by basic secretagogues and neurokinins. A number of commonly used small-molecule drugs (e.g., neuromuscular blocking agents, fluoroquinolones, vancomycin) have been recently shown to activate these receptors under in vitro experimental conditions, what results in mast cell degranulation. The above drugs are also known to cause IgE-mediated anaphylactic reactions in allergic patients. The new findings on mechanisms of drug-induced mast cell degranulation may modify the current management of drug hypersensitivity reactions. Clinical interpretation of mild drug-provoked hypersensitivity reactions, interpretation of skin test with a drug of interest or further recommendations for patients suspected of drug allergy are likely to be reconsidered. In the paper we discussed future directions in research on identification and differentiation of MRGPRX2-mediated and IgE-dependent mast cell degranulation in patients presenting clinical features of drug-induced hypersensitivity reactions.

SERPING1 genotyping of subjects suspicious for hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is important for clinical practice as well as for research reasons. Conventional approaches towards the detection of C1-INH-HAE-associated SERPING1 variants are cumbersome and time-demanding with many pitfalls. To take advantage of the benefits of next-generation sequencing (NGS) technology, we developed and validated a custom NGS platform that, by targeting the entire SERPING1 gene, facilitates genetic testing of C1-INH-HAE patients in clinical practice. In total, 135 different C1-INH-HAE-associated SERPING1 variants, out of the approximately 450 reported, along with 115 negative controls and 95 randomly selected DNA samples from affected family members of C1-INH-HAE index patients, were included in the forward and reverse validation processes of this platform. Our platform's performance, i.e. analytical sensitivity of 98.96%, a false negative rate of 1.05%, analytical specificity 100%, a false positive rate equal to zero, accuracy of 99.35%, and repeatability of 100% recommends its implementation as a first line approach for the genetic testing of C1-INH-HAE patients or as a confirmatory method. A noteworthy advantage of our platform is the concomitant detection of single nucleotide variants and copy number variations throughout the whole length of the SERPING1 gene, moreover providing information about the size and the localization of the latter. During our study, 15 novel C1-INH-HAE-related SERPING1 variants were detected., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Severe cutaneous adverse drug reactions (SCARs) represent life-threatening medical conditions and an appropriate causative diagnosis of these conditions is of the highest importance. Existing in vivo diagnostic methods are risky or are just contraindicated in these patients. Therefore, in vitro tests take on greater significance. In this survey, the studies on in vitro assays in SCARs were identified with a defined searching strategy and strict eligibility criteria. Different methods in the particular clinical manifestations and the groups of drugs were compared in respect to the diagnostic parameters obtained. The lymphocyte transformation test and IFNg-ELISpot (Interferon γ-Enzyme-linked immunospot assay) appeared to have the best evidence currently available. Further diagnostic assays, which are based mostly on distinct mechanisms of SCARs, may outdo previous assays but they still need confirmation in a larger group of patients and in more research centers. Data from pediatric populations and acute generalized exanthematous pustulosis (AGEP) patients are scarce. Some technical issues, limitations, and modifications of routine laboratory methods are also discussed., Competing Interests: The author declares no conflict of interest.

