- Open Access
Allergen immunotherapy in asthma; what is new?
© Passalacqua et al. 2016
- Received: 27 February 2015
- Accepted: 27 May 2015
- Published: 15 July 2015
The use and role of allergen immunotherapy (AIT) in asthma is still a matter of debate, and no definite recommendation about this is made in guidelines, both for the subcutaneous and sublingual routes. This is essentially due to the fact that most controlled randomised trials were not specifically designed for asthma, and that objective measures of pulmonary function were only occasionally considered. Nonetheless, in many trials, favourable results in asthma (symptoms, medication usage, bronchial reactivity) were consistently reported. There are also several meta analyses in favour of AIT, although their validity is limited by a relevant methodological heterogeneity. In addition to the crude clinical effect, a disease modifying action of AIT (prevention of asthma onset and long-lasting effects) have been reported. The safety is an important aspect to consider in asthma. Fatalities were rare: in Europe no fatality was reported in the last three decades, as in the United States in the last 4 years. Based on previous surveys, and common sense, uncontrolled asthma is still recognized as the most important risk factor for severe adverse events. On the contrary, there is no evidence that AIT can worsen or induce asthma. According to the available evidence, AIT can be safely used as add-on treatment when asthma is associated with rhinitis (a frequent condition), provided that asthma is adequately controlled by pharmacotherapy. AIT cannot be recommended or suggested as single therapy. When asthma is the unique manifestation of respiratory allergy, its use should be evaluated case by case.
- Allergen immunotherapy
- Sublingual immunotherapy
- Subcutaneous immunotherapy
- Allergic asthma
- Allergic rhinitis
- Adverse events
Main methodological limitations of the studies considering AIT in asthma
Patients should be selected matching asthma severity and, current asthma therapy
Asthma-related parameters should be the primary outcome
Sample size calculation
Based on asthma-related primary outcome
Pulmonary function tests/bronchial challenges should be included in primary outcomes
Should be uniformed (duration, doses, run-in etc.)
An optimal duration of the AIT course is not established
The optimal maintenance dose needs to be established for most allergens. Discrepancies among manufacturers
The knowledge on the effects, and safety, of AIT in asthma is based, in summary, on either historical clinical trials with SCIT, previous safety surveys and recent trials with SLIT. All these data, taken together are certainly not conclusive, but some suggestions applicable in the clinical practice can be derived [7, 8].
Ait in asthma: the clinical evidence
As mentioned above, in the large majority of clinical trials with SCIT and SLIT, rhinitis was the primary outcome studied, but in many studies part of the patients enrolled also suffered from concomitant asthma, thus, asthma-related outcomes could be analysed (for review see 3, 6–8).
A certain number of trials expecially with SLIT were, at some extent, designed to specifically investigate asthma [10–41], almost all showing significant effects on asthma symptoms, medications’ usage, or bronchial reactivity. Some studies specifically assessed the effect of AIT as inhaled corticosteroids sparing agent in asthma [21, 29, 37–40]. In the first of the two more recent studies , conducted with SCIT in 65 children for 8 months, a mean 50 % reduction in the dose of inhaled fluticasone was seen in the active group, who remained controlled. The other one  investigated 3 doses of SLIT in more than 600 adults for 1 year. With the highest dose, a significant reduction in mcg of corticosteroids was seen (p = 0.004) and the relative mean reduction was 42 %. The less recent studies involved smallest samples [21, 29, 39, 40]: overall demonstrated a steroid-sparing effect of AIT in asthma, but the extent of this effect was largely variable, and sometimes of uncertain clinical relevance. Finally, Marogna et al.  compared the effect, as add-on treatment, of inhaled budesonide and SLIT, and found that over a 3-year period, SLIT was overall more effective than budesonide in reducing symptoms and bronchial hyperreativity. Of note, some studies [11, 13, 21, 33, 34] reported only marginal effects on asthma, but in two of these studies all the patients (active and controls) had almost no asthma at baseline and during the trial [33, 34]. Despite the important limitations (small sample, no power calculation, variable inclusion criteria) the published studies substantially agree on the clinical efficacy of SCIT in asthma, induced by the most common allergens (grass, mite, pet dander).
