Nonsteroidal Anti-inflammatory Drugs Hypersensitivity Research Articles

Non-steroidal anti-inflammatory drug hypersensitivity in children

IntroductionThere are rather few publications about hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAID) in the paediatric age. In this study, we aimed to assess the frequency of confirmed NSAID hypersensitivity in children with a previous reported reaction to NSAID in order to investigate the role of the drug provocation test (DPT) in the diagnostic workup and to explore the factors associated with confirmed NSAID hypersensitivity. MethodsWe conducted a retrospective analysis of the clinical files from every patient under 18 years old who attended two Portuguese paediatric allergy outpatient clinics, from January 2009 to August 2014, due to a suspected NSAID hypersensitivity. ResultsWe included 119 patients, with a median age of nine years (P25–P75: 5–14). Ibuprofen was the commonest implicated NSAID in the patients’ reports (n=94–79%). After DPT, NSAID hypersensitivity was confirmed in nine (7.6%) patients, excluded in 93 (78.2%) and was inconclusive in 17 (14.3%). In the majority (n=95–79.8%), the reaction occurred in the first 24h after intake. Eighty-four patients (70.6%) reported only cutaneous manifestations and 18 (15.1%) had systemic symptoms. Anaphylaxis represented a relative risk to NSAID hypersensitivity confirmation. No association was found for atopy and the number of previous reactions. ConclusionIn our study, NSAID hypersensitivity was confirmed in a small proportion of the patients with a previous reported reaction. Ibuprofen was the most implicated drug with urticaria/angio-oedema as the commonest manifestation. Anaphylaxis was associated with confirmed drug hypersensitivity. The drug provocation test was essential to establish the diagnosis.

Phenotypical characterization of children with hypersensitivity reactions to NSAIDs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the main cause of drug-induced hypersensitivity in children. Many classifications have been proposed, focusing on adults. So far, no large study has deeply investigated a pediatric cohort. The aim of the present study was to describe a population of NSAID hypersensitive patients reporting a reaction during their childhood and to verify whether it is possible to classify pediatric patients, following the EAACI/ENDA classification. We conducted a historical prospective study including patients evaluated from 1996 to 2015 in the allergy unit of the Montpellier University Hospital. We included 635 patients. For each patient, we recorded clinical manifestations and possible comorbidities and tried to identify possible risk factors. NSAID hypersensitivity was diagnosed in 107 of 635 patients (16.9%). In this group, 43 patients (40.2%) could not be classified following the ENDA recommendations. The main discrepancies were on the patients' clinical manifestations and on their possible underlying diseases. We identified, on a multivariate analysis, some risk factors for NSAID hypersensitivity: chronic urticaria (OR 7.737, 3.375-18.296 95%CI), atopic status (OR 2.514, 1.504-4.364 95%CI), and allergic rhinoconjunctivitis (OR 1.799, 1.138-2.837 95%CI). On the basis of our results, we are proposing an adapted classification for NSAID hypersensitivity in children. The current ENDA classification does not seem to be adapted for pediatric patients; a modified version does. Our study could help allergists better understand the differences between adults and children in developing hypersensitivity reactions to NSAIDs, but further large-scale prospective longitudinal analyses are required to validate this new classification.

Nonsteroidal anti-inflammatory drug (NSAID) exacerbated respiratory disease phenotype: Topical NSAID and asthma control – A possible oversight link

