Quality Standards for Allergen Immunotherapy Clinics in Spain: Consensus Document.

BACKGROUND AND OBJECTIVE: Allergen immunotherapy clinics (AITCs) in Spain differ widely in terms of structure, organization, resources, and portfolio of services. Therefore, it is essential to unify treatment criteria and define quality standards for the most complex AITCs. Objective: To establish a series of recommendations that make it possible to guarantee quality and safety in the administration of immunotherapy and define quality standards for the most complex AITCs. METHODS: This project began with an online survey of 65 allergy departments/units throughout Spain in 2013. Next, a 2-phase consensus process was carried out. In the first phase, 10 experts defined and agreed on the standards using the RAND/UCLA Appropriateness method; in the second, the agreements were validated by means of a 2-round Delphi consultation with 84 experts. RESULTS: Consensus was reached on minimum safety and quality criteria in the administration of allergen immunotherapy, and 2 levels of highly complex AITCs were defined: accredited AITCs and accredited AITCs with excellence. Consensus was also reached on quality standards and accreditation criteria for both levels. CONCLUSIONS: This project is pioneering in terms of its purpose (the definition of quality standards for AITCs) and of the use of structured participation techniques (combination of the RAND/UCLA and Delphi methods). It enabled the design of minimum standards for quality and safety in administering AIT, as well as quality criteria for accreditation of AITCs supported by a broad panel of experts from the Spanish Society of Allergology and Clinical Immunology.

European Survey on Adverse Systemic Reactions in Allergen Immunotherapy (EASSI): a real-life clinical assessment.

BACKGROUND: Outside clinical trials, data on systemic reactions (SRs) due to allergen immunotherapy (AIT) are scarce. METHODS: A prospective, longitudinal, web-based survey of 'real-life' respiratory allergen immunotherapy (AIT) clinical practice was conducted in France, Germany and Spain. SRs were recorded and coded according to the Medical Dictionary for Regulatory Activities (MedDRA) and risk factors associated with SRs were identified. RESULTS: A total of 4316 patients (corresponding to 4363 ongoing courses of AIT) were included. A total of 109 SRs were recorded, and 90 patients (2.1%) presented at least one SR. Most of the SRs occurred in subcutaneous allergen immunotherapy (SCIT) (89%, n = 97). The most frequently reported symptoms were urticaria, rhinitis, dyspnoea and cough. Respiratory symptoms appeared before skin symptoms. Most SRs occurred during the up-dosing phase (75.8%) and were mild in severity (71.6%). Intramuscular adrenaline was administered in 17 SRs, but only 65% of these were subsequently classified as anaphylaxis. Independent risk factors for SRs during SCIT were as follows: the use of natural extracts (odds ratio, OR) [95% confidence interval (CI)] = 2.74 [1.61-4.87], P = 0.001), the absence of symptomatic allergy medications (1.707 [1.008-2.892], P = 0.047), asthma diagnosis (1.74 [1.05-2.88], P = 0.03), sensitization to animal dander (1.93 [1.21-3.09], P = 0.006) or pollen (1.16 [1.03-1.30], P = 0.012) and cluster regimens (vs rush) (4.18 [1.21-14.37], P = 0.023). A previous episode of anaphylaxis increased the risk for anaphylaxis in SCIT (OR [95% CI] = 17.35 [1.91-157.28], P = 0.01). CONCLUSION: AIT for respiratory allergy is safe, with a low number of SRs observed in real-life clinical practice. A personalized analysis of risk factors could be used to minimize SRs.

Specific allergen immunotherapy for the treatment of allergic asthma: a review of current evidence.

