Predictive models and applicability of artificial intelligence-based approaches in drug allergy.

PURPOSE OF REVIEW: Drug allergy is responsible for a huge burden on public healthcare systems, representing in some instances a threat for patient's life. Diagnosis is complex due to the heterogeneity of clinical phenotypes and mechanisms involved, the limitations of in vitro tests, and the associated risk to in vivo tests. Predictive models, including those using recent advances in artificial intelligence, may circumvent these drawbacks, leading to an appropriate classification of patients and improving their management in clinical settings. RECENT FINDINGS: Scores and predictive models to assess drug allergy development, including patient risk stratification, are scarce and usually apply logistic regression analysis. Over recent years, different methods encompassed under the general umbrella of artificial intelligence, including machine and deep learning, and artificial neural networks, are emerging as powerful tools to provide reliable and optimal models for clinical diagnosis, prediction, and precision medicine in different types of drug allergy. SUMMARY: This review provides general concepts and current evidence supporting the potential utility of predictive models and artificial intelligence branches in drug allergy diagnosis.

Human Neutrophils Couple Nitric Oxide Production and Extracellular Traps Formation in Allergic Asthma.

RATIONALE: Nitric oxide (NO) is elevated in the airways and serum of allergic asthmatic patients, suggesting an important role in asthma. NO production has been widely attributed to the canonical inducible nitric oxide synthase (iNOS). Much effort has been made to inhibit this enzyme with two outcomes: no asthma improvement; and partial NO reduction, suggesting the involvement of an iNOS-independent source. OBJECTIVES: Neutrophils produce NO under inflammatory conditions and their role in asthma has been overlooked. The present study analyzes their possible role as source of NO. METHODS: Our hypothesis was tested in 99 allergic patients with intermittent bronchial asthma and 26 healthy donors. NO production by blood and sputum neutrophils in response to allergens, anti-IgE, and anti-IgE receptors Abs was assessed by Griess, flow cytometry and confocal microscopy. Extracellular traps (ETs) formation, as a possible consequence of NO production, was quantified by western blot and confocal microscopy, and reactive oxygen species by luminol-enhanced chemiluminescence. RESULTS: Among blood and sputum granulocytes from allergic asthmatic patients, only neutrophils, produce NO by an IgE-dependent mechanism. This production is independent of NOS, but dependent on a reaction between L-arginine and reactive oxygen species from NOX2. NO and ETosis are induced in parallel, and NO amplifies ETs formation, which is a key mediator in asthma. CONCLUSIONS: Our findings reveal a novel role of neutrophils as the unique allergen/IgE-dependent NO source in allergic asthma enhancing ETs formation. These results suggest that NO produced by neutrophils needs further consideration in the treatment of allergic asthma.

Different Patterns of Response in Hypersensitivity Reactions to Arylpropionic Acid Derivatives.

BACKGROUND: Ibuprofen and other arylpropionic acid derivatives (APs) are among the most consumed nonsteroidal anti-inflammatory drugs worldwide at all age ranges; however, little is known about drug hypersensitivity reactions (DHRs) they induce. OBJECTIVE: To characterize in detail patients reporting DHRs to APs. METHODS: We prospectively evaluated patients with symptoms suggestive of AP-DHRs and analyzed their clinical characteristics, reported reactions, and diagnostic approaches. RESULTS: Six hundred sixty-two patients confirmed as hypersensitive to APs were included: 489 with cross-reactive reactions (CRs) (73.86%) and 173 with selective reactions (SRs) (26.13%). The percentage of subjects reporting reactions to ibuprofen and dexketoprofen was higher in CRs (P = .005 and P = .01, respectively), whereas naproxen and ketoprofen were more frequently involved in SRs (P = .0002 and P = .00001, respectively). The most frequent symptoms induced by ibuprofen, dexketoprofen, and naproxen were isolated angioedema and urticaria, combined or not with angioedema in both CRs and SRs. The result of nasal provocation test with lysine acetylsalicylate was positive in 156 cases (77.14% in patients showing exclusively respiratory symptoms, and in 68.18% of those with both cutaneous and respiratory involvement). To confirm diagnosis, drug provocation test with acetylsalicylic acid was required in 246 CR patients (50.3%), whereas in 28 SR patients (16.18%) drug provocation test with the culprit AP was required. CONCLUSIONS: Skin is the organ most commonly involved in AP-DHRs, with ibuprofen and dexketoprofen inducing most frequently CRs, and naproxen and ketoprofen SRs. More studies are necessary to clarify the underlying mechanism in DHRs induced by APs.

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.

Omics technologies in allergy and asthma research: An EAACI position paper.

