Retrospective study of tolerance to short initiation schedules in subcutaneous immunotherapy.

With the aim of evaluating tolerance to new shorter initiation schedules in subcutaneous immunotherapy everyday clinical practice, a study was carried out using Pangramin Plus with initiation periods between 3 (Cluster) and 6 (Plus) weeks. All the information was processed retrospectively and both systemic (SR) and local (LR) adverse reactions occurring between September 2002 and February 2003 were recorded. A total of 353 patients (261 Plus and 91 Cluster) were included and 2,886 doses were administered (2,166 in initiation and 720 in maintenance). Of these, 800 were with Grass mix extract, 1,141 Grass mix + Olea, 273 Olea, 73 Dermatophagoides mix and 599 Dermatophagoides pteronyssinus. As regards adverse reactions (AR), 2.8% of patients showed SR and 4.8% LR, 1.2% of doses caused some type of reaction (SR and LR in 0.3% and 0.9%, respectively). The initiation schedule, first dose or allergens resulted in no significant differences in the frequency of adverse reactions. The Grass mix extract showed the highest frequency of AR. Sixty-seven percent of SR and 68% of LR were delayed. 64% of these reactions resolved spontaneously while the rest responded favourably to treatment. Adrenaline was administered on one occasion for immediate asthma. There were no cases of anaphylactic shock, hospitalisation or life-threatening situations. Pangramin Plus tolerance, therefore, can be classified as good, similar to conventional schedules, but with the benefits of shorter initiation schedules.

Olerance of a cluster schedule with a house dust mite extract quantified in mass units: multicentre study.

The standardisation of allergenic extracts in micrograms of the major allergen has encouraged the search for new treatment schedules, with the purpose of shortening the number of visits and doses required to reach the maintenance dose without eliciting a greater risk of adverse reactions for the patients. With this objective, a prospective multicentre pharmacovigilance study was designed that included 200 patient with allergic rhinoconjunctivitis and/or allergic asthma sensitised to mites (Dermatophagoides pteronyssinu and/or farinae). The dose increment period was carried out using a cluster schedule, where the optimal dose wa reached after 4 visits, administering two doses in each visit. The duration of the study was 5 months and a total o 1902 doses were administered. At the end of the trial, 31 adverse reactions in 23 patients were recorded. Six of these were systemic (0.3% of t administered doses) recorded in 6 patients (3% of the sample). One was an immediate reaction (grade 1) and delayed (4 mild and 1 moderate). Two were asthmatic exacerbations, 2 cutaneous reactions, 1 rhinitis and 1 an unspecific symptom (not IgE-mediated). Two appeared upon administration of the first vial and the remaining 4 after administration of the third cluster. Therefore, the schedule tested presents an adequate tolerance profile, suggesting savings (compared to th conventional schedule of 13 doses per patient) of 1800 visits and 1000 treatment doses in the whole study.

Immunotherapy safety: a prospective multi-centric monitoring study of biologically standardized therapeutic vaccines for allergic diseases.

BACKGROUND: The fear of side-effects has led to strict regulations preventing a more widespread use of specific immunotherapy (SIT) in some countries, in spite of the low risk of systemic reactions (SRs) reported in well-controlled studies. The goal of the study was to carry out a prospective and multi-centric trial to evaluate the safety, risk factors and compliance degree of commercially available SIT. MATERIALS AND METHODS: The study was carried out in 14 allergy departments from Spain. Four-hundred and eighty-eight patients with rhinitis and/or asthma were submitted to treatment with biologically standardized allergen extracts commercially available. They were administered following the European Academy of Allergy and Clinical Immunology guidelines. RESULTS: Four hundred and twenty-three patients (86.7%) completed the treatment and remained under control at the end of the trial. Out of 17,526 administered doses, 17,368 doses (99.1%) were not associated with a reaction. Eighteen patients (3.7%) experienced 53 (0.3% of the doses) SRs. All immediate SRs were mild or moderate and responded well to ordinary treatment measures. There were no fatal reactions, anaphylactic shock or life-threatening reactions. A higher ratio of SRs was found among asthmatic and dust mite allergic patients, although multi-variable logistic analysis did not demonstrate any risk factor associated with SRs. There was also a subgroup of patients at risk for recurrent reactions, and therefore 40% of SRs had been avoided if the maximal number of SRs had been previously limited to only three SRs. CONCLUSIONS: This multi-centric study showed that SIT was a safe treatment with a very good compliance. Future guidelines of SIT should limit the maximal number of SRs.

