Allergen-specific immunotherapy provides immediate, long-term and preventive clinical effects in children and adults: the effects of immunotherapy can be categorised by level of benefit -the centenary of allergen specific subcutaneous immunotherapy

Clinical and Translational Allergy

M Beatrice Bilo³  Ulrich Wahn¹  Lars Jacobsen² 

[1] Children's Hospital Charité, Virchow Klinikum, Berlin, Germany;Allergy Learning and Consulting, Krokushaven 18, DK 2765 Smorum, Copenhagen, Denmark;Allergy Unit, Department Immunology, Allergy and Respiratory Diseases, University Hospital, Ancona, Italy

关键词: Prevention;    Long-term effect;    IgE;    IgG;    Antibodies;    Immunological mechanisms;    Specific immunotherapy;    Asthma;    Rhinitis;    Allergy;   

Others  :  794642
DOI  :  10.1186/2045-7022-2-8

 received in 2011-11-30, accepted in 2012-04-13,  发布年份 2012

【 摘 要 】

Allergen Specific Immunotherapy (SIT) for respiratory allergic diseases is able to significantly improve symptoms as well as reduce the need for symptomatic medication, but SIT also has the capacity for long-term clinical effects and plays a protective role against the development of further allergies and symptoms. The treatment acts on basic immunological mechanisms, and has the potential to change the pathological allergic immune response. In this paper we discuss some of the most important achievements in the documentation of the benefits of immunotherapy, over the last 2 decades, which have marked a period of extensive research on the clinical effects and immunological background of the mechanisms involved. The outcome of immunotherapy is described as different levels of benefit from early reduction in symptoms over progressive clinical effects during treatment to long-term effects after discontinuation of the treatment and prevention of asthma. The efficacy of SIT increases the longer it is continued and immunological changes lead to potential long-term benefits. SIT alone and not the symptomatic treatment nor other avoidance measures has so far been documented as the therapy with long-term or preventive potential. The allergic condition is driven by a subset of T-helper lymphocytes (Th2), which are characterised by the production of cytokines like IL-4, and IL-5. Immunological changes following SIT lead to potential curative effects. One mechanism whereby immunotherapy suppresses the allergic response is through increased production of IgG4 antibodies. Induction of specific IgG4 is able to influence the allergic response in different ways and is related to immunological effector mechanisms, also responsible for the reduced late phase hyperreactivity and ongoing allergic inflammation. SIT is the only treatment which interferes with the basic pathophysiological mechanisms of the allergic disease, thereby creating the potential for changes in the long-term prognosis of respiratory allergy. SIT should not only be recognised as first-line therapeutic treatment for allergic rhinoconjunctivitis but also as secondary preventive treatment for respiratory allergic diseases.

【 授权许可】

   
2012 Jacobsen et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Braunstahl GJ, Prins JB, Kleinjan A, Overbeek SE, Hoogsteden HC, Fokkens WJ: Nose and lung cross-talk in allergic airways disease. Clin Exp All Rev 2003, 3:38-42.
• [2]Togias A: Mechanisms of nose-lung interaction. Allergy 1999, 54(Suppl 57):94-105.
• [3]Cruz AA, Popov T, Pawankar R, Annesi-Maesano I, Fokkens W, Kemp J, Ohta K, Price D, Bousquet J: 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.
• [4]Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, Zuberbier T, Baena-Cagnani CE, Canonica GW, van Weel C, et al.: Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy 2008, 63(Suppl 86):8-160.
• [5]Ruokonen M, Kaila M, Haataja R, Korppi M, Paassilta M: Allergic rhinitis in school-aged children with asthma - still under-diagnosed and under-treated? A retrospective study in a children's hospital. Pediatr Allergy Immunol 2010, 21:e149-e154.