Meta analyses of AIT in ashtma
Author, Year (REF)
Type of AIT
Results (effect size, 95 % C.I.)
Abramson, 2010 
Symptoms −0.6 (−0.83 -0.35) significant
Medications −0.5 (−08 -0.3) significant
Erekoshima 2013 
Strength of evidence reported as “high” for both outcomes
Calamita, 2007 
Symptoms −0.38 (−0.79 0.03) not significant
Medications −0.9 (−1.9 -0.12) significant
Penagos, 2008 
Symptoms −1.18 (−2.1 -018) significant
Medication −1.63 (−2.8 -044) significant
Compalati, 2009 
Symptoms SMD 0.95 (1.74 0.15) significantabc
Medications SMD 1.48 (2.70 0.26) significant
There is still some debate about the comparison of efficacy between SLIT and SCIT. No study specifically addressed the problem for asthma, but a comprehensive view of the meta analyses suggest that the efficacy is overall the same . Similarly, there is no study in asthma comparing the effects of AIT and drugs. Rak et al.  demonstrated the superiority of nasal corticosteroids versus AIT in rhinitis but found that AIT only could decrease the seasonal bronchial hyperreactivity in asthmatic patients and Sheikh et al. evidenced the persisting effect of SCIT over inhaled steroids after discontinuation . Another trial  in asthmatic children showed that adding AIT to inhaled fluticasone did not cause a further improvement of symptoms, but SLIT only decreased non-bronchial symptoms. Finally, an open randomized trial of SLIT (as add-on treatment) versus inhaled budesonide alone in asthmatic patients, demonstrated an overall superiority of AIT over time . All these studies that were not randomized, properly powered or were designed as open trials limits the methodological value of the observations.
Safety aspects of ait in asthma
AIT implies the administration of extracts of substances (allergens) to which the subject is sensitized. This can lead to adverse reactions, that can be either local or systemic (SRs), this latter, spanning until anaphylaxis and death. The reported occurrence of SRs is largely variable, according to allergen, induction schedule, preparation and dose. The available data (on large populations) come from the surveys regularly performed in the USA with SCIT which [52, 53], reported about 50 deaths over a 50-year period with a risk of one death every 2.500.000 injections and one near-fatal reaction per million injections. Human errors and uncontrolled asthma were the most frequent causes of SCIT-induced adverse events [53, 54]. On the other hand, in the period 2008–2011 no further fatality due to SCIT was reported in the United States and SRs were about 0.1 % of injection visits . Evaluating those data, it must be kept in mind that the practice of SCIT profoundly differs between Europe and United States, where allergen mixes and higher concentrations are commonly used . Few systematic data is available in European countries [57, 58]. A recent multicenter observational study  suggested that systemic reactions are slightly more frequent in rhinitis with asthma than in rhinitis patients alone. According to the past observations and the few recent data, the scientific community agreed, as a prudential attitude, to consider uncontrolled/severe asthma as a major risk factor for severe adverse events of AIT [3, 5]. Despite no direct observation has been published, this attitude has been translated also to SLIT . In this regard, the safety of SLIT is overall superior to that of SCIT [6, 60], at least because no fatality has been reported until now, and only few cases of suspect/ascertained anaphylaxis have been described, none directly attributable to pre-existing asthma or to worsening of asthma . The potential of precipitating asthma has been considered in some studies A controlled dose-finding study of safety  involving 48 grass-allergic patients outside the pollen season and receiving up to 200 mcg Phl p 5, (about 40 times the SCIT dose) showed an incidence of side effects of 74 %, all of which were mild or moderate in intensity and all localized. Dahl et al.  assessed the safety of SLIT in asthma in more than 100 grass-allergic asthmatics. The number of side effects possibly linked to asthma (wheezing cough, dyspnoea) was similar between the active and placebo group, and there was no evidence of asthma aggravation.
