Spanish Society of Allergology and Clinical Immunology (SEAIC) Vision of Drug Provocation Tests.

The controlled drug provocation test (DPT) is currently considered the gold standard for the diagnosis of drug allergy. Adverse drug reactions (ADRs) are an increasingly common presenting complaint in both primary and specialized care. In Spain, ADRs are usually assessed via the allergology department, which rules out immunological mechanisms in up to 90% of cases. An adequate approach to ADRs clearly impacts the costs and efficacy of the treatments prescribed by other specialists. Consequently, if we did not use DPTs, patients would require more expensive, more toxic, and less effective treatments in many cases. In recent years, many new drugs have been developed. This document is intended to be a practical guideline for the management of DPTs according to the vision of the Spanish Allergology Society. The diagnostic work-up begins with a detailed clinical history. Skin tests are only useful for some medications, and in most cases the diagnosis can only be confirmed by DPT. Although cross-reactivity is common, DPTs can confirm the diagnosis and help to find an alternative drug. Programmed individualized patient management based on the type of drug to be studied and the patient´s comorbidities usually enables a solution to be found in most cases.

Clinical Practice Guidelines for Diagnosis and Management of Hypersensitivity Reactions to Quinolones.

The consumption of quinolones as first-line treatment has increased in recent years, leading to an increase in the incidence of hypersensitivity reactions (HSRs) to this antibiotic group. Both diagnosis and management of HSRs to quinolones are complex and controversial. These practical guidelines aim to provide recommendations for effective clinical practice. The recommendations were drafted by an expert panel that reviewed the literature regarding HSRs to quinolones and analyzed controversies in this area. Most HSRs to quinolones are immediate and severe. The risk for HSRs is higher in patients who report allergy to ß-lactams, moxifloxacininduced anaphylaxis, and immediate reactions than in patients who report reactions to quinolones inducing other symptoms. The usefulness of skin tests in diagnosing HSRs to quinolones is controversial, with sensitivity and specificity varying between studies. Most in vitro tests are produced in-house, with no validated commercial options. The basophil activation test has proven useful for diagnosing immediate reactions, albeit with diverse results regarding sensitivity. Drug provocation testing is currently the gold standard for confirming or excluding the diagnosis and for finding safe alternatives, although it is contraindicated in patients with severe reactions. Cross-reactivity between quinolones has proven controversial in several studies, with the lowest cross-reactivity reported for levofloxacin. Desensitization may be considered in allergy to quinolones when no other alternatives are available.

Spanish Guidelines for Diagnosis, Management, Treatment, and Prevention of DRESS Syndrome.

BACKGROUND AND OBJECTIVE: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a complex multisystemic severe drug hypersensitivity reaction whose diagnosis and management are troublesome. DRESS syndrome requires management by various specialists. The correct identification of the culprit drug is essential to ensure safe future therapeutic options for the patient. There are no previous Spanish guidelines or consensus statements on DRESS syndrome. Objective: To draft a review and guidelines on the clinical diagnosis, allergy work-up, management, treatment, and prevention of DRESS syndrome in light of currently available scientific evidence and the experience of experts from multiple disciplines. METHODS: These guidelines were drafted by a panel of allergy specialists from the Drug Allergy Committee of the Spanish Society of Allergy and Clinical Immunology (SEAIC), together with other medical specialists involved in the management of DRESS syndrome and researchers from the PIELenRed consortium. A review was conducted of scientific papers on DRESS syndrome, and the expert panel evaluated the quality of the evidence of the literature and provided grades of recommendation. Whenever evidence was lacking, a consensus was reached among the experts. RESULTS: The first Spanish guidelines on DRESS syndrome are now being published. Important aspects have been addressed, including practical recommendations about clinical diagnosis, identification of the culprit drug through the Spanish pharmacovigilance system algorithm, and the allergy work-up. Recommendations are provided on management, treatment, and prevention. Algorithms for the management of DRESS in the acute and recovery phases have been drawn up. Expert consensus-based stepwise guidelines for the management and treatment of DRESS syndrome are provided.

Specific immunotherapy in local allergic rhinitis: A randomized, double-blind placebo-controlled trial with Phleum pratense subcutaneous allergen immunotherapy.