BackgroundPatients with aspirin-exacerbated respiratory disease (AERD) also recently known as nonsteroidal anti-inflammatory drug (NSAID) exacerbated respiratory disease (NERD) must avoid aspirin and all other oral NSAIDs. The effect of topical NSAID (tNSAID), especially salicylates which are commonly present in topical medicated preparations, on asthma control of this phenotype is studied. MethodsThe study inclusion criteria were adults with: 1) NSAID hypersensitivity; 2) nasal polyposis/chronic rhinosinusitis; 3) not well-/poorly controlled asthma and 4) exposure to tNSAID. Patients were given verbal and written instructions to cease tNSAIDs exposure and asthma control was evaluated during the 6 months prior and after intervention. ResultsThere were eleven patients (ten females) with a mean age of 56.5 (range 37–71) years. Prior known oral NSAIDs hypersensitivity included aspirin (5), mefenamic acid (2), diclofenac (2), Synflex (2) and ibuprofen (1). All, except 2, had arthropathies or spinal disorders and were using tNSAID for a mean of 4.2 years. One, four and six patients were using over-the-counter medicated oil containing salicylates, NSAID gel/plasters and both respectively. All patients had cutaneous, with 4 having concomitant inhalational exposure to these tNSAIDs. The mean duration of asthma diagnosis and uncontrolled asthma were 25.2 and 4.5 years respectively. Except for 2 patients, there was no change in asthma maintenance medications pre and post-intervention. Asthma control significantly (p < 0.05) improved based on pre and post-intervention ACT score, number of exacerbations, FEV1 were 14.9 and 22.1, 1.9 and 0.43, 1.28L and 1.67L respectively. ConclusionsIt is paramount to eliminate not only oral but topical NSAID exposure in NERD phenotype asthmatic patients. When a long-standing asthma progressed to uncontrolled, a meticulous evaluation of tNSAIDs exposure is warranted especially if the patient has developed chronic pain.

Allergic Reactions to Metamizole: Immediate and Delayed Responses

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.

What we know about nonsteroidal anti-inflammatory drug hypersensitivity.

Nonsteroidal anti-inf lammatory drugs (NSAIDs) are widely prescribed for the treatment of inflammatory diseases, but their use is frequently related to hypersensitivity reactions. This review outlines our current knowledge of NSAID hypersensitivity (NHS) with regard to its pathogenic, molecular, and genetic mechanisms, as well as diagnosis and treatment. The presentation of NHS varies from a local (skin and/or airways) reaction to systemic reactions, including anaphylaxis. At the molecular level, NHS reactions can be classified as cross-reactive (mediated by cyclooxygenase inhibition) or selective (specific activation of immunoglobulin E antibodies or T cells). Genetic polymorphisms and epigenetic factors have been shown to be closely associated with NHS, and may be useful as predictive markers. To diagnose NHS, inhalation or oral challenge tests are applied, with the exclusion of any cross-reactive NSAIDs. For patients diagnosed with NHS, absolute avoidance of NSAIDs/aspirin is essential, and pharmacological treatment, including biologics, is often used to control their respiratory and cutaneous symptoms. Finally, desensitization is recommended only for selected patients with NHS. However, further research is required to develop new diagnostic methods and more effective treatments against NHS.

Aspirin-exacerbated respiratory disease: pathophysiological insights and clinical advances.

Asthma and chronic rhinosinusitis are heterogeneous airway diseases of the lower and upper airways, respectively. Molecular and cellular studies indicate that these diseases can be categorized into unique endotypes, which have therapeutic implications. One such endotype is aspirin-exacerbated respiratory disease (AERD), which encompasses the triad of asthma, aspirin (or nonsteroidal anti-inflammatory drug) hypersensitivity, and nasal polyposis. AERD has unique pathophysiological features that distinguish it from aspirin-tolerant asthma and other forms of chronic rhinosinusitis. This review details molecular and cellular features of AERD and highlights current and future therapies that are based on these insights.

Impact of -1607 1G/2G MMP1 gene polymorphism on the morbidity and clinical course of chronic rhinosinusitis with nasal polyps.

