Standardized Allergen Extracts Research Articles

Optimization of Allergen Standardization

Preparation of high quality allergen extracts is essential for the diagnosis and immunotherapy of allergic disorders. Standardization of allergen extracts concerns determination of the allergen unit, development of reference material and measurement of the overall IgE binding capacity of an allergen extract. Recently, quantification of individual allergens has been the main focus of allergen standardization because the allergenicity of most allergen extracts is known to be mainly dependent on the content of a small number of allergen molecules. Therefore, characterization of major allergens will facilitate the standardization of allergens. In this article, we review the current state of allergen standardization. In addition, we briefly summarize the components of allergen extracts that should be under control for the optimization of allergen standardization, since its adjuvant-like activities could play an important role in allergic reactions even though the molecule itself does not bind to the IgE antibodies from subjects.

Safety of ultra‐rush titration of sublingual immunotherapy in asthmatic children with tree‐pollen allergy

The recommendation to use sublingual-swallow immunotherapy (SLIT) in children and adults with allergic rhinitis has been established over the past decade. Recently, ultra-rush titration of SLIT has become more and more common, raising concerns about its safety in children with asthma. Fifty-four children with asthma and adolescents aged 6–14 with documented allergic disease because of tree pollen (birch and possibly alder and/or hazel) from 14 study centers in Germany participated in a randomized, double-blind, and placebo-controlled study. Twenty-seven were randomized to receive SLIT with standardized birch pollen allergen extract and the other 27 to receive placebo. An ultra-rush high-dose SLIT titration regimen reaching the maintenance dose of 300 index of reactivity (IR) within 90 min (30–90–150–300 IR) was used. The difference in mean PFR changes during ultra-rush titration between SLIT and placebo was not significant (p = 0.056). A 95% probability that SLIT does not decrease PFR during ultra-rush titration was demonstrated. Neither anaphylactic shock nor else serious systemic reactions to the study drug occurred. No serious adverse event assessed by the investigator as related to study drug treatment was reported.

Sensitization to Dermatophagoides, Blomia tropicalis, and Other Mites in Atopic Patients

Background. House dust mites (HDMs) are important causes of persistent allergic diseases, such as asthma and rhinitis. Various types of mites are found in the house dust of many countries, including Israel. Objective. To evaluate the prevalence of sensitization to various HDMs in patients with perennial allergic rhinitis and asthma Methods. Sensitization of 117 patients with persistent rhinitis who attended the Allergy and Asthma Center in Tel Aviv (Israel) was evaluated by a skin prick test (SPT) using standardized allergenic extracts. The tested mites were Dermatophagoides farinae (DF), Dermatophagoides pteronyssinus (DP), Lepidoglyphus destructor (LD), Blomia tropicalis (BT), Tyrophagus putrescentiae (TP), Acarus siro (AS), Glycyphagus domesticus (GD), Blomia kulagini (BK), and Tetranychus urticae (TU). Results. Most patients (n = 95, 81%) had a positive SPT to at least one mite extract. The three most frequent positive reactions were to DF (78%), DP (75%), and, unexpectedly, BT (77%). The correlation between DF and DP sensitization was higher than the correlation between DF or DP to BT (r = .78 versus r = .60, p < .05). Six patients had positive skin reactions to at least one mite species other than DF, DP or BT, mainly LD (n = 2, 2.1%) and BK (n = 4, 3.8%). Conclusions. The findings of this study identified the most ubiquitous mites to which Israeli patients with allergic rhinitis were sensitized and indicated the importance of BT as an allergen. Extracts of these mites may provide a more accurate diagnosis and effective treatment of respiratory diseases due to mite allergy in Israel and probably in other countries with similar climes.

