European Network For Drug Allergy Research Articles

Evaluation of different protocols for classification of pediatric hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: Children with underlying allergic disease should be a separate subgroup.

Background: Different recommendations for the classification of nonsteroidal anti-inflammatory drug hypersensitivity reactions (NSHSR) in children have been reported but a shortage still exists. Objective: The aim of the present study was to evaluate the inclusivity of two European Academy of Allergy and Clinical Immunology (EAACI) position paper classifications and to characterize the factors that underlie classification discordance in children. Methods: Patients with a history of NSHSR were evaluated with a standardized diagnostic protocol according to EAACI/ European Network for Drug Allergy (ENDA) recommendations. Children were classified and compared according to the EAACI 2013 and the pediatric EAACI/ENDA 2018 classifications. Subjects who were unclassified and those who were classified were compared. Results: Of 232 patients (median [interquartile range] age 6 years (4-11 years) with a history of NSHSR, 52 (22.4%) were confirmed with diagnostic tests. Thirty-six (69.2%) were classified as having cross-intolerance, whereas 16 patients (30.8%) were classified as selective responders. Eleven of the confirmed cases (21.2%) could not be categorized according to the 2013 EAACI classification, whereas this number was six adolescents (11.5%) when the 2018 EAACI/ENDA pediatric classification was used. Patients who were unclassified and who were all cross-intolerant were more likely to have atopic sensitization (p = 0.001) and asthma as an underlying disease (p = 0.03), higher serum eosinophil count (p = 0.022), and total immunoglobulin E levels (p = 0.007) compared with those who fit well into the classification. In multivariate regression analysis, the presence of atopic sensitization (adjusted odds ratio 20.36 [95% confidence interval, 2.14-193.48]; p = 0.009) was found to be the only significant underlying factor for an unclassified and/or blended phenotype. Conclusion: The 2013 EAACI classification resulted in a high rate of subjects who were unclassified. Despite better clinical utility, the recent pediatric EAACI/ENDA classification system still has shortcomings in terms of inclusivity for adolescents. Mostly, children with underlying allergic diseases could not be classified by the current guidelines. We propose to classify them as a separate pediatric cross-intolerance subgroup because the underlying mechanism may involve more than cyclooxygenase 1 inhibition.

Adverse Reaction to Ceftriaxone: How Far Can We Go to exclude an Allergy?

In the pediatric population, cephalosporins are one of the most often prescribed antibiotic groups. Currently, the European Network for Drug Allergy's (ENDA) standardized diagnostic techniques are widely used to diagnose beta lactam allergic reactions, which help physicians to confirm or exclude the allergy.
 Here, we report a case of an incorrectly labeled child of allergy to ceftriaxone after presenting a reaction minutes after the administration of the first dose of ceftriaxone. The allergic pathogenesis was suspected based on the clinical data (brief interval between the drug injection and the appearance of symptoms). we performed skin tests, intradermal tests (IDT) for ceftriaxone, which turn out negatives, then we found an alternative drug for the patient to use by testing ceftazidime and amoxicillin and finally, since the symptoms weren’t specific of an allergy reaction and more likely suggesting a vasovagal syncope, we pursued with an intravenous drug provocation test to ceftriaxone, those tests helped us to prove the innocence of ceftriaxone and enabled us to reassure the parents.
 Doctors should be mindful of the risks associated with avoiding specific antibiotic classes, particularly beta lactams, which are the most frequently recommended first-line antibiotics for pediatric patients and whose exclusion may complicate the management of certain pathologies. Such an approach may increase the number of infections, have an influence on antimicrobial stewardship, and have negative health economic effects on the public, it is crucial to avoid identifying a child as allergic without first performing an appropriate diagnostic workup.

A new classification option for NSAID hypersensitivity: Kalyoncu classification.