According to literature, and common sense, severe/uncontrolled asthma remains the main risk factor for side effects due to AIT, although for SLIT severe asthma have been not clearly demonstrated as a specific contraindication. In general, asthma is not an absolute contraindication to AIT, if the patient is well controlled with pharmacotherapy.
As a future perspective, an uniform reporting and grading of side effects would be desirable. This has recently been addressed by the World Allergy Organization, which proposed a grading system for systemic reactions due to SCIT/SLIT  and for local reactions due to SLIT .
Rhinitis is the most important independent risk factor for the development of asthma [1, 65], and in the natural history, usually rhinitis precedes asthma. AIT is an immune response modifier, thus it was hypothesized that it may alter the progression of the disease, reducing the risk of asthma onset. The preventive effect of AIT on the risk of developing asthma was quantified in some controlled trials only during the last decades. The Preventative Allergy Treatment study enrolled 205 children (aged 6–10 years) suffering from allergic rhinitis, and randomized to either drug therapy alone or drugs plus SCIT. After 3 years, the SCIT-treated patients developed significantly less asthma than the control group (odds ratio 2.5) . The beneficial effect of SCIT lasted at least 7 years after discontinuation . The same effect was demonstrated with SLIT. The first open controlled study  involved 113 children aged 5–14 years with seasonal rhinitis due to grass pollen, randomly allocated to medications plus SLIT or medications only. After 3 years, 8/45 SLIT subjects and 18/44 controls had developed asthma, with a relative risk of 3.8 for untreated patients. The other randomized open controlled trial  involved 216 children (5–17 years) suffering from rhinitis with/without intermittent asthma, randomly allocated 2:1 to drugs plus SLIT or drugs only. The prevalence of persistent asthma after 3 years of observation was 1.5 % in the SLIT group and 30 % for the control group.
It is true that there are only 3 studies addressing the preventive effect of AIT, involving less than 300 patients in total. Nonetheless, due to the relevance of this aspect, new trials with rigorous methodology are currently ongoing, such as the GAP study , which is involving more than 800 children in a 5-year double blind evaluation.
The literature on the clinical and immunological effects of AIT is abundant, and many guidelines and recommendations were prepared according to structured evaluation systems such as the GRADE . According to GRADE the essential requirement is that the methodology of the study is adequate (e.g. sample size, outcome, selection criteria, randomization), that is not always the case for AIT in asthma (Table 1), since many of the randomized controlled trials had important limitations (small number of patients, no objective measurement of respiratory function, no sample size calculation based on the objective parameters, variability of doses and protocols). This facts burden the meta-analyses, where the positive clinical results are counterbalanced by the high heterogeneity of the studies.
Indeed, beyond the methodological limitations, there is an abundant experimental evidence that AIT is effective in controlling symptoms and medications intake in patients with asthma (usually concomitant to rhinitis) . Thus, it should be confidently stated that SLIT and SCIT can be used together with asthma medications, when asthma is associated to rhinitis and the causal role of the allergen is clearly confirmed. Also when asthma is the only allergic disease (that is rare), AIT is expected to exert a beneficial effect. It does not seem that AIT can worsen asthma, whereas uncontrolled asthma remains a significant risk factor for adverse events. The disease-modifying effects of AIT in asthma prevention should be taken into account , although there are so far only 3 studies on this aspect. On the other hand, the cautious attitude towards the use of AIT in asthma is testified by the fact that the recently FDA approved products (tablet SLIT for ragweed and grass) do not have the indication for asthma, but only for rhinoconjunctivitis.
Overall, it has to be considered that asthma is per se a heterogeneous disease, with different endotypes  and different types of underlying inflammation. In addition, allergens are often but not always the unique triggers of the inflammatory reation. These facts can explain the variable efficacy of antinflammatory treatments, allergen avoidance strategies, and AIT itself. So far, an unequivocal biomarker capable of predicting the response to treatments has not been yet identified .
