Characterization of anaphylaxis reveals different metabolic changes depending on severity and triggers.

BACKGROUND: Despite the increasing incidence of anaphylaxis, its underlying molecular mechanisms and biomarkers for appropriate diagnosis remain undetermined. The rapid onset and potentially fatal outcome in the absence of managed treatment prevent its study. Up today, there are still no known biomarkers that allow an unequivocal diagnosis. Therefore, the aim of this study was to explore metabolic changes in patients suffering anaphylactic reactions depending on the trigger (food and/or drug) and severity (moderate and severe) in a real-life set-up. METHODS: Eighteen episodes of anaphylaxis, one per patient, were analysed. Sera were collected during the acute phase (T1), the recovery phase (T2) and around 2-3 months after the anaphylactic reaction (T0: basal state). Reactions were classified following an exhaustive allergological evaluation for severity and trigger. Sera samples were analysed using untargeted metabolomics combining liquid chromatography coupled to mass spectrometry (LC-MS) and proton nuclear magnetic resonance spectroscopy (1 H-NMR). RESULTS: 'Food T1 vs T2' and 'moderate T1 vs T2' anaphylaxis comparisons showed clear metabolic patterns during the onset of an anaphylactic reaction, which differed from those induced by drugs, food + drug or severe anaphylaxis. Moreover, the model of food anaphylaxis was able to distinguish the well-characterized IgE (antibiotics) from non-IgE-mediated anaphylaxis (nonsteroidal anti-inflammatory drugs), suggesting a differential metabolic pathway associated with the mechanism of action. Metabolic differences between 'moderate vs severe' at the acute phase T1 and at basal state T0 were studied. Among the altered metabolites, glucose, lipids, cortisol, betaine and oleamide were observed altered. CONCLUSIONS: The results of this exploratory study provide the first evidence that different anaphylactic triggers or severity induce differential metabolic changes along time or at specific time-point, respectively. Besides, the basal status T0 might identify high-risk patients, thus opening new ways to understand, diagnose and treat anaphylaxis.

Update on Quinolone Allergy.

PURPOSE OF REVIEW: Quinolones are a group of synthetic antibiotics widely use as first-line treatment for many infections. There has been an increase in the incidence of hypersensitivity reactions to quinolones in recent years, likely due to increased prescription. The purpose of this review is to summarize the clinical pictures, the methods used for diagnosing and the management of allergic reactions to quinolones. RECENT FINDINGS: Allergic reactions to quinolones can be immediate or delayed, being anaphylaxis and maculopapular exanthema respectively the most frequent clinical entities. A precise diagnosis is particularly difficult since clinical history is often unreliable, skin tests can induce false-positive results, and commercial in vitro test are not well validated. Therefore, drug provocation testing is considered the gold standard to establish diagnosis, which is not a risk-free procedure. Cross-reactivity between quinolones is difficult to predict due to the small number of patients included in the few published studies. Moreover, hypersensitivity to quinolones has also been associated with beta-lactam and neuromuscular blocking agent allergies, although further studies are needed to understand the underlying mechanisms. Avoidance of the culprit quinolone is indicated in patients with a diagnosis of hypersensitivity to these drugs. When quinolone treatment is the only therapeutic option available, desensitization is necessary. This review summarizes the complex diagnostic approach and management of allergic reactions to quinolones.

Respiratory allergy caused by house dust mites: What do we really know?

The house dust mite (HDM) is a major perennial allergen source and a significant cause of allergic rhinitis and allergic asthma. However, awareness of the condition remains generally low. This review assesses the links between exposure to HDM, development of the allergic response, and pathologic consequences in patients with respiratory allergic diseases. We investigate the epidemiology of HDM allergy to explore the interaction between mites and human subjects at the population, individual, and molecular levels. Core and recent publications were identified by using "house dust mite" as a key search term to evaluate the current knowledge of HDM epidemiology and pathophysiology. Prevalence data for HDM allergen sensitization vary from 65 to 130 million persons in the general population worldwide to as many as 50% among asthmatic patients. Heterogeneity of populations, terminology, and end points in the literature confound estimates, indicating the need for greater standardization in epidemiologic research. Exposure to allergens depends on multiple ecological strata, including climate and mite microhabitats within the domestic environment, with the latter providing opportunity for intervention measures to reduce allergen load. Inhaled mite aeroallergens are unusually virulent: they are able to activate both the adaptive and innate immune responses, potentially offering new avenues for intervention. The role of HDM allergens is crucial in the development of allergic rhinitis and asthma, but the translation of silent sensitization into symptomatic disease is still incompletely understood. Improved understanding of HDMs, their allergens, and their microhabitats will enable development of more effective outcomes for patients with HDM allergy.

