Non-allergic Hypersensitivity Research Articles

Aspirin desensitization in nonsteroidal anti-inflammatory exacerbated respiratory disease: The first prospective cohort in Chile.

Nonsteroidal anti-inflammatory exacerbated respiratory disease (N-ERD) is characterized by the Samter triad: chronic rhinosinusitis with nasal polyps, asthma, and nonallergic hypersensitivity to NSAIDs. Its diagnosis is based on a complete clinical history and an aspirin (ASA) challenge test. Medical treatments include biological drugs and ASA desensitization. This study aims to evaluate the clinical response of patients with N-ERD undergoing functional endoscopic surgery (FES), followed by ASA desensitization and maintenance treatment, being the first prospective cohort study carried out in Chile. We conducted 1-year follow-up of 12 patients with N-ERD treated with FES, desensitization, and maintenance with ASA. For each control, the medication score, sinonasal symptomatology (SNOT-22), PEF (peak expiratory flow), nasal polyposis (Lildholdt score), and the appearance of adverse effects were recorded. Computed tomography (CT) of the paranasal cavities was performed at baseline and at the 12-month follow-up to calculate the Lund-Mackay score. Patients presented a reduction of SNOT-22 after the FES, which was maintained at 12 months (p = 0.002); the symptoms that showed the greatest reduction were feeling embarrassed and nasal obstruction. The Lildholdt score was also significantly reduced (p = 0.001); in only three patients, the nasal polyps recurred, and all were small. The PEF showed a slight nonsignificant increase of 3.3%. In total, 75% of patients had an adverse effect, the most frequent being abdominal pain (66.7%), but none of the 12 patients required discontinuation of aspirin treatment in 1-year follow-up. The Lund-Mackay score had a significant reduction of 6.6 points (p < 0.001). ASA desensitization is safe and effective in reducing upper and lower respiratory symptoms in patients with N-ERD and delays the reappearance of nasal polyps, although it is not exempt from adverse effects, with the vast majority being mild.

Penilloic acid is the chief culprit involved in non-IgE mediated, immediate penicillin-induced hypersensitivity reactions in mice.

Metabolites/impurities (MIs) of penicillin are normally considered to be the main substances inducing immediate hypersensitivity reactions in penicillin treatment. Our previous research found that penicillin can cause non-allergic hypersensitivity reactions (NAHRs) by directly triggering vascular hyperpermeability and exudative inflammation. However, the chief culprits and underlying mechanisms involved in penicillin-induced NAHRs have not yet been fully elucidated. In this study, we used a combination of approaches including a mouse non-allergic hypersensitivity reaction model, UPLC-MS/MS analyses of arachidonic acid metabolites (AAMs), immunoblotting technique, and molecular docking, etc to investigate the culprits involved in penicillin-induced hypersensitivity reactions. We found penilloic acid, one of the main MIs of penicillin, could trigger NAHRs via inducing increased vascular permeability, while the other MIs did no exhibit similar effect. Penilloic acid-induced reactions were not IgE-dependent. Significantly increased arachidonic acids and cascade metabolites in lungs, and activation of RhoA/ROCK signaling pathway in the ears and lungs of mice were noticed after once administration of penilloic acid. This study revealed that penilloic acid was the chief culprit involved in penicillin-induced immediate NAHRs in mice, which mainly associated with direct stimulation of vascular hyperpermeability and exudative inflammation. The activations of AAMs and RhoA/ROCK signaling pathway played important roles in these reactions.

Skin Tests for the Exploration of Hypersensitivity Reactions Associated with Iodinated Contrast Media.

