Prevalence and Impact of Asthma and Allergy on Daily Life, Health Outcomes and Use of Healthcare Services in Children: A Population-Based Study.

INTRODUCTION: Studies on the prevalence of asthma and allergies often lack representation of the pediatric population, and their impact has not been examined using children without these diseases as a reference group. This study aimed to determine the prevalence of asthma and allergies in children under 14 years old in Spain and their impact on health-related quality of life, activities, healthcare utilization, and environmental and household exposure risk factors. METHODS: Data came from a Spanish population-based representative survey of children aged <14 years (N=6297). A sample of controls (1:4) from the same survey was matched using propensity score matching. Logistic regression models and population-attributable fractions were calculated to determine the impact of asthma and allergy. RESULTS: The population prevalence of asthma was 5.7% (95% CI: 5.0%, 6.4%), and of allergy was 11.4% (95% CI: 10.5%, 12.4. In children with lower percentiles of health-related quality of life (≤20th), 32.3% (95% CI, 13.6%, 47.0%) was attributed to asthma and 27.7% (95% CI: 13.0%, 40.0%) to allergy. Forty-four percent of restrictions in usual activity were attributed to asthma (OR: 2.0, p-value: <0.001), and 47.9% to allergy (OR: 2.1, p-value: <0.001). 62.3% of all hospital admissions were attributed to asthma (OR: 2.8, p-value: <0.001), and 36.8% (OR: 2.5, p-value: <0.001) of all specialist consults to allergy. CONCLUSIONS: The high prevalence of atopic disease and its impact on daily life and healthcare utilization call for an integrated healthcare system focused on children and caregivers' needs with continuity of care across education and healthcare settings.

Validation of a commercial allergen microarray platform for specific immunoglobulin E detection of respiratory and plant food allergens.

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.

Identification and Characterization of IgE-Reactive Proteins and a New Allergen (Cic a 1.01) from Chickpea (Cicer arietinum).

SCOPE: Chickpea (Cicer arietinum) allergy has frequently been reported particularly in Spain and India. Nevertheless, chickpea allergens are poorly characterized. The authors aim to identify and characterize potential allergens from chickpea. METHODS AND RESULTS: Candidate proteins are selected by an in silico approach or immunoglobuline E (IgE)-testing. Potential allergens are prepared as recombinant or natural proteins and characterized for structural integrity by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism (CD)-spectroscopy, and mass spectrometry (MS) analysis. IgE-sensitization pattern of Spanish chickpea allergic and German peanut and birch pollen sensitized patients are investigated using chickpea extracts and purified proteins. Chickpea allergic patients show individual and heterogeneous IgE-sensitization profiles with extracts from raw and boiled chickpeas. Chickpea proteins pathogenesis related protein family 10 (PR-10), a late embryogenesis abundant protein (LEA/DC-8), and a vicilin-containing fraction, but not 2S albumin, shows IgE reactivity with sera from chickpea, birch pollen, and peanut sensitized patients. Remarkably, allergenic vicilin, DC-8, and PR-10 are detected in the extract of boiled chickpeas. CONCLUSION: Several IgE-reactive chickpea allergens are identified. For the first time a yet not classified DC-8 protein is characterized as minor allergen (Cic a 1). Finally, the data suggest a potential risk for peanut allergic patients by IgE cross-reactivity with homologous chickpea proteins.

Allergen Recognition Patterns in Walnut Allergy Are Age Dependent and Correlate with the Severity of Allergic Reactions.

BACKGROUND: Walnut is an important elicitor of food allergy in children and adults with a high rate of severe reactions. Multicenter studies using a common clinical protocol and a comprehensive allergen are lacking. OBJECTIVE: To investigate potential correlations between molecular sensitization patterns and clinical characteristics of walnut-allergic patients. METHODS: A total of 91 walnut-allergic subjects and 24 tolerant controls from Switzerland, Germany, and Spain were included. Walnut allergy was established by food challenge in all but anaphylactic subjects. Specific IgE (sIgE) to walnut extract, rJug r 1 (2S albumin), rJug r 3 (nonspecific lipid transfer protein 1), nJug r 4 (11S globulin), rJug r 5 (PR-10 protein), 2 vicilin fractions, profiling, and cross-reactive carbohydrate determinant was determined by ImmunoCAP. A threshold of 0.10 kUA/L was used for positivity. RESULTS: Sensitivity of sIgE to walnut extract was 87% and increased to 96% for the sum of all walnut components. sIgE to walnut extract and all walnut components, except rJug r 5, was significantly higher in patients younger than 14 years at inclusion. Stratification by age at onset of walnut allergy led to similar results. All patients younger than 14 years had severe reactions, whereas 38% of patients 14 years or older were mild reactors. Severe reactors (n = 70) had higher sIgE levels than did mild reactors (n = 21) to walnut extract (P < .0001), rJug r 1 (P < .0001), nJug r 4 (P = .0003), and both vicilin fractions (P < .0001), but not to Jug r 3 and Jug r 5. CONCLUSIONS: Sensitization to walnut storage proteins is acquired in childhood and correlates with severe reactions. sIgE levels to storage proteins Jug r 1 and Jug r 4 and vicilin fractions, but not to nonspecific lipid transfer protein and PR-10 proteins, correlate with systemic reactions to walnut.