Main unresolved questions and unclear aspects are the optimal maintenance dose to use, the duration of treatment to obtain a satisfactory long term effect, and the appropriate use of objective outcomes. Probably, the most important questions are which children with rhinitis should receive AIT to prevent the future development of asthma, and which biomarkers are relevant to identify the potential responders.
- Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens. J Allergy Clin Immunol. 2014;133:621–31.View ArticlePubMedGoogle Scholar
- Cruz AA, Popov T, Pawankar R, Annesi-Maesano I, Fokkens W, Kemp J, et al. Common characteristics of upper and lower airways in rhinitis and asthma: ARIA update, in collaboration with GA (2) LEN. Allergy. 2007;62 Suppl 84:1–41.View ArticlePubMedGoogle Scholar
- Bousquet J, Lockey RF, Malling HJ. Allergen immunotherapy: therapeutical vaccines for allergic diseases.WHO Position Paper. J Allergy Clin Immunol. 1998;54(82):1–33.Google Scholar
- Cox L, Nelson H, Lockey R, Calabria C, Chacko T, Finegold I, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol. 2011;127(1 Suppl):S1–55.View ArticlePubMedGoogle Scholar
- Zuberbier T, Bachert C, Bousquet PJ, Passalacqua G, Walter Canonica G, Merk H, et al. GA2 LEN/EAACI pocket guide for allergen-specific immunotherapy for allergic rhinitis and asthma. Allergy. 2010;65:1525–30.View ArticlePubMedGoogle Scholar
- Canonica GW, Cox L, Pawankar R, Baena-Cagnani CE, Blaiss M, Bonini S, et al. Sublingual immunotherapy: World Allergy Organization position paper 2013 update. World Allergy Organ J. 2014;7(1):6.View ArticlePubMedPubMed CentralGoogle Scholar
- Passalacqua G, Canonica GW. Specific immunotherapy in asthma: efficacy and safety. Clin Exp Allergy. 2011;41:1247–55.View ArticlePubMedGoogle Scholar
- Passalacqua G. Specific immunotherapy in asthma: a synthetic review. J Asthma. 2014;51:29–33.View ArticlePubMedGoogle Scholar
- Canonica GW, Baena-Cagnani CE, Bousquet J, Bousquet PJ, Lockey RF, Malling HJ, et al. Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce. Allergy. 2007;62:317–24.View ArticlePubMedGoogle Scholar
- Hedlin G, Wille S, Browaldh L, Hildebrand H, Holmgren D, Lindfors A, et al. Immunotherapy in children with allergic asthma: effect on bronchial hyperreactivity and pharmacotherapy. J Allergy Clin Immunol. 1999;103(4):609–14.View ArticlePubMedGoogle Scholar
- Paranos S, Petrovic S. Early effects of rush immunotherapy with Dermatophagoides pteronyssinus in asthmatics. J Investig Allergol Clin Immunol. 1997;7(6):588–95.PubMedGoogle Scholar
- Adkinson Jr NF, Eggleston PA, Eney D, Goldstein EO, Schuberth KC, Bacon JR, et al. A controlled trial of immunotherapy for asthma in allergic children. N Engl J Med. 1997;336:324–31.View ArticlePubMedGoogle Scholar
- Hirsch T, Sahn M, Leupold W. Double-blind placebo-controlled study of sublingual Immunotherapy with house dust mite extract (D.pt.) in children. Pediatr Allergy Immunol. 1997;8:21–7.View ArticlePubMedGoogle Scholar
- Pajno GB, Morabito L, Barberio G. Clinical and immunological effects of long-term sublingual immunotherapy in asthmatic children sensitized to mite: a double-blind study. Allergy. 2000;55:842–9.View ArticlePubMedGoogle Scholar
- Bødtger U, Poulsen LK, Jacobi HH, Malling HJ. The safety and efficacy of subcutaneous birch pollen immunotherapy - a one-year, randomised, double-blind, placebo-controlled study. Allergy. 2002;57:297–305.View ArticlePubMedGoogle Scholar