• [6]Bousquet J, Gaugris S, Kocevar VS, Zhang Q, Yin DD, Polos PG, Bjermer L: Increased risk of asthma attacks and emergency visits among asthma patients with allergic rhinitis: a subgroup analysis of the investigation of montelukast as a partner agent for complementary therapy [corrected]. Clin Exp Allergy 2005, 35:723-727.
• [7]Linneberg A, Henrik NN, Frolund L, Madsen F, Dirksen A, Jorgensen T: The link between allergic rhinitis and allergic asthma: a prospective population-based study. The Copenhagen Allergy Study Allergy 2002, 57:1048-1052.
• [8]Settipane RJ, Hagy GW, Settipane GA: Long-term risk factors for developing asthma and allergic rhinitis: a 23-year follow-up study of college students. Allergy Proc 1994, 15:21-25.
• [9]Moller C, Dreborg S, Ferdousi HA, Halken S, Host A, Jacobsen L, Koivikko A, Koller DY, Niggemann B, Norberg LA, et al.: Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002, 109:251-256.
• [10]Ciprandi G, Buscaglia S, Pesce G, Pronzato C, Ricca V, Parmiani S, Bagnasco M, Canonica GW: Minimal persistent inflammation is present at mucosal level in patients with asymptomatic rhinitis and mite allergy. J Allergy Clin Immunol 1995, 96:971-979.
• [11]Silvestri M, Rossi GA, Cozzani S, Pulvirenti G, Fasce L: Age-dependent tendency to become sensitized to other classes of aeroallergens in atopic asthmatic children. Ann Allergy Asthma Immunol 1999, 83:335-340.
• [12]Linneberg A, Nielsen NH, Madsen F, Frolund L, Dirksen A, Jorgensen T: Pets in the home and the development of pet allergy in adulthood. The Copenhagen Allergy Study Allergy 2003, 58:21-26.
• [13]Cox L, Wallace D: Specific allergy immunotherapy for allergic rhinitis: subcutaneous and sublingual. Immunol Allergy Clin North Am 2011, 31:561-599.
• [14]Jacobsen L: Preventive aspects of immunotherapy: prevention for children at risk of developing asthma. Ann Allergy Asthma Immunol 2001, 87:43-46.
• [15]Noon L: Prophylactic inoculation against hay fever. Lancet 1911, 177:1572-1573.
• [16]Larche M, Akdis CA, Valenta R: Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol 2006, 6:761-771.
• [17]Casale TB, Stokes JR: Future forms of immunotherapy. J Allergy Clin Immunol 2011, 127:8-15.
• [18]Committee for Medicinal Products for Human Use: Guideline on the Clinical Development of Products for Specific Immunotherapy for the Treatment of Allergic Diseases. [http:/ / www.ema.europa.eu/ docs/ en_GB/ document_library/ Scientific_guideline/ 2009/ 09/ WC500003605.pdf] webciteEuropean Medicines Agency 2008.
• [19]Committee for Medicinal Products for Human Use: Guideline on Allergen Products: Production and Quality Issues. [http:/ / www.ema.europa.eu/ docs/ en_GB/ document_library/ Scientific_guideline/ 2009/ 09/ WC500003333.pdf] webciteEuropean Medicines Agency 2008.
• [20]Bousquet J, Van Cauwenberge P, Khaltaev N: Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001, 108:S147-S334.
• [21]Canonica GW, Baena-Cagnani CE, Bousquet J, Bousquet PJ, Lockey RF, Malling HJ, Passalacqua G, Potter P, Valovirta E: Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce. Allergy 2007, 62:317-324.
• [22]Batemann ED: GINA Report, Global Strategy for Asthma Management and Prevention. In GINA No 95-3659. National Heart, Lung and Blood Institute, National Institute of Health; 2009:1-92.
• [23]James LK, Durham SR: Update on mechanisms of allergen injection immunotherapy. Clin Exp Allergy 2008, 38:1074-1088.
• [24]Novak N, Bieber T, Allam JP: Immunological mechanisms of sublingual allergen-specific immunotherapy. Allergy 2011, 66:733-739.