Asthma is frequently associated with atopy, characterized by the production of specific immunoglobulin E in response to environmental allergens. Currently, two types of allergen immunotherapy (AIT) are used in clinical practice: subcutaneous and sublingual immunotherapy, both accepted as key components of the therapeutic repertoire for allergic rhinitis and conjunctivitis. However, their role in asthma remains controversial. The present document is aimed at providing the clinicians with a review of the evidence on the use of AIT in asthma, focusing on the most relevant aspects of its mechanism of action, its efficacy, and existing data on safety, tolerability, and cost-effectivity, both in pediatric and adult populations. A systematic search of MEDLINE, Cochrane, and Clinical Trials databases from 2000 to April of 2016 was carried out by a panel of experts from the Spanish Allergy and Clinical Immunology Scientific Society. Relevant studies prior to the year 2000 included in ulterior systematic reviews were also considered. More than 4000 articles were identified during the search and 241 were selected to retrieve available evidence on AIT, which was graded according to the Oxford classification. All the group members reviewed the resulting text until the final version reached the consensual agreement. A summary of recommendations on the more relevant topics are proposed. The role of AIT as a valuable therapeutic strategy for prevention of exacerbation and progressive decline in lung function is highlighted. Future research should include specific tools for asthma evaluation when assessing AIT effectiveness in asthmatic patients.

Evidence in immunotherapy for paediatric respiratory allergy: Advances and recommendations.

Allergic respiratory diseases are major health problems in paediatric population due their high level of prevalence and chronicity, and to their relevance in the costs and quality of life. One of the most important risk factors for the development of airway diseases in children and adolescents is atopy. The mainstays for the treatment of these diseases are avoiding allergens, controlling symptoms, and preventing them through sustained desensitization by allergen immunotherapy (AIT). AIT is a treatment option that consists in the administration of increasing amounts of allergens to modify the biological response to them, inducing long-term tolerance even after treatment has ended. This treatment approach has shown to decrease symptoms and improve quality of life, becoming cost effective for a large number of patients. In addition, it is considered the only treatment that can influence the natural course of the disease by targeting the cause of the allergic inflammatory response. The aim of this publication is to reflect the advances of AIT in the diagnosis and treatment of allergic respiratory diseases in children and adolescents reviewing articles published since 2000, establishing evidence categories to support the strength of the recommendations based on evidence. The first part of the article covers the prerequisite issues to understand how AIT is effective, such as the correct etiologic and clinical diagnosis of allergic respiratory diseases. Following this, the article outlines the advancements in understanding the mechanisms by which AIT achieve immune tolerance to allergens. Administration routes, treatment regimens, dose and duration, efficacy, safety, and factors associated with adherence are also reviewed. Finally, the article reviews future advances in the research of AIT.

Variation in allergen content in sublingual allergen immunotherapy with house dust mites.

BACKGROUND: Allergen immunotherapy is a treatment modality which can be applied using different vaccines. The aim of this study was to quantify and compare the allergen content of different house dust mites (HDM)' sublingual treatments and to review the evidence on their efficacy. METHODS: Five sublingual allergen immunotherapy (SLIT) products were ordered and purchased at an ordinary pharmacy and masked for blinding before the study was started. Detection of Dermatophagoides pteronyssinus and Dermatophagoides farinae allergens Der p 1, Der f 1, Der p 2 and Der f 2 was carried out by immunoblotting and fluorescent multiplex. A literature search for meta-analyses and systematic reviews that included SLIT-HDM products was performed. RESULTS: Der p 1 concentrations ranged from 0.6 to 14.5 µg/ml; similar figures were found for Der f 1 that ranged from 0.2 to 12.4 µg/ml. Der p 2+ Der f 2 ranged from 0.2 to 1.5 µg/ml. Data on efficacy are scarce for most of the five products. CONCLUSIONS: Substantial variations regarding allergen content were found among these five SLIT-HDM products. Therefore, it can be necessary to guarantee the quality of the SLIT-HDM products and to demonstrate their effectiveness before they are marketed. It seems necessary, for the moment, to take into account these characteristics of the products before prescribing.

Phase II/III clinical trial to assess the tolerability and immunological effect of a new updosing phase of Dermatophagoides mix-based immunotherapy.