BACKGROUND: Allergen immunotherapy has been shown to be an effective treatment for local allergic rhinitis (LAR) to house dust mites. Studies with pollen allergen immunotherapy are limited to observational studies. The aim of this study was to evaluate the clinical efficacy and safety of Phleum pratense subcutaneous immunotherapy (Phl-SCIT) in LAR. METHODS: In a randomized double-blind placebo-controlled study, 56 patients with moderate-severe LAR to grass pollen received Phl-SCIT with a depigmented polymerized pollen vaccine or placebo for the first year, and Phl-SCIT the second one. The blind was maintained throughout the study. Primary outcome was combined symptom medication score (CSMS) during grass pollen season (GPS). Secondary clinical outcomes included organ-specific symptoms, medication-free days, rhinitis severity and asthma control. Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), nasal allergen provocation test (NAPT), skin testing, serum levels of specific IgG4 and specific IgE and safety were also evaluated. RESULTS: Subcutaneous immunotherapy (SCIT) had a short-term and sustained effect with significant improvements of all primary and secondary clinical outcomes and RQLQ score. SCIT significantly increased serum sIgG4 levels and allergen tolerance, from the 6th to 24th months of treatment. At the end of the study, 83% of patients treated with ≥6 months of SCIT tolerated a concentration of P. pratense over 50 times higher than baseline, and 56% gave a negative NAPT. SCIT was well tolerated; six mild local reactions occurred, and there were no serious adverse events related to the study medication. CONCLUSIONS: Subcutaneous immunotherapy with depigmented polymerized allergen extracts is a safe and clinically effective treatment for LAR to P. pratense.

Immediate Reactions to More Than 1 NSAID Must Not Be Considered Cross-Hypersensitivity Unless Tolerance to ASA Is Verified.

BACKGROUND AND OBJECTIVES: Individuals who develop drug hypersensitivity reactions (DHRs) to chemically unrelated nonsteroidal anti-inflammatory drugs (NSAIDs) are considered cross-hypersensitive. The hallmark for this classification is that the patient presents a reaction after intake of or challenge with acetylsalicylic acid (ASA). Whether patients react to 2 or more NSAIDs while tolerating ASA remains to be studied (selective reactions, SRs). Objective: To identify patients with SRs to 2 or more NSAIDs including strong COX-1 inhibitors. METHODS: Patients who attended the Allergy Service of Hospital Infanta Leonor, Madrid, Spain with DHRs to NSAIDs between January 2011 and December 2014 were evaluated. Those with 2 or more immediate reactions occurring in less than 1 hour after intake were included. After confirming tolerance to ASA, the selectivity of the response to 2 or more NSAIDs was demonstrated by in vivo and/or in vitro testing or by controlled administration. RESULTS: From a total of 203 patients with immediate DHRs to NSAIDs, 16 (7.9%) met the inclusion criteria. The patients presented a total of 68 anaphylactic or cutaneous reactions (mean [SD], 4.2 [2.1]). Most reactions were to ibuprofen and other arylpropionic acid derivatives and to metamizole. Two different NSAIDs were involved in 11 patients and 3 in 5 patients. CONCLUSIONS: Patients with NSAID-induced anaphylaxis or urticaria/angioedema should not be considered cross-hypersensitive unless tolerance to ASA is verified.

A non-synonymous polymorphism in galectin-3 lectin domain is associated with allergic reactions to beta-lactam antibiotics.

Genetic predictors of beta-lactam (BL) allergy are mostly related to Immunoglobulin E (IgE) synthesis and atopy. Despite this context, little attention has been devoted to genes of IgE/FcɛRI pathway, such as galectin-3, a ß-galactoside-binding lectin, which binds to IgE. We evaluated the association of LGALS3 polymorphisms with BL allergy in 395 Spanish and 198 Italian cases, compared with 310- and 339-matched controls, respectively. The rs11125 predicted BL allergy with an odds ratio of 4.0 in Spanish population (P<0.0001). This association was replicated with an odds ratio of 5.1 in Italian population (P<0.0001); rs11125 predicted also increased serum level of total IgE in Spanish controls. These data are consistent with the predicted deleterious influence of Gln>His substitution produced by rs11125 on galactose-binding activity of galectin-3. In conclusion, LGALS3 is the strongest genetic predictor of BL allergy reported so far. This association reflects the influence of genes of IgE/FcɛRI pathway in this pathology.

