Sensitisation to Pollen Allergens in Children and Adolescents of Different Ancestry Born and Living in the Same Area.

Background: Allergy can start at early ages, with genetic and environmental factors contributing to its development. Aim: The study aimed to describe the pattern of sensitisation and allergy in children and adolescents of Spanish versus Moroccan ancestry but born in the same rural area of Spain. Methods: Participants were children and adolescents (3-19 years) of Spanish or Moroccan descent, born in Blanca, Murcia (Spain). A detailed questionnaire was completed, and skin prick tests were performed to assess reactions to the most prevalent pollen allergens (O. europaea, P. pratense, S. kali, C. arizonica, P. acerifolia, A. vulgaris and P. judaica) plus molecular components Ole e 1 and Ole e 7. The association with ancestry was verified by studying participants' parents. Results: The study included 693 participants: 48% were aged 3-9 years and 52%, 10-19 years; 80% were of Spanish descent and 20% of Moroccan descent. Sensitisation to Olea europaea, Phleum pratense, Salsola kali and Cupressus arizonica were slightly higher in the Spanish group. The only significant differences were observed in sensitisation to Ole e 1 (p=0.02). Rhinitis, conjunctivitis, and rhinitis plus asthma were significantly higher in the Spanish group (p=0.03, p=0.02, p=0.007, respectively). The sensitisation pattern differed between Spanish and Moroccan parents, and between Moroccan parents and their children, but not between Spanish parents and their children. Conclusion: Both environment and ancestry may influence sensitisation and symptoms. Although the environment seems to have a stronger influence, other factors may contribute to the differences in prevalence and in the clinical entities in people of Spanish versus Moroccan descent.

Skin Testing With Peach Peel Extract Versus Serum IgE to Pru p 3 as a Stronger Predictor of Peach-Induced Anaphylaxis.

The most important peach fruit allergen is Pru p 3, followed by Pru p 1, Pru p 4, and Pru p 7. We aimed to assess their role in subjects with peach fruit-induced allergy (anaphylaxis and OAS) and compare skin prick tests (SPT) vs. specific immunoglobulin E (sIgE) for predicting anaphylaxis. We also selected a control group. SPT included prevalent inhalant and plant food allergens plus peach peel extract. The sIgE to Pru p 1, Pru p 3, Pru p 4, and Pru p 7 were quantified. Compared with controls (n = 42), cases (n = 41) were younger (P = 0.003), more frequently female (P < 0.05) and had higher SPT positivity to peach peel (44% vs. 2.4%, P < 0.0001). There were significant differences in sensitization to several pollens: Olea europaea, Artemisia vulgaris, Prunus persica, Platanus acerifolia (all P < 0.001); and fruits: apple (P < 0.04), peanut (P < 0.002), tomato (P < 0.005), and melon (P < 0.05). Pru p 3 sIgE was detected in 61% of all cases (85% anaphylaxis and 38% OAS; P < 0.01 each) and 5% of controls (P < 0.001). Pru p 4 sIgE was present in 19% of cases and 7% of controls. The sIgE to Pru p 1 and Pru p 7 were not found. The odds ratio to predict anaphylaxis for peach peel SPT was 113 (confidence interval [CI], 20-613; P < 0.0001); for sIgE to Pru p 3, 22 (CI, 5.3-93; P < 0.0001); and for SPT positivity to selected plant food allergens, 5 (CI, 1-19; P < 0.05). In our study group, SPT with peel peach extract was a better predictor of anaphylaxis than Pru p 3 sIgE or other variables considered. The role of sIgE to Pru p 1, Pru p 4, and Pru p 7 seemed negligible.

Lack of Major Involvement of Common CYP2C Gene Polymorphisms in the Risk of Developing Cross-Hypersensitivity to NSAIDs.