Iodinated contrast media (ICM) are responsible for multiple side effects, especially hypersensitivity reactions. These reactions can either be authentic allergies or non-allergic hypersensitivity reactions. Skin tests (prick and intradermal tests) are simple to perform and can be of great help, especially if the ICM needs to be re-used. The aim of the study was to assess the characteristics of the patients in whom skin tests were performed and the results of these tests. This is a retrospective study from June 2014 to June 2019. All included patients had at least one episode of hypersensitivity reaction to ICM and underwent skin tests. We included 35 patients aged 18 to 85 years. The iopromide was the most implicated ICM. The reactions were mainly cutaneous (n=30) and immediate (n=27). The skin tests were negative, except for two patients. The re-use of ICM occurred in 11 patients: 9 with an ICM other than the one suspected and two patients with the same ICM. Among these patients, 5 did not have any premedication. Two of them had a second hypersensitivity reaction, the first with another ICM and the second with the same ICM. One of the main pillars of allergic exploration is ICM skin testing, not only to prevent a recurrence, but also to allow patients to benefit from ICM re-use, which are sometimes essential.

Les tests cutanés sont-ils utiles pour le diagnostic des réactions d’hypersensibilité aux antalgiques-antipyrétiques-anti-inflammatoires non stéroïdiens ? Contre

Reactions to nonopioid analgesics, antipyretics and nonsteroidal anti-inflammatory drugs (NSAIDs) may result from a specific/allergic hypersensitivity (HS), either IgE-mediated (immediate and very early reactions) or mediated by T-lymphocytes (delayed reactions), or from a non-specific/non-allergic HS (pharmacological « intolerance »), with a frequent cross-reactivity between the various chemical families of drugs, including paracetamol and, sometimes, coxibs. In patients with suspected allergic HS, diagnosis is usually based on a convincing clinical history and/or provocation tests (PT) showing that the patients react to the suspected drug (±other drugs in the same chemical family) but tolerate other (families of) drugs. However, although immediate and non-immediate-reading skin tests (ST) are specific when performed with non-irritant concentrations, they have a low sensitivity (≤25–30 %) and are not validated. In patients with non-allergic HS, skin tests are useless and diagnosis is based on a convincing clinical history and/or responses in PT. Considering also the low diagnostic value of in vitro tests, diagnosis of HS to analgesics-antipyretics-NSAIDs, whether allergic or non-allergic, is primarily based on clinical history of the patients and their responses in PT, and international consensus do not recommend skin tests.

Lymphocyte transformation test: History and current approaches

Drug-induced hypersensitivity reactions encompass a variety of different clinical phenotypes ranging from harmless rashes to fatal reactions. They can be classified into allergic (i.e. drug allergy) and non-allergic reactions (i.e. non-allergic hypersensitivity). Drug allergies in turn can either be antibody (e.g. IgE) or T cell-mediated.One of the diagnostic tools for the in vitro detection of drug allergy is the lymphocyte transformation test (LTT) which is based on the activation and expansion of the drug-specific memory T cells following co-incubation of the patient's peripheral mononuclear cells (PMBC) with the suspected drug in vitro. The read-out parameter in the classical LTT is T cell proliferation which can be measured as counts per minute following the addition of radiolabeled thymidine to the cell culture. However, in the course of time different modifications of the classical LTT with regard to the read-out parameters and methods have been proposed. Likewise, variations of the LTT platform itself have been described in the literature.This review article describes the development of the classical LTT and its use in the context of drug allergy detection and summarizes the modifications which have been published over time.

Ammonia level as a proxy of asparaginase inactivation in children: A strategy for classification of infusion reactions.

Allergic hypersensitivity reactions related to enzyme asparaginase may occur during intravenous infusion of drugs and other adverse reactions (non-allergic hypersensitivity and hyperammonemia), which do not require discontinuation of therapy as the first case. It makes differential diagnoses between infusion reactions essential to assure the team regarding the right decision to make after the adverse event. This study evaluated a pharmacovigilance strategy of differentiating infusion reactions to asparaginase in pediatric patients, based on the measurement of serum ammonia and the classification of the reactions by clinical symptoms and severity. We included children, diagnosed with ALL, and treated with native Escherichia coli asparaginase in a university hospital. The professional team monitored and evaluated all asparaginase infusions for continuity of treatment (rechallenge), seeing the measurement of serum ammonia and classification of reactions for type and severity grade. Data from this monitoring was collected retrospectively. Chi-square and Mann-Whitney tests were used to compare the ratios between serum ammonia concentration posterior and before asparaginase infusion. 245 infusions in 32 patients were monitored, and 19 reactions were observed in 17 children (53%). Three children have hyperammonemia and continue their treatment. The variation of the serum ammonia levels before and after the infusion was statistically significant, comparing the groups with no reaction or hyperammonemia versus the group with the hypersensitivity reaction. The pharmacovigilance strategy applied in the hospital investigated was a useful and inexpensive tool that supported clinical decision-making and enabled the maintenance of asparaginase therapy for three (9,4%) patients followed up.