Allergen analysis in 816 patients with chronic allergic dermatoses

Objective To assess the distribution of common allergens in atopic dermatitis, chronic urticaria and chronic eczema. Methods Skin prick tests were performed on the flexor surface of forearm of 816 patients with different chronic allergic dermatoses (including atopic dermatitis, chronic urticaria and chronic eczema) using standard allergen extracts, 0.1% histamine solution (positive control ) and physiological saline (negative control). Statistical analysis was carried out by the chi-square test. Results The sensitization rate to dust mite, which varied from 50.0% to 78.6%, was highest among the tested allergens, followed by that to animal hair (7.1%-21.4%) and mould (7.1%-14.3%). Also, statistically different sensitization rates to these three allergens were observed between patients with atopic dermatitis, chronic urticaria and chronic eczema (all P ＜ 0.01 ), and atopic dermatitis patients showed the highest sensitization rate to all the three allergens. No significant difference was observed in the sensitization rate to shrimp among the three groups of patients (P ＞ 0.05), although among food allergens, it was the most common sensitizing allergen with a sensitization rate of 6.6% to 14.3%. A relative increment was observed in the sensitization rate to tuna (9.5%)in patients with urticaria as well as in that to egg, milk and celery (7.1%-14.3%) in patients with atopic dermatitis; furthermore, a statistical difference was noted in the sensitization rate to the four allergens among the three groups of patients (all P ＜ 0.05). Conclusions Inhaled allergens are common sensitizing agents in chronic allergic skin diseases; dust mite predominates in these allergens, especially in patients with atopic dermatitis who exhibit the highest sensitization rate. Key words: Skin tests; Pricking needling; Allergens; Observation

Étude des sensibilisations aux aéroallergènes chez les enfants asthmatiques âgés de plus de trois ans et habitant dans la zone Nord de lima (Pérou)

Objectives Determine the sensitization status to aeroallergens of asthmatic children older than three years of age in a hospital center North of Lima, Peru. Patients and methods A descriptive, cross-sectional study involving 493 asthmatic children older than 3 years of age was carried out to determine the frequency of sensitization to common aeroallergens. Prick-tests using 12 commercial, standardized allergen extracts ( Dermatophagoides pteronyssinus, Dermatophagoides farinae, Blomia tropicalis, Alternaria, Cladosporium, Penicilium, Aspergillus, Trichophyton, dog and cat dander, Blattella germanica, and a three grass-pollen mix) were carried out on 348 of these children. Total serum IgE levels (UI/ml) were determined in 202 of these children and spirometric parameters (FVC, FEV1, and MEF 25–75, both pre- and post-B 2 bronchodilation) were performed in 95 of them. Results The mean age of the 493 asthmatic children was 6.2 years; 313 (63%) also had allergic rhinitis. 44/95 (46.3%) had positive spirometric parameters. There were significant differences between pre- and post-B 2 values in the following spirometric parameters: for FEV1, 111.1 versus 115.1 ( p = 0.004); for MEF 25–75, 93.7 versus 102.8 ( p = 0.002). For FVC, the difference (108.7 versus 111.0) was not significant ( p = 0.062). The mean total serum IgE value was significantly different between the aeroallergen-sensitized group and the group not sensitized to these aeroallergens (846.0 UI/ml versus 343.3 UI/ml, p = 0.001). In 306/348 (88%), there was sensitization to at least one aeroallergen. By group, 80.5% were sensitized to house dust mites, 44.5% to an animal dander, 42.2% to moulds and 4.3% to pollens. Sensitization to common house dust mites increased with the children's age. Conclusion Most asthmatic children older than 3 years of age in North of Lima, Peru were sensitized to one or more aeroallergen, mainly to house dust mites.

Standardization of allergen products: 1. Detailed characterization of GMP‐produced recombinant Bet v 1.0101 as biological reference preparation

Standardization of allergen extracts requires the availability of well-characterized recombinant allergens, which can be used as reference standards provided by the European regulatory authorities. The objective of this study was the detailed physicochemical and immunological characterization of rBet v 1.0101, which shall be used in a ring trial within the framework of the Biological Standardization Programme BSP090 of the European Directorate for Quality of Medicines and Healthcare. Recombinant Bet v 1.0101 Y0487 was produced under good manufacturing practice conditions and analysed by an array of physicochemical and immunological methods for identity, quantity, homogeneity, folding and denaturation, aggregation state and stability in solution, as well as biological activity. Batch Y0487 was shown to contain monomeric and well-folded protein being identical with rBet v 1.0101, as determined by mass spectrometry. SDS-PAGE, isoelectric focusing, deamidation analysis and size-exclusion chromatography with light scattering revealed sample homogeneity of >99.9%. Upon storage at +4 degrees C batch Y0487 retained the monomeric state up to 3 months. Protein quantification determined by amino acid analysis was found coinciding with half-maximal inhibition of serum IgE in ELISA. Biological activity of batch Y0487 was shown to be comparable to natural Bet v 1 by IgG and IgE immunoblotting, as well as basophil and T-cell activation. Recombinant Bet v 1.0101 Y0487 was characterized extensively by physicochemical and immunological methods. It was shown highly stable, monomeric and immunologically equivalent to its natural counterpart. Thus, it represents an appropriate candidate reference standard for Bet v 1.