Drug hypersensitivity in children: report from the pediatric task force of the EAACI Drug Allergy Interest Group.

When questioned, about 10% of the parents report suspected hypersensitivity to at least one drug in their children. However, only a few of these reactions can be confirmed as allergic after a diagnostic workup. There is still a lack of knowledge on drug hypersensitivity (DH) epidemiology, clinical spectrum, and appropriate diagnostic methods particularly in children. Meanwhile, the tools used for DH management in adults are applied also for children. Whereas this appears generally acceptable, some aspects of DH and management differ with age. Most reactions in children are still attributed to betalactams. Some manifestations, such as nonsteroidal anti-inflammatory drug-associated angioedema and serum sickness-like reactions, are more frequent among young patients as compared to adults. Risk factors such as viral infections are particularly frequent in children, making the diagnosis challenging. The practicability and validity of skin test and other diagnostic procedures need further assessment in children. This study presents an up-to-date review on epidemiology, clinical spectrum, diagnostic tools, and current management of DH in children. A new general algorithm for the study of these reactions in children is proposed. Data are presented focusing on reported differences between pediatric and adult patients, also identifying unmet needs to be addressed in further research.

Immediate hypersensitivity reactions to ibuprofen and other arylpropionic acid derivatives.

BACKGROUND: Although ibuprofen and other arylpropionic acid derivatives (APs) are the most common medicines involved in hypersensitivity drug reactions (HDRs) to NSAIDs, no patient series studies have been performed regarding immediate selective reactions (SRs) to these drugs. OBJECTIVE: To characterize patients with immediate selective HDRs to ibuprofen and other APs through clinical history and challenge. METHODS: Subjects who developed an HDR to APs less than 1 h after drug intake were included. Tolerance to aspirin was assessed and challenge was performed with ibuprofen in all cases, and additionally with the culprit drug (if different) in those patients that tolerated ibuprofen. Serum tryptase levels and tryptase immunohistochemical staining in skin biopsies were also assessed in some patients with a positive DPT to ibuprofen. RESULTS: From a total of 245 patients with a confirmed history of HDRs to APs, 17% were classified as selective immediate hypersensitivity reactors by both clinical history and challenge. A selective response to naproxen and dexketoprofen with tolerance to ibuprofen was found in 16 of 20 cases. Significant differences in serum tryptase levels were observed between 2 and 24 h in the 11 cases that were studied further. CONCLUSIONS: Within the group of patients with HDRs to NSAIDs, APs can induce immediate SRs. Within this group, selective responses to a single drug or responders to several APs may exist, suggesting potential immunological cross-reactivity.

The Genetics of Drug Hypersensitivity Reactions.

DHRs are induced by various mechanisms and encompass a heterogeneous set of potentially life-threatening clinical entities. In addition to environmental effects, individual factors play a key role in this intricate puzzle. However, despite commendable efforts in recent years to identify individual predisposing factors, our knowledge of the genetic basis of these reactions remains incomplete. In this manuscript, we summarize current research on the genetics of DHRs, focusing on specific immune-mediated reactions (immediate and nonimmediate) and on pharmacologically mediated reactions (cross-intolerance to nonsteroidal anti-inflammatory drugs). We also provide some thoughts on potential technological approaches that would help us to decipher the molecular mechanisms underlying DHRs. We believe this manuscript will be of interest not only for allergists and basic researchers in the field, but also for clinicians from various areas of expertise who manage these reactions in their clinical practice.

Seasonal Local Allergic Rhinitis in Areas With High Concentrations of Grass Pollen.