Assessment of immediate and non-immediate hypersensitivity contrast reactions by skin tests and provocation tests: A review.

Introduction:Allergic and nonallergic hypersensitivity reactions to iodinated contrast media (ICM) and gadolinium-based contrast media are classified as immediate or non-immediate hypersensitivity reactions (IHR and NIHR), respectively. Skin tests and provocation tests are recommended for the evaluation of hypersensitivity reactions to contrast agents; however provocations are not common in clinical practice.Methods:A MEDLINE search was conducted to investigate studies comprising both skin tests and provocation tests that evaluated hypersensitivity reactions to ICM.Results:Nineteen studies were identified that reported on skin tests, followed by provocations. In the case of IHR to ICM, 65/69 (94%) patients with a positive skin test for the culprit media tolerated a challenge with a skin-test-negative alternative ICM. In IHR to ICM with a negative skin test for the culprit media, provocations were positive in 3.2%–9.1% patients. In the case of a NIHR to ICM with a positive skin test, provocation with a skin-test-negative agent was tolerated in 75/105 (71%) of cases. In NIHR with a negative skin test for the culprit agent, re-exposure to the culprit or an alternative was positive in 0%–34.6% patients. Provocations with the same ICM in skin test positive patients with IHR or NIHR were positive for a majority of the patients, although such provocation tests were rarely performed. Data on hypersensitivity reactions, skin tests and provocations with gadolinium-based contrast media were limited; however, they exhibited a pattern similar to that observed in ICM.Conclusion:In both ICM and gadolinium-based contrast media, the risk of an immediate repeat reaction is low when skin tests are negative. In contrast, a provocation with a skin-test-positive contrast medium showed a high risk of an immediate repeat hypersensitivity reaction. Therefore, a thorough medical history is necessary, followed by skin tests. A provocation is recommended, for diagnostic work-up, when the diagnosis is uncertain.

Non-steroidal anti-inflammatory drugs (NSAIDs) – exacerbated respiratory disease: epidemiology, pathogenesis, clinical findings and management

Non-steroidal anti-inflammatory drugs (NSAIDs) exacerbated respiratory disease (N-ERD) are characterized by non-allergic hypersensitivity (intolerance) to NSAIDs and aspirin in patients with asthma and/or eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP). Asthma in N-ERD patients is usually characterized by eosinophilic inflammation, tends to become severe and intractable, and needs chronic oral corticosteroid therapy. For some patients recurrent CSwNP is more significant problem due to nasal congestion, anosmia, and multiple repeated surgeries. Intolerance to aspirin and other NSAIDs limits the choice of pain relievers and antipyretics. Accidental use of these medications can lead to dangerous consequences, including anaphylaxis. This review presents the current understanding of the N-ERD pathogenesis and perspective trends in therapy.