• [25]Shamji MH, Durham SR: Mechanisms of immunotherapy to aeroallergens. Clin Exp Allergy 2011, 41:1235-1246.
• [26]Passalacqua G, Durham SR: Allergic rhinitis and its impact on asthma update: allergen immunotherapy. J Allergy Clin Immunol 2007, 119:881-891.
• [27]Rak S, Lowhagen O, Venge P: The effect of immunotherapy on bronchial hyperresponsiveness and eosinophil cationic protein in pollen-allergic patients. J Allergy Clin Immunol 1988, 82:470-480.
• [28]Walker SM, Varney VA, Gaga M, Jacobson MR, Durham SR: Grass pollen immunotherapy: efficacy and safety during a 4-year follow-up study. Allergy 1995, 50:405-413.
• [29]Walker SM, Pajno GB, Lima MT, Wilson DR, Durham SR: Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial. J Allergy Clin Immunol 2001, 107:87-93.
• [30]Ebner C, Siemann U, Bohle B, Willheim M, Wiedermann U, Schenk S, Klotz F, Ebner H, Kraft D, Scheiner O: Immunological changes during specific immunotherapy of grass pollen allergy: reduced lymphoproliferative responses to allergen and shift from TH2 to TH1 in T-cell clones specific for Phl p 1, a major grass pollen allergen [see comments]. Clin Exp Allergy 1997, 27:1007-1015.
• [31]Hamid QA, Schotman E, Jacobson MR, Walker SM, Durham SR: Increases in IL-12 messenger RNA + cells accompany inhibition of allergen-induced late skin responses after successful grass pollen immunotherapy [see comments]. J Allergy Clin Immunol 1997, 99:254-260.
• [32]Wilson DR, Nouri-Aria KT, Walker SM, Pajno GB, O'Brien F, Jacobson MR, Mackay IS, Durham SR: Grass pollen immunotherapy: symptomatic improvement correlates with reductions in eosinophils and IL-5 mRNA expression in the nasal mucosa during the pollen season. J Allergy Clin Immunol 2001, 107:971-976.
• [33]Wachholz PA, Nouri-Aria KT, Wilson DR, Walker SM, Verhoef A, Till SJ, Durham SR: Grass pollen immunotherapy for hayfever is associated with increases in local nasal but not peripheral Th1: Th2 cytokine ratios. Immunology 2002, 105:56-62.
• [34]Ozdemir C, Kucuksezer UC, Akdis M, Akdis CA: Specific immunotherapy and turning off the T cell: how does it work? Ann Allergy Asthma Immunol 2011, 107:381-392.
• [35]Aalberse RC, Stapel SO, Schuurman J, Rispens T: Immunoglobulin G4: an odd antibody. Clin Exp Allergy 2009, 39:469-477.
• [36]James LK, Shamji MH, Walker SM, Wilson DR, Wachholz PA, Francis JN, Jacobson MR, Kimber I, Till SJ, Durham SR: Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies. J Allergy Clin Immunol 2011, 127:509-516.
• [37]Durham SR, Ying S, Varney VA, Jacobson MR, Sudderick RM, Mackay IS, Kay AB, Hamid QA: Grass pollen immunotherapy inhibits allergen-induced infiltration of CD4+ T lymphocytes and eosinophils in the nasal mucosa and increases the number of cells expressing messenger RNA for interferon-gamma. J Allergy Clin Immunol 1996, 97:1356-1365.
• [38]Savolainen J, Jacobsen L, Valovirta E: Sublingual immunotherapy in children modulates allergen-induced in vitro expression of cytokine mRNA in PBMC. Allergy 2006, 61:1184-1190.
• [39]Nouri-Aria KT, Wachholz PA, Francis JN, Jacobson MR, Walker SM, Wilcock LK, Staple SQ, Aalberse RC, Till SJ, Durham SR: Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J Immunol 2004, 172:3252-3259.
