Allergic Reactions to Metamizole: Immediate and Delayed Responses

[EN] Background: Pyrazolones are the most common causes of selective nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. We studied a large group of patients with immediate and delayed selective responses to metamizole. Methods: Patients with suspicion of hypersensitivity to metamizole were evaluated. We verified acetylsalicylic acid tolerance and classified patients as immediate or delayed responders if they showed symptoms less or more than 24 h after metamizole administration. Skin tests were performed and if negative, a basophil activation test (BAT) was performed on immediate responders. If it was negative, we performed a drug provocation test (DPT) with metamizole. Results: A total of 137 patients were included: 132 reacted within 24 h (single NSAID-induced urticaria/angioedema/ anaphylaxis; SNIUAA) and 5 after 24 h (single NSAID-induced delayed hypersensitivity reaction; SNIDHR). Most SNIUAA patients developed anaphylaxis (60.60%); for SNIDHR, maculopapular exanthema was the most frequent entity (60%). Skin testing was positive in 62.04% of all cases and BAT in 28% of the SNIUAA patients with negative skin tests. In 5.1% of the cases, DPT with metamizole was needed to establish the diagnosis. In 22.62% of the cases, diagnosis was established by consistent and unequivocal history of repeated allergic episodes in spite of a negative skin test and BAT. Conclusions: SNIUAA to metamizole is the most frequent type of selective NSAID hypersensitivity, with anaphylaxis being the most common clinical entity. It may occur within 1 h after drug intake. SNIDHR occurs in a very low percentage of cases. The low sensitivity of diagnostic tests may be due to incomplete characterization of the chemical structures of metamizole and its metabolites.The present study has been supported by the Institute of Health ‘Carlos III’ of the Ministry of Economy and Competitiveness [grants cofounded by European Regional Development Fund (ERDF), Red de Reacciones Adversas a Alergenos y Farmacos (RD12/0013/0001 and PI15/01317)] and by Consejeria de Salud de la Junta de Andalucía (PI-0463-2013).Blanca-López, N.; Pérez-Sanchez, N.; Agúndez, JA.; García-Martín, E.; Torres, MJ.; Cornejo-Garcia, JA.; Perkins, JR.... (2016). Allergic Reactions to Metamizole: Immediate and Delayed Responses. International Archives of Allergy and Immunology. 169(4):223-230. https://doi.org/10.1159/000444798S223230169

Asthma and rhinitis induced by selective immediate reactions to paracetamol and non-steroidal anti-inflammatory drugs in aspirin tolerant subjects