BACKGROUND: Immunologically enhanced subcutaneous specific immunotherapy (SCIT) has been developed with a fast and simplified updosing phase containing equal parts of the house dust mites (HDM) Dermatophagoides pteronyssinus and Dermatophagoides farinae (Dermatophagoides mix) adsorbed on aluminum hydroxide. OBJECTIVE: To evaluate the tolerability and immunological impact of the updosing phase of this new allergen extract formulation. MATERIAL AND METHODS: We performed a multicenter, open-label, single-arm, phase II/III clinical trial. The inclusion criteria were a clinical history of rhinitis/conjunctivitis due to HDM (with/without asthma) and sensitization to HDM (positive specific IgE and skin prick test). Five updosing injections of Dermatophagoides mix (300, 600, 3000, 6000, and 15000 SQ+) were administered at weekly intervals with 1 maintenance injection (15000 SQ+) 2 weeks after the last updosing injection. Two days after each visit, patients were contacted by telephone to follow up on any adverse events. IgE-blocking factor, IgG4, and immediate skin reactivity were evaluated. RESULTS: The sample comprised 102 patients (mean [SD] age, 29.3 [7.7] years; male, 52.9%). There were 117 adverse drug reactions (ADR): 101 were local, regardless of reaction size, in 48 (47.1%) patients and 7 were systemic (all grade I) in 5 (4.9%) patients. All ADRs were mild, except for 1, which was moderate. Six weeks of treatment led to statistically significant increases in IgE-blocking factor and IgG4, as well as a significant reduction in immediate skin reactivity. CONCLUSION: This new updosing phase of Dermatophagoides mix-based immunotherapy had a good tolerability profile and induced a significant immunological effect.

Are basophil activation and sulphidoleukotriene determination useful tests for monitoring patients with peach allergy receiving sublingual immunotherapy with a Pru p 3-enriched peach extract?

INTRODUCTION: Treatment of food allergy essentially consists of food avoidance, but immunotherapy with food is emerging as a new therapeutic option. OBJECTIVE: To evaluate clinical improvement and immunological changes in patients with peach allergy following sublingual immunotherapy (SLIT) with a Prup3 quantified peach extract. METHODS: A randomized, double-blind, placebo-controlled clinical trial with peach SLIT was conducted. We assessed clinical efficacy after 6 months of treatment by means of double-blind, placebo-controlled oral challenges with peach and also evaluated immunological changes (basophil activation test [BAT] and determination of sulphidoleukotriene production) following stimulation with peach peel and pulp, rPrup3, rMald 1, and rMal d 4 stimulation. We also measured specific IgE and IgG4 to Pru p3. RESULTS: After 6 months of SLIT (T6), the active group showed a 3-fold improvement in tolerance to Prup3 and a significant increase in IgE to rPrup3 and in sLT production following stimulation with peach peel and rPrup3. There was also a significant increase in BAT results after stimulation with rPrup3 at 1 month of SLIT (T1). Statistically significant between-group differences were only observed for BAT with peach peel and pulp at T1 and T6 and for BAT with rPru p3 at T6. No changes were observed in BAT with rMal d 1 or rMal d 4 or in IgG4 levels to nPrup3. CONCLUSIONS: SLIT with a Pru p 3 quantified peach extract is clinically effective and leads to an increase in basophil activation and sulphidoleukotriene production following stimulation with rPru p3 and peach peel in the first months of treatment.

Allergen-specific immunotherapy: update on immunological mechanisms.

UNLABELLED: Immunotherapy selectively modulates the allergen-specific immune response. It involves the gradual administration of increasing amounts of allergen for the purpose of inducing protective immunological changes and it is the only curative approach for specific type I allergy. AIM: Description of the allergic inflammation.- Comprehension of the early cellular changes after specific immunotherapy has been initiated. Exposure of the mechanisms involved in tolerance induction by regulatory T cells (Treg) with the inhibition of the Th2 responses. Comprehension of IL-10 and transforming growth factor (TGF- ) roles. Explanation of specific IgE, IgG and IgA changes. Description of the suppression of inflammatory responses during immunotherapy.

Analysis of mite allergic patients in a diverse territory by improved diagnostic tools.

