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Background Immediate reactions to β-lactams are the most common causes of anaphylactic reactions and can be life-threatening. The few known genetic factors influencing these reactions suggest a link with atopy and inflammation. Objective We performed a fine-mapping genome-wide association study of the genetic predictors of β-lactam allergy to better understand the underlying mechanisms. Methods We studied 387 patients with immediate allergic reactions to β-lactams and 1124 paired control subjects from Spain. We replicated the results in 299 patients and 362 paired control subjects from Italy. Results We found significant associations with the single nucleotide polymorphisms rs4958427 of ZNF300 (c.64-471G>A, P = 9.9 × 10 −9 ), rs17612 of C5 (c.4311A>C [p.Glu1437Asp], P = 7.5 × 10 −7 ), rs7754768 and rs9268832 of the HLA-DRA | HLA-DRB5 interregion ( P = 1.6 × 10 −6 and 4.9 × 10 −6 ), and rs7192 of HLA-DRA (c.724T>G [p.Leu242Val], P = 7.4 × 10 −6 ) in an allelic model, with similar results in an additive model. Single nucleotide polymorphisms of HLA-DRA and ZNF300 predicted skin test positivity to amoxicillin and other penicillins but not to cephalosporins. A haplotype block in HLA-DRA and the HLA-DRA | HLA-DRB5 interregion encompassed a motif involved in balanced expression of the α- and β-chains of MHC class II, whereas rs7192 was predicted to influence α-chain conformation. HLA-DRA rs7192 and rs8084 were significantly associated with allergy to penicillins and amoxicillin ( P = 6.0 × 10 −4 and P = 4.0 × 10 −4 , respectively) but not to cephalosporins in the replication study. Conclusions Gene variants of HLA-DRA and the HLA-DRA | HLA-DRB5 interregion were significant predictors of allergy to penicillins but not to cephalosporins. These data suggest complex gene-environment interactions in which genetic susceptibility of HLA type 2 antigen presentation plays a central role. [ABSTRACT FROM AUTHOR]

Background: Beta‐lactams generate different allergenic determinants that induce selective or cross‐reactive drug hypersensitivity reactions (DHRs). We aimed to identify the drugs involved, the selectivity of the response, the mechanism, and the value of the different diagnostic tests for establishing a diagnosis in children evaluated for DHRs to beta‐lactams. Methods: Prospective study evaluating children aged under 16 years reporting DHRs to beta‐lactams. Reactions were classified as immediate and non‐immediate reactions. The workup included sIgE, skin testing, and drug provocation tests (DPTs) for immediate reactions and patch testing and DPTs for non‐immediate ones. Results: Of the 510 children included, 133 were evaluated for immediate reactions and confirmed in 8.3%. Skin test/in vitro IgE contributed to diagnosing half of the cases. Selective reactions occurred with amoxicillin (63%), followed by common penicillin determinants (27%) and cephalosporins (0.9%). Among non‐immediate reactions (11.4% of the 377 children evaluated), most required DPTs, 52.7% of which were positive at 6–7 days of drug challenge. Selective reactions were identified with amoxicillin (80%), penicillin G (7.5%), cephalosporins (7.5%), and clavulanic acid (5%). Urticaria and maculopapular exanthema were the most frequent entities. Conclusions: There were few confirmed cases of either type of reaction. Skin testing proved less valuable in non‐immediate reactions, over half of which would also have been lost in a short DPT protocol. Selective responders to amoxicillin were more likely to have non‐immediate reactions, while clavulanic acid selectivity was exclusive to the non‐immediate typology. Over half the cases with DPTs required 6–7 days of treatment for DHR confirmation. [ABSTRACT FROM AUTHOR]

Peach tree allergens are present in fruit, pollen, branches, and leaves, and can induce systemic, respiratory, cutaneous, and gastrointestinal symptoms. We studied the capacity of peach fruit/Pru p 1, Pru p 3, Pru p 4, Pru p 7 and peach pollen/Pru p 9 for inducing symptoms following oral or respiratory exposure in a large group of subjects. We included 716 adults (aged 21 to 83 y.o.) exposed to peach tree pollen and fruit intake in the study population. Participants completed a questionnaire and were skin tested with a panel of inhalant and food allergens, including peach tree pollen, Pru p 9 and peach fruit skin extract. Immunoglobulin E antibodies (SIgE) to Pru p 1, Pru p 3, Pru p 4 and Pru p 7 were quantified. Sensitised subjects underwent oral food challenge with peach fruit and nasal provocation test with peach tree pollen and Pru p 9. The prevalence