Systemic tolerability of specific subcutaneous immunotherapy with index-of-reactivity–standardized allergen extracts administered using clustered regimens: a retrospective, observational, multicenter study

Subcutaneous immunotherapy is an etiological therapy for certain IgE-mediated diseases. It is usually administered in 2 phases: induction and maintenance. Administration in clustered schedules during the induction phase may be a valid alternative to reach the maintenance dose early if the treatment is well tolerated. To compare the tolerability of different clustered schedules in subcutaneous immunotherapy with standardized allergen extracts administered and to identify factors associated with increased risk of systemic reactions (SRs). Retrospective, observational, multicenter study in patients with allergic respiratory disease. Data from 1,147 patients were collected. Thirty-nine patients (3.4%) experienced 42 SRs (0.6% of doses). According to the European Academy of Allergy and Clinical Immunology SR grading system, there were 7 grade 0 reactions (16.7%), 26 grade 1 reactions (61.9%), 8 grade 2 reactions (19.0%), and 1 grade 3 reaction (2.4%). There were no grade 4 SRs (anaphylactic shock). We observed a higher risk of SRs in patients who received an initial dose higher than 0.3 index of reactivity (IR); only 2 reactions occurred after administration of the initial dose of the regimen, both with 0.4 IR. The remainder appeared in subsequent injections, although never with a dose lower than 0.35 IR. Clustered regimens with IR-standardized extracts are an alternative to classic immunotherapy thanks to their low incidence of SRs compared with other rapid regimens during the induction phase. The ideal clustered regimen should start at an initial dose no greater than 0.35 IR to minimize the incidence of SRs.

Allergen-specific immunotherapy of allergy and asthma: current and future trends

Allergen-specific immunotherapy is the only immunomodulatory and etiological therapy of allergy and asthma. Conventional specific immunotherapy (SIT) with whole-allergen extract is antigen specific, effective on multiple organs, efficient on asthma in defined conditions, provides long-lasting protection and is cost effective. Moreover, SIT is able to prevent the course of rhinitis to asthma. SIT has its drawbacks: the long duration of treatment, the unsatisfactory standardization of allergen extracts and a questionable safety level. Novel approaches are aimed at drastically reducing adverse anaphylactic events, shortening the duration of therapy and improving its efficacy. Novel promising approaches have based their formulation on a limited set of recombinant allergens or chimeric molecules as well as on hypoallergenic allergen fragments or peptides. The simultaneous use of adjuvants with immunomodulatory properties may contribute to improve both the safety and efficacy of allergen-SIT of allergy and asthma.

The European Union Biological Standardization Program: Detailed Characterization of GMP-produced Recombinant Bet v 1.0101 and Phl p 5.0109 as Candidate Reference Standards

RATIONALE: Standardization of allergen extracts requires availability of well-characterized recombinant allergens used as reference standards provided by the European regulatory authorities. The objective of this study was the detailed physicochemical and immunological characterization of rBet v 1.0101 and rPhl p 5.0109, which shall be used in a ring trial within the framework of the Biological Standardization Program BSP090 of the European Directorate for Quality of Medicines and Healthcare (EDQM).

Treatment of grass pollen allergy: focus on a standardized grass allergen extract - Grazax®.