Cross-hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) is a relatively common, non-allergic, adverse drug event triggered by two or more chemically unrelated NSAIDs. Current evidence point to COX-1 inhibition as one of the main factors in its etiopathogenesis. Evidence also suggests that the risk is dose-dependent. Therefore it could be speculated that individuals with impaired NSAID biodisposition might be at increased risk of developing cross-hypersensitivity to NSAIDs. We analyzed common functional gene variants for CYP2C8, CYP2C9, and CYP2C19 in a large cohort composed of 499 patients with cross-hypersensitivity to NSAIDs and 624 healthy individuals who tolerated NSAIDs. Patients were analyzed as a whole group and subdivided in three groups according to the main enzymes involved in the metabolism of the culprit drugs as follows: CYP2C9, aceclofenac, indomethacin, naproxen, piroxicam, meloxicam, lornoxicam, and celecoxib; CYP2C8 plus CYP2C9, ibuprofen and diclofenac; CYP2C19 plus CYP2C9, metamizole. Genotype calls ranged from 94 to 99%. No statistically significant differences between patients and controls were identified in this study, either for allele frequencies, diplotypes, or inferred phenotypes. After patient stratification according to the enzymes involved in the metabolism of the culprit drugs, or according to the clinical presentation of the hypersensitivity reaction, we identified weak significant associations of a lower frequency (as compared to that of control subjects) of CYP2C8*3/*3 genotypes in patients receiving NSAIDs that are predominantly CYP2C9 substrates, and in patients with NSAIDs-exacerbated cutaneous disease. However, these associations lost significance after False Discovery Rate correction for multiple comparisons. Taking together these findings and the statistical power of this cohort, we conclude that there is no evidence of a major implication of the major functional CYP2C polymorphisms analyzed in this study and the risk of developing cross-hypersensitivity to NSAIDs. This argues against the hypothesis of a dose-dependent COX-1 inhibition as the main underlying mechanism for this adverse drug event and suggests that pre-emptive genotyping aiming at drug selection should have a low practical utility for cross-hypersensitivity to NSAIDs.

A meta-analysis on allergen-specific immunotherapy using MCT® (MicroCrystalline Tyrosine)-adsorbed allergoids in pollen allergic patients suffering from allergic rhinoconjunctivitis.

BACKGROUND: The World Allergy Organization and the European Academy of Allergy and Clinical Immunology recommend to perform product-specific meta-analyses for allergen-specific immunotherapies because of the high degree of heterogeneity between individual products. This meta-analysis evaluates the efficacy and safety of Glutaraldehyde-modified and MCT® (MicroCrystalline Tyrosine)-adsorbed allergoids (MATA). METHODS: The databases MEDLINE, LILACS, embase, LIVIVO, Web of Science and Google (Scholar) were searched for publications on MATA up to June 2019. Primary endpoint was the combined symptom and medication score (CSMS). Secondary endpoints were single scores, immunogenicity and improvement of allergic condition. Secondary safety endpoints were the occurrence of side effects. A random effects model was applied with (standardized) mean differences ([S]MDs) including confidence intervals (CI). Heterogeneity was analyzed using the I2 index and publication bias using Egger's test and Funnel plots. Subgroups were analyzed regarding age and asthma status. RESULTS: Eight randomized double-blind placebo-controlled trials were selected for efficacy and 43 publications for safety analysis. In total, 4531 patients were included in this analysis including eight studies containing data on children and adolescents. AIT with MATA significantly reduced allergic symptoms and medication use with a SMD for CSMS of -0.8 (CI: -1.24, -0.36) in comparison to placebo. Heterogeneity was moderate between the studies. The total symptom score (-1.2 [CI: -2.11, -0.29]) and the total medication score (-2.2 [CI: -3.65, -0.74]) were also significantly reduced after MATA treatment. Patient's condition improved significantly after treatment with MATA, with an odds ratio of 3.05 (CI: 1.90, 4.90) when compared to placebo. The proportion of patients, who developed side effects was 38% (CI: 19%, 57%). No serious side effects occurred. Safety in the subgroups of asthmatic patients, children and adolescents did not differ from the overall patient population. CONCLUSIONS: This meta-analysis reveals a large body of evidence from publications investigating MATA. MATA significantly improved allergic symptoms and reduced the use of anti-allergic medication in comparison to placebo, with an excellent safety profile. Especially for children and asthmatic patients, the use of MATAs can be considered as safe, because the safety profiles in these groups did not differ from the total patient population.

