In vitro assays in severe cutaneous adverse drug reactions : are they still research tools or diagnostic tests already?

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

Life-threatening laryngeal attacks in hereditary angioedema patients

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

Residential proximity to major roadways is associated with increased prevalence of allergic respiratory symptoms in children

[b]introduction and objective[/b]. 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. [b]materials and methods[/b]. 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. [b]results[/b]. 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. [b]conclusions[/b]. 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

Mas-related G protein-coupled receptor-X2 (MRGPRX2) in drug hypersensitivity reactions

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

Drug hypersensitivity reactions and desensitization in oncology

Objawy nadwrażliwości na leki przeciwnowotworowe obejmują świąd, rumień, zaczerwienienie twarzy, gorączkę, tachykardię, duszność, osutki skórne, ból głowy, osłabienie, wymioty, uczucie pieczenia, zawroty głowy i obrzęk. W prewencji stosuje się leki przeciwhistaminowe, steroidy, a także zwalnia się szybkość podawania leku. Chociaż liczba raportowanych reakcji nadwrażliwości na leki przeciwnowotworowe jest niewielka, to leki alternatywne są zwykle mniej skuteczne lub kosztowniejsze. U pacjentów, którzy przebyli ciężkie reakcje nadwrażliwości, szybka desensytyzacja umożliwia zastosowanie optymalnego leczenia pierwszego wyboru z powodu pierwotnej choroby nowotworowej lub jej nawrotu. Czasową kliniczną tolerancję uzyskuje się dzięki podawaniu małych, stopniowo wzrastających dawek leku podejrzanego o wywołanie reakcji nadwrażliwości. Dotychczas protokoły desensytyzacji opisano dla taksanów, platynowców, doksorubicyny i innych leków przeciwnowotworowych.Symptoms of hypersensitivity reactions to antineoplastic agents include pruritus, erythema, facial flushing, fever, tachycardia, dyspnea, rash/hives, headache, chills, weakness, vomiting, burning sensations, dizziness, and edema. Prevention consists of histamine receptor antagonists, steroids and slowing down the infusion rate. Although the reported incidence of hypersensitivity reactions to antineoplastic agents is considered to be low, alternative treatment is usually less effective or hardly available, because of high costs. Rapid desensitization allows patients, who experienced severe hypersensitivity reactions to receive effective first-line therapy for their primary or recurrent cancer. Temporary clinical tolerance is achieved by administering small incremental doses of drug suspected to induce hypersensitivity reaction. So far, desensitization protocols have been described for taxens, platins, doxorubicin and other antineoplastic agents

Recombinant Human-C1 inhibitor is effective and safe for repeat hereditary angioedema attacks

BackgroundHereditary 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.ObjectiveThis study evaluated the efficacy and safety of rhC1INH (50 IU/kg) for the treatment of multiple HAE attacks in an open-label extension study.MethodsTime 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.ResultsForty-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.ConclusionsA 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

A novel deep intronic "SERPING1" variant as a cause of hereditary angioedema due to C1-inhibitor deficiency

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