Treatment of HAE Attacks in the Icatibant Outcome Survey: An Analysis of Icatibant Self-Administration versus Administration by Health Care Professionals.

BACKGROUND: Icatibant, a selective bradykinin B2 receptor antagonist for the treatment of acute hereditary angio-oedema (HAE) attacks in adults, can be administered by health care professionals (HCPs) or self-administered. This analysis compared characteristics and outcomes of acute HAE attacks treated with self-administered and HCP-administered icatibant in a real-world setting. METHODS: The Icatibant Outcome Survey (Shire, Zug, Switzerland; NCT01034969) is an international observational study monitoring the safety and effectiveness of icatibant treatment. Descriptive retrospective analyses were performed (February 2008 to December 2012). RESULTS: Icatibant was used in 652 attacks in 170 patients with HAE type I/II. Most icatibant injections were self-administered (431/652, 68.5%). The proportion of self-treated attacks increased over time (40.3% in 2009 vs. 89.7% in 2012). The median time to administration was significantly shorter in self- versus HCP-treated attacks (1.5 vs. 2.4 h; p = 0.016). Earlier treatment (<2 h after onset) was significantly associated with a shorter median time to resolution (2.5 vs. 5.0 h; p = 0.032) and attack duration (3.0 vs. 14.0 h; p < 0.0001), regardless of administration method. Patients self-administered icatibant for attacks of all severities; overall, 34.7% of severe and 30.2% of very severe attacks were HCP treated. Logistic regression analysis did not find use of long-term prophylaxis, attack location or gender to be predictive for self-administration. CONCLUSIONS: The proportion of HAE attacks treated with self-administered icatibant increased over time. Patients successfully self-administered icatibant for a wide variety of HAE attacks, demonstrating that icatibant is generally well tolerated and effective for self-administration. Self-administration of icatibant provides a complementary option to HCP administration, enabling optimization of patient care.

An ultra-sensitive homologous chemiluminescence immunoassay to tackle penicillin allergy.

Penicillin is one of the most widely used antibiotics to treat bacterial infections in clinical practice. The antibiotic undergoes degradation under physiological conditions to produce reactive compounds that in vivo bind self-proteins. These conjugates might elicit an immune response and trigger allergic reactions challenging to diagnose due to the complex immunogenicity. Penicillin allergy delabeling initiatives are now part of antibiotic stewardship programs and include the use of invasive and risky in vivo tests. Instead, the in vitro quantification of specific IgE is highly useful to confirm immediate allergy to penicillins. However, discrepant results associated with the low sensitivity and accuracy of penicillin allergy in vitro tests have limited their routine diagnostic use for delabeling purposes. We aimed to develop a homologous chemiluminescence-based immunochemical method for the reliable determination of specific IgE to penicillin G, using unprecedented synthetic human-like standards. The synthetic standard targets the major antigenic determinant of penicillin G and the paratope of Omalizumab, acting as human-like specific IgE. It is a potent calibrator, highly stable, easy, and inexpensive to produce, overcoming the limitations of the pooled human serum preparations. The developed method achieved a good agreement and strong positive relationship, reaching a detection limit below 0.1 IU mL-1 and excellent reproducibility (RSD <9%). The clinical sensitivity of the assay significantly increased (66%), doubling the accuracy of the reference method with an overall specificity of 100%. The new diagnostic strategy compares favorably with results obtained by the standard procedure, paving the way towards the standardization of penicillin allergy testing, and enhancing the detection sensitivity of specific IgE in serum to tackle reliably ß-lactam allergy delabeling.

Clinical Characterization and Diagnostic Approaches for Patients Reporting Hypersensitivity Reactions to Quinolones.

BACKGROUND: Quinolones are the second most frequent cause of hypersensitivity reactions (HSRs) to antibiotics. A marked increase in the number of patients with HSRs to quinolones has been detected. OBJECTIVE: To describe the clinical characteristics of patients with HSRs to quinolones and present methods for their diagnosis. METHODS: Patients attending the allergy unit due to reactions suggestive of HSRs to quinolones were prospectively evaluated between 2005 and 2018. Diagnosis was achieved using clinical history, skin tests (STs), basophil activation tests (BATs), and drug provocation tests (DPTs) if ST and BAT results were negative. RESULTS: We included 128 subjects confirmed as having HSRs to quinolones and 42 found to be tolerant. Anaphylaxis was the most frequent entity in immediate HSRs and was most commonly induced by moxifloxacin. Patients were evaluated a median of 150 days (interquartile range, 60-365 days) after the reaction. Of patients who underwent ST and BAT, 40.7% and 70%, respectively, were positive. DPT with a quinolone was performed in 48 cases, giving results depending on the culprit drug: when moxifloxacin was involved, 62.5% of patients gave a positive DPT result to ciprofloxacin, whereas none reacted to levofloxacin. The risk of HSR was 96 times higher in subjects who reported moxifloxacin-induced anaphylaxis and 18 times higher in those reporting immediate reactions compared with clinical entities induced by quinolones other than moxifloxacin and nonimmediate reactions. CONCLUSIONS: The diagnosis of HSR to quinolones is complex. The use of clinical history is essential as a first step. BAT shows higher sensitivity than STs. DPTs can be useful for finding safe alternative quinolones.