Deep sequencing of prostaglandin-endoperoxide synthase (PTGE) genes reveals genetic susceptibility for cross-reactive hypersensitivity to NSAID.

BACKGROUND AND PURPOSE: Cross-reactive hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) is a relatively common adverse drug event caused by two or more chemically unrelated drugs and that is attributed to inhibition of the COX activity, particularly COX-1. Several studies investigated variations in the genes coding for COX enzymes as potential risk factors. However, these studies only interrogated a few single nucleotide variations (SNVs), leaving untested most of the gene sequence. EXPERIMENTAL APPROACH: In this study, we analysed the whole sequence of the prostaglandin-endoperoxide synthase genes, PTGS1 and PTGS2, including all exons, exon-intron boundaries and both the 5' and 3' flanking regions in patients with cross-reactive hypersensitivity to NSAIDs and healthy controls. After sequencing analysis in 100 case-control pairs, we replicated the findings in 540 case-control pairs. Also, we analysed copy number variations for both PTGS genes. KEY RESULTS: The most salient finding was the presence of two PTGS1 single nucleotide variations, which are significantly more frequent in patients than in control subjects. Patients carrying these single nucleotide variations displayed a significantly and markedly lower COX-1 activity as compared to non-carriers for both heterozygous and homozygous patients. CONCLUSION AND IMPLICATIONS: Although the risk single nucleotide variations are present in a small proportion of patients, the strong association observed and the functional effect of these single nucleotide variations raise the hypothesis of genetic susceptibility to develop cross-reactive NSAID hypersensitivity in individuals with an impairment in COX-1 enzyme activity.

NSAID-induced reactions: classification, prevalence, impact, and management strategies.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the leading cause of hypersensitivity drug reactions. The different chemical structures, cyclooxygenase 1 (COX-1) and/or COX-2 inhibitors, are taken at all ages and some can be easily obtained over the counter. Vasoactive inflammatory mediators like histamine and leukotriene metabolites can produce local/systemic effects. Responders can be selective (SR), IgE or T-cell mediated, or cross-intolerant (CI). Inhibition of the COX pathway is the common mechanism in CI, with the skin being the most frequent organ involved, followed by the lung and/or the nose. An important number of cases have skin and respiratory involvement, with systemic manifestations ranging from mild to severe anaphylaxis. Among SR, this is the most frequent entity, often being severe. Recent years have seen an increase in reactions involving the skin, with many cases having urticaria and/or angioedema in the absence of chronic urticaria. Aspirin, the classical drug involved, has now been replaced by other NSAIDs, with ibuprofen being the universal culprit. For CI, no in vivo/in vitro diagnostic methods exist and controlled administration is the only option unless the cases evaluated report repetitive and consistent episodes with different NSAIDs. In SR, skin testing (patch and intradermal) with 24-48 reading can be useful, mainly for delayed T-cell responses. Acetyl salicylic acid (ASA) is the test drug to establish the diagnosis and confirm/exclude CI by controlled administration. Desensitization to ASA has been extensively used in respiratory cases though it can also be applied in those cases where it is required.

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

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

NSAIDs hypersensitivity: questions not resolved.