Immunotherapy is the only treatment for allergy that has the potential to alter the natural course of the disease. Sublingual immunotherapy (SLIT) for grass pollen-induced rhino-conjunctivitis has been developed to make immunotherapy available to a broader group of allergic patients. In the largest clinical programme ever conducted with allergen-specific immunotherapy, over 1,700 adults and 260 children have been exposed to Grazax(®). Grazax is formulated as an oral lyophilisate (tablet) for sublingual administration, containing 75,000 SQ-T standardized allergen extract of grass pollen from Phleum pratense. Grazax is indicated for treatment of grass pollen-induced rhinitis and conjunctivitis in adult patients with clinically relevant symptoms and diagnosed with a positive skin prick test and/or specific IgE test to grass pollen. In phase I trials doses from 2,500 to 1,000,000 SQ-T were tested. All doses were well tolerated and 75,000 SQ-T, with approximately 15 mug major allergen protein, was chosen as the optimal dose. Three phase III trials are ongoing, one being a long-term trial. Results from GT-08 trial first and second treatment years showed a reduction of 30% and 36%, respectively, in daily rhino-conjunctivitis symptom scores and a reduction of 38% and 46% of daily rhino-conjunctivitis medication scores compared with placebo over the entire grass pollen season. Subjects treated with Grazax also had an increased number of well days and improved quality of life, and more subjects experienced excellent rhino-conjunctivitis control. The most common adverse events related to Grazax are local reactions, such as pruritus, edema mouth, ear pruritus, throat irritation, and sneezing. We conclude that Grazax is efficacious and safe for treatment of rhino-conjunctivitis due to grass pollen allergy.

The CREATE project without parietaria pollen: can it be true?

The March issue of Allergy featured an interesting article by Dr van Ree: The CREATE project development of certified reference materials for allergic products and validation of methods for their quantification (1). It represents, in our opinion, a great effort and a decisive step to achieve a shared standardization of allergen extracts for the diagnosis and treatment of allergic disorders. Nevertheless, Parietaria pollen and its allergens were not mentioned on the manuscript. Thousands of patients, both adults and children suffer from seasonal asthma and rhinitis caused by sensitization to pollens of the Urticaceae family (Parietaria judaica and Parietaria officinalis) (2); in Croatia, France, Greece, Israel, Italy, Spain, Turkey, and in other Mediterranean countries, Parietaria pollen is a common cause of sensitization to inhalant allergens. The pivotal role of Parietaria (pellitoryof-the-wall) in the Mediterranean area along with that of Grass and Olive tree was confirmed recently (3, 4). In this context, the risk for the authors of the CREATE project, seemingly without allergens of Urticaceae family, is to cut off, by the technological and scientific progress, the patients in South of Europe. We agree with the authors that the current system of allergens standardization in not tenable as an international system of standardization; however, in our opinion, a yardstick for Parietaria could also be used by the researchers to improve, in future, symptoms and quality of life of the patients allergic to allergens of Urticaceae family.

Double-blind, placebo-controlled evaluation of grass pollen specific immunotherapy with oral drops administered sublingually or supralingually

Forty-one patients suffering from grass pollen allergy underwent specific immunotherapy with standardized allergen extract consisting of six grass pollens (H-Al per os) administered either sublingually or supralingually for one year. In order to investigate clinical and immunological changes induced by the administration of allergens via the oral mucosa, the double-blind, placebo-controlled, randomized design of the trial with 30 other patients enrolled in placebo groups was applied. Specific immunotherapy with oral drops administered sublingually or supralingually was performed in the same way, keeping the drops under or on the tongue, respectively, for 1-2 min before swallowing them; at the end of the trial the cumulative dose of the allergen was almost 20 times higher than that of the subcutaneous therapy with corresponding allergen preparation. Data about symptoms scores and drugs intake during grass pollen season, as well as skin reactivity, levels of specific IgG and IgE antibodies, before the study and after the study's completion, were obtained. It was found that both routes of administration are effective according to subjective clinical parameters and drug consumption, with a highly significant reduction of symptoms and drug intake favoring sublingual administration where a reduction of more than 60% was achieved. Only sublingual active group showed a significant increase in Dactylis glomerata-specific IgG serum levels. Adverse effects were limited to a small number of generally mild local and/or systemic reactions. The results suggest that the administration of allergens via the oral mucosa is safe and clinically effective, favoring the sublingual rather than supralingual route.

Blocking Antibody Is Generated in Allergic Rhinitis Patients during Specific Immunotherapy Using Standardized Japanese Cedar Pollen Extract

Background: Japanese cedar pollen is by far the most important cause of allergic rhinitis in Japan. In this study, we assessed the induction of blocking antibody during specific immunotherapy (SIT) using a recently standardized allergen extract from Japanese cedar pollen. Methods: Basophils from nonallergic subjects were passively sensitized with serum samples prepared from pollinosis patients before and after SIT; all patients showed good clinical efficacy. The cells were then stimulated with the standardized allergen, and histamine release was measured. In most experiments, the basophil stimulation buffer contained 1% serum. Results: Pollinosis patients’ sera obtained both before and after SIT showed essentially similar sensitizing capacity for basophils. Basophil degranulation in response to a relatively low concentration of pollen extract was effectively suppressed by addition of post-SIT serum samples, indicating the presence of blocking antibody. The blocking antibody was IgG, and its potency varied widely among the donor patients. Conclusions: The standardized allergen extract from Japanese cedar pollen is useful not only for clinical application in SIT, but also for testing for induction of blocking antibody during SIT.