BACKGROUND: Local allergic rhinitis (LAR) is a phenotype of allergic rhinitis characterized by the presence of a localized immune response in the nasal mucosa of patients with negative skin prick test (SPT) results and undetectable serum specific IgE (sIgE). It unknown whether LAR is limited to areas with low or moderate aeroallergen exposure. OBJECTIVE: To explore the presence of LAR and the clinical and immunological characteristics of this entity in geographic areas with high grass pollen loads. METHODS: A cross-sectional observational study was carried out in 2 hospitals in central Spain (Madrid and Ciudad Real). Sixty-one patients with seasonal rhinitis and negative SPT results and undetectable serum sIgE were evaluated using a clinical questionnaire, determination of serum total IgE, and a nasal allergen provocation test (NAPT) with Phleum species. The response to NAPT was monitored using assessment of nasal symptoms, acoustic rhinometry, and determination of sIgE, tryptase, and eosinophil cationic protein in the nasal cavity. RESULTS: Seasonal LAR was detected in 37 patients (61%) using the techniques described above. Eleven percent of patients with LAR were adolescents or children, and 14% reported onset of rhinitis in childhood. Most patients reported persistent-moderate seasonal nasal symptoms, and 41% reported worsening of the disease during the last 2 years. Conjunctivitis was the most common comorbidity, affecting 95% of cases. CONCLUSIONS: LAR to grass pollen is relevant in patients with seasonal symptoms indicative of allergic rhinitis but with a negative skin test result who live in areas with high allergenic pollen loads. This entity should be included the differential diagnosis of rhinitis.

Is the ISAC 112 Microarray Useful in the Diagnosis of Pollinosis in Spain?

BACKGROUND: Multiple sensitization is frequent among pollen-allergic patients. The goal of this study was to determine the diagnostic accuracy of the ImmunoCAP ISAC 112 (ISAC112) microarray in allergy to pollen from several taxa and its clinical utility in a Spanish population. METHODS: Specific IgE was determined in 390 pollen-allergic patients using the ISAC112 microarray. Diagnostic accuracy (sensitivity, specificity, predictive values, and area under the ROC curve) was calculated for the diagnosis of allergy to pollen from grass (n=49), cypress (n=75), olive tree (n=33), plane tree (n=63), and pellitory of the wall (n=17) and compared with that of the singleplex ImmunoCAP immunoassay. RESULTS: The sensitivity of the ISAC112 microarray ranged from 68.2% for allergy to plane tree pollen to 93.9% for allergy to grass pollen. The specificity was >90%. The AUC for the diagnosis of allergy to plane tree pollen was 0.798, whereas the AUC for the remaining cases was ≥0.876. The accuracy of ISAC112 was higher than that of ImmunoCAP for plane tree pollen and similar for the remaining pollens. The frequency of sensitization to most species-specific allergenic components and profilins varied between the different geographical regions studied. A total of 73% of pollen-allergic patients were sensitized to species-specific components of more than 1 pollen type. CONCLUSIONS: The ISAC112 microarray is an accurate tool for the diagnosis of allergy to pollen from grass, cypress, olive tree, plane tree, and pellitory of the wall. The features of the ISAC112 microarray are similar or superior (in the case of plane tree pollen) to those of ImmunoCAP. This microarray is particularly useful for the etiologic diagnosis of pollinosis in patients sensitized to multiple pollen species whose pollination periods overlap.

Selective immediate responders to amoxicillin and clavulanic acid tolerate penicillin derivative administration after confirming the diagnosis.

BACKGROUND: An increasing number of patients show immediate selective hypersensitivity reactions to clavulanic acid (CLV) and amoxicillin (AX), probably due to their increased prescription. The maintenance of this response should be established. OBJECTIVE: To assess that the immediate hypersensitivity selective response to AX or to CLV is maintained after repeated administration of penicillin G (PG)/penicillin V (PV) and AX. METHODS: Patients with proven immediate hypersensitivity to AX (Group A) or CLV (Group B) were included. Diagnosis was performed using skin tests with major and minor determinants of PG (PPL/MDM), AX and CLV and by drug provocation test (DPT) if required. Selectivity was established by confirming tolerance to PG/PV (Group A) and to PG/PV and AX (Group B). The maintenance of the selective response was verified by repeating DPT, 15 days after the initial investigation, with the same procedure. RESULTS: Of 51 patients, 78% belonged to Group A and 22% to Group B. Most had anaphylaxis. In Group A, 72% were skin test positive; 28% required DPT. In Group B, 63% were skin test positive; 37% required DPT. Only two AX-selective cases developed positive responses after re-provocation with PG/PV. No cases selective for CLV developed a positive response to PG, PV or AX. DISCUSSION: The selective response to AX appears consistent, and a response to penicillin determinants only develops in a minority of cases. For the case of CLV, the selective response appears not to be modified by exposure to penicillin determinants, meaning that patients with CLV allergy can take penicillin derivatives safely.