Allergic diseases and asthma are heterogenous chronic inflammatory conditions with several distinct complex endotypes. Both environmental and genetic factors can influence the development and progression of allergy. Complex pathogenetic pathways observed in allergic disorders present a challenge in patient management and successful targeted treatment strategies. The increasing availability of high-throughput omics technologies, such as genomics, epigenomics, transcriptomics, proteomics, and metabolomics allows studying biochemical systems and pathophysiological processes underlying allergic responses. Additionally, omics techniques present clinical applicability by functional identification and validation of biomarkers. Therefore, finding molecules or patterns characteristic for distinct immune-inflammatory endotypes, can subsequently influence its development, progression, and treatment. There is a great potential to further increase the effectiveness of single omics approaches by integrating them with other omics, and nonomics data. Systems biology aims to simultaneously and longitudinally understand multiple layers of a complex and multifactorial disease, such as allergy, or asthma by integrating several, separated data sets and generating a complete molecular profile of the condition. With the use of sophisticated biostatistics and machine learning techniques, these approaches provide in-depth insight into individual biological systems and will allow efficient and customized healthcare approaches, called precision medicine. In this EAACI Position Paper, the Task Force "Omics technologies in allergic research" broadly reviewed current advances and applicability of omics techniques in allergic diseases and asthma research, with a focus on methodology and data analysis, aiming to provide researchers (basic and clinical) with a desk reference in the field. The potential of omics strategies in understanding disease pathophysiology and key tools to reach unmet needs in allergy precision medicine, such as successful patients' stratification, accurate disease prognosis, and prediction of treatment efficacy and successful prevention measures are highlighted.

Next-generation sequencing and genotype association studies reveal the association of HLA-DRB3*02:02 with delayed hypersensitivity to penicillins.

BACKGROUND: Nonimmediate (delayed)-allergic reactions to penicillins are common and some of them can be life-threatening. The genetic factors influencing these reactions are unknown/poorly known/poorly understood. We assessed the genetic predictors of a delayed penicillin allergy that cover the HLA loci. METHODS: Using next-generation sequencing (NGS), we genotyped the MHC region in 24 patients with delayed hypersensitivity compared with 20 patients with documented immediate hypersensitivity to penicillins recruited in Italy. Subsequently, we analyzed in silico Illumina Immunochip genotyping data that covered the HLA loci in 98 Spanish patients with delayed hypersensitivity and 315 with immediate hypersensitivity compared to 1,308 controls. RESULTS: The two alleles DRB3*02:02:01:02 and DRB3*02:02:01:01 were reported in twenty cases with delayed reactions (83%) and ten cases with immediate reactions (50%), but not in the Allele Frequency Net Database. Bearing at least one of the two alleles increased the risk of delayed reactions compared to immediate reactions, with an OR of 8.88 (95% CI, 3.37-23.32; p < .0001). The haplotype (ACAA) from rs9268835, rs6923504, rs6903608, and rs9268838 genetic variants of the HLA-DRB3 genomic region was significantly associated with an increased risk of delayed hypersensitivity to penicillins (OR, 1.7; 95% CI: 1.06-1.92; p = .001), but not immediate hypersensitivity. CONCLUSION: We showed that the HLA-DRB3 locus is strongly associated with an increased risk of delayed penicillin hypersensitivity, at least in Southwestern Europe. The determination of HLA-DRB3*02:02 alleles in the risk management of severe delayed hypersensitivity to penicillins should be evaluated further in larger population samples of different origins.

Subjects develop tolerance to Pru p 3 but respiratory allergy to Pru p 9: A large study group from a peach exposed population.

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.

Targeted inhibition of allergen-induced histamine production by neutrophils.

Histamine is a critical inflammatory mediator in allergic diseases. We showed in a previous work that neutrophils from allergic patients produce histamine in response to allergens to which the patients were sensitized. Here, we investigate the molecular mechanisms involved in this process using peripheral blood neutrophils. We challenged these cells in vitro with allergens and analyzed histamine release in the culture supernatants. We also explored the effect of common therapeutic drugs that ameliorate allergic symptoms, as well as allergen-specific immunotherapy. Additionally, we examined the expression of histidine decarboxylase and diamine oxidase, critical enzymes in the metabolism of histamine, under allergen challenge. We show that allergen-induced histamine release is dependent on the activation of the phosphoinositide 3-kinase, mitogen-activated protein kinase p38, and extracellular signal-regulated kinase 1/2 signaling pathways. We also found a contribution of the phosphatase calcineurin to lesser extent. Anti-histamines, glucocorticoids, anti-M3-muscarinic receptor antagonists, and mainly ß2 -receptor agonists abolished the allergen-dependent histamine release. Interestingly, allergen-specific immunotherapy canceled the histamine release through the downregulation of histidine decarboxylase expression. Our observations describe novel molecular mechanisms involved in the allergen-dependent histamine release by human neutrophils and provide new targets to inhibit histamine production.