The European Network for Drug Allergy (ENDA) proposed a consensus document for hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) in 2011. A subgroup of patients with NSAIDs-exacerbated respiratory disease (NERD) develop urticaria/angioedema type reactions in response to NSAIDs. The Kalyoncu classification might be a novel option to classify patients with NSAID hypersensitivity (NH). In this study, we compare the ENDA and the Kalyoncu classifications. This study enrolled a total of 196 patients. NH reaction types were categorized as asthma, rhinitis, urticaria/angioedema and anaphylaxis. Based on the reaction history and oral provocation test findings, patients were grouped according to ENDA and Kalyoncu classifications. The mean age of the 196 patients was 40.32±13.28 years, and 130 (66.3%) of them were female. Under the ENDA and Kalyoncu classifications, the most common NH subgroups were NERD (32%), and isolated NH (34.2%), the least prevalent NH subgroups were single NSAID-induced delayed reactions (SNIDR) (1.5%), and pseudo Samter's syndrome (11.7%). Our research revealed that the Kalyoncu classification is more descriptive of patients with NERD exhibiting urticaria/angioedema-type reactions. It also provides future risk assessment for development of NERD. For controversial cases, the Kalyoncu classification can be utilized as a new complimentary option alone or in conjunction with ENDA classification.

Severe cutaneous adverse drug reactions: diagnostic approach and genetic study in a Brazilian case series.

<b>Background.</b> Severe cutaneous adverse reactions (SCAR) are potentially fatal reactions. Genetic predisposition is involved in their pathogenesis related to drugs and ethnicities, however in a mixed population these relationships are still unknown. The aim of this study was to describe phenotypes, suspect drugs and HLA-alleles related to SCAR, identified by a systematized approach in a Brazilian case series. <b>Methods.</b> Patients who were diagnosed with SCAR between March 2011 and July 2019 at our university hospital were included. European Network for Drug Allergy (ENDA) questionnaire was used to collect clinical and laboratory data and algorithms for assessment of drug causality were applied. Socio-demographic variables included age, gender and skin color/ethnicity. Drug patch tests (DPT) and HLA-A, -B, -DRB1 typing were carried out. <b>Results</b>. A total of 74 patients were included: 36 (48.64%) with SJS/TEN, 32 (43.24%) DRESS/DIHS, 3 (4.05%) AGEP, 2 (2.70%) overlap(DRESS/SJS and DRESS/AGEP) and 1 (1.35%) GBFDE. The median age was31.5 years (IQR = 14-52.25), most were female (n = 44/59.46%) and brown (n = 38/51.35%). Anticonvulsants (n = 32/43.24%) were the largest group involved and antibiotics (n = 26/35.13%) were the second most common. Two patients with DRESS died during the acute phase. Positive DPT were shown only in anticonvulsant associated DRESS. HLA related to abacavir, allopurinol and carbamazepine were identified. <b>Conclusions.</b> A systematized approach allowed the phenotypic characterization of SCAR. The HLA-A*31:01, B*57:01 and B*58:01 alleles were identified, reinforcing the causality in SCAR by CBZ, ABC and ALLO in the Brazilian population.

Allergies and COVID-19 vaccines: An ENDA/EAACI Position paper.

Anaphylaxis, which is rare, has been reported after COVID-19 vaccination, but its management is not standardized. 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. 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. 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.

The controversy of drug hypersensitivity in patients with cystic fibrosis and review of the literature.

