Adjuvants in Allergen-Specific Immunotherapy: Modulating and Enhancing the Immune Response.

Allergen-specific immunotherapy (AIT) is the only treatment that can affect the natural course of allergic diseases such as allergic asthma, allergic rhinitis, and IgE-mediated food allergy. Adjuvants are used to induce a quicker, more potent, and longer-lasting immune response. Only 4 compounds are used as adjuvants in currently marketed AIT products: aluminum hydroxide, calcium phosphate, microcrystalline tyrosine (MCT), and monophosphoryl lipid A (MPL). The first 3 adjuvants are delivery systems with a depot effect, although they may also have immunomodulatory properties. These first-generation adjuvants are still widely used, especially aluminum hydroxide. However, aluminum is subject to limitations. MCT is the depot formulation of L-tyrosine; it enhances IgG production without inducing a significant increase in IgE, is biodegradable, and has good local and systemic tolerability. In turn, MPL is an immunostimulatory agent that is the only second-generation adjuvant currently used for AIT. In addition, multiple adjuvants are currently being studied, including immunostimulatory sequences (ISSs), nanoparticles (liposomes, virus-like particles, and biodegradable polymers), and phosphatidylserine derivatives. In a murine model of allergic bronchial inflammation by sensitization to olive pollen, the specific IgE level was significantly higher in sensitized mice treated with olive pollen and aluminum hydroxide. However, specific IgE levels were significantly reduced and bronchial hyperreactivity significantly improved in sensitized mice treated with olive pollen and bacterial derivatives (MPL or ISSs).

Olive, grass or both? Molecular diagnosis for the allergen immunotherapy selection in polysensitized pollinic patients.

BACKGROUND: Grass and olive are the most frequently pollens that induce seasonal allergic rhinitis in Spain. Cross-reactivity due to panallergens shared by them and overlapping pollination complicates the recognition of allergy-causing agents, making it difficult to identify the most appropriate allergen immunotherapy (AIT) to use. The aim of this study was to determine the sensitization pattern to major grass and olive pollen allergens using component-resolved diagnostics in patients with seasonal allergic rhinitis (SAR) and positive skin prick test to grass and olive pollens and evaluate how knowledge of the sensitization patterns might influence AIT prescription. METHODS: After informed written consent, a total of 1263 patients were recruited. A serum determination of specific IgE levels to Ole e 1 and Phl p 1 + 5 was performed to all patients. A comparison was made before and after obtaining the specific IgE results, and differences in diagnosis were stated. RESULTS: At the 0.35 kU/l cut-off point, 71.2% of patients were positive to Ole e 1 and Phl p 1 + 5, 14% were positive only to Phl p 1 + 5 and 12% were positive only to Ole e 1. Based on available clinical data and skin prick test results, 922 (73%) patients would have been indicated for a mixture of grass and olive pollens for AIT. In 56.8% of patients, there was non-coincidence in the composition of AIT that would be selected before and after investigators received the in vitro data. CONCLUSION: The diagnostic accuracy of the recombinant allergen-specific IgE test could help to improve the selection of specific-allergen immunotherapy in polysensitized patients.

Diagnosis and treatment of allergic rhinitis in children: Results of the PETRA study

Background: Good control of allergic rhinitis (AR) in children is desirable because it is associated with diseases such as asthma. The aim of this analysis of the PETRA study was to characterize its diagnosis and treatment in Spanish children. Methods: Data were analysed for paediatric patients (age 5-17 years, inclusive) included in the PETRA study, which included consecutive patients with allergic rhinitis attending respiratory specialists throughout Spain. Demographic information, disease characteristics (duration, severity according to the Allergic Rhinitis and its Impact on Asthma [ARIA] classification), diagnostic procedures, treatments and physicians’ attitudes to treatment were recorded. Results: Of the original sample of 1043 patients, 260 children were included (mean age, 11.7 years; 56.2% boys; 61.9% allergic to house dust mites (HDM) and 38.1% allergic to grass pollen). By ARIA classification, 180/260 (69.4%) had persistent AR and 176/280 (63%) had moderate disease. Asthma was reported in 89/161 (55%) with HDM allergy and 44/99 (45%) with grass pollen allergy. Symptomatic treatment was prescribed in 98.5%, although disease control had been no better than poor in 57.3%. Allergen specific immunotherapy was administered to 56.9%, and was used more often for HDM AR. When asked why specific immunotherapy was not prescribed, two-thirds of the investigators preferred a wait-and-see approach, prescribing immunotherapy if symptoms worsened or asthma developed. Conclusions: Paediatric patients treated by specialists for allergic rhinitis have moderate or severe disease. Symptomatic treatment was extensively prescribed but often did not achieve good disease control. Many specialists preferred a wait-and-see approach before prescribing immunotherapy(AU)