of sensitisation to peach fruit was 5% and most of these had SIgE to Pru p 3, with a very low proportion to Pru p 4 SIgE and no SIgE to Pru p 1 and Pru p 7. In only 1.8%, anaphylaxis was the clinical entity induced. Cases with positive skin tests to peach and SIgE to Pru p 3 presented a good tolerance after oral challenge with peach fruit. The prevalence of skin sensitisation to peach tree pollen was 22%, with almost half recognising Pru p 9. This induced respiratory symptoms in those evaluated by nasal provocation. In a large population group exposed to peach fruit and peach tree pollen, most individuals were tolerant, even in those with SIgE to Pru p 3. A positive response to Pru p 9 was associated with respiratory allergy. [ABSTRACT FROM AUTHOR]

Background: The presence of SARS‐CoV‐2 RNA in plasma has been linked to disease severity and mortality. We compared RT‐qPCR to droplet digital PCR (ddPCR) to detect SARS‐CoV‐2 RNA in plasma from COVID‐19 patients (mild, moderate, and critical disease). Methods: The presence/concentration of SARS‐CoV‐2 RNA in plasma was compared in three groups of COVID‐19 patients (30 outpatients, 30 ward patients and 30 ICU patients) using both RT‐qPCR and ddPCR. Plasma was obtained in the first 24h following admission, and RNA was extracted using eMAG. ddPCR was performed using Bio‐Rad SARS‐CoV‐2 detection kit, and RT‐qPCR was performed using GeneFinder™ COVID‐19 Plus RealAmp Kit. Statistical analysis was performed using Statistical Package for the Social Science. Results: SARS‐CoV‐2 RNA was detected, using ddPCR and RT‐qPCR, in 91% and 87% of ICU patients, 27% and 23% of ward patients and 3% and 3% of outpatients. The concordance of the results obtained by both methods was excellent (Cohen's kappa index = 0.953). RT‐qPCR was able to detect 34/36 (94.4%) patients positive for viral RNA in plasma by ddPCR. Viral RNA load was higher in ICU patients compared with the other groups (P <.001), by both ddPCR and RT‐qPCR. AUC analysis revealed Ct values (RT‐qPCR) and viral RNA load values (ddPCR) can similarly differentiate between patients admitted to wards and to the ICU (AUC of 0.90 and 0.89, respectively). Conclusion: Both methods yielded similar prevalence of RNAemia between groups, with ICU patients showing the highest (>85%). RT‐qPCR was as useful as ddPCR to detect and quantify SARS‐CoV‐2 RNAemia in plasma. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Metamizole is a pain-killer drug that has been banned in some countries because of its toxicity, but it is still used in many countries due to its effective analgesic and antispasmodic properties. Although large variability in the biodisposition and adverse effects of metamizole are known, factors underlying this variability are poorly understood. We analyzed the urinary recovery of metabolites, as well as the association of these profiles with genetic and non-genetic factors, in a group of 362 healthy individuals. Gender and functional polymorphisms are strongly related to metabolic profiles. N -demethylation of the active metabolite MAA is diminished in carriers of the CYP2C19*2 allele and in NAT2 -slow acetylators. Acetylation of the secondary metabolite AA is decreased in men, in drinkers and in NAT2-slow acetylators with a differential effect of NAT2*5 and NAT2*6 alleles. The formylation of MAA is diminished in older subjects and in carriers of defect CYP2C9 and CYP2C19 alleles. Two novel arachidonoyl metabolites were identified for the first time in humans. Women and NAT2-slow acetylators show higher concentrations, whereas the presence of the rapid CYP2C19*17 allele is associated with lower concentrations of these metabolites. All genetic associations show a gene-dose effect. We identified for the first time genetic and non-genetic factors related to the oxidative metabolism of analgesic drug metamizole, as well as new active metabolites in humans. The phenotypic and genetic factors identified in this study have a potential application as biomarkers of metamizole biotransformation and toxicity. [ABSTRACT FROM AUTHOR]