ENGLISH VERSION: PERSONALIZED DESENSITIZATION WITH ACETYLSALICYLIC ACID IN PATIENTS WITH HYPERSENSITIVITY TO NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Aims: Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) has various mechanisms and represents different clinical syndromes from anaphylaxis to severe bronchospasm. The prevalence of aspirin hypersensitivity among patients with asthma and nasal polyps reaches 25.6%. Respiratory reactions associated with aspirin or other NSAIDs are not immunological. The basis of these reactions is non-allergic hypersensitivity of the cross-reactive type. Desensitization followed by long-term aspirin therapy is an effective method of treating hypersensitivity to aspirin or other NSAIDs. Using aspirin 600-1200 mg/day can significantly alleviate the symptoms of asthma, allergic rhinitis. Methods: We successfully applied aspirin desensitization for method of patients with hypersensitivity to NSAIDs. According to the method, an hour before the desensitization, daily montelukast 10 mg was taken orally, then aspirin every 3 hours. Results: Three patients underwent desensitization of aspirin. The dose was selected individualy depending on the clinical manifestations of drug-induced adverse reactions (AR). ARs during desensitization were treated by iv dexamethasone administration. Subsequent doses did not cause AR. Doses of aspirin were increased to a maximum of 1250 mg daily, and were continued for the long-term use. Conclusion: It is possible to conclude that the initial dose of aspirin should be 16-40mg; it is possible to increase the dose if the initial dosage is well tolerated; symptoms of moderate intolerance are treated by 4-8 mg iv dexamethasone; prior to desensitization, we recommended to use montelukast 10 mg, it is safe to practice desensitization of aspirin according to a personalized technique by a specialist in an intensive care unit.

The pseudoallergen receptor MRGPRX2 on peripheral blood basophils and eosinophils: Expression and function.

Mas-related G protein-coupled receptor X2 (MRGPRX2) is regarded as a mast cell-specific receptor mediating non-IgE-dependent activation. We aimed to investigate whether human basophils and eosinophils express functional MRGPRX2. Flow cytometry, immunocytochemistry, immunofluorescence, Western blot, and RT-PCR were performed in highly purified peripheral blood basophils and eosinophils of atopic and nonatopic donors. To assess functional activity, fluorescent avidin-based degranulation assay, calcium mobilization, cytokine production in supernatants, assessment of viability/apoptosis, and tricolor granulocyte activation test were used. MRGPRX2 was significantly expressed by basophils and eosinophils but not neutrophils. Functional capacity was shown by anti-MRGPRX2 mAb-induced calcium influx and concentration-dependent induction of degranulation. Sequential stimulation in the calcium mobilization assay gave no evidence for desensitization or receptor internalization. Anti-MRGPRX2 mAb significantly promoted survival. Inhibition of apoptosis could be due to released IL-3, IL-5, and GM-CSF found in supernatants. Short-term incubation with IL-3 dose-dependently upregulated MRGPRX2 expression in both, stimulation for 24hours with anti-IgE, C5a, fMLP, and IL-3 in basophils and by IL-3, IL-5, and IL-33 in eosinophils. Among known mast cell MRGPRX2 agonists ciprofloxacin but not PMX-53 was functional on basophils and eosinophils. In basophils of allergic subjects, tricolor granulocyte activation test using grass pollen demonstrated MRGPRX2 upregulation associated with degranulation and CD63 expression. Unraveling the regulation and signaling mechanisms of MRGPRX2 on basophils and eosinophils might enable the development of new therapeutic strategies to prevent or inhibit allergic and nonallergic hypersensitivity. Moreover, addressing MRGPRX2 might have potential for diagnostic purposes in (drug) hypersensitivity.

Efficacy and Safety of Infliximab Tolerance Induction in Patients with Inflammatory Bowel Diseases who Experienced Acute Infusion Reactions

Background and Aims: One of the reasons for the failure of infliximab (IFX) is immediate hypersensitivity reactions (IHR). We aimed to report the efficacy and safety of a tolerance induction protocol in inflammatory bowel diseases (IBD) patients who had previously experienced IHR during IFX infusions. Patients and Methods: We reported all cases of IBD patients who had previously experienced IHR due to IFX and who were submitted to a standardized protocol of tolerance induction to IFX from 2010 to 2015. Results: IHR occurred in a majority of patients (69%) during the first 3 infusions and for half of them after a period of IFX withdrawn. Skin prick tests were negative and only 2 intradermal tests were positive. Basophil activation tests and antidrug antibody measurements were performed in 8 out of 16 patients and were positive in 3 and 4 patients respectively. Induction of tolerance was successful in 69% of patients and IFX was pursued with clinical efficacy > 1 year in 7 patients (44%). Allergologic investigations were not predictive of tolerance induction success. Conclusion: A majority of IHR to IFX infusions occurred during the beginning or restarting of treatment and was related to a nonallergic hypersensitivity. Induction of tolerance to IFX is feasible and effective and may safely allow retreatment of IFX in almost 70% of IBD patients.

