Efficacy of transdermal immunotherapy with biodegradable microneedle patches in a murine asthma model.

BACKGROUND: House dust mite (HDM) is a well-known cause of asthma. Allergen-specific immunotherapy (AIT) can only modify the natural course of the disease. Conventional routes of HDM AIT are subcutaneous or sublingual. Subcutaneous immunotherapy (SCIT) has a disadvantage of systemic hypersensitive reaction, and the sublingual immunotherapy has a disadvantage of local allergic reaction and low drug adherence. OBJECTIVE: To overcome the weak points of conventional AIT, we developed a HDM loaded biodegradable microneedle patch (MNP) for transdermal immunotherapy (TDIT). We aim to demonstrate the efficacy of TDIT in murine asthma model triggered by HDM compared with conventional SCIT. METHODS: To make HDM asthma mouse model, 5-week-old BALB/c female mice were sensitized and challenged by intranasal administration of HDM. The mice were divided into 5 groups: sham, asthma, low (10 µg) and high dose (100 µg) SCIT, and TDIT (10 µg). To make HDM loaded MNP, droplet-born air blowing method was used. Airway hyperresponsiveness and allergic inflammation markers were analysed by bronchoalveolar lavage fluid, immunohistochemistry, serum immunoglobulin (Ig) analysis, and lung cytokine assays. RESULTS: Airway hyperresponsiveness was ameliorated by TDIT. Eosinophilic inflammation in bronchoalveolar lavage was improved without adverse reactions. Reduction of Th2 (IL-4, IL-5, and IL-13) cytokines, and HDM-specific IgE, induction of Treg (IL-10, TGF-ß), Th1 (IFN-γ) cytokines were observed. Eosinophilic infiltration, goblet cell hyperplasia, and subepithelial fibrosis were also alleviated by TDIT. These changes were more significant in the TDIT group than in subcutaneous AIT group. CONCLUSION: In conclusion, HDM loaded biodegradable TDIT is a novel treatment option to treat asthma which showed more effectiveness and may have better safety profiles than conventional SCIT.

Successful transdermal allergen delivery and allergen-specific immunotherapy using biodegradable microneedle patches.

Allergen-specific immunotherapy (SIT) is an effective treatment modality for allergic diseases such as atopic dermatitis (AD). However, frequent visits over a 3-year period as well as looming adverse events tend to discourage patient compliance. Therefore, a more convenient, effective, and safe method of SIT is needed. For several decades, use of microneedles has been promoted as an efficient and precise transdermal drug delivery method. In this study, we developed Dermatophagoides farinae (D. farinae) extract (DfE)-loaded microneedle patches, and evaluated their safety and efficacy as a novel SIT method. After 4 weeks of patch application, efficient allergen delivery and successful induction of immune response to DfE were demonstrated in mice, with no apparent adverse events. AD-induced NC/Nga mice received microneedle immunotherapy (MNIT) (10 µg), subcutaneous immunotherapy (SCIT) (10 µg), SCIT (100 µg), or placebo. Both MNIT (10 µg) and SCIT (100 µg) treatments improved clinical and histologic manifestations of AD skin lesions, altered immunoglobulin production, dampened Th2 cellular response, and boosted Treg infiltrates, without significant side effects; whereas SCIT (10 µg) or placebo subsets failed to show any effects. Based on the favorable safety and efficacy profiles demonstrated in mice by MNIT in the current study, we believe that MNIT may serve as a new SIT modality.

Evidencia Orientada a Pacientes (EOP): ¿Qué hay sobre el uso de inmunoterapia subcutánea alérgeno específica en asma y rinitis alérgica? / What about the use of specific allergen subcutaneous immunotherapy in asthma and allergic rhinitis?

La inmunoterapia alérgeno específica (ITA) consiste en la administración de cantidades crecientes del alérgeno al cual el paciente es sensible con el propósito de modular la respuesta inmune a ese alérgeno, y se propone como una opción terapéutica en pacientes con rinitis alérgica. A partir de una viñeta clinica de un paciente con esta patología, el médico de familia que lo asiste se pregunta si la ITA podría disminuir la intensidad y duración de los síntomas y su eficacia perdurar a largo plazo. Después de realizar una búsqueda bibliografica, resumir y evaluar la bibliografía encontrada, se concluye que dicha terapia podría reducir la severidad de los síntomas, la frecuencia de uso de medicación de rescate, y sostener su eficacia clínica luego de la interrupción del tratamiento. Sin embargo, sus riesgos, sus costos, los inconvenientes en el regimen de aplicación y la dificultad para determinar cuando finalizar la inmunoterapia; sumados a la heterogeneidad de estudios incluidos en las revisiones sistemáticas que evalúan su eficacia, hacen imprescindible que el paciente y su médico discutan en forma conjunta las ventajas y desventajas de su utilización. (AU)