En sujetos con anti-inflamatorios no esteroideos (AINES) se agravan las enfermedades respiratorias (ERNE) y los síntomas son desencadenados por el ácido acetilsalicílico (AAS) y otros potentes inhibidores COX-1 y, en algunos casos, por la debilidad de la COX-1 o los inhibidores selectivos de la COX-2. El mecanismo está relacionado con la prostaglandina vía inhibición y la liberación de leucotrienos. Los sujetos que reaccionan a un solo AINES y toleran otros se consideran respondedores selectivos, y a menudo presentan urticaria y/o angioedema y anafilaxia (SNIUAA). Un mecanismo inmunológico está implicado en estas reacciones. Sin embargo, la evidencia anecdótica sugiere que los respondedores selectivos que presentan síntomas de las vías respiratorias también pueden existir en los síntomas respiratorios. Nuestro objetivo fue determinar si los sujetos pueden desarrollar respuestas selectivas a los AINES/paracetamol que se manifiestan como vías respiratorias superiores/inferiores de los síntomas respiratorios. Para ello, estudiamos informes de pacientes con rinitis y/o asma inducida por el paracetamol o un único NSAID que tolera la ASA. Una evaluación alergológica plus reto, controlados con ASA, se llevó a cabo. Si la tolerancia ASA se encuentra, se procede a una provocación oral con el fármaco responsable. La aparición de los síntomas fue supervisada por un cuestionario clínico, midiendo el FEV1 y/o las vías respiratorias nasales y los cambios de volumen pre y post-desafío. De un total de 21 casos iniciales, hemos confirmado la aparición de problemas nasales y/o manifestaciones bronquiales en diez, caracterizados por una disminución significativa en el VEF1% y/o una disminución en el volumen de la cavidad nasal tras la administración del fármaco. Todos los casos tolerados cuentan con ASA. Esto demuestra que los sujetos con tolerante ASA presentan manifestaciones sistémicas de rinitis y/o asma inducida por el paracetamol o un único NSAID sin piel. Se requiere más investigación para saber si estos pacientes representan un nuevo fenotipo clínico para ser incluido dentro de la actual clasificación de las reacciones de hipersensibilidad a AINES.In subjects with non-steroidal anti-inflammatory drugs (NSAIDs)- exacerbated respiratory disease (NERD) symptoms are triggered by acetyl salicylic acid (ASA) and other strong COX-1 inhibitors, and in some cases by weak COX-1 or by selective COX-2 inhibitors. The mechanism involved is related to prostaglandin pathway inhibition and leukotriene release. Subjects who react to a single NSAID and tolerate others are considered selective responders, and often present urticaria and/or angioedema and anaphylaxis (SNIUAA). An immunological mechanism is implicated in these reactions. However, anecdotal evidence suggests that selective responders who present respiratory airway symptoms may also exist. Our objective was to determine if subjects might develop selective responses to NSAIDs/paracetamol that manifest as upper/lower airways respiratory symptoms. For this purpose, we studied patients reporting asthma and/or rhinitis induced by paracetamol or a single NSAID that tolerated ASA. An allergological evaluation plus controlled challenge with ASA was carried out. If ASA tolerance was found, we proceeded with an oral challenge with the culprit drug. The appearance of symptoms was monitored by a clinical questionnaire and by measuring FEV1 and/or nasal airways volume changes pre and post challenge. From a total of 21 initial cases, we confirmed the appearance of nasal and/or bronchial manifestations in ten, characterized by a significant decrease in FEV1% and/or a decrease in nasal volume cavity after drug administration. All cases tolerated ASA. This shows that ASA tolerant subjects with asthma and/or rhinitis induced by paracetamol or a single NSAID without skin/systemic manifestations exist. Whether these patients represent a new clinical phenotype to be included within the current classification of hypersensitivity reactions to NSAIDs requires further investigation.Trabajo patrocinado por: Programa Miguel Servet. Ref CP14/00034, para José Antonio Cornejo García Ministerio de Economía y Competitividad y Instituto Nacional de Salud Carlos III y Fondos FEDER. Programa Sara Borrell. Ref. CD14/00242, para James R. Perkins Ministerio de Economía y Competitividad e Instituto Nacional de Salud Carlos III y Fondos FEDER. Becas FISPI12/02247, FISPI13/02598, FISPI15/00726 y FIS PI15/00303 Servicio Público de Salud de Andalucía. Becas PI-0279-2012 y PI-0463- 2013 Junta de Extremadura y Fondos FEDER. Beca GR15026peerReviewe

Identification of Novel Biomarkers for Drug Hypersensitivity After Sequencing of the Promoter Area in 16 Genes of the Vitamin D Pathway and the High-Affinity IgE Receptor.

The prevalence of allergic diseases and drug hypersensitivity reactions (DHRs) during recent years is increasing. Both, allergic diseases and DHRs seem to be related to an interplay between environmental factors and genetic susceptibility. In recent years, a large effort in the elucidation of the genetic mechanisms involved in these disorders has been made, mostly based on case-control studies, and typically focusing on isolated SNPs. These studies provide a limited amount of information, which now can be greatly expanded by the complete coverage that Next Generation Sequencing techniques offer. In this study, we analyzed the promoters of sixteen genes related to the Vitamin D pathway and the high-affinity IgE receptor, including FCER1A, MS4A2, FCER1G, VDR, GC, CYP2R1, CYP27A1, CYP27B1, CYP24A1, RXRA, RXRB, RXRG, IL4, IL4R, IL13, and IL13RA1. The study group was composed of patients with allergic rhinitis plus asthma (AR+A), patients with hypersensitivity to beta-lactams (BLs), to NSAIDs including selective hypersensitivity (SH) and cross-reactivity (CR), and healthy controls without antecedents of atopy or adverse drug reactions. We identified 148 gene variations, 43 of which were novel. Multinomial analyses revealed that three SNPs corresponding to the genes FCER1G (rs36233990 and rs2070901), and GC (rs3733359), displayed significant associations and, therefore, were selected for a combined dataset study in a cohort of 2,476 individuals. The strongest association was found with the promoter FCER1G rs36233990 SNP that alters a transcription factor binding site. This SNP was over-represented among AR+A patients and among patients with IgE-mediated diseases, as compared with control individuals or with the rest of patients in this study. Classification models based on the above-mentioned SNPs were able to predict correct clinical group allocations in patients with DHRs, and patients with IgE-mediated DHRs. Our findings reveal gene promoter SNPs that are significant predictors of drug hypersensitivity, thus reinforcing the hypothesis of a genetic predisposition for these diseases

Allergic Reactions to Metamizole: Immediate and Delayed Responses.