Nadwrażliwość alergiczna i niealergiczna na antybiotyki. Wytyczne Sekcji Nadwrażliwości na Leki Polskiego Towarzystwa Alergologicznego

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Kurek M, Poziomkowska-Gęsicka I, Wiśniewska M. Allergic and non-allergic hypersensitivity to antibiotics. Guidelines of the Section of Drug Hypersensitivity of the Polish Society of Allergology. Alergologia Polska - Polish Journal of Allergology. 2018;5(1):23-37. doi:10.5114/pja.2018.74445. APA Kurek, M., Poziomkowska-Gęsicka, I., & Wiśniewska, M. (2018). Allergic and non-allergic hypersensitivity to antibiotics. Guidelines of the Section of Drug Hypersensitivity of the Polish Society of Allergology. Alergologia Polska - Polish Journal of Allergology, 5(1), 23-37. https://doi.org/10.5114/pja.2018.74445 Chicago Kurek, Michał, Iwona Poziomkowska-Gęsicka, and Małgorzata Wiśniewska. 2018. "Allergic and non-allergic hypersensitivity to antibiotics. Guidelines of the Section of Drug Hypersensitivity of the Polish Society of Allergology". Alergologia Polska - Polish Journal of Allergology 5 (1): 23-37. doi:10.5114/pja.2018.74445. Harvard Kurek, M., Poziomkowska-Gęsicka, I., and Wiśniewska, M. (2018). Allergic and non-allergic hypersensitivity to antibiotics. Guidelines of the Section of Drug Hypersensitivity of the Polish Society of Allergology. Alergologia Polska - Polish Journal of Allergology, 5(1), pp.23-37. https://doi.org/10.5114/pja.2018.74445 MLA Kurek, Michał et al. "Allergic and non-allergic hypersensitivity to antibiotics. Guidelines of the Section of Drug Hypersensitivity of the Polish Society of Allergology." Alergologia Polska - Polish Journal of Allergology, vol. 5, no. 1, 2018, pp. 23-37. doi:10.5114/pja.2018.74445. Vancouver Kurek M, Poziomkowska-Gęsicka I, Wiśniewska M. Allergic and non-allergic hypersensitivity to antibiotics. Guidelines of the Section of Drug Hypersensitivity of the Polish Society of Allergology. Alergologia Polska - Polish Journal of Allergology. 2018;5(1):23-37. doi:10.5114/pja.2018.74445.

Reactions related to asparaginase infusion in a 10-year retrospective cohort.

IntroductionAlthough it is an essential component of the treatment of acute lymphoid leukemia in children, asparaginase causes adverse reactions that sometimes make it impossible to use it fully. Hypersensitivity reactions are the most frequent and may lead to early discontinuation of treatment. The present study aimed to investigate suspicions of adverse reactions during the infusion of asparaginase in a pediatric cohort.MethodsA retrospective observational study was carried out at a university pediatric institute in the state of Rio de Janeiro. Information regarding clinical features and characteristics of adverse reactions was collected from hospital medical records. Suspicions of adverse reactions were classified regarding causality and severity.ResultsSeventy-three suspicions of adverse reactions were recorded during asparaginase infusion in 72 children in the study period. Allergic hypersensitivity reactions were suspected in 60.5% of the cases. Of these, 25% of the reactions occurred during induction and 61.1% in concomitant use with vincristine, findings that diverge from other studies. High-risk classification and younger age were considered risk factors for these reactions. A total of 72.4% of the reactions were classified as grade 1 or 2, which suggest that not all are related to antibody formation; this highlights the importance of differential diagnosis with other reactions, such as non-allergic hypersensitivity and hyperammonemia.ConclusionThe implementation of the differential diagnosis of reactions related to infusion of asparaginase with ammonia dosage and classification of the grade of reactions is crucial to facilitate the identification and proper management of each type of reaction.

In Vivo Cysteinyl Leukotriene Release in Allergic and Nonallergic Immediate Hypersensitivity Reactions during Anesthesia.