Correlation between impulse oscillometry parameters and asthma control in an adult population.

Purpose: Impulse oscillometry (IOS) has been proposed as an alternative test to evaluate the obstruction of small airways and to detect changes in airways earlier than spirometry. In this study, we sought to determine the utility and association of IOS parameters with spirometry and asthma control in an adult population. Patients and methods: Adults 14-82 years of age with asthma were classified into uncontrolled asthma (n=48), partially controlled asthma (n=45), and controlled asthma (n=49) groups, and characterized with fractional exhaled nitric oxide (FENO), IOS, and spirometry in a transversal analysis planned as a one-visit study. The basic parameters evaluated in IOS are resistance at 5 Hz (R5), an index affected by the large and small airway; resistance at 20 Hz (R20), an index of the resistance of large airways; difference between R5 and R20 (R5-R20), indicative of the function of the small peripheral airways; reactance at 5 Hz (X5), indicative of the capacitive reactance in the small peripheral airways; resonance frequency (Fres), the intermediate frequency at which the reactance is null, and reactance area (XA), which represents the total reactance (area under the curve) at all frequencies between 5 Hz to Fres. Results: There were statistical differences between groups in standard spirometry and IOS parameters reflecting small peripheral airways (R5, R10, R5-R20, Fres, XA and X5) (P<0.001). Accuracy of IOS and/or spirometry to discriminate between controlled asthma vs partially controlled asthma and uncontrolled asthma was low (AUC=0.61). Using linear regression models, we found a good association between spirometry and IOS. In order to evaluate IOS as an alternative or supplementary method for spirometry, we designed a predictive model for spirometry from IOS applying a penalized regression model (Lasso). Then, we compared the original spirometry values with the values obtained from the predictive model using Bland-Altman plots, and the models showed an acceptable bias in the case of FEV1/FVC, FEV1%, and FVC%. Conclusion: IOS did not show a discriminative capacity to correctly classify patients according to the degree of asthma control. However, values of IOS showed good association with values of spirometry. IOS could be considered as an alternative and accurate complement to spirometry in adults. In a predictive model, spirometry values estimated from IOS tended to overestimate in low values of "real" spirometry and underestimate in high values.

[R-ALERGO. Allergy-healthy routes in Valencia]. / R-ALERGO. Rutas alergosaludables en Valencia.

R-ALERGO is a project developed by researchers from the Universitat Politècnica de València and the Hospital Universitario La Fe (Valencia, Spain). The main objective of the project is to create a mobile application identifying, within the city of Valencia, the most favorable routes for allergic individuals. The application is developed using nine environmental variables with a potential effect on the development of clinical manifestations in allergic individuals. The application combines the use of spatial analysis based on network technology and implemented with a geographic information system software. The first 01 version is under evaluation for a Healthy app hallmark. The next step in this project is to design a clinical validation process to test its usefulness in allergic individuals.

Randomized dose-response study of subcutaneous immunotherapy with a Dermatophagoides pteronyssinus extract in patients with respiratory allergy.

AIM: To evaluate the efficacy of Dermatophagoides pteronyssinus (DPT) subcutaneous immunotherapy in allergic rhinoconjunctivitis patients. PATIENTS & METHODS: This 17-week double-blind study randomized 136 patients (95 evaluable) to five dose groups of DPT depot extract (0.0625-0.75 skin prick test [SPT] units) or placebo, administered in a six updosing schedule. RESULTS: A dose-response was observed for clinical efficacy (allergen concentration needed to induce a positive nasal provocation test response from baseline to final visit) and safety (adverse reactions). Local and systemic reactions occurred with 14.8 and 6.4% of administered doses, respectively; a single anaphylactic reaction occurred in each of Groups 3, 4 and 5 (0.3% of doses). CONCLUSION: The risk-benefit profile appeared most favorable with a DPT dose of 0.125 SPT units.