BACKGROUND: There are few studies comparing the sensitization with mite allergens from different mite species which could potentially be the cause of allergy. OBJECTIVE: To improve the diagnosis of mite allergic patients from a diverse territory in which D. pteronyssinus/D. farinae mites together with storage mites could be present in the environment. METHODS: Four hundred and seventy-seven patients (both children and adults) from different regions, covering the main mite prevalent areas of Spain, were recruited. sIgE to eight allergens was measured together with SPT to whole mite extracts, level of mite allergen exposure, and specific IgG(4) . BAT and CAST was performed in a subgroup of patients. RESULTS: D. pteronyssinus and L. destructor were more prevalent in Atlantic areas, whereas D. farinae predominate in Mediterranean areas. About 90% of patients were sensitized to group 1 and/or group 2 allergens. Group 2 was the most prevalent, and the IgE response/intensity of sensitization in BAT was higher. sIgE to Der p 2/Der f 2 was almost fully cross-reactive, but no cross-reactivity was detected with Lep d 2. Group 1 allergens were also cross-reactive, but in some patients a species-specific response was observed. sIgE to Lep d 2 was associated with SPT results to storage mites. Sensitization to Der p 1 was more frequent in children, whereas Lep d 2 sensitization was more frequent in adults. A higher ratio IgE/IgG(4) to Der p 2 was associated with the presence of allergic asthma. CONCLUSION: An improved diagnosis algorithm has been established. Group 2 allergens seem to have a leading role in mite allergy, but as group 1 sensitization could be species-specific in some patients and its prevalence is higher in children, an adequate balance on major mite species and major allergens must be consider in the design of mite allergy vaccines.

Sublingual immunotherapy in peach allergy: monitoring molecular sensitizations and reactivity to apple fruit and Platanus pollen.

BACKGROUND: Peach allergy is prevalent, persistent, and potentially severe and as such is a target for immunotherapy. Our aims were to evaluate the profile of sensitization to Rosaceae allergens and the effects of sublingual peach immunotherapy on immunoglobulin (Ig) E levels to these allergens, to monitor for neosensitizations, and to check if this treatment modified other Rosaceae fruit and pollen-related sensitizations. METHODS: A double-blind placebo-controlled trial was conducted on 56 peach-allergic patients who received, sublingually, a standardized peach extract quantified in mass units of Pru p 3, or placebo for 6 months. IgE to recombinant (r) Mal d 1, rMal d 4, rPru p 3, and natural (n) Art v 3 and skin prick test (SPT) reactivity to Platanus pollen and apple extracts evaluated before treatment (T0), after 1 month (T1) and after and 6 months (T6) were recorded. RESULTS: In total, 18.5% of patients recognized rMal d 1, 83.3%, rPru p 3, 24.1%, rMal d 4, and 25.9% nArt v 3. IgE to Pru p 3 rose from T0 to T1 in both the active group (P = .003) and the placebo group (P = .022), and remained elevated at T6 in the active group (P = .001). IgE to other purified allergens did not change significantly and no relevant neosensitizations were detected. SPT reactions to peach decreased from T0 to T6 in the active group (P < 0.05). Reactivity to peach (T1 and T6) and apple (T6) was lower in the active group than in the control group. CONCLUSIONS: The main allergen was Pru p 3. Changes in rPru p 3 IgE levels and in peach and apple extract SPT were induced by sublingual immunotherapy.

An epidemiological survey of hymenoptera venom allergy in the Spanish paediatric population.

UNLABELLED: Hypersensitivity reactions to hymenoptera venom are infrequent in paediatric patients. A study was made to determine the incidence of this pathology in children, based on an epidemiological survey targeted to all members of the SEICAP (Sociedad Española de Inmunología Clínica y Alergia Pediátrica/Spanish Society of Paediatric Clinical Immunology and Allergy), and designed to collect the data on patients under 17 years of age diagnosed with hymenoptera venom allergy. RESULTS: The data corresponding to 175 patients (135 males) were collected. The mean age was 9.9 ± 3.6 years. Seventeen percent (32 patients) were the offspring of beekeepers, and 68.9% had experienced previous stings. The causal insect was Apis melifera, implicated in 55 cases, followed by Polistes dominulus (33 cases). In 151 patients (83.9%) the condition consisted of a local reaction. The most frequent systemic response was urticaria and angio-oedema. Fourteen patients suffered anaphylactic shock. The diagnosis was based on skin test (intradermal and prick) and/or specific IgE testing. Three treatment categories were established: (a) prevention and educational measures; (b) symptomatic treatment with oral antihistamines as well as self-injectable adrenalin; and (c) immunotherapy. In this context, 135 patients underwent immunotherapy with a mean duration of 3.5 ± 1.7 years (range 2-5 years) - with excellent tolerance. The starting regimen was predominantly conventional (92 patients). CONCLUSIONS: The results of this survey show hypersensitivity reactions to hymenoptera venom to be infrequent in paediatrics, though with a strong impact upon patient quality of life.