Cystic fibrosis (CF) is reported to be a risk factor for drug hypersensitivity. However, there are conflicting data about true prevalence of drug hypersensitivity in children with CF. The suspicious drug hypersensitivity reactions (DHRs) of children with CF were enquired by the European Network for Drug Allergy (ENDA) questionnaire, and skin tests and/or drug provocation tests were performed according to the established guidelines. Two hundred and nineteen children (48.9% boys; median [IQR] age, 8.4years [4.8-12.4years]) with cystic fibrosis were included in the study, among which 22 patients with 24suspected DHRs were evaluated. Most of the suspected DHRs were of non-immediate (n=16, 66.6%) type, and the offending drugs were amoxicillin-clavulanic acid (n=7), macrolides (n=4), trimethoprim-sulfamethoxazole (TMP/SMX) (n=2), piperacillin-tazobactam (n=1), pancrelipase (n=1), and ursodeoxycholic acid (n=1). Eight (33.3%) of the DHRs were classified as immediate (ceftriaxone [n=2], ceftazidime [n=2], meropenem [n=1], AmBisome [n=2], and vancomycin [n=1]). The main clinical presentations were maculopapular eruption (41.6%) and urticaria (37.5%), accompanied by angioedema (8.3%), flushing (12.5%), and vomiting (8.3%). Nine skin tests (with beta-lactam protocol in 6 patients) and 24 DPTs were performed, and none of the skin tests revealed a positive result; however, 2 DPTs with TMP/SMX were positive. Actual drug hypersensitivity was demonstrated in 2 of 219 patients (0.9%) with non-beta-lactam antibiotics. These results conflict with previous researches that showed higher drug hypersensitivity rates but are consistent with some recent studies. Allergological diagnostic workup is mandatory in patients with cystic fibrosis in case of a suspicious DHR.

Descriptive Analysis of Cross-Reactive Anaphylaxis as a Different Clinical Subtype of Nonsteroidal Anti-Inflammatory Drug (NSAID) Hypersensitivity

Introduction: The European Network of Drug Allergy and the European Academy of Allergy and Clinical Immunology have classified hypersensitivity reactions induced by nonsteroidal anti-inflammatory drugs (NSAIDs) into 5 phenotypes according to the pathophysiology, clinical manifestations, number of drugs involved, and the presence of underlying diseases. This classification does not include anaphylaxis as part of NSAID cross-reactivity. The objective of this study was to characterize a group of patients with anaphylactic NSAID cross-reactivity. Method: This was a retrospective, descriptive, observational study. Patients who developed anaphylaxis to one NSAID plus another acute reaction (anaphylactic or not) to at least one other NSAID of a different chemical group were included. Demographic and clinical characteristics and the diagnostic approach were studied. Results: A total of 38 patients were included, 28 (73.7%) of whom were women. The mean age was 40 ± 17.7 years. The main organs affected in the anaphylactic reaction were the skin and the respiratory system, occurring in 35 (92.1%) and 33 (86.8%) patients, respectively. Thirty-two (84.3%) patients presented with cutaneous and respiratory involvement simultaneously. The main anti-inflammatory agent involved in anaphylactic reactions was acetylsalicylic acid in 9 (23.7%) patients, followed by dipyrone in 8 (21.1%). The most frequent allergic comorbidity was rhinitis in 20 (52%) patients. Skin tests were performed in 15 (39.5%) patients, showing positivity in 12 (80%), mainly to mites. A total of 36 of 38 patients were challenged with alternative drugs, and 35 (97.2%) tolerated meloxicam and/or etoricoxib. Conclusion: In the present study, NSAID cross-anaphylaxis was more frequent in women, and acetylsalicylic acid and dipyrone were the main triggers. Rhinitis was the main allergic comorbidity, and there was a high incidence of atopy. The majority tolerated selective COX-2 NSAIDs.

Behind the scene: Paracetamol hypersensitivity in children

Paracetamol, a non-steroidal anti-inflammatory drug, is commonly being used for fever and pain relief worldwide. The aim of this study was to evaluate children with a suspected history of paracetamol hypersensitivity. Sixty patients who were referred to our clinic in between January 2015 and December 2018 with a suspected history of paracetamol hypersensitivity were included. Reactions were classified according to the European Network for Drug Allergy (ENDA)/Global Allergy and Asthma European Network classification and European Academy of Allergy and Clinical Immunology (EAACI)/ENDA Position Paper. Diagnoses were confirmed by skin tests and oral challenge tests (OCTs). In those with verified paracetamol hypersensitivity, an OCT with a strong COX-1 inhibitor was performed to classify the type of the reaction to refer as either selective or cross-intolerance hypersensitivity. A subsequent OCT with a selective COX-2 inhibitor was performed in those cross-intolerant patients to find out a safe alternative drug. Sixty OCTs with paracetamol were performed to patients with a median age of 8.5 years, and hypersensitivity to paracetamol was verified in 8 patients. Four children were classified as selective responders, and 3 were classified as cross-intolerant after OCT with a COX-1 inhibitor. Overall, skin test positivity for paracetamol was detected in only one patient, in whom OCT with paracetamol was negative. In all 3 cross-intolerant patients, a safe alternative non-steroidal anti-inflammatory drug was identified after an OCT with a selective COX-2 inhibitor. OCT stands as the gold-standard procedure in verifying the diagnosis of patients with paracetamol-induced drug hypersensitivity, as well as, in defining the type of reactions and finding out safe alternative drugs.