- Grembiale RD, Camporota L, Naty S, Tranfa CM, Djukanovic R, Marsico SA. Effects of specific immunotherapy in allergic rhinitic individuals with bronchial hyperresponsiveness. Am J Respir Crit Care Med. 2000;162:2048–52.View ArticlePubMedGoogle Scholar
- Arvidsson MB, Löwhagen O, Rak S. Effect of 2-year placebo-controlled immunotherapy on airway symptoms and medication in patients with birch pollen allergy. J Allergy Clin Immunol. 2002;109:777–83.View ArticlePubMedGoogle Scholar
- Basomba A, Tabar AI, de Rojas DH, García BE, Alamar R, Olaguíbel JM, et al. Allergen vaccination with a liposome-encapsulated extract of Dermatophagoides pteronyssinus: a randomized, double-blind, placebo-controlled trial in asthmatic patients. J Allergy Clin Immunol. 2002;109:943–8.View ArticlePubMedGoogle Scholar
- Guerra F, Daza JC, Almeda E. Immunotherapy with a depigmented, polymerized vaccine of Olea europaea pollen allergens. Significantly reduces specific bronchial and skin test reactivity in sensitized patients after one year of treatment. J Investig Allergol Clin Immunol. 2003;13:108–17.PubMedGoogle Scholar
- Varney VA, Tabbah K, Mavroleon G, Frew AJ. Usefulness of specific immunotherapy in patients with severe perennial allergic rhinitis induced by house dust mite: a double-blind, randomized, placebo-controlled trial. Clin Exp Allergy. 2003;33:1076–82.View ArticlePubMedGoogle Scholar
- Maestrelli P, Zanolla L, Pozzan M, Fabbri LM. Regione Veneto Study Group on the “Effect of immunotherapy in allergic asthma”. Effect of specific immunotherapy added to pharmacologic treatment and allergen avoidance in asthmatic patients allergic to house dust mite. J Allergy Clin Immunol. 2004;113:643–9.View ArticlePubMedGoogle Scholar
- Arvidsson MB, Löwhagen O, Rak S. Allergen specific immunotherapy attenuates early and late phase reactions in lower airways of birch pollen asthmatic patients: a double blind placebo-controlled study. Allergy. 2004;59:74–80.View ArticlePubMedGoogle Scholar
- Ferrer A, García-Sellés J. Significant improvement in symptoms, skin test, and specific bronchial reactivity after 6 months of treatment with a depigmented, polymerized extract of Dermatophagoides pteronyssinus and D. farinae. J Investig Allergol Clin Immunol. 2003;13:244–51.PubMedGoogle Scholar
- Mirone C, Albert F, Tosi A, Mocchetti F, Mosca S, Giorgino M, et al. Efficacy and safety of subcutaneous immunotherapy with a biologically standardized extract of Ambrosia artemisiifolia pollen: a double-blind, placebo-controlled study. Clin Exp Allergy. 2004;34:1408–14.View ArticlePubMedGoogle Scholar
- Ameal A, Vega-Chicote JM, Fernández S, Miranda A, Carmona MJ, Rondón MC, et al. Double-blind and placebo-controlled study to assess efficacy and safety of a modified allergen extract of Dermatophagoides pteronyssinus in allergic asthma. Allergy. 2005;60:1178–83.View ArticlePubMedGoogle Scholar
- Wang H, Lin X, Hao C, Zhang C, Sun B, Zheng J, et al. A double-blind, placebo-controlled study of house dust mite immunotherapy in Chinese asthmatic patients. Allergy. 2006;61:191–7.View ArticlePubMedGoogle Scholar
- Ferrer M, Burches E, Peláez A, Muñoz A, Hernández D, Basomba A, et al. Double-blind, placebo-controlled study of immunotherapy with Parietaria judaica: clinical efficacy and tolerance. J Investig Allergol Clin Immunol. 2005;15:283–92.PubMedGoogle Scholar
- Roberts G, Hurley C, Turcanu V, Lack G. Grass pollen immunotherapy as an effective therapy for childhood seasonal allergic asthma. J Allergy Clin Immunol. 2006;117:263–8.View ArticlePubMedGoogle Scholar