Background: Cancer patients often have weakened immune systems, resulting in a lower response to vaccines, especially those receiving immunosuppressive oncological treatment (OT). We aimed to assess the impact of OT on the humoral and T-cell response to the B.1 lineage and Omicron variant following COVID-19 vaccination in patients with solid and hematological neoplasms., Methods: We conducted a prospective study on cancer patients, stratified into OT and non-OT groups, who received a two-dose series of the COVID-19 mRNA vaccine and a booster six months later. The outcomes measured were the humoral (anti-SARS-CoV-2 S IgG titers and ACE2-S interaction inhibition capacity) and cellular (SARS-CoV-2 S-specific T-cell spots per million PBMCs) responses against the B.1 lineage and Omicron variant. These responses were evaluated four weeks after the second dose (n = 98) and eight weeks after the booster dose (n = 71)., Results: The humoral response after the second vaccine dose against the B.1 lineage and Omicron variant was significantly weaker in the OT group compared to the non-OT group (q-value<0.05). A booster dose of the mRNA-1273 vaccine significantly improved the humoral response in the OT group, making it comparable to the non-OT group. The mRNA-1273 vaccine, designed for the original Wuhan strain, elicited a weaker humoral response against the Omicron variant compared to the B.1 lineage, regardless of oncological treatment or vaccine dose. In contrast, T-cell responses against SARS-CoV-2, including the Omicron variant, were already present after the second vaccine dose and were not significantly affected by oncological treatments., Conclusions: Cancer patients, particularly those receiving immunosuppressive oncological treatments, should require booster doses and adapted COVID-19 vaccines for new SARS-CoV-2 variants like Omicron. Future studies should evaluate the durability of the immune response and the efficacy of individualized regimens., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Clavulanate, a beta-lactam associated with amoxicillin, is frequently prescribed in patients at all ages. Recent data implicate amoxicillin-clavulanate in up to 80% of beta-lactam allergy cases. We assessed clavulanate's role in inducing allergic reactions to this combination treatment, with a focus on selective immediate reactions., Methods: Adults (≥ 16 years) reporting a history of immediate reactions to amoxicillin-clavulanate were evaluated through a beta-lactam allergological workup, using modified European Academy of Allergy and Clinical Immunology guidelines. Patients first underwent skin testing, and if negative, drug provocation tests. Expected outcomes were: Group A, subjects with immediate reaction to classical penicillin group determinants (penicilloyl polylysine, minor determinants mixture, and/or penicillin G); Group B, subjects with selective immediate reaction to amoxicillin; Group C, subjects with selective immediate reaction to clavulanate and Group D, those immediate reactions with co-sensitization to clavulanate plus penicillin group determinants or amoxicillin., Results: Of 1,170 included patients, 104 had immediate reactions: 36.5% to penicillin group determinants (Group A), 26.9% to amoxicillin (Group B), 32.7% to clavulanate (Group C), and 3.8% to clavulanate plus penicillin determinants or amoxicillin (Group D). Diagnosis was made by skin testing in 79%, 75% and 47% of the patients, respectively, in the first 3 groups ( P < 0.001). Drug provocation tests were necessary to establish most other diagnoses. Anaphylaxis predominated over urticaria/angioedema in all groups., Conclusions: Selective immediate reactions to clavulanate accounted for over a third of cases with confirmed reactions after amoxicillin-clavulanate intake, with more than half experiencing anaphylaxis. Within this group, skin test sensitivity was below 50%. People taking amoxicillin-clavulanate may also be co-sensitized to both drugs., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2023 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Increasing age is associated with severity and higher mortality of COVID-19. Telomere shortening is associated with higher risk of infections and may be used to identify those patients who are more likely to die. We evaluated the association between relative telomere length (RTL) and COVID-19 mortality. RTL was measured in patients hospitalized because of COVID-19. We used Kaplan-Meier method to analyze survival probabilities, and Cox regression to investigate the association between RTL and mortality (30 and 90 days). Six hundred and eight patients were included in the analysis (mean age =72.5 years, 41.1% women, and 53.8% Caucasic). During the study period, 75 people died from COVID-19 and 533 survived. Lower RTL was associated with a higher risk of death in women either at 30 (adjusted hazard ratio [HR] (aHR) = 3.33; 95% confidence interval [CI] = 1.05-10.00; p = 0.040) and at 90 days (aHR = 3.57; 95%CI = 1.23-11.11; p = 0.019). Lower RTL was associated with a higher risk of dying of COVID-19 in women. This finding suggests that RTL has an essential role in the prognosis of this subset of the population., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: MicroRNAs (miRNAs) have a crucial role in regulating immune response against infectious diseases, showing changes early in disease onset and before the detection of the pathogen. Thus, we aimed to analyze the plasma miRNA profile at COVID-19 onset to identify miRNAs as early prognostic biomarkers of severity and survival., Methods and Results: Plasma miRNome of 96 COVID-19 patients that developed asymptomatic/mild, moderate and severe disease was sequenced together with a group of healthy controls. Plasma immune-related biomarkers were also assessed. COVID-19 patients showed 200 significant differentially expressed (SDE) miRNAs concerning healthy controls, with upregulated putative targets of SARS-CoV-2, and inflammatory miRNAs. Among COVID-19 patients, 75 SDE miRNAs were observed in asymptomatic/mild compared to symptomatic patients, which were involved in platelet aggregation and cytokine pathways, among others. Moreover, 137 SDE miRNAs were identified between severe and moderate patients, where miRNAs targeting the SARS CoV-2 genome were the most strongly disrupted. Finally, we constructed a mortality predictive risk score (miRNA-MRS) with ten miRNAs. Patients with higher values had a higher risk of 90-days mortality (hazard ratio = 4.60; p -value < 0.001). Besides, the discriminant power of miRNA-MRS was significantly higher than the observed for age and gender (AUROC = 0.970 vs. 0.881; p  = 0.042)., Conclusions: SARS-CoV-2 infection deeply disturbs the plasma miRNome from an early stage of COVID-19, making miRNAs highly valuable as early predictors of severity and mortality.

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., Competing Interests: EAFG and EFC are employees of Inmunotek laboratories. The remaining authors declare that they do not have any conflicts of interest., (© 2022 Somoza et al.)

Background: Anaphylaxis, which is rare, has been reported after COVID-19 vaccination, but its management is not standardized., Method: 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., Results: 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., Conclusions: 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., (© 2022 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: metabolic changes through SARS-CoV-2 infection has been reported but not fully comprehended. This metabolic dysregulation affects multiple organs during COVID-19 and its early detection can be used as a prognosis marker of severity. Therefore, we aimed to characterize metabolic and cytokine profile at COVID-19 onset and its relationship with disease severity to identify metabolic profiles predicting disease progression., Material and Methods: we performed a retrospective cross-sectional study in 123 COVID-19 patients which were stratified as asymptomatic/mild, moderate and severe according to the highest COVID-19 severity status, and a group of healthy controls. We performed an untargeted plasma metabolic profiling (gas chromatography and capillary electrophoresis-mass spectrometry (GC and CE-MS)) and cytokine evaluation., Results: After data filtering and identification we observed 105 metabolites dysregulated (66 GC-MS and 40 CE-MS) which shown different expression patterns for each COVID-19 severity status. These metabolites belonged to different metabolic pathways including amino acid, energy, and nitrogen metabolism among others. Severity-specific metabolic dysregulation was observed, as an increased transformation of L-tryptophan into L-kynurenine. Thus, metabolic profiling at hospital admission differentiate between severe and moderate patients in the later phase of worse evolution. Several plasma pro-inflammatory biomarkers showed significant correlation with deregulated metabolites, specially with L-kynurenine and L-tryptophan. Finally, we describe a strong sex-related dysregulation of metabolites, cytokines and chemokines between severe and moderate patients. In conclusion, metabolic profiling of COVID-19 patients at disease onset is a powerful tool to unravel the SARS-CoV-2 molecular pathogenesis., Conclusions: This technique makes it possible to identify metabolic phenoconversion that predicts disease progression and explains the pronounced pathogenesis differences between sexes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ceballos, Virseda-Berdices, Resino, Ryan, Martínez-González, Peréz-García, Martin-Vicente, Brochado-Kith, Blancas, Bartolome-Sánchez, Vidal-Alcántara, Albóniga-Díez, Cuadros-González, Blanca-López, Martínez, Martinez-Acitores, Barbas, Fernández-Rodríguez and Jiménez-Sousa.)