Background: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) may affect health-related quality of life (HRQoL). A specific HRQoL questionnaire for adult patients with C1-INH-HAE, the HAE-QoL, has recently been developed in Spain., Objective: The objective of this study was to perform a cross-cultural validation and psychometric study of the HAE-QoL in an international setting., Methods: Cross-cultural adaptation of the Spanish HAE-QoL draft version and an international rating phase with experts were performed. The resultant version of the HAE-QoL, a clinical questionnaire, and Short Form 36-item Health Survey Version 2.0 (SF-36v2) were pilot tested internationally. Item reduction was based on both descriptive and exploratory factor analysis. Psychometric properties were assessed., Results: Cross-cultural adaptation of the HAE-QoL was performed in 18 countries. The draft version of the HAE-QoL was pilot tested in 332 patients, and accurate data were obtained from 290 patients from 11 countries. The reduction process resulted in a new version with 25 items and 7 dimensions (treatment difficulties, physical functioning and health, disease-related stigma, emotional role and social functioning, concern about offspring, perceived control over illness, and mental health). Strong psychometric properties were observed (Cronbach's α 0.92; test-retest reliability 0.87). Convergent validity showed mild to moderate correlations with SF-36v2 physical and mental component summaries (0.45 and 0.64, respectively) and with SF-36v2 dimensions (P < .004). HAE-QoL scores discriminated significantly among severity groups (median: asymptomatic 133.5 vs severe 84.0; P < .001); between patients with and without long-term prophylaxis (median: 101 vs 90; P = .001); and between patients with and without psychiatric and/or psychological care (median: 74 vs 103; P ≤ .001)., Conclusions: The HAE-QoL, currently available in 18 languages, showed good reliability and validity evidence., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Hereditary angioedema (HAE) caused by a deficiency in functional C1 esterase inhibitor (C1INH) is characterized by recurrent episodes of cutaneous and/or mucosal/submucosal tissue swelling affecting multiple anatomic locations. Previous studies demonstrated efficacy of recombinant human C1INH (rhC1INH) for acute HAE attacks., Objective: This study evaluated the efficacy and safety of rhC1INH (50 IU/kg) for the treatment of multiple HAE attacks in an open-label extension study., Methods: Time to onset of symptom relief and time to minimal symptoms were assessed using a Treatment Effect Questionnaire (TEQ), a visual analog scale, and a 6-point ordinal scale Investigator Score., Results: Forty-four patients received rhC1INH, and a single dose was administered for 215 of 224 (96%) attacks. Median time to beginning of symptom relief based on TEQ for the first 5 attacks was 75.0 (95% CI, 69-89) minutes, ranging from 62.5 (95% CI, 48-90) to 134.0 (95% CI, 32-119) minutes. Median time to minimal symptoms using TEQ for the first 3 attacks was 303.0 (95% CI, 211-367) minutes. rhC1INH was well tolerated. There were no discontinuations due to adverse events. No thrombotic or anaphylactic events were reported, and repeat rhC1INH treatments were not associated with neutralizing anti-C1INH antibodies., Conclusions: A single 50-IU/kg dose rhC1INH was effective for improving symptoms of an HAE attack with sustained efficacy for treatment of subsequent attacks. rhC1INH had a positive safety profile throughout the study. This study supports repeated use of rhC1INH over time in patients with HAE attacks., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The in vitro diagnosis of delayed drug hypersensitivity reactions remains a research problem. We measured drug-specific IFNγ release in peripheral blood mononuclear cells sampled from patients with drug-induced maculopapular exanthema and the age- and sex-matched control group. This is the first study to directly cross-compare an ultrasensitive assay based on an emerging electrochemiluminescence technology (ECL), the standard lymphocyte proliferation assay and three following tests detecting IFNγ at different steps of its production: intracellular in CD3+CD4+ cells (flow cytometry), secretion at the single cell level (enzyme-linked immunospot assay), bulk content in cell culture supernatant (enzyme-linked immunosorbent assay, ELISA). The highest rate of drug-positive responses were recorded for ELISA and ECL tests (56.25%). No false-positive responses were observed--all tests were negative in the control group. We demonstrated that IFNγ-detecting ELISA is not less efficient than ECL test, however, it is easily available and cheap, which makes it a potential method of choice in the future.

Introduction and Objective: Numerous epidemiologic studies have reported increased risk of allergic rhinitis and asthma in relation to 'western life-style', which represents diversity of factors. We hypothesized that residential proximity to major roadways, reflecting an exposure to traffic-related air pollution, is associated with prevalence of allergic respiratory symptoms in children., Materials and Methods: A total of 8290 individuals of two age groups: 16 year olds and 7 year olds from Krakow, Poland were included. We used the Polish version of the International Study of Asthma and Allergy in Childhood supplemented with a question concerning the distance between a responder's house and a high traffic density road: below 200 m, from 200-500 m, or more than 500 m., Results: Children and adolescents with a residential proximity closer to a major roadway had more frequent asthma-related symptoms in the last 12 months and at any time in the past. Consistent with the increased frequency of asthmatic symptoms, responders residing within 200 meters complained more often of sneezing, runny or blocked nose accompanied by itchy-watery eyes and hay fever in comparison to responders who resided 200-500 meters from a major roadway. The lowest rate of nasal symptoms was observed in residents living in the distance to major roads (> 500 meters). The rate of positive answers decreased in a distant-dependent manner., Conclusions: Our findings suggest an important spatial relationship between the distance from a major roadway and the evaluated respiratory symptoms. The results emphasize the need for more comprehensive air quality policies within urban areas with increased motor vehicle density.