Intradermal Tests With Drugs: An Approach to Standardization.

Background: Intradermal tests (IDTs) are performed and interpreted differently in drug allergy centers making valid comparison of results difficult.Objective: To reduce method-related and intercenter variability of IDTs by the introduction of a standardized method.Materials and methods: In 11 centers of the European Network for Drug Allergy, IDTs were prospectively performed with saline and with amoxicillin (20 mg/ml) using (1) the local method and (2) the standardized European Network in Drug Allergy (ENDA) method (0.02 ml). The diameters of the initial injection wheal (Wi) for the different volumes and sites injected obtained from each center were analyzed.Results: The most reproducible method was to fill a syringe with test solution, then expel the excess fluid to obtain exactly 0.02 ml. The median Wi diameter with 0.02 ml injection using the standardized method was 5 mm [range 2–10 mm; interquartile range (IQR) 5–5 mm; n = 1,096] for saline and 5 mm (range 2–9 mm; IQR = 4.5–5 mm; n = 240) for amoxicillin. IDT injection sites did not affect the Wi diameter. Training improved precision and reduced the variability of Wi diameters.Conclusion: Using the standardized IDT method described in this multicenter study helped to reduce variability, enabling more reliable comparison of results between individuals and centers.

Clinical value of in vitro tests for the management of severe drug hypersensitivity reactions.

Drug hypersensitivity reactions (DHRs) occasionally present with severe cutaneous adverse reactions (SCARs) which result in a high risk of morbidity and mortality. Although SCARs are rare, the occurrence could lead to a significant increase in healthcare and economic burden, especially when more than one possible culprit drug is implicated. Therefore, the accurate identification of the culprit drug(s) is important for correct labeling and subsequent patient education and avoidance. To date, clinical evaluation using causality assessment has limitations because the assessment may be inaccurate due to the overlapping timelines when multiple drugs are initiated/continued. Moreover, drug provocation tests (DPTs) which is the gold standard in diagnosis, are contraindicated, and in vivo skin tests may also be associated with risks of triggering SCAR. The European Network for Drug Allergy recommended that in vitro tests, if available, should be performed before any in vivo tests. Basophil activation tests and lymphocyte transformation tests, could serve as reliable in vitro tests for both immediate and delayed-type DHR. Many academic medical centers with affiliated laboratory services offer these tests in the diagnostic evaluation of SCARs in clinical practice. This not only complements identification of the culprit drug(s), but may also be used to test for potentially non cross-reactive alternatives, hence avoiding DPTs. In this review, we summarize the roles of in vitro tests in identifying the culprit drug(s) in SCARs, issues with utilization and interpretation of test results, and our experience in clinical practice.

Discrepancies in the diagnosis and classification of nonsteroidal anti-inflammatory drug hypersensitivity reactions in children

BackgroundHypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently encountered in daily clinical practice. The aim of this study was to determine the confirmation rates, risk factors of NSAID hypersensitivity in children and to try to classify them with a standardized diagnostic protocol. MethodsAll patients with a suspicion of NSAID-induced hypersensitivity were evaluated with European Network for drug Allergy (ENDA) recommendations. The children were classified as selective responders (SRs) or cross-intolerant (CI) depending on the drug provocation test (DPT) results. ResultsWe evaluated 106 children with a suspicion of NSAID hypersensitivity. NSAID hypersensitivity was confirmed with tests in 31 patients; 4 (12.9%) were diagnosed by skin tests and 27 (87.1%) by DPTs and two patients with a history of anaphylaxis by medical records. Eleven patients (33.3%) were classified as SRs, whereas twenty-two (66.6%) children as CIs. SRs and CIs were further classified as NSAID-induced urticaria/angioedema (n = 8), NSAID-exacerbated cutaneous disease (n = 6) and NSAID-exacerbated respiratory disease (n = 1) and single NSAID-induced urticaria/angioedema and/or anaphylaxis (n = 11). Eight (24.2%) patients could not be categorized according to ENDA/GA2LEN classification; one CI patient could not be classified based on pathomechanisms, seven CIs could not be categorized based on the underlying disease and clinical manifestations. A reaction within an hour of drug intake (aOR:3.0, 95% confidence interval: 1.18–7.67, p = 0.021), a history with multiple NSAIDs hypersensitivity (aOR:2.9, 95% confidence interval: 1.16–7.60, p = 0.022), and family history of atopy (aOR:4.0, 95% confidence interval: 1.50–10.82, p = 0.006) were found as the independent risk factors related to confirmed NSAID hypersensitivity. ConclusionsThis study suggests the presence of different phenotypes which do not fit into the current classifications in children with NSAID hypersensitivity.

Basal serum tryptase is not a risk factor for immediate-type drug hypersensitivity during childhood.

High serum basal tryptase (sBT) levels have been identified as a risk factor for both venom- and food-induced severe allergic reactions. The aim of this study was to compare sBT levels in children with different severity of actual drug hypersensitivity reactions (DHRs) with those of age- and sex-matched controls without any history of DHRs. Patients between 0 and 18 years of age with a history of immediate-type DHRs manifested in 0-6 h after the culprit drug intake were included. Following ENDA (European Network for Drug Allergy) inquiries, patients were evaluated with skin and/or provocation tests to define the actual drug-hypersensitive patients. Serum BT levels were determined for both patients and controls. Of 345 children, 106 patients (30.7%) [(58.5% male), median age (interquartile range) 8.0 years (4.2-12.2)] were diagnosed as drug hypersensitive. Ninety-eight controls were also included. The sBT levels of drug-hypersensitive patients with and without anaphylaxis and the control group were similar [2.6 (2.0-3.6) μg/l vs. 2.8 (1.6-4.3) μg/l vs. 2.6 (1.8-3.6) μg/l, respectively, (p > 0.05)]. The sBT levels of the patients with sole cutaneous symptoms 2.8 (1.6-4.3) μg/l, mild anaphylaxis 3.0 (1.9-4.9) μg/l, and moderate-to-severe anaphylaxis 2.6 (2.0-3.6) μg/l were also comparable (p > 0.05). The onset of DHRs [those occurring in 1 h (n = 87) or in 1-6 h (n = 19) after the drug intake], positive results with skin tests with the culprit drug, or the classification of the patients according to different age groups [(0-2 years), (2-6 years), (6-12 years), (12-18 years)] did not correlate with sBT levels. The sBT levels in children with actual drug hypersensitivity would not be a risk factor for severe systemic reactions on the contrary to children with allergic reactions to food or insect venom.

Different Phenotypes of Non-Steroidal Anti-Inflammatory Drug Hypersensitivity during Childhood

