Epinephrine auto-injectors: information, education, training and acceptance

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Current practice of allergy diagnosis and the potential impact of regulation in Europe.

In the European Union (EU), the regulatory framework regarding diagnostic allergen extracts is currently in the process of being implemented at the national level. Due to these regulations, the initial and periodic renewal expenses for the registration of diagnostic allergen extracts may render extract production unprofitable. Consequently, many extracts may be at risk of removal from the market. The current survey, which was conducted by a task force of the European Academy of Allergy and Clinical Immunology, aimed to assess the current practice of allergy diagnosis in Europe. This survey revealed that skin tests continue to be the main diagnostic procedure and are used as the first option in almost two-third of all types of allergic diseases and in 90% of individuals suffering from respiratory allergies. Therefore, there is a need to ensure the availability of high-quality allergen extracts to maintain the common diagnostic procedures used by EU professionals. To reach this goal, it is necessary to align efforts and establish active partnerships between manufacturers, relevant scientific societies, consumer organizations and authorities to maintain the availability of these diagnostic tools.

Immunotherapy is allergen-specific: a double-blind trial of mite or timothy extract in mite and grass dual-allergic patients.

BACKGROUND: One hundred years ago, Noon [Lancet 1911;1:1572-1573], using conjunctival provocation testing (CPT), was the first to demonstrate the effectiveness of subcutaneous immunotherapy (SCIT) in grass-allergic subjects with hay fever. In this centenary year, we present data that, by use of CPT and allergen-specific IgG, replicate this observation and additionally confirm the allergen specificity of SCIT by using a double-blind design employing either grass or mite SCIT in dual grass- and mite-allergic individuals. METHODS: Twenty adults (11 females) with perennial rhinoconjunctivitis and exacerbation of symptoms during the grass pollen season and in the autumn had immediate skin and conjunctival sensitivity and raised specific IgE to both Dermatophagoides farinae and Phleum pratense. Participants were randomly assigned to either timothy or D. farinae immunotherapy for 3 years. CPT and specific IgG tests to both allergens were performed annually. After 3 years, subjects gave their blinded overall evaluation. RESULTS: Six mild-to-moderate general reactions occurred in 2 timothy- and 4 mite-treated patients. Four of these patients and 2 other patients withdrew from the study. Seven patients in each group completed the study. After 3 years of immunotherapy, the timothy CPT threshold concentration had increased 16- fold in timothy-treated patients (p < 0.05; between-group change, p < 0.05). The increase in the mite CPT threshold in mite- compared to grass-treated patients was 31-fold (p < 0.05). The overall assessment of conjunctival sensitivity was highly significant in favour of treatment (p < 0.015), as was that of allergen-specific IgG (p < 0.0001). CONCLUSIONS: Allergen immunotherapy is allergen species-specific, as judged by decreased conjunctival sensitivity and changes in allergen-specific IgG concentrations.

Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study.

BACKGROUND: 3-year subcutaneous specific immunotherapy (SIT) in children with seasonal allergic rhinoconjunctivitis reduced the risk of developing asthma during treatment and 2 years after discontinuation of SIT (5-year follow-up) indicating long-term preventive effect of SIT. OBJECTIVE: We evaluated the long-term clinical effect and the preventive effect of developing asthma 7-years after termination of SIT. METHODS: One hundred and forty-seven subjects, aged 16-25 years with grass and/or birch pollen allergy was investigated 10 years after initiation of a 3-year course of SIT with standardized allergen extracts of grass and/or birch or no SIT respectively. Conjunctival provocations were performed outside the season and methacholine bronchial provocations were performed during the season and winter. Asthma was assessed by clinical evaluation. RESULTS: The significant improvements in rhinoconjunctivitis and conjunctival sensitivity persisted at the 10-year follow-up. Significantly less actively treated subjects had developed asthma at 10-year follow-up as evaluated by clinical symptoms [odds ratio 2.5 (1.1-5.9)]. Patients who developed asthma among controls were 24/53 and in the SIT group 16/64. The longitudinal treatment effect when adjusted for bronchial hyper-responsiveness and asthma status at baseline including all observations at 3, 5 and 10 years follow-up (children with or without asthma at baseline, n = 189; 511 observations) was statistically significant (P = 0.0075). The odds ratio for no-asthma was 4.6 95% CI (1.5-13.7) in favor of SIT. CONCLUSION: A 3-year course of SIT with standardized allergen extracts has shown long-term clinical effects and the potential of preventing development of asthma in children with allergic rhinoconjunctivitis up to 7 years after treatment. CLINICAL IMPLICATION: Specific immunotherapy has long-term clinical effects and the potential of preventing development of asthma in children with allergic rhino conjunctivitis up to 7 years after treatment termination.

Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children.