[Executive Summary of ARIA 2019: Integrated care pathways for allergic rhinitis in Argentina, Spain and Mexico]. / Resumen ejecutivo de ARIA 2019: Vías integradas de atención para la rinitis alérgica en Argentina, España y México.

The health and economic impact of allergic diseases are increasing rapidly, and changes in management strategies are required. Its influence reduces the capacity of work and school performance by at least a third. The ICPs of the airways (integrated care pathways for respiratory diseases) are structured multidisciplinary healthcare plans, promoting the recommendations of the guidelines in local protocols and their application to clinical practice. This document presents an executive summary for Argentina, Mexico, and Spain. Next-generation ARIA guidelines are being developed for the pharmacological treatment of allergic rhinitis (AR), using the GRADE-based guidelines for AR, tested with real-life evidence provided by mobile technology with visual analogue scales. It is concluded that in the AR treatment, H1-antihistamines are less effective than intranasal corticosteroids (INCS), in severe AR the INCS represent the first line of treatment, and intranasal combination INCS + anti-H1 is more effective than monotherapy. However, according to the MASK real-life observational study, patients have poor adherence to treatment and often self-medicate, according to their needs.

El impacto sanitario y económico de las enfermedades alérgicas está aumentando rápidamente y se necesitan cambios en las estrategias para su manejo. Su influencia reduce al menos en un tercio la capacidad de desempeño laboral y escolar. Los ICP (Vías Integradas de Atención) de las enfermedades de las vías respiratorias son planes de atención estructurados y multidisciplinarios, que promueven las recomendaciones de las guías en protocolos locales y su aplicación a la práctica clínica. En este documento se presenta un resumen ejecutivo para Argentina, México y España. Se desarrollan las guías ARIA de próxima generación para el tratamiento farmacológico de la rinitis alérgica (RA) utilizando las pautas basadas en GRADE para RA, probadas con evidencia de la vida real proporcionada por tecnología móvil basada en escalas visuales analógicas. Se concluye que en el tratamiento de la RA, los antihistamínicos anti-H1 son menos efectivos que los corticoides intranasales (CINS), que en la rinitis gravelos CINS representan la primera línea de tratamiento, y que la combinación intranasal de CINS + anti-H1 es más eficaz que la monoterapia. Sin embargo, según el estudio MASK observacional en vida real, los pacientes tienen pobre adherencia al tratamiento y frecuentemente se automedican de acuerdo con sus necesidades.

Analysis of comorbidities and therapeutic approach for allergic rhinitis in a pediatric population in Spain.

BACKGROUND: Allergic rhinitis (AR) is the most common chronic disease in children. The main objective of this study was to analyze the comorbidities and therapeutic approaches for AR in a Spanish pediatric population. METHODS: Children aged 6 to 12 years with AR were included in an observational, cross-sectional, multicenter study. RESULTS: 1,275 children were recruited from 271 centers. AR was intermittent in 59.5% of cases, persistent in 40.5%, seasonal in 60.7%, and perennial in 39.3% of patients. The most frequent comorbidities were conjunctivitis (53.6%), asthma (49.5%), atopic dermatitis (40%), rhinosinusitis(26.1%), otitis media (23.8%), and adenoid hypertrophy (17.3%). Overall, patients with persistent, moderate or severe, AR were more likely to present comobidities, except for food allergy and urticaria. The most common drugs used for treatment of AR were oral antihistamines(76%), nasal corticosteroids(49%) and a combination of both (45%). Antihistamines and nasal corticosteroids were used on demand (<18 days) in 38 and 41% of patients, respectively; for 18-30 days in 22 and 27%; for 1-3 months in 31 and 29%; and for more than 3 months in 8 and 3%, respectively. Eye drops were used in 32% and specific immunotherapy in 21% of patients. CONCLUSION: Comorbidities are frequent in children with AR, supporting the notion of allergy as a systemic disease. Severity and duration of AR were significantly associated with presence of most of comorbidities. The most common drugs used for AR treatment were oral antihistamines, followed by nasal corticosteroids and a combination of both used on demand.