The optimal immunotherapy cluster schedule in clinical practice.

The efficacy of injective immunotherapy is no longer a matter of debate, but concerns about its safety and compliance problems (because of the number of visits required for the build-up phase) are limiting factors for wider usage. Different schedules have, therefore, been used in clinical trials with the aim of improving both safety and compliance. We investigated the effects on tolerance of modifications to the starting allergenic dose, of the pharmaceutical presentation of the allergen (aqueous or depot), of the change of the number and volume of the daily administrations through progressive adjustments of the so-called clustered schedule. We took the rate of local and/or systemic side effects as the primary criterion, and were able to gradually reduce the rate of systemic reactions per dose and per patient from 4.1% and 65% to 0.3% and 2.6%, respectively, through four progressive modifications of the starting schedule. According to our data, it is possible to reach the maintenance dose in only four visits with 2 administrations per visit. This was achieved either by switching from aqueous to depot extracts or by using depot extracts from the beginning. These results have been obtained without any kind of premedication and with a wide range of allergens, including mites, epithelia, pollens, and honeybee venom. We have shown that the number of injections administered following the conventional schedule could be reduced by 75%, shortening the build-up phase by 38.5%, without increasing the rate of side effects. We think clustered schedules could lead to a better compliance and to a broader use of injective immunotherapy.

Tolerance of a cluster schedule on the treatment of seasonal allergic respiratory disease with pollen extracts quantified in mass units.

In order to evaluate the tolerance of a cluster schedule on specific immunotherapy (SIT), 306 patients were included in a multicenter study. The patients were suffering from rhinoconjunctivitis with/without asthma, caused by sensitization to olive and/or grass pollen. SIT was administered subcutaneously according to a cluster schedule in which the maintenance dose is reached after four visits (3 weeks). The extracts were biologically standardized with major allergens quantified in mass units. Local reactions appeared in 7.2% of the patients and 1.3% of the doses. Systemic reactions (SR) were recorded in 1.2% of the doses administered to 9.5% of the patients. No anaphylactic shock was registered, and all the SR responded fully and rapidly to treatment. There was no difference in SR according to diagnosis or allergen extract used. The majority of SR occurred with the administration of vial of higher concentration (Vial 2: 7 SR (22%), Vial 3: 32 SR (78%), p < 0.05). Of the 32 SR recorded with Vial 3, 13 (41%) were immediate, with no existing association between dose administered and appearance of SR. However, of the 18 delayed SR (56%), 14 occurred after the administration of the first two doses of Vial 3 and four occurred after administration of the second two doses (78% vs 22%, p < 0.05). On the other hand, this regime realized an important saving in cost and time compared to the conventional schedule (1581 fewer doses and 2754 fewer visits were necessary to reach the optimal dose). Considering all these factors, the clinical profile of the proposed regime may be qualified as good. However, future studies are necessary in order to better adjust the schedule to avoid the delayed SR that occurred after the administration of the first two doses of Vial 3.

Clustered schedules in allergen-specific immunotherapy.

BACKGROUND: Injective immunotherapy is traditionally performed with a build-up phase lasting 3 to 4 months. The costs, decreasing compliance from both patients and clinicians and inconveniences due to this schedule may be overcome using different schedules. METHODS AND RESULTS: A revision of the published papers with clustered schedules has been made. Attention has been focussed on tolerance and its relationships with relevant parameters such as kind of extract (aqueous or depot), allergens and their pharmaceutical presentation, schedule followed, use or not of a premedication, clinical manifestations of patients before treatment. For a better revision, papers dealing with clustered schedules have been divided into two groups. The first group includes 20 papers not designed to study the clustered schedule but using it to study other parameters affected by specific immunotherapy. The second group includes 9 papers specifically or mainly designed to study the clustered schedule. A huge difference in the rate of side effects could be assessed among different papers, even in studies run with similar allergens from the same producer and with a similar schedule. CONCLUSIONS: Summarizing the results of the revision, the following conditions seem to lead to the optimal tolerance of the clustered schedule: use of a premedication; use of a depot preparation; use of no more than 4 administrations per cluster; administration of 1-2 clusters per week and of 4 to 6 clusters in total. These results seem promising but further efforts are required to better define the optimal clustered schedule.