BACKGROUND: A 3-year course of specific immunotherapy (SIT) in children with hay fever to grass and/or birch pollen significantly reduced the risk of developing asthma. To investigate the long-term preventive effect, we performed a follow up--2 years after termination of immunotherapy. METHODS: A total of 183 children, aged 6-14 years with grass and/or birch pollen allergy could be investigated 2 years after discontinuation of SIT or no treatment. Conjunctival provocation tests (CPTs) and methacholine bronchial provocation tests were carried out during the season and winter after 5 years. The development of asthma was assessed by clinical evaluation. RESULTS: The significant improvement in hay fever and CPT results observed after 3 years of SIT persisted at the 5-year follow-up. No difference in bronchial responsiveness to methacholine was found after 5 years because of spontaneous improvement during the follow-up period in the control patients. The immunotherapy-treated children had significantly less asthma after 5 years as evaluated by clinical symptoms [odds ratio 2.68 (1.3-5.7)] in favor of SIT for prevention of development of asthma and significantly less patients reported an increase in asthma scores (P < 0.01). CONCLUSION: Immunotherapy for 3 years with standardized allergen extracts of grass and/or birch shows long-term clinical effect and preventive effect on development of asthma in children with seasonal rhinoconjunctivitis.

Variability of airborne cat allergen, Fel d1, in a public place.

Allergen exposure is a risk to develop an IgE-mediated sensitization. The amount of allergen inhaled per unit time should be related to the amount present in the air, i.e. airborne allergen. Thus, measuring allergen levels in the air would be more relevant than measuring allergen levels in dust. Allergens are present in the air in very minute quantities and usually become airborne after disturbance. Large variation of allergen levels have been found in dust. In this study, we measured variability of airborne cat allergen, Fel d1, in a public place using a high-volume air-sampler. We also studied the distribution and relationship between dust and airborne cat allergens in homes and schools. Air samples were collected at three different airflow rates, i.e. 55, 40, and 30 m3 of air per hour. The concentration of airborne Fel d1 in the community gymnastic hall varied from 1 to 10 pg/m3 within a period of 3 weeks, at airflow rates 55-30 m3/h. The coefficient of variation for repeated samplings was 14-43% (day-to-day variation) and 27-38% (within-day variation). As expected, higher levels of airborne cat allergens were found in homes with cats than in cat-free environments. There was a significant relationship between cat allergen levels in dust and air (r=0.7, P<0.01). Our study demonstrates that when measuring airborne cat allergen a large variation is observed within a day and between days. The large variability of measurement may be explained by the disturbance in the environments. We suggest, that when exposure assessment is made the environment in question should be analyzed, if possible in several occasions.

'EUROPART'. Airborne particles in the indoor environment. A European interdisciplinary review of scientific evidence on associations between exposure to particles in buildings and health effects.

The relevance of particle mass, surface area or number concentration as risk indicators for health effects in non-industrial buildings has been assessed by a European interdisciplinary group of researchers (called EUROPART) by reviewing papers identified in Medline, Toxline, and OSH. Studies dealing with dermal effects or cancer or specifically addressing environmental tobacco smoke, house dust-mite, cockroach or animal allergens, microorganisms and pesticides were excluded. A total of 70 papers were reviewed, and eight were identified for the final review: Five experimental studies involving mainly healthy subjects, two cross-sectional office studies and one longitudinal study among elderly on cardiovascular effects. From most studies, no definite conclusions could be drawn. Overall, the group concluded that there is inadequate scientific evidence that airborne, indoor particulate mass or number concentrations can be used as generally applicable risk indicators of health effects in non-industrial buildings and consequently that there is inadequate scientific evidence for establishing limit values or guidelines for particulate mass or number concentrations.

Seasonal differences of peak expiratory flow rate variability and mediators of allergic inflammation in non-atopic adolescents.