- Blumberga G, Groes L, Haugaard L, Dahl R. Steroid-sparing effect of subcutaneous SQ-standardised specific immunotherapy in moderate and severe house dust mite allergic asthmatics. Allergy. 2006;61:843–8.View ArticlePubMedGoogle Scholar
- García-Robaina JC, Sánchez I, de la Torre F, Fernández-Caldas E, Casanovas M. Successful management of mite-allergic asthma with modified extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae in a double-blind, placebo-controlled study. J Allergy Clin Immunol. 2006;118:1026–32.View ArticlePubMedGoogle Scholar
- Niu CK, Chen WY, Huang JL, Lue KH, Wang YJ. Efficacy of sublingual immunotherapy with high-dose mite extracts in asthma: A multi-center, double-blind, randomized, and placebo-controlled study in Taiwan. Respir Med. 2006;100:1374–83.View ArticlePubMedGoogle Scholar
- Tabar AI, Lizaso MT, García BE, Gómez B, Echechipía S, Aldunate MT, et al. Double-blind, placebo-controlled study of Alternaria alternata immunotherapy: clinical efficacy and safety. Pediatr Allergy Immunol. 2008;19:67–75.PubMedGoogle Scholar
- Pham-Thi N, Scheinmann P, Fadel R, Combebias A, Andre C. Assessment of sublingual immunotherapy efficacy in children with house dust mite-induced allergic asthma optimally controlled by pharmacologic treatment and mite-avoidance measures. Pediatr Allergy Immunol. 2007;18:47–57.View ArticlePubMedGoogle Scholar
- Dahl R, Stender H, Rak S. Specific immunotherapy with SQ standardized grass allergen tablets in asthmatics with rhinoconjunctivitis. Allergy. 2006;61:185–90.View ArticlePubMedGoogle Scholar
- Stelmach I, Kaczmarek-Woźniak J, Majak P, Oszlowiek-Chlebna M, Jerzynska A. Efficacy and safety of high-doses sublingual immunotherapy in ultra-rush scheme in children allergic to grass pollen. Clin Exp Allergy. 2009;39:401–8.View ArticlePubMedGoogle Scholar
- Bergmann KC, Demoly P, Worm M, Fokkens WJ, Carrillo T, Tabar AI, et al. Efficacy and safety of sublingual tablets of house dust mite allergen extracts in adults with allergic rhinitis. J Allergy Clin Immunol. 2014;133:1608–14.View ArticlePubMedGoogle Scholar
- Zielen S, Kardos P, Madonini E. Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: a randomized controlled trial. J Allergy Clin Immunol. 2010;126:942–9.View ArticlePubMedGoogle Scholar
- Mosbech H, Deckelmann R, de Blay F, Pastorello EA, Trebas-Pietras E, Andres LP, et al. Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2014;134:568–75.View ArticlePubMedGoogle Scholar
- Costa JC, Plácido JL, Silva JP, Delgado L, Vaz M. Effects of immunotherapy on symptoms, PEFR, spirometry, and airway responsiveness in patients with allergic asthma to house-dust mites (D. pteronyssinus) on inhaled steroid therapy. Allergy. 1996;51:238–44.View ArticlePubMedGoogle Scholar
- Ozdemir C, Yazi D, Gocmen I, Yesil O, Aydogan M, Semic-Jusufagic A, et al. Efficacy of long-term sublingual immunotherapy as an adjunct to pharmacotherapy in house dust mite-allergic children with asthma. Pediatr Allergy Immunol. 2007;18:508–15.View ArticlePubMedGoogle Scholar
- Marogna M, Spadolini I, Massolo A, Berra D, Zanon P, Chiodini E, et al. Passalacqua G Long-term comparison of sublingual immunotherapy vs inhaled budesonide in patients with mild persistent asthma due to grass pollen. Ann Allergy Asthma Immunol. 2009;102:69–75.View ArticlePubMedGoogle Scholar
- Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010;8:CD001186. Aug 4.Google Scholar