Immediate hypersensitivity reactions occurring during anesthesia are classified as allergic when skin tests and mast cell tryptase are positive and as nonallergic when negative results are obtained. Cysteinyl leukotrienes (cysLTs) are potent mediators synthesized by mast cell and eosinophil that induce bronchial constriction. They could play a role in hypersensitivity reactions. cysLT C4, D4, and E4 concentrations were measured by a competition immunoassay in serial plasma samples obtained prospectively from 21 anesthetized controls and retrospectively from 34 patients who reacted at induction of anesthesia (24 with allergic and 10 with nonallergic reactions). In controls, the median (interquartile range) cysLT concentration was 0.83 (0.69 to 1.02) μg/l before anesthesia and was unchanged 30 min, 6 h, and 24 h afterward. In the patients with allergic reactions, the values were highly increased 30 to 60 min after the reaction (17.9 [7.8 to 36.0] μg/l), while the patients with nonallergic reactions had less increased values (7.3 [3.0 to 11.5] μg/l). The difference between the three groups was significant (P < 0.0001). Increased values persisted during the 24 h of observation. Concentrations were significantly higher in patients with bronchospasm (P = 0.016). cysLTs appear to be an important mediator of allergic and nonallergic immediate hypersensitivity reactions. These findings might open a new field for management of patients with hypersensitivity reactions, especially nonallergic ones.

Proteomics Study on Nonallergic Hypersensitivity Induced by Compound 4880 and Ovalbumin.

Nonallergic hypersensitivity reaction (NHR) accounts for more than 77% of all immune-mediated immediate hypersensitivity reactions and has become a serious threat to public health. Here, proteomics was used to study the NHR mechanism of two typical substances, the compound 4880 and ovalbumin. Twelve different proteins were suggested as potential biomarkers for examining the NHR mechanism, and our results revealed that the mechanism mainly encompassed 2 processes, i.e., generation and effect processes. The generation process could be classified as direct stimulation, complement (classical and alternative), coagulation, kallikrein-kinin, and integrated pathways. Thus glutathione peroxidase 1, terminal complement complex (complement factor 4d and Bb), coagulation 13, kininogen-1, and IgE could be used as candidate biomarkers for the indication of the corresponding pathways respectively, the proteins were further confirmed by ELISA. And the effect process was mainly composed of histamine as well as proteins such as DCD and MYLPF, which could be used as important indices for the symptoms of NHR. Our study differs from previous studies in that C4880 was found to not only be involved in the direct stimulation pathway, but also in the activated complement and kallikrein-kinin pathways through the coagulation pathway. We also report for the first time that ovalbumin-induced NHR could be a combination of the coagulation, classical complement, and integrated pathways.

Prevention of nonsteroidal inflammatory drug-induced urticaria and/or angioedema

BackgroundUrticaria and/or angioedema (U/AE) are the most frequent and less severe forms of nonallergic hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). Management of NSAID-induced U/AE includes (1) the avoidance of the culprit drug and of cyclooxygenase (COX) 1 inhibitors, (2) the use of weak COX-2 inhibitors, and/or (3) desensitization to aspirin. Because these possibilities may have drawbacks, we tested the possibility of preventing NSAID-induced U/AE by the administration of antihistamines and/or a combination of antihistamines and leukotriene antagonists. ObjectiveTo test the preventive effect of antihistamines and/or leukotriene antagonists on the development of U/AE in patients with a history of NSAID hypersensitivity confirmed by a positive challenge result. MethodsA single, placebo-controlled, oral challenge using the culprit NSAID was applied to 65 patients with a history of NSAID-induced U/AE. In the case of recurrence of the symptoms, another oral challenge was performed under premedication with antihistamines alone or combined antihistamines and leukotriene antagonists. ResultsA total of 59 of 65 patients (90%) tolerated a normal dose of NSAID, confirming previous data on the poor reproducibility of nonallergic hypersensitivity reactions to NSAIDs on challenge. Of the 6 patients who experienced recurrence of the U/AE on NSAID challenge, antihistamines and combined antihistamines and leukotriene antagonists prevented the hypersensitivity reactions in 2 and 3 of them, respectively. Only 1 patient still developed a moderate NSAID-induced urticaria despite the double premedication. ConclusionTreatment with NSAIDs at normal doses is possible and well tolerated in patients who have experienced NSAID-induced U/AE, which could be prevented by the concomitant use of antihistamines and leukotriene antagonists.