Progress in understanding hypersensitivity reactions to nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs), the medications most commonly used for treating pain and inflammation, are the main triggers of drug hypersensitivity reactions. The latest classification of NSAIDs hypersensitivity by the European Academy of Allergy and Clinical Immunology (EAACI) differentiates between cross-hypersensitivity reactions (CRs), associated with COX-1 inhibition, and selective reactions, associated with immunological mechanisms. Three phenotypes fill into the first group: NSAIDs-exacerbated respiratory disease, NSAIDs-exacerbated cutaneous disease and NSAIDs-induced urticaria/angioedema. Two phenotypes fill into the second one: single-NSAID-induced urticaria/angioedema/anaphylaxis and single-NSAID-induced delayed reactions. Diagnosis of NSAIDs hypersensitivity is hampered by different factors, including the lack of validated in vitro biomarkers and the uselessness of skin tests. The advances achieved over recent years recommend a re-evaluation of the EAACI classification, as it does not consider other phenotypes such as blended reactions (coexistence of cutaneous and respiratory symptoms) or food-dependent NSAID-induced anaphylaxis. In addition, it does not regard the natural evolution of phenotypes and their potential interconversion, the development of tolerance over time or the role of atopy. Here, we address these topics. A state of the art on the underlying mechanisms and on the approaches for biomarkers discovery is also provided, including genetic studies and available information on transcriptomics and metabolomics.

Eicosanoid mediator profiles in different phenotypes of nonsteroidal anti-inflammatory drug-induced urticaria.

BACKGROUND: The role of arachidonic acid metabolites in NSAID-induced hypersensitivity has been studied in depth for NSAID-exacerbated respiratory disease (NERD) and NSAID-exacerbated cutaneous disease (NECD). However, no information is available for NSAID-induced urticarial/angioedema (NIUA), despite it being the most frequent clinical entity induced by NSAID hypersensitivity. We evaluated changes in leukotriene and prostaglandin metabolites for NIUA patients, using patients with NECD and single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) for comparison. METHODS: Urine samples were taken from patients with confirmed NSAID-induced urticaria and healthy controls, at baseline and at various time intervals after ASA administration. Eicosanoid measurement was performed using high-performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. RESULTS: No differences were found between groups at baseline. Following ASA administration, LTE4 and 9α,11ß-PGF2 levels were increased in both NIUA and NECD patients compared to baseline, rising initially, before decreasing toward initial levels. In addition, the levels of these metabolites were higher in NIUA and NECD when compared with the SNIUAA and control groups after ASA administration. No changes were found with respect to baseline values for SNIUAA and control groups. CONCLUSIONS: We present for the first time data regarding the role of COX-1 inhibition in NIUA. Patients with this entity show a similar pattern eicosanoid levels following ASA challenge to those with NECD. Further studies will help ascertain the cell populations involved and the underlying molecular mechanisms.

NSAIDs-hypersensitivity often induces a blended reaction pattern involving multiple organs.

Non-steroidal anti-inflammatory drugs (NSAIDs)-induced hypersensitivity reactions are classified by the European Network on Drug Allergy (ENDA) as either cross-reactive or selective. The former is the most frequent type and includes patients with exclusively respiratory symptoms (NSAIDs-exacerbated respiratory disease, NERD) or exclusively cutaneous symptoms: NSAIDs-induced urticaria/angioedema (NIUA); and NSAIDs-exacerbated cutaneous disease (NECD). However, although not reflected in the current classification scheme (ENDA), in clinical practice a combination of both skin and respiratory symptoms or even other organs such as gastrointestinal tract symptoms (mixed or blended reactions) is frequently observed. This entity has not been sufficiently characterised. Our aim was to clinically characterize blended reactions to NSAIDs, comparing their clinical features with NERD and NIUA. We evaluated patients with symptoms suggestive of hypersensitivity to NSAIDs who attended the Allergy Unit of the Regional University Hospital of Malaga (Malaga, Spain) between 2008 and 2015. We included 880 patients confirmed as cross-reactive based on clinical history, positive nasal provocation test with lysine acetylsalicylate (NPT-LASA), and/or positive drug provocation test (DPT) with acetylsalicylic acid (ASA), who were classified as blended (261; 29.6%), NERD (108; 12.3%) or NIUA (511; 58.1%). We compared symptoms, drugs, underlying diseases and diagnostic methods within and between groups. Among blended patients the most common sub-group comprised those developing urticaria/angioedema plus rhinitis/asthma (n = 138), who had a higher percentage of underlying rhinitis (p < 0.0001) and asthma (p < 0.0001) than NIUA patients, showing similarities to NERD. These differences were not found in the sub-group of blended patients who developed such respiratory symptoms as glottis oedema; these were more similar to NIUA. The percentage of positive NPT-LASA was similar for blended (77%) and NERD groups (78.7%). We conclude that blended reactions are hypersensitivity reactions to NSAIDs affecting at least two organs. In addition to classical skin and respiratory involvement, in our population a number of patients also develop gastrointestinal symptoms. Given the high rate of positive responses to NPT-LASA in NERD as well as blended reactions, we suggest that all patients reporting respiratory symptoms, regardless of whether they have other associated symptoms, should be initially evaluated using NPT-LASA, which poses less risk than DPT.