- Erekosima N, Suarez-Cuervo C, Ramanathan M, Kim JM, Chelladurai Y, Segal JB, et al. Effectiveness of subcutaneous immunotherapy for allergic rhinoconjunctivitis and asthma: A systematic review. Laryngoscope. 2013. doi:10.1002/lary.24295.PubMedGoogle Scholar
- Calamita Z, Saconato H, Bronhara Pelà A, Atallah AN. Efficacy of Sublingual immunotherapy in asthma. Systematic review of randomized clinical trials. Allergy. 2006;61:1162–72.View ArticlePubMedGoogle Scholar
- Penagos M, Passalacqua G, Compalati E, Tarantini F, Canonica GW. Metaanalysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age. Chest. 2008;133:599–609.View ArticlePubMedGoogle Scholar
- Compalati E, Passalacqua G, Bonini M, Canonica GW. The efficacy of sublingual immunotherapy for house dust mites respiratory allergy: results of a GA2LEN meta-analysis. Allergy. 2009;64:1570–9.View ArticlePubMedGoogle Scholar
- Di Bona D, Plaia A, Scafidi V, Di Lorenzo G. Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: A systematic review and meta-analysis. J Allergy Clin Immunol. 2010;126:558–66.View ArticlePubMedGoogle Scholar
- Calderón MA, Casale TB, Togias A, Bousquet J, Durham SR, Demoly P. Allergen-specific immunotherapy for respiratory allergies: from meta-analysis to registration and beyond. J Allergy Clin Immunol. 2011;127:30–8.View ArticlePubMedGoogle Scholar
- Rak S, Heinrich C, Jacobsen L, Scheynius A, Venge P. A double-blinded, comparative study of the effects of short preseason specific immunotherapy and topical steroids in patients with allergic rhinoconjunctivitis and asthma. J Allergy Clin Immunol. 2001;108:921–8.View ArticlePubMedGoogle Scholar
- Shaikh WA. Immunotherapy vs inhaled budesonide in bronchial asthma: an open, parallel, comparative trial. Clin Exp Allergy. 1997;27:1279–84.View ArticlePubMedGoogle Scholar
- Pajno GB, Vita D, Parmiani S, Caminiti L, La Grutta S, Barberio G. Impact of sublingual immunotherapy on seasonal asthma and skin reactivity in children allergic to Parietaria pollen treated with inhaled fluticasone propionate. Clin Exp Allergy. 2003;33:1641–7.View ArticlePubMedGoogle Scholar
- Reid MJ, Lockey RF, Turkeltaub PC, Platt-Mills TA. Survey of fatalities from skin testing and immunotherapy. J Allergy Clin Immunol. 1993;92:6–15.View ArticlePubMedGoogle Scholar
- Bernstein DI, Wanner M, Borish L, Liss GM. Immunotherapy Committee American Academy Allergy Asthma Immunology. Twelve years of survey of fatal reactions to allergen injections and skin testing 1990–2001. J Allergy Clin Immunol. 2004;113:1129–36.View ArticlePubMedGoogle Scholar
- Aaronson DW, Gandhi TK. Incorrect allergy injections: allergists’ experiences and recommendations for prevention. J Allergy Clin Immunol. 2004;113:1117–21.View ArticlePubMedGoogle Scholar
- Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. AAAAI and ACAAI surveillance study of subcutaneous immunotherapy, Year 3: what practices modify the risk of systemic reactions? Ann Allergy Asthma Immunol. 2013;110:274–8.View ArticlePubMedGoogle Scholar
- Cox L, Jacobsen L. Comparison of allergen immunotherapy practice patterns in the United States and Europe. Ann Allergy Asthma Immunol. 2009;103:451.View ArticlePubMedGoogle Scholar
- Ragusa RF, Passalacqua G, Gambardella R, Campanari S, Barbieri MM, Scordamaglia A, et al. Nonfatal systemic reactions to subcutaneous immunotherapy : a 10 years experience. J Invest Allergol Clin Immunol. 1997;7:151–4.Google Scholar
- Moreno C, Cuesta-Herranza J, Fernandez-Tavora L, Alvarez-Cuesta E. Immunotherapy safety: a prospective multi-centric monitoring study of biologically standardized therapeutic vaccines for allergic diseases. Clin Exp Allergy. 2004;34:527–31.View ArticlePubMedGoogle Scholar