PURPOSE OF REVIEW: NSAIDs are the drugs most frequently involved in hypersensitivity reactions (HSR). These are frequently prescribed at all ages. HSR are of great concern and can affect people at any age. These drugs can induce reactions by stimulating the adaptive immune system (IgE or T cell), known as selective responders or more frequently by abnormalities in biochemical pathways related with prostaglandin metabolism. These are known as cross-intolerant. With some exceptions, skin testing and in-vitro studies are of little value in selective responders. RECENT FINDINGS: In the last years, several classifications have been provided based on clinical symptoms, time interval between drug intake and appearance of symptoms, response to other nonchemically related NSAIDs and the underlying disease. Based on this classification, several well differentiated categories within each group of entities cross-intolerant and selective responders are now recognized. The most complex groups for evaluation are cross-intolerant in which three major groups exist: NSAIDs exacerbated respiratory disease, NSAIDs exacerbated cutaneous disease and NSAIDs-induced urticaria/angioedema in the absence of chronic spontaneous urticaria. Within the selective responders, there are two mechanisms involved: drug-specific IgE or T-cell effector responses. New entities have been added to this classification like mixed reactions within the cross-intolerant category, that must manifest as anaphylaxis and multiple immediate selective reactions. SUMMARY: The precise evaluation of patients with NSAIDs hypersensitivity following established guidelines will improve not only our understanding but also the management of these entities. As the number of patients affected with NSAIDs is important, further studies are warranted.

Acetyl Salicylic Acid Challenge in Children with Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs Differentiates Between Cross-Intolerant and Selective Responders.

BACKGROUND: Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) in children are becoming a great concern. Most studies have focused on adults, with noted discrepancies observed in the classification of hypersensitivity reactions to NSAIDs in children when compared with adults. OBJECTIVE: To phenotype a group of children with hypersensitivity reactions to NSAIDs, including paracetamol, and analyze the degree of agreement with the entities reported in adults and how they fit the proposed classifications. METHODS: The study comprised 116 children aged 0.5 to 14 years, with a clinical history indicative of hypersensitivity reactions to NSAIDs. They all underwent a single-blind oral provocation test with acetyl salicylic acid, except in those cases when this was the suspected drug, in which case the challenge was done first with ibuprofen. If positive, cross-intolerance was established and if negative, an oral provocation test with the culprit drug was performed to establish a selective response or exclude allergy. RESULTS: Of the 26% diagnosed as hypersensitive to NSAIDs, 83% were cross-intolerant and 17% selective reactors. The highest significant differences between reactors and nonreactors were observed in the time to reaction after drug intake and the clinical entity (P < .0001), followed by drug involved and age (P < .01). CONCLUSIONS: From the total number of cases confirmed with NSAID hypersensitivity, 83% were cross-intolerant. In cross-intolerant reactions, both cutaneous and respiratory manifestations are common. Acetyl salicylic acid challenge as the first approach proved to be safe and useful to establish the diagnosis.

Practical approach to the treatment of NSAID hypersensitivity.

INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently involved in drug hypersensitivity reactions (DHR). NSAIDs are prescribed for different processes and some NSAIDs can be obtained over the counter. Areas covered: We analyse the practical approaches for managing and treating NSAID-DHR considering the five major groups of entities recognised, divided into two categories: those responding to strong COX-1 inhibitors and possibly weak COX-1 or selective COX-2 inhibitors named cross-intolerant (CI), and those induced by a single drug or drug group with good tolerance to strong COX-1 inhibitors, known as allergic reactions (SR). An analysis of the recent literature indicates that two approaches can be followed for CI: to give acetyl salicylic acid to confirm NSAID hypersensitivity or to give alternative drugs to provide a solution for the treatment of pain, fever, inflammation or other conditions. Desensitisation approaches have been undertaken, but mainly for CI cases with respiratory airway involvement and they are very rarely used for CI with cutaneous involvement or SR. Expert commentary: DHR to NSAIDs are now recognised as one of the most important problems in the evaluation and management of drug allergy. Because no diagnostic tests exist, important resources are needed to evaluate these patients.

FCERI and Histamine Metabolism Gene Variability in Selective Responders to NSAIDS.