Diagnosis and treatment of allergic rhinitis in children: results of the PETRA study.

BACKGROUND: Good control of allergic rhinitis (AR) in children is desirable because it is associated with diseases such as asthma. The aim of this analysis of the PETRA study was to characterise its diagnosis and treatment in Spanish children. METHODS: Data were analysed for paediatric patients (age 5-17 years, inclusive) included in the PETRA study, which included consecutive patients with allergic rhinitis attending respiratory specialists throughout Spain. Demographic information, disease characteristics (duration, severity according to the Allergic Rhinitis and its Impact on Asthma [ARIA] classification), diagnostic procedures, treatments and physicians' attitudes to treatment were recorded. RESULTS: Of the original sample of 1043 patients, 260 children were included (mean age, 11.7 years; 56.2% boys; 61.9% allergic to house dust mites (HDM) and 38.1% allergic to grass pollen). By ARIA classification, 180/260 (69.4%) had persistent AR and 176/280 (63%) had moderate disease. Asthma was reported in 89/161 (55%) with HDM allergy and 44/99 (45%) with grass pollen allergy. Symptomatic treatment was prescribed in 98.5%, although disease control had been no better than poor in 57.3%. Allergen specific immunotherapy was administered to 56.9%, and was used more often for HDM AR. When asked why specific immunotherapy was not prescribed, two-thirds of the investigators preferred a wait-and-see approach, prescribing immunotherapy if symptoms worsened or asthma developed. CONCLUSIONS: Paediatric patients treated by specialists for allergic rhinitis have moderate or severe disease. Symptomatic treatment was extensively prescribed but often did not achieve good disease control. Many specialists preferred a wait-and-see approach before prescribing immunotherapy.

Efficacy of high-dose sublingual immunotherapy in children allergic to house dust mites in real-life clinical practice

Background: The aim of the study was to evaluate the efficacy and safety of high-dose mite sublingual immunotherapy (SLIT) administered in children with allergic rhinitis in real-life clinical practice. More over, we analysed the clinical course of asthma severity. Methods: Retrospective, observational, monocentre study. Medical records of patients treated between 2001 and 2008 were reviewed. Patients received a standardised Dermatophagoide spteronyssinus + Dermatophagoides farinae extract (300 IR/ml) manufactured by Stallergenes (Staloral® 300). Patients were evaluated before SLIT initiation and at 6, 12, 24, 36 and 48 months. Global assessment of SLIT efficacy was measured using a visual analogue scale (VAS) and a rhinitis medication consumption score (RMCS). A global asthma score was used to estimatethe clinical course of asthma severity. Results: We obtained data from 78 patients, 43.6% male. The mean (±SD) age was 11.0 ± 3.0 years. Most patients (69.2%) suffered from allergic rhinitis plus asthma. Patient evaluation of allergy severity (VAS) revealed a highly significant improvement between baseline and six months (p<0.001, Wilcoxon test): 4.0 ± 1.7 cm vs. 7.3 ± 4.6 cm. This improvement was maintained throughout the four-year follow-up period. The use of medications (RMCS) was significantly reduced in the first six months (4.6±2.5 points at baseline vs. 0.8±1.6 points atsix months visit, p<0.001, Wilcoxon test) and remained very low until the end of follow-up. We did not find a temporal improvement in asthma severity. Conclusions: This retrospective study indicates that high-dose SLIT in children with rhinitis caused by house dust mites is well-tolerated and could be an effective treatment (AU)

Alternating Polistes-Vespula venom immunotherapy: a therapeutic strategy to resolve a diagnostic deficiency.