Component-resolved diagnosis of pollen allergy based on skin testing with profilin, polcalcin and lipid transfer protein pan-allergens.

BACKGROUND: Allergy diagnosis needs to be improved in patients suffering from pollen polysensitization due to the existence of possible confounding factors in this type of patients. OBJECTIVE: To evaluate new diagnostic strategies by comparing skin responses to pan-allergens and conventional allergenic extracts with specific IgE (sIgE) to purified allergen molecules. METHODS: One thousand three hundred and twenty-nine pollen-allergic patients were diagnosed by a combination of an in vitro method with a panel of 13 purified allergens, including major allergens and pan-allergens, using a high-capacity screening technology (ADVIA-Centaur) and skin prick test (SPT) to pan-allergens and conventional extracts. RESULTS: There was a high concordance (kappa index) between in vitro (sIgE to major allergens) and in vivo (SPT to conventional extracts) methods in patients who were not sensitized to pan-allergens, but SPT with conventional extracts failed to diagnose patients with sensitization to pan-allergens. In patients who were simultaneously sensitized to polcalcins and profilins, there was a duplication both in the number of sensitizations to major allergens and in the years of disease evolution. There was a statistical association between sensitization to profilins and/or lipid transfer proteins and food allergy (P<0.0001). CONCLUSION: The novel diagnostic strategy has proven to be a valuable tool in daily clinical practice. Introduction of routine SPT to pan-allergens is a simple and feasible way of improving diagnostic efficacy. Patients sensitized to pan-allergens should be tested by an adequate panel of allergenic molecules in order to identify the allergens that are responsible for the allergic disease.

Randomized double-blind, placebo-controlled trial of sublingual immunotherapy with a Pru p 3 quantified peach extract.

BACKGROUND: Peach allergy is highly prevalent in the Mediterranean area; it is persistent and potentially severe, and therefore a prime target for immunotherapy. We aimed to study the efficacy and safety of sublingual immunotherapy (SLIT) with a peach extract quantified in mass units for Pru p 3, the peach lipid transfer protein. METHODS: Randomized, double-blind, placebo-controlled (DBPC) clinical trial. The main efficacy outcome was the change in the response to a DBPC food challenge (DBPCFC) with peach. Secondary efficacy outcomes were the changes in skin prick test (SPT), and in specific immunoglobulin E (IgE) and IgG(4) to Pru p 3. Tolerance was assessed with a careful recording of adverse events. RESULTS: After 6 months of SLIT, the active group tolerated a significantly higher amount of peach (three- to ninefold), presented a significant decrease (5.3 times) in SPT, and a significant increase in IgE and IgG(4) to Pru p 3. No significant changes were observed within the placebo group. Statistically significant inter-group differences were only observed in the SPT and IgG(4) responses. No serious adverse events were reported. Systemic reactions were mild, and observed with a similar frequency in both groups. Local reactions were significantly more frequent in the active group (three times) and 95% of them restricted to the oral cavity. CONCLUSION: In this first exploratory clinical trial, SLIT for peach allergy seems to be a promising therapeutic option that could modify the clinical reactivity of the patients to peach intake and the underlying immunological response with a good tolerance.

[Henna tattooing in children: natural or temporary?]. / Tatuaje de henna en niños: ¿natural y temporal?