Pyrazolones are the most common causes of selective nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. We studied a large group of patients with immediate and delayed selective responses to metamizole. Patients with suspicion of hypersensitivity to metamizole were evaluated. We verified acetylsalicylic acid tolerance and classified patients as immediate or delayed responders if they showed symptoms less or more than 24 h after metamizole administration. Skin tests were performed and if negative, a basophil activation test (BAT) was performed on immediate responders. If it was negative, we performed a drug provocation test (DPT) with metamizole. A total of 137 patients were included: 132 reacted within 24 h (single NSAID-induced urticaria/angioedema/anaphylaxis; SNIUAA) and 5 after 24 h (single NSAID-induced delayed hypersensitivity reaction; SNIDHR). Most SNIUAA patients developed anaphylaxis (60.60%); for SNIDHR, maculopapular exanthema was the most frequent entity (60%). Skin testing was positive in 62.04% of all cases and BAT in 28% of the SNIUAA patients with negative skin tests. In 5.1% of the cases, DPT with metamizole was needed to establish the diagnosis. In 22.62% of the cases, diagnosis was established by consistent and unequivocal history of repeated allergic episodes in spite of a negative skin test and BAT. SNIUAA to metamizole is the most frequent type of selective NSAID hypersensitivity, with anaphylaxis being the most common clinical entity. It may occur within 1 h after drug intake. SNIDHR occurs in a very low percentage of cases. The low sensitivity of diagnostic tests may be due to incomplete characterization of the chemical structures of metamizole and its metabolites

The Diamine Oxidase Gene Is Associated with Hypersensitivity Response to Non-Steroidal Anti-Inflammatory Drugs

<div><p>Non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity drug reactions. Histamine is released in the allergic response to NSAIDs and is responsible for some of the clinical symptoms. The aim of this study is to analyze clinical association of functional polymorphisms in the genes coding for enzymes involved in histamine homeostasis with hypersensitivity response to NSAIDs. We studied a cohort of 442 unrelated Caucasian patients with hypersensitivity to NSAIDs. Patients who experienced three or more episodes with two or more different NSAIDs were included. If this requirement was not met diagnosis was established by challenge. A total of 414 healthy unrelated controls ethnically matched with patients and from the same geographic area were recruited. Analyses of the SNPs rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742 and rs1049793 in the <em>HDC</em>, <em>HNMT</em> and <em>DAO</em> genes were carried out by means of TaqMan assays. The detrimental DAO 16 Met allele (rs10156191), which causes decreased metabolic capacity, is overrepresented among patients with crossed-hypersensitivity to NSAIDs with an OR  = 1.7 (95% CI  = 1.3–2.1; Pc  = 0.0003) with a gene-dose effect (P = 0.0001). The association was replicated in two populations from different geographic areas (Pc  = 0.008 and Pc  = 0.004, respectively).</p> <h3>Conclusions and implications</h3><p>The <em>DAO</em> polymorphism rs10156191 which causes impaired metabolism of circulating histamine is associated with the clinical response in crossed-hypersensitivity to NSAIDs and could be used as a biomarker of response.</p> </div

Fatigue and Dyspnoea as Main Persistent Post-COVID-19 Symptoms in Previously Hospitalized Patients:Related Functional Limitations and Disability

BACKGROUND: Multicentre studies focussing on specific long-term post-COVID-19 symptoms are scarce. OBJECTIVE: The aim of this study was to determine the levels of fatigue and dyspnoea, repercussions on daily life activities, and risk factors associated with fatigue or dyspnoea in COVID-19 survivors at long term after hospital discharge. METHODS: Age, gender, height, weight, symptoms at hospitalization, pre-existing medical comorbidity, intensive care unit admission, and the presence of cardio-respiratory symptoms developed after severe acute respiratory syndrome coronavirus 2 infection were collected from patients who recovered from COVID-19 at 4 hospitals in Madrid (Spain) from March 1 to May 31, 2020 (first COVID-19 wave). The Functional Impairment Checklist was used for evaluating fatigue/dyspnoea levels and functional limitations. RESULTS: A total of 1,142 patients (48% women, age: 61, standard deviation [SD]: 17 years) were assessed 7.0 months (SD 0.6) after hospitalization. Fatigue was present in 61% patients, dyspnoea with activity in 55%, and dyspnoea at rest in 23.5%. Only 355 (31.1%) patients did not exhibit fatigue and/or dyspnoea 7 months after hospitalization. Forty-five per cent reported functional limitations with daily living activities. Risk factors associated with fatigue and dyspnoea included female gender, number of pre-existing comorbidities, and number of symptoms at hospitalization. The number of days at hospital was a risk factor just for dyspnoea. CONCLUSIONS: Fatigue and/or dyspnoea were present in 70% of hospitalized COVID-19 survivors 7 months after discharge. In addition, 45% patients exhibited limitations on daily living activities. Being female, higher number of pre-existing medical comorbidities and number of symptoms at hospitalization were risk factors associated to fatigue/dyspnoea in COVID-19 survivors 7 months after hospitalization