Background: Although non-steroidal anti-inflammatory drug hypersensitivity (NSAID-H) has been widely studied in adults, there is still a lack of data regarding the features and phenotypes of NSAID-H in children. Our aim was to define risk factors and different phenotypes according to clinical patterns. Methods: Patients with a history of reaction to any NSAIDs referred between January 2012 and October 2014 were included. After completing a European Network for Drug Allergy (ENDA) questionnaire, initial skin and/or oral provocation tests (OPTs) were performed for the offending drug. Additional OPTs were done with aspirin in case of NSAID-H to determine cross-reactivity. NSAID-hypersensitive patients were defined as being either a selective responder (SR) or cross-intolerant (CI) and further categorized according to either the ENDA/GA²LEN classification or an alternative scheme by Caimmi et al. [Int Arch Allergy Immunol 2012;159:306-312]. Results: Among 121 patients [58.7% male, average age 7.8 years (4.7-10.8)] with 161 NSAID-related reactions, 110 patients with 148 reactions were assessed. NSAID-H was diagnosed in 30 (27%) patients with 37 (25%) reactions. Multivariate regression analysis revealed that an immediate-type reaction and respiratory symptoms during the reaction increased the risk of a reproducible NSAID-related reaction (OR 3.508, 95% CI 1.42-8.7, p = 0.007; OR 3.951, 95% CI 1.33-11.77, p = 0.014, respectively). Additional OPTs revealed 13 SRs and 14 CIs. A family history of allergic disease was more frequent in CIs compared to SRs (57.1 vs. 15.4%, p = 0.031). Reactions belonging to CIs were more frequently characterized by angioedema compared to those of SRs (81.3 vs. 46.2%, p = 0.019). SRs and CIs were further classified as single NSAID-induced urticaria/angioedema and/or anaphylaxis (n = 13), NSAID-induced urticaria/angioedema (n = 7), NSAID-exacerbated cutaneous disease (n = 2) and NSAID-exacerbated respiratory disease (n = 1). Four CIs could not be categorized according to either classification system. One SR could not be categorized according to ENDA/GA²LEN. Conclusion: During childhood, NSAID-H exhibits different phenotypes and the majority of them can be categorized with current classification systems; however, classifications based on adult data may not exactly fit NSAID-H in paediatric patients.

Evaluation of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs according to the latest classification.

The consensus document for hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) proposed by the European Network for Drug Allergy (ENDA) interest group (2011) was revised in 2013. We aimed to evaluate the usability of the latest NSAID hypersensitivity classification of ENDA. A total of 370 patients with a history of hypersensitivity reactions to NSAIDs among the 1250 outpatients referred for suspected drug allergy between July 2013 and June 2014 were evaluated, and 308 patients who were confirmed as having NSAID hypersensitivity were included in this study. After confirming the diagnosis, a single-blind placebo-controlled drug provocation test was performed with aspirin or diclofenac to categorize the patients according to the ENDA classification. The reactions not meeting the ENDA classification criteria were grouped as blended reactions. Among the 308 patients (224 female, mean age 42.12 ± 13.24), the leading cause of hypersensitivity reactions was metamizol (30.5%) followed by aspirin (30.2%). The most common NSAID hypersensitivity subgroup was SNIUAA (46.4%) and the least common type was SNIDR (1.6%). Cross-reactivity was identified in 50.3% of the patients. In five patients (1.6%), the hypersensitivity reactions to NSAIDs did not meet the ENDA classification: Three patients experienced anaphylaxis with different NSAIDs, one patient encountered anaphylaxis with one NSAID and urticaria with other NSAIDs, and the last patient had angioedema with different NSAIDs. The latest ENDA classification for NSAID hypersensitivity is generally a practical and useful instrument for clinicians. We only point out that anaphylaxis with different NSAIDs can be seen in a small group of patients.

The Absence of CYP3A5*3 Is a Protective Factor to Anticonvulsants Hypersensitivity Reactions: A Case-Control Study in Brazilian Subjects.