Sublingual-oral administration of standardized allergenic extracts: phase 1 safety and dosing results

European studies provide a preponderance of evidence for sublingual allergen immunotherapy (SLIT) safety and efficacy, but they use allergen products that differ from those expected to be approved in the United States. To determine the safety and tolerability of 4 US-licensed standardized SLIT allergenic extracts. Adults 18 to 50 years old with allergic rhinitis with or without asthma due to timothy grass pollen, short ragweed pollen, house dust mite, or cat hair allergy completed a single-session dose escalation followed by an 8-week, open-label daily course of SLIT. Participants documented the presence and severity of adverse effects and adherence using a daily electronic diary. Ninety-one participants initiated treatment, and 77 completed the phase 1 testing. Maximum tolerable doses ranged from 50 to 2,090 BAU for cat hair and dust mite extract, 31 to 91 Amb a 1 Units for short ragweed pollen extract, and 50 to 21,090 BAU for timothy grass pollen extract. During the 8-week treatment course, 98.9% of participants reported at least 1 mild, 70.4% at least 1 moderate, and 13.6% at least 1 severe adverse effect. Most adverse effects (94.6%) were rated as mild, 5.2% as moderate, and 0.1% as severe; nasal and oral-mucosal adverse effects were most commonly reported. No life-threatening adverse reactions occurred in more than 4,500 administered doses. Daily sublingual-oral dosing of standardized allergenic extracts at maximum tolerable doses was generally well tolerated. These results are a first step toward establishing the safety of US-licensed SLIT extracts when appropriately self-administered and monitored.

Sensitisation to aeroallergens in Brazilian adolescents living at the periphery of large subtropical urban centres

To evaluate the sensitization to aeroallergens determined by skin prick test (SPT) in Brazilian adolescents, and to correlate its positivity with the diagnosis of asthma and/or rhinitis based on the written questionnaire (WQ) of ISAAC phase III study. A total of 996 adolescents (387 boys) were selected by systematic samples. A standard allergen extracts panel (positive/negative control, D pteronyssinus [Dpt], P americana [Pa], B germanica [Bg], dog, cat, fungal and grass mix) was used and its positivity compared with positive responses to asthma, rhinitis or both. Positive SPT to at least one allergen was observed in 466 adolescents (46.8 %), with sensitisation to Dpt in 79.1 %. Positivity to more than one allergen occurred in 232 students (49.8 %). The frequency of positive SPTs was significantly higher among adolescents with asthma (OR = 2.16), rhinitis (OR = 1.69), and asthma and rhinitis (OR = 2.03). Positive SPT to four or more allergens were higher among asthmatics (OR = 2.6) and among adolescents with asthma and rhinitis (OR = 3). A high sensitisation rate to aeroallergens was observed, significantly higher among those with asthma, rhinitis or a combination of both, especially in multiple sensitisations.

Ranitidine (150 mg daily) inhibits wheal, flare, and itching reactions in skin-prick tests

H(1)-receptor antagonists are known to suppress reactions in skin-prick tests (SPTs); however, the effect of H(2)-receptor antagonists, which are widely used in our everyday practice, remains unclear. The aim of this study was to determine the influence of ranitidine on wheal, flare, and itching sensation in SPTs. Twenty-one atopic patients (5 women and 16 men) with an average age of 28.04 years (SD, +/-8.24) were tested with histamine, codeine, negative control solution, and standard allergen extracts. Ranitidine (150 mg daily), loratadine (10 mg daily), or placebo were given to the volunteers for 5 days in a double-blind manner with 14 days of washout period. SPTs were applied to the volar surface of a forearm. There was no difference in wheal, flare, and itching between SPTs performed after placebo and washout period. The analysis revealed a statistically significant suppression of wheal and flare by ranitidine and loratadine (p = 0.013 and <0.00001, respectively, for wheals after allergens solutions tests, Wilcoxon rank-sum test). We found a significant suppression of itching induced by ranitidine (reduction of 26.85%; p = 0.005) and loratadine (29.6%; p = 0.005) as compared with placebo (p = 0.068 versus washout). Our data show a suppressive effect of ranitidine on the wheal, flare, and itching sensation in SPT. Because the sensitivity and specificity of skin testing requires withholding medication that could change the skin reactivity, it seems important to take into account the possible influence of H(2)-receptor antagonists on allergy diagnosis and therapy.