Aspirin Exacerbated Respiratory Disease

Aspirin Exacerbated Respiratory Disease

Les réactions d’hypersensibilité allergique et non allergique aux antalgiques non opiacés, antipyrétiques et anti-inflammatoires non stéroïdiens chez l’enfant : épidémiologie, aspects cliniques, physiopathologie, diagnostic et prévention

Non-opioid analgesics, antipyretics and nonsteroidal anti-inflammatory drugs are widely used, but suspected allergic reactions to these drugs are rare, especially in children. Most frequent reactions are cutaneous (urticaria, angioedema) and respiratory (rhinitis, asthma). Other reactions (anaphylaxis, potentially harmful toxidermias) are rare. In a few patients, reactions may result from a specific (allergic) hypersensitivity, with positive responses in prick and intradermal tests (anaphylaxis, immediate urticaria and/or angioedema) and in intradermal and patch tests (non-immediate reactions). However, most reactions result from a non-specific (non-allergic) hypersensitivity (intolerance), with a frequent cross-reactivity between the various families of analgesics, antipyretics and nonsteroidal anti-inflammatory drugs, including paracetamol. Based on a convincing clinical history and/or positive responses in challenge tests, intolerance to non-opioid analgesics, antipyretics and nonsteroidal anti-inflammatory drugs has been diagnosed in 13 to 50% of the patients with allergic-like reactions to these drugs. Risk factors are a personal atopy and age. Prevention is based on administration of other (families of) analgesics, antipyretics and nonsteroidal anti-inflammatory drugs in patients with allergic hypersensitivity to these drugs. In patients with non-allergic hypersensitivity, prevention is based on administration of drugs with a low cyclo-oxygenase-1 inhibitory activity (if tolerated). Desensitization is efficient in patients with respiratory reactions, but does not work in patients with mucocutaneous reactions and anaphylaxis.

Educational case series: β‐lactam allergy and cross‐reactivity

Penicillins and cephalosporins are the most widely used antibiotics for the treatment of common infections, and they are the two main classes of β-lactams. On the basis of the time of appearance of the reaction after drug intake and for diagnostic purposes, hypersensitivity reactions to β-lactams have been classified as immediate or non-immediate. The diagnostic evaluation of allergic reactions to β-lactams has changed over the last decade, for several reasons. In many countries, major and minor determinants for skin testing are not available. In immediate allergic reactions, the sensitivity of skin testing is decreasing. For non-immediate reactions, skin testing appears to be less sensitive than previously reported. The drug provocation test is still necessary for diagnosis. In this education review series, we described three cases of β-lactam allergy: first, a child with an IgE-mediated allergy to benzyl-penicillin; second, a child with a non-allergic hypersensitivity to amoxicillin; and in the third patient, we will discuss about cross-reactivity between penicillins and cephalosporins. These cases are correlated with the practical management of evaluating β-lactam allergy.

Angiodema due to oral acitretin and isotretinoin

Angioedema may be caused by nonsteroidal antiinflammatory drugs, angiotensin- converting enzyme inhibitors, radiocontrast media, antibiotics, sea food etc. It can involve an allergic (IgE-mediated) or non-allergic hypersensitivity reaction, both with a similar clinical presentation. While angioedema due to isotretionin has been described previously, this is the first description of angiodema due to acitretin. We report two uncommon cases of palpebral and labial angiodema due to retinoids, by acitretin and oral isotretinoin respectively: a 48-year-old man with psoriasis and a 24-year-old woman with severe acne resistant to antibiotics and topical drugs. In both cases the reaction persisted through-out treatment with these drugs, but resolved quickly after discontinuation. Reintroduction of the drugs brought on angioedema again.