Drug hypersensitivity can occur with almost any drug and may range widely in clinical severity from mild pruritus, acute urticaria or angioedema to life-threatening anaphylaxis. Affected patients usually avoid the suspected drug in the future, but in selected cases the particular drug is essential for optimal therapy due to unavailable or ineffective alternative therapy. Under these circumstances, desensitization may be performed. Desensitization protocols have been developed and are used for antibiotics, sulfonamides, non-steroidal antiinflammatory drugs, insulins, biologic agents, and many others. Desensitization procedure is based on the induction of a temporary state of tolerance of a substance responsible for a hypersensitivity reaction. Gradually increasing doses of the drug are administered to the patient over several hours to a few days, until the total cumulative therapeutic dose is achieved and tolerated. Hypersensitivity to acetylsalicylic acid is a common indication to desensitization in a daily practice. A few protocols for this drug have been described. Recently, 7 patients hypersensitive to acetylsalicylic acid have been desensitized in our department due to cardiologic and rheumatologic reasons. In this group, desensitization procedures were performed successfully and the patients could continue pharmacotherapy with aspirin.

Background: Routine qualification for specific immunotherapy (SIT) is based on clinical history and skin prick tests (SPT) or specific IgE (sIgE). In cases of discordance between these two, basophil activation test (BAT) may be decisive. The aim of the present study was to determine the specificity and sensitivity of BAT, sIgE, and SPT, and to analyse cases, in which clinical data and SPT alone would result in wrongful qualification for SIT., Patients and Methods: BAT results and sIgE levels to Dermatophagoides pteronyssinus (Dp) and Dermatophagoides farinae (Df) were determined in 52 pediatric patients qualified for SIT based on clinical history and positive SPT. The group included 21 children qualified for SIT with birch or timothy grass, used as reference for specificity and sensitivity calculations for BAT, sIgE and SPT., Result: The sensitivity and specificity of BAT, using SPT as "gold standard" was 96.9% and 88.9% for Dp, and 89.3% and 100% for Df, respectively and the sensitivity and specificity of sIgE were 89.7%, 88.9% for Dp, and 92.9% and 94.4% for Df. When using BAT as "gold standard", the sensitivity and specificity of SPT was 90% and 90.5% for Dp, 92% and 84,6% for Df, and these indices for sIgE were 87.1% and 90.5% for Dp, 100% and 87.5% for Df. BAT did not confirm the initial qualification for SIT in 2 patients, revealing an unspecific basophil activation. Negative nasal provocation test ultimately confirmed the false-positive SPT, which could be explained by the co-existence of urticaria in those children. In further 2 children qualified for SIT with timothy and birch, BAT revealed lack of reactivity to respective allergens. Altogether BAT helped in avoiding unnecessary SIT in 4 out of 52 children (7.7%)., Conclusions: In most cases, SPT, sIgE and BAT provide comparable information, however, SPT results care is advised in patients with co-existing urticaria. BAT is useful in verifying the actual relevance of allergens selected for SIT and helps in avoiding long-lasting, arduous, costly, and ineffective immunotherapy of wrongly qualified cases.

One possible origin of the type I hypersensitivity reaction is reaction of drugs such as acetylsalicylic acid and its metabolites being complexed with human serum albumin. Albumin, being transporting molecule abundant in blood plasma is able to bind large array of ligands varying from small single carbon particles to long hydrophobic tailed lipidic acids (e.g. myristic acid). This non specificity is possible because of multi domain scaffold and large flexibility of inter-domain loops, which results in serious reorientation of domains. Hypothesis that acetylsalicylic acid metabolites may play indirect role in activation of allergic reaction has been tested. Binding of acetylsalicylic acid metabolites in intra-domain space causes significant increase of liability of domains IIIA and IIIB. One of metabolites, salicyluric acid, once is bound causes distortion and partial unfolding of helices in domains IA, IIB and IIIB. Changed are both directions and amplitude of relative motions as well as intra-domain distances. In result albumin is able to cross-link of adjacent IgE receptors which subsequently starts allergic reaction.