Clustered schedules in allergen-specific immunotherapy

Background: Injective immunotherapy is traditionally performed with a build-up phase lasting 3 to 4 months. The costs, decreasing compliance from both patients and clinicians and inconveniences due to this schedule may be overcome using different schedules. Methods and results: A revision of the published papers with clustered schedules has been made. Attention has been focussed on tolerance and its relationships with relevant parameters such as kind of extract (aqueous or depot), allergens and their pharmaceutical presentation, schedule followed, use or not of a premedication, clinical manifestations of patients before treatment. For a better revision, papers dealing with clustered schedules have been divided into two groups. The first group includes 20 papers not designed to study the clustered schedule but using it to study other parameters affected by specific immunotherapy. The second group includes 9 papers specifically or mainly designed to study the clustered schedule. A huge difference in the rate of side effects could be assessed among different papers, even in studies run with similar allergens from the same producer and with a similar schedule. Conclusions: Summarizing the results of the revision, the following conditions seem to lead to the optimal tolerance of the clustered schedule: use of a premedication; use of a depot preparation; use of no more than 4 administrations per cluster; administration of 1-2 clusters per week and of 4 to 6 clusters in total. These results seem promising but further efforts are required to better define the optimal clustered schedule (AU)

Introducción: La inmunoterapia subcutánea conlleva una fase de incremento de dosis que dura de 3 a4 meses. El coste, la baja aceptación tanto de pacientes como de médicos y los inconvenientes debidos a este esquema convencional, pueden verse mejorados siguiendo pautas alternativas de tratamiento. Método y resultados: Se ha realizado una revisión de los trabajos publicados siguiendo esquemas cluster. La atención se ha centrado en la tolerancia y su relación con parámetros relevantes tales como tipo de extracto (acuoso o depot), alergenos y sus presentaciones farmacéuticas, pauta empleada, uso o no de premedicación y diagnóstico clínico de los pacientes estudiados. Para una revisión mejor, los tra-bajos que siguen pautas cluster han sido divididos en 2 grupos. El primer grupo incluye 20 trabajos no enfocados para el estudio de esquemas cluster sino para valorar otros parámetros relacionados con la inmunoterapia específica. El segundo grupo incluye 9 trabajos diseñados específicamente para estudiar pautas cluster. Se ha observado una gran variabilidad en la tasa de efectos adversos entre los diferentes trabajos, incluso en aquellos estudios desarrollados con alergenos similares producidos por un mismo fabricante y con una pauta similar. Conclusiones: Parece observarse que hay unos determinados factores que podrían influir en la tolerancia óptima de pautas cluster: uso de premedicación; empleo de extractos depot; administración inferior a 4 inyecciones por visita-cluster, pautas cluster con administraciones no superiores a 2 visitas por semana y de 4 a 6 visitas-cluster en total. Estos resultados parecen prometedores, pero se requiere más información para poder definir una pauta de cluster óptima (AU)

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)

Mercurialis annua: characterization of main allergens and cross-reactivity with other species.

A multicentric study was conducted to evaluate the frequency of Mercurialis annua pollen sensitization in several areas of Spain and to select a population sample to characterize the main allergenic components in M. annua pollen. Patients were recruited from six hospitals in Spain. Out of 420 patients sensitized to pollens, 195 (46.4%) showed positive skin tests to M. annua, thus evidencing the high level of sensitization to the pollen of this plant in Spain. Thirty-seven sera with RAST class values to M. annua > or = 3 were selected for SDS-PAGE immunoblotting analysis. Two main allergenic components with molecular weights of 15.8 and 14.1 kD were detected in 59 and 51% of the sera, respectively, and they were identified as profilins. Isolation of the relevant allergens was made by affinity chromatography on a poly-L-proline-Sepharose column, followed by gel filtration and anion exchange chromatography in the micropreparative SMARTs System. A significant but low antigenic cross-reactivity between M. annua and Olea europaea, Fraxinus elatior, Ricinus communis, Salsola kali, Parietaria judaica and Artemisia vulgaris was demonstrated by several in vitro techniques.