Allergen- specific immunotherapy involves the administration of increasing amounts of the allergen to which the patient is sensi-tive for the purpose of modulating the immune response to that allergen, and it is proposed as an optional treatment in patients with allergic rhinitis. From a clinical vignette with a patient with this condition, a family physician wonders if the specific allergen immunotherapy may diminish the intensity and duration of symptoms and whether its efficacy will be long lasting. After search-ing, summarizing and evaluating the retrieved literature it is concluded that such therapy could reduce the severity of symptoms and the utilized rescue medication. It also maintained its clinical efficacy after discontinuation of treatment. However, risks, costs, disadvantages of its implementation and the difficulty in determining when to finish immunotherapy; coupled with the heterogene-ity of studies included in the systematic reviews assessing its effectiveness makes it essential that the patient and doctor discuss jointly its use. (AU)

Epicutaneous immunotherapy for food allergy as a novel pathway for oral tolerance induction.

Epicutaneous immunotherapy is a developing technique, aiming at desensitizing patients with food allergy with less risks that oral ingestion or injection could generate. Several clinical trials have been performed and are currently running, in milk and peanut allergy, assessing the safety of the technique and its efficacy. Preclinical models indicate a major role in the mechanisms of desensitization, for example, Tregs and epigenetic modifications.

Comparison of microneedles and adhesive-tape stripping in skin preparation for epicutaneous allergen delivery.

BACKGROUND: Epicutaneous immunotherapy targets the network of dendritic cells in the epidermis. Allergen exposure of the dermal layers should be limited as these contain mast cells and blood vessels, which increases the risk for local and systemic allergic reactions. METHODS: This intraindividually controlled trial included 20 subjects with birch pollen allergy. Three areas of the volar forearms were treated by repeated adhesive-tape stripping, single-prick lancet piercing and microneedle array application. Four 10-fold dilutions of allergen extract were applied to each area and the IgE-mediated immediate-phase reactions and cell-mediated eczema were assessed. RESULTS: Allergen application after tape stripping led to an immediate-phase reaction in 2 subjects (10%) at the highest allergen concentration of 10 HEP/ml. Both prick needle and microneedle pretreatment resulted in immediate-phase reactions in all subjects (100%). The reactivity pattern, however, differed significantly: 95% of the reactions after pricking occurred at concentrations of ≤0.1 HEP/ml, whereas 50% of the reactions after microneedle preparation were noted at ≥1 HEP/ml. In 3 subjects (15%), eczema was observed on the microneedle-treated skin area. No serious adverse events occurred. CONCLUSIONS: Microneedles enhance stratum corneum penetration when compared to tape stripping. However, they do not resolve the problem of mast cell-mediated local reactions, possibly due to diffusion into the dermis. The occurrence of eczema after the microneedle treatment suggests induction of dendritic cell-mediated T cell responses. Therefore, skin preparation with microneedles may be a promising method for epicutaneous allergen immunotherapy.

Double-blind, placebo-controlled, dose-ranging study of new recombinant hypoallergenic Bet v 1 in an environmental exposure chamber.

BACKGROUND: Recombinant allergens offer a tool for improving specific immunotherapy (SIT). OBJECTIVE: To find the optimal dose of a new hypoallergenic folding variant of recombinant Bet v 1 (rBet v 1-FV) as SIT for patients with birch pollen allergy. METHODS: Before SIT, thirty-seven adult patients were exposed for eight hours in an environmental exposure chamber (EEC) to birch pollen at an average concentration of 3500 ± 500 grains/m(3) , then randomized to four maintenance dose groups of rBet v 1-FV and one placebo group: 20 µg (n = 7), 80 µg (n = 8), 160 µg (n = 7), 320 µg (n = 8), and placebo (n = 7). Patients were treated for 10 weeks with weekly injections and then re-exposed in the EEC. The optimal dose for SIT was assessed using efficacy results from the EEC, IgG responses, and tolerability. RESULTS: Thirty-six patients were evaluable for efficacy assessment. The total symptom score significantly decreased in all active groups compared with placebo (-18.8% for placebo patients; -71.9%, P = 0.0022 for 20 µg; -75.6%, P = 0.0007 for 80 µg; -81.8%, P = 0.0009 for 160 µg; -78.3%, P = 0.0003 for 320 µg). IgG1 increased significantly in all active groups compared to placebo. All four active doses were well tolerated, no serious adverse event occurred; two Grade II reactions, according to EAACI classification, were observed, one in each of the 160- and 320-µg groups. CONCLUSIONS: Considering efficacy, immunological response, and tolerability, a maintenance dose of 80 µg of rBet v 1-FV appears to be the ideal dose for allergen immunotherapy in birch pollen allergic patients.