Polyps within the nose and nasal sinuses are symptoms of both local conditions such as chronic bacterial or fungal rhinosinusitis, and systemic diseases such as cystic fibrosis, hypogammaglobulinemia, NSAID hypersensitivity syndrome, bronchial asthma as well as Kartagener's syndrome, Young's syndrome, Churg-Strauss' syndrome and Woakes' syndrome. The pathomechanism responsible for formation of nasal polyps remains a matter of dispute as well as the subject of numerous studies. Despite the proven role of metalloproteinases and their inhibitors in the pathomechanism of inflammation, the role of their respective polymorphisms has not been fully confirmed to date. 1. The assessment of genetic predisposition to chronic rhinosinusitis with nasal polyps on the basis of the analysis of 1G/2G polymorphism at position -1607 of the MMP1 gene; 2. Determination of correlation between the variability of MMP1 gene and the natural history of chronic rhinosinusitis with nasal polyps; 3. Determination of the relationship between epidemiological or clinical features and the results of genotyping of patients with chronic rhinosinusitis with nasal polyps Material and method The study included 206 patients subjected to surgical treatment due to chronic rhinosinusitis with nasal polyps and 463 healthy volunteers hospitalized at the Department of Otolaryngology and Oncological Laryngology of the Medical University of Łódź. The analysis of 1G/2G polymorphism at position -1607 of the MMP1 gene was based on TaqMan® SNP Genotyping Assays (Applied Biosystems, USA). The 1G/2G polymorphic variants at position -1607 of the MMP1 gene did not predispose patients to CRSNP+, although a trend towards increased risk of the disease could be observed in the mutated allele (InsG) carriers. However, the correlation was not statistically significant (OR 1.175; 95%CI 0.5391-1.1142; p=0.16822). In comparison to wild-type homozygotic genotype, the carriers of -1607 1G/2G mutated allele (InsG) were characterized by: 1. significantly younger age at which surgical treatment was required following conservative treatment that had proven insufficient to control CRSNP+ (p=0.025); 2. significantly higher rate of recurrence requiring surgical intervention (p=0.002); 3. trend towards higher intensity of sinus-related symptoms as assessed using a VAS scale; 4. more frequent incidence of CRSNP+ with hypersensitivity to aspirin (correlation on the border of significance, p=0.054); 5. less common bronchial asthma comorbidity (p=0.021); 6. family history of CSRNP+ (p=0.045). The 1G/2G polymorphism at position -1607 of the MMP1 gene may impact patients' predisposition to chronic rhinosinusitis with nasal polyps. Polymorphic variants are consistent with overall morbidity and may constitute risk variants. The status of a carrier of mutated (G insertion) allele with regard to the 1G/2G polymorphism at position -1607 within the MMP1 gene may determine a pathological phenotype associated with a more severe clinical course of CRSNP+ including earlier onset and disease recurrence.