BACKGROUND: In Mediterranean regions, double sensitization to Polistes and Vespula species is frequent in patients reacting to an unidentified wasp sting. Since both genera are present, it is often difficult to determine which insect is responsible and, consequently, select venom for immunotherapy. When a specific diagnosis cannot be made, a new therapeutic strategy should be undertaken. METHODS: We performed a case-control study in which 37 patients who were allergic to venom from Vespula and Polistes species received a 3-year schedule of alternating immunotherapy. Twenty monosensitized patients (10 to Vespula and 10 to Polistes) received conventional venom immunotherapy (VIT) during the same period. All 57 patients received the same number of injections. The effectiveness of VIT was assessed by means of re-sting, which was performed yearly. Serum specific immunoglobulin (Ig) E and IgG4 were also studied, RESULTS: All the cases tolerated all the stings. One control patient developed a mild systemic reaction after the first-year Vespula sting but tolerated subsequent re-stings. Both cases and controls reached significant changes in levels of IgE and IgG4 after VIT (P < .04 at minimum). The cases developed a response as expected, although this was less intense than in the control group. In the Polistes control subgroup, sIgE to Polistes decreased to under baseline levels, after a marked initial increase; this decrease was not observed in the Vespula subgroup. CONCLUSION: An alternating VIT strategy is appropriate and provides protection to patients sensitized to Vespula and Polistes.

Efficacy of high-dose sublingual immunotherapy in children allergic to house dust mites in real-life clinical practice.

BACKGROUND: The aim of the study was to evaluate the efficacy and safety of high-dose mite sublingual immunotherapy (SLIT) administered in children with allergic rhinitis in real-life clinical practice. Moreover, we analysed the clinical course of asthma severity. METHODS: Retrospective, observational, monocentre study. Medical records of patients treated between 2001 and 2008 were reviewed. Patients received a standardised Dermatophagoides pteronyssinus+Dermatophagoides farinae extract (300 IR/ml) manufactured by Stallergenes (Staloral(®) 300). Patients were evaluated before SLIT initiation and at 6, 12, 24, 36 and 48 months. Global assessment of SLIT efficacy was measured using a visual analogue scale (VAS) and a rhinitis medication consumption score (RMCS). A global asthma score was used to estimate the clinical course of asthma severity. RESULTS: We obtained data from 78 patients, 43.6% male. The mean (± SD) age was 11.0 ± 3.0 years. Most patients (69.2%) suffered from allergic rhinitis plus asthma. Patient evaluation of allergy severity (VAS) revealed a highly significant improvement between baseline and six months (p < 0.001, Wilcoxon test): 4.0 ± 1.7 cm vs. 7.3 ± 4.6 cm. This improvement was maintained throughout the four-year follow-up period. The use of medications (RMCS) was significantly reduced in the first six months (4.6 ± 2.5 points at baseline vs. 0.8 ± 1.6 points at six months visit, p < 0.001, Wilcoxon test) and remained very low until the end of follow-up. We did not find a temporal improvement in asthma severity. CONCLUSIONS: This retrospective study indicates that high-dose SLIT in children with rhinitis caused by house dust mites is well-tolerated and could be an effective treatment.

Predicting patients at high-risk of systemic reactions to cluster allergen immunotherapy: a pilot prospective observational study.