Platelet-activating factor nasal challenge induces nasal congestion and reduces nasal volume in both healthy volunteers and allergic rhinitis patients.

BACKGROUND: Platelet-activating factor (PAF) is a lipid mediator produced by most inflammatory cells. Clinical and experimental findings suggest that PAF participates in allergic rhinitis (AR) pathogenesis. The aim was to assess the PAF ability to induce clinical response in nasal airway after local stimulation. METHOD: Ten nonatopic healthy volunteers (HVs) and 10 AR patients out of pollen season were enrolled. PAF increasing concentrations (100, 200, and 400 nM) were instilled into both nasal cavities (0, 30, and 60 minutes, respectively). Nasal symptoms (congestion, rhinorrhea, sneezing, itching, and total 4 symptom score and nasal volume between the 2nd and 5th cm (Vol(2-5)) using acoustic rhinometry (AcR), were assessed at -30, 0, 30, 60, 90, 120, and 240 minutes. RESULT: PAF increased individual and total nasal symptom score in both HVs and seasonal AR (SAR) patients from 30 to 120 minutes (maximum score at 120', p < 0.05). Nasal obstruction was the most relevant and lasting nasal symptom. PAF also induced a significant reduction of Vol(2-5) at 90' (27%), 120' (38.7%), and 240' (36.4%). No differences in the response to PAF nasal challenge were observed between HVs and SAR subjects in either clinical symptoms or AcR. CONCLUSION: This is the first description of PAF effects on human nasal mucosa using a cumulative dose schedule and evaluated by both nasal symptoms and AcR. Nasal provocation with PAF showed long-lasting effects on nasal symptoms and nasal obstruction in HVs and in patients with SAR. Nasal challenge may be a useful tool to investigate the role of PAF in AR and the potential role of anti-PAF drugs.

Graph based study of allergen cross-reactivity of plant lipid transfer proteins (LTPs) using microarray in a multicenter study.

The study of cross-reactivity in allergy is key to both understanding. the allergic response of many patients and providing them with a rational treatment In the present study, protein microarrays and a co-sensitization graph approach were used in conjunction with an allergen microarray immunoassay. This enabled us to include a wide number of proteins and a large number of patients, and to study sensitization profiles among members of the LTP family. Fourteen LTPs from the most frequent plant food-induced allergies in the geographical area studied were printed into a microarray specifically designed for this research. 212 patients with fruit allergy and 117 food-tolerant pollen allergic subjects were recruited from seven regions of Spain with different pollen profiles, and their sera were tested with allergen microarray. This approach has proven itself to be a good tool to study cross-reactivity between members of LTP family, and could become a useful strategy to analyze other families of allergens.

The involvement of thaumatin-like proteins in plant food cross-reactivity: a multicenter study using a specific protein microarray.

Cross-reactivity of plant foods is an important phenomenon in allergy, with geographical variations with respect to the number and prevalence of the allergens involved in this process, whose complexity requires detailed studies. We have addressed the role of thaumatin-like proteins (TLPs) in cross-reactivity between fruit and pollen allergies. A representative panel of 16 purified TLPs was printed onto an allergen microarray. The proteins selected belonged to the sources most frequently associated with peach allergy in representative regions of Spain. Sera from two groups of well characterized patients, one with allergy to Rosaceae fruit (FAG) and another against pollens but tolerant to food-plant allergens (PAG), were obtained from seven geographical areas with different environmental pollen profiles. Cross-reactivity between members of this family was demonstrated by inhibition assays. Only 6 out of 16 purified TLPs showed noticeable allergenic activity in the studied populations. Pru p 2.0201, the peach TLP (41%), chestnut TLP (24%) and plane pollen TLP (22%) proved to be allergens of probable relevance to fruit allergy, being mainly associated with pollen sensitization, and strongly linked to specific geographical areas such as Barcelona, Bilbao, the Canary Islands and Madrid. The patients exhibited >50% positive response to Pru p 2.0201 and to chestnut TLP in these specific areas. Therefore, their recognition patterns were associated with the geographical area, suggesting a role for pollen in the sensitization of these allergens. Finally, the co-sensitizations of patients considering pairs of TLP allergens were analyzed by using the co-sensitization graph associated with an allergen microarray immunoassay. Our data indicate that TLPs are significant allergens in plant food allergy and should be considered when diagnosing and treating pollen-food allergy.