House Dust Mite Respiratory Allergy: An Overview of Current Therapeutic Strategies.

Although house dust mite (HDM) allergy is a major cause of respiratory allergic disease, specific diagnosis and effective treatment both present unresolved challenges. Guidelines for the treatment of allergic rhinitis and asthma are well supported in the literature, but specific evidence on the efficacy of pharmacotherapy treatment for known HDM-allergic patients is weaker. The standard diagnostic techniques--skin prick test and specific IgE testing--can be confounded by cross-reactivity. However, component-resolved diagnosis using purified and recombinant allergens can improve the accuracy of specific IgE testing, but availability is limited. Treatment options for HDM allergy are limited and include HDM avoidance, which is widely recommended as a strategy, although evidence for its efficacy is variable. Clinical efficacy of pharmacotherapy is well documented; however, symptom relief does not extend beyond the end of treatment. Finally, allergen immunotherapy has a poor but improving evidence base (notably on sublingual tablets) and its benefits last after treatment ends. This review identifies needs for deeper physician knowledge on the extent and impact of HDM allergy in respiratory disease, as well as further development and improved access to molecular allergy diagnosis. Furthermore, there is a need for the development of better-designed clinical trials to explore the utility of allergen-specific approaches, and uptake of data into guidance for physicians on more effective diagnosis and therapy of HDM respiratory allergy in practice.

Phase I study of subcutaneous allergen immunotherapy with Dermatophagoides pteronyssinus in patients with allergic rhinoconjunctivitis with or without asthma.

AIM: A double-blind placebo-controlled study was conducted according to EMA guidelines, to evaluate safety, tolerability and short-term treatment effects of three updosing regimens of Dermatophagoides pteronyssinus subcutaneous allergen immunotherapy. PATIENTS & METHODS: Forty-eight patients were randomized to groups: A (six weekly doses), B (eight weekly doses) or C (eight doses, two clustered doses over 3 weeks).  RESULTS: The most frequent adverse events were local reactions. No serious adverse events were found. Severe systemic reactions were reported more frequently in Group C. Decreased cutaneous responses and increased specific IgGs were shown in all active groups, even within the short-term. CONCLUSION:  Dermatophagoides pteronyssinus subcutaneous allergen immunotherapy in depot presentation exhibited good safety and tolerability. Group A seemed to show the best profile for further clinical development.

[Algorithm for diagnosis and treatment of hereditary angioedema as a tool for management]. / Algoritmo de diagnóstico y tratamiento del angioedema hereditario como herramienta para su manejo.

INTRODUCTION: Hereditary angioedema is a disease with low prevalence and high heterogeneity with regards to the severity of the clinical picture, which makes the diagnosis difficult and requires the need for early start of specific treatment in order to prevent complications. OBJECTIVE: To propose a decision algorithm for hereditary angioedema (HAE), based on the evidence available on the diagnosis, clinical assessment, and treatment. The aim is to present the available therapeutic options as well as a decision algorithm to select the most efficient therapy at each time. MATERIAL AND METHODS: Literature search by means of PubMed and other relevant sources. RESULTS: four decision algorithms have been developed for HAE; diagnosis of bradikinin-mediated angioedema, treatment of acute attacks and short and long-term prophylaxis for HAE due to C1 inhibitor deficiency. CONCLUSIONS: The application of a decision algorithm based on the clinical variables helps to select the most efficient therapeutic option at each time and may be a useful tool for the therapeutic approach.

Introducción: El angioedema hereditario es una enfermedad rara de baja prevalencia y gran heterogeneidad en la gravedad del cuadro clínico, lo que dificulta su diagnóstico, y establece la necesidad de iniciar un tratamiento precoz y específico con el fin de evitar complicaciones. Objetivo: Proponer un algoritmo de decisión en el angioedema hereditario (AEH), basado en la evidencia disponible, sobre el diagnóstico, valoración clínica y tratamiento. Se trata de presentar opciones terapéuticas disponibles, así como un algoritmo de decisión para seleccionar el tratamiento más eficiente en cada momento. Material y Métodos: Revisión bibliográfica mediante una búsqueda a través de PubMed y otras fuentes de interés. Resultados: Se han desarrollado cuatro algoritmos de decisión para el AEH; diagnóstico de angioedema mediado por bradicinina, tratamiento del ataque agudo y profilaxis a corto y largo plazo del AEH por déficit del inhibidor C1. Conclusiones: La aplicación de un algoritmo de decisión, en función de unas variables clínicas, ayuda a la selección de la opción terapéutica más eficiente en cada momento y puede ser un instrumento de utilidad en el abordaje terapéutico.