OBJECTIVE: The purpose of this study was to identify factors associated with increased risk of adverse systemic reactions to cluster allergen immunotherapy and to create a preliminary predictive clinical model. METHODS: In a prospective observational study, the tolerance of 611 patients with seasonal respiratory diseases who were receiving cluster immunotherapy was monitored and all systemic reactions were recorded. Associations between potential prognostic factors (sex, age, respiratory disease, severity, duration of disease, previous immunotherapy, nonseasonal symptoms, skin prick test, total immunoglobulin (Ig) E, specific IgE, treatment schedule, allergenic composition, batch, date of treatment, habitat, place of residence) and systemic reactions were estimated. Multivariate stepwise logistic regression analysis was used to build a predictive clinical model and estimate the probability of systemic reactions to cluster immunotherapy. RESULTS: Sixty-five patients (10.6%) suffered systemic reactions. Only 7 independent risk factors were retained in the final model: age over 14 years (odds ratio [OR], 2.6), previous immunotherapy (OR, 0.3), skin prick test positive to Chenopodium album (white goosefoot) (OR, 3.0), elevated specific IgE to grass pollen (OR, 2.3), elevated specific IgE to olive pollen (OR, 4.1), olive pollen 100% composition (OR, 2.6) and treatment schedule (OR, 1, 1.6 or 7.1, depending on the cluster immunotherapy schedule). CONCLUSIONS: This predictive model, derived from simple clinical variables, has excellent ability to assess individual risk of suffering systemic reactions to cluster allergen immunotherapy. Detecting high-risk patients can help clinicians to prevent and eliminate many severe adverse reactions to cluster immunotherapy.

Tolerance and short-term effect of a cluster schedule with pollen-extracts quantified in mass-units.

We performed a prospective, multicenter study to assess the tolerance and possible short-term effects of allergen vaccines administered according to a cluster schedule in the months immediately preceding the onset of the pollen season. The study was carried out in eight centers and included 191 patients (children and adults) with allergic respiratory disease due to sensitization to olive tree and/or grass pollen. Of these, 34 patients acted as controls and the remaining patients received immunotherapy administered in the initiation phase according to a cluster schedule of eight doses injected on four visits. After 3 months of treatment, significant differences were found between the two groups in medication consumption (antihistamines in drops and oral formulations: p = 0.045 and p = 0.001, respectively; short-acting beta2-agonist treatments: p = 0.004) and respiratory symptoms (wheezing and coughing: p = 0.035 and 0.014, respectively). The cytokine profile (interleukin [IL]-4, 5, 10 and 2, interferon [IFN-gamma], and tumor necrosis factor [TNF-alpha]) was determined before the start of treatment and at the end of follow-up (4-5 months). Levels of IL-4, 5 and 10 (Th2 profile) decreased while those of IL-2, IFN-gamma, and TNF-alpha (Th1 profile) decreased. These differences were more marked in the active group than in the control group but were not statistically significant. No severe adverse effects were recorded. This study shows that the schedule tested had an acceptable tolerance profile and produced significant changes in symptom and medication scores after a few months of treatment. A double-blind, placebo-controlled study is needed to confirm these results.

Informe sobre el mapa de protocolización de la alergología en España / Inform of protocolization map in Allergologic to Spain

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Perfil asistencial de una pauta agrupada de inmunoterapia con extractos de pólenes absorbidos en hidróxido de aluminio / Assistential profile of a cluster immunotherapy schedule with aluminium hydroxide-absorbed pollen extracts