Validation of ARIA (Allergic Rhinitis and its Impact on Asthma) classification in a pediatric population: the PEDRIAL study.

Allergic rhinitis (AR) is the commonest chronic disease in children. Allergic Rhinitis and its Impact on Asthma (ARIA) classification based on symptom duration (intermittent vs. persistent) and severity (mild vs. moderate/severe) has not been yet validated in children. Thus our objective was to validate ARIA classification in children, after determining the severity and duration of AR in a pediatric population, using ARIA definitions. Children aged 6-12 with a diagnosis of AR were included in an observational, cross-sectional, multicenter study. Patients were classified according to ARIA guidelines. AR symptoms were assessed using the Total Four Symptoms Score (T4SS). Severity was also evaluated by the patient using a visual analogue scale (VAS). Comparisons were made by means of a statistical analysis. One thousand two hundred and seventy-five children from 271 centers were included. Among them, 59.5% had intermittent and 40.5% persistent AR, while 60.7% seasonal and 39.3% perennial according to dated classification, with significant differences existing between one classification and another; 89.7% had moderate/severe rhinitis. Significantly higher T4SS and VAS scores were obtained in moderate/severe compared to mild AR. In our experience, the current ARIA classification can be considered a valid tool also in children from 6- to 12-yr old.

Anaphylaxis to wheat flour-derived foodstuffs and the lipid transfer protein syndrome: a potential role of wheat lipid transfer protein Tri a 14.

BACKGROUND: Food allergy to wheat-derived foodstuffs is on the rise. Tri a 14, a wheat flour lipid transfer protein (LTP) allergen, has been described as a major allergen associated with baker's asthma and wheat food allergy. Cross-reactivity among LTP allergens leads to the so-called 'LTP syndrome'. METHODS: Eight adult patients showing anaphylaxis after ingestion of wheat-derived foodstuffs were selected. A homemade wheat extract, purified natural (n) and recombinant (r) Tri a 14, and peach fruit and Artemisia pollen LTP allergens Pru p 3 and Art v 3 were subjected to skin prick test, specific IgE determination (ELISA) and IgE immunodetection assays. RESULTS: All tests were positive in the 8 selected patients with the homemade extract. Positive skin prick test responses to nTri a 14, Pru p 3 and Art v 3 were found in 5/8, 6/8 and 4/4 patients, respectively. Specific IgE determined by ELISA assays was detected in 6 to nTri a 14 and rTri a 14, in 4 to Pru p 3 and in 3 to Art v 3 out of 8 individual sera tested, whereas all these sera showed IgE binding to nTri a 14 and Pru p 3 in immunodetection after SDS-PAGE separation. CONCLUSIONS: Tri a 14 seems to be a relevant allergen in patients with anaphylaxis after ingestion of wheat flour foodstuffs, according to in vitro and in vivo results. Clinical history of the analyzed patients, together with sensitization to peach Pru p 3 and Artemisia pollen Art v 3, suggests that 6 of them suffer from LTP syndrome.

In vitro cross-reactivity between tomato and other plant allergens.

BACKGROUND: Cross-reactivity among fruits and different pollen and fruit species has been extensively reported. OBJECTIVES: To investigate the in vitro cross-reactivity between tomato and pollen, fruit, and latex extracts and to identify the proteins involved. METHODS: A serum pool was prepared from 18 individuals residing on the Spanish Mediterranean coast (9 men and 9 women; mean [SD] age, 27.4 [10.1] years) who had positive skin prick test reactions to tomato peel. Extracts from 10 pollens, 12 fruits, and latex were tested. Levels of specific IgE to each extract were measured. The allergenic profile was evaluated by means of immunoblot. The percentage of inhibition between extracts and tomato peel extract was analyzed by means of CAP inhibition, and the allergens implicated were elucidated by immunoblot inhibition. RESULTS: For pollens, the highest specific IgE values were obtained for grasses. Most pollen extracts showed a capacity of inhibition similar to that of tomato peel extract; high percentages were obtained with Artemisia vulgaris and Poa pratensis. The most strongly inhibited allergens in tomato corresponded to bands of 32 and 45 kDa. For fruits, the highest value of specific IgE was detected for peach. High percentages of inhibition were obtained with peach and hazelnut. No inhibition was detected with latex. Peach, chestnut, and melon inhibited high molecular weight bands (32 and 45 kDa) and a band of approximately 10 kDa. CONCLUSIONS: Cross-reactivity between tomato and pollen and fruit extracts has been demonstrated. Allergens with a high molecular weight range seem to be responsible in pollen extracts. A 10-kDa band seems to be responsible in Platanus acerifolia, Salsola kali, peach, chestnut, and melon.