The high-affinity IgE receptor (Fcε RI) is a heterotetramer of three subunits: Fcε RIα, Fcε RIß, and Fcε RIγ (αßγ2) encoded by three genes designated as FCER1A, FCER1B (MS4A2), and FCER1G, respectively. Recent evidence points to FCERI gene variability as a relevant factor in the risk of developing allergic diseases. Because Fcε RI plays a key role in the events downstream of the triggering factors in immunological response, we hypothesized that FCERI gene variants might be related with the risk of, or with the clinical response to, selective (IgE mediated) non-steroidal anti-inflammatory (NSAID) hypersensitivity. From a cohort of 314 patients suffering from selective hypersensitivity to metamizole, ibuprofen, diclofenac, paracetamol, acetylsalicylic acid (ASA), propifenazone, naproxen, ketoprofen, dexketoprofen, etofenamate, aceclofenac, etoricoxib, dexibuprofen, indomethacin, oxyphenylbutazone, or piroxicam, and 585 unrelated healthy controls that tolerated these NSAIDs, we analyzed the putative effects of the FCERI SNPs FCER1A rs2494262, rs2427837, and rs2251746; FCER1B rs1441586, rs569108, and rs512555; FCER1G rs11587213, rs2070901, and rs11421. Furthermore, in order to identify additional genetic markers which might be associated with the risk of developing selective NSAID hypersensitivity, or which may modify the putative association of FCERI gene variations with risk, we analyzed polymorphisms known to affect histamine synthesis or metabolism, such as rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742, and rs1049793 in the HDC, HNMT, and DAO genes. No major genetic associations with risk or with clinical presentation, and no gene-gene interactions, or gene-phenotype interactions (including age, gender, IgE concentration, antecedents of atopy, culprit drug, or clinical presentation) were identified in patients. However, logistic regression analyses indicated that the presence of antecedents of atopy and the DAO SNP rs2052129 (GG) were strongly related (P < 0.001 and P = 0.005, respectively) with selective hypersensitivity to ibuprofen. With regard to patients with selective hypersensitivity to ASA, men were more prone to develop such a reaction than women (P = 0.011), and the detrimental DAO SNP rs10156191 in homozygosity increased the risk of developing such hypersensitivity (P = 0.039).

Asthma and Rhinitis Induced by Selective Immediate Reactions to Paracetamol and Non-steroidal Anti-inflammatory Drugs in Aspirin Tolerant Subjects.

In subjects with non-steroidal anti-inflammatory drugs (NSAIDs)- exacerbated respiratory disease (NERD) symptoms are triggered by acetyl salicylic acid (ASA) and other strong COX-1 inhibitors, and in some cases by weak COX-1 or by selective COX-2 inhibitors. The mechanism involved is related to prostaglandin pathway inhibition and leukotriene release. Subjects who react to a single NSAID and tolerate others are considered selective responders, and often present urticaria and/or angioedema and anaphylaxis (SNIUAA). An immunological mechanism is implicated in these reactions. However, anecdotal evidence suggests that selective responders who present respiratory airway symptoms may also exist. Our objective was to determine if subjects might develop selective responses to NSAIDs/paracetamol that manifest as upper/lower airways respiratory symptoms. For this purpose, we studied patients reporting asthma and/or rhinitis induced by paracetamol or a single NSAID that tolerated ASA. An allergological evaluation plus controlled challenge with ASA was carried out. If ASA tolerance was found, we proceeded with an oral challenge with the culprit drug. The appearance of symptoms was monitored by a clinical questionnaire and by measuring FEV1 and/or nasal airways volume changes pre and post challenge. From a total of 21 initial cases, we confirmed the appearance of nasal and/or bronchial manifestations in ten, characterized by a significant decrease in FEV1% and/or a decrease in nasal volume cavity after drug administration. All cases tolerated ASA. This shows that ASA tolerant subjects with asthma and/or rhinitis induced by paracetamol or a single NSAID without skin/systemic manifestations exist. Whether these patients represent a new clinical phenotype to be included within the current classification of hypersensitivity reactions to NSAIDs requires further investigation.