Fundamento: Las pautas convencionales de iniciación de inmunoterapia se utilizan ampliamente a causa de su seguridad bien conocida, pero no se ha demostrado que constituyan un procedimiento óptimo. En los últimos años se han publicado algunas experiencias que avalan la seguridad de pautas agrupadas. Objetivo: Conocer de forma práctica las ventajas asistenciales de una pauta agrupada para extractos de pólenes estandarizados biológicamente y absorbidos en hidróxido de aluminio, en las condiciones de administración controlada en unidades asistenciales de inmunoterapia. Métodos: 139 pacientes alérgicos a pólenes (Olea, gramíneas, Chenopodium, Plantago) se trataron con Pangramín Depot® (ALK-Abelló, España) mediante una pauta de 4 visitas y 10 dosis, siguiendo las recomendaciones de la EAACI en dos unidades de inmunoterapia de Andalucía. El 72 por ciento de ellos tenían rinoconjuntivitis y asma y el 28 por ciento restante sólo rinoconjuntivitis. Se perseguía alcanzar la dosis máxima recomendada por el fabricante. Resultados: Los pacientes hicieron un total de 585 visitas a las unidades de inmunoterapia y recibieron 1.433 dosis. Seis pacientes (4,3 por ciento) presentaron otras tantas reacciones locales inmediatas (0,4 por ciento de las inyecciones) y un paciente (0,7 por ciento) sufrió una reacción sistémica leve (0,07 por ciento de las dosis) consistente en exantema urticarial.Todos alcanzaron la dosis de mantenimiento propuesta por el fabricante, sin abandonos ni exclusiones. Conclusiones: La pauta analizada ahorra considerablemente visitas, es bien aceptada por los pacientes y muestra un perfil de seguridad que permite su utilización habitual. Se propone la realización de otros trabajos que investiguen su utilidad para mejorar la eficacia y conocer el mecanismo de acción (AU)

Búsqueda de una pauta idónea para iniciación de inmunoterapia con un extracto de Alternarla tenuis / Investigation of an adequate immunotherapy initiation schedule with an Alternarla tenues extract

Fundamento: No se ha establecido la pauta de iniciación óptima para un extracto de hongos. En este trabajo se estudia la seguridad de la iniciación con un extracto de Alternaria tenuis estandarizado biológicamente, mediante pautas agrupadas progresivas. en pacientes seleccionados de acuerdo con los criterios establecidos en las guías internacionales. Métodos: Se realiza un estudio de cohortes históricas con 108 pacientes (4 - 28 años: 97 por ciento asmáticos) que recibieron tratamiento con Pangrarnín Depot (A. tenuis) mediante los siguientes esquemas: pauta 1: 4 visitas/10 inyecciones (n=60): pauta 2: 4 visitas/8 inyecciones (n=9): pauta 3: 3 visitas/9 inyecciones (n=6) y pauta 4: 3 visitas/6 inyecciones (n=33). Se aplicaron las guías europeas de administración controlada en tres centros españoles de alergia y se procedió al registro de reacciones mediante la misma normativa. Resultados: Los 108 pacientes realizaron 402 visitas y recibieron 944 dosis. En la pauta 1 aparecieron una reacción local y dos sistémicas leves (grado II). dentro de los 30 minutos de observación y con rápida respuesta al tratamiento. No hubo reacciones en las otras tres pautas. Todos los pacientes alcanzaron la dosis de mantenimiento recomendada por el fabricante. Conclusiones: Las cuatro pautas valoradas han mostrado ser bien toleradas. La más sencilla de ellas (3 visitas/6 dosis) es una alternativa válida para el tratamiento de rutina de pacientes bien seleccionados. en condiciones controladas (AU)

Estudio prospectivo de seguridad de inmunoterapia agrupada con extractos acuosos de pólenes / A prospective study of the safety of cluster immunotherapy with aqueous pollen extracts

Fundamento: Si la fase de iniciación de inmunoterapia convencional pudiera acortarse sensiblemente, con un nivel de seguridad similar al de las pautas convencionales actualmente en uso, se obtendrían numerosos beneficios para los pacientes y para el sistema sanitario. En el presente trabajo se monitoriza la seguridad de una pauta agrupada para extractos de pólenes administrados de forma controlada por alergólogos, y se analiza su perfil asistencial. Métodos: En tres Unidades de Inmunoterapia de España se han administrado tratamientos acuosos de Lolium perenne 100 por ciento, Olea europaea 100 por ciento o Lolium-Olea 50 por ciento de dos fabricantes, a 158 pacientes diagnosticados de rinoconjuntivitis y asma, mediante una pauta agrupada de 12 dosis y 4 visitas, siguiendo estrictamente la normativa de la EAACI. Resultados: Se administraron 2.009 dosis en 740 visitas, con un ahorro de 1.783 dosis y 3.052 visitas sobre un programa convencional acuoso. Diez pacientes (6,3 por ciento del total de pacientes) desarrollaron 12 reacciones sistémicas (0,6 por ciento del total de dosis), todas ellas leves, durante los 30 minutos protocolizados de observación. La respuesta al tratamiento ordinario fue excelente. Salvo 3 pacientes que abandonaron por propia iniciativa, los 155 restantes (98 por ciento) alcanzaron la dosis máxima convencional e iniciaron su mantenimiento adecuadamente. Treinta y dos pacientes (20 por ciento del total de pacientes) desarrollaron reacciones locales y 10 (6,3 por ciento del total), reacciones inespecíficas que motivaron algunos retrasos en la pauta. Conclusiones: La inmunoterapia agrupada es una alternativa a la convencional en la administración de rutina en las Unidades de Inmunoterapia. Es necesario ensayar nuevas pautas y conocer el comportamiento de extractos depot de pólenes (AU)