Adverse Drug Reactions of Ranitidine: A Pharmacovigilance Study in Korea

S A T U R D A Y Inmaculada Do~ na, MD, PhD, Francisca G omez, MD, PhD, Tahia D. Fernandez, PhD, Adriana Ariza, PhD, Arturo Ruiz, MD, Maria Isabel S anchez Rivas, Cristina De Leyva, Maria Isabel Monta~nez, Antonio Guzman, Miguel Blanca, MD, PhD, Maria J. Torres, MD, PhD; Allergy Service, IBIMA-Regional University Hospital of Malaga-UMA, M alaga, Spain, Allergy Unit, IBIMA-Regional University Hospital of Malaga, M alaga, Spain, Research Laboratory, IBIMA-Regional University Hospital of Malaga-UMA, Malaga, Spain, Allergy Unit, Regional University Hospital of M alaga-IBIMA, UMA, M alaga, Spain, Allergy Unit, Regional University Hospital of Malaga-IBIMA, UMA, Malaga, Spain, Research Laboratory, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, Spain, Pharmacy Unit, Regional University Hospital of Malaga-IBIMA, UMA, M alaga, Spain, Allergy Unit, Regional University Hospital of M alaga, IBIMA, UMA, M alaga, Spain. RATIONALE: Pyrazolones are the most common cause NSAIDs hypersensitivity. We studied a large group of patients with immediate and nonimmediate selective responses (SR) to dipyrone. METHODS: Patients with suspiction of hypersensitivity to dipyronewere evaluated. We verified acetilsalicilic acid-tolerance and classified patients as immediate or non-immediate responders if they showed symptoms less or more than 1hour after dipyrone administration. Skin tests were performed and if negative, basophil activation test (BAT) for immediate responders. If negative results, we performed drug provocation test (DPT) with dipyrone. RESULTS: A total of 137 patients were included: 114 reacted within one hour (single NSAID-induced urticaria/angioedema/anaphylaxis; SNIUAA); 23 after one hour (single-NSAID-induced delayed hypersensitivity reactions; SNIDHR). More specifically, 73.72% reacted within 30 minutes; 9.48% 30-60 minutes; 6.56% 1-2 hours; 3.64% 2-8 hours and 6.56% after over 24 hours. Most SNIUAA patients developed anaphylaxis (66.66%, p50.0001); for SNIDHR urticaria was more frequent (52.17%, p50.014). Skin testing was positive for 62.04% of all cases and BAT for 35.89% of SNIUAA patients with negative skin tests. In 5.1% cases DPT with dipyrone was needed. In 22.62% of cases DPT was not indicated, being diagnosed by repeated allergic episodes in spite of negative skin and BAT. CONCLUSIONS: SNIUAA to dipyrone is the most frequent group with anaphylaxis being the most common clinical entity. It may occur with interval longer than 1hour. The SNIDHR occur in a very low percentage. The low sensitivity of diagnostic tests may be due to incomplete characterization of the chemical structures of dipyrone and its metabolites.

Allergic Reactions to Dipyrone: Immediate and Non-Immediate Responses

S A T U R D A Y Inmaculada Do~ na, MD, PhD, Francisca G omez, MD, PhD, Tahia D. Fernandez, PhD, Adriana Ariza, PhD, Arturo Ruiz, MD, Maria Isabel S anchez Rivas, Cristina De Leyva, Maria Isabel Monta~nez, Antonio Guzman, Miguel Blanca, MD, PhD, Maria J. Torres, MD, PhD; Allergy Service, IBIMA-Regional University Hospital of Malaga-UMA, M alaga, Spain, Allergy Unit, IBIMA-Regional University Hospital of Malaga, M alaga, Spain, Research Laboratory, IBIMA-Regional University Hospital of Malaga-UMA, Malaga, Spain, Allergy Unit, Regional University Hospital of M alaga-IBIMA, UMA, M alaga, Spain, Allergy Unit, Regional University Hospital of Malaga-IBIMA, UMA, Malaga, Spain, Research Laboratory, IBIMA, Regional University Hospital of Malaga, UMA, Malaga, Spain, Pharmacy Unit, Regional University Hospital of Malaga-IBIMA, UMA, M alaga, Spain, Allergy Unit, Regional University Hospital of M alaga, IBIMA, UMA, M alaga, Spain. RATIONALE: Pyrazolones are the most common cause NSAIDs hypersensitivity. We studied a large group of patients with immediate and nonimmediate selective responses (SR) to dipyrone. METHODS: Patients with suspiction of hypersensitivity to dipyronewere evaluated. We verified acetilsalicilic acid-tolerance and classified patients as immediate or non-immediate responders if they showed symptoms less or more than 1hour after dipyrone administration. Skin tests were performed and if negative, basophil activation test (BAT) for immediate responders. If negative results, we performed drug provocation test (DPT) with dipyrone. RESULTS: A total of 137 patients were included: 114 reacted within one hour (single NSAID-induced urticaria/angioedema/anaphylaxis; SNIUAA); 23 after one hour (single-NSAID-induced delayed hypersensitivity reactions; SNIDHR). More specifically, 73.72% reacted within 30 minutes; 9.48% 30-60 minutes; 6.56% 1-2 hours; 3.64% 2-8 hours and 6.56% after over 24 hours. Most SNIUAA patients developed anaphylaxis (66.66%, p50.0001); for SNIDHR urticaria was more frequent (52.17%, p50.014). Skin testing was positive for 62.04% of all cases and BAT for 35.89% of SNIUAA patients with negative skin tests. In 5.1% cases DPT with dipyrone was needed. In 22.62% of cases DPT was not indicated, being diagnosed by repeated allergic episodes in spite of negative skin and BAT. CONCLUSIONS: SNIUAA to dipyrone is the most frequent group with anaphylaxis being the most common clinical entity. It may occur with interval longer than 1hour. The SNIDHR occur in a very low percentage. The low sensitivity of diagnostic tests may be due to incomplete characterization of the chemical structures of dipyrone and its metabolites.