• [40]Francis JN, James LK, Paraskevopoulos G, Wong C, Calderon MA, Durham SR, Till SJ: Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity. J Allergy Clin Immunol 2008, 121:1120-1125.
• [41]Jutel M, Akdis M, Budak F, Aebischer-Casaulta C, Wrzyszcz M, Blaser K, Akdis CA: IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol 2003, 33:1205-1214.
• [42]Robinson DS, Larché M, Durham S: Tregs and allergic disease. J Clin Invest 2004, 114:1389-1397.
• [43]Akdis CA, Akdis M: Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol 2011, 127:18-27.
• [44]Kepley CL, Cambier JC, Morel PA, Lujan D, Ortega E, Wilson BS, Oliver JM: Negative regulation of FcepsilonRI signaling by FcgammaRII costimulation in human blood basophils. J Allergy Clin Immunol 2000, 106:337-348.
• [45]Wurtzen PA, Lund G, Lund K, Arvidsson M, Rak S, Ipsen H: A double-blind placebo-controlled birch allergy vaccination study II: correlation between inhibition of IgE binding, histamine release and facilitated allergen presentation. Clin Exp Allergy 2008, 38(8):1290-1301.
• [46]Wachholz PA, Soni NK, Till SJ, Durham SR: Inhibition of allergen-IgE binding to B cells by IgG antibodies after grass pollen immunotherapy. J Allergy Clin Immunol 2003, 112:915-922.
• [47]van Neerven RJ, Knol EF, Ejrnaes A, Wurtzen PA: IgE-mediated allergen presentation and blocking antibodies: regulation of T-cell activation in allergy. Int Arch Allergy Immunol 2006, 141:119-129.
• [48]van Neerven RJ, Wikborg T, Lund G, Jacobsen B, Brinch-Nielsen A, Arnved J, Ipsen H: Blocking antibodies induced by specific allergy vaccination prevent the activation of CD4+ T cells by inhibiting serum-IgE-facilitated allergen presentation. J Immunol 1999, 163:2944-2952.
• [49]Scadding GW, Shamji MH, Jacobson MR, Lee DI, Wilson D, Lima MT, Pitkin L, Pilette C, Nouri-Aria K, Durham SR: Sublingual grass pollen immunotherapy is associated with increases in sublingual Foxp3-expressing cells and elevated allergen-specific immunoglobulin G4, immunoglobulin A and serum inhibitory activity for immunoglobulin E-facilitated allergen binding to B cells. Clin Exp Allergy 2010, 40:598-606.
• [50]Matricardi PM, Kuna P, Panetta V, Wahn U, Narkus A: Subcutaneous immunotherapy and pharmacotherapy in seasonal allergic rhinitis: A comparison based on meta-analyses. J Allergy Clin Immunol 2011, 128:791-799.
• [51]Corrigan CJ, Kettner J, Doemer C, Cromwell O, Narkus A: Efficacy and safety of preseasonal-specific immunotherapy with an aluminium-adsorbed six-grass pollen allergoid. Allergy 2005, 60:801-807.
• [52]Bodtger 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.
• [53]Arvidsson MB, Lowhagen 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.
• [54]Williams A, Henzgen M, Rajakulasingam K: Additional benefit of a third year of specific grass pollen allergoid immunotherapy in patients with seasonal allergic rhinitis. Eur Ann Allergy Clin Immunol 2007, 39:123-126.
• [55]Frew AJ, Powell RJ, Corrigan CJ, Durham SR: Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006, 117:319-325.
• [56]Garcia-Robaina JC, de la TF, Sanchez I, Fernandez-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, 118:1026-1032.
• [57]Durham SR, Walker SM, Varga EM, Jacobson MR, O'Brien F, Noble W, Till SJ, Hamid QA, Nouri-Aria KT: Long-term clinical efficacy of grass-pollen immunotherapy [see comments]. N Engl J Med 1999, 341:468-475.