Influence of age on IgE response in peanut-allergic children and adolescents from the Mediterranean area.

BACKGROUND: Peanut allergens are common triggers of food allergy. Analyses of sensitization patterns, relationships with other allergens, clinical symptoms, and variation with age are needed. We studied sensitization to Ara h 2, Ara h 9, and Pru p 3 in a peanut allergic children/adolescents and the relationship with peach and pollen. METHODS: Peanut allergic patients aged between 1 and 20 years old were classified into two groups: A) allergic to peanut only and B) allergic to peach and peanut. The IgE response was measured to Ara h 2, Ara h 9, and Pru p 3. RESULTS: Of 964 subjects evaluated, 28% were allergic to peanut. From this group, 68% were also sensitized to pollen. Urticaria was the most frequent entity followed by anaphylaxis and OAS. Fifty-eight percent had Ara h 2- and/or Ara h 9-specific IgE. More than half reported symptoms with peanut alone (Group A) and 35% to peanut and peach (Group B). We observed significant differences in sex, age, onset of symptoms, and sensitization to Artemisia between groups. IgE response to Ara h 2 was more frequent in Group A, and Ara h 9 and Pru p 3 in Group B. We observed a decrease in sensitization to Ara h 2 and an increase to Ara h 9 and Pru p 3 with increasing age. CONCLUSION: Peanut allergy is frequent in subjects with allergy to plant foods, with Ara h 2 and Ara h 9 being two important allergens. In younger patients, Ara h 2 predominates over Ara h 9. The reverse was observed in older patients.

Hypersensitivity Reactions to Nonsteroidal Anti-inflammatory Drugs in Children and Adolescents: Selective Reactions.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used throughout the world to treat pain and inflammation; however, they can trigger several types of drug hypersensitivity reactions (DHRs) in all age groups. Although most such reactions occur through activation of the leukotriene pathway without specific immunological recognition (cross-intolerance), a significant number of DHRs to NSAIDs are due to immunological mechanisms (selective reactions [SRs]). SRs are thought to be induced by specific IgE antibodies or by T cells. In this manuscript, we focus on SRs, which are of great concern in children and adolescents and comprise a heterogeneous set of clinical pictures ranging from mild entities such as urticaria/angioedema to potentially life-threatening conditions such as Stevens-Johnson syndrome/toxic epidermal necrolysis. Paracetamol and ibuprofen are the most frequent elicitors of IgE-mediated SRs, although pyrazolones have also been implicated. T cell-mediated reactions are infrequent in children but have been associated with ibuprofen, naproxen, and dipyrone. In this review, we analyze the available literature on SRs in children and adolescents, with emphasis on epidemiological data, mechanisms, and drugs involved, as well as on diagnostic procedures.

Hypersensitivity to Nonsteroidal Anti-inflammatory Drugs in Children and Adolescents: Cross-Intolerance Reactions.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used worldwide and are responsible for several types of drug hypersensitivity reactions (DHRs) in all age groups. The 2 major groups of DHRs to NSAIDs are those induced by immunological mechanisms (selective reactions) and those where inflammatory mediators are released through activation of the prostaglandin-leukotriene pathway without specific immunological recognition (cross-intolerance). In the present review, we focus on cross-intolerance reactions, which are the most frequent DHRs and are becoming a topic of major interest in children and adolescents. Paracetamol and ibuprofen are the drugs that most frequently cause DHRs in children; other NSAIDs are responsible for reactions in adolescents. In vivo and in vitro tests are of limited diagnostic value, with some exceptions for the less common selective reactions. In cross-intolerance, the clinical history and controlled administration are in many instances the only way to establish a diagnosis and look for alternatives. The clinical history is diagnostic when consistent symptoms occur repeatedly after exposure to NSAIDs with different chemical structures. Cutaneous and respiratory symptoms often co-occur in young children. The natural history of these reactions in children is unknown, and some patients can develop tolerance over time. Atopy remains a major risk factor for cross-intolerant reactions. The increasing interest in hypersensitivity to NSAIDs with improvements in patient phenotyping and the information provided by pharmacogenetics will improve our understanding and management of these reactions in the near future.