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.

Copy number variation in ALOX5 and PTGER1 is associated with NSAIDs-induced urticaria and/or angioedema.

OBJECTIVE: Cross-intolerance to NSAIDs is a class of drug hypersensitivity reaction, of which NSAIDs-induced urticaria and/or angioedema (NIUA) are the most frequent clinical entities. They are considered to involve dysregulation of the arachidonic acid pathway; however, this mechanism has not been confirmed for NIUA. In this work, we assessed copy number variations (CNVs) in eight of the main genes involved in the arachidonic acid pathway and their possible genetic association with NIUA. MATERIALS AND METHODS: CNVs in ALOX5, LTC4S, PTGS1, PTGS2, PTGER1, PTGER2, PTGER3, and PTGER4 were analyzed using TaqMan copy number assays. Genotyping was carried out by real-time quantitative PCR. Individual genotypes were assigned using the CopyCaller Software. Statistical analysis was carried out using GraphPad prism 5, PLINK, EPIDAT, and R version 3.1.2. RESULTS AND CONCLUSION: A total of 151 cases and 139 controls were analyzed during the discovery phase and 148 cases and 140 controls were used for replication. CNVs in open reading frames were found for ALOX5, PTGER1, PTGER3, and PTGER4. Statistically significant differences in the CNV frequency between NIUA and controls were found for ALOX5 (Pc=0.017) and PTGER1 (Pc=1.22E-04). This study represents the first analysis showing an association between CNVs in exonic regions of ALOX5 and PTGER1 and NIUA. This suggests a role of CNVs in this pathology that should be explored further.

Déficit adquirido de factor X en leucemia mielomonocítica crónica: reporte de un caso / Isolated factor X deficiency in chronic myelomonocytic leukemia: Report of one case

Bleeding disorders are commonly associated with hemato-oncologic diseases. We report a 68 years old male with a chronic myelomonocytic leukemia derived from a long lasting mielodysplastic syndrome that did not respond to treatment with Azacitidine. The patient was hospitalized due to tonic clonic seizures. A CAT scan showed a hematoma in the frontal lobe. A new assessment of hemostasis revealed an isolated deficiency of Factor X. We speculate that this deficit could be secondary to consumption due to the chronic Myelomonocytic Leukemia.

Association study of genetic variants in PLA2G4A, PLCG1, LAT, SYK, and TNFRS11A genes in NSAIDs-induced urticaria and/or angioedema patients.

NSAIDs-induced urticaria and/or angioedema (NIUA) is the most frequent entity of hypersensitivity reactions to NSAIDs. The underlying cause is considered to be because of a nonspecific immunological mechanism in which mast cells are key players. We studied the association of nine single nucleotide polymorphisms in five genes involved in mast cell activation (SYK, LAT1, PLCG1, PLA2G4A, and TNFRSF11A) in 450 NIUA patients and 500 controls. We identified several statistically significant associations when stratifying patients by symptoms: PLA2G4A rs12746200 (urticaria vs. controls, Pc=0.005). PLCG1 rs2228246 (angioedema vs. controls; Pc=0.044), and TNFRS11A rs1805034 (urticaria+angioedema vs. controls; Pc=0.041). The frequency of haplotype PLCG1 rs753381-rs2228246 (C-G) in angioedema-NIUA patients was lower than that in controls (Pc=0.040). In addition, the haplotype frequency of TNFRS11A rs1805034-rs35211496 (C-T) was higher among urticaria-NIUA and urticaria+angioedema-NIUA patients than the controls (Pc=0.045 and 0.046). Our results shed light on the involvement of variants in genes related to non-immunological mast cell activation in NIUA.

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

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.