• [58]Durham SR, Emminger W, Kapp A, Colombo G, de Monchy JG, Rak S, Scadding GK, Andersen JS, Riis B, Dahl R: Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet. J Allergy Clin Immunol 2010, 125:131-138.
• [59]Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S: Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database of Systematic Reviews 2007, (1):CD001936. DOI: 10.1002/14651858.CD001936.pub2
• [60]Radulovic S, Calderon MA, Wilson D, Durham S: Sublingual immunotherapy for allergic rhinitis. Cochrane Database of Systematic Reviews 2010, (12):CD002893. DOI: 10.1002/14651858.CD002893.pub2
• [61]Abramson MJ, Puy RM, Weiner JM: Injection allergen immunotherapy for asthma. Cochrane Database of Systematic Reviews 2010, (8):CD001186. DOI: 10.1002/14651858.CD001186.pub2
• [62]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, 61:843-848.
• [63]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, 126:942-949.
• [64]Taegtmeyer AB, Steurer-Stey C, Spertini F, Bircher A, Helbling A, Miedinger D, Schafroth S, Scherer K, Leuppi JD: Allergic rhinitis in patients with asthma: the Swiss LARA (Link Allergic Rhinitis in Asthma) survey. Curr Med Res Opin 2009, 25:1073-1080.
• [65]Allen DB: Effects of inhaled steroids on growth, bone metabolism and adrenal function. Expert Rev Respir Med 2007, 1:65-74.
• [66]Jacobsen L: Primary and secondary endpoints in clinical trials. Arb Paul Ehrlich Inst Bundesamt Sera Impfstoffe Frankf A M 2009, 96:96-104.
• [67]Pfaar O, Kleine-Tebbe J, Hormann K, Klimek L: Allergen-specific immunotherapy: which outcome measures are useful in monitoring clinical trials? Immunol Allergy Clin North Am 2011, 31:289-309. x
• [68]Hoiby AS, Strand V, Robinson DS, Sager A, Rak S: Efficacy, safety, and immunological effects of a 2-year immunotherapy with Depigoid birch pollen extract: a randomized, double-blind, placebo-controlled study. Clin Exp Allergy 2010, 40:1062-1070.
• [69]Pfaar O, Robinson DS, Sager A, Emuzyte R: Immunotherapy with depigmented-polymerized mixed tree pollen extract: a clinical trial and responder analysis. Allergy 2010, 65:1614-1621.
• [70]Hafner D, Reich K, Matricardi PM, Meyer H, Kettner J, Narkus A: Prospective validation of 'Allergy-Control-SCORE(TM)': a novel symptom-medication score for clinical trials. Allergy 2011, 66:629-636.
• [71]Durham SR, Birk AO, Andersen JS: Days with severe symptoms: an additional efficacy endpoint in immunotherapy trials. Allergy 2011, 66:120-123.
• [72]Varney VA, Gaga M, Frew AJ, Aber VR, Kay AB, Durham SR: Usefulness of immunotherapy in patients with severe summer hay fever uncontrolled by antiallergic drugs [see comments]. BMJ 1991, 302:265-269.
• [73]Varney VA, Edwards J, Tabbah K, Brewster H, Mavroleon G, Frew AJ: Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebo-controlled trial. Clin Exp Allergy 1997, 27:860-867.
• [74]Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S, Emminger W, Rivas MF, Ribel M, Durham SR: Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006, 118:434-440.
• [75]Didier A, Malling HJ, Worm M, Horak F, Jager S, Montagut A, de BO, Andre C, Melac M: Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol 2007, 120:1338-1345.
• [76]Drachenberg KJ, Heinzkill M, Urban E, Woroniecki SR: Efficacy and tolerability of short-term specific immunotherapy with pollen allergoids adjuvanted by monophosphoryl lipid A (MPL) for children and adolescents. Allergol Immunopathol (Madr) 2003, 31:270-277.