Although aromatic anticonvulsants are usually well tolerated, they can cause cutaneous adverse drug reactions in up to 10% of patients. The clinical manifestations of the antiepileptics-induced hypersensitivity reactions (AHR) vary from mild skin rashes to severe cutaneous drug adverse reactions which are related to high mortality and significant morbidity. Genetic polymorphisms in cytochrome P450 genes are associated with altered enzymatic activity and may contribute to the risk of AHR. Here we present a case-control study in which we genotyped SNPs of CYP2C19, 2C9 and 3A5 of 55 individuals with varying severities of AHR, 83 tolerant, and 366 healthy control subjects from São Paulo, Brazil. Clinical characterization was based on standardized scoring systems and drug patch test. All in vivo investigation followed the ENDA (European Network of Drug Allergy) recommendations. Genotype was determined by real time PCR using peripheral blood DNA as a template. Of all 504 subjects, 65% were females, 45% self-identified as Afro-American, 38% as Caucasian and 17% as having non-African mixed ascendancy. Amongst 55 subjects with AHR, 44 had severe cutaneous drug adverse reactions. Of the 46 drug patch tests performed, 29 (63%) were positive. We found a strong association between the absence of CYP3A5*3 and tolerant subjects when compared to AHR (p = 0.0002, OR = 5.28 [CI95% 2.09–14.84]). None of our groups presented positive association with CYP2C19 and 2C9 polymorphisms, however, both SNPs contributed to separation of cases and tolerants in a Classification and Regression Tree. Our findings indicate that drug metabolism genes can contribute in the tolerability of antiepileptics. CYP3A5*3 is the most prevalent CYP3A5 allele associated with reduced enzymatic function. The current study provides evidence that normal CYP3A5 activity might be a protective factor to aromatic antiepileptics-induced hypersensitivity reactions in Brazilian subjects.

Actual drug allergy during childhood: Five years’ experience at a tertiary referral centre

BackgroundDrug hypersensitivity reactions (DHR) are common in the paediatric population, representing a public health problem. Recent studies have confirmed that the frequency of drug allergy is overestimated by both parents and physicians. The aim of this study is to determine the prevalence and risk factors of actual drug allergies in children admitted to a tertiary referral allergy centre. MethodsMedical records covering the period of 2005–2010 of children with a history of DHR were reviewed. Demographic features of the patients and results of skin and drug provocation tests were noted. The European Network for Drug Allergy (ENDA) questionnaire was filled by using medical records and making phone calls with parents. ResultsNinety-six patients with 140 DHRs were evaluated. Seventeen children had confirmed drug allergy by positive skin tests (n=11) and drug provocation tests (n=5). One patient underwent severe anaphylaxis and subsequent cardiac arrest during infusion of the drug, and therefore diagnostic tests were not performed. Actual drug allergy was more frequent in children with chronic diseases (58.8% vs. 26.5%, p=0.018) and histories of anaphylaxis during DHR (58.8% vs. 24%, p=0.001). The patients’ history of anaphylaxis [OR: 5.789, 95%CI: 1.880–17.554, p=0.002], sweating [OR: 7.8, 95%CI: 1.041–58.443, p=0.046] and dyspnoea [OR: 5.230, 95%CI: 1.836–14.894, p=0.002] during suspicious DHRs increased the risk for actual drug allergy. ConclusionActual drug allergy was determined in 17.7% of the patients with a suspicious DHR. Having a history of anaphylaxis during suspected drug reactions as well as symptoms of sweating and dyspnoea increased the risk for actual drug allergy.

Çocuklarda Tek Non-steroid Anti-inflamatuar İlaç ile Oluşan Hipersensitivite Reaksiyonları

Non-steroidal anti-inflammatory drug (NSAID) hypersensitivity is one of the most common drug-related reactions in children. According to European Network for Drug Allergy, NSAID hypersensitivity is mainly divided into two groups: single drug induced IgE or T cell-mediated reactions and cross-reactive reactions due to inhibition of cyclooxygenases. These major groups are classified in phenotypes according to the clinical findings and the presence of the underlying diseases. However, it may not sometimes be so easy to classify each patient according to these phenotypes. In this presentation, three children who had single NSAID-induced reactions but different clinical presentations have been described. Also, two of these children had some manifestations common to cross-reactive types of NSAID hypersensitivity which further complicated phenotyping.