Genetic Variants of Thymic Stromal Lymphopoietin in Nonsteroidal Anti-Inflammatory Drug-Induced Urticaria/Angioedema.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequent agents involved in hypersensitivity drug reactions, with NSAID-induced urticaria and/or angioedema (NIUA) being the most common entity. Mast cells are key players in NIUA and are activated by thymic stromal lymphopoietin (TSLP). This cytokine functions through recognition by its receptor, composed of IL7Rα (interleukin-7 receptor alpha) and TSLPR (TSLP receptor). These genes have been previously associated with other inflammatory diseases. METHODS: We assessed the genetic association between single nucleotide polymorphisms (SNPs) in TSLP, IL7R and TSLPR and NIUA in Spanish individuals, using genotyped and imputed data. A total of 369 unrelated NIUA patients and 580 NSAID-tolerant control subjects were included, and 6 SNPs in TSLP, 6 in IL7R and 3 in TSLPR were genotyped. Further variants were imputed using Mach and the 1,000 Genomes Project (Phase 3) data. Association testing and statistical analyses were performed with Mach2dat and R. RESULTS: A total of 139 SNPs were tested for association following quality control. Two SNPs in TSLP (rs1816678 and rs764917) showed a nominal association (p = 0.033 and 0.024, respectively) with NIUA, although these results were not statistically significant after correcting for multiple comparisons. CONCLUSIONS: Although TSLP, IL7R and TSLPR are important genes involved in the development of the inflammatory response, we found no significant genetic association with NIUA in our population for common SNPs in these genes.

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.

Review: High-performance computing to detect epistasis in genome scale data sets.

It is becoming clear that most human diseases have a complex etiology that cannot be explained by single nucleotide polymorphisms (SNPs) or simple additive combinations; the general consensus is that they are caused by combinations of multiple genetic variations. The limited success of some genome-wide association studies is partly a result of this focus on single genetic markers. A more promising approach is to take into account epistasis, by considering the association of multiple SNP interactions with disease. However, as genomic data continues to grow in resolution, and genome and exome sequencing become more established, the number of combinations of variants to consider increases rapidly. Two potential solutions should be considered: the use of high-performance computing, which allows us to consider a larger number of variables, and heuristics to make the solution more tractable, essential in the case of genome sequencing. In this review, we look at different computational methods to analyse epistatic interactions within disease-related genetic data sets created by microarray technology. We also review efforts to use epistatic analysis results to produce biomarkers for diagnostic tests and give our views on future directions in this field in light of advances in sequencing technology and variants in non-coding regions.

Unravelling adverse reactions to NSAIDs using systems biology.

We introduce the reader to systems biology, using adverse drug reactions (ADRs), specifically hypersensitivity reactions to multiple non-steroidal anti-inflammatory drugs (NSAIDs), as a model. To disentangle the different processes that contribute to these reactions - from drug intake to the appearance of symptoms - it will be necessary to create high-throughput datasets. Just as crucial will be the use of systems biology to integrate and make sense of them. We review previous work using systems biology to study related pathologies such as asthma/allergy, and NSAID metabolism. We show examples of their application to NSAIDs-hypersensitivity using current datasets. We describe breakthroughs in high-throughput technology and speculate on their use to improve our understanding of this and other drug-induced pathologies.

HLA-DRA variants predict penicillin allergy in genome-wide fine-mapping genotyping.

BACKGROUND: Immediate reactions to ß-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 ß-lactam allergy to better understand the underlying mechanisms. METHODS: We studied 387 patients with immediate allergic reactions to ß-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 ß-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.