Background: Patients with hereditary C1-inhibitor deficiency have recurrent attacks of angioedema, preferably treated with C1-inhibitor concentrate. A recombinant human C1-inhibitor (rHuC1INH) was developed, derived from milk from transgenic rabbits. This study was undertaken to investigate the effects of rHuC1INH in the treatment of acute angioedema attacks in patients with a hereditary C1-inhibitor deficiency., Study Design and Methods: Patients with hereditary C1-inhibitor deficiency were treated with rHuC1INH (at a dose of 100 U/kg) within 8 hours after onset of an acute attack. Time to initiation of relief and time to minimal symptoms were reported by both the patient and the treating physician., Results: Thirteen severe angioedema attacks in 9 patients with hereditary C1-inhibitor deficiency were treated with rHuC1INH. There was rapid improvement of clinical conditions for all attacks, with approximately 80 percent of treated patients experiencing symptom relief within 2 hours and minimal symptoms within 12 hours. There were no drug-related adverse events or immunogenic reactions to C1-inhibitor or rabbit proteins., Conclusion: The transgenically produced rHuC1INH was successfully used in the treatment of acute angioedema attacks in patients with hereditary C1-inhibitor deficiency.

The irrational use of medication, by which we understand the administration of drugs for indications where their effectiveness has not been confirmed, the disregard of restrictions and warnings against their use, and the use of drug combinations which do not increase the therapeutic effect but to the contrary increase the risk of adverse drug reactions, is a serious problem encountered in paediatric pharmacotherapy. Each year the centres for monitoring of adverse drug reactions receive many reports, the analysis of which show that the reasons of occurrence of adverse drug reactions after drug administration, are specifically due to irrational use of medications. In order to prevent in an active way the occurrence, of adverse drug reactions following drug administration it is worthwhile to bring to attention the reasons for their occurrence which not infrequently bring about pathological effects. Our work which is based on reports received by the Regional Centre for Adverse Drug Reactions Monitoring in Krakow concerning the occurrence of adverse drug reactions in an attempt to bring to attention in our view important problems in current pharmacotherapy.

Hereditary angioedema (HAE) is a rare condition, resting on attacks of edema in various localizations, potentially life-threatening if in facial, laryngeal, pharyngeal or gastrointestinal area. The disease is caused by deficiency or impaired activity of C1 inhibitor, therefore C1 inhibitor infusion is the the essential treatment and the only efficient method in an acute attack of HAE. Nowadays C1 inhibitor applied in our patients is obtained from human plasma, what restricts the availability of the drug and carries relevant risks. After many years of research it came to the synthesis of the recombinant protein with features of human C1 inhibitor. Its first usage in Poland took place-in two HAE patients with severe edema in 2004. The course and efficiency of this treatment is reported in the paper. Recombinant human C1 inhibitor occurred efficient and safe in presented case of severe angioedema.

The main discussed issues in the study are: epidemiology and the most important conceptions explaining pathomechanism of exercise-induced bronchospasm. Presented recommendations concern physical activities, prophylactic and pharmacological treatment in exercise-induced asthma. The study contains description of diagnostic exercise challenge tests principles and performance procedures. Problem of exercise-induced bronchial asthma related to practice sports is underlined. Reasons and symptoms of exercise-induced anaphylaxis are presented.

Inhalation challenges with agents causing occupational asthma are presented. We discuss their meaning among other diagnostic method, safety requirements, indications and contraindications. The study contains the description of most frequent delivery procedures as well as rules of assessment of bronchial response and result interpretation.

The aim of this study was to evaluate the occurrence of occupational allergic diseases of the respiratory system and skin. The study was carried out in a population of 17,600 employees of Huta im. T. Sendzimira (T. Sendzimir Steelworks) in 1992-96. During this period 543 employees were referred to the Occupational Diseases Department with a suspection of occupational allergy. Connection between the kind of occupation and disease was confirmed in 215 cases. 104 (48%) suffered from upper respiratory tract diseases or bronchial asthma and 111 patients (52%) suffered from allergic skin disease as contact dermatitis of the hand or generalized dermatitis. The analysis showed that allergic skin diseases occurred more frequently in 1992-94 and allergenic respiratory diseases were more frequent in 1995-96. Industrial dust containing metals (nickel, chrome, iron, cooper) turned out to be the main allergic factor. The highest prevalence was observed in the Rolling-Mill Department, Chemistry of Coke Department and Incombustible Materials Department. 33% of patients suffering from allergic respiratory diseases and 10% suffering from allergic skin diseases had a family predisposition to allergy (features of atopy).