[Practice patterns in Mexican allergologists about specific immunotherapy with allergens]. / Patrones de práctica de alergó1ogos mexicanos en cuanto a inmunoterapia específica con alergenos.

BACKGROUND: Immunotherapy has been practiced since over a hundred years. Since the first applications up today changes have occurred in the preparation, dose and duration of the treatment, as well as in the extracts used. Guidelines have been published in Mexico and other countries to try to unify these practice patterns of immunotherapy. PARTICIPANTS AND METHODS: By means of a questionnaire, sent in various occasions to all members of the Colegio Mexicano de Inmunología Clínica y Alergia (CMICA) and of the Colegio Mexicano de Pediatras, Especialistas en Inmunología y Alergia (CoMPedIA) we tried to get a picture of the daily practice patterns of immunotherapy in the allergist's office. Results will be presented in a descriptive manner. RESULTS: A response rate of 61 (17%) was obtained from the College members. For immunotherapy allergists use locally made and imported extracts, generally mixed in their office (20% over 10 allergens in one bottle). Eighty percent adds bacterial vaccine at some point and 60% uses sublingual immunotherapy. Most use Evans without albumin as diluent, don't routinely premedicate, reach maintenance treatment after more than six months and 46% recommends a maximum duration of immunotherapy of two years or less. CONCLUSIONS: We present a diagnosis on the current situation of practice patterns concerning allergen immunotherapy among the members of both Mexican colleges of allergists. The methods used by the allergists for indication, preparation and administration are quite diverse.

[Adverse reactions to skin tests and immunotherapy in the practice of Mexican allergologists]. / Reacciones adversas a pruebas cutáneas e inmunoterapia en la práctica de alergó1ogos mexicanos.

BACKGROUND: Immunotherapy is the only curative treatment recommended for allergic rhinoconjunctivitis and asthma, in which small amounts of allergen are administered sublingually or subcutaneously until the maximum tolerated dose has been reached. However, local or systemic adverse reactions (AR) -rarely even fatal- an occur. In Mexico there is no nationwide data on adverse reactions. OBJECTIVE: To document the frequency of adverse reactions secondary to skin tests (ST) or immunotherapy (IT) in the allergist's office in Mexico, paying special attention to fatal and near fatal allergic reactions. PARTICIPANTS AND METHODS: We mailed a survey to all members of the Mexican Colleges of Allergy (CMICA) and Pediatric Allergy (CoMPedIA). RESULTS: A response rate of 59 (16%) for the adverse reactions part of the questionnaire was obtained from the College members. We found a near fatal reaction rate of 0.005 cases per year per allergy practice for skin testing and the same number -0.005 cases- for immunotherapy. This can be extrapolated to a total of 1.5 cases per year in the whole country of Mexico. No fatalities were reported. CONCLUSIONS: In Mexico the frequency of severe or near fatal adverse reactions to immunotherapy or skin tests is low and no fatal case has been reported till today.

Gene gun immunization with clinically relevant allergens aggravates allergen induced pathology and is contraindicated for allergen immunotherapy.