Polymorfism Of CYP2C9 And 3A5 and carbamazepine hypersensitivity reactions in Brazilian subjects

Background The cytochrome P450 2C9 and 3A5 enzymes are predominantly found in the human liver, and have important functions in the metabolism of antiepileptics. Genetic polymorphisms in these genes are associated with altered enzymatic activities and may give rise to the risk of drug hypersensitivity. Therefore, we analyze the association between CBZ hypersensitivity reactions (CHR) and polymorphisms of CYP2C9 and 3A5 in a population of Sao Paulo, Brazil. Methods Case-control study in which we genotyped the SNP of CYP2C9 (rs1057910, rs1799853) and 3A5 (rs776746) of samples obtained from 52 subjects with varying severities CHR, 82 tolerants, and 366 control subjects, all from Sao Paulo, Brazil. According to the alleles presente, each subject was classified as normal, decrease or increased funcion for the enzyme. The phenotype was evaluated based on standardized scoring systems using an adapted ENDA (European Network of Drug Allergy) questionnaire, medical records and on the clinical follow-up. The patch test with the culprit drug was performed according the ENDA recommendations.

A UK national survey of investigations for beta‐lactam hypersensitivity – heterogeneity in practice and a need for national guidelines – on behalf of British Society for Allergy and Clinical Immunology (BSACI)

Beta lactams (BL) are the most widely prescribed antibiotics in the UK and the commonest cause of hypersensitivity reactions. There are no UK guidelines for BL testing and the most relevant guidelines were devised by the European Network for Drug Allergy (ENDA) on behalf of the European Academy of Allergy and Clinical Immunology. Delivery of allergy services differs across Europe, so this survey was designed to investigate how closely UK practice adhered to these guidelines. An online survey, using surveymonkey.com software, was sent to all consultants offering an allergy service in the UK and who were members of either BSACI or 'Travellers' (Immunology consultant group). The response rate was 48% (n=81/165) and BL allergy testing was undertaken by 78% of respondents. All responders requested SsIgE, although four responders stated they rarely requested. Skin testing was undertaken by 87% of respondents who perform beta lactam testing with 17% undertaking skin prick testing (SPT) only, 77% SPT followed by intra-dermal testing (IDT) if the former were negative or indeterminate and 6% SPT and IDT in all cases. The drugs, doses and protocols for skin testing varied considerably. Drug provocation testing was undertaken by 87% of respondents who undertake beta lactam testing with significant heterogeneity in protocols. Respondents that investigated ≤ 20 patients per year demonstrated lower adherence to ENDA recommendations compared to those who saw > 20. Following positive testing, 79% advised avoidance of all penicillins only and the remainder advised additional drug avoidance. This survey revealed variation in the investigation and management of BL hypersensitivity in the UK with some centres reporting procedures that could potentially put patients at risk of anaphylaxis if allergy was falsely excluded. This survey highlights an urgent need for evidence based national guidelines and standardisation of practice.

Diagnosis of penicillin allergy revisited: the value of case history, skin testing, specific IgE and prolonged challenge

Skin testing in duplicate, correlation between case history of immediate and nonimmediate reactions and challenge outcome and prolonged oral treatment with penicillin in the diagnostic evaluation of allergic reactions to β-lactam antibiotics, mimicking real-life situations, have only been addressed in few studies. A total of 342 patients suspected of having β-lactam allergy were investigated according to the European Network for Drug Allergy (ENDA) guidelines and patients found to be negative in the ENDA program were supplemented with a 7-day oral treatment with penicillin. Skin testing with penicillins was performed in duplicate. Patients with case histories of reactions to other β-lactams were also subsequently challenged with the culprit drug. Nineteen patients were IgE-sensitized to penicillin. Then, intracutaneous tests (ICTs) were performed, in which 35 patients tested positive for allergy, 21 with delayed and 14 with immediate reactions. Only three patients tested positive for the major (PPL) and/or minor (MDM) penicillin determinants, all being positive for penicillin G in ICT. The remaining 291 patients were challenged with penicillin: 10 tested positive in single-dose challenge and 23 tested positive in the 7-day challenge. A total of 17 of 78 patients with a negative penicillin challenge tested positive during challenges with other β-lactams. We found no correlation between case histories of immediate and nonimmediate reactions and reaction time during challenge. The data suggest that case history is often insufficient to discriminate between immediate reactors and nonimmediate reactors. A 7-day challenge with the culprit β-lactam may yield more positive reactions than the accepted one- or 2-day challenge. Interpretation of skin testing should be made with caution.