• [77]DuBuske LM, Frew AJ, Horak F, Keith PK, Corrigan CJ, Aberer W, Holdich T, von Weikersthal-Drachenberg KJ: Ultrashort-specific immunotherapy successfully treats seasonal allergic rhinoconjunctivitis to grass pollen. Allergy Asthma Proc 2011, 32:239-247.
• [78]Balda BR, Wolf H, Baumgarten C, Klimek L, Rasp G, Kunkel G, Muller S, Mann W, Hauswald B, Heppt W, et al.: Tree-pollen allergy is efficiently treated by short-term immunotherapy (STI) with seven preseasonal injections of molecular standardized allergens. Allergy 1998, 53:740-748.
• [79]Klimek L, Mewes T, Wolf H, Hansen I, Schnitker J, Mann WJ: The effects of short-term immunotherapy using molecular standardized grass and rye allergens compared with symptomatic drug treatment on rhinoconjunctivitis symptoms, skin sensitivity, and specific nasal reactivity. Otolaryngol Head Neck Surg 2005, 133:538-543.
• [80]Brehler R, Kahlert H, Thum Oltmer S: Hypoallergenic preparations in SCIT. Immunological features and their impact on clinical efficacy and safety, exemplary for the allergoids Allergovit®, Acaroid® and a folding variant of the recombinant birch pollen major allergen Bet v 1. Allergo Journal 2010, 19:477-484.
• [81]Jutel M, Jaeger L, Suck R, Meyer H, Fiebig H, Cromwell O: Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol 2005, 116:608-613.
• [82]Hedlin G, Graff Lonnevig V, Heilborn H, Lilja G, Norrlind K, Pegelow K, Sundin B, Lowenstein H: Immunotherapy with cat- and dog-dander extracts. V. Effects of 3 years of treatment. J Allergy Clin Immunol 1991, 87:955-964.
• [83]Haugaard L, Dahl R, Jacobsen L: A controlled dose-response study of immunotherapy with standardized, partially purified extract of house dust mite: clinical efficacy and side effects. J Allergy Clin Immunol 1993, 91:709-722.
• [84]Pichler CE, Marquardsen A, Sparholt S, Lowenstein H, Bircher A, Bischof M, Pichler WJ: Specific immunotherapy with Dermatophagoides pteronyssinus and D. farinae results in decreased bronchial hyperreactivity. Allergy 1997, 52:274-283.
• [85]O'Byrne PM: Allergen-induced airway inflammation and its therapeutic intervention. Allergy Asthma Immunol Res 2009, 1:3-9.
• [86]Rosewich M, Schulze J, Eickmeier O, Telles T, Rose MA, Schubert R, Zielen S: Tolerance induction after specific immunotherapy with pollen allergoids adjuvanted by monophosphoryl lipid A in children. Clin Exp Immunol 2010, 160:403-410.
• [87]Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S, Emminger W, Riis B, Gronager PM, Durham SR: Sublingual grass allergen tablet immunotherapy provides sustained clinical benefit with progressive immunologic changes over 2 years. J Allergy Clin Immunol 2008, 121:512-518.
• [88]Dolz I, Martinez-Cocera C, Bartolome JM, Cimarra M: A double-blind, placebo-controlled study of immunotherapy with grass-pollen extract Alutard SQ during a 3-year period with initial rush immunotherapy. Allergy 1996, 51:489-500.
• [89]Niggemann B, Jacobsen L, Dreborg S, Ferdousi HA, Halken S, Host A, Koivikko A, Koller DY, Norberg LA, Urbanek R, et al.: Five-year follow up on the PAT study: Specific immunotherapy and long-term prevention of asthma in children. Allergy 2006, 61:855-859.
• [90]Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, Host A, Koivikko A, Norberg LA, Valovirta E, Wahn U, et al.: Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy 2007, 62:943-948.
• [91]Durham SR, Emminger W, Kapp A, de Monchy JG, Rak S, Scadding GK, Wurtzen PA, Andersen JS, Tholstrup B, Riis B, et al.: SQ-standardized sublingual grass immunotherapy: Confirmation of disease modification 2 years after 3 years of treatment in a randomized trial. J Allergy Clin Immunol 2012, 129(3):717-725.