Background: As the use of multiplex-specific immunoglobulin E (sIgE) detection methods becomes increasingly widespread, proper comparative validation assessments of emerging new platforms are vital., Objective: To evaluate the clinical and technical performance of a newly introduced microarray platform, Allergy Explorer (ALEX) (MacroArray Diagnostics), in the diagnosis of pollen (cypress, grass, olive), dust mite (Dermatophagoides pteronyssinus), mold (Alternaria alternata), fruit (apple, peach), and nut (walnut, hazelnut and peanut) allergies and to compare it with those of the ImmunoCAP Immuno Solid-phase Allergen Chip (ISAC) 112 microarray and the ImmunoCAP singleplex method (ThermoFisher Scientific)., Methods: We enrolled 153 patients with allergy and 16 controls without atopy. The sIgE assays were conducted using ISAC112, ALEX version 2 (ALEX2), and ImmunoCAP for whole extracts and major components. Technical validation of ALEX2 was performed by measuring repeatability and interassay, interbatch, and interlaboratory reproducibility., Results: When measured globally (detection by 1 or more allergen components), ALEX2 had adequate sensitivity and specificity for most of the allergens studied, comparable in general with that of ISAC112 (except for olive pollen and walnut) and similar to that of ImmunoCAP whole extract measurements. Component-by-component analysis revealed comparable results for all techniques, except for Ole e 1 and Jug r 3, in both ISAC112 and ImmunoCAP comparisons, and Alt a 1, when compared with ISAC112. Continuous sIgE levels correlate with sIgE by ImmunoCAP. Good reproducibility and repeatability were observed for ALEX2., Conclusion: ALEX2 has sound technical performance and adequate diagnostic capacity, comparable in general with that of ISAC112 and ImmunoCAP., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Background: The link between coagulation system disorders and COVID-19 has not yet been fully elucidated. Aim: Evaluating the association of non-previously reported coagulation proteins with COVID-19 severity and mortality. Design: Cross-sectional study of 134 COVID-19 patients recruited at admission and classified according to the highest COVID-19 severity reached (asymptomatic/mild, moderate, or severe) and 16 healthy control individuals. Methods: Coagulation proteins levels (antithrombin, prothrombin, factor&#95;XI, factor&#95;XII, and factor&#95;XIII) and CRP were measured in plasma by the ProcartaPlex Panel (Invitrogen) multiplex immunoassay upon diagnosis. Results: We found higher levels of antithrombin, prothrombin, factor XI, factor XII, and factor XIII in asymptomatic/mild and moderate COVID-19 patients compared to healthy individuals. Interestingly, decreased levels of antithrombin and factors XI, XII, and XIII were observed in those patients who eventually developed severe illness. Additionally, survival models showed us that patients with lower levels of these coagulation proteins had an increased risk of death. Conclusion: COVID-19 provokes early increments of some specific coagulation proteins in most patients. However, lower levels of these proteins at diagnosis might "paradoxically" imply a higher risk of progression to severe disease and COVID-19-related mortality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ceballos, Ryan, Blancas, Martin-Vicente, Vidal-Alcántara, Peréz-García, Bartolomé, Churruca-Sarasqueta, Virseda-Berdices, Martínez-González, Brochado-Kith, Rava, Vilches-Medkouri, Blanca-López, Ramirez Martinez-Acitores, Moreira-Escriche, De Juan, Resino, Fernández-Rodríguez and Jiménez-Sousa.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Macías, García-Menaya, Martí, Cordobés, Jurado-Escobar, Cornejo-García, Torres, Blanca-López, Canto, Blanca, Laguna, Bartra, Rosado, Fernández, García-Martín and Agúndez.)