Variations in peak expiratory flow (PEF) and serum eosinophil mediators were studied in healthy adolescents. Twenty-five boys and 31 girls, 11-16 years of age (mean age 14.3 years), were selected and investigated during the birch pollen season of 1995; 45 were also investigated during the autumn of the same year. The PEF was measured twice daily and eosinophil mediators in serum and in urine were measured by radioimmunoassay (RIA) once during the birch pollen season and once in autumn. The type values of the daily PEF variation, expressed in amplitude percentage mean, were 6.4 and 3.9%, mean values were 7.35 and 6.74%, and the 95th percentiles were 18 and 14%, during the birch pollen season and autumn, respectively. The 95th percentiles were 41 and 38 microg/l for serum eosinophil cationic protein (s-ECP), 74 and 62 microg/l for serum eosinophil protein X (s-EPX), 987 and 569 microg/l for serum myeloperoxidase (s-MPO), and 165 and 104 microg/mmol for urinary eosinophil protein X/urinary creatinine (u-EPX/u-creatinine), during the birch pollen season and autumn, respectively. The levels of the eosinophil mediators decreased significantly from May (n = 56) to November (n = 45), for s-ECP from a median value of 14 microg/l to 7 microg/l (p= 0.001), for s-EPX from a median value of 28 microg/l to 20 microg/l (p= 0.001), and for the neutrophil mediator, s-MPO, from a median value of 440 g/l to 292 g/l (p< 0.001). The PEF variability decreased significantly (p= 0.037), from spring (n = 55; median 8%, 95% confidence interval [CI] 7.8-10.19) to autumn (n = 44; median 6%, 95% CI 6.1-8.9). A significant correlation was found between the levels of s-ECP and s-EPX (rs = 0.7, p< 0.001), between s-ECP and s-MPO (rs = 0.6, p< 0.001), between s-EPX and s-MPO (rs = 0.4, p< 0.005), and between s-EPX and u-EPX/u-creatinine (rs = 0.6, p< 0.0001), in the birch pollen season (n = 56) and in the autumn (n = 45). There was a positive correlation found in PEF variability between the two seasons (n = 43; rs = 0.5, p= 0.0006). No other correlation was found between PEF variability and any other parameters. The difference in the levels of eosinophil mediators between seasons in non-atopic, healthy children is unexplained. Normal limits for mediators were higher and PEF variability was almost the same as has been reported in adults. When using normal values, seasonal influences should be considered.

A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force.

This report has been prepared by an EAACI task force representing the five EAACI Sections and the EAACI Executive Committee composed of specialists that reflect the broad opinion on allergy expressed by various clinical and basic specialties dealing with allergy. The aim of this report is to propose a revised nomenclature for allergic and related reactions that can be used independently of target organ or patient age group. The nomenclature is based on the present knowledge of the mechanisms which initiate and mediate allergic reactions. However, the intention has not been to revise the nomenclature of nonallergic hypersensitivity.

Biologic activity of Dermatophagoides siboney and Blomia tropicalis allergens in exposed and unexposed mite-allergic individuals. Effect of patient selection on the biologic standardization of mite extracts.

BACKGROUND: This study aimed to investigate the influence of patient selection criteria, i.e., mite-allergic individuals exposed and not exposed to Dermatophagoides siboney and Blomia tropicalis, on the biologic activity of mite extracts. Determination of the potency of mite extracts in vivo requires selection of patients with a clinical history of mite allergy. In Scandinavia, there are some anamnestic criteria for mite allergy, whereas in the tropics, where patients are continuously exposed to high levels of mites, selection of patients with mite allergy by clinical history is difficult. METHODS: A total of 210 Cuban asthmatics with continuous symptoms, and 43 Swedes with a clinical history of mite allergy were investigated. Skin prick tests were performed with D. siboney, D. pteronyssinus, D. farinae, B. tropicalis, Acarus siro, Lepidoglyphus destructor, and Tyrophagus putrescentiae extracts. For analysis of the biologic activity of mite extracts, Cuban patients were divided into four groups: 1) all patients skin-test-positive to mites 2) patients positive to mites, but not to other inhalant allergens 3) patients reacting most to the mite species analyzed 4) patients reactive only to mites and reacting most to the mite species analyzed. The biologic potency was calculated according to the Nordic Guidelines. RESULTS: Due to cross-reactivity between mites, Swedish mite-sensitive patients, with a clear clinical history of mite allergy, but not exposed to D. siboney and B. tropicalis, were more skin reactive to these mites than were Cubans. The estimated potency increased gradually to >200% in group 4. In group 1 Cubans, the reactivity to all mites but B. tropicalis was lower than that in mite-sensitive Swedes. CONCLUSIONS: According to the influence of patient selection criteria on the estimation of the potency of mite extracts, the determination of the biologic activity of allergenic extracts in subjects without a clear-cut clinical history should be replaced by new methods when available.

Cross-reactivity between Dermatophagoides siboney and other domestic mites. II. Analysis of individual cross-reacting allergens after SDS-PAGE and Western blotting inhibition.