Gene gun immunization has been associated with the induction of a heterologous type of immune response characterized by a T(H)1-like immune reaction on the cellular level, i.e. generation of IFN-gamma secreting CD8(+) T-cells, yet a T(H)2 biased serology as indicated by high IgG1:IgG2a ratios and induction of IgE. Nevertheless, gene gun immunization using the model molecule beta-galactosidase has been argued to prevent IgE induction and to promote T(H)1 cells with respect to allergy DNA immunization. In our current study, we evaluated the potential of gene gun immunization to prevent type I allergic reactions comparing beta-galactosidase with two clinically relevant allergens, and further investigated the effect of gene gun immunization on relevant lung parameters. BALB/c mice were immunized with plasmids encoding the birch pollen allergen Bet v 1, the grass pollen allergen Phl p 5, or the model molecule beta-galactosidase, either by gene gun or intradermal injection followed by sensitization and intranasal provocation with the respective allergen. IgG1 and IgG2a antibody titers were determined by ELISA. IgE levels were evaluated in a rat basophil release assay. The severity of eosinophilia was determined in bronchoalveolar lavages, and the overall infiltrate was analyzed by histology on lung paraffin sections. Gene gun immunization induced a T(H)2-biased immune reaction, which did not prevent from production of IgE after subsequent sensitization. This T(H)2 effect was influenced by the nature of the antigen, with a more pronounced T(H)2-bias for the allergens Bet v 1 and Phl p 5 compared to beta-galactosidase. Gene gun immunization with all three antigens promoted eosinophil influx into the lung and did not alleviate lung pathology after intranasal provocation. In contrast to needle injection of plasmid DNA, which triggers a clearly T(H)1-biased and allergy-preventing immune response, gene gun application fails to induce anti-allergic reactions with all tested antigens and is therefore contraindicated for allergen-specific immunotherapy.

Analysis of the burden of treatment in patients receiving an EpiPen for yellow jacket anaphylaxis.

BACKGROUND: Venom immunotherapy (VIT) is a treatment with established efficacy for the prevention of repeated anaphylactic reactions in patients with Hymenoptera allergy, which also allows patients to discontinue carrying an EpiPen. Despite their merits, both treatments can have negative aspects potentially important to patients. OBJECTIVE: We examined possible negative aspects of the EpiPen in comparison with VIT as perceived by patients. METHODS: Positive and negative aspects of both treatments were measured by using a burden of treatment questionnaire together with statements about the EpiPen. RESULTS: One hundred ninety-three patients were included, of whom 94 consented to randomization: 47 received VIT, and 47 received the EpiPen. Of the remaining 99, 75 chose VIT, and 26 chose the EpiPen. Of the patients receiving VIT, 91.5% were (extremely) positive about their treatment, and 85% would choose VIT again. Of the patients receiving the EpiPen, only 48% were positive about their treatment, and even of these patients, 68% preferred to be treated with VIT after 1 year of carrying the EpiPen. Although most patients indicated that it is reassuring to carry an EpiPen and makes them feel safe, many patients also indicated that it is inconvenient and troublesome. Especially patients who were negative about the EpiPen indicated that they would not dare use the EpiPen if necessary and were afraid at possible side effects. CONCLUSION: In contrast to VIT, the EpiPen is perceived as burdensome by most patients with venom allergy. For most patients, an EpiPen is an unsuitable definitive treatment. CLINICAL IMPLICATIONS: As VIT enables patients with venom allergy to get rid of the EpiPen, patients should be offered VIT.

Accidental needle sticks, the Occupational Safety and Health Administration, and the fallacy of public policy.

BACKGROUND: Current Occupational Safety and Health Administration (OSHA) guidelines mandate the use of safety needles when allergy injections are given. Safety needles for intradermal testing remain optional. Whether safety needles reduce the number of accidental needle sticks (ANSs) in the outpatient setting has yet to be proven. OBJECTIVE: To determine the rate of ANSs with new (safety) needles vs old needles used in allergy immunotherapy and intradermal testing. METHODS: Allergy practices from 22 states were surveyed by e-mail. RESULTS: Seventy practices (28%) responded to the survey. Twice as many ANSs occurred in practices giving immunotherapy when using new needles vs old needles (P < .01). The rate of ANSs was roughly the same for intradermal testing with new needles vs old needles. CONCLUSIONS: These findings further question whether OSHA's guidelines for safety needle use in outpatient practice need revision and if allergy practices might be excluded from the requirement to use safety needles.

Un brote por Mycobacterium chelonae, subespecie abscessus asociado a hiposensibilización en pacientes alérgicos

Se estudiaron trece pacientes sometidos a hiposensibilización, quienes presentaron abcesos subcutáneos después de la inyección aeroalergenos (A.E.A). El examen microbiológico del material obtenido permitió identificar Mycobacterium chelonae subespecies abscessus, en 11 de ellos: A estas cepas se le practicaron pruebas de sensibilidad a diferentes drogas. La evolución de los pacientes dependió del tamaño, tipo y número de lesiones, además del tipo de tratamiento empleado. No se presentaron manifestaciones sistémicas en ningún paciente. M. chelonae puede ser introducido iatrogénicamente a las personas que se someten a cualquier tipo de procedimiento invasivo.