Background: β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE., Objective: We sought to identify genetic predisposing factors for immediate reactions to β-lactam antibiotics., Methods: Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort., Results: Genome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P = 2 × 10 -14 ); this was in linkage disequilibrium with HLA-DRB1∗10:01 (odds ratio, 2.93; P = 5.4 × 10 -7 ) and HLA-DQA1∗01:05 (odds ratio, 2.93, P = 5.4 × 10 -7 ). Haplotype analysis identified that HLA-DRB1∗10:01 was a risk factor even without the HLA-DQA1∗01:05 allele. The association with HLA-DRB1∗10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1∗10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P = 4.1 × 10 -9 ). No association with HLA-DRB1∗10:01 was identified in 268 patients with delayed hypersensitivity reactions to β-lactams., Conclusions: HLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response., Methods: A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients., Results: The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) (p < 0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non-survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%], p): RNAemia (3.92 [1.183-12.968], 0.025), viral RNA load (N1) (1.962 [1.244-3.096], 0.004); viral RNA load (N2) (2.229 [1.382-3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia)., Conclusions: SARS-CoV-2 RNAemia and viral RNA load in plasma are associated with critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease.

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., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Scope: Tomato has become one of the most consumed vegetables worldwide, but its intake is often accompanied by an increasing risk of inducing allergic symptoms. The aim of the work was the identification of new seed-specific allergens associated with severe symptoms in patients allergic to this edible vegetable., Methods and Results: We used 22 sera from well-defined tomato-allergic patients. Tomato seed proteins were purified and analyzed for biochemical and immunological characterization. A mixture of two associated IgE-binding nsLTPs was purified from tomato seeds. Both allergens, Sola l 7 and Sola l 6, displayed primary structure differences with respect to their counterpart, Sola l 3, from tomato pulp/peel. They retained the ability to bind IgE from 71.4% of patients with severe symptoms. The purified proteins induced positive basophil activation test and skin prick test, and displayed cross-reactivity with homologous allergens from peanut and sunflower seeds, among others., Conclusion: We herein described two novel allergens from tomato seeds that belong to the nonspecific lipid transfer protein family classes 1 and 2, respectively. This is the first work associating IgE reactivity to these proteins with severe symptoms of certain tomato-allergic patients. Therefore, they are optimal candidates for clarifying the diagnosis of the tomato allergy., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This review focuses on local allergic rhinitis, a new phenotype of allergic rhinitis, commonly misdiagnosed as nonallergic rhinitis. It has gained attention over last decade and can affect patients from all countries, ethnic groups and ages, impairing their quality of life, and is frequently associated with conjunctivitis and asthma. Diagnosis is based on clinical history, the demonstration of a positive response to nasal allergen provocation test and/or the detection of nasal sIgE. A positive basophil activation test may support the diagnosis. Recent studies have demonstrated that allergen immunotherapy is an effective immune-modifying treatment, highlighting the importance of early diagnosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Beta-lactam antibiotics (BLs) are the most frequent cause of hypersensitivity reactions mediated by specific immunological mechanisms, with two main types, IgE reactions or T-cell-dependent responses. From a practical point of view, these reactions can be classified into immediate, for those appearing within 1 h after drug intake, and non-immediate, for those appearing at least 1 h after and usually within 24 h of BL administration. The clinical symptoms differ according to this classification. Urticaria and anaphylaxis are the most frequently recorded symptoms in immediate reactions and maculopapular exanthema and delayed urticaria in non-immediate reactions. Although the exact diagnostic approach differs depending on the underlying mechanism, it is based on the performance of skin testing, laboratory tests, and drug provocation tests.T cells are a key factor in all types of hypersensitivity reactions to BLs, regulating both IgE production or acting as effector cells, with a different profile of cytokine production. A Th1 pattern is observed in both CD4(+) and CD8(+) peripheral T cells in non-immediate reactions, whereas a Th2 pattern is expressed in CD4(+) T cells in immediate reactions.