Multiple nonsteroidal anti-inflammatory drug hypersensitivity without hypersensitivity to aspirin

Multiple nonsteroidal anti-inflammatory drug hypersensitivity without hypersensitivity to aspirin

The value of the clinical history for the diagnosis of immediate nonsteroidal anti-inflammatory drug hypersensitivity and safe alternative drugs in children.

Diagnosing hypersensitivity reactions that develop as a result of nonsteroidal anti-inflammatory drugs (NSAID) with a history is mostly misleading, and skin tests and/or provocation tests are needed for a definitive diagnosis. To determine the frequency of actual NSAID hypersensitivity and whether there are any parameters in the history to predict NSAID hypersensitivity. In addition, to determine safe alternative drugs for children who are diagnosed with actual NSAID hypersensitivity. Children with a history of NSAID hypersensitivity were evaluated by an allergist. Safe alternatives in children with a confirmed NSAID hypersensitivity were found by oral provocation tests. Sixty-four patients who were admitted with a suspicion of immediate-type reaction to NSAIDs were included in the study. The median age of the patients was 6 years old (range, 1-17 years), and 37 of the patients (57.8%) were boys. We performed skin tests for suspected NSAID in 35 patients (54.7%). Of these, two had positive results. Provocation tests were performed with 62 patients whose skin test results were negative or for whom skin tests were not available. During the provocation tests, 16 patients (25.8%) developed reactions. Low- and high-dose acetaminophen, nimesulide, and tolmetin sodium were used to find safe alternative drugs. Two patients developed reactions to high-dose acetaminophen but no reaction to nimesulide and tolmetin sodium. When statistically significant parameters were analyzed in a logistic regression model, the presence of multiple NSAIDs hypersensitivity in the patient history (odds ratio 26.6 [95% confidence interval, 1.47-481.63]; p = 0.026) and the emergence of a reaction within an hour (odds ratio 26.4 [95% confidence interval, 1.73-403.11]; p = 0.019) were found as the independent factors to predicted actual NSAID hypersensitivity. The emergence of a reaction within an hour of taking the drug and the presence of multiple NSAIDs hypersensitivity history increased the possibility of actual NSAID hypersensitivity. Nimesulide, low-dose acetaminophen, and tolmetin sodium could be used as safe alternative drugs in patients with multiple NSAIDs hypersensitivity.

Predictive value of a negative oral provocation test in patients with hypersensitivity to analgesics.

Nonsteroidal anti-inflammatory drugs (NSAIDs) take first or second place as the cause of drug-induced hypersensitivity reactions. The oral provocation test (OPT) is a gold standard for the diagnosis of NSAID hypersensitivity. We investigated which analgesics patients took after a negative OPT and determined the proportion of patients that experienced a hypersensitivity reaction despite a negative OPT. We selected 115 patients (67.8% female, age 54.9 ± 16.7 years) with a negative aspirin OPT and a convincing history of immediate hypersensitivity to aspirin or NSAIDs. In a telephone survey, we identified the analgesics taken after the OPT and possible adverse events. The mean follow-up time was 5.1 ± 2.0 years. All subjects needed at least one analgesic drug. Despite the negative outcome of the aspirin OPT, only 33.9% of subjects took aspirin and 0.9% had a hypersensitivity reaction. The negative predictive value (NPV) of the aspirin OPT was 97.4%. Overall, 16 (13.9%) subjects experienced a hypersensitivity reaction, 12 of which occurred after taking a drug not tested with the OPT. The NPV of the OPT for all NSAIDs was 96.4%. Our results support the available data that most subjects do not re-take the tested drug regardless of the high NPV of the OPT.