The presence of latex can induce false-positive skin tests in subjects tested with penicillin determinants.

Latex allergens are ubiquitous, and exposure may occur from different sources in the medical environment and in daily life. The observation that subjects with latex allergy were skin test positive to major and minor determinants of penicillins led our group to carry out an investigation to try to explain these findings. A group of 20 subjects with a history of allergy to latex and with positive skin tests for, but good tolerance of, penicillins was studied. The presence of latex contaminants was studied by RAST and RAST inhibition. Sixteen of the subjects were positive to at least one of the penicillin determinants used, and 14 (87%) of these were positive to at least two determinants. Repetition of skin tests using the container without a stopper changed the skin test results to negative in almost all cases, indicating that some trace contaminants had still been present. RAST-inhibition studies showed that in all penicillin determinants there were trace amounts of latex allergens varying between 3 and 0.03 micrograms/ml. These results indicate that skin tests with penicillin in subjects allergic to latex may give false-positive results and lead to such patients being falsely diagnosed as allergic to betalactams when penicillins are stored in containers with rubber stoppers.

Cross-reactivity between a penicillin and a cephalosporin with the same side chain.

BACKGROUND: The cross-reactivity between penicillins and cephalosporins can be influenced by different factors, which are not all well known. The chemical structure of the side chain may contribute to the cross-reactivity. OBJECTIVE: The study was carried out in allergic subjects who are selectively responsive to amoxicillin to determine allergenic cross-reactivity with a cephalosporin containing a side chain identical to that of amoxicillin, cefadroxil, and one containing a different side chain, cefamandole. METHODS: Allergic subjects with a selective response to amoxicillin were chosen according to the following criteria: history of an immediate allergic reaction to amoxicillin, negative skin test responses to benzylpenicilloyl and minor determinant mixture of benzylpenicillin, negative RAST response to benzylpenicilloyl, and good tolerance to benzylpenicillin and phenoxymethyl penicillin challenges. In addition, subjects had to have a positive skin test response to amoxicillin and/or positive RAST response to amoxicilloyl or, if these test results were negative, a positive challenge test response to amoxicillin. In vivo cross-reactivity to cefadroxil was assessed by giving oral cefadroxil at increasing doses from 5 to 500 mg. In vitro cross-reactivity was determined by RAST inhibition studies with amoxicilloyl RAST disks and the following monomeric conjugates in the fluid phase: amoxicillin-butylamine, cefadroxil-butylamine, and the side chain para-hydroxy-phenylglycine. Tolerance to cefamandole was determined by giving 100 mg and then 500 mg parenterally. RESULTS: Twenty-one patients with a selective response to amoxicillin were included in the study. Eight subjects (38%) had a positive response to cefadroxil, and none reacted to cefamandole. In vitro RAST inhibition studies indicated that cefadroxil-butylamine monomers cross-reacted with amoxicillin butylamine and the side chain contributed relevantly to the inhibition. CONCLUSIONS: These results indicate that the percentage of cross-reactivity between penicillins and cephalosporins with an identical side chain is high and that this critical part of the molecule seems to be an important contributor to these results. The value is higher than previously reported data from similar studies of non-side-chain-related cephalosporins.