Aim: Acute urticaria/angioedema (AUA) induced by cross-intolerance to NSAIDs is the most frequent clinical entity in hypersensitivity reactions to drugs. In this work, we conducted a genome-wide association study in Spanish and Han Chinese patients suffering from NSAID-induced AUA., Materials & Methods: A whole-genome scan was performed on a total of 232 cases (112 Spanish and 120 Han Chinese) with NSAID-induced AUA and 225 unrelated controls (124 Spanish and 101 Han Chinese)., Results: Although no polymorphism reached genome-wide significance, we obtained suggestive associations for three clusters in the Spanish group (RIMS1, BICC1 and RAD51L 1) and one region in the Han Chinese population (ABI3BP). Five regions showed suggestive associations after meta-analysis: HLF, RAD51L1, COL24A1, GalNAc-T13 and FBXL7. A majority of these genes are related to Ca(2+), cAMP and/or P53 signaling pathways., Conclusion: The associations described were different from those related to the metabolism of arachidonic acid and could provide new mechanisms underlying NSAID-induced AUA.

Background: Delayed-type hypersensitivity to glatiramer acetate is rare, and the underlying immunological mechanisms are not completely understood., Objective: To study the immunologic response in 2 patients with multiple sclerosis who developed maculopapular exanthema related with the administration of glatiramer acetate., Methods: The allergologic study included general blood tests, viral serologic tests, and skin tests (patch and intradermal tests). The immunologic study was performed in skin biopsy specimens by immunohistochemistry and in the peripheral blood by flow cytometry and the lymphocyte transformation test., Results: Skin test results were negative in both patients, and the diagnosis was confirmed by a drug provocation test. The evaluation of the acute phase showed an increase in the percentage of CD8 T lymphocytes (>50%) and the percentage of cells expressing skin-homing receptor (cutaneous lymphocyte-associated antigen) (>70%) and chemokine receptors (CCR4 and CXCR3) at T1. A positive proliferative response was observed in T lymphocytes (stimulation index [SI] = 3.5 in patient 1 and 3.59 in patient 2), especially the CD8(+) subpopulation (SI = 5.5 and 4.6 in patients 1 and 2, respectively), and NK lymphocytes (SI = 3.9 and 8.5 in patients 1 and 2, respectively) after glatiramer acetate stimulation., Conclusion: This study demonstrates the important role of T(H)1 cells expressing skin-homing receptors in delayed-type hypersensitivity reactions to glatiramer acetate. A lymphocyte transformation test revealed a specific glatiramer acetate recognition by T lymphocytes and NK lymphocytes., (Copyright © 2012 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

NSAIDs are the most important group of drugs involved in hypersensitivity drug reactions, and include heterogeneous compounds with very different chemical structures. These reactions can be IgE dependent (immediate reactions), T cell-mediated (non-immediate), or induced by a non-specific immunological mechanism related with the blocking of the COX-1 enzyme and the shunting to the lipooxygenase pathway (cross-intolerant reactions). Cutaneous symptoms are the most frequent, with ibuprofen, naproxen and diclofenac being common culprit drugs worldwide, although others can be involved because patterns of consumption and exposure rates vary between countries. A very important proportion of immunological reactions are immediate, with urticaria and anaphylaxis being the typical clinical manifestations. Non-immediate reactions comprise a number of heterogeneous entities ranging from mild exanthema to severe TEN or DRESS syndrome, as well as organ-specific reactions such as hepatitis or pneumonitis. Cross-intolerant reactions appear to non-chemically related drugs, and involve respiratory airways, skin or both. In vivo diagnostic tests are based on the capacity of the skin to respond to the culprit drug, but their sensitivity is in many instances rather low. The approach for in vitro testing consists of either detecting specific IgE antibodies or studying the proliferation of T lymphocytes toward the eliciting drug. No appropriate tests are yet available for the in vitro validation of cross-intolerance reactions, although techniques based on the stimulation of basophils have been proposed. Based on these findings, the diagnostic approach is often based on the controlled administration of the drug to assess tolerance. In this work we review current knowledge on hypersensitivity reactions to NSAIDs, including diagnostic approach and genetic studies.