Adverse reactions to nonsteroidal anti-inflammatory drugs and hypersensitivity to lipid transfer proteins.

Adverse reactions to nonsteroidal anti-inflammatory drugs and hypersensitivity to lipid transfer proteins.

Long-term clinical effects of aspirin-desensitization therapy among patients with poorly controlled asthma and non-steroidal anti-inflammatory drug hypersensitivity: An exploratory study

BackgroundAccording to the Global Initiative for Asthma (GINA), the levels of asthma symptom control can be divided into controlled, partially controlled and uncontrolled asthma. Optional therapy for non-steroidal anti-inflammatory drugs (NSAIDs)-hypersensitive asthmatics uses aspirin desensitization, but until now, this therapy is not established in difficult to treat cases. The aim of this study was to evaluate the efficacy of aspirin desensitization in patients with poorly controlled asthma. MethodsPatients with poorly controlled asthma, NDAIDs hypersensitivity and aspirin desensitization were included in the retrospective study. The data were compared to those obtained from patients with controlled asthma and aspirin therapy. Lung function, levels of asthma symptom control, asthma medication, the size of nasal polyps (NP) and smell function were evaluated over 18 months. ResultsThirty-two patients were included in the study (uncontrolled/partially controlled asthma n=12; controlled asthma n=20). After 18 months of follow-up, the patients with poorly controlled asthma had significantly increased forced expiratory volume in 1s (FEV1) values, as compared to the baseline (66–82%; p=0.02), the levels of asthma control improved significantly (p<0.01). The asthma medication was reduced. In the group of controlled asthma the FEV1 values did not increase significantly (91.9–92.4%; p>0.05) and the asthma medication was constant. In relation to nasal parameters the sense of smell improved significantly in both groups, NP-scores did not differ significantly. ConclusionsPatients with a poorly controlled asthma and NSAIDs hypersensitivity profit from an add-on aspirin therapy.

Nonsteroidal anti-inflammatory drug hypersensitivity among children.

Nonsteroidal anti-inflammatory drugs (NSAID) are the second-most frequent drugs that cause hypersensitivity reactions among children. Studies related to NSAIDs hypersensitivity in children are limited. In this study, we aimed to evaluate children admitted with suspicion of NSAIDs reaction. Between January 1, 2011, and November 30, 2014, we included patients with suspicion of NSAIDs hypersensitivity in our clinic. For evaluation, skin tests and oral provocation tests with the drug (suspected or alternative) were proposed. Reactions were classified and defined according to the latest European Academy of Allergy and Clinical Immunology position paper on NSAID hypersensitivity. During the study period, 123 patients (with 136 drug reactions) were admitted to our clinic with suspected NSAID hypersensitivity. The mean (standard deviation) age of the patients, 67 female (55%), was 83.10 ± 56.05 months. Thirteen patients described reactions to more than one chemically unrelated NSAID, and 110 patients described reactions with chemically similar drugs. Eight patients were not included because they did not have provocation tests. Thus, 115 patients were evaluated. A hundred and thirty provocations were performed. Twenty patients (17.4%) were diagnosed with NSAID hypersensitivity (13 patients diagnosed by provocation tests and 7 patients diagnosed according to their history). The most frequently encountered agent was ibuprofen (50% [10/20]). Eighty percent (16 patients) of the reactions were considered "non-cross-reactive type." Fifteen patients (75%) were classified as having single-NSAID-induced urticaria and/or angioedema, three patients were classified as having NSAID-induced urticaria and/or angioedema, one patient was classified as having NSAID-exacerbated respiratory disease, and the other patients were classified as having single-NSAID-induced delayed hypersensitivity reactions. Detailed history and drug provocation tests are important to verify NSAID hypersensitivity. The most common type is the non-cross-reactive type, and, in our study, the most common responsible drug was ibuprofen.