BACKGROUND: Dermatophagoides siboney (Ds) cross-reacted with other mite allergens in mite-allergic patients. The aim of this study was to investigate the cross-reactivity between individual allergens responsible for this cross-reactivity. METHODS: The inhibition of IgE binding to Ds allergens was investigated by non-reducing SDS-PAGE and Western blotting. Nitrocellulose membranes were incubated with a pool of sera from mite-sensitive asthmatics, after the addition of serial dilutions of D. farinae (Df), D. pteronyssinus (Dp), D. microceras (Dm), Lepidoglyphus destructor (Ld), Tyrophagus putrescentiae (Tp), Acarus siro (As) and Blomia tropicalis (Bt). N-terminal amino acid sequences and amino acid analysis of the purified major allergens, Der s 1, 2 and 3, were performed after transfer to polyvinylidene difluoride membranes. RESULTS: The inhibition was higher with Df(86%), Dp (54%) and Dm (49%) extracts than with Ld (20%), Tp (11%), As (18%) and Bt (6%). The dose-response inhibition showed a diverse pattern for the individual allergens. Despite the high cross-reactivity between the pyroglyphid mites, some proteins of Ds were less inhibited, e.g. by the Df and Dp 80-kD protein, and by the Dm and Dp 52-, 37-, 30- and 14-kD allergens. The 65-, 62-, 37- and 30-kD proteins were always inhibited more than 50% by all the mite extracts at the maximum concentration used. The 80-, 52-, 43-, 27- and 14-kD proteins cross-reacted to a lesser extent. Individual allergens of Ds were much less inhibited by non-pyroglyphid mites. However, at the highest concentration, Ld also inhibited most of the Ds allergens. All the ten selected allergens were inhibited to some extent by the heterologous mite extracts. The N-terminal sequences of Der s 1, 2 and 3 allergens showed higher homology to Df and Dm than to Dp. The homology of the group 2 allergens was higher than that of the group 1 allergens. CONCLUSION: The individual allergens of Ds were more similar to Df and Dm than to Dp. There was a limited and variable cross-reactivity with non-pyroglyphid mites. No single allergen was unique for Ds.

Concentrations of cat (Fel d1), dog (Can f1) and mite (Der f1 and Der p1) allergens in the clothing and school environment of Swedish schoolchildren with and without pets at home.

To investigate whether our hypothesis that cat and dog owners bring allergens to public areas in their clothes was true or not, we studied the levels of Fel d1, Can f1, Der p1 and Der f1 in dust from the clothes and classrooms of children in a Swedish school. We also investigated the levels of allergen in different areas in the four classrooms used by the children. Thirty-one children were selected in four classes, forming three groups: cat owners, dog owners and children without a cat or dog at home. Furthermore, a group of children with asthma was included. Cat and dog allergens were detected in all 57 samples from clothes and classrooms. Mite allergen Der f1 was detected in low concentrations in 6 out of 48 and Der p1 in 5 out of 46 samples investigated. The concentrations of Can f1 were higher than those of Fel d1 in samples from clothes (geometric mean: 2676 ng/g fine dust and 444 ng/g) and classrooms (Can f1: 1092 ng/g, Fel d1: 240 ng/g). The dog owners had significantly higher concentrations of Can f1 (8434 ng/g fine dust) in their clothes than cat owners (1629 ng/g, p < 0.01), children without cat or dog (2742 ng/g, p < 0.05) and children with asthma (1518 ng/g, p < 0001). The cat owners did not have significantly higher levels of Fel d1 (1105 ng/g) in their clothes compared to the other three groups. (D: 247 ng/g, nCnD: 418 ng/g) but the levels were significantly higher than for all children without a cat at home (345 ng/g, p < 0.05). No concentrations of mite allergen and low concentrations of Fel d1 and Can f1 were found in the children's hair. There were significantly higher concentrations of Fel d1 and Can f1 in dust from curtains than in samples from floors and bookshelves (p < 0.05). There was no significant difference between the allergen concentrations in samples from curtains and from desks and chairs, including the teachers' chairs, the only upholstered furniture in the rooms. Our results support the hypothesis that cat and dog owners bring allergens to public areas in their clothes and support other studies showing that textiles and upholstered furniture function as reservoirs of cat and dog allergens. Thus, children with asthma and other allergic diseases will be exposed to cat and dog allergens at school and by contact with pet owners, even if they avoid animal allergens at home.

Mite allergens. Collection, determination, expression of results, and risk levels for sensitization and symptom induction.

The presence of mite allergens in dust can be determined by counting mites at different stages of development in dust and by determination of the major allergen content (Der p 1 ) in dust and air, which is crucially important to allergic patients. For comparison of results, similar methods for collection of dust and air must be used. Due to their size, mite bodies and fecal particles are airborne only directly after disturbance. Special filters should be used for dust collection, and upholstered surfaces should be vacuumed for 2 min/m2 (minimum 4 m2) and hard surfaces for 1 min/m2 (minimum 8 m2). Heavy contaminations should be removed. Preferably, the method given in the ISAAC study should be followed. Samples should be deep-frozen for at least some days to kill the mites. ELISA techniques, preferably using polyclonal antibodies and antigen with all isoforms present, should be used for determination of allergens. The allergen load has been given in ng/g of dust, but allergen/m2 or per sample area should be preferred. Allergen in the air should be given in pg/m3. A tentative limit of 2000 ng/g was proposed for sensitization and asthma. This limit is still valid on a population basis, but recent data indicate that highly susceptible young children become sensitized at concentrations 10-100 times lower and that ng levels of cat allergen/m3, as found in schools, induce chronic asthma.