Anti-IgE-Antikörper und spezifische Immuntherapie (SIT)

For patients with a confirmed association between allergic sensitization and disease (allergic rhinitis or asthma), SIT is indicated as the only current treatment option with curative capabilities. However, the application of SIT is limited by the relative high risk for severe side-effects and the possibility of weak or delayed efficacy especially for patients with severe allergic asthma. Therefore a combination of omalizumab, a monoclonal anti-IgE antibody, and SIT might be useful for the treatment of allergic diseases. There are now published three clinical studies, which demonstrated consistently that the combination of active immunization with standardised allergen extracts (SIT) and passive immunization with anti-IgE antibody (omalizumab) was superior to SIT alone in reducing symptoms and rescue medication use in patients with allergic rhinitis and in patients with moderate allergic asthma and comorbid allergic rhinitis. Moreover, pre-treatment with omalizumab prior to an intensified rush immunotherapy compared to SIT alone significantly decreased the otherwise high rates of allergic side effects, including anaphylaxis reactions, in patients with ragweed-induced allergic rhinitis. Conclusion: Combination of omalizumab with SIT for treatment of patients with allergic is safe and reduced symptom load in a statistically significant and clinically meaningful manner. The clinical implication of these findings is that also patients with moderate to severe allergic asthma pretreated with anti-IgE might prospectively benefit from a SIT as a causal treatment option.

Stability of standardized grass, dust mite, cat, and short ragweed allergens after mixing with mold or cockroach extracts

Limited data are available on the immunochemical compatibilities of standardized and nonstandardized allergen extracts in immunotherapy vaccines. Extract combinations recommended in immunotherapy practice parameters are based primarily on theoretical considerations rather than on actual product compatibilities. To determine the stabilities of standardized grass, short ragweed, dust mite, and cat extracts after mixing with fungal and cockroach extracts at final product concentrations similar to those recommended for maintenance immunotherapy injections. Mixtures were prepared using individual products from multiple sources at variable glycerin concentrations and were analyzed after storage for up to 1 year at 2 degrees C to 8 degrees C. Quantitative analyses included radial immunodiffusion assays for cat Fel d 1 and short ragweed Amb a 1 and human IgE enzyme-linked immunosorbent assay inhibitions for meadow fescue grass and dust mite allergens. Immunoblot analyses provided qualitative patterns of IgE binding. Meadow fescue grass allergens were unstable after mixing with fungal or cockroach extracts but were highly compatible with dust mite extracts from numerous commercial sources. Fescue and dust mite allergen recoveries varied considerably when mixed with different mold extracts. The presence of cockroach extracts reduced dust mite allergen potencies but retained moderate levels of cat and short ragweed allergen activities. In all cases examined, glycerin provided concentration-dependent improvements in allergen recoveries. Several allergen extract combinations generally regarded as unstable by current practice parameters seem to possess considerable biochemical compatibilities. Use of these mixtures in immunotherapy vaccines is supported for practitioners seeking to optimize formulations, doses, and treatment regimens for their patients.

Quantification of Art v 1 and Act c 1 being major allergens of mugwort pollen and kiwi fruit extracts in mass-units by ion-exchange HPLC-UV method

A simple ion-exchange HPLC-UV method was developed for determination of major allergens from mugwort pollen and kiwi fruit extracts in mass-units. The separation of Art v 1 and Act c 1 from other components in the extracts was achieved in one step. The extinction coefficients used in the study were theoretically determined and compared to the extinction coefficients determined by gravimetry. We also reported a close correlation of the major allergen contents with the overall allergenic potency of the extracts determined by inhibition ELISA. This method could be a useful tool for standardization of allergenic extracts for clinical use.

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

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. We evaluated the long-term clinical effect and the preventive effect of developing asthma 7-years after termination of SIT. 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. 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. 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. 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.