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.

Genetic basis of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs.

NSAIDs are the main triggers of hypersensitivity reactions to drugs. However, the full genetic and molecular basis of these reactions has yet to be uncovered. In this article, we have summarized research from recent years into the effects of genetic variants on the different clinical entities induced by NSAID hypersensitivity, focusing on prostaglandin and leukotriene-related genes as well as others beyond the arachidonic acid pathway. We introduce recent contributions of high-throughput approaches including genome-wide association studies as well as available information from epigenetics and next-generation sequencing. Finally, we give our thoughts on future directions in this field, including the scope for bioinformatics and systems biology and the need for clear patient phenotyping. The full genetic and molecular basis of clinical entities induced by NSAIDs hypersensitivity has yet to be uncovered, and despite commendable efforts over recent years, no clinically proven genetic markers currently exist for these disorders. It is clear that we will continue to find more about these reactions in the coming years, concurrently with improvements in technology and experimental techniques, and a precise definition of different phenotypes.

Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug–related urticaria and angioedema

Nonsteroidal anti-inflammatory drug (NSAID)-induced urticarial and angioedema reactions are among the most commonly encountered drug hypersensitivity reactions in clinical practice. Three major clinical phenotypes of NSAID-induced acute skin reactions manifesting with angioedema, urticaria, or both have been distinguished: NSAID-exacerbated cutaneous disease, nonsteroidal anti-inflammatory drug-induced urticaria/angioedema (NIUA), and single NSAID-induced urticaria and angioedema. In some patients clinical history alone might be sufficient to establish the diagnosis of a specific type of NSAID hypersensitivity, whereas in other cases oral provocation challenges are necessary to confirm the diagnosis. Moreover, classification of the type of cutaneous reaction is critical for proper management. For example, in patients with single NSAID-induced reactions, chemically nonrelated COX-1 inhibitors can be safely used. However, there is cross-reactivity between the NSAIDs in patients with NSAID-exacerbated cutaneous disease and NIUA, and thus only use of selective COX-2 inhibitors can replace the culprit drug if the chronic treatment is necessary, although aspirin desensitization will allow for chronic treatment with NSAIDs in some patients with NIUA. In this review we present a practical clinical approach to the patient with NSAID-induced urticaria and angioedema.

Short-term ibuprofen treatment and pulmonary function in children with asthma.

To investigate the association between ibuprofen use and pulmonary function in children with Asthma. Ninety 9- to 10-year-old children were classified into 3 groups: Study group, mild to moderate stable asthmatic children with self-reported aspirin allergy and no history of anaphylaxis; Allergy control group: atopic children (allergic rhinitis/atopic dermatitis); Healthy control group: non-atopic healthy children. None of the participants in the atopic and healthy control groups had a history of aspirin allergy. All received ibuprofen 4 times a day for 3 consecutive days. Forced expiratory volume in the first second (FeV1) and fractional exhaled nitric oxide (FeNO) measurements were performed before and after ingestion of ibuprofen daily for 3 days. In the study group, a decrease in FeV1 and increase in FeNO levels were observed after taking ibuprofen for 2 days. The atopic control group showed only an increase in FeNO but not FEV1. In the healthy control group, both FeV1 and FeNO were unchanged from baseline. The results showed that cross-reactive non-steroidal anti-inflammatory drug hypersensitivity may exist between ibuprofen and aspirin. This raises the possibility that asthma exacerbation could be mediated by ibuprofen ingestion.