- Schiappoli M, Ridolo E, Senna G, Alesina R, Antonicelli L, Asero R, et al. A prospective Italian survey on the safety of subcutaneous immunotherapy for respiratory allergy. Clin Exp Allergy. 2009;39:1569–74.View ArticlePubMedGoogle Scholar
- Cox LS, Linnemann DL, Nolte H, Weldon D, Finegold I, Nelson HS. Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol. 2006;117:1021–35.View ArticlePubMedGoogle Scholar
- Calderón MA, Simons FE, Malling HJ, Lockey RF, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy. 2012;67:302–11.View ArticlePubMedGoogle Scholar
- Kleine-Tebbe J, Ribel M, Herold DA. Safety of a SQ-standardised grass allergen tablet for sublingual immunotherapy: a randomized, placebo-controlled trial. Allergy. 2006;61:181–4.View ArticlePubMedGoogle Scholar
- Cox L, Larenas Linneman D, Lockey RF, Passalacqua G. Speaking a common language in immunotherapy. WAO grading of systemic reactions. J Allergy Clin Immunol. 2010;125:569–74.View ArticlePubMedGoogle Scholar
- Passalacqua G, Baena Cagnani C, Bousquet J, Canonica GW, Cox L, Durham S, et al. Grading local side effects of sublingual immunotherapy for respiratory allergy: Speaking the same language. J Allergy Clin Immunol. 2013;132:93–8.View ArticlePubMedGoogle Scholar
- Shaaban R, Zureik M, Soussan D, Neukirch C, Heinrich J, Sunyer J, et al. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet. 2008;372:1049–57.View ArticlePubMedGoogle Scholar
- Möller C, Dreborg S, Ferdousi HA, Halken S, Høst A, Jacobsen L, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol. 2002;109:251–6.View ArticlePubMedGoogle Scholar
- Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, Høst A, et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007;62:943–8.View ArticlePubMedGoogle Scholar
- Novembre E, Galli E, Landi F, Caffarelli C, Pifferi M, De Marco E, et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2004;114:851–7.View ArticlePubMedGoogle Scholar
- Marogna M, Tomassetti D, Bernasconi A, Colombo F, Massolo A, Businco A, et al. Preventive effects of sublingual immunotherapy in childhood: an open randomized controlled study. Ann Allergy Asthma Immunol. 2008;101:206–11.View ArticlePubMedGoogle Scholar
- Valovirta E, Berstad AK, de Blic J, Bufe A, Eng P, Halken S, et al. Design and recruitment for the GAP trial, investigating the preventive effect on asthma development of an SQ-standardized grass allergy immunotherapy tablet in children with grass pollen-induced allergic rhinoconjunctivitis. Clin Ther. 2011;33:1537–46.View ArticlePubMedGoogle Scholar
- Brozek JL, Bousquet J, Baena-Cagnani CE, Bonini S, Canonica GW, Casale TB, et al. Grading of recommendations assessment, development and evaluation working group. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 2010;126:466–70.View ArticlePubMedGoogle Scholar
- Jutel M. Allergen-Specific Immunotherapy in Asthma. Curr Treat Options Allergy. 2014;1:213–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Passalacqua G, Canonica GW. Specific immunotherapy: beyond clinical scores. Ann Allergy Asthma Immunol. 2011;107:401–6.View ArticlePubMedGoogle Scholar
- Agache IO. From phenotypes to endotypes to asthma treatment. Curr Opin Allergy Clin Immunol. 2013;13:249–56.View ArticlePubMedGoogle Scholar
- Leung TF, Ko FW, Wong GW. Recent advances in asthma biomarker research. Ther Adv Respir Dis. 2013;7:297–308.View ArticlePubMedGoogle Scholar
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