• [92]Mosbech H, Osterballe O: Does the effect of immunotherapy last after termination of treatment? Follow-up study in patients with grass pollen rhinitis. Allergy 1988, 43:523-529.
• [93]Jacobsen L, Nuchel PB, Wihl JA, Lowenstein H, Ipsen H: Immunotherapy with partially purified and standardized tree pollen extracts. IV. Results from long-term (6-year) follow-up. Allergy 1997, 52:914-920.
• [94]Hedlin G, Heilborn H, Lilja G, Norrlind K, Pegelow KO, Schou C, Lowenstein H: Long-term follow-up of patients treated with a three-year course of cat or dog immunotherapy. J Allergy Clin Immunol 1995, 96:879-885.
• [95]Des-Roches A, Paradis L, Knani J, Hejjaoui A, Dhivert H, Chanez P, Bousquet J: Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. V Duration of the efficacy of immunotherapy after its cessation Allergy 1996, 51:430-433.
• [96]Kettner J, Mussler S, Narkus A, Häfner D: Considerable 6 years post treatment long-term effect of pre-seasonal subcutaneous specific immunotherapy (SCIT) with a high-dose hypoallergenic grass pollen preparation. [abstract]. Allergy 2011, 66:296.
• [97]Eng PA, Reinhold M, Gnehm HP: Long-term efficacy of preseasonal grass pollen immunotherapy in children. Allergy 2002, 57:306-312.
• [98]Eng PA, Borer-Reinhold M, Heijnen IA, Gnehm HP: Twelve-year follow-up after discontinuation of preseasonal grass pollen immunotherapy in childhood. Allergy 2006, 61:198-201.
• [99]Novembre E, Galli E, Landi F, Caffarelli C, Pifferi M, De ME, Burastero SE, Calori G, Benetti L, Bonazza P, et al.: Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 2004, 114:851-857.
• [100]Johnstone DE, Dutton A: The value of hyposensitization therapy for bronchial asthma in children-a 14-year study. Pediatrics 1968, 42:793-802.
• [101]Grembiale RD, Camporota L, Naty S, Tranfa CM, Djukanovic R, Marsico SA: Effects of specific immunotherapy in allergic rhinitic individuals with bronchial hyperresponsiveness [In Process Citation]. Am J Respir Crit Care Med 2000, 162:2048-2052.
• [102]Johnstone DE, Crump L: Value of hyposensitization therapy for perennial bronchial asthma in children. Pediatrics 1961, 61:44.
• [103]Des-Roches A, Paradis L, Menardo JL, Bouges S, Daures JP, Bousquet J: Immunotherapy with a standardized Dermatophagoides pteronyssinus extract VI Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997, 99:450-453.
• [104]Pajno GB, Barberio G, De Luca F, Morabito L, Parmiani S: Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study Clin Exp Allergy 2001, 31:1392-1397.
• [105]Purello-D'Ambrosio F, Gangemi S, Merendino RA, Isola S, Puccinelli P, Parmiani S, Ricciardi L: Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not. A retrospective study Clin Exp Allergy 2001, 31:1295-1302.
• [106]Marogna M, Spadolini I, Massolo A, Canonica GW, Passalacqua G: Randomized controlled open study of sublingual immunotherapy for respiratory allergy in real-life: clinical efficacy and more. Allergy 2004, 59:1205-1210.
• [107]World Health Organization: Prevention of Allergy and Allergic Asthma. WHO report 2002.
• [108]Allergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, placebo-controlled trial: first results of ETAC. Early Treatment of the Atopic Child Pediatr Allergy Immunol 1998, 9:116-124.
• [109]Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F: Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006, 354:1998-2005.
• [110]Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, Bacharier LB, Lemanske RF, Strunk RC, Allen DB, et al.: Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006, 354:1985-1997.