Design of tomato fruits with reduced allergenicity by dsRNAi-mediated inhibition of ns-LTP (Lyc e 3) expression.

Plant genetic engineering has the potential to introduce new allergenic proteins into foods but, at the same time, it can be used to remove established allergens. Here, we report the molecular characterization of Lyc e 3, a new tomato (Lycopersicon esculentum) allergen, and the efficient down-regulation of its expression in transgenic tomato plants. Following the identification of an immunoglobulin E (IgE)-binding 9-kDa polypeptide in tomato peel, designated Lyc e 3, its partial amino acid sequence was determined by N-terminal protein sequencing. Sequence comparison revealed that Lyc e 3 encodes a nonspecific lipid transfer protein (ns-LTP). In plants, ns-LTPs are encoded by large gene families which differ in primary amino acid sequence, expression and proposed cellular function. To identify Lyc e 3 encoding complementary DNAs (cDNAs), public tomato expressed sequence tag (EST) databases were screened for ns-LTP sequences. Following this strategy, two cDNAs, LTPG1 and LTPG2, with high homology to the N-terminal sequence of Lyc e 3, were identified. Ectopic expression of LTPG1 and LTPG2 in Escherichia coli, followed by immunoblotting, verified their IgE reactivity. Subsequently, transgenic tomato plants constitutively expressing LTPG1- or LTPG2-specific double-stranded RNA interference (dsRNAi) constructs were created and tested for the suppression of Lyc e 3 accumulation. Efficient silencing of Lyc e 3 was documented by Northern and Western blotting. In both cases, Lyc e 3 accumulation was decreased to levels below the detection limit (less than 0.5% of the wild-type protein). The allergenic potential of Lyc e 3-deficient tomato fruits was tested by measuring histamine release from sensitized human basophils stimulated with transgenic and parental lines. These assays revealed a strong (10- to 100-fold) decrease in histamine release of human basophils challenged with transgenic fruit extracts when compared with control extracts. These results demonstrate the feasibility of creating low allergenic tomato fruits by means of dsRNAi inhibition.

Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract.

BACKGROUND: Food allergy may be life-threatening, and patients affected need to receive accurate diagnoses and treatment. Hazelnut has often been implicated as responsible for allergic reactions, and trace quantities can induce systemic reactions. OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerance of sublingual immunotherapy with a standardized hazelnut extract in patients allergic to hazelnut. METHODS: This was a randomized, double-blind, placebo-controlled study. Inclusion criteria were a history of hazelnut allergy and positive skin prick test and double-blind placebo-controlled food challenge results. Patients were then randomly assigned into 2 treatment groups (hazelnut immunotherapy or placebo). Efficacy was assessed by double-blind, placebo-controlled food challenge after 8 to 12 weeks of treatment. Blood samples were drawn for measurement of specific IgE, IgG(4), and serum cytokines before and after treatment. RESULTS: Twenty-three patients were enrolled and divided into 2 treatment groups. Twenty-two patients reached the planned maximum dose at 4 days. Systemic reactions were observed in only 0.2% of the total doses administered. Mean hazelnut quantity provoking objective symptoms increased from 2.29 g to 11.56 g (P = .02; active group) versus 3.49 g to 4.14 g (placebo; NS). Moreover, almost 50% of patients who underwent active treatment reached the highest dose (20 g), but only 9% in the placebo. Laboratory data showed an increase in IgG(4) and IL-10 levels after immunotherapy in only the active group. CONCLUSION: Our data confirm significant increases in tolerance to hazelnut after sublingual immunotherapy as assessed by double-blind, placebo-controlled food challenge, and good tolerance to this treatment.