BACKGROUND: Tattoos of natural red/brown henna obtained from the indigenous tree Lawsonnia have been traditionally performed with a few side-effects. Nowadays black henna tattoos are usually performed even in children. The addition of several chemical agents to improve its cosmetic properties has increased the risk of developing contact dermatitis after exposure. Our aim is to determine the causative agents of contact dermatitis in two children wearing henna tattoos. MATERIAL AND METHODS: Case 1: A 12-year-old girl with no atopy presented local vesicles 10 hours after a black henna tattoo was applied. She had presented similar symptoms with a previous tattoo. Case 2: A 7-year-old atopic boy presented vesicles 2 weeks after a black henna tattoo was applied. He had dyed his hair previously without side effects. Both patients cured, after 3-4 weeks of treatment with topic corticosteroids, with residual hypo-pigmentation. Skin prick test with natural and commercial henna and epicutaneous test with TRUE-TEST, PABA derivatives compounds tests, textile dyes and natural and commercial henna were performed. RESULTS: The epicutaneous tests were positive for p-Metilaminophenol, p-Aminobencene, p-Phenilendiamine and p-Toluenodiamine in both patients. The first patient had also positive tests for Benzocaine, Hydroquinone, Isobutyl p-aminobenzoate, Yellow 1 and Orange 1 disperse; the second one for Red 1 and Orange 1 disperse. In both cases the prick and epicutaneous tests for henna were negative. CONCLUSIONS: Two children presented contact dermatitis after black henna tattoo due to added additives such as paraphenilendiamine.

Biological standardization and maximum tolerated dose estimation of an Alternaria alternata allergenic extract.

BACKGROUND: The manufacture of allergenic extracts from the mold Alternaria alternata is influenced by factors such as strain variability, allergenic origin, culturing conditions and extraction process, which affect the reproducibility of the preparations intended for diagnostic and therapeutic use. OBJECTIVES: To select the most adequate antigenic source of A. alternata extracts and determine its maximum tolerated dose (MTD) to be used in a subsequent immunotherapy efficacy clinical trial. METHODS: Twenty-one patients monosensitized to A. alternata were involved in a biological standardization process of A. alternata extracts. Four different mold strains were cultured and used to produce extracts by three different methods, each incorporating proteins from different origins: culture filtrate, buffer extractable fraction and cellular antigens. The selected extract, characterized as in-house reference (IHR) preparation was used in a MTD finding immunotherapy study. Serum IgE, IgG, IgG1 and IgG4 specific of complete extract and purified natural and recombinant forms of Alt a 1 were determined by different EIA methods. RESULTS: Culture filtrate extract containing the allergens secreted to the spent medium was shown to be the most adequate option for establishing an IHR preparation for A. alternata extract manufacturing. A maximum dose of 1670 UBE, equivalent to 0.1 microg Alt a 1, was determined as MTD for immunotherapy. One year of administration of such a dose at monthly intervals elicited pronounced immunological changes with statistically significant decreases in IgE and increases in IgG4, both estimated with whole extract or purified Alt a 1. CONCLUSION: A high quality natural A. alternata extract has been developed and preliminarily tested to define its MTD for subsequent determination of the optimal dose in an immunotherapy efficacy clinical trial.

Comparative analysis of the bronchodilator response measured by impulse oscillometry (IOS), spirometry and body plethysmography in asthmatic children.

BACKGROUND: Asthma is common among young children. The assessment of respiratory resistance by the impulse oscillometry system (IOS), based on the superimposition of respiratory flow by short-time impulses, requires no patient active collaboration. AIM: We evaluated the baseline repeatability and bronchodilator response of IOS indices in preschool children, their correlation with spirometry and whole body plethysmography, and differences between atopic and nonatopic children. PATIENTS AND METHODS: Thirty-three asthmatic children (3-6 yrs.) underwent IOS measurement (R5rs, R20rs and X5rs) by triplicate at the baseline, after placebo and after salbutamol inhalation. Spirometry (FEV1) and whole body plethysmography (sRaw) were made at the baseline and after salbutamol. Baseline within-test (coefficient of variation: CV%) and between-test repeatability (baseline-placebo) were addressed. Bronchodilator response was evaluated by the SD index (change in multiples of the between-test repeatability). RESULTS: Baseline repeatability for R5rs was 4.1%. Its values decreased by 2SD after salbutamol inhalation, and correlated with FEV1 and sRaw at both, baseline (r=-0.51 and r=0.49) and post-salbutamol (r=-0.63 and r=0.54). A trend towards correlation between salbutamol-induced changes in R5rs and in sRaw (r=0.33) was observed. Atopic and non-atopic children showed no differences in lung function. CONCLUSION: IOS was well accepted by young asthmatic children and provided reproducible and sensitive indices of lung function. Resistance values obtained by IOS at low frequency (R5rs) were reproducible and correlated with spirometry and plethysmographic values.